Current Prostate Cancer Clinical Trials in the Boston Area

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 TAX 327 Randomize Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles Docetaxel 30 mg/m2/wk 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 Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21 days Docetaxel 60 mg/m2 d 2 Estramustine 280 mg d1-5* Dexamethasone 20 mg, tid d 1 & 2 N=1006 SWOG 9916 N=770 Randomize *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 # at Risk 338 336 # of Median Deaths in Months 217 17.5 235 15.6 100% 80% 60% 40% 20% 0% 0 12 Months 24 D+E M+P HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 36 48 Overall Survival: Tax 327 Tannock et al. N Engl J Med 2004:351;1502-1512 1.0 0. 9 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Probability of Surviving 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 36 Combined: D 3 wkly: D wkly: Mitoxantrone Median survival (mos) 18.2 18.9 17.3 16.4 Hazard ratio 0.83 0.76 0.91 – P-value 0.03 0.009 0.3 – 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 100 Percent Survival APC8015 (n=82) Placebo (n=45) P = 0.01 (log-rank) HR = 1.7 (95% CI: 1.126, 2.563) 75 50 25 0 0 10 20 30 Survival (months) 40 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 A N D O M I Z E Docetaxel/Prednisone + Placebo HRPC Docetaxel/Prednisone + Bevacizumab S U R V I V A 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