Current Prostate Cancer Clinical Trials in the Boston Area

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Current Prostate Cancer Clinical Trials in the
Boston Area

• Oliver Sartor, M.D.
• Lank Center for Genitourinary Oncology
• Dana Farber Cancer Institute
• Harvard Medical School

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How do we know what we think we know?

• Studies performed in test tubes are nearly
  worthless in predicting human benefit
• Studies in animal models of cancer rarely predict
  efficacy in humans with disease
• Observational studies (epidemiologic studies)
  have many potential uncontrolled biases

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How do we know what we think we know?

• Clinical anecdotes are interesting but often
  impossible to replicate in larger populations
• Retrospective studies can be helpful but may
  contain biases, incomplete followup, and changes
  over time
• Prospective clinical trials with defined entry
  criteria and defined end points allow the best
  and most reliable conclusions to be drawn

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Who Benefits from Clinical Trials?

• Patients
• Expedited access to new agents and access to
  research nurses/staff (often wonderful people!)
• Physicians/Universities
• Academic advancement via authorship and
  presentations at symposia and meetings
• Financial support from clinical trial contracts
  and (possibly) consulting
• Sponsors
• Data from trials may support an FDA approval, or
  expanded use, thereby enhancing profitability

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What do Patients Risk in Clinical Trials?

• Lack of efficacy for promising agents
• Most drugs fail in clinical trials
• Unsuspected toxicities for new agents
• Delays in potentially effective treatments, if
  trials are substituted for efficacious
  alternatives
• More intensive testing than standard care, which
  means more time and possibly more expense
• Randomization to standard therapies instead of
  promising agents
• Is the standard really standard?

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What is risked in clinical trials?

• Physician/Institution
• Authorship often goes to a select group of
  investigators many contributors are not
  recognized by authorship
• IRBs and regulatory issues can take immense
  efforts that add costs which are often not
  reimbursed
• Separating insurance costs from trial-sponsored
  costs can be logistically difficult yet improper
  cost allocations can lead to potential fraud
• Investigators spend additional time and effort
  discussing trials and informed consents with
  patients interfere with busy practices and
  schedules
• Poor outcomes may mean loss of credibility

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What is risked in clinical trials

• Sponsor
• Unexpected toxicity can bring severe financial
  consequences (Merck-Vioxx debacle)
• Larger trials and longer followup means larger
  financial risks
• Lack of efficacy, particularly in late stage
  trials, can mean financial losses and poor
  returns on invested capital
• Wasted time, effort, and expense is a part of
  every failed trial and a stigma is attached to
  those who implement such an effort

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Phase III Docetaxel Studies in HRPC Demonstrating
Survival Benefit
Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
TAX 327
Randomize
Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5
on 1 off x 6 cycles
N1006
Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21
days up to 10 cycles
SWOG 9916
Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21
days
Randomize
N770
Docetaxel 60 mg/m2 d 2 Estramustine 280 mg
d1-5 Dexamethasone 20 mg, tid d 1 2
Warfarin and aspirin
Tannock et al. N Engl J Med 20043511502-1512
Petrylak et al. N Engl J Med 20043511513-1520.
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Overall Survival Petrylak et al. N Engl J Med
20043511513-1520
at Risk
of Deaths
Median
in Months
DE
338
217
17.5
MP
336
235
15.6
HR 0.80 (95 CI 0.67, 0.97), p 0.01
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Overall Survival Tax 327 Tannock et al. N Engl
J Med 20043511502-1512
1.0
Docetaxel 3 wkly
0. 9
Docetaxel wkly
0.8
Mitoxantrone
0.7
0.6
Probability of Surviving
0.5
Median survival Hazard
(mos) ratio P-value Combined 18.2 0.83 0.03
D 3 wkly 18.9 0.76 0.009 D wkly
17.3 0.91 0.3 Mitoxantrone 16.4
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
36
Months
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Clinical Trial 1 (05-043)For Intermediate and
High Risk Disease Radiation Hormones /-
Chemotherapy

• Why is this important?
• Better understand if we can improve survival for
  intermediate and high risk patients
• Clinical trial now accruing
• DFCI, BWH, St. Annes in Fall River
• What are the treatments?
• Everyone gets radiation hormones for 6 months
• Randomized (50) patients get docetaxel
  chemotherapy both before and during radiation

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Clinical Trial 2 (RTOG 0521)For High Risk
Disease Radiation Hormones /- Chemotherapy

• Why is this important?
• Better understand if we can improve survival for
  high risk patients
• Clinical trial now accruing
• MGH, St. Annes in Fall River, NSMC in Peabody,
  South Surburban Oncology Center in Quincy
• What are the treatments?
• Everyone gets radiation hormones for 2 years
• 50 of patients get docetaxel chemotherapy after
  radiation is complete

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A PSA Vaccine/GMCSF Approach

• Vaccinia and Fowl Pox Virus engineered to contain
  PSA
• GMCSF can modulate immune responses and PSA by
  itself

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GM-CSF Alone Alters PSA Kinetics in Patients with
Rising PSA After Definitive Local TherapyRini et
al, J Clin Oncol 2199-105, 2003
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Clinical Trial 3 (ECOG 9802)For PSA Recurrence
after Initial Surgery/Radiation Novel
Vaccine/GMCSF

• Why is this important?
• Better understand if PSA kinetics are affected by
  a novel vaccine therapy for patients with PSA
  recurrence after initial radiation or surgery
• Clinical trial now accruing at BIDMC
• What are the treatments?
• Everyone gets novel vaccine GMCSF

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Bone is an Active Metabolic Tissue



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Clinical Trial 4 (06-022) Progressive
Non-Metastatic Prostate Cancer Despite Hormonal
Therapy Denusomab or Placebo

• Why is this important?
• Tests whether or not a new antibody that alters
  bone metabolism can delay the onset of bone
  metastases in prostate cancer which is
  progressing despite hormonal treatment
• Where is it open?
• MGH
• What is the Treatment
• Denusomab, an antibody that alters bone
  metabolism and strengthens bone, or placebo

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Vaccination with Antigen (GM-CSF/PAP) Loaded
Antigen Presenting Cells (APCs)Provenge
Dendreon Corp
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Sipuleucel-T Results D9901 Overall Survival
Phase 3 Trial D9901
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Clinical Trial 5 (Dendreon 9902B) For
Asymptomatic or Minimally Symptomatic Patients
with Progressive Prostate Cancer Despite Hormonal
Therapy A Novel Cancer Vaccine

• Why is this important?
• Tests whether or not a novel cancer vaccine can
  prolong survival
• Where is it open?
• Lahey (soon at BIDMC, DFCI)
• What is the treatment?
• Novel Vaccine or placebo that requires extraction
  of normal cells from the blood stream of all
  patients

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Angiogenesis
Angiogenesis development of new blood vessels
from existing vasculature Central Hypothesis -
any increase in tumor size must be preceded by an
increase in tumor vasculature. This increase in
tumor vasculature is stimulated by the tumor.
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CALGB 90401 Phase III Trial Of
Docetaxel/Prednisone Bevacizumab
R A N D O M I Z E
Docetaxel/Prednisone Placebo
SURV I VAL
HRPC
Docetaxel/Prednisone Bevacizumab
n 1020
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Clinical Trial 6 (CALGB 90401)Docetaxel /-
Bevacizumab for Progressive Metastatic Prostate
Cancer Despite Hormonal Therapy

• Why is this important?
• Tests whether or not an anti-angiogenesis
  antibody can prolong survival in prostate cancer
• Where is it open?
• 13 sites in the Boston area
• What is the Treatment
• Docetaxel /- Bevacizumab (Avastin), an antibody
  that inhibits new blood vessel formation

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Prostate Cancer Basic Statistics

• What you find depends on how, when, where, and
  how hard you look
• United States
• Autopsy prostate cancer 50 of men over 50
• Clinical prostate cancer 17 of men gt 50
• Death from prostate cancer 3.0 of men gt 50

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Effect of Gleason Score on Survival in Untreated
Localized DiseaseAlbertson et al. J Urol 162439
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Prognosis as a Function of Age and Gleason Score
Localized DiseaseAlbertsen et al. JAMA 280
975-80
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Clinical Trial ConceptFor Low Risk Disease
Surveillance

• Why is this important?
• Better understand who progresses and who does not
  so that unnecessary treatments can be minimized
• Now in the design phase at DFCI
• Who will be eligible?
• Gleason 6 or less, PSA 10 or less, low clinical
  stage disease
• Patients are followed with PSA, molecular
  studies, DRE, MRI, and re-biopsies to better
  understand and define progression

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Summary

• Boston area residents have an extraordinary group
  of talented investigators in prostate cancer at
  multiple treatment locations
• Understand the standard treatments for your
  disease and consider a clinical trial if the
  risk/benefit ratio is appropriate in your
  particular case

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Selected Phone Numbers

• Lahey Clinic 781-744-8027  
• UMASS 508-856-0011
• Dana-Farber 617-582-8480
• BIDMC 617-667-9925
• MGH 877-726-5130
• St.Annes 508-675-5688