Noel Clarke

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Prostate Cancer Trials Update

• Noel Clarke

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• NCRI Prostate Clinical Studies Group

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TRIALS IN NCRI PROSTATE CSG PORTFOLIO
Active surveillancen300T1/T2, PSAlt15, Glslt7
MRC PR10 (RADICALS)n4000(Imm/Def RT 0/6/24m
HT)Localised, post-RP
MAPSn800 (Pelvic training)Post-RP
EORTC 22991n800 (RT/-HT)Localised, RT
PROTECTn1200(RP, RT, Surveillance)Localised,
screen detected
Localised choosing RP
HEMI-HIFUn40 (HIFU)Localised or locally
advancedGlslt7
Localised choosing RT
Localised choosing WW
Screen detected?
Other localised
CV247n200 (CV247, salicylic acid)Watch wait
typeor WACN guidelines
CHHIPngt450 (IMRT intensity)Localised, choosing
RT
Prostate cancer patient
Locally advanced
Pre-treated, relapsing local
http//pfsearch.ukcrn.org.uk/Disease.aspx?TopicID
1GroupID11
Epidemiology
UK Genetic PCa Studyn21000Any stage
MRC PR08 (STAMPEDE)n3300 (HT /- docetaxel,
zoledronic acid, celecoxib)M0 or M or high-risk
pre-treated
Painful bone metastates
Newly diagnosed metastatic
KEY
Hormone refractory
Yes
RIBn580 (RT, ibandronate)Bone metastases
No
MRC PR09 (PATCH)n200 (AS, HRT)M0 or M or
high-risk pre-treated
Limited Centres
Nationwide
DA vs DASn260 (/- stilboestrol)Androgen-indepe
ndent
EORTC 30985n1512 (Intermittent HT)Stage D2
Not yet open
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Submissions for approval/funding of prostate
trials made to CTAAC between February 2003 and
December 2005
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New Trials
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RADICALS Radiotherapy and Androgen Deprivation
In Combination After Local Surgery
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Trial principles

• Trial protocol with two separate randomisations
• All post-RP patients will be eligible
• Trial design will help to define clinical
  practice in this area of current uncertainty
• Address the 2 most important questions for
  post-RP patients
• Need for, and timing of, post-operative
  radiotherapy
• immediate (adjuvant) vs deferred
  (delayed/salvage)
• Use and duration of androgen deprivation
• none vs short (6 months) vs long (24 months)
• Not both of these questions are relevant to all
  RP patients

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RADICALS randomised comparisons Flow diagram
All Groups
Radical prostatectomy
Assess need for RT
Time
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RADICALS randomised comparisons Flow diagram
Uncertain Group
Radical prostatectomy
Assess need for RT
Uncertain group
RANDOMISE
Immediately after surgery
Time
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RADICALS randomised comparisons Flow diagram
Uncertain Group
Radical prostatectomy
Assess need for RT
Uncertain group
Adjuvant RT
RANDOMISE
Immediately after surgery
RANDOMISE
Monitor on trial
Immediately after surgery
RT no HT
RT short HT
RT long HT
Time
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RADICALS randomised comparisons Flow diagram
Uncertain Group
Radical prostatectomy
Assess need for RT
Uncertain group
Adjuvant RT
RANDOMISE
Immediately after surgery
RANDOMISE
Monitor on trial
Immediately after surgery
RT no HT
RT short HT
RT long HT
Trial follow-up
Early salvage RT
At rising PSA
RANDOMISE
RT no HT
RT short HT
RT long HT
Time
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RADICALS randomised comparisons Flow diagram
Uncertain Group
Radical prostatectomy
Assess need for RT
Uncertain group
Adjuvant RT
RANDOMISE
Immediately after surgery
RANDOMISE
Monitor on trial
Immediately after surgery
RT no HT
RT short HT
RT long HT
Trial follow-up
Early salvage RT
At rising PSA
RANDOMISE
RT no HT
RT short HT
RT long HT
Trial follow-up
Outcome measures
Time
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RADICALS randomised comparisons Flow diagram
Immediate Group
Radical prostatectomy
Assess need for RT
Immediate RT group
Immediately after surgery
RANDOMISE
RT no HT
RT short HT
RT long HT
Trial follow-up
Outcome measures
Time
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RADICALS randomised comparisons Flow diagram
Deferred Group
Radical prostatectomy
Assess need for RT
Deferred RT group
Monitor, not on trial
Time
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RADICALS randomised comparisons Flow diagram
Deferred Group
Radical prostatectomy
Assess need for RT
Deferred RT group (Monitored off trial, now PSA
rising)
Early salvage RT
At rising PSA
RANDOMISE
RT no HT
RT short HT
RT long HT
Trial follow-up
Outcome measures
Time
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RADICALS randomised comparisons Flow diagram
All Groups
Radical prostatectomy
Assess need for RT
Uncertain group
Immediate RT group
Adjvuant RT
RANDOMISE
Immediately after surgery
RANDOMISE
Monitor on trial
Immediately after surgery
RT no HT
RT short HT
RT long HT
Deferred RT group (Monitored off trial, now PSA
rising)
Trial follow-up
Early salvage RT
At rising PSA
RANDOMISE
RT no HT
RT short HT
RT long HT
Trial follow-up
Outcome measures
Time
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RADICALS randomised comparisons Flow diagram
All Groups
Radical prostatectomy
Assess need for RT
Uncertain group
Immediate RT group
Adjuvant RT
RANDOMISE
Immediately after surgery
RANDOMISE
Monitor on trial
Immediately after surgery

• Note
• Patients can be randomised between
• three HT arms or
• any two HT arms

RT no HT
RT short HT
RT long HT
Deferred RT group (Monitored off trial, now PSA
rising)
Trial follow-up
Early salvage RT
At rising PSA
RANDOMISE
RT no HT
RT short HT
RT long HT
Trial follow-up
Outcome measures
Time
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RADICALS randomised comparisons Flow diagram
All Groups
Radical prostatectomy
Assess need for RT
Uncertain group
Immediate RT group
Adjuvant RT
RANDOMISE
Immediately after surgery
RANDOMISE
Monitor on trial
Immediately after surgery
RT no HT
RT short HT
RT long HT
Deferred RT group (Monitored off trial, now PSA
rising)
Trial follow-up
Early salvage RT
At rising PSA
RANDOMISE
RT no HT
RT short HT
RT long HT
Trial follow-up
Outcome measures
Time
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Guidance flow diagram for assigning patients to
risk groups

• Permissive allocation to RT groups
• Use or uncertainty of use of RT decided by
  clinician and patient
• Flow chart for guiding discussions would be
  provided

Radical prostatectomy
Assess
Immediate RT
PSA gt0.1 more than 4 weeks post-op
Yes
No
Stage pT3 or pT4
Yes
No
Gleason 8-10
Uncertain RT (Randomise)
Yes
No

Gleason 7 margin positive
Yes
No
Gleason 7 pre-op PSAgt10
Yes
No
Gleason 7, margin negative pre-op PSAlt10
Yes
No
Deferred RT

Gleason lt6
Yes
No
Discuss with Chief Investigator
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Outcome measures Primary Disease-specific
survival (death after PCa progression) Secondary
Freedom from treatment failure Clinical
progression-free survival Overall
survival Duration of androgen
deprivation Quality of life
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REGISTER
RADICALS biology cohort Flow diagram
All Groups
Radical prostatectomy
Assess need for RT
Uncertain group
Immediate RT group
Deferred RT group
Flag with ONS or Cancer Registeries for survival
OPTIONAL SUBSTUDY
Compare survival by genetic factors
Time
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REGISTER
RADICALS surgical QL cohort Flow diagram
Assess QL
All Groups
Radical prostatectomy
Assess QL
Assess need for RT
OPTIONAL SUBSTUDY
Time
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STAMPEDE
Systemic Therapy in Advancing or Metastatic
Prostate cancer Evaluation of Drug Efficacy
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TRIAL DESIGN PATIENT ELIBILIGY CRITERIA
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Design rationale

• International, five-stage, multi-arm, randomised
  controlled trial
• Permits rapid comparison and testing of the main
  treatment options that are currently available
• Need to do this before any of these therapies
  become widely used as first line therapy without
  adequate evaluation and before a new array of
  treatments become available

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Trial Design
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Main Eligibility Criteria

• Newly diagnosed high risk patients with one of
• Stage T3/4 N0 M0 and
• PSA ? 40ng/ml or
• Gleason sum score 8-10
• Stage Tany N M0 or Tany Nany M
• Multiple sclerotic bone metastases with a PSA ?
  100ng/ml
• Previously treated relapsing patients with either
• PSA ? 4ng/ml and rising with doubling time less
  than 6 months.
• PSA ? 20ng/ml

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Inclusion Criteria (1)

• FOR ALL PATIENTS
• Intention to treat with long term hormone therapy
• Fit for all protocol treatment and follow up. WHO
  performance status 0-2.
• Have completed the appropriate pre-trial
  investigations
• Adequate haematological function neutrophil
  count gt1.5x109/l and platelets gt100x109/l

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Inclusion Criteria (2)

• FOR ALL PATIENTS
• Adequate renal function Serum creatinine lt1.5
  ULN
• Adequate liver function ALT or AST lt1.5 ULN,
  bilirubin ltULN
• Written informed consent
• Willing and expected to comply with follow-up
  schedule

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Exclusion Criteria (1)

• Prior systemic therapy for locally advanced or
  metastatic prostate cancer
• Metastatic brain disease or leptomeningeal
  disease
• Any other previous or current malignant disease
  which, in the judgement of the responsible
  physician, is likely to interfere with STAMPEDE
  treatment or assessment
• Symptomatic peripheral neuropathy ? grade 2 (NCI
  CTC)
• Any surgery (e.g. TURP) performed within the past
  4 weeks

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Exclusion Criteria (2)

• Renal insufficiency with estimated creatinine
  clearance lt30ml/min
• Patients who have been on a Cox-2-inhibitor for
  at least 6 months prior to trial entry
• Patients with confirmed cardiovascular history
  including
• a. Severe/unstable angina
• b. Myocardial infarction
• c. Severe cardiac failure (NYHA II-IV)
• d. Cerebrovascular disease (e.g. stroke or
  transient ischemic episode)
• Patients who are scheduled to have major dental
  extractions in the

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Trial Design Stages

• Stage Outcome Measures
• Primary Secondary
• Pilot Safety
  Feasibility
• Efficacy I-III Failure-free survival
  Overall survival
• 
  Toxicity
• Skeletal-related events
• Efficacy IV Overall survival
  Failure-free survival
• 
  Toxicity
• Skeletal-related events
• Quality of life

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Statistical Issues

• Randomisation ratio (ABCDEF) is to be
  211111 i.e. two control arm patients for
  every research arm patients)
• Sample Size
• Pilot Phase 210 patients
• Efficacy Stage I 115 Failure-free survival
  events
• Efficacy Stage II 225 FFS events
• Efficacy Stage III 450 FFS events
• Efficacy Stage IV 440 Deaths

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CURRENT STATUS ACCRUAL REPORT
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Current Protocol Status

• Current Protocol Version is 3.0, date 11 July 06
• Protocol amended to include details of the
  following
• 1)   Radiotherapy guidelines
• 2)   Translational studies
• 3) AA alone bicalutamide
• 4)  Osteonecrosis of the jaw

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Current Recruitment Status

• First patient randomised to feasibility phase
• 17th October 2005
• Target
• feasibility Phase target is 210 patients
• Actual
• 109 patients have been randomised
• Observed
• An average of 10 patients per month are being
  randomised
• Participation
• out of 17 accredited pilot sites, 16 have
  randomised a patient

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Recruitment Table
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Accrual Figures Per Month
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Observed Vs Expected
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Trial timelines
Oct 2005
Pilot 19 UK sites, 18 months Safety
feasibility
Spring 2007
Efficacy UK and international sites,
7yrs Failure-free survival Overall survival
Spring 2014
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Trial Management Group

• CI Nick James Oncologist Birmingham
• John Anderson Urologist Sheffield
• Noel Clarke Urologist Manchester
• David Dearnaley Oncologist Sutton
• John Dwyer Patient representative Stockport
• Philip Pollock Data Manager MRC CTU
• Malcolm Mason Oncologist Cardiff
• John Masters Pathologist London
• Rachel Morgan Statistician MRC CTU
• Rick Popert Urologist London
• Karen Sanders Trial Manager MRC CTU
• Max Parmar Statistician MRC CTU
• Marc Schulper Health Economist York
• Andrew Stanley Pharmacist Birmingham
• Jim Stansfeld Patient representative Hampshire
• Matthew Sydes Trial Statistician MRC CTU

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PATCH TRIAL Prostate Adenocarcinoma
TransCutaneous Hormone Therapy
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Trial Design
Diagnosis Locally advanced, metastatic or
relapsing prostate cancer about to start androgen
deprivation therapy
Randomise 21
Transcutaneous Oestrogen Patches
LHRH analogues
Transcutaneous Oestrogen Patches
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Background Osteoporosis in Men

• 45 of men receiving ADT for at least 2 years
  will have at least 1 fracture within 7 years
  (Krupsi et al.Cancer 2004 101)
• Morbidity, such as loss of independent living
  equal between men and women after fracture but
  mortality is higher in men. Annual cost of
  osteoporotic fracture in men in UK estimated to
  be 236 million (Pandi et al. Best Practical Best
  Clin Rheumatol 2001 15)

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PATCH Hypothesis

• Oestrogen administered in a way that avoids
  first pass hepatic metabolism could be an
  effective therapy for prostate cancer without the
  high incidence of CVS toxicity

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Background Pilot Study

• Single centre, 20 patients
• All patients tolerated the patches well
• No CVS toxicity (ischaemic heart disease, stroke,
  DVT or PE)

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Transdermal Estradiol PatchesResponse 2 x 2
patches per week
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Trial Design Outcome Measures

• Primary Endpoint
• Cardiovascular morbidity
• Secondary Endpoints
• Castrate levels of hormones, tumour control
• Toxicity-osteoporosis, hot flushes, anaemia and
  gynaecomastia
• Quality of Life

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Trial Design Eligible Patients

• Newly diagnosed-histologically confirmed
• T3/4 Nx M0 PSA gt20ng/ml, gleason gt6
• Tany N M0 or Tany Nany M
• Multiple bone metastases PSA gt 50ng/ml
• Relapsing after radical surgery or RT
• PSAgt4ng/ml doubling lt 6 months
• PSA gt20ng/ml

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Trial Design Exclusion Criteria

• No previous hormone therapy
• CVS exclusions
• -Stroke or transient ischaemic attack (TIA)
• -Deep vein thrombosis or pulmonary embolism
• -Myocardial infarction
• -Severe angina or heart failure

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Trial Design Therapy Regimens
ARM A
ARM B
LHRH Therapy
Oestrogen Patches
Given as local practice Prostap given with
short course anti-androgens indefinitely
3 patches changed twice weekly for 4 weeks Check
Testosterone 2 patches changed twice weekly
indefinitely
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START trial Standard Treatment Against
Restricted Treatment A proposed intergroup
trial
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START Trial proposal

• Randomized phase 3 intergroup trial of Standard
  Treatment Against Restricted Treatment (START)
• Good risk (PSA lt 10, Gleason lt6, T1c/T2a)
• Randomized between active surveillance with
  selective delayed intervention and definitive
  therapy (RP/Brachy/External XRT)
• Primary end point DSS
• Secondary end points OS, QOL
• Equivalence trial
• N1210-2000

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Surveillance protocol

• PSA, DRE q 3 months x 2 years, then q 6 months
• 10 core biopsy at baseline, and year 2, 5, and
  every 3 years thereafter
• Indication for intervention
• PSA DT lt 3 years (20 patients)
• Progression to predominant Gleason 4 pattern
  (5 of patients)
• Patient preference (10 patients)

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Support for START Trial

• Prioritized 1 by NCIC CTG GU group
• LOI to CTEP supported by CALGB
• Support from leadership of
• SWOG
• ECOG
• RTOG
• TROG (Trans-Tasmanian Radiation Oncology Group)
• EORTC
• NCRI UK Pilot of 5 Centres

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The Future

• New Trial Proposals Needed
• Trial Development Working Groups
• Areas of Weakness
• Over-treatment Issue
• The High Risk Localised Case Adjuvant Therapies
• Imaging Studies
• HRPC New Phase 2 Agents / Multi-Centre Phase 3
  RCTs

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