African American Men and Prostate Cancer Management Option for Clinical PROSPECT Trial Participation in an Immunotherapy Study Jennifer Harris, PharmD Medical Science Liaison Bavarian Nordic, Inc.
Prostate Cancer: Overview Overall the most common cancer in men of all races One in six American men of all races will develop prostate cancer in their lifetime One in thirty three men will die of prostate cancer The second most common cause of cancer-related death in men of all races The incidence of prostate cancer is expected to rise (aging population) Source: U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999 2009 Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2013. Available at: http://www.cdc.gov/uscs.
2012 Prostate Cancer Facts African Americans There were approximately 35,110 cases of prostate cancer among African American men in 2011, accounting for 40% of all cancers diagnosed in African American men. Between 2003-2007, the average annual prostate cancer incidence rate among African American men was 229.4 cases per 100,000 men, which was 60% higher than the incidence in white men The only well-established risk factors for prostate cancer are age, race, and family history of the disease. African American men and Jamaican men of African descent have the highest prostate cancer incidence rates worldwide. The reasons for this are not clear, but may in part reflect genetic factors that vary in populations originating in different parts of the world Source: American Cancer Society; Cancer Facts & Figures For African Americans 2011-2012
Possible Reasons for differences in stage of disease at diagnosis and mortality African American vs. White Americans Less frequent access to health care (less frequent PSA screening) Lower quality care (less treatment options) Genetic predisposition Biological factors (higher PSA levels, difference is diet) More aggressive disease due to later detection? More aggressive disease due to genetic and biology?
Tumor volume and activity Natural History of Prostate Cancer PROSTVAC-VF in pre-chemotherapy Setting of mcrpc Localized HSPC Recurrent HSPC Non-metastatic CRPC (D0.5) Metastatic CRPC Start of chemotherapy Death Hormone treatment (Androgen Ablation) Local treatment Immunotherapy Hormone dependent Non-metastatic No pain Castration-resistant Metastatic Pain ( symptomatic ) 15 20 years
What is Immunotherapy? Immunotherapy stimulates the immune system to help fight foreign invaders and other conditions including cancer. This can be accomplished by using a vaccine, antibody therapy, or non specific immunotherapies. The body's immune system reacts to antigens. Antigens are anything that causes the immune system to respond, like germs, viruses, and parasites or tumor antigens. When an antigen is found, the response of the immune system is to kill the antigen and anything it may be attached to.
Prostate Cancer A Good Target for an Immunotherapeutic Approach with a Cancer Vaccine Prostate cancer is generally slow-growing Time to generate a specific immune response Limited tolerability of chemotherapy in elderly men with prostate cancer Less use of immunosupressive chemotherapy Limited number of standard treatments for metastatic disease Unique tumor-associated antigen (PSA) to create targeted anti-tumor effect Tumor burden patient selection Treatment response
Participation in Clinical Trials African Americans Questions In general, do less African Americans participate in Clinical Trials than White Americans? Why don t more African Americans participate in clinical Trials? How can a person be sure that a clinical trial is safe? Does drug effectiveness vary across races? Response In a recent poll, only 27 percent of black American respondents were willing to participate in a clinical trial, versus 39 percent of white respondents. There is a general distrust of the medical/healthcare system amongst some African Americans, and perhaps many, based on personal experience. In addition, historical events have given African Americans reason to mistrust clinical trials. An Institutional Review Board (IRB) must approve all studies involving human or animal subjects in advance. An IRB's main responsibility is to protect the public from harm and look carefully at each study's methods to make sure the research is safe, Some drugs, like ACE inhibitors, have been shown through clinical trials to be less effective in African Americans. To be sure, there needs to be sufficient numbers of patients of all races represented in a clinical trial population.
PROSTVAC-VF
What is PROSTVAC-VF Immunotherapy? Tumor antigen gene Costimulatory molecule genes PSA Induction of tumorspecific immune responses (T-cells) Vaccines: (rv-psa-tricom) (rf-psa-tricom)
PROSTVAC-VF Therapeutic Prostate Cancer Vaccine Candidate PROSTVAC-VF is comprised of 2 component viral vectors: o A recombinant vaccinia virus (PROSTVAC-V) to prime the immune system o A recombinant fowlpox virus (PROSTVAC-F) to boost immune response PROSTVAC-VF is delivered through 7 subcutaneous injections: o One priming vaccination o Six booster vaccinations (monthly) PROSTVAC-VF is designed to induce immune responses specifically directed against prostate cancer cells
PROSTVAC-VF Randomized Phase II Study
PROSTVAC-VF Phase 2 Randomized Controlled Study Design Asymptomatic Minimally symptomatic Metastatic Castration Resistant Prostate Cancer PROSTVAC-VF + GM-CSF Empty Vector + Placebo P R O G R E S S I O N Treated at physician discretion Crossover Treated at physician discretion S U R V I V A L
PROSTVAC-VF Randomized Phase 2 Endpoints Primary endpoint: Progression-free survival at 6 months Results: No impact on short-term progression-free survival No marked impact on PSA Secondary endpoints: Overall survival, time to onset of opioid use, quality of life
PROSTVAC-VF Randomized Phase 2 Overall Survival Results Survival (% of patients) 100 80 Significantly extended overall survival N Deaths Median Control 40 37 16.6 PROSTVAC 82 65 25.1 Δ 8.5 months p=0.0061 60 25.1 Months Hazard ratio 0.56 (95% CI 0.37 0.85) 40 16.6 Months 20 0 Months 0 12 24 36 48 60 Reference: Kantoff et al., Journal of Clinical Oncology, January 2010
PROSTVAC-VF Randomized Phase 2 Common Adverse Events Well Tolerated Adverse Event (%) PROSTVAC-VF (n = 82) Control (n = 40) Injection Site Reactions Erythema 58.5 55.0 Pain 35.4 35.0 Swelling 28.0 12.5 Pruritus 20.7 10.0 Induration 12.2 15.0 General Disorders Fatigue 42.7 20.0 Pyrexia 18.3 15.0 Peripheral Edema 13.4 10.0 Chills 14.6 2.5 GI Disorders Constipation 11.0 15.0 Diarrhea 8.5 15.0 Nausea 20.7 5.0 Musculoskeletal & Connective Tissue Disorders Arthralgia 12.2 25.0 Nervous System Disorders Dizziness 12.2 7.5 Adapted from Kantoff et al., JCO 2010
PROSPECT Global Phase 3 PROSTVAC-VF Clinical Study
PROSPECT A Global Clinical Study for Metastatic Prostate Cancer Study size 1,200 patients Up to 250 sites 13 countries and counting Study duration 5 months treatment period Long Term Follow Up Principal Investigators: Lead PI: Dr. James Gulley, National Cancer Institute Co-PI: Dr. Phil Kantoff, Dana-Farber Cancer Institute
PROSPECT US sites (active)
PROSPECT Who is eligible to participate? Documented asymptomatic or minimally symptomatic mcrpc Documented bone metastases and/or lymph node metastases No other metastases No scheduled opioid narcotics for persistent cancer-related pain Have not yet received chemotherapy Life expectancy > 1 year
PROSPECT Endpoints Primary Efficacy Endpoint Overall survival Secondary Efficacy Endpoint Proportion of event-free patients at six months compared to placebo Safety Endpoints Number of adverse events compared to placebo
PROSPECT Phase 3 Clinical Study Design Non/Minimally symptomatic metastatic Castration Resistant Prostate Cancer N = 1200 (1:1:1) A PROSTVAC-VF + low dose adjuvant GM-CSF B C PROSTVAC-VF Vector Placebo Long Term Follow Up S U R V I V A L FDA-approved study design Three-arm study evaluating overall survival in two separate comparisons: The investigational vaccine plus low dose adjuvant GM-CSF (A) versus control (C) The investigational vaccine without GM-CSF (B) versus control (C)
PROSPECT PROSTVAC-VF Treatment Schedule PROSTVAC-V or Placebo PROSTVAC-F or Placebo Wk1 Wk3 Wk5 Wk9 Wk13 Wk17 Wk21 1 s.c. Prime 6 s.c. Boosts 5 mo Adjuvant GM-CSF (low-dose: 100 µg) or Placebo s.c. Day 1-4 for each administration
Participation of African Americans
PROSTVAC-VF Randomized Studies Participation of African Americans 11.5% in the PROSTVAC phase 2 trial were Black men 6% Black men in Sipuleucel-T registration trial 1 ~10% Black men currently enrolled in ongoing PROSTVAC phase 3 trial Can participation be increased? 1 Kanthoff et al., NEJM 2010
Minority Recruitment Goals Minority Recruitment Enroll African American patients up to the level of representation in the general US population (13.6%, 2010 US census) Target study centers in the areas of high African American populations (Georgia, Louisiana, North Carolina, South Carolina) Tailor advertising and recruitment tools to African American groups Enlist the help of patient advocacy groups