Current Prostate Cancer Clinical Trials in the Boston Area by sammyc2007

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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
   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
  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
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
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?
   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
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
            Phase III Docetaxel Studies in HRPC
              Demonstrating Survival Benefit
                                              Mitoxantrone 12 mg/m2
TAX 327                                       Prednisone 10 mg q day
                                              Q 21 days up to 10 cycles


                           Randomize
                                              Docetaxel 30 mg/m2/wk
       N=1006                                 Prednisone 10 mg q day
                                              5 on; 1 off x 6 cycles

                                              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
                           Randomize




                                              Q 21 days
      N=770
                                              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 2004:351;1502-1512; Petrylak et al. N Engl J Med 2004;351:1513-1520.
                    Overall Survival
           Petrylak et al. N Engl J Med 2004;351:1513-1520


100%                                            # at    # of    Median
                                                Risk   Deaths in Months
                                          D+E   338     217       17.5
80%                                       M+P   336     235       15.6

                                 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
60%


40%


20%


 0%
       0              12             24           36          48
                            Months
                                       Overall Survival: Tax 327
                                         Tannock et al. N Engl J Med 2004:351;1502-1512
                           1.0

                           0. 9                                                           Docetaxel 3 wkly
                                                                                          Docetaxel wkly
                           0.8
Probability of Surviving




                                                                                          Mitoxantrone
                           0.7

                           0.6

                           0.5

                           0.4                       Median
                                                     survival    Hazard
                           0.3                        (mos)       ratio        P-value
                                      Combined:       18.2           0.83      0.03
                           0.2        D 3 wkly:       18.9           0.76      0.009
                                      D wkly:         17.3           0.91       0.3
                           0.1
                                      Mitoxantrone    16.4            –          –
                           0.0
                                  0             6               12              18       24          36
                                                                      Months
        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. Anne’s 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
    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. Anne’s 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
  A PSA Vaccine/GMCSF Approach

• Vaccinia and Fowl Pox Virus engineered to
  contain PSA
• GMCSF can modulate immune responses
  and PSA by itself
GM-CSF Alone Alters PSA Kinetics in Patients
with Rising PSA After Definitive Local Therapy
           Rini et al, J Clin Oncol 21:99-105, 2003
    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
Bone is an Active Metabolic Tissue
     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
Vaccination with Antigen (GM-CSF/PAP)
Loaded Antigen Presenting Cells (APCs)
       Provenge: Dendreon Corp

          Leukapheresis                 PAP-GM-CSF
                                        “Antigen”



                            Isolation of APC



Patient              Antigen-loaded
                     APCs
                                   Sipuleucel-T Results:
                                  D9901 Overall Survival
                                                                   APC8015 (n=82)
                        100
                                                                   Placebo (n=45)
                                                                 P = 0.01 (log-rank)
     Percent Survival




                        75
                                                                      HR = 1.7
                                                               (95% CI: 1.126, 2.563)
                        50


                        25


                         0
                              0    10          20         30          40
                                        Survival (months)
Phase 3 Trial #D9901
  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
                     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.
   CALGB 90401: Phase III Trial Of
  Docetaxel/Prednisone + Bevacizumab

           R    Docetaxel/Prednisone
           A                           S
           N         + Placebo         U
           D                           R
HRPC       O                           V
           M                           I
           I                           V
           Z    Docetaxel/Prednisone   A
           E      + Bevacizumab        L



n = 1020
  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
        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 > 50
  – Death from prostate cancer: ~3.0% of men > 50
Effect of Gleason Score on Survival in
     Untreated Localized Disease
          Albertson et al. J Urol 162:439
Prognosis as a Function of Age and
 Gleason Score: Localized Disease
       Albertsen et al. JAMA 280: 975-80
        Clinical Trial Concept
  For 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
                 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
       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.Anne’s 508-675-5688

								
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