MRC Clinical Trials Unit STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy Sponsor number:MRC PR08 ISRCTN

MRC Clinical Trials Unit

STAMPEDESystemic Therapy in Advancing or

Metastatic Prostate cancer: Evaluation of Drug Efficacy

Sponsor number: MRC PR08ISRCTN number: ISRCTN78818544EUDRACT number: 2004-000193-31CTA number: 00316/0026/001-0001


Design rationale

STAMPEDE uses multi-arm multi-stage methodology

MAMS design permits rapid comparison and concurrent testing of treatments

Currently using 1 investigational drug + research radiotherapy

Issues in applying multi-arm multi-stage (MAMS)- methodology to a clinical trial in prostate cancer:the MRC STAMPEDE trial. M.Sydes et al., Trials.10. 39.http://www.trialsjournal.com/content/10/1/39 (Open access)


Trial Design Stages

Stage Outcome MeasuresPrimary Secondary

Pilot Safety Feasibility

Activity I-III Failure-free survival Overall survivalToxicity

Skeletal-related events

Efficacy IV Overall survival Failure-free survivalToxicity

Skeletal-related eventsQuality of life


Current comparison Design: Protocol v10


Timelines: initial plans

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

ADT-aloneA

ADT + zoledronic acidB

ADT + docetaxelC

ADT + celecoxibD

ADT + zoledronic acid + docetaxelE

ADT + zoledronic acid + celecoxibF

Past accrual

Possible future accrual Follow-up


Accrual: end of Activity Stage II

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

ADT-aloneA


ADT + docetaxelC

ADT + celecoxibD



Past accrual



Timelines: from Nov-2011

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

ADT + celecoxibD



ADT + abirateroneG

ADT-alone

Past accrual



Timelines: from Jan-2013

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

ADT + celecoxibD



ADT + abirateroneG

ADT-alone

H ADT + RT

Past accrual


M1 only


Timelines: from March-2013

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

A


ADT + docetaxelC

ADT + celecoxibD



ADT + abirateroneG

ADT-alone

H ADT + RT

Past accrual


M1 only


PATIENT SELECTION CRITERIA


Main Inclusion Criteria

Newly diagnosed high risk patients T3/4 N0 M0 with: • At least two of:PSA≥40ng/ml or Gleason sum score 8-10• And intention to treat with radical radiotherapy (unless there is a

contra-indication; exemption must be sought in advance of consent, after discussion with MRC CTU)

Newly diagnosed metastatic or nodal disease• Stage Tany N+ M0 or Tany Nany M+

Previously treated relapsing patients with either• PSA 4ng/ml and rising with doubling time < 6 months• PSA 20ng/ml• N+• M+


Histological confirmation of prostate cancer

Intention to treat with long term HT

WHO PS 0,1 or 2

Adequate cardiovascular history

No major dental extractions planned within next 2 years

Please see protocol section 4.1 and 4.2 for complete details about inclusion and exclusion

Inclusion/Exclusion Criteria


Selection criteria for M1/RT comparison

• Newly diagnosed prostate cancer

• Demonstrable M1 disease

• No contraindication to radiotherapy

• No previous radical prostatectomy

• Meets all other eligibility criteria

Protocol section 4.3 for more information


Cardiovascular exclusion criteria

• Patients with significant cardiovascular disease such as:

• MI less than 6 months prior to randomisation

• Arterial thrombotic events less than 6 months prior to randomisation

• Clinically significant cardiac failure requiring treatment (NYHA II-IV)

• Cerebrovascular disease less than 2 years prior to randomisation

• Close cardiovascular monitoring recommended for patients in arm G


Hormone Therapy Before Randomisation

It is preferable that patients are not started on hormones prior to randomisation but if they are then:

• No more than 12 weeks of LHRH before randomisation

• Orchidectomy should be performed no more than 12 weeks before randomisation

• Patients with bilateral orchidectomy should start treatment within 4 weeks from surgery

• No more than 14 weeks of anti-androgens before randomisation

• PSA measurement MUST be taken before HT treatment starts!


Clarification of HT prior randomisation

See Appendix L


Screening Procedures

Patients identified• CT or MRI of pelvis and abdomen• Bone Scan (or equivalent imagining)• Chest X-ray (unless chest included in CT) • ECG• PSA Test

Within 8 Weeks of Randomisation• Blood Tests• (See protocol section 4.3)


TREATMENT ADMINISTRATION


Hormone Therapy

Three acceptable approaches:

• Bilateral orchidectomy • Total or sub-capsular

• LHRH agonist or antagonist• Used according to local practice• Prophylactic anti-androgens recommended

Anti-androgen monotherapy is not allowed


Abiraterone Treatment

• Recommended dose is 4 x 250mg tablets as a single daily dose.

• Taken with low dose prednisone or prednisolone. Recommended dose of steroid is 5mg

• Taking the tablets with food increases systemic exposure to abiraterone. Abiraterone must not be taken with food. It should be taken at least two hours after eating and no food should be eaten for at least one hour after taking abiraterone. Tablets should be swallowed whole with water.


Abiraterone - Monitoring

Patients on arm G require additional monitoring.

• Patients will require 2 weekly U+Es, LFTs and blood pressure measurement for the first 12 weeks

• In the event of a missed dose of either abiraterone, prednisone or prednisolone, treatment should be resumed the following day with the usual daily dose.

• Please refer to protocol appendix G


Abiraterone: Hepatotoxicity

• If ALT > 5x ULN (Grade 3 toxicity) treatment should be withheld.

• Following LFT return to baseline or Grade 1 reintroduce at reduced dose (750mg daily). Serum transaminases should be monitored every two weeks for three months & monthly thereafter

• If hepatotoxicity recurs after the first dose reduction, treatment discontinued.

• For severe hepatotoxicity (ALT ≥20x ULN), treatment should be discontinued & not be reintroduced.

• Please refer to appendix G2 of the updated STAMPEDE protocol


Contra-indication to abiraterone

• Abiraterone inhibits enzymes CYP1A2 and CYP2D6• Interactions with:

• Betablockers/cardiac drugs• Antidepressants• Analgesics• Anti-fungal agents• Macrolide antibiotics• Antiviral drugs for HIV infection• Antitubercolosis drugs• Anticonvulsants

See Appendix section G.4.3 for more details


Radiotherapy


Radiotherapy in STAMPEDE


Standard-of-care radiotherapy

• N0M0 patients: Investigators should give radiotherapy (RT) to patients with N0M0 disease, in accordance with the recent data from the PR07 and SPCG trials

• If there is an intention to omit radiotherapy in patients with N0M0 disease this must be discussed with the MRC CTU before consent

• N+M0 patients: the benefit of radiotherapy in this group is at present uncertain. Investigators will be asked to state their intention with regard to planned radiotherapy in this group at randomisation

• Recommended type, timing and dose in protocol section 6

• Intention to use RT stated at randomisation• ensure no bias towards particular combinations of

systemic therapy with radiotherapy

• RT given 6 to 9 months after randomisation


Standard-of-care radiotherapy


•The use of radiotherapy to the prostate will retard progression of the metastases in men presenting with metastatic prostate cancer

Research radiotherapy: Hypothesis


Supporting evidence: metastatic renal carcinoma

SWOG 8949 EORTC 30947

Flanigan RC et al. NEJM 345(23):1655-9.Mickisch GHJ et al. Lancet 358:966-70.


Weckermann JCO 2009; 27(10): 1549-56

Supporting evidence: prostate cancer

Inference: The primary tumour may be required to stimulate disseminated tumour cells to grow into metastases

Pre-prostatectomy Post-prostatectomy


Widmark et al The Lancet 2009 373, 301-308

Early separation of OS curves

Supporting evidence: SPCG-7

Other relevant trial: UK & Canada: MRC PR07 /NCIC PR.3


Research (M1) Prostate Radiotherapy

•RT schedule chosen by doctor and patient if allocated

•RT to start within 4 weeks after randomisation

•Conformal RT or Intensity Modulated RT



Selection criteria:

•Newly diagnosed prostate cancer

•Demonstrable M1 disease (excluding local nodes)

•No contraindication to RT (e.g. no previous pelvic RT)

•No previous radical prostatectomy




Radiotherapy

For patients who receive a primary or research course of radiotherapy

• Radiotherapy detail form• Radiotherapy acute toxicity form


• No capacity issues raised following survey circulated in Q1 2012

• M1/RT schedules as excess treatment cost

• 1 patient recruited month = 2 patients/year arm H• Should be minimal impact

• NCRN adopted trial

Cost of radiotherapy


• No additional RTQA in sites that has participated in clinical trials of prostate cancer irradiation • RT01, CHHIP, PIVOTAL, RADICALS

• For sites which have not participated in such trials, central review of plans for two non-trial patients

• All current STAMPEDE centres in UK delivering RT already have RTQA

Radiotherapy Quality Assurance


ASSESSMENTS & FOLLOW-UP


• General PIS for all patients

• Identify which pt could not be allocated to arm H

• Verbally inform pts whether could or could not be allocated to arm H

• Record correctly pt disease category on CRF

• Arm G patients to be re-consented at first available follow up (patients on treatment only)

• Send copy of signed consent form to MRC CTU

Identification and consent


Follow-up schedule

6 weekly 0 to 24 weeks12 weekly up to 2 years 6 monthly up to 5 yearsAnnually thereafter

Follow-up dates will be sent to you on a treatment and follow-up schedule each time you randomise a patient.

Please complete a follow-up form for each visit


Assessment of Treatment Failure

Types of progression:

1. Biochemical2. Local3. Lymph node4. Distant metastatic5. Skeletal related event

Each type of progression only needs to be reported once.

Please complete an ‘additional treatment update form’ if a patient receives additional treatment for a progression that you have already reported.


Assessment of Treatment Failure – Arm G

For M+ patients, treatment should continue until clinical disease progression

PSA progression + radiological progression (appearance of new lesions or progression of existing lesions) + clinical progression (defined as new cancer-related symptoms).

• It is accepted that these flexible criteria for stopping treatment with abiraterone are open to the investigator’s interpretation and discretion.

• Patients might continue treatment beyond the first progression event.

• All progressions must be reported as per the other arms.


Assessment of Treatment Failure – Arm G

For N0M0 patients or N+M0 patient undergoing radical radiotherapy• Treatment duration = 2 years or disease progression as defined

for M+ patients, whichever is the sooner.

For patients with N+M0 disease not planned for radical radiotherapy, • Treatment duration = to continue as for patients with M1 disease

until disease progression

Please call the trial team if you are unsure about whether a patient should stop taking abiraterone.


Defining PSA Nadir & PSA Failure Categories

• PSA Nadir• Lowest reported PSA level • Between randomisation and 24 weeks

• PSA Failure• Depends on baseline PSA measurement and PSA nadir• 3 possible PSA failure categories, A, B and C


Defining PSA Relapse

3 PSA failure categories: • PSA Failure Category A – Failed at time zero

• PSA Failure Category B – Relapse occurs when PSA increases by 50% above nadir

• PSA Failure Category C – Relapse occurs when PSA increases by 50% above nadir or goes above 4ng/ml, whichever is greatest

PSA progression letters are sent out every 3 months for patients whom we have received their 24 week follow-up form.

Alternatively please check appendix K for details of how to calculate the progression value.


DRUG SUPPLY


• Janssen• Supplying free Abiraterone

• Abiraterone• Ordered by centre pharmacist directly from B&C• Pre-labelled with generic and trial-specific labels

Drug Supply & Support


Safety Reporting

• ICH GCP Safety Reporting definitions apply to STAMPEDE• Protocol section 11: Events Terms and Definitions • Definition of an event depends on four factors:• Seriousness

• was the event serious?

Any adverse event or reaction that: •Results in death•Is life-threatening•Requires hospitalisation or prolongation of existing hospitalisation•Consist of a congenital anomaly or birth defect•Other important medical condition

• Causality• was it related to the trial treatment?

• Expectedness• were the symptoms recognised side-effects of the treatment?• NOT ‘we didn’t expect that to happen!’• use List of Expected Toxicities


STAMPEDE: Clarifications and Exceptions

• The term “life threatening” refers to an event in which the patient was at risk of death at the time of the event

• Hospitalisation is defined as an inpatient admission; hospitalisation of pre-existing conditions do not constitute an SAE

• Pregnancy occurring in a STAMPEDE patient’s partner must be reported to the MRC CTU within the same timelines as an SAE and classified as “other important medical condition”


Notifications and responsibilities

• Investigators must notify the MRC CTU of all SAEs from the time of randomisation until 30 days after the last protocol treatment

• SAEs in Arm A patients must be reported until 2 years and 2 months or progression

• SARs and SUSARs must be notified indefinitely • Causality, expectedness and seriousness should be

assessed by a clinician responsible for the care of the patient

• SAEs must be notified using the appropriate SAE form by fax (fax number 02076704818)


Trial specific exemptions

• Disease progression

• Death as result of disease progression

• Elective hospitalisation and surgery for treatment of locally advanced or metastatic cancer or its complications

• Elective hospitalisation for pre-existing conditions that have not been exacerbated by trial treatment

• Elective hospitalisation for pre-existing conditions to simplify treatment or procedures


Associated undesirable effects for RT

See Appendix G for more details on both abiraterone and RT


STAMPEDE Accrual: July 2013

Total recruitment (July 2013): 4500 patients


Current Recruitment Status

First patient• 17th October 2005

Accrual targets• Pilot Phase target was 210 patients• Pilot Phase target achieved in

March 2007• Overall target approximately 3300

patients – (440 OS events on control

arm)Observed accrual

• 4500 patients• Record month: July 2013 (159

patients recruited)• 123 participating centres; 8 Swiss

centres


Patient Characteristics

Age (years) at randomisation median (quartiles) 65 (37-94)

PSA (ng/ml) at randomisation median (quartiles) 65 (23-188)

WHO performance status (0 Vs 1 Vs 2+)3193 vs 858 vs

46

Bone mets at randomisation n (%) 2150 (52%)

RT planned n (%) 1189 (29%)

Type of HT: (LHRH vs bicalutamide vs orchidectomy)4019 vs 54 vs

19

Data from April 2013


Patient characteristics

Newly diagnosed M1 61%

Newly diagnosed N+M0 21%

Newly diagnosed N0M0 14%

Previously treated 3%

Bone mets at randomisation 2,150 (52%)

Liver mets at randomisation 61 (1.5%)

Lung mets at randomisation 104 (3%)

Distant node mets at randomisation 761 (19%)

Other mets at randomisation 173 (4%)


New comparison arm

• TMG considering further new research arm

• Survey sent to sites in early Feb for one possible new comparison: Enzalutamide + Abiraterone


Case Report Forms


Case Report Forms

Please visit the STAMPEDE trial website to download the CRFs - http://www.stampedetrial.org/centres/information_for_centres/crfs_and_completion_guidelines.aspx


Prior to randomisation

These 4 forms should be filled out prior to randomisation:

1. Bone density risk factor questionnaire2. Randomisation form3. Baseline form4. Cardiovascular form


Randomisation CRF


Randomisation CRF


Randomisation pack

Each time you randomise a patient we will send you a pack which contains:

• Randomisation confirmation • Treatment schedule• FTA elute card kit & pathology form for the next patient


TRIAL COMMITTEESAND CONTACTS


Trial Management Group

Nick James Oncologist; CI, Chair, Birmingham, UKNoel Clarke Urologist; Vice-Chair Manchester, UKMalcolm Mason Oncologist; Vice-Chair Cardiff, UK

Alastair Ritchie Trial Surgeon MRC CTUDavid Dearnaley Oncologist Sutton, UKChris Parker Oncologist Sutton, UKRobert Millman Patient representative Stockport, UKJohn Masters Pathologist London, UKMartin Russell Oncologist Glasgow, UKMarc Schulper Health Economist York, UKAndrew Stanley Pharmacist Birmingham, UKGeorge Thalmann Oncologist Bern, CHDaniel Aebersold Clinical Oncologist Bern, CHEstelle Cassoly Trial Coordinator SAKK, CH

Claire Amos Clinical Project Manager MRC CTU, UKFrancesca Schiavone Clinical Trial Manager MRC CTU, UKAlanna Brown Clinical Trial Manager MRC CTU, UK Dominic Hague Data Manager MRC CTU, UKKatie Ward Data Manager MRC CTU, UKPeter Vaughan Data Manager MRC CTU, UKMelissa Spears Trial Statistician MRC CTU, UKMax Parmar CTU Director MRC CTU, UKMatthew Sydes CTU Lead/Senior Trial Statistician MRC CTU, UK


Contact us

Web: www.stampedetrial.org

MRC Francesca Schiavone Clinical Trial ManagerT: +44 (0) 207 670 4632 E: [email protected]

Alanna BrownClinical Trial ManagerT: +44 (0) 207 670 4882 E: [email protected]

Dominic Hague, Katie WardSTAMPEDE Data ManagersT: +44 (0) 207 670 4809 / 4794 / 4947 E: [email protected]

Documents

MRC Clinical Trials Unit STAMPEDE Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy Sponsor number:MRC PR08 ISRCTN