Tarceva consolidation 2 years - GCIG · The th4 Ovarian Cancer Consensus Conference has recognised the necessity of additional research of adapted therapy for elderly patients with

Tarceva consolidation 2 years Primary Chemotherapy Control Patients closed / 835 Leading EORTC Participating AGO-AUSTRIA, ANZGOG, GINECO, MRC/NCIC, MANGO

Tarceva Trial EORTC 55041

RANDOMISED PHASE III STUDY OF ERLOTINIB VERSUS OBSERVATION IN PATIENTS WITH NO

EVIDENCE OF DISEASE PROGRESSION AFTER FIRST LINE, PLATINUM-BASED CHEMOTHERAPY FOR HIGH-RISK STAGE I AND STAGE II-IV OVARIAN EPITHELIAL,

PRIMARY PERITONEAL, OR FALLOPIAN TUBE CANCER

Carbo Topo vs Chemo (CT or CG) in recurrent Platinum-sensitive ovarian cancer Patients closed 550 Leading NOGGO/AGO-OVAR Participating AGO-AUSTRIA, GEICO

HECTOR

R

System. Lymphadenectomy

pelvic

para-aortic

no Lymphadenectomy

epithelial invasive ovarian cancer

FIGO IIB - IV

ECOG 0/1 and no CI against LNE

no visible extra- and intra-abdominal

tumor residuals

no bulky lymph nodes

Endpoints: OS, PFS, QoL Strata: centre, PS ,age

Lymphadenectomy In Ovarian Neoplasms AGO – OVAR OP.3 (LION)

640

Supported by Deutsche Forschungsgemeinschaft

Carbo Paclitaxel +/- BIBF 1120 (Vargatef) Patients 1300 (2:1 random) Leading AGO-OVAR

Participating AGO-Austria, BGOG, GINECO, MANGO, MITO, NSGO, US Oncology

AGO-OVAR-12

First line weekly carboplatin and paclitaxel vs every 3 weeks

carboplatin/paclitaxel in patients with ovarian cancer:

Phase III multicenter trial MITO – 7

(MITO, MANGO, GINECO)

Trial design • Aim of the trial is to compare the efficacy in terms of

PFS, and to compare quality of life of weekly administration of carboplatin plus carboplatin (experimental arm) versus every 3 weeks administration of the same drugs (standard arm) in 1°-line advanced ovarian, tubal and peritoneal cancer

RANDOM

Carboplatin AUC 2 Paclitaxel 60 mg/m2

day 1,8 15 - every 21days

Carboplatin AUC 6

Paclitaxel 175 mg/m2

day 1 - every 21days

Enrollement closed March 2012 after 829 pts randomized

CALYPSO Publications 7 publications have been published since last GCIG meeting

A multi-centre, open-label, randomised, two-arm phase III trial

of bevacizumab plus chemotherapy

versus chemotherapy alone

in patients with platinum-resistant, epithelial ovarian, fallopian tube or primary

peritoneal cancer

AURELIA: Avastin Use in REsistant ovarian epitheLIAl cancer

Oral presentation at ASCO 2012 (sat June 2)

of the Primary Endpoint

ICON6 A Randomised Trial of Concurrent Cediranib

(with Platinum-based Chemotherapy) and Maintenance Cediranib in Women with Platinum-Sensitive Relapsed Ovarian

Cancer

http://www.cancerresearchuk.org/�

JGOG3017 Randomized Phase III Trial of Paclitaxel plus Carboplatin (TC) Therapy

versus Irinotecan plus Cisplatin (CPT-P) Therapy as a First Line Chemotherapy for Clear Cell Carcinoma of the Ovary

Ovarian Clear Cell Carcinoma FIGO stage Ic-Ⅳ

RANDOMIZATION

Paclitaxel 175 mg/m2 IV, Day1 Carboplatin AUC 6 IV, Day1 Q21, 6 Cycles

Irinotecan 60 mg/m2 IV, Day1, 8, 15 Cisplatin 60 mg/m2 IV, Day1 Q28, 6 Cycles

Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, Response rate Accrual Goal: 662 patents

iPocc Trial IntraPeritoneal therapy for Ovarian Cancer with Carboplatin

(GOTIC-001 / JGOG3019)

Epithelial ovarian, Fallopian tube or Primary peritoneal cancer FIGO stage II−IV

Including Bulky Tumor

RANDOMIZATION

Paclitaxel 80 mg/m2 IV Day1,8,15 Carboplatin AUC 6 IV

Q21, 6-8 Cycles

Paclitaxel 80 mg/m2 IV Day1,8,15 Carboplatin AUC 6 IP

Q21, 6-8 Cycles

Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL Accrual Goal: 746 patents

A Randomized Phase II/III Trial of 3 Weekly Intraperitoneal versus Intravenous Carboplatin in Combination with Intravenous Weekly Dose-Dense Paclitaxel

for Newly Diagnosed Epitherial Ovarian, Fallopian Tube and Primary Peritoneal Cancer

Study Status

• Recruiting • JGOG: 105 pts (as of Mai 31, 2012) • International collaboration under discussion:

Korea, Australia, Singapore, Shanghai

17

Avastin and weekly pacLItaxel use in sEx cord-stromal ovariaN tumORs

18

A European, randomized, open label, phase II trial of bevacizumab plus weekly paclitaxel followed by maintainance with bevacizumab monotherapy versus weekly paclitaxel followed by observation in patients with relapsed ovarian sex-cord stromal tumors

Ovarian sex-cord stromal tumors (SCSTs) are rare neoplasms (7% of ovarian malignancies)

New approaches are seeked to improve clinical outcome of SCSTc patients.

Tumors are well vascularised, suggesting that angiogenesis is important for tumor development.

38% response rate and 63% clinical benefit rate in 8 patients with recurrent ovarian granulosa cell tumors treated with bevacizumab To Investigate the clinical interest of combining bevacizumab to weekly paclitaxel for the treatment of recurrent sex-cord stromal tumors previously treated by platinum-based chemotherapy.

19

20

Bevacizumab 15mg/Kg every 3 weeks

Paclitaxel alone

80mg/m², IV, at D1, D8 and D15

every 4 weeks

Paclitaxel 80mg/m², IV, D1, D8 and D15

every 4 weeks +

Bevacizumab 10mg/kg, IV, D1 and D15

RANDOMISATION

Maximum of 6 cycles Up to 1 year or until PD / intolerance

Arm A

Arm B

Standard

surveillance

Standard of care

PD or Toxicity

Bevacizumab 15mg/Kg every 3 weeks

Standard of care

PD or Toxicity

PRIMARY OBJECTIVE Clinical benefit rate (non-progression rate after 6 months of treatment)

60 patients Enrollment period : 36 months First Patient In : October 2012 Treatment + maintenance : 18 months Last Patient Out of Maintenance : April 2017 Follow-up : 36 months Last Patient Out : April 2020

21

Leading Group ◦ GINECO ( Coordinating investigator : Isabelle Ray-Coquard )

Participating Groups ◦ MITO and MANGO JGCO ◦ ANZGOG , AGO, EORTC , GEICO (tbc)

22

Histologically confirmed diagnosis of ovarian (SCST) including the following cell types: granulosa cell tumors (adults and juveniles types), granulosa cell-theca cell tumor, Sertoli-Leydig cell tumors, malignant steroïd cell tumors, gynandroblastoma, unclassified SCST and mixed tumors

Documented relapse of SCST defined by progression of disease (evaluated by RECIST 1.1) At least one measurable site of disease as defined by RECIST 1.1

•Tumors within a previously irradiated field will be designated as “non-target” lesions unless progression is documented or a biopsy is obtained to confirm persistence > 90 days following completion of radiotherapy.

Patients must have been pre-treated with at least 1 prior line of platinum-based chemotherapy Adequate bone marrow, liver and renal functions Adequate coagulation panel Adequate neurologic function: only neuropathy (sensory and motor) grade ≤ 2 (CTCAE v4.0) are allowed ECOG Performance status of 0, 1, or 2 Normal left ventricular ejection fraction (FEVG ≥ 50%)

Elderly Women Ovarian Cancer Multicenter, randomized trial of carboplatin +/- paclitaxel in vulnerable

elderly patients with stage IIB-IV advanced ovarian cancer

23

The 4th Ovarian Cancer Consensus Conference has recognised the necessity of additional research of adapted therapy for elderly patients with ovarian cancer.

Other options than the standard 3-weekly carboplatin-paclitaxel regimen are used in routine practice for patients considered as the most vulnerable. However there is no randomized trial on how to select patients which could most benefit of one of this regimen.

GINECO has recently described a Geriatric Vulnerability Score (GVS) in a population of elderly patients with advanced ovarian cancer. This score allows to discriminate vulnerable patients.

To assess the feasibility of completing 6 courses of chemotherapy without progression or unacceptable toxicity of three different chemotherapy regimens in a population of elderly patients defined as vulnerable with ovarian cancer.

. 24

25

PRIMARY OBJECTIVE Treatment success : completion of the 6 planned courses of chemotherapy without disease progression at 6 months or unacceptable toxicity.

Bras A : carboplatine AUC 5 + paclitaxel 175mg/m² q21 X 6 cycles

Bras B : carboplatine AUC 5 q21 X 6 cycles

Bras C : carboplatine AUC 2 + paclitaxel 60 mg/m² hebdo (j1, j8, j15) q28 x 6 cycles

Patient >70 years old GVS* > 3

*GVS (Geriatric Vulnerability Score) = Sum of geriatric covariates scores found to predict poor survival : A ADL score <6; IADL score <25, HADS score <14, albuminemia <35g/L and lymphopenia <1G/L.

240 patients

Enrollment period : 24 months First Patient In : Q2 2012 Follow-up : 24 months Last Patient Out : Q2 2016

Leading Group GINECO ( Coordinating investigator : Claire Leger-Falandry)

Participating Groups

AGO, MITO, ANZGOG, JGOG, Canada,

26

27

Woman >70 years old

Histologically or cytologically proven FIGO stage IIb to IV epithelial ovarian cancer or peritoneal primary and fallopian tube. A cytological proof is accepted if associated with a CA125 above the normal value and a radiological pelvic mass.

GVS (Geriatric Vulnerability Score)≥3. GVS is the sum of geriatric covariates scores found to predict poor survival : ADL score <6; IADL score <25, HADS score <14, albuminemia <35g/L and lymphopenia <1G/L.

Neutrophils ≥1.500/mm3 and platelets ≥ 100.000/mm3.

No icterus.

28

Prior history of cancer ,excepted in situ cancer of the cervix, in situ urothelial cancer, cured basocellular cancer and any other cancer treated and in complete remission for more than 2 years.

Planned interval debulking surgery

Prior history of chemotherapy

Prior history of radiotherapy which may affect patient tolerability to chemotherapy

Major perturbations of liver biology : Bilirubin > 2 fold the upper normal limit (UNL) of the laboratory, SGOT-SGPT >3 fold UNL.

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Optimal and Suboptimal Disease (through April 2011) • Primary Endpoint: PFS

GOG0252: IP Therapy

Open: 27-Jun-2009 Closed: 29-Oct-2011 Accrual: 1560 pts (250 suboptimal) Walker J. for GOG, pending

Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 IV (d1,8,15) Bevacizumab (C2-6)

Cisplatin 75 mg/m2 (IP) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2-6)

I

III

II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1,8,15) Bevacizumab (C2-6)

Bevacizumab q21d x 16



IV Carbo IP Carbo IP Cisplatin

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Suboptimal residual disease, amended to permit NACT-ICS • Primary Endpoint: PFS • Incorporation of early perfusion-based CT imaging (ACRIN 6695)

GOG0262: Dose-Dense Integration

Open: 27-SEP-2010 Closed: 08-FEB-2012 (temp closure) Target Accrual: 700 pts (with imaging) Chan J. for GOG, pending

Carboplatin AUC=6 Paclitaxel 80 mg/m2 (d1,8,15) +/- Bevacizumab (C2-6)$

I

II

Bevacizumab q21d$

Bevacizumab q21d$

Carboplatin AUC=6 Paclitaxel 175 mg/m2 (d1) +/- Bevacizumab (C2-6) $

$ Use of Bevacizumab to be determined by patient and physician choice prior to randomization

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Clinical Stage I-IV, PS 0-3, Elect PCS or NACT-ICS • Elect single-agent or combination chemotherapy with PKs • Age >70 with no more than 25% age <75 • Primary Endpoints: Completion of 4 cycles without DLT

and impact of IADL score on treatment

GOG0273: Elderly Patients

Open: 15-AUG-2011 Closed: Target Accrual: 185 pts Von Gruenigen V. for GOG, pending

Carboplatin AUC=5 Paclitaxel 135 mg/m2 (d1) G-CSF

I x4

Carboplatin AUC=5 II x4

Optional ICS Optional ChemoRx

GOG PARPi: Proposed Phase III Design

• High-grade extrauterine serous and endometrioid tumors, Stage I-C, II, III, IV • Election for neoadjuvant therapy with interval cytoreduction (biospecimens) • Election for intraperitoneal (IP) cisplatin or intravenous (IV) carboplatin • Primary endpoint OS incorporating interim analysis (PFS)

x 6 II

x 6 I Paclitaxel 175 mg/m2 (3 h) Carboplatin AUC 6 (IV)* Placebo d -1 to 4 PO#

x 6 IV

x 6 III

PARPi daily PO

PARPi daily PO

Paclitaxel 175 mg/m2 (3 h) Carboplatin AUC 6 (IV)* PARPi d -1 to 4 PO#

Paclitaxel 175 mg/m2 (3 h) Carboplatin AUC 6 (IV)* Placebo d -1 to 4 PO#

Paclitaxel 175 mg/m2 (3 h) Carboplatin AUC 6 (IV)* PARPi d -1 to 4 PO#

Placebo daily PO

Placebo daily PO

* Patients electing intraperitoneal therapy will receive cisplatin 75 mg/m2

# Dose and schedule of PARPi with concurrent chemotherapy pending

JGOG 3109: Dose-Dense and IP

Paclitaxel 80 mg/m2 (D1,8,15) Carboplatin AUC = 6 IV

• Epithelial Ovarian or Peritoneal • Stage II – IV • No prior therapy • Stratified: residual disease,

stage, and global region • Primary endpoint: PFS • Secondary endpoint: OS

I

II

Sugiyama T, for JGOG, pending

x6

x6

Open: May 2010 Closed: April 2013 (projected) Accrual: 746 pts (120 Phase II)

Paclitaxel 80 mg/m2 (D1,8,15) Carboplatin AUC = 6 IP

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer • Presumptive Stage III-C, CA125:CEA >25 • Primary Endpoint: OS (PCS vs NACT-ICS) • Secondary Endpoints: PFS, Costs, Predictive Biomarkers for Cytoreduction • Bifactorial Randomization: Metformin vs Placebo • Serial Tumor Biopsies (NACT-ICS)

GOG OVM1201: PCS vs NACT-ICS

Open: JAN-2013 Closed: Target Accrual: 780 pts Chi D. for GOG, pending

* Carboplatin AUC=6 (IV), Paclitaxel 175 mg/m2 or Cisplatin 75 mg/m2 (IP), Paclitaxel 135 mg/m2 (IV) D1, 60 mg/m2 (IP) D8

I PCS ChemoRx (IV or IP) x6* Metformin (concurrent and maintenance)

II Bx ChemoRx (IV) x3* ICS ChemoRx

(IV or IP) x3* Placebo (concurrent and maintenance)

CANVAS Protocol Discussion and CVac Safety Overview GCIG Meeting

Jonathan Berek, MD Stanford University

• CANVAS is a well designed global clinical study of CVac treatment of Ovarian Cancer patients in first remission

• The study should provide pivotal data for potential registration of CVac as a treatment option for ovarian cancer

• The study is large (800 completing patients) and will require up to 150 centers worldwide to achieve recruitment goals

Request to GCIG

• Centers of excellence for ovarian cancer • High potential recruitment • High visibility for the study • Future studies: easier adoption of centers

of excellence • Known Key Opinion Leaders • Excellent communication

Why GCIG and COGi?

• Autologous dendritic cells • Primed with mucin-1 after apheresis and

culture • Mucin-1 supplied as a fusion protein with

mannan and GST to facilitate uptake by dendritic cells

• Product frozen and delivered cryopreserved to sites as needed

• Thawed and injected into four sites intradermally

What is CVac?

• Mucin-1 (MUC1) well established target

• Autologous dendritic cell approach (safety)

• Intradermal route: single apheresis

• PFS primary endpoint as surrogate for, and complement to OS

• Blinded interim analysis to avoid futility or ethics concerns

• Placebo control

• QoL, Pharmacoeconomics and OS endpoints

CANVAS CVac Study Rationale

• Optimal debulking (<1cm3 residual tumor)

• Plan for platinum/taxane 1st line therapy

• Informed consent

• MUC1 expressing tumor

• Other criteria

Patient Eligibility

Rationale for Population

Criteria Rationale

Epithelial ovarian cancer

• Supported by phase 1& 2 trials • Orphan indication (unmet need) • Generally overexpresses MUC1 (85%+) • Considered immunogenic

After optimal debulking (<1cm3)

• Need time to evaluate effect of CVac (4-8+ months post treatment) • Receptive immune system • Debulking is strongly correlated to t-cell environment, remission and progression free time

Treat after 1st line chemo and remission

• High likelihood of extended remission • Clinician & patient acceptance • Manufacturing & logistics feasibility

• Surface epithelial stromal tumor (89.7%) – Papillary serous cystadenocarcinoma – “borderline” adenocarcinoma – Adenocarcinoma – Endometrioid tumor – Serous cystadenocarcinoma – Papillary adenocarcinoma – Mucinous cystadenocarcinoma – Clear cell ovarian tumor – Mucinous adenocarcinoma – Cystadenocarcinoma

Types of Ovarian Cancer accepted (Mucin-1 positive only)

• Mucin-1 negative Carcinoma – Sex cord stromal tumor – Mullerian Tumor (mixed, carcinosarcoma)

• Germ Cell Tumor – Teratoma – Dysgerminoma – Epidermoid – Brenner Tumor

Types of ovarian cancer not accepted

• Mucinous Adenocarcinoma of the Peritoneum

May be accepted if mucin-1 positive

• DSMB reviews to date support progression of the study

• Six SAE (two standard of care, four CVac)

• Abdominal pain (resolved) requiring hospitalization (1 CVac, 1 SOC)

• One death (cerebral hemorrhage) in SOC

• Disease progression and hospitalization prior to receiving CVac (CVac)

• Disease progression requiring debulking surgery (CVac)

• Disease progression requiring taxotere with febrile neutropenia (CVac)

• Pain on injection (mild) 7/36 receiving CVac

Safety Profile CVac from of CAN-003

• Randomized, double blind, placebo controlled study

• Patients recruited immediately post first surgery

• Dosing commences after chemotherapy and complete remission

• Powered 90% to detect HR of 0.77 for PFS and OS using 1000 patients, 800 dosed

CANVAS Design

06.01.11

Females ≥ 18 years of age at screening with a confirmed diagnosis of Stage III or IV epithelial ovarian, primary peritoneal, or fallopian tube cancer

Have undergone optimal debulking surgery, defined as ≤ 1 cm of residual tumor Eligible for, and plan to undergo standard platinum and taxane first-line chemotherapy Signed an ICF Willing and able to complete study procedures within the study timelines Mucin 1-positive tumor as determined by central immunohistopathology Adequate renal function: serum creatinine ≤ 1 mg/dL Adequate liver function: serum glutamic oxaloacetic transaminase/aspartate

aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) ≤ 2 × upper limit of normal (ULN) and serum bilirubin ≤ 1.5 × ULN unless Gilbert’s syndrome has previously been confirmed for the patient.

Adequate bone marrow function: white blood cells (WBCs) ≥ 3.0 K/µL, absolute neutrophil count (ANC) ≥ 1,500/mm3, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000/mm3

Life expectancy of at least 12 months at the time of screening as judged by the investigator

Not pregnant, and if of childbearing potential, agrees to use adequate birth control (hormonal or barrier method of birth control or abstinence) prior to study entry, for the duration of the study, and for 3 months after the last dose of study agent.

Inclusion Criteria

o Non-epithelial ovarian cancer, including ovarian germ cell, sarcoma, mixed Mullerian tumors, or mucinous carcinoma of the peritoneum

o Malignancy other than EOC, except those that have been in CR for a minimum of 3 years, and except carcinoma in-situ of the cervix or basal cell and squamous cell carcinomas of the skin that have been adequately treated

o Treatment with any investigational product (for any condition) within 4 wks of screening o Concurrent treatment with any immunomodulating or immunotherapeutic agent (for

any condition) within 4 weeks of screening o Evidence of severe or uncontrolled cardiac disease, including myocardial infarction or

unstable angina within 6 months of screening, congestive heart failure, or ventricular arrhythmias requiring medication

o Clinically significant abnormalities as measured by ECG o Active uncontrolled infection o Uncontrolled hypertension o Diagnosed immunodeficiency or autoimmune disorder o Infection with human immunodeficiency virus(HIV) or hepatitis B or C viruses (HBV, HCV) o Pregnant or lactating o Evidence or history of central nervous system metastasis o Any other health condition that would preclude participation in the study in the

judgment of the principal investigator.

Exclusion Criteria

Have achieved complete remission as evidenced by the baseline radiological scan ≤ 32 weeks after randomization; complete remission is defined as no detectable lesion, no relevant abnormalities on physical examination, and a normal CA-125 level

Have completed at least three cycles of platinum- and taxane-based first-line chemotherapy, with or without concurrent bevacizumab

Have not withdrawn consent from study participation

Remain willing and able to complete study procedures within the study timelines

Adequate bone marrow function: WBCs ≥ 3.0 K/µL, ANC ≥ 1,500/mm3, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000/mm3

Adequate renal function: serum creatinine ≤ 1 mg/dL

Adequate liver function: SGOT/AST and SGPT/ALT ≤ 2 × ULN and serum bilirubin ≤ 1.5 × ULN

Not pregnant, and if of childbearing potential, agrees to use adequate birth control (hormonal or barrier method of birth control or abstinence) prior to study entry, for the duration of the study, and for 3 months after the last dose of study agent

Have not developed another type of malignancy, except carcinoma in-situ of the cervix or basal cell and squamous cell carcinomas of the skin that have been adequately treated

Have not been treated with any investigational product (for any condition) between screening and baseline

Have not been treated with any immunomodulating or immunotherapeutic agent (for any condition) between screening and baseline

No other health condition or reason that would preclude participation in the study in the judgment of the principal investigator.

Baseline Inclusion/Exclusion Criteria

• Screening (~1000 to obtain 800 dosed) • 1:1 randomization (CVac:placebo) • Leukapheresis for all. Second leukapheresis for less

than 5% of patients (both arms) to make more CVac • 1st line tx (per investigator standards) • Confirm remission (CT, CA-125, physical) • 800 dosed at baseline; 6 doses over 48 wks

(4,8,12,24,36,48 weeks) • CT (MRI) ~every 8 weeks • EOS at 620 PFS events (PD or death) • Blinded interim analysis by DSMB ( 400 events)

Design Overview

• Proper diagnosis (EOC) • Compliance with MNC collection SOPs • Randomization and scheduling - ICAN • Patient in complete remission • Baseline < 32 weeks from randomization • Intradermal injections • CT, QoL performed accurately on schedule • PFS evaluations standardized

Most important issues

• Leukapheresis scheduling & logistics • Placebo & sham apheresis: ?ethics issue • Frequency of CT/ MRI and contrast agents

– Radiation exposure – Radiology manual supports lack of potential toxicity

• Retention and Follow Up of patients

CAN-004 complex issues

• Very low potential for toxicity • Easy administration • No major changes from standard of care • Unmet area of need

Positives about the trial

• Total Countries –14 countries

• Number of EC Approval(s): – Europe – 9 countries with EC approvals (Austria,

Germany, France, Poland, Latvia, Estonia, Lithuania, Ukraine, Romania)

– Australia – 2 out 5 sites EC and TGA approved – USA – 4 IRB approvals – Asia – under evaluation

• Total Sites Participating – 99 have been selected to date

CANVAS Status

Manufacturing – Manufacturing Authorization in EU

– Manufacturing Authorization in AU

– Manufacturing underway in US

– Import of placebo in EU underway

Regulatory – TGA – approval in Australia protocol v2.0

– FDA – approval in US, protocol v2.0

– VHP – addressed issues

– Non VHP – approval in Ukraine for protocol v.1

– Submission to CA in Belarus, Bulgaria, Latvia, Lithuania, Poland, Romania

CANVAS Achievements 2

58

Christopher Nicodemus , MD FACP Senior Advisor

Oregovomab Front Line Chemo-Immunotherapy Phase II Protocol

GCIG & COGI 1 June 2012

Chicago

59 A Randomized Controlled Study of First Line Chemotherapy versus Chemo-immunotherapy

Quest Pharmatech Edmonton, Alberta Madi Madiyalakan, PhD CEO

Project Sponsor

The Oregovomab Clinical Advisory Board Dr. Christopher Nicodemus (Scientific and Operational Consultant)

Professor Ignace Vergote Professor Thomas Ehlen

Professor William McGuire

Quest Project team Mr. Thomas Woo (Operations)

Ms. Connie Sykes (Regulatory Affairs)

Cellular Immunology- Pittsburgh Dr. Lisa Butterfield

Study Chair Italy: Professor Roberto Angioli US COGI Chair: Professor Jonathan Berek

Special Thanks to Professor Sergio Pecorelli

60 Status of Oregovomab Program – June 2012

Oregovomab/CA125 immunization was unable to improve outcomes in a phase III maintenance mono-immunotherapy study of ovarian cancer

Maintenance setting inappropriate to elicit vigorous cellular immunity with immunization (Berek et. al., JCO 2009)

Paradoxically, Immunization as same day combination chemo-immunotherapy induced superior tumor specific immunity in a pilot study Effect Schedule Dependent Platinum/taxane in front line immune stimulatory (Braly et.al. JIT, 2009)

Additional Phase II clinical data to justify a phase III trial design needed Protocol ongoing at sites in Italy and COGI sites in US; 13 patients dosed Opportunity for additional sites Developing data for definitive phase III protocol to follow

Quest Pharmatech, Edmonton, Alberta Acquired rights to the technology Advancing Further Development with multiple products and indications

61 Background and Rationale

Oregovomab, Monoclonal anti-CA125 Antigen specificity:

– CA125, present on >80% of all non-mucinous ovarian carcinomas; >95% in FIGO III/IV

– Binds to a unique epitope within Group A (OC125-like) Isotype:

– Mouse IgG1κ Affinity:

– 1.1x1010 M-1 for CA125 antigen Immunohistochemistry:

– Stains specifically ovarian carcinomas expressing CA125 Pharmacology:

Binds tumor antigen, to create immune complex “vaccine” for antigen processing

No direct effects (ADCC, CDC, receptor blockage)

62 Oregovomab Mechanism of Action

Oregovomab binds CA125 and forms immune complexes

The complexes are processed and cross- presented by dendritic cells to activate specific T cells (CD4 and CD8)

CA125-B43.13 Complex CA125 conjugated with

FITC (green) pre-incubated with MAb-

B43.13-Cy3 (red) added to day 5 DC for 30

min. before fixation; yellow: co-localized

complex

0 2 4 6 8 10 12 14 16 18

Negative Control, RPMI + 10% hAB

Positive Control, PMA + Ionomycin

B43.13 (2.5 µg/mL)

CA125 (50 U/mL)

CA125 (500 U/mL)

CA125 (5000 U/mL)

B43.13 (2.5 µg/mL) + CA125 (50 U/mL)

B43.13 (2.5 µg/mL) + CA125 (500 U/mL)

B43.13 (2.5 µg/mL) + CA125 (5000 U/mL)

IFN-γ Positive Cells [% of T cells]

CD4CD8

Two rounds of in vitro stimulation

63 CA125-B43.13 IC But Not CA125 Co-localize with LAMP-1, A Marker for Late Endosomes

1 h Pulse CA125-Cy3 and LAMP

1-FITC

6 h Chase 19 h Chase

CA125-Cy3 + B43 and LAMP 1-

FITC

Late Endosomes

• CA125 is present in early but not in late endosomes. The overall distribution of CA125-Cy3 does not change even after a 19 h chase period

• CA125 given as immune complex is present in early and late endosomes after a 6 h chase (red arrow) Data Quest Pharmatech

64 Combinatorial Immunotherapy

Schedule of IT in combination important Chemotherapeutics impacts character of

immune response Not always immune suppressive Modulate regulatory environment, ie. T reg Quality of antigen processing, ie. apoptotic

tumor as source of antigen Assessed in pre-clinical in vitro and in

vivo models and clinical trial (Braly et al)

65 Taxane treated tumor cells complexed with anti-CA125

induced optimal Lymphocyte mediated tumor lysis

CTL Assay

0

10

20

30

40

50

60

70

75:1 25:1 8:1 2.5:1

Effector:Target Ratio

% S

peci

fic L

ysis

B43.13

TAXOL

TAXOL+B43.13

FREEZE/THAW

FREEZE/THAW+B43.13

UNLOADED DC

Experimental Model: in vitro antigen presentation and cytotoxic lymphocyte induction • B43.13 (oregovomab) in combination with paclitaxel resulted in the highest induction of CTL activity,

higher than drug treated cells or antibody-coated live cells alone • Necrotic tumor cells (freeze/thaw group) did not induce a CTL response

Data Quest Pharmatech

66 Study 18 (Braly et al JIT, 2009) Front-Line Chemo-Immunotherapy Pilot Phase II Study

Randomized to schedule cycles 1,3,5: Arm A: concurrent with CTX Arm B: one week following CTX

Ovarian CancerInformed Consent

Endpoint for Primary Analysis

Arm A: OvaRex® concurrent with Carboplatin/Paclitaxeln=20

A

Arm B: OvaRex® 8-Days After Carboplatin/Paclitaxeln=20

B

Lab Sample CollectionRoutine Testing: baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeksPBMC Collection: pre-surgery, prior to cycle 5, cycle 5 plus 24 weeksImmune Testing: pre-surgery, baseline, prior to cycle 3, cycle 5, cycle 5 plus 24 weeks

A A A A AB B BB B

DiagnosisCycle 1

Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 812 WeeksPastCycle 5

24 WeeksPastCycle 5

Follow-Up6 additionalOvaRex® dosesUp to 2 Years

Tumor / Node /Ascites Collection

Surgery (Staging Laparotomy)Randomization and Treatment

Presumptive Stage III/IV Ovarian Cancer

Ovarian CancerInformed Consent



A


B


A Arm A: OvaRex® concurrent with Carboplatin/Paclitaxeln=20

A


B Arm B: OvaRex® 8-Days After Carboplatin/Paclitaxeln=20

B



A A A A AB B BB B

DiagnosisCycle 1

Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 812 WeeksPastCycle 5

24 WeeksPastCycle 5

Follow-Up6 additionalOvaRex® dosesUp to 2 Years

Tumor / Node /Ascites Collection

Surgery (Staging Laparotomy)Randomization and Treatment

Presumptive Stage III/IV Ovarian Cancer

NOTE: Patients Enrolled Prior to Resection; majority had Complex disease, that was not to be optimally cytoreduced

67

67

0

100

200

300

400

500

600

700

800

HA

MA

ng/

mL

Arm A N=17 Arm B N=19 MaintenanceN=100

Median HAMA levels Measured at 6 or 8 wks

Schedule Arm A: concurrent with chemotherapy infusion Schedule Arm B: antibody one week following infusion

Kinetics of Immune Response with Chemo-immunotherapy: Influence of Dose Schedule and

Comparison to Previous Maintenance Study

Front-Line Chemo-enhanced Immunotherapy Pilot Phase II Study

Data Quest Pharmatech

68 CA125-specific T cell Responses

Pre Post0

25

50

75

100

125

150

175

200

IFN

- γ S

pots

/105 C

ells

Pre Post0

25

50

75

100

125

150

175

200

IFN

- γ S

pots

/105

Cel

ls

P=0.04 P=0.150

44%

Arm A-same day Arm B-one week delay

21%

ELISPOT No In vitro Stimulation Step

This assay format could not detect specific T cells in the circulation from vaccination studies in the maintenance setting doisng post front line

Braly 2009 and Quest data

69 Correlation Clinical Response to CA125-specific T-cell Response

CA125-Specific T cell Responses

0 10 20 300

25

50

75

100

125

Time (months)

Perc

ent P

FS

CA125-Specific T cell Response

0 10 20 300

25

50

75

100

125respondersnon-responders

Time (months)

Perc

ent s

urvi

val

70 Safety Experience

Adverse Events Consistent with Expectations in Front Line Post Operative Setting

Toxicity associated with chemotherapy as expected

Allergic Reaction associated with antibody infusion seen on occasion Generally managed by slowing or stopping infusion Antihistamine Corticosteroid associated with paclitaxel may minimize

this issue Therapy generally easily administered

71 Conclusions

Concurrent Chemo-immunotherapy is immune response enhancing Simultaneous day infusion cycle 1,3,5

preferred schedule Safety profile satisfactory and readily

managed Quest conducting randomized phase II in

optimal population with no residual disease in US and Europe prior to Phase III program

72

May 16, 2012 72

Presumptive Stage III/IV Ovarian Cancer Surgery (staging laparotomy /optimal debulking)

Randomization and treatment

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 5 + 12 weeks

Cycle 5 + 13 weeks


Follow-up Up to 3 years

Lab Sample Collection: Routine testing: baseline, prior to cycle 1, cycle 3, cycle 5, cycle 5 +12 weeks, cycle 5 + 13 weeks Urinalysis: baseline, prior to cycle 5 + 12 weeks, cycle 5 + 13 weeks HAMA + CA125: baseline, prior to cycle 3, cycle 5, cycle 5 + 12 weeks ELISPOT: baseline, prior to cycle 5, cycle 5 + 12 weeks, cycle 5 + 13 weeks DTH: baseline, cycle 5 + 12 weeks, cycle 5 + 13 weeks

Oregovomab concurrent with carboplatin-paclitaxel

1 1 1

1

Oregovomab alone

Confirmatory Phase II Protocol Schematic

73 Oregovomab Chemo-immunotherapy Protocol

Objective: Confirm and extend Simultaneous Oregovomab-Carboplatin-Paclitaxel observations to justify a definitive phase III study with newly manufactured antibody

Design: Randomized parallel study of standard chemotherapy vs standard of care chemotherapy plus oregovomab

Patients: Optimally resected (no measurable residual disease ) Stage III/IV Epithelial Ovarian Cancer Patients; CA125 >100 prior to resection

Sample Size: N=80

Treatments: Standard of Care carboplatin paclitaxel chemotherapy x 6 cycles vs Standard of Care Carboplatin Paclitaxel chemotherapy x 6 cycles with oregovomab 2mg IV infused at cycle 1,3,5 and then at cycle 5 plus 12 weeks. Long Term Outcomes survey follow up.

Endpoints: • CA125 specific ELISPOT • Antibody response (HAMA) • DTH to oregovomab • Progression free survival • Survival • Safety Profile

74 Time and Events Schedule VISIT Schedule

VISIT

Screening Cycle 1 Cycle 3 Cycle 5 C5 +12 C5 +13 (term )

Follow Up Survey

Screen & Randomize

X

Dose IT (CIT arm only)

X X X X

Clinical Evaluations x x x x x x

Radiological Data Collection (SOC)

x x

x

x

x

x

Safety Evaluations (central lab & AE)

x x x x x x

HAMA x x x x

ELISPOT and Flow x x x

DTH (C & CIT Arms)

x x

FU Survey (Relapse and Survival)

Quarterly

75 Additional Initiatives

Other Clinical & Preclinical studies with oregovomab and other tumor antigen specific antibodies in development Addition of adjuvant (TLR and cytokine and

combinations) Assessment of gemcitabine (alternative to

taxane with different schedule effects) CA125, MUC1, PSA other targets

OV21, an International IP Trial

Co chairs : Helen Mackay Diane Provencher

A PHASE II/III STUDY OF INTRAPERITONEAL (IP) PLUS INTRAVENOUS (IV) CHEMOTHERAPY VERSUS IV

CARBOPLATIN PLUS PACLITAXEL IN PATIENTS WITH EPITHELIAL OVARIAN CANCER OPTIMALLY DEBULKED AT

SURGERY FOLLOWING NEOADJUVANT INTRAVENOUS CHEMOTHERAPY:

A Gynecologic Cancer Intergroup (GCIG) Trial led by the NCIC CTG NCIC CTG : OV.21 NCRI: UCL08/0379

GEICO: 0902 SWOG: Activation process, 4 centres

http://www.gcig.igcs.org/index.html�

Basic Design A : Phase II Patients with EOC

3-4 cycles neoadjuvant chemo

Initial surgery: < 1 cm residual

3 cycles IV IV Taxol 135 mg/m2 IV Carboplatin AUC 5*

3 cycles IP/IV IV Taxol 135 mg/m2

IP Carboplatin AUC 5*

Day 8th

IV Taxol 60 mg/m2 Day 8th

IP Taxol 60 mg/m2

Rando

Optimal Surgery

Shorter course

3 cycles IP/IV IV Taxol 135 mg/m2 IP Cisplatin 75 mg/m2

Day 8th

IP Taxol 60 mg/m2

* Measured GFR: AUC 5; calculated GFR: AUC 6


92 patients as of May 2012

NCIC-CTG OV21 NCRI UCL 08/0379

SWOG GEICO 0902

Phase II


N = 64 Patients N = 21 Patients

N = 7 Patients


OV21 Report

NO SAEs

Compliance rate: Intraoperative randomization (+ 80%)

Concerns:

Recruit more patients Competitive PHARMA trials< QoL link to PROMIS initiative?

NCIC-CTG OV21 NCRI UCL 08/0379 SWOG GEICO 0902

Invitation to working group – Friday, June 1st, 5pm


Update to design of ICON8 • ICON8 Currently addresses dose fractionation question - both carboplatin and paclitaxel Currently no bevacizumab arm • Carboplatin-paclitaxel + bevacizumab Increasingly ‘standard of care’ for high-risk ovarian cancer

– ICON7 OS analysis expected 2013

Widely licensed and widely available

Diagnosis of Stage IC-IV EOC/PPC/FTC

Immediate Primary Surgery (IPS)

Arm 1 6 cycles

Arm 2 6 cycles

Arm 3 6 cycles

Arm 1 3 cycles

Arm 2 3 cycles

Arm 3 3 cycles

Arm 1 3 cycles

Arm 2 3 cycles

Arm 3 3 cycles

Delayed Primary Surgery (DPS)

Arm 1 Carboplatin AUC 5 q3w (control) Paclitaxel 175mg/m2 q3w

Arm 2 Carboplatin AUC 5 q3w Paclitaxel 80mg/m2 q1w


Target sample size: 1485 over 3 years Current trial status: 130 randomised (on schedule)

Cycle 3 d15 omitted

Randomise 1:1:1 Randomise 1:1:1

Delayed Primary Surgery (planned)



Arm 1 6 cycles






Delayed Primary Surgery (planned) Immediate Primary Surgery (IPS)


ICON8 – current design

New proposal • Two parallel randomisations

– ICON8A and B

• To address additional questions – Does weekly paclitaxel produce same benefit as Bev? – Does addition of Bev improve weekly paclitaxel further – Is Bev safe and effective in patients undergoing delayed primary

surgery?

Current ICON8 regimens

Arm 2 6 cycles

Arm 3 6 cycles

Arm 1 6 cycles

Randomise 1:1:1

Diagnosis of Stage IC-III EOC/PPC/FTC

Eligibility criteria • Stage IC-II or III with <1cm residual after immediate primary surgery • III with >1cm residual disease after primary surgery, IV, or primary chemotherapy with delayed primary surgery only if;

• contraindications to bevacizumab • patient declines bevacizumab • or if not able to participate in ICON8B

ICON 8A

Arm 1 Carboplatin AUC 5 q3w Paclitaxel 175mg/m2 q3w Bevacizumab 7.5mg/kg q3w



ICON 8B

ICON7 winner

JGOG3016 winner



Arm 1 6 cycles

Arm 2 6 cycles

Arm 3 6 cycles

Arm 1 * 3 cycles

Arm 2 3 cycles

Arm 3* 3 cycles

Arm 1* 3 cycles

Arm 2 3 cycles

Arm 3* 3 cycles

Delayed Primary Surgery (DPS)

Bevacizumab maintenance to continue for maximum of 16 cycles in arms 1 and 3

Cycle 3d15 PTX omitted





Arm 1 6 cycles






Delayed Primary Surgery (planned) Immediate Primary Surgery (IPS) and residual >1cm

Diagnosis of Stage IIIC-IV EOC/PPC/FTC

* Bevacizumab omitted from cycles 3 and 4

ICON 8B

Preferred design • A non-inferiority trial to test whether Carbo-weekly

Taxol (Arm 2) has equivalent PFS efficacy to Carbo-Taxol + Bev (Arm 1) – if yes, is Carbo-weekly Taxol + Bev (Arm 3) superior to either? – if no, is Carbo-weekly Taxol +Bev (Arm 3) superior to Carbo-

Taxol +Bev (Arm 1)?

• BUT, requires 2500 patients (2100 PFS events) assuming HR of ≥ 0.87 – not feasible given the target population without multi-

multinational collaboration

Alternative approach • Power for two superiority analyses:

– Carbo-weekly Taxol + Bev (Arm 3) over Carbo-weekly Taxol (Arm 2)

– Carbo-weekly Taxol + Bev (Arm 3) over Carbo-Taxol + Bev (Arm 1)

– ~300/380 per arm for 80%/90% power, HR=0.75, 2α=0.025

• Predefine non-inferiority bound for Arm 2 vs Arm 1 [≥0.87 for PFS?]

• Subject to results of superiority comparisons, include exploratory

test of non-inferiority [Arm 2 vs Arm 1]

• Indirect comparisons using network meta analysis methods

Carboplatin-Paclitaxel q3w

Carboplatin-Paclitaxel q3w + Bevacizumab

Carboplatin-Paclitaxel q1w

Carboplatin-Paclitaxel q1w + Bevacizumab

GOG218: Stge III sub-opt debulked & Stge IV post surgery ICON7: Stge IC-IV; high-risk sub-group Stge III sub-opt debulked & Stge IV

JGOG3016: Stge II-IV ICON8A: Stge IC-IV

GOG262: Stge III sub-opt debulked & Stge IV post surgery ICON8B: Stge III sub-opt debulked/primary chemo & Stge IV

ICON8B: Stge III sub-opt debulked, primary chemo & Stge IV

Other trials: MITO-7, Stge IC-IV, C-Pq3w vs wCwP 60mg/m2




ICON 8B

A GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/- bevacizumab compared with oxaliplatin and capecitabine +/- bevacizumab as

first line chemotherapy in patients with mucinous Epithelial Ovarian Cancer (mEOC)

Cancer Research UK & UCL Cancer Trials Centre

For more information email: [email protected]


The mEOC study is a multi-national collaboration with the Gynecologic Oncology Group, USA (GOG)

• Primary Aims: The primary aim of this trial is to determine whether chemotherapy with oxaliplatin + capecitabine improves the survival of patients with mucinous ovarian cancer, compared to standard chemotherapy with carboplatin + paclitaxel. In addition, we aim to determine whether Bevacizumab improves overall survival of patients with mucinous epithelial ovarian cancer.

• Secondary Objectives: Progression free survival, response rates, toxicity, quality of life (QoL) • QoL: All patients will be assessed using FACT-O TOI, FACT/GOG-NTX Subscale and EQ-5D QoL

questionnaires. • Translational research: Patients may opt to donate a sample of their tumour taken at time of

surgery, for future research.

Trial Objectives

2x2 Factorial Trial Design mEOC FIGO stages II–IV OR recurrent stage I; No previous chemotherapy; >18yrs; PS=0-2

Randomise (332 patients – 83 patients in each arm)

Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 x 21-day cycles

Oxaliplatin 130 mg/m2 Capecitabine 850mg/m2 bd 6 x 21-day cycles

Carboplatin AUC 5/6* Paclitaxel 175mg/m2 6 x 21-day cycles Bevacizumab 15mg/kg given every 3 weeks for 5 or 6** cycles

Oxaliplatin 130 mg/m2

Capecitabine 850mg/m2

bd 6 x 21-day cycles Bevacizumab 15mg/kg given every 3 weeks for 5 or 6** cycles Clinical assessment every 6 weeks

for 36 weeks Telephone call at week 3 between every 6-week visit Bevacizumab 15mg/kg given every 3 weeks for 12 cycles

Clinical assessment every 6 weeks for 36 weeks

Response assessment: CT scans are carried out post cycle 3 of chemo, 1 month after completion of cycle 6, then 3 monthly for Year 1 Follow up: 3 monthly years 1-2, 6 monthly years 3-5

*The carboplatin dose depends on the method used to obtain GFR. If GFR has been estimated, AUC=6, if GFR has been measured, AUC=5

**Bevacizumab can be omitted from the first cycle of if chemotherapy must be started within 4 weeks of surgery.

96

• Histological diagnosis of mucinous ovarian carcinoma

• FIGO stage II-IV, recurrent stage I

• Aged 18 or above

• Life expectancy >3 months

• No previous chemotherapy for ovarian cancer or radiotherapy

• ECOG performance status 0, 1 and 2

• Adequate haematological, renal and hepatic function

• Adequate neurological function (sensory & motor ≤ grade 1)

• Urine dipstick for proteinuria <2+

• Adequate coagulation parameters • Include patients with synchronous primary endometrial carcinoma (if Grade 1 or 2, stage 1A) • Include patients with previous malignancies successfully treated with chemotherapy over 5 years ago e.g. breast, colorectal carcinoma.

Patient eligibility


Targets: Start date – January 2010; Planned end date – May 2014 First patient in – 4th March 2010 UK Sites: 16 patients in the trial. 36 sites open. 7 UK sites in set-up. European Sites: In set-up NSGO: Denmark (2), Finland (3), Norway (4) (Awaiting QP release in Finland) MANGO/MITO: Italy (22) (Awaiting amendment approval for labels and new PIS) GINECO: France (28) (Amendments to contract and site registration documents ) DGOG: Holland (5-8) (Country Master label to be approved) GOG-0241 sites: 7 patients in the trial. 79 sites open.


Issues with site-up UK: • Oxaliplatin and Capecitabine funding – not standard treatment for ovarian cancer

– Some sites can claim this as an Excess Treatment cost but this has been an issue at others

European: • European funding to run the trial has taken a long time to source • Negotiating contracts • Multiple demands from Roche Global regarding Bevacizumab supply and QP sign-off

MITO TRIALS

GCIG MEETING

Chicago June, 2012

Liposomal doxorubicin vs carboplatin/paclitaxel in recurrent

ovarian cancer patients with platinum-free interval between 6-12 months

MITO–8, ENGOT OV-1, AGO-OVAR 2.16

RANDOM

LIPOSOMAL DOXORUBICIN

40 mg/m2

day1 every 28 days

CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/m2

day1 every 21 days

Cross-over at Progression

CARBOPLATIN AUC 5 + PACLITAXEL 175 mg/m2

day1 every 21gg

LIPOSOMAL DOXORUBICIN 40 mg/m2

day1 every 28 days

Trial design • The objective of this trial is the efficacy determined

through analysis of overall survival (OS) of the different sequence (CP→PLD vs PLD→CP) in recurrent ovarian cancer patients with platinum-free interval 6-12 months

• Median Overall Survival: • expected (control arm): 18 months

• auspicated (experimental arm): 27 months • Alpha error: 0.05, bilateral

• Power: 80% • 193 events (progression) are needed

• 253 patients are to be enrolled (planned in 4 yr)

Statistics

MITO8 – New Amendment

• Proposal submitted to IDMC, AGO, BGOG, MANGO

• MITO decision Topotecan or gemcitabine allowed as single agent non platinum therapy

• Amendment submitted to EC

Pathway to diagnosis of ovarian cancer: an observational retrospective

multicentered study MITO 12

Study objectives

• Describe frequency and duration of symptoms in the 12 months preceding ovarian cancer diagnosis

• Describe time intervals (weeks) of sentinel events – onset of first persistent symptoms – first physician visit – Cyto-histological diagnosis of ovarian cancer

• Classify diagnostic delays according to the expanded Andersen’s model of total patient delay.

Pathway to diagnosis of ovarian cancer:

an observational retrospective multicentred study Ti

me

Inte

rval

s in

wee

ks

Cooperative Group Enrolling Centres Patients

MITO 30 458

MANGO 4 53

GINECO 7 9

BGOG 1 9 TOTAL 42 529

Coordinating centre: Clinical Trials Unit National Cancer Institute Naples • https://www.usc-intnapoli.net • Web-based procedures

– Register to be authorized user – Identify study of interest (MITO-12 ) and adhere – Download documents and submit for Ethics

Committee evaluation – Study data entry

• Research nurse coordinator:

[email protected]

Weekly Paclitaxel vs weekly Paclitaxel and Pazopanib in patients with

resistant/refractoryovarian cancer: Phase II randomized multicenter trial

MITO - 11

RANDOM

Pazopanib 800 mg/day Paclitaxel 80 mg/mq

day 1,8 15 - every 28days

Paclitaxel 80 mg/mq

day 1, 8, 15 - every 28 days

21/72 patients enrolled

Phase II study on ET-743 (Yondelis®) 1.3 mg/mq q 21 in BRCA1 and BRCA2 mutation carrier

and BRCAness phenotype advanced ovarian cancer patients

MITO 15 Primary objective:

objective response rate [CR + PR] Inclusion criteria:

At least 2 previous platinum based chemotherapy lines (no limitation in the number of previous chemotherapy lines)

Measurable disease Stratification:

Platinum sensitive/resistant


TRANSLATIONAL STUDY: Evaluation of single nucleotide polymorphisms (SNPs) ERCC1 C118T, ERCC1

C8092A, XPD Lys751Gln, XPD Asp312Asn, and XPG Asp1104His

• Secondary surgery +HIPEC vs Secondary surgery alone in recurrent platinum sensitive ovarian cancer

• Phase II randomized multicenter trial HORSE MITO 17

RANDOM

Secondary surgery followed by platinum based

chemotherapy

Secondary surgery + HIPEC followed by platinum based

chemotherapy


A multicenter randomized study in patients with epithelial ovarian cancer

with bevacizumab plus chemo vs chemo at progression after first line

chemo + bevacizumab

MITO – 16

Mango OV2

Background • Bevacizumab improves PFS when added to first line

carboplatin-paclitaxel (GOG 218, ICON7) • Bevacizumab improves PFS when added to

carboplatin-gemcitabine in platinum sensitive recerrences (OCEAN)

• Two possible different indications for bevacizumab in the market

• Ipothesis that treatment in multiple lines of therapy improves the outcome (never proved prospectively)

• Positive results at ASCO for colon cancer

MITO 16-Mango OV2

• 3 different projects

– Fist line phase IV study with traslational end point (only in Italy)

– Phase II study in second line resistant/refractory (Not yet

approved)

– Phase III study in platinum sensitive recurrent patients

Chemonaive Stage III - IV OC, PP or FT

cancer

Bevacizumab 15 mg/kg q3w with CBDCA+Paclitaxel 6 cycles + followed by Bevacizumab for 15 months (GOG 218)

First line phase IV

trial 400 patients planned

END POINTS - Biological biomarkers

- Clinical prognostic and predictive factors

Patients with platinum sensitive ovarian cancer

progressing after first line carbo-tax+bevacizumab

II line chemo 6-8 cycles CBDCA+PLD, CBDCA+Gem,

CBDCA+Pacl (plat sens)

Randomized phase III

II line chemo 6-8 cycles CBDCA+PLD, CBDCA+Gem,

CBDCA+Pacl (plat sens)

+ Bevacizumab 10/15

mg/kg q2-3w until progression

Phase III trial in platinum

sensitive pts

Statistical design • primary endpoint: PFS (defined as occurrence of progression or death

without progression) • secondary endpoint: OS (no cross-over must be allowed by protocol),

RR, traslational • two-tailed significance level: 0.05 • power 90% • median expected PFS in the standard arm: 8 months (from the OCEAN

study) • median expected PFS in the experimental arm: 12 months • HR to be detected: 0.67 (from the OCEAN study) • one interim analysis for rejecting both null (H0) and alternative

hypothesis (H1) at the half of the required events • Calculation of sample size according to previous assumptions: • number of event required: 263 • number of event required at first interim analysis:132 • with 400 patients to be recruited and an enrolment rate of 20 patients

per month, the expected study duration should range from 22 to 24 months

Administrative information

• Academic trial according to the italian law

• NCI of Naples sponsor

• Data center: MANGO and MITO

• Planned study start May 2012

• Roche support

• Translational end points

Thank you for attention

Documents

Tarceva consolidation 2 years - GCIG · The th4 Ovarian Cancer Consensus Conference has recognised the necessity of additional research of adapted therapy for elderly patients with