CONFIDENTIAL ViP: A prospective, phase II, double …...CONFIDENTIAL ViP: A prospective, phase II, double blinded, multicentre, randomised clinical trial comparing combination gemcitabine

CONFIDENTIAL

ViP: A prospective, phase II, double blinded, multicentre, randomised clinical trial comparing combination gemcitabine and

Vandetanib therapy with gemcitabine therapy alone in locally advanced or metastatic pancreatic carcinoma

National Cancer Research Institute (NCRI)

Study Sponsor / Co-sponsors: The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Prescot Street, Liverpool L7 8XP

The University of Liverpool, Research and Business Services, The Foresight Centre, 3 Brownlow Street, Liverpool L69 3GL

ISRCTN Number: 74555382 EudraCT number: 2010-021951-26 Protocol version: 6 Date: 26th April 2013

EudraCT No: 2010-021951-26 Page 3 of 84

VIP Protocol Version: 6 Date: 26/04/2013

General Information

This document describes the VIP trial and provides information about procedures for entering patients and treating into it. The protocol should not be used as an aide-memoir or guide for the treatment of other patients. Every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to the registered investigators in the trial, but centres entering patients for the first time are advised to contact the coordinating centre (Cancer Research UK Liverpool Cancer Trials Unit (LCTU)) to confirm they have the most up to date version. Clinical problems relating to this trial should be referred to the relevant Chief Investigator via LCTU.

Statement of Compliance

This study is designed to comply with the guideline developed by the International Conference on Harmonisation (ICH) for Good Clinical Practice (GCP) and will be conducted in compliance with the protocol, LCTU Standard Operating Procedures and EU Directive 2001/20/EC, transposed into UK law as the UK Statutory Instrument 2004 No 1031: Medicines for Human Use (Clinical Trials) Regulations 2004 and all subsequent amendments.

UK Registration

This study will have National Research Ethics Service (NRES) approval and hold a Clinical Trials Authorisation issued by the Medicines and Healthcare Products Regulatory Agency (MHRA). Each centre must also undergo Site Specific Assessment by the relevant Trust Research and Development Department (or Local Research Ethics Committee for Non-NHS Sites) and NHS sites must be granted Research and Development Approval from each Trust where the trial will be carried out.

Randomisation

Tel: 0151 794 8935/795 5294 Fax: 0151 794 8010

(Monday – Friday: 09:00 – 17:00)



Contact Details: Institutions

Co-Sponsors:

Trial Management and

Monitoring:

Translational Laboratory:

The Royal Liverpool and Broadgreen University Hospitals NHS Trust Prescot Street, Liverpool. L7 8XP and The University of Liverpool

Research and Business Services, The Foresight Centre, 3 Brownlow Street, Liverpool. L69 3GL

Liverpool Cancer Trials Unit University of Liverpool, 1st Floor, Block C, Waterhouse Building 3 Brownlow Street Liverpool. L69 3GL Tel: +44 (0)151 794 8935 Fax: +44 (0)151 794 8930

Liverpool GCLP Facility

Division of Surgery and Oncology 5th Floor UCD Block Royal Liverpool University Hospital Daulby Street Liverpool Tel: 0151 706 4184 Fax: 0151 706 5826



Contact Details: Individuals Individuals - Authorised to Sign the Protocol and Amendments on

behalf of the Sponsor: Chief Investigator (CI):

Professor Gary Middleton

Consultant Medical Oncologist

School of Cancer Sciences

College of Medical and Dental Sciences

University of Birmingham

Edgbaston B15 2TT

Tel: 0121 4158237

Email: [email protected]

Charlotte Rawcliffe/Stacey

Carruthers

Operational /Deputy Operational

Director

Cancer Research UK: Liverpool Cancer Trials Unit

University of Liverpool,

1st

Floor, Block C, Waterhouse Building

3 Brownlow Street Liverpool.

L69 3GL

Tel: (0) 151 794 8938/8167

Email: [email protected] / [email protected]

Professor Gary Middleton

Consultant Medical Oncologist

University of Birmingham

School of Cancer Sciences,

College of Medical and Dental Sciences,

Edgbaston,

Birmingham

B15 2TT

Tel: 0121 4147144


Medical Expert who will Advise on

Protocol Related Clinical Queries

(If other than CI):

Medical Expert who will Evaluate SAE Reports (If other than CI):

Ms Paula Ghaneh

Reader in Surgery/Assistant director LCTU

Department of Molecular and Clinical Cancer Medicine

University of Liverpool

5th Floor UCD Building

Daulby Street

Liverpool

L69 3GA

Tel: 0151 706 4170/4062

Fax: 0151 706 5826


Ms Paula Ghaneh (see opposite)

OR Dr Syed Hussain

Senior Clinical Lecturer and Consultant in Medical Oncology Department of Molecular and Clinical Cancer Medicine

University of Liverpool

5th Floor UCD Building

Daulby Street

Liverpool

L69 3GA

Tel: 0151 706 4177

Fax: 0151 706 5826


Dr Richard Griffiths

Consultant in Medical Oncology

The Clatterbridge Cancer Centre NHS Foundation Trust

Clatterbridge Road

Bebington

Wirral

CH63 4JY

Tel:0151 334 1155 ext 5068

Fax: 0151 482 7621


Dr Joseph Sacco

Consultant in Medical Oncology

The Clatterbridge Cancer Centre NHS Foundation Trust

Clatterbridge Road

Bebington

Wirral

CH63 4JY


mailto:[email protected]



Tel:0151





Contact Details: Individuals

Trial Co-ordinator: Trial Statistician:

Miss Zaira Yunus

VIP Trial Co-ordinator


University of Liverpool,

1st

Floor, Block C, Waterhouse Building

3 Brownlow Street Liverpool.

L69 3GL

Tel: 0151 794 8935

Fax: 0151 794 8010


Mr Richard Jackson

Statistician


(Address above same as Zaira Yunus)

Tel: 0151 794 8834

Fax:


Data Manager: Trial Monitor: Ms Emma Parr

VIP Data Manager



Tel: (0) 151 795 5294

Fax: (0) 151 794 8010


Mr James Clayton

ViP Trial Monitor



Tel: (0) 151 794 8248

Fax: (0) 151 794 8010







Contact Details: Independent Oversight Committees

Independent Safety and Data Monitoring Committee (ISDMC)

Independent Statistician: Independent Clinician (Chair) Independent Clinician

Dr Roger Ahern Institute of Cancer Research 15 Cotswold Rd, Belmont Sutton, Surrey SM2 5NG Tel: 0208 722 4149 Fax: 0208 770 7876 Email: [email protected]

Mr Chris Russell Tel: 01753 882264 Email: [email protected]

Dr Riyaz Shah Kent Oncology Centre Maidstone Kent ME16 9QQ Tel: 01622 227 035 Fax: 01622 225 261


Independent Members of the Trial Steering Committee (TSC)

Chairman Independent Clinician Lay Member

Professor Janet Dunn Health Sciences Research Institute Room T1.02 Warwick Clinical Trials Unit The University of Warwick Gibbett Hill Campus Conventry CV4 7AL Tel: 02476 575847 Email: [email protected]

Dr Elizabeth Toy Royal Devon & Exeter Hospital Barrack Road Exeter Devon EX2 5DW Tel: 01392 411 611 Email: [email protected]

Mr Paul Morris c/o Zaira Yunus








TABLE OF CONTENTS

1 Protocol Summary .............................................................................................. 12

2 Background Information ..................................................................................... 14 2.1 Introduction ............................................................................................... 14 2.2 Rationale ................................................................................................... 15

3 Objectives .......................................................................................................... 18 3.1 Primary Objective ....................................................................................... 18 3.2 Secondary Objectives .................................................................................. 18 3.3 Exploratory Objectives ................................................................................ 18

4 Investigational Plan and Study Population ............................................................ 19 4.1 Inclusion Criteria ........................................................................................ 19 4.2 Exclusion Criteria ........................................................................................ 19 4.3 Investigational Plan ..................................................................................... 21

5 Potential Risks and Benefits ................................................................................ 23 5.1 Potential Risks ............................................................................................ 23 5.2 Known Potential Benefits ............................................................................ 24

6 Selection of Centres/Clinicians ............................................................................ 26 6.1 Centre/Clinician Inclusion Criteria ................................................................. 26 6.2 Centre/Clinician Exclusion Criteria ................................................................ 26

7 Patient transfers and withdrawals ....................................................................... 27 7.1 Patient Transfers ........................................................................................ 27 7.2 Withdrawal from Trial Intervention .............................................................. 27 7.3 Withdrawal from Trial Completely ................................................................ 27

8 Enrolment and Randomisation ............................................................................ 29 8.1 Screening .................................................................................................. 29 8.2 Enrolment/ Baseline ................................................................................... 29 8.3 Randomisation ........................................................................................... 29 8.4 Unblinding ................................................................................................. 30

9 Trial Treatments ................................................................................................. 31 9.1 Trial Introduction ........................................................................................ 31 9.2 Non Investigational Medicinal Products (NIMPS) ............................................ 31 9.3 Investigational Medicinal Products ............................................................... 33 9.4 Placebo ..................................................................................................... 37 9.5 Accountability Procedures for Study Treatment/s .......................................... 37 9.6 Assessment of Compliance with Study Treatment/s........................................ 37 9.7 Concomitant Medications/Treatments .......................................................... 38 9.8 Overdoses ................................................................................................. 38 9.9 Co-enrolment Guidelines ............................................................................. 39

10 Assessments and Procedures ............................................................................... 40 10.1 Schedule of Trial Procedures ........................................................................ 40 10.2 Procedures for Assessing Efficacy ................................................................. 44 10.3 Procedures for Assessing Safety ................................................................... 44 10.4 Patient Pain Assessment .............................................................................. 44 10.5 Loss to Follow-up........................................................................................ 45 10.6 Trial Closure ............................................................................................... 45



11 TRANSLATIONAL SUBSTUDIES ............................................................................. 46 11.1 Sample Collection ....................................................................................... 46 11.2 Tissue Samples ........................................................................................... 46

12 Statistical Considerations .................................................................................... 48 12.1 Introduction ............................................................................................... 48 12.2 Primary Endpoint ........................................................................................ 48 12.3 Secondary Endpoint(s) ................................................................................ 48 12.4 Method of Randomisation ........................................................................... 48 12.5 Sample Size ................................................................................................ 48 12.6 Interim Monitoring and Analyses .................................................................. 49 12.7 Statistical Analysis Plans .............................................................................. 49

13 Pharmacovigilance .............................................................................................. 50 13.1 Terms and Definitions ................................................................................. 50 13.2 Notes on Adverse Event Inclusions and Exclusions .......................................... 51 13.3 Notes on Serious Adverse Event Exclusions ................................................... 52 13.4 Reporting of Pregnancy ............................................................................... 52 13.5 Notes Severity / Grading of Adverse Events ................................................... 52 13.6 Relationship to Trial Treatment .................................................................... 53 13.7 Reference Safety Information ...................................................................... 53 13.8 Expectedness ............................................................................................. 54 13.9 Adverse Event Reporting Procedures ............................................................ 54 13.10 Follow-up After Adverse Events.................................................................... 56 13.11 Responsibilities – Investigator ...................................................................... 56

14 Ethical Considerations ......................................................................................... 58 14.1 Ethical Considerations ................................................................................. 58 14.2 Ethical Approval ......................................................................................... 58 14.3 Informed Consent Process ........................................................................... 58 14.4 Study Discontinuation ................................................................................. 59

15 Regulatory Approval ........................................................................................... 60

16 Trial Monitoring ................................................................................................. 61 16.1 Risk Assessment ......................................................................................... 61 16.2 Source Documents ...................................................................................... 61 16.3 Data Capture Methods ................................................................................ 62 16.4 Monitoring at LCTU ..................................................................................... 62 16.5 Clinical Site Monitoring ............................................................................... 65 16.6 Records Retention ...................................................................................... 66

17 Indemnity .......................................................................................................... 67

18 Financial Arrangements ...................................................................................... 68

19 Trial Oversight Committees ................................................................................. 69 19.1 Trial Management Group (TMG) .................................................................. 69 19.2 Trial Steering Committee (TSC) ..................................................................... 69 19.3 Independent Data and Safety Monitoring Committee (IDSMC) ........................ 69

20 Publication ......................................................................................................... 70

21 Protocol Amendments ........................................................................................ 71 21.1 Version 1 (25/JAN/2011) ............................................................................. 71 21.2 Version 2 (16/AUG/2011) ............................................................................ 71 21.3 Version 3 (14/DEC/2011) ............................................................................. 71



21.4 Version 4 (23/FEB/2012) ............................................................................. 72 21.5 Version 5 (13/DEC/2012) ............................................................................. 72 21.6 Version 6 (26/APR/2013) ............................................................................. 73

22 REFERENCES ....................................................................................................... 74 Appendix A: Prescription for vandetanib / placebo ........................................................... 76 Appendix B: Example of vandetanib / placebo label .......................................................... 77 Appendix C: Medications Generally Accepted by Authorities to Have a Known Risk of Causing Torsades De Pointes (Tdp)................................................................................................... 78 Appendix D: Vandetanib / placebo diary sheet ................................................................. 83 Appendix E: RECIST Criteria Version 1.1 .......................................................................... 84



GLOSSARY

AE Adverse Event ALP Alkaline Phosphatase ALT Alanine Aminotransferase AR Adverse Reaction ARDS Acute Respiratory Distress Syndrome AST Aspartate Aminotransferase CI Chief Investigator CRF Case Report Form CT Computerised Tomography CTU Clinical Trials Unit ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group EGFR Epidermal Growth Factor Receptor EORTC European Organisation for Research and Treatment of Cancer GP General Practitioner HR Hazard Ratio IB Investigator’s Brochure IDSMC Independent Data and Safety and Monitoring Committee IEC Independent Ethical Committee IMP Investigational Medicinal Product IWRS Interactive Web Response System LBBB Left Bundle Branch Block LCTU Cancer Research UK Liverpool Cancer Trials Unit MREC Multi-centre Research Ethics Committee NPSA National Patient Safety Agency NYHA New York Heart Association PD Progressive Disease PFS Progression Free Survival PI Principal Investigator PK Pharmacokinetics PS Performance Status RECIST Response Evaluation Criteria In Solid Tumours R&D Research & Development SAE Serious Adverse Event SAR Serious Adverse Reaction SPC Summary of product characteristics SUSAR Suspected Unexpected Serious Adverse Reaction SVC Superior Vena Cava Syndrome TSC Trial Steering Committee UAR Unexpected Adverse Reaction ULRR Upper Limit Of Reference Range VEGFR Vascular Endothelial Growth Factor Receptor WHO World Health Organisation



1 Protocol Summary

Title: VIP: A prospective, phase II, placebo-controlled, multicentre, randomised clinical trial comparing combination gemcitabine and vandetanib therapy with gemcitabine therapy alone in locally advanced or metastatic pancreatic carcinoma

Phase: II

Target Disease: Locally advanced or metastatic pancreatic carcinoma

Sample Size: 140 patients

Number of Sites: Approximately 20 centres in the UK.

Study Duration: The planned treatment duration per patient will be until progression of

disease, unacceptable toxicity or withdrawal of consent. Participation in the

study will be until withdrawal of consent or death.

Patients who stop treatment before having developed progressive disease (PD) will be assessed every 12 weeks for response until PD occurs.

Study Arms: Arm A (standard therapeutic arm): Placebo orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

Arm B: Vandetanib orally once a day continuously at 300 mg/day together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

Objectives: Primary:

To assess whether survival times for patients receiving gemcitabine

plus vandetanib are longer than for those patients receiving

gemcitabine alone as first line treatment for advanced pancreatic

cancer.

Secondary:

To compare between the two treatment groups: o progression-free survival time (PFS)

o objective response rate

o disease control rate

o toxicity and safety

o patient pain assessment

Exploratory: To discover possible biomarkers to predict additional benefit of

vandetanib over gemcitabine alone for subsequent validation in

larger scale studies.



PROTOCOL SUMMARY - continued

Schematic of Study Design:

70 subjects

Arm B

Gemcitabine +

Vandetanib

Gemcitabine +

Placebo

70 subjects

Arm A

Primary Endpoint: Overall Survival

140 patients aged 18 or above with histologically or cytologically proven advanced ductal

adenocarcinoma of pancreas or undifferentiated carcinoma of the pancreas.

Randomisation in 1:1 ratio stratified by the following:

Stage of disease: locally advanced or metastatic disease

ECOG performance status: 0/1 versus 2



2 BACKGROUND INFORMATION

2.1 Introduction Pancreatic cancer is a significant health problem for which there is a huge unmet therapeutic need and which carries a uniquely poor prognosis, with incidence rates and mortality rates being almost equivalent. In the UK there were 7,632 newly diagnosed cases in 2005 with 7,315 people dying of the disease in 2006. Even in the small number of patients who have resectable disease, the five year survival rates are only around 10%. The outcome for patients treated with radiotherapy for locally advanced disease and chemotherapy for metastatic disease is dismal: the most active chemotherapy regimens seldom achieve response rates of over 20%. There has been a significant growth in our knowledge of the molecular characteristics of the disease and improvements in treatment outcome will only be achieved with the integration of novel therapies targeted to these abnormalities. To date, the only agent which has resulted in statistically improved survival when added to gemcitabine compared with gemcitabine alone is the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (1). The adjusted hazard ratio (HR) for survival (OS) for combination therapy compared with gemcitabine was 0.82 and 0.77 for progression free survival (PFS). These data have been criticised mainly on account of the very marginal differences in the point estimates particularly median OS but clearly erlotinib has a biologically pertinent effect in this disease: rash is a class effect of EGFR inhibitors and is a proven surrogate for outcome advantage in numerous trials across multiple tumour types. Where tissue levels of the drug are sufficient to inhibit keratinocyte EGFR and cause rash they are sufficient to inhibit tumoral EGFR and impact on the biology of the disease. In PA.3, Cox regression analysis showed significantly improved survival in those patients developing rash (HR = 0.74) with median survival in those with no rash, grade 1 rash and grade 2 rash being 5.3, 5.8 and 10.5 months respectively. Furthermore, there is a strong correlation between EGFR activation (and hence a degree of reliance upon EGFR driven growth and survival) and sensitivity to erlotinib in xenograft models (2). About 1/3 pancreatic cancers harbour activated EGFR as measured by Tyr1068 phosphorylation. The only trial to demonstrate an incremental improvement in efficacy for the addition of another drug to the gemcitabine/erlotinib combination is AVITA (conducted in patients with metastatic disease alone (3)). Although this trial failed to reach its primary end-point of improved OS with the addition of bevacizumab, PFS was significantly prolonged with an HR of 0.73 and there was a strong trend for improved response rate (13.5% vs 8.6% for bevacizumab vs placebo). Thus, there is a strong clinical evidence-based rationale for building upon and further investigating the impact of dual EGFR and vascular endothelial growth factor receptor (VEGFR) blockade in pancreatic cancer.



2.2 Rationale

Vandetanib (Caprelsa™, ZD6474) is a potent inhibitor of the tyrosine kinase activity of kinase insert domain-containing receptor (KDR), an endothelial cell receptor for vascular endothelial growth factor (VEGF), and also possesses activity against epidermal growth factor receptor (EGFR) (reviewed in (4)).In recombinant enzyme assays the IC50 for VEGFR-2 kinase activity was 40nm and for VEGFR-3 110nm: this latter activity may impact on lymphangiogenesis and lymph node spread of tumour cells. The IC50 for EGFR tyrosine kinase activity is 500nm and the IC50 for the inhibition of EGF-stimulated HUVEC proliferation 170nm. This EGFR effect is biologically relevant, with the inhibition of growth of a number of cancer cell lines by vandetanib being highly correlated with the degree of gefitinib–mediated growth inhibition, with very similar IC50 values for both agents in cells harbouring both wt and mutant EGFR (5). There was no expression of VEGFR-2 mRNA in any of these cell lines. In an L3.6pl orthoptic pancreatic cancer model vandetanib administration led to reduced tumoural microvessel density, decreased the number of proliferating tumour cells, significantly reduced tumour growth, and decreased both lymph node and liver metastases (6). It is likely that the impact on lymph node metastases is via VEGFR-3 inhibition as VEGFR-2 or EGFR inhibition in this model has no impact on metastasis to lymph nodes.

Vandetanib inhibits a third tyrosine kinase and this may significantly augment the therapeutic impact of dual VEGFR/EGFR inhibition in pancreatic cancer. The RET gene encodes a transmembrane tyrosine kinase that acts as a receptor for members of the glial-derived neurotrophic factor (GDNF) family. The vandetanib IC50 for the isolated RET kinase domain was the same as for the RET/PTC3 fusion at 100nm (7). Vandetanib abolished EGF stimulated autophosphorylation of NIH3T3 cells transfected with EGFR/RET and reduced EGFR/RET dependant ERK phosphorylation, whereas gefitinib had no such effect. Vandetanib inhibited the proliferation of RET/PTC3 transformed cells and significantly reduced tumour growth in xenografts. In a Drosophila model targeting RET isoforms to the developing eye vandetanib was equally as effective at reversing the RET-mediated defects in transgenic flies expressing wild type RET as flies harbouring MEN2 related mutations (8). An immunohistochemical evaluation of 51 resected pancreatic adenocarcinomas demonstrated positivity for GDNF in 43% of cases, neurturin in 65%, Artemin in 75% (strong staining in 33%) and 65% positivity for RET (strong in 49%) (9). The intensity of RET staining was greater in the cancer cells than in the ductal cells. RET expression was significantly negatively correlated with survival (and lymphatic invasion) and GDNF expression with intra-pancreatic neural invasion. Migration of pancreatic cancer cells can be markedly induced by GDNF by both chemotactic and chemokinetic mechanisms (10). GDNF was found to be expressed in the human coeliac plexus and this has lead to the hypothesis that the neural invasion of pancreatic cancer is via a GDNF gradient produced by the peripheral ganglion cells. This effect is mediated via both Ras-Raf-MAPK and PI3K pathway signalling (11) and both pathways are also implicated the GDNF-initiated increased MMP-9 expression and activity in pancreatic cancer cells (12). Artemin also significantly increases the invasiveness of pancreatic cancer cells but did not appear to influence MMP-9 expression. Very high levels of cancer-associated artemin protein was seen in spite of little increase in mRNA expression suggesting import of protein to the pancreas presumably from the dorsal root ganglia in an attempt to restore neuronal integrity in the face of damage from pancreatic cancer progression. Finally, in spite of similar expression of GDNF receptors the strength of GDNF-induced pancreatic cancer cell invasion (and proliferation) is very variable and seems to be highly dependent on the presence of the G691S polymorphism (13). Cells robustly responding to GDNF harboured the polymorphism whereas wild type cells were much less invasive when exposed to GDNF. The effect



was found to be mediated via RAS/ERK signalling and GDNF strongly activated ERK in G691S RET positive cells. Overexpression of G691S RET in wt MIA PaCA-2 and PANC-1 cells showed marked increase in ERK phosphorylation and a 400% increase in invasion above baseline. The polymorphism was found in 37% of resected tumours. 31% demonstrated the polymorphism in normal pancreas but there was evidence that in some tumours the polymorphism occurred as a result of somatic mutation (3/52 wild type control tissues with heterozygous G691S tumours). In this trial vandetanib will be combined with gemcitabine and outcome compared with gemcitabine alone given that gemcitabine monotherapy remains a regulatory standard of care and a globally accepted trial comparator. In the L3.6pl orthoptic model the combination of gemcitabine and vandetanib led to a significant reduction in tumour weight compared with both gemcitabine and vandetanib monotherapy and very significantly reduced the development of liver, lymph node and peritoneal metastases (6). In vitro the combination was synergistic with regards to the inhibition of pancreatic cancer cell proliferation with a 2 log fold increase in sensitivity compared to gemcitabine monotherapy with single digit nanomolar IC50s (14). Vandetanib led to a significant increase in the deoxycytidine/RRM1 x RRM2 ratio and this may underly some of the synergy between these two drugs. After discussion with Vandetanib team at Astra Zeneca an initial dose of 300mg/day of vandetanib in combination with gemcitabine has been selected for use in the VIP study. There are 3 Phase I studies (2 ongoing) where vandetanib is being evaluated in combination with either gemcitabine alone or gemcitabine along with a second chemotherapeutic agent.

TRIAL A: The largest of the Phase I trials, is ongoing, and being conducted in solid tumours with an expanded phase in pancreatic and biliary tract tumours. Two doses of vandetanib were evaluated in this trial, 200 and 300mg / day in combination with standard doses of gemcitabine (1000mg/m2 over 30min on Day 1, 8 and 15) and capecitabine in the first line setting. There was one dose limiting toxicity (DLT) in this study at 200mg (grade 4 neutropenia) in 6 patients, therefore the 300mg dose was evaluated. In 15 patients receiving 300mg/day of vandetanib in combination with gemcitabine / capecitabine, no DLTs were observed. The recommended dose of vandetanib from this study is 300mg/day in combination with gemcitabine and capecitabine.

TRIAL B: The second Phase I trial is ongoing and being conducted in patients with solid tumours (20 patients enrolled) that include 12 patients with advanced pancreatic cancer. Two doses of vandetanib were evaluated in this trial, 200 and 300mg / day in combination with gemcitabine (1000mg/m2 given every two weeks) and oxaliplatin, in the second / third line setting. There was one dose limiting toxicity (DLT) at 200mg (grade 4 deep vein thrombosis in a patient with urothelial carcinoma) in 9 patients, therefore the 300mg dose was evaluated. In 11 patients receiving 300mg/day of vandetanib in combination with gemcitabine / oxaliplatin, no DLTs were observed at this dose level.

TRIAL C (Piercarlo et al, submitted): The third Phase I study was conducted using gemcitabine in combination with gemcitabine in patients with advanced pancreatic cancer in the first line setting. This was a small study conducted in 15 patients; 3 patients received vandetanib at 100mg/day in combination with gemcitabine (1000mg/m2 over 30min on Day 1, 8 and 15) with no DLTs observed. Twelve more patients were treated with vandetanib at 300 mg/day in combination with gemcitabine. The investigators initially considered there to be no DLTs on 300mg vandetanib, however, in review they considered that there were 3 DLTs: grade III aphasia, grade III non-febrile neutropenia and grade III elevation of ALP, AST and ALT. The investigators then considered that 100mg was the recommended vandetanib dose.



Although the investigators in TRIAL C considered vandetanib at 100mg/day as the recommended starting dose, they had initially considered 300mg as the recommended dose. The investigators then re-evaluated the data and subsequently considered 3 AEs that occurred on 300mg to be DLTs. In reviewing the AEs they considered to be DLTs at 300mg, one of them, a grade 3 afebrile neutropenia, is not a standard criterion used to define a DLT (usually grade 3 febrile neutropenia or grade 4 afebrile netropenia). Thus, it could be considered that there were only 2 DLTs observed in 12 patients receiving 300mg vandetanib. Therefore, based on the totality of the Phase I data collected thus far of vandetanib in combination with gemcitabine, it is recommend by Astra Zeneca that the starting dose of vandetanib be 300mg/day. In addition, the VIP study includes a protocol for dose reductions of vandetanib with grade 3 or higher AEs.

Rationale for the collection of additional samples for biomarker discovery

There are currently no known markers that are predictive of response or resistance to VEGF signalling inhibitors including vandetanib. By collecting and storing serial samples of plasma and serum for the first months of treatment with vandetanib it will be possible to explore relationship between changes in biomarkers and tumour response as measured by changes in tumour size and RECIST responses and to explore the mechanisms underlying the biological response and resistance to VEGF signalling inhibitors. In addition, analysis of biomarkers isolated from archival tumour material may add to our knowledge of factors affecting the response to inhibition of VEGF signalling. It is likely that additional information and assays for biomarkers that are important for the response to vandetanib will become available in the future. We will also analyse biomarkers that may predict for specific benefit to the EGFR and RET inhibition effect of vandetanib, in particular, tumoural levels of activated EGFR as measured by Tyr1068 phosphorylation, the expression of GDNF-associated ligands and RET and the expression of the G691S RET polymorphism.



3 OBJECTIVES

3.1 Primary Objective

To assess whether overall survival time using gemcitabine plus vandetanib is longer than that using gemcitabine alone as first line treatment for advanced pancreatic cancer

3.2 Secondary Objectives

To compare between the two treatment groups

- progression free survival (PFS)

- objective response rate

- disease control rate

- toxicity and safety

- patient pain assessment

3.3 Exploratory Objectives

To discover possible biomarkers to predict additional benefit of vandetanib over gemcitabine alone for subsequent validation in larger scale studies.



4 Investigational Plan and Study Population

4.1 Inclusion Criteria

1. Age ≥ 18 years.

2. Histologically or cytologically proven pancreatic ductal adenocarcinoma or undifferentiated carcinoma of the pancreas.*

3. Locally advanced or metastatic disease precluding curative surgical resection or definitive locally directed therapies such as chemo radiation. Patients who have relapsed following previously resected Pancreatic Cancer can be included.

4. Contrast enhanced computerised tomography (CT) scan of the thorax, abdomen and pelvis within 28 days prior to commencing treatment.

5. Unidimensionally measurable disease as shown by CT scan, in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) guidelines (version 1.1).

6. ECOG performance status 0, 1 or 2 where the investigator feels that treatment with combination chemotherapy, for example FOLFIRINOX, is not appropriate.

7. Platelets ≥100 x 109/l; WBC ≥ 3 x 109/l; neutrophils ≥ 1.5 x 109/l at entry.

8. Documented Life expectancy > 3 months.

9. Informed written consent

*Patients will be approached for consenting to provide either an additional core of tissue material for biomarker discovery at the same time as a diagnostic biopsy or in those patients that have already had a diagnostic biopsy to undergo a second biopsy after randomisation into the trial. Neither of these biopsies is compulsory. Patients who don't wish to have extra tissue taken for Biomarker discovery will be approached for consent to released surplus tissue from the original diagnostic specimen if this exists see section 10 for further details.

4.2 Exclusion Criteria

1. Laboratory results:

Serum bilirubin ≥ 1.5x the upper limit of reference range (ULRR).

Haemoglobin < 10G/dl

Creatinine clearance < 30 mL/minute (calculated by Cockcroft-Gault formula)**. Patients with a creatinine clearance of ≥30mL/minute and <50mL/minute should begin vandetanib on a reduced dose of 200mg.

Potassium, ≤4.0 mmol/L despite supplementation; or > 5.5 mmol/L

Magnesium below the normal range despite supplementation, or > 1.23 mmol/L

Serum calcium is > 2.9 mmol/L. In cases where serum calcium is below the normal range this can be substituted with the value for calcium adjusted for albumin, if this is below the normal range despite supplementation patients should be excluded.



Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or alkaline phosphatase (ALP) >2.5 x ULRR or > 5x ULRR if judged by the investigator to be related to liver metastases.

2. Medical or psychiatric conditions compromising informed consent.

3. Intracerebral metastases or meningeal carcinomatosis.

4. Major surgery within 4 weeks or incompletely healed surgical incision before starting study therapy.

5. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.

6. Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome (SVC), New York Heart Association (NYHA) classification of heart disease ≥2 within 3 months before entry; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia.

7. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation), which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded.

8. QTc prolongation with other medications that required discontinuation of that medication.

9. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age.

10. Presence of left bundle branch block (LBBB).

11. QTc with Bazett’s correction that is un-measurable or 480 msec on screening ECG. (Note: If

a subject has a QTc interval 480 msec on screening ECG, the screening ECG may be repeated up to two times and the ECGs must be at least 24 hours apart. The average QTc of the ECGs (either two or three) must be <480msec in order for the patient to be eligible. Patients who are receiving a drug that has a risk of inducing Torsades-de-Pointes (see appendix C) are excluded if QTc is ≥ 460 msec.

12. Any concurrent medication with a known risk of inducing Torsades-de-Pointes that cannot be stopped 2 weeks prior to first dose (please see Appendix C). Any concurrent medication with a possible or conditional risk of inducing Torsades de Pointes, that in the investigator’s opinion cannot be discontinued, are allowed; however, these patients must be monitored closely (please see Appendix C).

13. Concomitant medications that are potent inducers (e.g rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital and St. John’s Wort) of CYP3A4 function.

14. Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg).

15. Currently active diarrhoea that may affect the ability of the patient to absorb the vandetanib or tolerate diarrhoea secondary to vandetanib should that occur as a side effect.



16. Malabsorption syndrome which may impair the absorption of vandetanib (e.g. partial gastrectomy, small bowel resection), This may include previous partial gastrectomy and small bowel resection or active Crohn’s disease, ulcerative colitis.

17. Pregnancy or breast feeding.

18. Previous chemotherapy for locally advanced and metastatic disease. Adjuvant chemotherapy for resected pancreatic cancer will be permitted provided that chemotherapy was completed > 12 months previously.

19. Radiotherapy within the last 4 weeks prior to start of study treatment.

20. Concurrent malignancies or invasive cancers diagnosed within past 5 years except for adequately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix or resected pancreatic cancer.

21. Chemotherapy directed at tumour apart from that described in this protocol.

22. All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be a condom.

** An EDTA blood test to assess the patient kidney function can be used as an alternative, please consult the Liverpool Cancer Trials Unit to discuss.

4.3 Investigational Plan

It is planned to perform this study in approximately 20 UK centres with a centre defined as the primary institution of the clinical investigator. Recruitment will be competitive and 140 patients will be randomised in a 1:1 fashion with the recruitment period planned for Q3 2011 – Q3 2013. Randomisation will be stratified by ECOG performance status (PS) (0/1 vs 2) and stage (locally advanced vs metastatic).

Baseline radiographic assessment of disease will be performed within 28 days prior to first treatment and first treatment will be delivered within 7 days of randomisation or the earliest screening procedure, e.g. blood samples, CT scan whichever is sooner, as follows:

Arm A (standard therapeutic arm). – Gemcitabine and Placebo

Placebo orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

Arm B (experimental arm) – Gemcitabine and Vandetanib

Vandetanib orally once a day continuously at 300 mg/day together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

Patients will be seen on a weekly basis for administration of gemcitabine during the time they are on active treatment and will be treated until disease progression. At the completion of therapy, an end-of therapy visit must be completed within 7 days after the decision is made to discontinue all therapy. This must be a full assessment consisting of physical exam, Performance Status, ECG



haematology and chemistry profile and toxicity/AE assessments, after which follow up will then occur every 12 weeks.

No further anti-tumour treatment will be initiated until progression of disease. AE information will be collected until at least 30 days after the last dose of study therapy is administered or until all study therapy-related AEs have resolved, stabilised or been deemed irreversible and a 30 day safety follow up should be performed at this point.



5 POTENTIAL RISKS AND BENEFITS

5.1 Potential Risks

5.1.1 Vandetanib

Vandetanib produces repolarisation abnormalities in human myocardium that are consistent with blockade of the IKR (potassium) channel. The most consistent electrophysiological effects are a change in T-wave morphology (flattening, broadening or notching) and prolongation of the QT interval, both of which occur more commonly as the dose is increased.

Vandetanib can cause rash, diarrhoea and hypertension, all of which appear to be dose-related and are likely to be related to the pharmacologic activity of vandetanib.

The drug-related AEs seen with vandetanib monotherapy are also expected to occur in combination with chemotherapy. All drug-related AEs expected to occur in association with the concomitant chemotherapeutic agent(s) (as defined and listed in the package insert[s]) will be expected to occur when used in combination with vandetanib. The relevant product information for the concomitant chemotherapy should be used to determine these expected, drug-related AEs.

The following precautionary measures will also be put in place:

Vandetanib should not be administered to pregnant women. A negative pregnancy test should be confirmed before administration of vandetanib for all women of childbearing age.

The exposure to vandetanib is unchanged whether given in the fasted state or with food and thus a restriction on dosing with food is not required.

Exposure to vandetanib is increased with renal impairment thus caution must be adopted if being given to such patients, especially those with severe renal impairment where the exposure could potentially double. Patients with creatinine clearance ≥ 30mL/minute and <50mL/minute should be started at a reduced dose of 200mg.

There is no known antidote for vandetanib, and treatment of AEs associated with its use should be for the underlying adverse symptoms.

If a patient develops torsades-de-pointes or ventricular tachycardia, vandetanib therapy must be stopped. Vandetanib may be resumed at a lower dose when the arrhythmia has resolved and the ECG QT interval has returned to normal, if clinically appropriate.

Reversible posterior leukoencephalopathy syndrome, a syndrome of subcortical vasogenic oedema diagnosed on magnetic resonance imaging of the brain, has been diagnosed in a patient receiving vandetanib. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function and hypertension, as the syndrome is expected to be reversible if vandetanib is stopped.

There is no specific treatment for an overdose of vandetanib. In clinical trials, single doses of 1200 mg have been given to healthy volunteers with minimal symptoms. Chronic dosing of 600 mg has resulted in diarrhoea and other AEs. In case of overdose, vandetanib therapy may be interrupted, and any adverse reactions treated symptomatically.

As discussed previously, a pancreatic cancer specific phase I trial of gemcitabine and vandetanib has been completed (Piercarlo et al, submitted) with recommended doses of the two drugs in combination being the same as the single agent doses. The toxicity of the 2 drugs is not overlapping and there is no evidence from the phase I that either drug potentiates the toxicity of the other drug



5.1.2 Gemcitabine

The occurrence of haematological toxicity including neutropenia and thrombocytopenia which requires dose adjustment will be specified in section 9.2.1 Non-haematological toxicity.

Pulmonary: Dyspnoea is seen in approximately 1 in 10 patients; this is usually mild and rarely requires intervention. More significant injury is described, including bronchospasm and also cases of Acute Respiratory Distress Syndrome (ARDS), interstitial pneumonitis and pulmonary oedema. Whilst rare, patients presenting with significant increasing shortness of breath need to be investigated to exclude these possibilities.

Gastrointestinal: Abnormalities of liver transaminase enzymes occur in about two thirds of patients, but they are usually mild, non-progressive and rarely necessitate stopping treatment. Nevertheless, gemcitabine should be used with caution in patients with impaired liver function. Nausea and vomiting are reported in one third of patients and are easily manageable with standard anti-emetics.

Renal: Mild proteinuria and haematuria are reported in 50% of patients, but are rarely clinically significant and are not usually associated with any change in serum creatinine. Nevertheless in very rare instances, cases of haemolytic uraemic syndrome have been reported. Hence, gemcitabine should be used with caution in patients with impaired renal function.

Allergy: A rash is seen in approximately 25% of patients and sometimes associated with pruritus. The rash is usually mild, not dose-limiting and responds to local therapy.

Oedema: This occurs in approximately 30% of patients. Sometimes facial or pulmonary oedema may occur. It is usually mild to moderate, rarely dose-limiting and is usually reversible after stopping gemcitabine treatment.

Flu-like illness: 20% of patients complain of fever, headache, back pain, chills, myalgia, asthenia and anorexia. Paracetamol may produce symptomatic relief.

5.2 Known Potential Benefits

The study described herein is being performed to investigate whether the addition of Vandetanib to Gemcitabine provides improvement in overall survival over the use of Gemcitabine alone. This is a pivotal study in this indication and will represent the landmark data for whether there is additional benefit with Vandetanib in pancreatic cancer.

Gemcitabine monotherapy, the control arm and backbone of the experimental arm, remains a standard of care in this disease. The only study that has shown improved outcome with the addition of another drug to Gemcitabine, over Gemcitabine alone, is the PA.3 study adding Erlotinib. The only study showing additional benefit over Gemcitabine and Erlotinib with the addition of a further drug is the AViTA study which showed improved progression-free survival with the addition of Bevacizumab to the Gemcitabine/Erlotinib combination. Vandetanib inhibits the same target as Erlotinib, i.e. EGFR, and the same target as Bevacizumab, i.e. VEGF.

The background summarises the theoretical basis for RET inhibition in this disease, and Vandetanib is the only RET inhibitor in clinical development which also has significant inhibitory activity against EGFR and VEGF.

At ASCO 2010, data was presented as showing a superiority of FOLFIRINOX over Gemcitabine monotherapy in pancreatic cancer patients with a performance status of 0-1, and clearly this regimen represents a further standard of care. Whilst this data awaits publication and peer review, it seems unlikely that this aggressive triple combination chemotherapy would be appropriate for all



patients with pancreatic cancer, including those who are indeed performance status 0 or 1. The inclusion criteria to this study state that patients will be eligible who have been considered for triplet combination chemotherapy and found not to be appropriate for such an approach.



6 SELECTION OF CENTRES/CLINICIANS

Each participating Centre (and investigator) has been identified on the basis of:

Having at least one lead clinician with a specific interest in, and responsibility for supervising, treating and managing patients with advanced pancreatic cancer

Showing enthusiasm to participate in the study

Ensuring that sufficient time, staff and adequate facilities are available for the trial.

Providing information to all supporting staff members involved with the trial or with other elements of the patient’s management.

Acknowledging and agreeing to conform to the administrative and ethical requirements and responsibilities of the study, including signing up to Good Clinical Practice (GCP) and other regulatory documentation

Suitable MDT meeting structure to identify patients and ensure the pathologists and surgeons are involved in patient screening to ensure the required samples are made available for the associated biomarker studies

6.1 Centre/Clinician Inclusion Criteria

a. Positive Site Specific Assessment (SSA) by Local Research and Development (R&D) approval b. Signed Research Site Agreement including material transfer clauses c. Receipt of evidence of completion of (a) & (b) by LCTU d. Completion and return of “Signature and Delegation Log” to LCTU e. Curriculum Vitae (CV) including a record of International Conference for Harmonisation (ICH)

of GCP training – Principal Investigator (PI) f. CV including a record of ICH GCP training – Other personnel on the delegation log g. Clinical Study Protocol Receipt Form h. Investigator Brochures Receipt Form i. Local laboratory accreditation/Quality Check j. Completion of pharmacy practice form k. Completion of test SAE reported via web l. Completion of translational study questionnaire m. Local laboratory reference ranges n. Patient information sheet, consent form and GP letter on trust headed paper

6.2 Centre/Clinician Exclusion Criteria Those centres that do not fulfil the above inclusion criteria will not be permitted to participate in the trial.



7 PATIENT TRANSFERS AND WITHDRAWALS

7.1 Patient Transfers

In consenting to the trial, patients are consented to trial treatment, follow-up and data collection. If voluntary withdrawal from trial treatment occurs, the patient should be asked to allow continuation of scheduled evaluations, complete an end-of-study evaluation, and be given appropriate care under medical supervision until the symptoms of any adverse event (AE) are resolved or the subject’s condition becomes stable.

For patients moving from the area, every effort should be made for the patient to be followed-up at another participating trial centre and for this trial centre to take over responsibility for the patient or for follow-up via GP.

A copy of the patient CRFs should be provided to the new site. The patient will have to sign a new consent form at the new site, and until this occurs, the patient remains the responsibility of the original centre. The LCTU should be notified in writing of patient transfers.

7.2 Withdrawal from Trial Intervention

Patients may be withdrawn from treatment for any of the following reasons:

1. Patient decision to discontinue treatment.

2. Each regimen will be continued until evidence of disease progression as assessed by CT scan and evaluated according to RECIST, and whilst still deriving clinical benefit from treatment.

3. Intolerable adverse effects as judged by the investigator or the patient.

Patients must withdraw from treatment for any of the following reasons:

1. Pregnancy.

2. Recurrent grade 3 or 4 drug related toxicity despite dose modification.

3. Serious systemic allergic reaction to any of the study drugs e.g. angio-oedema, anaphylaxis.

4. Should they miss 2 consecutive cycles of gemcitabine and vandetanib administrations or 3 non-consecutive cycles during the entire treatment course (1 cycle of gemcitabine and vandetanib administrations is defined as 3 weeks of gemcitabine followed by a one weeks rest and 28 days of vandetanib. Cycle 1 which is an 8 week cycle should be classed as two separate cycles for the purpose of counting towards withdrawal criteria).

5. If trial treatment has been withheld for greater than 3 weeks due to toxicity and has not be

resolved to CTCAE grade 1.

Following withdrawal from study treatment, an end of study visit will take place and all patients other than those who choose to withdraw from the study entirely will continue to be followed up in the study by 3 monthly hospital visits until death or consent from the entire study is withdrawn. Reason(s) for withdrawal from study treatment must be recorded in the Case Report Form.

Patients withdrawn will not be substituted.

7.3 Withdrawal from Trial Completely

Patients who withdraw from the trial for other reasons have previously consented to follow-up in the trial. Data up to this time can be included in the trial if anonymised. They may need to reaffirm



that they consent to follow-up through usual NHS mechanisms. If the patient explicitly states their wish not to contribute further data to the study, a withdrawal CRF should be completed.



8 ENROLMENT AND RANDOMISATION

8.1 Screening

Screening will be performed upon a patient’s possible eligibility for the study and must be documented on the LCTU web portal “Screening and Enrolment log”. Screening details should be entered into the portal and this will automatically generate a screening number and a confirmation email with these details will be sent to site staff. The screening log can be printed at any time off the Portal to allow for storage in the Investigator Site File.

Step-by-step guides will be issued to research site staff and the process will also be demonstrated during site initiations.

Start of screening is defined as the patient being first discussed for eligibility in the local MDT meeting this should be followed by the signing of the Informed Consent Form and if eligible for the trial randomisation. Patient hospitals notes should be screened by the research team prior to the patient being approached to ensure no obvious exclusion/inclusion criterion are not met.

8.2 Enrolment/ Baseline

Trial specific screening activities will be performed after patients have consented to trial participation and signed the informed consent form. Assessments can only be used for screening if performed within 28 or 7 days prior to the first dose of treatment (see section 10.1 for details). Investigations performed for the purposes of diagnosis and staging may be used as screening assessments provided they are performed within this time frame. The following screening assessments should be performed:

Written Informed Consent

Confirmation of diagnosis (Histology/cytology)

Complete Demography and medical history

Concomitant medication

Physical examination and Medical Review

ECOG performance status

12-lead ECG

CT scan of chest, abdomen and pelvis

Haematological / clinical chemistry

Vital signs

Translational Blood Samples

CA19-9

Pregnancy test (women of child-bearing potential only)

8.3 Randomisation

Patients who have given informed consent and have been found to comply with all inclusion and exclusion criteria will be randomised by trained staff at the LCTU.



To ensure essential entry criteria are fulfilled, randomisation can only occur following the completion and forwarding of the trial randomisation documents by the investigators:

Completed Randomisation and Baseline Forms (4 pages) signed by an Investigator

A copy of the Signed Consent Form

Anonymised copy of the pathology report

Anonymised copy of screening haematology/serum chemistry

A copy of the concomitant medication from (if applicable)

Anonymised copy of the randomisation ECG printout(s)

The randomisation documents should be faxed to the LCTU on Monday - Friday from 09:00 to 17:00, fax number: 0151 794 8010. Prior to faxing documents, site staff should telephone 0151 794 0151 794 8935/795 5294 to inform the LCTU staff of the incoming randomisation fax.

Personnel from the LCTU will review the randomisation documents; confirm eligibility and record essential demographic data. The patient will then be randomly allocated a trial treatment and given a unique trial number through an IWRS (interactive web response system). The randomisation form will be annotated with details of the kit number(s) and the patient trial number and returned by fax/email to the investigator at site. The IWRS system will also send confirmation of randomisation and kit numbers to all site staff.

This trial number should then be filled in on each subsequent page of the patients CRF. Each centre will be provided with kits of packaged drugs. The packaging and tablets will appear identical for both active and placebo treatments. The label attached to each package of blinded study material will have a unique treatment kit number that is linked to the randomisation scheme. The IWRS will allocate the treatment and will provide the appropriate kit number and this will be recorded on the randomisation form, as well as a confirmation email being sent to site. The kit number allocated to the patient will only be available at that centre. Trial treatment should start within 7 days of randomisation or the earliest screening procedure, e.g. blood samples, CT scan whichever is sooner.

8.4 Unblinding

The treatment code must not be broken except in medical emergencies when the appropriate management of the patient necessitates knowledge of the treatment randomisation. Individual treatment codes indicating the patient’s treatment will be available from the IWRS 24/7.

Principal and Co-Investigators are able to access the IWRS via a website- www.fisheracts.com using individual access codes. Study specific user guides and PIN details will be sent to PIs after site activation and the trial site will be instructed on the method for breaking the blind. There is also a 24/7 IWRS freephone helpdesk number- 00 800 1012 1960. Patients will be issued with a contact card to carry with them at all times. This should include details of unblinding contact at site and arrangements at each site should be made to cover unblinding 24/7

Randomisation – Tel: 0151 794 8935/795 5294 Fax: 0151 794 8010

(Note that the LCTU is open from 09:00 – 17:00, Monday – Friday, excluding public holidays)

http://www.fisheracts.com/



9 Trial Treatments

9.1 Trial Introduction

Baseline radiographic assessment of disease will be performed within 28 days prior to first dose of treatment and first treatment will be delivered within 7 days of randomisation or the earliest screening procedure, e.g. blood samples, CT scan whichever is sooner as follows:

Arm A (standard therapeutic arm). Placebo orally once a day continuously together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles. Arm B. Vandetanib orally once a day continuously at 300 mg/day together with Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 7 consecutive weeks, followed by a one week break, followed by Gemcitabine 1000mg/m2 weekly as a 30 minute infusion for 3 weeks followed by a one week break in subsequent cycles.

The planned treatment duration per patient will be until progressive disease (PD) is observed. The duration of study participation is estimated to be an average of 4-6 months and will be until progression on CT scanning, stable disease but with obvious symptomatic progression, unacceptable toxicity or withdrawal of consent. Patients who stop treatment before having developed PD will be assessed every 12 weeks for response until PD occurs.

The end-of-therapy visit should occur within 7 days of documented PD or the decision is made to discontinue all therapy. At this visit a full assessment consisting of physical exam, performance status, ECG, haematology and chemistry profile and toxicity/AE assessments will be performed.

No further anti-tumour treatment will be initiated until progression of disease. AE information will be collected until at least 30 days after the last dose of study therapy is administered or until all study therapy-related AEs have resolved, stabilised or been deemed irreversible and a 30 day safety follow up should be performed at this point.

9.2 Non Investigational Medicinal Products (NIMPS)

9.2.1 Gemcitabine

9.2.1.1 Formulation, Packaging, Labelling, Storage and Stability

Gemcitabine is a nucleoside analogue interfering with DNA replication and will not be subject to any special packaging or labelling. Gemcitabine will be prescribed from hospital stock and will not be supplied as part of this study.



Manufacturer: Generic gemcitabine sourced from manufacturers listed on

electronic Medicines Compendium are allowed for use in the

study.

http://emc.medicines.org.uk

Formulation: Lyophilised powder for solution for intravenous infusion or

solution (ready reconstituted) for intravenous infusion.

Packaging, Storage and Stability. Please refer to the specific SmPC for individual product

Supplier’s name The local hospital pharmacy

Active Ingredient name /Dose Gemcitabine /1g and 200mg

9.2.2 Prescription / Dispensing of Investigational Products

Prescription of gemcitabine can be done according to local practice however a copy of each prescription must be retained for dose checking by the trial monitor.

9.2.3 Preparation, Dosage and Administration of Gemcitabine

Gemcitabine will be prepared according to local policy. Gemcitabine must be handled according to the instructions within the corresponding Summary of Products Characteristics (Please refer to current Gemcitabine SmPCs supplied by the appropriate manufacturer: http://emc.medicines.org.uk/searchresults.aspx?term=gemcitabine&searchtype=QuickSearch). 1000mg/m2 gemcitabine, up to a maximum dose of 2500mg, must be given as an intravenous infusion, the lyophilized powder being diluted in normal saline, over 30 minutes unless haematological toxicity occurs requiring dose adjustment as described in section 9.2.4.

9.2.4 Dose Modifications

9.2.4.1 Haematological Toxicity – Dose Adjustment

Gemcitabine administration should be given according to the absolute neutrophil and platelet counts. At the initiation of a cycle the neutrophil count should be at least 1.5 x 109/l and platelet count, 1.0 x 109/l. Dose modifications of gemcitabine within a cycle should be performed according to the following tables: Table 1: Dose adjustment following reduced neutrophil count

Absolute neutrophil count (x 109/l) Dose modification

> 1.0 100% dose

0.5-1.0 75% dose

< 0.5 Omit for one week

Table 2: Dose adjustment following reduced platelet count

Platelet count (x 109/l) Dose modification

> 100 100% dose

50-100 75% dose

< 50 Omit for one week

http://emc.medicines.org.uk/

http://emc.medicines.org.uk/searchresults.aspx?term=gemcitabine&searchtype=QuickSearch



Neutropenic sepsis: Gemcitabine should be omitted during an episode of fever associated with a neutrophil < 0.5 x 109/l.

9.2.4.2 Dose Modification in Subsequent Courses

Following dose reduction: Patients who have had a dose reduction due to decreased neutrophil or platelet count should have their next dose according to neutrophil and/or platelet count on the day of gemcitabine administration, i.e. they can have their dose escalated back to 100% dose if their blood count is adequate. However if after dose reduction to 75%, their blood count in the next gemcitabine administration is still inadequate i.e. neutrophil count between 0.5-1.0 or platelet count between 50-100, same dose at 75% should be given. Following omission of Gemcitabine administration for one week: On the day of next gemcitabine treatment, give above dose according to neutrophil and/or platelet count on that day. Following omission of Gemcitabine administration for two or three weeks: Give 75% of dose in all subsequent courses even if neutrophil and/or platelet count has recovered completely. Following neutropenic sepsis: Following an episode of febrile neutropenia, all subsequent courses should be given at 75% dose.

9.2.4.3 Non-Haematological Toxicity

Modifications are not required normally. In exceptional cases treatment delay may be necessary until the toxicity has resolved. If this happens, a 25% dose reduction should be made for subsequent courses if the investigator feels this is appropriate but for significant pulmonary complications, particularly pneumonitis and ARDS gemcitabine treatment should be stopped.

9.3 Investigational Medicinal Products

9.3.1 Vandetanib

9.3.1.1 Formulation, Packaging, Labelling, Storage and Stability

Vandetanib is a potent inhibitor of the tyrosine kinase activity of VEGFR-2, an endothelial cell receptor for VEGF, for use in the treatment of patients with solid tumours, administered either in combination or as monotherapy. In addition, vandetanib inhibits the tyrosine kinase activity of the EGFR and the RET tyrosine kinase.



Laboratory Name ZD6474

Formulation White film-coated tablets

Active Ingredient Name / Dose Vandetanib / 100mg

Excipients Vandetanib, calcium hydrogen phosphate, microcrystalline cellulose, sodium starch glycollate, povidone, sodium lauryl sulphate and magnesium stearate, with a film coating containing HPMC, polyethylene glycol 300 and titanium dioxide.

Pack Size(s) Tablets packed in high density polyethylene (HDPE) bottles with child resistant and tamper evident caps.

Manufacturer’s name AstraZeneca

Supplier’s name Fisher Clinical Services

Storage The tablets should be stored in the original pack until use. For further information investigators should refer to the investigational product label.

Vandetanib will be labelled according to regulatory requirements (see Appendix B).

Pharmacy will not need to do any re-labelling of the vandetanib / placebo. All study drugs will be provided to sites in labelled bottles which will be blinded, once the site has been activated by the Liverpool Cancer Trials Unit. The material will arrive at site ready to be dispensed to patients, local Pharmacy will need to confirm shipment of the drug to the site through the IWRS. When a patient is randomised by staff at the LCTU using IWRS, kit number(s) to be dispensed to the patient will be allocated and an email sent to the site confirming these details. All investigator products must be kept in a secure place appropriate storage conditions. A description of the appropriate storage and shipment conditions is specified on the investigational product label and investigator brochure. The stored study drug supplies must be accessible to authorized staff only. The storage area must also have adequate control of temperature in order to maintain stability and potency of study drug supplies. The tablets should be stored in the original pack until use. For further information, investigators should refer to the investigational product label.

9.3.2 Prescribing and distribution of Vandetanib

Investigational products may only be prescribed to a trial patient by the principal investigator or sub investigator named in the: 1. Study delegation log Research site pharmacies must maintain a drug accountability log, template logs will be provided by the LCTU; however sites may use their own provided they have been approved by the study team at site initiation. A copy of the Vandetanib prescription must be retained with the drug accountability Log. Please see appendix A for an example of the prescription sheet to be used.

9.3.3 Preparation, Dosage and Administration of Vandetanib

Vandetanib will be taken orally continuously once a day at a dose of 300mg in the morning. If the subject inadvertently does not take the dose in the morning and the next dose is scheduled for 12 hours later or more, the patient should take that day’s dose. However, if a subject misses taking



their scheduled dose and it is less than 12 hours until they are supposed to take the next dose, , the patient should skip that dose and take the next dose at the normal time.. If vomiting occurs within 30 minutes after vandetanib tablets are swallowed, the dose should be replaced only if all the intact tablets can be actually seen and counted. Otherwise the dose should be missed and the next dose prescribed taken. All missed/vomited doses should be captured in the patient drug diary.

9.3.4 Dose Modifications

For guidance on the management of QTc prolongation, see below. Also refer to Appendix C, Medications Known to Prolong the QT Interval and/or Induce Torsades De Pointes (Tdp). For all toxicities, a maximum of 2 dose reductions will be permitted as illustrated in Table 3. The dose of study treatment may be withheld for up to 3 weeks until the toxicity has resolved to CTCAE grade 1 or better, and then study treatment may be restarted. Dose reduction/re-challenge for each toxicity criterion will be managed as discussed in the sections that follow. If toxicity recurs at 100mg or previous toxicity has not resolved within 3 weeks the patient should be withdrawn from study treatment.

Table 3: Dose Reduction for Vandetanib

Original

dose

Reduced

dose

Vandetanib dispensed for reduced

dose

Tablets per daily dose

300 mg 200 mg 100-mg Vandetanib tablets 2

200 mg 100 mg 100-mg Vandetanib tablets 1

9.3.4.1 Management of gastrointestinal toxicity

Nausea, vomiting, or both may be controlled with antiemetic therapy as per local policy. Diarrhoea should be treated as per local policy for the management of diarrhoea with tyrosine kinase inhibitors in order to avoid dose modification or interruption, if possible. Electrolyte supplementation with regular laboratory monitoring should be used, when appropriate, to maintain electrolytes within normal limits and to prevent an increased risk of QTc prolongation. No dose modifications should be made because of Grade 1 or 2 diarrhoea. If Grade 3 diarrhoea develops, vandetanib should be withheld until diarrhoea resolves to Grade 1 or below. Upon recovery, treatment may resume at a permanently reduced dose as per the above table. If Grade 3 or 4 diarrhoea recurs after dose reduction to the lowest dose (100mg), the patient must permanently discontinue study treatment. If vandetanib must be withheld for more than 3 weeks for resolution of diarrhoea, the patient must not restart treatment with study medication.

9.3.4.2 Management of cutaneous toxicity

It is strongly recommended that all patients follow a program of sun-protective measures while receiving study therapy and for 3 to 4 weeks after discontinuing study therapy (wearing additional clothing or sunscreen). The aim is to reduce the risk of development of skin rash, or minimise the severity of skin rash, and to minimise the requirement for dose reduction of study therapy. If a patient develops a skin rash, the following actions are recommended to the Investigator for the management of this reaction:



If the rash is mild then the use of topical hydrocortisone should be employed and if the rash is macular and/orpustular, topical clindamycin should be instituted. If the skin reaction worsens or does not improve the additional use of an oral tetracycline is advised. If there is no improvement with this regimen then dose interruption should be considered and the use of oral prednisolone 25mg for a week reducing by 5mg every 4 days should be considered. Grade 3 rash mandates for stopping the vandetanib and on recovery a dose reduction must be affected as per the above table. Recrudescence of rash should be treated as outlined as above. A further dose reduction will be permitted. If a grade 3 or grade 4 rash should recur at 100mg vandetanib the drug should be permanently discontinued.

9.3.4.3 Electrocardiogram safety monitoring

Patients will have ECGs performed to monitor QTc interval (using Bazett’s correction) as outlined in the study plan (Section 10.1).

Management of Patients with QTc Prolongation

For a single QTcB value of >500msec, vandetanib must be withheld. Electrocardiograms (ECGs) will be performed at least once per week (done on the same day each week) along with electrolytes, until QTcB falls ≤480msec. Vandetanib treatment may be resumed at a permanently lower dose after the QTcB returns to ≤480msec. Post the QTcB prolongation period: if vandetanib (at the reduced dose) is restarted after the QTcB prolongation has resolved, ECGs and electrolytes (including calcium and magnesium) must be obtained at 3, 8 and 12 weeks following the start of the lower dose. Serum Potassium levels should be maintained at 4mEg/L or higher and serum magnesium and serum calcium should be kept within normal range to reduce the risk of QT prolongation. ECG and electrolyte monitoring can then resume at every 12 weeks at the normal visit schedule for the patient. Vandetanib dose reductions should be managed as outlined in section 9.3.4. If a patient has a QTcB value of >500msec at the lowest dose of vandetanib (100mg daily), vandetanib must be permanently discontinued.

9.3.4.4 Management of Patients with renal impairment

No adjustment in starting dose is required for patients with mild renal impairment (creatinine clearance of 50mL/min or more). Patients with moderate renal failure, defined as creatinine ≥30mL/min and <50mL/min, should begin vandetanib at a reduced dose of 200mg. Review of data from study 58 (refer to vandetanib IB) showed that 5 out of 6 patients (83%) with moderate renal failure who received vandetanib had a dose reduction to 200mg due to an adverse event of QT prolongation, compared to 36% of the patients in the entire vandetanib treatment arm. The time of in trial dose reduction ranged from 9 days to 193 days. One patient had a further a further reduced dose to 100mg due to an adverse event. Caution must be taken in patients with severe renal impairment, as clinical experience in this population is limited and exposure to vandetanib may be twice that in patients with no renal impairment.

9.3.4.5 Other toxicity

If grade 2 toxicity occurs and advice on dose reduction has not been stated above for that toxicity, dose modifications should be made at the discretion of the investigator.



If any other grade 3 or 4 toxicity that is not outlined above develops and is considered attributable to vandetanib, the following actions are recommended to the Investigator:

Vandetanib should be withheld until the toxicity resolves to grade 1 or below. Upon recovery, treatment may resume at a permanent reduced dose.

If vandetanib must be withheld for more than 3 weeks for resolution of toxicity, the patient will not restart treatment with study medication.

If grade 3 or 4 toxicity recurs after 2 dose reductions, the patient must permanently discontinue study treatment.

If blood pressure cannot be stabilized with increased antihypertensive medication, study treatment must be discontinued and cannot be resumed until blood pressure is controlled to baseline level.

Patients with CTCAE grade 3 or 4 hypertension should discontinue study treatment and cannot resume therapy until blood pressure is controlled to baseline level. Therapy should then be re-started at a permanently reduced dose.

If study treatment must be interrupted for more than 3 weeks to allow for toxicity to resolve, the patient’s study participation will be discontinued.

9.4 Placebo

The placebo will be the identical to the Vandetanib and have the same composition apart from the active substance. Patients on placebo should be treated as if on Vandetanib unless in a medical emergency when the unblinding procedure section 8.6 should be followed.

9.5 Accountability Procedures for Study Treatment/s

The investigator or designated study personnel are responsible for maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, including study drug accidentally or deliberately destroyed. All discrepancies between amounts of study drug dispensed and amounts returned must be documented. Under no circumstances will the investigator allow the investigational drug to be used other than as directed by the protocol without prior approval. If appropriate, drug storage, drug dispensing, and drug accountability should be delegated to the pharmacy section of the investigative site. Any remaining vandetanib / placebo tablets must be kept for inspection by the monitor and must then be destroyed.

9.6 Assessment of Compliance with Study Treatment/s

In order to confirm compliance with vandetanib and placebo administration, patients’ will be given a vandetanib / placebo diary sheet to be completed each day (Appendix D). Research Nurses will collect the unused tablets and completed diary cards and record any circumstances of non-compliance in the patient notes and on the CRF. The returned medication should be sent to the site pharmacy for storage inspection by the monitor at their next visit. Trial monitors will also perform source data verification as appropriate.



9.7 Concomitant Medications/Treatments

Caution should be observed and increased ECG monitoring should be implemented when vandetanib is administered in patients receiving drugs known to cause Torsades-de-Pointes (TdP), appendix C of this protocol lists the drugs accepted to cause TdP. Investigators will need to periodically check the Arizona CERT website (http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm) for updates to the tables listed in Appendix C.

Concomitant use of the known potent inducers of CYP3A4: rifampicin, phenytoin, carbamazepine, barbiturates and St. John's Wort are not allowed within 2 weeks of study or during the study. Until the effect of CYP3A4 inducers in the exposure to vandetanib in humans has been assessed, the co-administration of such inducers with vandetanib is not allowed.

However, it has been shown that CYP3A4 inhibitors for example, ketoconazole, itraconazole, voriconazole, moxifloxacin, clarithromycin, telithromycin and ritonavir, have little effect on the exposure to vandetanib in humans, and therefore these can be co-administered with vandetanib.

In vitro data has shown vandetanib inhibits CYP2D6 and CYP2C8. Based on the maximum steady state total plasma concentrations observed in patients the I/Ki ratio for both these is less than 0.10, and a SimCYP simulation for the potential inhibition of CYP2D6 (lower IC50 and Ki), concluded there would be little effect on CYP2D6 substrates. Thus substrates of both CYP2D6 and CYP2C8 may be co-administered with vandetanib.

Interactions between vandetanib and metformin, and vandetanib and digoxin are described in

the vandetanib Investigator Brochure. Patients receiving concomitant metformin and

vandetanib should be monitored as appropriate, and may require a lower dose of metformin.

Patients receiving concomitant digoxin and vandetanib should be monitored as appropriate. No additional treatment known to have an effect on the patient’s cancer may be used during treatment with gemcitabine +/- vandetanib, except:

Palliative radiotherapy for painful bony metastases.

Bisphosphonates for treatment of bone pain or hypercalcaemia.

Currently, limited information is available regarding the safety and therapeutic benefit of the

combination of vandetanib and radiotherapy. The investigator may use their discretion as to

whether to continue vandetanib during radiation therapy ensuring careful safety monitoring. Any

lesions which have been subjected to palliative radiotherapy will not be further considered evaluable

unless evidence of disease progression has occurred based on RECIST Criteria (version 1.1).

There is no clinically relevant PK interaction between vandetanib and gemcitabine. Body surface area calculation and the use of dose capping will be performed according to local guidelines. The treatment of extravasation should be as per local policy.

9.8 Overdoses

Gemcitabine There is no antidote for overdosage of gemcitabine. In the event of a suspected overdosage, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.

http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm



Vandetanib There is no specific treatment for an overdose of vandetanib. In clinical trials, single doses of 1200 mg have been given to healthy volunteers with minimal symptoms. Chronic dosing of 600 mg has resulted in diarrhoea and other AEs. In case of overdose, vandetanib therapy may be interrupted, and any adverse reactions treated symptomatically.

9.9 Co-enrolment Guidelines

During participation in this trial, participants will not be allowed to take part in studies with investigational agents. Participation in non-interventional studies which will not materially affect the use of study medication or confound any primary or secondary outcome measures is allowed.



10 ASSESSMENTS AND PROCEDURES

10.1 Schedule of Trial Procedures Table 4: Schedule of Study Procedures (screening to week 20)

Study phase Screening Randomised Treatment Week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Day 28 7 1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127 134

Visit window (days)

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Histology/cytology X#

Informed consent X

Inclusion criteria X

Randomisation X

Demography & medical history

X

Medical Review X##+

X X X X X X X X X X X X X X X X

Physical examination X+ X X X X X

Vital signs X X X X X X X X X X X X X X X X X

Performance status X X X X X X

ECG X X X X X X

Haematology X+ X X X X X X X X X X X X X X X X

Serum Chemistry X+ X X X X X X X X X X X X X X X X

Genomic/Proteomic Sampling-Blood

X X

Biomarker Assays/ Tissue$ X

$ X

$

CT scan (RECIST) X* X

CA19-9 X X X X X

Concomitant Therapy X X X X X X X X X X X X X X X X X

Adverse events X X X X X X X X X X X X X X X X

Patient pain assessment X X X X X X X X X X X X X X X X

Gemcitabine treatment X X X X X X X X X X X X X X X X

Study medication dispensing

X X X X X

vandetanib / placebo treatment

X X X X X X X X X X X X X X X X X X X X



Pregnancy test X

# No time limit.

## In view of relatively limited data in the combination of vandetanib and gemcitabine, patients are to be reviewed by a physician prior to randomisation. Patients should have a medical review each time they attend for gemcitabine infusion either by a physician or an individual specified on the delegation log suitably qualified to make the assessment (e.g. ViP research nurse).

+ If screening bloods, medical review and physical examination are obtained within 3 days before day 1, then they will be considered to be the baseline.

A 12-lead ECG must be performed at screening (within 7 days before first dose of trial treatment). The screening QTc must be < 480msec. If the QTc value on the first ECG is not <480, a second ECG should be done (at least 24 hours after the first) and the average reading of the two ECGs will be used to determine eligibility. If the QTc value on the second ECG is still not <480, a third and final ECG can be done (at least 24 hours after the second) and the average of all 3 used to determine eligibility. The date that eligibility was ascertained is when the 7 day to treatment window begins. If, after the 3

rd ECG, the average still violates the exclusion criteria, the patient is not eligible for the

trial. Baseline QTc will be determined on, day 1, by one 12-lead ECG to be performed pre-dose. If the screening QTc is obtained within 3 days before day 1, then the screening

QTc will be considered to be the baseline, and a repeat ECG will not be necessary on day 1. When possible, ECGs should be performed at the same time throughout the study (performed 4-8 hours after the patient takes their oral medication). ECGs must be done at weeks 1, 2, 4, 9, 12, every 12 weeks whilst on study treatment and at discontinuation. Additional ECGs may be required as clinically indicated (ECGs to be consistent with the chemotherapy schedule, where relevant.)

If QTc prolongation occurs instructions as outlined in section 9.3.4.3 should be followed

* CT scans of chest, abdomen and pelvis will be performed every 3 months. Clearly if investigators feel that a patient is clinically progressing, a CT scan to document progression will be required before the next 3 month time point. CT scan is only necessary during follow-up if no disease progression at time of treatment withdrawal. Adverse event are assessed according to NCI CTCAE version 4.02.

Following week 8 gemcitabine will be administered three weeks on and one week off i.e., day 1, day 8 and day 15 of each 28 day cycle with no gemcitabine on day 22.

Patients should be treated with therapy until progression of disease, patient choice or unacceptable toxicity.

The use of vandetanib / placebo as a monotherapy in this study in a maintenance context is not permitted because there is no data on the activity of vandetanib as a monotherapy in this disease setting.

Dose banding / rounding: Dose banding should be undertaken as per local policy.

Following the end of study visit, patients will be contacted every six weeks to obtain information about survival and about subsequent systemic anti-cancer therapy. All patients will continue to be followed for survival in all cases other than those who withdraw consent.



An Independent Data and Safety Monitoring Committee (IDSMC) will be established prior to the inclusion of the first patient in the trial and will meet to assess the safety data and recommend early discontinuation of the study for safety reasons or continuation of the study for full patient accrual. Detailed toxicity data will be reviewed after the first 20 patients are randomised.

$ The biomarker assay and tissue collection is not a compulsory part of the study. Please see translation section 11 for more details.

Table 5: Schedule of Study Procedures (week 21 to End of Study)

Study phase Further 12 weeks treatment periods (repeat until treatment withdrawal)

End of Study Treatment

Follow-up End of Study

Week 21 22 23 24 25 26 27 28 29 30 31 32 - Every 12 weeks

£

-

Day 141 148 155 162 169 176 183 190 197 204 211 218 - - -

Visit window (days) 1 1 1 1 1 1 1 1 1 1 1 1 - 6 -

Medical Review X X X X X X X X X

Physical examination X X X X X

Vital signs X X X X X X X X X X X

Performance status X X X X X

ECG# X X X

Haematology X X X X X X X X X

Serum Chemistry X X X X X X X X X

Genomic/Proteomic Sampling-Blood

X

CT scan (RECIST) X X

CA19-9 X X X X

Concomitant Therapy X X X X X X X X X X X

Adverse events X X X X X X X X X X X X

Patient pain assessment X X X X X X X X X X X X

Gemcitabine treatment X X X X X X X X X

Study medication dispensing X X X

vandetanib / placebo treatment

X X X X X X X X X X X X

1st

subsequent therapy X

Reason for discontinuation X X

Death Form Completed X



£ First follow-visit must be 12 weeks after the previous study related scan, then every 12 weeks thereafter. Only applicable should the patient be able to complete the form. Follow-up CT scan only required if no disease progression at the time of treatment withdrawal. # ECGs must be performed every 12 weeks until the patient is no longer taking study treatment



10.2 Procedures for Assessing Efficacy

10.2.1 Length of Survival

Survival will be measured from date of randomisation to date of death from any cause or censor date. Patients remaining alive will be censored at the last date seen alive at last follow up. Survival estimates will be calculated using the method of Kaplan and Meier and the log-rank test or an appropriate equivalent will be used to assess differences in survival between the two treatment arms. Bonferroni or other equivalent adjustments will be used to adjust for multiple comparisons. Any treatment effect will be adjusted by stratification factors and other identified prognostic factors, including baseline biochemical factors, using stratified log-rank analyses and in a multivariate setting using Cox proportional hazards and/or random effects modelling. Hazard ratios of the treatment effect (without significance testing) within identified prognostic subgroups will be estimated and presented graphically with tests of heterogeneity.

10.2.2 Time to Progression

Time to progression will be measured from date of randomisation to date of progressive disease (as measured by CT) or death. Patients who have not progressed or died at the time of statistical analysis will be censored at the time of their latest objective tumour assessment, including patients who are lost to follow up or have withdrawn consent. Time to progression will also be estimated using the method of Kaplan and Meier and compared across treatment groups and across important patient characteristic or histological groups using the log-rank test.

10.2.3 Objective Response and Disease Control Rate

Response will be assessed in accordance with RECIST Guidelines (Appendix E) and the proportions of patients achieving complete or partial responses and disease control will be compared across treatments using descriptive statistics (with 95% confidence intervals) and using Pearson’s chi-square test with continuity correction, Fishers Exact test or equivalent.

10.2.4 CA19-9

Longitudinal analysis of CA19-9 over total time will also be compared. Assessment of CA19-9 will take place at the screening visit, week 5, week 9, week 13, week 17, week 21, week 25, week 29 and then every 4 weeks thereafter.

10.3 Procedures for Assessing Safety Safety will be assessed through the reporting of adverse events as described in Section 13. Formal toxicity assessments will be performed at each study visit as described in Section 9. Adverse events will be described using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.02, which can be accessed at the following website: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40_conversion

10.4 Patient Pain Assessment The Patient Pain Assessment should be carried out every week prior to the scheduled administration of gemcitabine treatment, at the end of study treatment visit, at every follow-up visit after stopping trial treatment and at the end of the study if the patient is able to. Patients should complete a 2 question form and the answers should be transcribed by the nursing staff on to the appropriate CRF page. Nursing staff should ensure the patient returns the form before treatment and that they are completed correctly. The original form should be retained as a source document for verification by the trial monitor. If a patient is deemed too unwell to receive treatment the form should still be completed.

http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40_conversion



10.5 Loss to Follow-up

If any of the trial patients are lost to follow up, contact will initially be attempted through the PI at each centre. If the PI at the trial centre is not the patient’s usual clinician responsible for their speciality care then follow-up will also be attempted through this clinician. Where all of these attempts are unsuccessful, the patient’s GP will be asked to provide follow-up information to the recruiting centre.

10.6 Trial Closure

Investigators will be informed when patient recruitment is to cease. Trial enrolment may be stopped at a site when the total requested number of subjects for the trial has been obtained. The IDSMC may recommend to the TSC that the trial be stopped prematurely. Such premature termination/suspension of the trial will be notified to the MHRA and MREC as required. The trial will be considered formally “closed” when all patients have been followed up until death and all outstanding data has been collected.



11 TRANSLATIONAL SUBSTUDIES

11.1 Sample Collection

11.1.1 Genomic/Proteomic Sampling

In addition to the patient’s routine haematology blood samples, a further 20ml (approx) of blood (2 x 10 ml) will be taken, at specified time points throughout the study. Blood for translational work will be taken using BD Vacutainer tubes, one 10 ml draw for plasma and cells in K2E tubes and one 8.5ml draw in SSTBD Vacutainer for serum. These samples will be stored under appropriate conditions within the GCLP Laboratories, University of Liverpool, for up to 10 years from study start and will be used in future genomic and proteomic analysis. Plasma and Serum will be taken prior to the start of treatment, at week 13 (Table 4) and then at every 12 weeks thereafter. Blood samples for translational work must be taken before the administration of gemcitabine. If a patient is deemed too unwell to receive treatment, every effort should still be made to take the samples. The plasma will be used for analysis of circulating DNA and work on biomarkers in pancreas cancer. Cell pellets will be used for genomic analysis of SNPS (Single Nucleotide Polymorphisms) in the genes relevant to the targets of Vandetanib to discover biomarkers predictive of benefit with the drug. We may also investigate SNPs as possible indicators to a genetic pre-disposition for pancreatic cancer The serum will betemporarily stored at site and then shipped to Liverpool ECMC GCLP Facility.An aliquot of the serum will be sent to Biodesix for Veristrat analysis. The serum will also be analysed in the GCLP Laboratories for a panel of cytokines, chemokines and growth factors including VEGF and EGF.

11.2 Tissue Samples

The tissue collection is NOT compulsory as part of the study. However the tissue will be very important to the translational work and the LCTU and the Liverpool ECMC will provide support as much as possible to facilitate collection.

The inclusion of patients into the VIP trial should be considered at the outset of initial patient assessment at the MDT. It is anticipated that the diagnostic work-up of potentially eligible patients will be discussed through a pancreatico-bilary MDT with the pathologist, radiologist and referring doctor so as to maximise tissue collection.

There are three pathways for collecting biopsy samples for the translation work (Please see figure 1).

1) Patient undergoing a diagnostic biopsy

If a patient is being evaluated/discussed who has not previously undergone a biopsy and is being referred for a biopsy procedure and the research team feel that after the procedures the patient might be eligible for the VIP study, the patient should be approached before the diagnostic biopsy to consent to and provide an extra biopsy sample for research. This research sample will be taken at the same point as the diagnostic one and should be Formalin Fixed Paraffin Embedded preparation and should be clearly labelled by the pathology team as for research and transferred to the University of Liverpool.

We ask that the patient are approached to provide a research sample at the same time as the diagnostic procedure are done so using the Pancreas Diagnostic Biopsy Research Sample Collection Patient Information Sheet and corresponding Informed Consent Form to allow an extra sample to be taken at the time of diagnostic biopsy for research.

2) Patients already having already undergone a diagnostic biopsy

If a patient is entered into the trial and has already under their diagnostic biopsy they should be approached to see if they will consent and undergo a further biopsy for the purpose of the trial. Patients should be approached using the



VIP: Pancreas Biopsy Research Sample Patient Information Sheet and corresponding Informed Consent Form. If the patient agrees up to 2 cores can be taken. As a minimum 1 core for Formalin Fixed Paraffin Embedded preparation and an additional core to be placed in ‘All Protect’ solution which will be provided by the Co-ordinating centre. Both the samples should be labelled appropriately for the trial and transferred to the University of Liverpool. 3) Patients refusing the second biopsy Any patient participating in the trial who does not wish to have extra tissue taken should be approached to see if they will consent to allowing us to use any surplus tissue from the diagnostic biopsy. It is anticipated that in many cases this will provide very little tissue but in some patient particular where a core biopsy has been taken there may be enough unstrained slides and/or sections to allow IHC evaluation as part of the Biomarker Discovery program in this study. Tissue samples will be for a biomarker repository for both predictive and prognostic purposes. In particular a range of studies will be performed to define useful biomarkers for each of the three main pathways which vandetanib inhibits – angiogenesis, EGFR signalling and RET signalling. Appropriately labelled blocks will be sent to the GCLP Laboratories, University of Liverpool after collection for central storage. Figure 1: Process for requesting and collecting Biopsy samples for translational work

Patient indentified at the Local HPB MDT meeting as having suspected pancreatic cancer

Patient sent for diagnostic biopsy and request made at the same

time for extra sample for research purposes.

Research Biopsy PIS

Research Biopsy ICF

Patient randomised into ViP study

Request repeat biopsy to obtain research sample for

ViP Study

VIP Research Biopsy PIS

VIP Research Biopsy ICF

VIP Tissue Bank

Patient Agrees

Diagnostic Biopsy

Patient Refuses

Request the collection of any surplus tissue from the original biopsy for use in

research.

Research Biopsy

(Formalin Fixed)

Research (diagnostic) Biopsy

(Formalin Fixed)

Research Biopsy (Formalin Fixed)

Research Biopsy (All protect)

Process for requesting and collecting of biopsy samples for translational work for the ViP trial

Patient sent for diagnostic biopsy? Patient has already undergone diagnostic biopsy?

Patient Refuses Patient Agrees

Eligible patients randomised into

ViP study



12 STATISTICAL CONSIDERATIONS

12.1 Introduction

This trial is a parallel group study in which patients will be randomised between the experimental treatment (gemcitabine and vandetanib) and the control treatment (gemcitabine therapy and placebo). The principal comparison will be between survival times of subjects from randomisation to death from any cause. An interim analysis will be conducted part way through the study with the sole purpose of stopping the trial if it is futile to continue due to the lack of evidence of relative efficacy in the experimental treatment arm.

12.2 Primary Endpoint

Overall survival (OS) time in patients receiving gemcitabine and vandetanib therapy versus gemcitabine alone.

12.3 Secondary Endpoint(s)

Comparison between the two treatment groups for: o Progression-free survival time o objective response rate o disease control rate o toxicity and safety o Patient Pain assessment

To discover possible biomarkers to predict additional benefit of vandetanib for subsequent validation in larger

scale studies.

12.4 Method of Randomisation

The research nurse / doctor will randomise a patient to either vandetanib or placebo by contacting the LCTU as outlined in section 8.3.

Randomisation of patients will allocate treatment via block randomisation and stratified by the following:

Stage of disease: locally advanced or metastatic disease

ECOG performance status: 0/1 versus 2

12.5 Sample Size

The sample size for this study is to be 120 patients: 60 on gemcitabine and vandetanib therapy and 60 on gemcitabine therapy and placebo. The study will have sufficient power if 100 deaths are observed, and it is anticipated that recruitment of 120 patients over 18 months, with follow up of all surviving subjects for a further 12 months, will be sufficient for the observation of 100 deaths.

VIP for a 1-sided test and for significance level 0.10, 100 deaths are required to ensure 90% power of detecting a hazard ratio of 0.6. Using published data from two recent pancreatic cancer trials in which the control arm received gemcitabine alone, calculations showed that 120 patients needed to be recruited overall within the accrual period with a 12 month follow-up period in order that 100 deaths would be observed. Full details of the sample size calculations are included in the document “Proposal for the Design and Analysis of the VIP Study.”

An additional 20 patients are to be randomised to ensure that sufficient quality translational materials are collected. The impact of these extra patients will be to increase the number of events at the planned final analysis to 109 resulting in an overall power of 91.8%. These extra patients also allow for the possibility for some patients to be lost to follow up and ensures that a power of 90% will be maintained.



12.6 Interim Monitoring and Analyses A single interim analysis is planned at a point where 50 deaths have been observed. It is anticipated that this analysis will occur following the end of trial recruitment. The purpose of the analysis will be to determine whether early conclusions can be made. No decision on early termination of the trial will be made as it is anticipated that recruitment will have ended. At the interim analysis the estimated hazard ratio (E : C) will be computed from a stratified Cox proportional hazard model, as planned for the final primary analysis. The Interim analysis will be assessed using a one-sided test assessed at a 0.1 significance level. The inclusion of the futility analysis reduces the type I error rate from 0.1 to 0.096. Thus if the study does continue after the interim analysis, the primary analysis (conducted ignoring the futility analysis) will be conservative. The power of the study incorporating the futility analysis will be 0.89 if the true hazard ratio is 0.6. The findings of this interim analysis will be reviewed by an Independent Data Monitoring and Safety Committee (IDSMC) prior to the conclusion concerning stopping or continuing the trial being finalised.

12.7 Statistical Analysis Plans A single statistical analysis plan will be produced during the course of the trial. This document will detail how the final analysis and interim analysis shall be carried out as well as including all relevant information for inspection by the IDSMC. This document will be approved by the Trial Steering Committee (TSC) and the IDSMC prior to any analysis being carried out. The primary outcome, (overall survival) is defined as the difference in time between randomisation and death from any cause or the censor date. Survival analysis will be carried out when all patients have a minimum of 1 year follow-up after randomisation. The primary analysis will be a Cox proportional hazards regression analysis or equivalent, stratified by ECOG performance status and stage to compare overall survival on the combination treatment with that on gemcitabine alone. The outcome will be regarded as promising if the one-sided p-value indicating superiority of the experimental treatment is less than 0.10. Survival curves will be estimated by the method of Kaplan and Meier. For the secondary outcomes, progression-free survival will be analysed in a similar manner to overall survival. The proportions of patients achieving complete or partial responses and disease control will be compared across treatments using descriptive statistics (with 95% confidence intervals) and using Pearson’s chi-square test with continuity correction, Fishers Exact test or equivalent. The proportion of grade 3/4 toxicity will also be compared across treatments using a similar approach.



13 PHARMACOVIGILANCE

13.1 Terms and Definitions

The following definitions have been adapted from European Directive 2001/20/EC and ICH GCP E6, they should be used when dealing with any adverse events occurring in patients on the VIP trial. Adverse Event (AE) An adverse event is defined as any untoward medical occurrence [i.e. any unfavourable or unintended sign including abnormal laboratory results, symptom or disease] in a research participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. AEs include the following:

All suspected adverse medication reactions.

All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity.

Apparently unrelated illnesses, including the worsening of a pre-existing illness.

Injury or accidents. Note that if a medical condition is known to have caused the injury or accident, the medical condition and the accident should be reported as two separate AEs.

Abnormalities in physiological testing or physical examination findings that require clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Laboratory abnormalities that require clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test) unless they are associated with an already reported clinical event. Laboratory abnormalities associated with a clinical event (e.g. elevated liver enzymes in a patient with jaundice) should be described in the comments of the report of the clinical event rather than listed as a separate AE.

Adverse Reaction (AR) Any untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject. Unexpected Adverse Reaction (UAR) An adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in: a) In the case of a product with a marketing authorization, in the summary of product characteristics for that product b) In the case of any other investigational medicinal product, in the investigator's brochure relating to the trial in question. Serious Adverse Event (SAE) Any adverse event, adverse reaction or unexpected adverse reaction, respectively, that:

Results in death.

Is life-threatening* (subject at immediate risk of death).

Requires in-patient hospitalisation or prolongation of existing hospitalisation**.



Results in persistent or significant disability or incapacity.

Consists of a congenital anomaly or birth defect.

Other important medical events***. *Life-threatening in the definition of “serious” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is a precautionary measure for continued observation. Hospitalisations for a pre-existing condition, including elective procedures that have not worsened, do not constitute an SAE.

***Other important medical events that may not result in death, be life-threatening, or require hospitalisation may be considered a serious adverse event/experience when, based upon appropriate medical judgment, they may jeopardise the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Serious Adverse Reaction (SAR) A SAE as defined above that is considered related to any dose of the Investigational Medicinal Product (IMP) administered to that participant. Suspected Unexpected SAR (SUSAR) Any suspected adverse reactions related to an IMP that is both unexpected and serious.

13.2 Notes on Adverse Event Inclusions and Exclusions

13.2.1 Include

An exacerbation of a pre-existing illness

An increase in frequency or intensity of a pre-existing episodic event/condition

A condition (even though it may have been present prior to the start of the trial) detected after trial drug administration

Continuous persistent disease or symptoms present at baseline that worsens following the administration of the study/trial treatment

Laboratory anomalies that require clinical intervention or further investigation (unless they are associated with an already reported clinical event)

Abnormalities in physiological testing or physical examination that require further investigation or clinical intervention

Injury or accidents

13.2.2 Do Not Include

Medical or surgical procedures- the condition which leads to the procedure is the adverse event

Pre-existing disease or conditions present before treatment that do not worsen

Situations where an untoward medical occurrence has occurred e.g. cosmetic elective surgery

Overdose of medication without signs or symptoms

The disease being treated or associated symptoms/signs unless more severe than expected for the patient’s condition.



13.3 Notes on Serious Adverse Event Exclusions

The following events do not need to be reported to the LCTU as a Serious Adverse Event:

Any planned or elective admission to a hospice for palliative care as a result of disease progression

Any hospital admission, due to biliary sepsis or obstructive jaundice as a result of biliary stent blockage These events are expected in this group of patients and will not be related to the trial treatments.

13.4 Reporting of Pregnancy

If a patient or their partner becomes pregnant during treatment or in the six months following treatment, a completed Pregnancy Report Form must be faxed to the LCTU within 24 hours of learning of its occurrence. (Should you need a copy of the Pregnancy Report Form please contact the trial coordinator.) On pregnancy outcome, the final Pregnancy Report Form should be faxed to the LCTU 30 days after the outcome. The final Pregnancy Report Form is used to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy follow-up information on this form also includes an assessment of the possible relationship to the trial medication of any pregnancy outcome. Pregnancy outcomes should also be collected for the female partners of male patient participating in the trial. Consent to report information regarding these pregnancy outcomes should be obtained from the mother prior to completion and faxing of the final Pregnancy Report Form. Any SAE experienced during pregnancy must be reported on the SAE form. The LCTU will report all pregnancies to the Trial Sponsor(s), Astra Zeneca, MHRA and MREC.

13.5 Notes Severity / Grading of Adverse Events

The assignment of the severity/grading should be made by the investigator responsible for the care of the participant using the definitions below. Regardless of the classification of an AE as serious or not, its severity must be assessed according to medical criteria alone using the following categories: Mild: does not interfere with routine activities Moderate: interferes with routine activities Severe: impossible to perform routine activities Life threatening Death A distinction is drawn between serious and severe AEs. Severity is a measure of intensity (see above) whereas seriousness is defined using the criteria in section 13.1, hence, a severe AE need not necessarily be a Serious Adverse Event. For example, a headache may be severe in intensity, but would not be classified as serious unless it met one of the criteria for serious events section 13.1.

Pregnancies must be reported by faxing a completed Pregnancy Report Form sent within 24 hours of becoming aware of the event to the

Liverpool Cancer Trials Unit Fax. No: 0151 794 8930

Pregnancy outcomes must be reported by faxing a completed final Pregnancy Report Form 30 days following the outcome to the Liverpool Cancer Trials Unit Fax. No. 0151 794 8930



Severity of any AE will be graded according to the World Health Organisation (WHO) toxicity criteria/National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.02, where applicable. For each episode, the highest severity grade attained should be reported. If an AE occurs that is not listed in the WHO/CTCAE, the Investigator will evaluate its severity using the definitions in Table 7. Table 7: Definition of Severity of Adverse Events

Mild Grade 1 - Does not interfere with subject's usual function (awareness of symptoms or signs, but easily tolerated [acceptable]).

Moderate Grade 2 - Interferes to some extent with subject's usual function (enough discomfort to interfere with usual activity [disturbing]).

Severe Grade 3 - Interferes significantly with subject's usual function (incapacity to work or to do usual activities [unacceptable])

Life Threatening Grade 4 - Results in risk of death, organ damage, or permanent disability (unacceptable)

Death Grade 5 – Results in death (unacceptable)

13.6 Relationship to Trial Treatment

The assignment of the causality should be made by the investigator responsible for the care of the participant using the definitions in Table 8. If any doubt about the causality exists the local investigator should inform the study coordination centre who will notify the Chief Investigator. In the case of discrepant views on causality between the investigator and others, the MHRA will be informed of both points of view. Table 8: Definitions of Causality

Relationship Description

None There is no evidence of any causal relationship. N.B. An alternative cause for the AE should be given

Unlikely There is little evidence to suggest there is a causal relationship (e.g. the event did not occur within a reasonable time after administration of the trial medication). There is another reasonable explanation for the event (e.g. the participant’s clinical condition, other concomitant treatment).

Possibly There is some evidence to suggest a causal relationship (e.g. because the event occurs within a reasonable time after administration of the trial medication). However, the influence of other factors may have contributed to the event (e.g. the participant’s clinical condition, other concomitant treatments).

Probably There is evidence to suggest a causal relationship and the influence of other factors is unlikely.

Highly Probable There is clear evidence to suggest a causal relationship and other possible contributing factors can be ruled out.

Any event grading as possibly, probably or highly probably related to the medicinal product will be classed as either adverse reaction or serious adverse reaction.

13.7 Reference Safety Information



The reference safety information for vandetanib and gemcitabine is:

Section 5.4 of the vandetanib Investigator Brochure. The current version applicable to the trial is available on the LCTU portal (www.lctu.org.uk/)

The appropriate section within the SPC for the brand of gemcitabine that investigator site is using must be referred to:


13.8 Expectedness

The CI or delegated other will evaluate each SAE as to whether it is expected or not. The event is considered as “unexpected” if the nature and severity of the event is not consistent with the information about the medicinal product in question set out in the appropriate Summary of Product Characteristics (SmPC) or Investigators Brochure (IB) reference document. The exception to this is those events listed in section 13.3. All events judged by the CI or delegated other to be possibly, probably, or highly probably related to the IMP, graded as serious and unexpected will be reported as a SUSAR.

13.9 Adverse Event Reporting Procedures

All new Adverse Events (AEs) that occur either before receiving study medication or 30 days following the last dose of trial treatment do not need to be recorded in the case report form and are not part of the expedited reporting procedure. Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed above. These should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of drug dependency or drug abuse.

13.9.1 Non serious ARs/AEs

All such events, whether expected or not, should be recorded in the weekly visit pages of the CRF or, if a field for the event is not provided there, in the AE Form online on the LCTU Pharmacovigilance MACRO database (see web address below) within 30 days after completion of the final treatment cycle.

https://www.lctu.org.uk/macro/default.aspx

. Instructions and training will be provided at site initiation.

13.9.2 Serious ARs/AEs/SUSARs

Serious Adverse Events (SAEs)

Investigators MUST REPORT ALL SERIOUS ADVERSE EVENTS (SAEs), including disease related as well as treatment related events that occur during and within 30 days following the last dose of trial treatment.

SAEs occurring in patients who have NOT received any study treatment do not need to reported to the sponsor (i.e. patients consented but not yet randomised)

http://www.lctu.org.uk/





SAEs must be reported within 24 hours of sites becoming aware of them by entering information in the LCTU Pharmacovigilance MACRO database. The web address for SAE entry on to the database is: https://www.lctu.org.uk/macro/default.aspx

Steps for reporting:

i. The online SAE form should be completed by the responsible investigator i.e. the consultant named on the ‘signature list and delegation of responsibilities log’ who is responsible for the patient’s care. The investigator should assess the SAE for the likelihood that it is a response to an investigational medicine. In the absence of the responsible investigator the form should be completed and signed by a designated member of the site trial team. The responsible investigator should check the SAE form, make changes as appropriate and sign as soon as possible. The initial report shall be followed by detailed, written reports. When an SAE form has been added an email is sent to the person completing the form, the Principal Investigator at the site and the VIP trial team.

ii. Once data has been entered onto MACRO it will be available immediately to the LCTU (who will be notified by email when an SAE is entered)

iii. The responsible investigator must notify their R&D department of the event (as per standard local procedure). iv. In the case of an SAE the subject must be followed-up until clinical recovery is complete and laboratory results

have returned to normal, or until the event has stabilised. Follow-up may continue after completion of protocol treatment if necessary.

v. Follow-up information is noted on the same SAE form within the LCTU Pharmacovigilance MACRO database. The SAE type drop down question at the top of the form should be changed to ‘follow-up’. Extra, annotated information and/or copies of test results may be provided separately.

vi. The patient must be identified by trial number, date of birth and initials only. The patient’s name should not be used on any correspondence.

The Investigator must institute appropriate therapeutic action and follow-up measures in accordance with Good Medical Practice but should notify the study co-ordinator of such actions.

The minimum dataset required for a preliminary report should include the following.

Research subject trial number and initials.

Date of onset of event.

Brief description of event and CTCAE (v4) grade.

Causality relationship.

Dated signature of investigator/co-investigator and clearly printed name. Date of last administration of study drug.

Causality relationship.

Dated signature of investigator/co-investigator and clearly printed name.

PLEASE ENSURE THAT MULITPLE SERIOUS ADVERSE EVENTS ARE REPORTED SEPARATELY TO THE LCTU. ONE SAE REPORT SHOULD ONLY RELATE TO ONE OVERALL DIAGNOSIS.




In the event of a problem with the MACRO database (power failure, server failure etc) SAE’s should be reported by faxing a completed SERIOUS ADVERSE EVENT FORM to the Liverpool Cancer Trials Unit, Fax: 00 44 151 794 8010.. Blank Serious Adverse Event forms can be obtained by contacting the VIP team on 0151 795 5294 or by logging onto the LCTU portal (www.lctu.org.uk) and a copy of the form can either be emailed or faxed as required. The ViP team will acknowledge receipt of the SAE on the same day if sent on a working day between 9am – 5pm or the next working day. If an acknowledgment is not received by site they should contact the LCTU. If all computer and fax systems have failed and an SAE needs to urgently be reported, as a last resort an answer phone message can be left on 0151 795 5294 detailing the SAE.

Suspected Unexpected Serious Adverse Reaction (SUSAR)

The Chief Investigator and the Liverpool Cancer Trials Unit will ensure that all SUSARs are reported to the co-sponsors, Competent Authorities (MHRA Clinical Trials Unit) and Ethical Committees within the following timelines.

Fatal or life threatening SUSARs within 7 days after receiving the initial information.

All other SUSARs with 15 days after receiving the information.

The Chief Investigator and the Liverpool Cancer Trials Unit will inform all investigators of SUSARs as they occur. All SUSARs are managed in accordance with the LCTU Pharmacovigilance SOPs and the VIP Pharmacovigilance plan

Annual Reporting to MHRA and MREC

From September 2011 the sponsor will submit a Development Safety Update Report (DSUR). The DSUR will present a comprehensive annual review and evaluation of pertinent safety information collected during the reporting period relating to the Investigational Medicinal Product it will cover the following 4 areas: (1) Examine whether the information obtained by the sponsor during the reporting period is in accordance with previous knowledge of the investigational drug’s safety (2) Describe new safety issues that could have an impact on the protection of clinical trial subjects (3) Summarise the current understanding and management of identified and potential risks (4) Provide an update on the status of the clinical investigation/development programme and study results.

13.10 Follow-up After Adverse Events

All adverse events should be followed until satisfactory resolution or until the investigator responsible for the care of the participant deems the event to be chronic or the patient to be stable. Serious adverse events will be followed-up until progressive disease or death. When reporting SAEs and SUSARs the investigator responsible for the care of the participant should apply the following criteria to provide information relating to event outcomes: resolved; resolved with sequelae (specifying with additional narrative); not resolved / ongoing; ongoing at final follow-up; fatal or unknown.

13.11 Responsibilities – Investigator

The Investigator is responsible for reporting all AEs that are observed or reported during the study, regardless of their relationship to study product.

http://www.lctu.org.uk/



All SAEs must be reported immediately by the investigator to the LCTU on an SAE form unless the SAE is specified in the protocol or Investigator Brochure as not requiring immediate reporting. All other adverse events should be reported on the regular progress/follow-up reports.

13.11.1 Maintenance of Blinding

Systems for SUSAR and SAR reporting should, as far as possible, maintain blinding of individual clinicians and of trials staff involved in the day-to-day running of the trial. Unblinding clinicians may be unavoidable if the information is necessary for the medical management of particular patients. The safety of patients in the trial always takes priority. In each report, seriousness, causality and expectedness should be evaluated for all of the trial treatments unless criteria have been fulfilled and unblinding has taken place.

Cases that are considered serious, unexpected and possibly, probably or almost certainly related to one of the trial therapies (i.e. possible SUSARs) would have to be unblinded at the clinical trials unit prior to reporting to the regulator and re-evaluated for expectedness in light of the administered treatment.



14 ETHICAL CONSIDERATIONS

14.1 Ethical Considerations The VIP trial will be conducted in accordance with, but not limited to, the Human Rights Act 1998, the DPA, Freedom of Information Act 2000 subject to the provisions of sections 41 and 43 thereof, the EU Clinical Trials Directive, the Medicines for Human Use (Clinical Trials) Regulations 2004, the Medicines Act 1968, the Human Tissue Act 2004, ICH GCP, the Declaration of Helsinki 1996 and the NHS Research Governance Framework for Health and Social Care, as amended from time to time. Patients will be asked to consent that data are recorded, collected, stored and processed and may be transferred to other countries, in accordance with any national legislation implementing the EU Data Protection Directive (95/46/EC) and to allow a copy of their completed signed consent form to be sent to the Liverpool Cancer Trials Unit. This study may be terminated at the request of the Chief Investigator, IDSMC, Independent Ethics Committee or the MHRA if, during the course of the study, concerns about the safety of further dosing emerge. The Chief Investigator will update the ethics committee and regulatory authority of any new information related to the study drug as and when appropriate.

14.2 Ethical Approval The trial protocol has submitted to the West London REC 2 Research Ethics Committee (MREC REF:11/LO/0097 ) for review and received the favourable opinion on the 04/07/2011 Local approval to conduct the trial at each NHS Trust participating will be sort from the local Research & Development (R&D). A copy of this approval will be forwarded to the LCTU with a copy of the PIS and CF on local headed paper before patients are entered.

14.3 Informed Consent Process Informed consent is a process initiated prior to an individual agreeing to participate in a trial and continues throughout the individual’s participation. Informed consent is required for all patients participating in LCTU coordinated trials. In obtaining and documenting informed consent, the investigator should comply with applicable regulatory requirements and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Discussion of objectives, risks and inconveniences of the trial and the conditions under which it is to be conducted are to be provided to patients by staff with appropriate experience. An appropriate Patient Information and Consent Forms, describing in detail the trial interventions/products, trial procedures and risks will be approved by an independent ethical committee (IEC) and the patient will be asked to read and review the document. Upon reviewing the document, the investigator will explain the research study to the patient and answer any questions that may arise. A contact point where further information about the trial may be obtained will be provided After being given adequate time to consider the information, the patient will be asked to sign the informed consent document. A copy of the informed consent document will be given to the patient/representative for their records, sent to the LCTU with the randomisation paperwork and a copy placed in the medical records, with the original retained in the Investigator Site File. After the patient has entered the trial, the clinician must remain free to give alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the best interest of the patient. However, the reason for doing



so should be recorded and the patient will remain within the trial for the purpose of follow-up and data analysis according to the treatment option to which they have been allocated. Similarly, the patient remains free to withdraw at any time from the protocol treatment and trial follow-up by without giving reasons and without prejudicing the further treatment. The rights and welfare of the patients will be protected by emphasising to them that the quality of medical care will not be adversely affected if they decline to participate in this study. Patients may withdraw from the trial at any time by revoking the informed consent. All patients will continue to be followed for survival in all cases other than those who withdraw consent. Patients will be approached separately with information and consent forms for the extra biopsy sample requested for the translational work.

14.4 Study Discontinuation The reason for discontinuation of study treatment/study should be clearly documented and the end of treatment and end of study CRFs completed.



15 REGULATORY APPROVAL

This trial has been registered with the MHRA and has been granted a Clinical Trial Authorisation (CTA). The CTA reference is 04196/0017/001-0001 and approval was given on 01/04/2011.



16 TRIAL MONITORING

Central and site monitoring is conducted to ensure protection of patients participating in the trial, and that trial procedures, trial intervention administration, and laboratory and data collection processes are of high quality and meet sponsor and, when appropriate, regulatory requirements. A risk assessment will be carried out to determine the level of monitoring required, and a subsequent monitoring plan will be developed to document who will conduct the central (and potentially site) monitoring, at what frequency monitoring will be carried out and the level of detail at which monitoring will be conducted.

16.1 Risk Assessment In accordance with the LCTU SOPs a risk assessment has been completed in partnership with:

Representatives of the Trial Sponsors

Chief Investigator

Trial Coordinator

Trial Statistician

LCTU Operational Director In conducting this risk assessment, the contributors considered potential patient, organisational and study hazards, the likelihood of their occurrence and resulting impact should they occur. The outcome of the risk assessment is expressed as a percentage, assigned according to the following categories: Score ≤ 33% = Low risk Score > 34 to ≤67% = Moderate risk Score > 68 to ≤ 100% = High Risk The risk assessment resulted in an overall percentage risk of 21% and thus this trial is considered low risk.

16.2 Source Documents Source Data Source data are all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). (ICH E6, 1.51). Source Documents Original documents and data records include: hospital records, clinical and office charts, laboratory notes,

memoranda, subjects‟ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy and laboratory departments involved in the clinical trial (ICH E6, 1.52). 62



In order to resolve possible discrepancies between information appearing in the CRF and any other patient related documents, it is important to know what constitutes the source document and therefore the source data for all information in the CRF. Data recorded in the CRF should be consistent and verifiable with source data in source

documents other than the CRF (e.g. medical record, laboratory reports and nurses‟ notes). Each participating site should maintain appropriate medical and research records for this trial, in compliance with ICH E6 GCP, Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of subjects. For data where no prior record exists and which are recorded directly in the CRF (e.g. inclusion/exclusion criteria, adverse events and Quality of life questionnaires), the CRF will be considered the source document, unless otherwise indicated by the investigator.

In addition to the above, date(s) of conducting informed consent including date of provision of patient information, trial screening number, trial number, study treatment and the fact that the patient is participating in a clinical trial should be added to the patients’ medical record contemporaneously.

16.3 Data Capture Methods Trial data will be captured using paper case report forms with the exception of adverse and serious adverse events, which will be captured electronically

16.3.1 Case Report Forms

The study case report form (CRF) is the primary data collection instrument for the study. All data requested on the CRF must be recorded. All missing data must be explained. If a space on the CRF is left blank because the procedure was not done or the question was not asked, write “N/D”. If the item is not applicable to the individual case, write “N/A”. All entries should be printed legibly in black ink. If any entry error has been made, to correct such an error, draw a single straight line through the incorrect entry and enter the correct data above it. All such changes must be initialled and dated. DO NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain entries, print the clarification above the item, then initial and date it. CRF pages will be available for sites to download from a trial website: (http://www.lctu.org.uk/trial/trials_open.asp?id=72)

16.4 Monitoring at LCTU There are a number of monitoring features in place at the LCTU to ensure reliability and validity of the trial data.

16.4.1 Green Light Process The Green Light Process in place at the LCTU means that no patients can be randomised at a particular site without the green light being given. It ensures that all approvals must be in place, all contracts/agreements signed and all trial-specific and ICH GCP training received by site research staff before patients can enter the trial. In the case of the ViP study this will be a two stage process, a partial greenlight will be given to sites (by the Trial Co-ordinator (TC)) once all the required documentation is in place and the site will be open to recruitment. Access to screening numbers will be given at this stage which are necessary for randomisation to take place. On recruitment of the first patient, the site will temporarily be closed so that an audit check can be conducted by the ViP team at the LCTU, mainly to ensure that subjects who have consented to the collection of biopsies, have been obtained. If everything is in order at this stage the TC will issue the full greenlight to sites.

http://www.lctu.org.uk/trial/trials_open.asp?id=72



16.4.2 Site Research Staff

All site research staff involved in the trial must be included on the delegation log. The PI at each site signs off on the delegation log only those staff members he/she feels are able and competent to complete the assigned tasks. The delegation log provides clearly defined delegation of responsibility thus ensuring site research staff are aware of their responsibilities, and is continuously checked (as part of the data management plan) against staff named on CRFs, SAE reports and randomisation forms.

The TC ensures that all delegated staff have documented trial-specific training (on the protocol, SAE reporting and consent process) all of which is provided at site initiation (either on site or by teleconference) by the TC and on a continuous basis throughout the trial when new staff are added to the delegation log. Sites are supplied with copies of training aids presented at site initiation to provide a constant reminder of key trial issues. Delegated site research staff must also submit their CV and provide the date of their last ICH GCP training. In order to ensure that site research staff maintain up to date ICH GCP training (to be renewed every 2 years as suggested by ICH GCP), an automated email reminder is sent to site research staff when their next ICH GCP training is due. Non-NHS staff must have honorary contracts and evidence of CRB checks must be obtained for staff (when necessary by UK law).

Automated 6-monthly email reminders (from site opening) are sent to sites requesting that an updated delegation log is faxed to LCTU. On receipt of updated delegation logs, the TC ensures that new staff have submitted their CVs and date of last ICH GCP training, as well as providing them with trial-specific training.

Pharmacy staff must complete drug accountability logs for each patient whenever trial drug is dispensed, and these are checked (as part of the data management plan) against drug administration details (dose, date dispensed, batch number, expiry date and who dispensed each administered treatment) recorded on CRFs by the research nurses. Automated email reminders are sent to pharmacies (after induction, and annually during maintenance, for each patient) requesting that a copy of the drug accountability log is sent to LCTU.

16.4.3 Oversight Committees The IDSMC is an independent multidisciplinary group consisting of at least one statistician and at least one clinician that, collectively, have experience in the management of oncology and in the conduct of randomised clinical trials. They are responsible for safeguarding the interests of trial participants, assessing the safety and efficacy of the interventions during the trial and for monitoring the overall progress and conduct of the clinical trial.

The TSC is limited and includes an independent Chairman and two additional independent expert members (one being a statistician) and a lay/consumer representative, along with members of the TMG. Among other things, the TSC takes responsibility for monitoring and supervising the progress of the trial, considering recommendations from the IDSMC and advising the TMG on all aspects of the trial.

16.4.4 Safety Reports

Monthly safety reports are generated by the TC which allows monitoring of SAE and ADR reporting rates across sites. The IDSMC also regularly review AE and SAE reporting, and the TC prepares Annual Safety Reports for submission to the MHRA and REC. Any concerns raised by the IDSMC or inconsistencies noted at a given site may prompt additional training at sites, with the potential for the TC to carry out site visits if there is suspicion of unreported AEs in patient case notes. Additional training will also be provided if unacceptable delay in safety reporting timelines (as outlined in the pharmacovigilance plan) is noted at a given site.

16.4.5 Randomisation

The TC verifies that all site research staff have attended trial-specific training relating to eligibility screening and the informed consent/randomisation process. Prior to randomisation, the TC/Data Manager (DM) carry out a check of all consent forms sent to the LCTU. This includes checking that the patient is eligible, the correct versions of the Patient Information Sheet (PIS) and Patient Informed Consent (PIC) Forms have been used, and the patient and clinician signatures are present and dated on the same day. Automated 6-monthly email reminders (from site opening) are



sent to sites requesting that they fax a copy of the screening log to the LCTU. On receipt of this screening log, the DM carries out a check of all randomised patients to ensure that at least 24 hours lapsed between the informed consent discussion and randomisation.

16.4.6 Patient Confidentiality

All LCTU and site research staff have received ICH GCP training and are thus aware of the importance of patient confidentiality. The TC/DM consistently check that the CRFs sent to LCTU are all anonymised and are identifiable only by trial number (except for signed consent forms, which are stored in a locked cabinet in the LCTU). The TC will monitor site performance on maintaining patient confidentiality and will provide additional training if a particular site sends any patient identifiers to LCTU (other than on the signed consent form).

16.4.7 Recruitment

The TC will produce monthly recruitment reports, to allow the IDSMC, TSC and TMG to regularly review recruitment across sites. Slow or inconsistent recruitment will trigger further action centrally. The TC may liaise directly with site staff in order to query reasons for slow recruitment and try to resolve any problems that could impact recruitment. TC will check that the trial is being actively promoted at sites, and site recruitment schedules will be reviewed during the course of the trial as necessary.

16.4.8 Protocol violations/Deviations

All protocol violations and deviations are recorded by the TC in the trial site status database, and are included in the regular IDSMC reports. The TC sends details of all protocol violations and deviations to the CI as soon as the LCTU is made aware of such occurrences, and any that are considered to be a potential serious breach would be forwarded immediately to the Co-sponsors. Details of all other protocol violations and deviations are sent to the Co-sponsors on a monthly basis for their review. If it is noted that a particular site is making consistent protocol violations or deviations, additional training will be provided by the TC.

16.4.9 Withdrawals, losses to follow up and missing data

The TC will produce reports on withdrawals, losses to follow-up and the quantity of missing CRFs/data across sites for review by the LCTU business meeting, TMG, TSC and IDSMC. Identified problems will be discussed and remedial action taken as necessary.

As outlined in the data management plan, the TC/DM will check that the withdrawal CRF is completed for all withdrawn patients (including the reasons for withdrawal). The TC will compare withdrawal rates and reasons for withdrawal across centres, paying particular attention to withdrawals close to date of randomisation. If a certain site experiences an excessive rate of withdrawals, additional training on the informed consent procedure will be provided.

16.4.10 Data management plan

CRF data entered into the MACRO database will be centrally monitored by the LCTU to ensure that data collected are consistent with adherence to the trial protocol. The MACRO database used for this trial includes validation features which will alert the user to certain inconsistent or missing data on data entry. If any problems are identified via automated validation or central monitoring, a query is raised within the MACRO database and emailed to site. A complete log of discrepancies and data amendments is automatically generated by MACRO, including the date of each change, the reason for the change and the person who made the change, thus providing a complete audit trail. Automated email reminders are generated by the database if follow up data from a scheduled patient visit is overdue.



Additional site training will be carried out if recurring problems are noted with data from a certain site, such as consistently incorrect or incomplete data, a backlog of unresolved queries, or unacceptable time delays in submitting CRFs.

16.4.11 Statistical monitoring

Central statistical monitoring is carried out by the trial statistician prior to the production of each IDSMC report. The statistician checks trial numbers to ensure there are no duplicated or missing numbers, and that randomisation dates for consecutive trial numbers are in the correct order. Eligibility criteria and informed consent are checked to ensure all are documented and satisfied. Monitoring is used to highlight suspicions of fraudulent data (by carrying out range checks for unusual values, checking for consistency within participants and comparing data across sites to highlight inconsistencies), as well as providing a record of the degree of missing CRFs and follow up visits, and missing baseline and outcome data. Safety and withdrawal data are also reviewed for completeness. If there is compelling evidence to suggest that data from a particular site may be fraudulent, the TC may request a site visit to carry out source document verification of patient case notes and other source documentation.

16.4.12 LCTU staff

All LCTU staff will receive regular ICH GCP training, have in-house training records and undergo regular Individual Performance Review (IPR) sessions, all of which are used to ensure that appropriate training is received and any problems identified and resolved in a timely fashion.

16.5 Clinical Site Monitoring

16.5.1 Direct access to data

In order to perform their role effectively, monitors and persons involved in Quality Assurance and Inspection will need direct access to primary subject data, e.g. patient records, laboratory reports, appointment books, etc. Because this affects the patient’s confidentiality, this fact is included on the Patient Information Sheet and Informed Consent Form.

16.5.2 Confidentiality

Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. Case report forms will be labelled with patient initials and unique trial screening and/or trial number. Blood and urine samples and paraffin blocks will be transferred to the Liverpool Experimental Cancer Medicine Centre GCLP laboratory and will be identifiable by unique trial number only. Consent forms sent to the LCTU as part of the randomisation process may contain patient identifiers for the purpose of monitoring as described in the trial risk assessment. Such information will be stored in secure, locked cabinets.

The LCTU will request consent from all patients to obtain information from the NHS Information Centre (Medical Research Information Service).

16.5.3 Quality Assurance and Quality Control of Data

Systems of quality assurance, including all elements described in this protocol have been/will be implemented within relevant institutions with responsibility for this trial. Quality control is applied to each stage of data handling to ensure that data are accurate, reliable and processed correctly. The VIP Investigational sites, facilities, laboratories and all data (including sources) and documentation must be available for GCP audit and inspection by competent or IEC. Such audits/inspections may take place at any site where trial related activity is taking place (the Sponsors site(s), Cancer Research UK (CR-UK) Liverpool Cancer Trials Unit or at any investigators site including laboratories, pharmacies etc.)



The site staff should assist in all aspects of audit/inspection and be fully cognisant of the LCTU communication strategy for multicentre trials. This includes management systems for the GREEN light process prior to drug release to site, conforming to the total Quality Management System currently operating within the LCTU.

16.6 Records Retention The investigator at each investigational site must make arrangements to store the essential trial documents, (as defined in Essential Documents for the Conduct of a Clinical Trial (ICH E6, Guideline for Good Clinical Practice)) including the Investigator Trial File, until the LCTU informs the investigator that the documents are no longer to be retained.

In addition, the investigator is responsible for archiving of all relevant source documents so that the trial data can be compared against source data after completion of the trial (e.g. in case of inspection from authorities). The investigator is required to ensure the continued storage of the documents, even if the investigator, for example, leaves the clinic/practice or retires before the end of required storage period. Delegation must be documented in writing.

The LCTU undertakes to store originally completed CRFs and separate copies of the above documents for the same period, except for source documents pertaining to the individual investigational site, which are kept by the investigator only. Essential documents should be retained until at least 2 years after last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the Investigational Product. These documents should be retained for a longer period however if required by applicable regulatory requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the investigator/institution as to when these documents no longer need to be retained.

Verification of appropriate informed consent will be enabled by the provision of copies of participants’ signed informed consent/assent forms being supplied to the LCTU by recruiting centres. This requires that name data will be transferred to the LCTU, which is explained in the PISC. The LCTU will preserve the confidentiality of participants taking part in the study and the University of Liverpool is a Data Controller registered with the Information Commissioners Office.



17 INDEMNITY

VIP is jointly sponsored by The Royal Liverpool & Broadgreen University Hospital NHS Trust and the University of Liverpool and will be co-ordinated by the LCTU in the University of Liverpool. The Royal Liverpool & Broadgreen University Hospital NHS Trust and the University of Liverpool does not hold insurance against claims for compensation for injury caused by participation in a clinical trial and they cannot offer any indemnity. As this is an investigator-initiated study, The Association of the British Pharmaceutical Industry (ABPI) guidelines for patient compensation by the pharmaceutical industry do not apply. However, in terms of liability: NHS Trust and Non-Trust Hospitals have a duty of care to patients treated, whether or not the patient is taking part in a clinical trial, and they are legally liable for the negligent acts and omission of their employees. Compensation is therefore available in the event of clinical negligence being proven. The Royal Liverpool & Broadgreen University Hospital NHS Trust and the University of Liverpool does not accept liability for any breach in the hospital’s duty of care, or any negligence on the part of employees of hospitals. This applies whether the hospital is an NHS Trust or not. Clinical negligence is defined as: “A breach of duty of care by members of the health care professions employed by NHS bodies or by others consequent on decisions or judgments made by members of those professions acting in their professional capacity in the course of their employment, and which are admitted as negligent by the employer or are determined as such through the legal process”.

The University of Liverpool has vicarious liability for the actions of its staff, when through the course of their employment they are involved in the design and initiation of a clinical trial, including but not limited to the authorship of the Clinical Trial Protocol. The University of Liverpool has appropriate insurance in place to cover this liability.



18 FINANCIAL ARRANGEMENTS

This is a non-commercial trial, and no direct payments are available to cover the costs associated with patient recruitment, treatment administration, follow-up visits, data collection or reasonable travel expenses. The trial is part of the NCRN and AstraZeneca collaboration portfolio and is endorsed by Cancer Research UK, consequently having automatic endorsement from the National Cancer Research Network (NCRN) and UK Clinical Research Network (UKCRN). These organisations will be responsible for providing local investigators with the necessary research infrastructure. Vandetanib and placebo will be provided free of charge by AstraZeneca.



19 Trial Oversight Committees

19.1 Trial Management Group (TMG) A Trial Management Group (TMG) will be formed comprising the Chief Investigator, other lead investigators (clinical and non-clinical) and members of the Liverpool Clinical Trials Unit. The TMG will be responsible for the day-to-day running and management of the trial and will meet approximately 3 times a year.

19.2 Trial Steering Committee (TSC) The VIP Trial Steering Committee will consist of an independent chairperson, 2 independent experts in the field of pancreatic cancer, a biostatistician and up to seven Principal Investigators. The role of the TSC is to provide overall supervision for the trial and provide advice through its independent Chairman. The ultimate decision for the continuation of the trial lies with the TSC.

19.3 Independent Data and Safety Monitoring Committee (IDSMC) The independent Data and Safety Monitoring Committee (IDSMC) will consist of an independent chairperson plus 2 independent members, one of whom is an expert in the field of pancreatic cancer, and an expert in medical statistics. The ISDMC will be responsible for reviewing and assessing recruitment, interim monitoring of safety and effectiveness, trial conduct and external data. The ISDMC will first convene following the randomisation of the first 20 patients to make an assessment on toxicity and safety and will then define frequency of subsequent meetings (at least annually). Details of the interim analysis and monitoring are provided in section 9. The ISDMC will provide a recommendation to the Trial Steering Committee concerning the continuation of the study.



20 PUBLICATION

The results from different centres will be analysed together and published as soon as possible. Individual clinicians must undertake not to submit any part of their individual data for publication without the prior consent of the Trial Management Group. The Trial Management Group will form the basis of the Writing Committee and advice on the nature of publications. The Uniform Requirements for Manuscripts Submitted to Biomedical Journals (http://www.icmje.org/) will be respected. All publications shall include a list of participants, and if there are named authors, these should include the trial’s Chief Investigator(s), Statistician(s) and Trial Manager(s) involved at least. If there are no named authors (i.e. group authorship) then a writing committee will be identified that would usually include these people, at least. The ISRCTN allocated to this trial should be attached to any publications resulting from this trial. The members of the TSC and IDSMC should be listed with their affiliations in the Acknowledgements / Appendix of the main publication.

http://www.icmje.org/



21 PROTOCOL AMENDMENTS

21.1 Version 1 (25/JAN/2011) Original approved version

21.2 Version 2 (16/AUG/2011) Main changes from version 1: Date: 25/01/11

Change to protocol study rationale 300mg Vandetanib After an internal review with the CI, Astra Zeneca and the Liverpool Cancer Trials Unit (LCTU) of the original study rationale it was felt that the evidence for the use of 300mg of Vandetanib in the study needed to be made clearer and more robust. Therefore two further phase I trials using Vandetanib treatment in solid tumours, including patients with both pancreatic and biliary tract cancers, were included as evidence. These trials were included to demonstrate that the 300mg dose of Vandetanib in combination with gemcitabine is the best regimen to illicit a response and will not give significant dose limiting toxicities. Hence section 2.2 of the protocol was amended. Change to Pharmacy section in Protocol After feedback from the pharmacy departments at two of the centres changes were made to make the pharmacy section (section 9) clearer in terms of dealing with certain toxicities and to allow for a clearer distinction between investigational and non-investigational medicinal products Addition of Patient Pain Assessment A patient pain assessment has been added to the trial protocol and study schedule Changes to Safety Events Reporting Procedure Adverse Event reporting procedures were revised to reflect the introduction of remote data entry for adverse event reporting within the LCTU. The original protocol required SAEs and AEs to be reported within the regulatory timelines to the LCTU via fax. This was updated as a new system allowing research staff to enter data on line was implemented for this trial. Administrative changes Administrative changes were made throughout the protocol to reflect the appointment of new staff, changes to address.etc.

21.3 Version 3 (14/DEC/2011) Main changes from version 2: Date: 16/Aug/2011 Changes to safety information The Investigator Brochure for vandetanib was updated from version 12 to 13 and stipulated that patients with moderate renal impairment (creatinine clearance ≥ 30mL/min and < 50mL) should be started on a reduced dose of vandetanib of 200mg. The exclusion criteria in the protocol was updated to reflect this change, as well as the addition of an exclusion stating patients with a low haemoglobin (<10G/dl) should be excluded from the trial. Toxicity Management



Section 9.3.4.5 of the protocol for management of other toxicities has been updated to provide clarification for management of grade 2 toxicities. Changes in trial personnel The clinical co-ordinators reviewing SAE’s were updated and trial monitor contact details added.

21.4 Version 4 (23/FEB/2012) Main Changes from version 3: Date: 14/Dec/2011 Schedule of trial procedures The protocol and schedule of trial procedures has been updated to reflect the IB schedule for ECGs, which stipulates an additional ECG at 24 weeks and then 12 weekly whilst the patient is on study treatment and then an ECG at the end of treatment. Another change to the schedule is that the weekly medical review can be conducted by either a physician or an individual specified on the delegation log suitably qualified to make the assessment (e.g. ViP research nurse). Drug dose Clarification has been provided in Section 9.3 on taking missed doses and procedure if vomiting occurs. The dose modifications for management of gastrointestinal toxicity have been updated so that grade 3 and grade 4 re-occurring diarrhoea are treated in the same way in accordance with the vandetanib IB. The ECG safety monitoring has also been updated, specifically the QTcB value at which vandetanib should be withheld this has been lowered from >550msec to >500msec. Drugs Associated with Torsades de Pointes The list of drugs associated with torsades de pointes has been updated in accordance with the updated list found on www.QTdrugs.com

21.5 Version 5 (13/DEC/2012) Main changes from version 4: Date: 23/Feb/2012 Protocol summary (section 1) Removal of the end of study definition and the addition of a definition of when patients’ participation comes to an end. Investigational plan (section 4.3) Removal of the length of survival censorship for patients alive at end of study or during follow-up. Withdrawal from trial intervention (section 7.2) Clarification on cycle 1 being missed and it counting towards withdrawal criteria. Concomitant Medications/Treatments (section 9.7)

http://www.qtdrugs.com/



Updated to include new guidance from version 14 of the Investigator Brochure describing interactions between vandetanib and metformin, as well as vandetanib and digoxin. Visit Schedule (Section 10.1) The visit schedule has been updated to stipulate that the medical review and physical examination completed for screening can be used for baseline if within 3 days of day 1 (start of treatment). Reference Safety Information (section 13.7) This section has been added to clarify the reference safety information for vandetanib. Adverse Event Reporting Procedures (section 13.9) Statement included stating that multiple SAEs should be reported on separate SAE forms. Appendix C All three tables updated to reflect the updated list of drugs associated with TdP on the Arizona CERT website. A statement has been added that investigators need to periodically check the Arizona CERT website for the most up to date tables. Table A information has been clarified to ensure that that it is clear none of the drugs listed in this table are taken 2 weeks prior to randomisation or during study treatment. Table B and C advice has been updated with information on additional ECG and electrolyte monitoring that should be conducted if patients are taking drugs listed in these tables whilst on study treatment.

21.6 Version 6 (26/APR/2013) Main changes from version 5: Date: 13/Dec/2012 The sample size number has been updated throughout the protocol to reflect the additional 20 patients to be recruited, bringing the total to 140. Section 12.5 (Sample size) has also been updated explaining the reason for the additional patients and the impact on final analysis.



22 REFERENCES

1. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol. 2007 May 20;25(15):1960-6 2. Harsha HC, Jimeno A, Molina H, Mihalas AB, Goggins MG, Hruban RH, Schulick RD, Kamath U, Maitra A, Hidalgo M, Pandey A. Activated epidermal growth factor receptor as a novel target in pancreatic cancer therapy. J Proteome Res. 2008 Nov;7(11):4651-8. 3. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009 May 1;27(13):2231-7. 4. Ryan AJ, Wedge SR. ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br J Cancer. 2005 Jun;92 Suppl 1:S6-13. Review. 5. Arao T, Fukumoto H, Takeda M, Tamura T, Saijo N, Nishio K. Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474. Cancer Res. 2004 Dec 15;64(24):9101-4. 6. Conrad C, Ischenko I, Köhl G, Wiegand U, Guba M, Yezhelyev M, Ryan AJ, Barge A, Geissler EK, Wedge SR, Jauch KW, Bruns CJ. Antiangiogenic and antitumor activity of a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor model. Anticancer Drugs. 2007 Jun;18(5):569-79. 7. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro M. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002 Dec 15;62(24):7284-90. 8. Vidal M, Wells S, Ryan A, Cagan R. ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Res. 2005 May 1;65(9):3538-41. 9. Ito Y, Okada Y, Sato M, Sawai H, Funahashi H, Murase T, Hayakawa T, Manabe T. Expression of glial cell line-derived neurotrophic factor family members and their receptors in pancreatic cancers. Surgery. 2005 Oct;138(4):788-94. 10. Okada Y, Takeyama H, Sato M, Morikawa M, Sobue K, Asai K, Tada T, Kato T, Manabe T. Experimental implication of celiac ganglionotropic invasion of pancreatic-cancer cells bearing c-ret proto-oncogene with reference to glial-cell-line-derived neurotrophic factor (GDNF). Int J Cancer. 1999 Mar 31;81(1):67-73 11. Veit C, Genze F, Menke A, Hoeffert S, Gress TM, Gierschik P, Giehl K. Activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase is required for glial cell line-derived neurotrophic factor-induced migration and invasion of pancreatic carcinoma cells. Cancer Res. 2004 Aug 1;64(15):5291-300. 12. Ceyhan GO, Giese NA, Erkan M, Kerscher AG, Wente MN, Giese T, Büchler MW, Friess H. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg. 2006 Aug;244(2):274-81. 13. Sawai H, Okada Y, Kazanjian K, Kim J, Hasan S, Hines OJ, Reber HA, Hoon DS, Eibl G. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 2005 Dec 15;65(24):11536-44.

http://www.ncbi.nlm.nih.gov/pubmed/17452677?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum




























14. Bianco C, Giovannetti E, Ciardiello F, Mey V, Nannizzi S, Tortora G, Troiani T, Pasqualetti F, Eckhardt G, de Liguoro M, Ricciardi S, Del Tacca M, Raben D, Cionini L, Danesi R Synergistic antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, with gemcitabine and ionizing radiation against pancreatic cancer. Clin Cancer Res. 2006 Dec 1;12(23):7099-107. 15. Collett, D. (2003). Modelling survival data in medical research. Second Edition. Boca Raton: Chapman and Hall/CRC. 16. Whitehead, J. (2001). Predicting the duration of sequential survival studies. Drug Information Journal 35, 1387-1400






Appendix A: Prescription for vandetanib / placebo

Patient Label

Protocol:

VANDETANIB / PLACEBO for VIP study

Diagnosis: Locally advanced or metastatic pancreatic carcinoma Allergies:

Clinic Patient Study Number: …………...

Date Date Date Date Date Date

Clinic Clinic Clinic Clinic Clinic Clinic

ORAL CHEMO- DRUGS Dose

No of Month(s)

Supply Dose

No of Month(s)

Supply Dose

No of Month(s)

Supply Dose

No of Month(s)

Supply Dose

No of Month(s)

Supply Dose

No of Month(s)

Supply

VANDETANIB 300mg / PLACEBO ONCE daily

Concomitant use of the known inducers of CYP3A4 are not permitted within 2 weeks of the study or during the study (e.g. S rifampicin, phenytoin, carbamazepine, barbiturates and t. John’s Wort).

Dr Signature

Quantity Dispensed

Dispensed By / Checked By

Given to patient by:

Pharmacy Signature (Protocol drug & dose check )



Appendix B: Example of vandetanib / placebo label



Appendix C: Medications Generally Accepted by Authorities to Have a Known Risk of

Causing Torsades De Pointes (Tdp)

It has been recognized for a number of years that certain prescription medications can prolong the QT/QTc interval and cause a form of acquired Long QT syndrome, known as drug induced LQTS. The drugs that prolong the QT interval and/or have a risk of inducing Torsades de Pointes (TdP) are listed in tables A, B and C below, study investigators will need to periodically check the Arizona CERT website (http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm) for updates to these tables . The drugs listed are divided into three groups based on their known or perceived risk of causing TdP: Table A. Drugs that are generally accepted by authorities to have a risk of causing Torsades de Pointes

Concomitant use of these drugs is NOT allowed 2 weeks prior to randomisation (at least four weeks for

levomethadyl) or for the duration of study treatment. These drugs should also not be taken for up to 4 weeks

following discontinuation of study treatment:

Table A

Drug (Generic Names) Drug Class (Clinical Usage) Comments

Amiodarone Anti-arrhythmic (heart rhythm) F>M, TdP risk regarded as low

Arsenic trioxide Anti-cancer (leukaemia)

Astemizole Antihistamine (allergic rhinitis

Azithromycin Antibiotic/bacterial infection

Bepridil Anti-anginal (heart pain) F>M

Chlorpromazine Anti-psychotic/antiemetic (schizophrenia/nausea)

Chloroquine Anti-malaria (malaria infection)

Cisapride GI stimulant (stimulates GI motility)

Citalopram Anti-depressant (depression)

Clarithromycin Antibiotic (bacterial infection)

Disopyramide Anti-arrhythmic (heart rhythm) F>M

Dofetilide Anti-arrhythmic (heart rhythm) F>M

Domperidone Anti-nausea (nausea)

Droperidol Sedative/hypnotic (anaesthesia adjunct)

Erythromycin Antibiotic/GI stimulant (infection/GI motility)

F>M

Escitalopram Anti-depressant/ Major depression/ Anxiety disorders





Table A


Flecainide Anti-arrhythmic (abnormal heart rhythm)

Halofantrine Anti-malarial (malaria infection) F>M

Haloperidol Anti-psychotic (schizophrenia, agitation)

TdP risk with I.V. or excess dosage

Ibutilide Anti-arrhythmic (heart rhythm) F>M

Levomethadyl Opiate agonist (narcotic dependence)

Mesoridazine Anti-psychotic (schizophrenia)

Methadone Opiate agonist (pain control/ narcotic dependence)

F>M

Moxifloxacin Antibiotic (bacterial infection)

Pentamidine Anti-infective (pneumocystis pneumonia)

F>M

Pimozide Anti-psychotic (Tourette’s tics) F>M, TdP Cases in Literature

Probucol Antilipemic (hypercholesterolemia)

Procainamide Anti-arrhythmic (heart rhythm)

Quinidine Anti-arrhythmic (abnormal heart rhythm)

F>M

Sevoflurane Anaesthetic, general/anaesthesia

Label warning for patients with congenital long QT or patients taking QT prolonging drugs

Sotalol Anti-arrhythmic (heart rhythm) F>M

Sparfloxacin Antibiotic (bacterial infection)

Terfenadine Antihistamine (allergic rhinistis)

Thioridazine Anti-psychotic (schizophrenia)

Vandetanib (Does not apply for this study)

Anti-cancer (thyroid cancer)

Table B: Drugs that in some reports may be associated with Torsades de Pointes but at this time lack substantial

evidence of causing Torsades de Pointes.

Concomitant use of these drugs is not allowed 2 weeks prior to randomisation or for the duration of study treatment. However these drugs may be allowed at the discretion of the Investigator, if considered absolutely necessary. In such cases, the patient must be closely monitored, including regular checks of QTcB and electrolytes. For patients who start on the drugs in this group while on the study treatment, the ECG must be checked within 24 hours of commencing the concomitant medication and then at least once per week while the patient remains on the medication. If QTc prolongation is detected, section 9.3.4.3 of the protocol should be followed. The frequency of ECG



monitoring could revert to the standard schedule if no QTcB prolongation has been noted during 4 weeks of co-administration.

Table B

Drug (Brand Names) Drug Class (Clinical Usage) Comments

Alfuzocin Alpha 1-blocker (Benign prostatic hyperplasia)

Artenimol + piperaquine Anti-malarial

Amantadine Dopaminergic/Anti-viral/Anti-infective (Parkinson’s disease)

Atazanavir Protease inhibitor (HIV)

Chloral hydrate Sedative (sedation/insomnia)

Clozapine Anti-psychotic (schizophrenia)

Dolasetron Anti-nausea (nausea and vomiting)

Dronedarone Anti-arrhytmic (atrial fibrillation)

Eribulin Anti-cancer/metastatic breast neoplasias

Famotidine H2-receptor antagonist (peptic ulcer/GERD)

Fingolimod Immunosuppressant (multiple sclerosis)

Felbamate Anti-convulsant (seizures)

Foscarnet Antiviral (HIV infection)

Fosphenytoin Anticonvulsant (seizures)

Gatifloxacin Antibiotic (bacterial infection)

Gemifloxacin Antibiotic (bacterial infection)

Granisetron Anti-nausea (nausea and vomiting)

Iloperidone Antipsychotic (atypical/schizophrenia)

Indapamide Diuretic (stimulates urine & salt loss)

Isradipine Anti-hypertensive (high blood pressure)

Lapatinib Anti-cancer (breast cancer, metastatic)

Levofloxacin Antibiotic (bacterial infection)

Lithium Anti-mania (bipolar disorder)



Table B

Drug (Brand Names) Drug Class (Clinical Usage) Comments

Mirtazapine Anti-depressant

Moexipril/HCTZ Anti-hypertensive (high blood pressure)

Nicardipine Anti-hypertensive (high blood pressure)

Nilotinib Anti-cancer (Leukemia)

Octreotide Endocrine (acromegaly/carcinoid diarrhoea)

Ofloxacin Antibiotic (bacterial infection)

Ondansetron Anti-emetic (nausea and vomiting)

Oxytocin Oxytocic (labor stimulation)

Paliperidone Antipsychotic (atypical schizophrenia)

Perflutren lipid microspheres Imaging contrast agent (Echocardiography)

Quetiapine Anti-psychotic (schizophrenia)

Ranolazine Anti-anginal (chronic angina)

Risperidone Anti-psychotic (schizophrenia)

Roxithromycin Antibiotic (bacterial infection)

Sertindole Antipsychotic (atypical anxiety/schizophrenia)

Sunitinib Anti-cancer (RCC/GIST)

Tacrolimus Immune suppressant

Tamoxifen Anti-cancer (breast cancer)

Telithromycin Antibiotic (bacterial infection)

Tizanidine Muscle relaxant

Vardenafil Phosphodiesterase inhibitor (vasodilator)

Venlafaxine Antidepressant (depression)

Voriconazole Anti-fungal (fungal infection)

Ziprasidone Anti-psychotic (schizophrenia)

Table C: Drugs that in some reports that have been weakly associated with Torsades de Pointes but that are unlikely to be a risk for torsades de pointes when used in usual recommended dosages and in patient without other risk factors.



These drugs are allowed; however require additional safety monitoring as described for table B.

Table C


Amisulpride Antipsychotic (atypical) Risk of TdP with overdose

Amitriptyline Tricyclic antidepressant (depression)

Risk of TdP with overdosage

Ciprofloxacin Antibiotic (bacterial infection) Drug interaction risk – metabolic inhibitor

Clomipramine Tricyclic antidepressant (depression)

Desipramine Tricyclic antidepressant (depression)

Risk of TdP with overdosage

Diphenhydramine Antihistamine (allergic rhinitis/insomnia)

Risk of QT increase/TdP in overdosages

Doxepin Tricyclic antidepressant (depression)

Fluconazole Anti-fungal (fungal infection) Drug interaction risk – metabolic inhibitor. Can also increase QT at high doses – 800mg/day

Fluoxetine Anti-depressant (depression)

Galantamine Cholinesterase inhibitor (dementia/alzheimer’s)

Imipramine Tricyclic antidepressant (depression)

Risk of TdP with excess dosage

Itraconazole Anti-fungal (fungal infection) Drug interaction risk – metabolic inhibitor

Ketoconazole Anti-fungal (fungal infection) Prolongs QT & Drug interaction risk – metabolic inhibitor

Nortriptyline Tricyclic antidepressant (depression)

Paroxetine Anti-depressant (depression)

Protriptyline Tricyclic antidepressant (depression)

Ritonavir Protease inhibitor (HIV)

Sertraline Anti-depressant (depression)

Solifenacin Muscarinic receptor antagonist (treatment for overactive bladder)

Trazodone Anti-depressant (depression insomnia)

Trimethoprim-Sulfa Antibiotic (bacterial infection) Also available in DS (double strength)



Appendix D: Vandetanib / placebo diary sheet



Appendix E: RECIST Criteria Version 1.1

http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf

http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf