Vaccine and Antibody Treatment of Prostate Cancer
Condition: Prostatic Neoplasms
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will evaluate the side effects of a fixed dose of vaccine and GM-CSF with
      increasing doses of anti-CTLA-4 antibody in patients with advanced prostate cancer. The
      vaccine consists of a "priming vaccine" called PROSTVAC/TRICOM, made from vaccinia virus, and
      a "boosting vaccine" called PROSTVAC-F/TRICOM, made from fowlpox virus. GM-CSF is a chemical
      that boosts the immune system, and anti-CTLA-4 antibody is a protein that may improve
      anti-tumor activity and the response to the vaccines. DNA is inserted into the priming and
      boosting vaccine viruses to cause production of proteins that enhance immune activity and
      also to produce prostate specific antigen (PSA)-a protein that is normally produced by the
      patient's tumor cells.

      Patients 18 years of age and older with androgen-insensitive prostate cancer that has spread
      beyond the original site may be eligible for this 7-month study. Candidates must have disease
      that has worsened despite treatments with hormones and up to one chemotherapy regimen. Their
      tumor must produce PSA, and they must have no history of allergy to eggs or egg products
      Candidates are screened with a medical history and physical examination, blood and urine
      tests, electrocardiogram, pathological confirmation of the diagnosis and presence of the PSA
      marker, chest x-rays, imaging studies to assess the extent of tumor, and, if clinically
      indicated, a cardiologic evaluation.

      Participants receive the priming vaccination on study day 1. After 2 weeks and then again
      every 4 weeks while on the study, they receive a boosting vaccine. All vaccines are injected
      under the skin. On the day of each vaccination and daily for the next 3 days, patients
      receive an injection of GM-CSF to increase the number of immune cells at the vaccination
      site. On the day of the first six boosting vaccinations, they receive anti-CTLA-4 antibody as
      an infusion through a vein over 90 minutes.

      Patients are monitored for safety and treatment response with the following tests and
      procedures:

        -  Blood and urine tests monthly, or more often if needed, to monitor liver, kidney, and
           other organ function.

        -  Imaging studies to assess the tumor before starting treatment, again around study days
           99 and 183, and then every 3 months after that while on study.

        -  Apheresis (a procedure for collecting immune cells called lymphocytes) to measure the
           immune response to treatment. Apheresis is done three times: before starting the study
           and again around study days 99 and 183. For this procedure, blood is collected through a
           needle in an arm vein. The blood circulates through a machine that separates it into its
           components by spinning, and the lymphocytes are extracted. The rest of the blood is
           returned to the patient through the same needle. This will only be done in participants
           who have the tissue marker HLA-A2 (about 50% of patients).

      Patients whose disease responds to treatment and who do not develop severe side effects may
      continue treatment beyond the initial 7-month study period on vaccine alone (without the
      antibody). After treatment is completed, patients are monitored for up to 15 years. This
      includes a medical history and physical examination for 5 years following the last
      vaccination. Information beyond 5 years is collected once a year by telephone.
    

Detailed description: 
      Background:

        -  Adenocarcinoma of the prostate is the most common cancer diagnosis in American males,
           and the second leading cause of cancer death.

        -  The proposed vaccine strategy represents a third-generation design that elicits a T-cell
           immune response to cells expressing PSA and has been shown to break tolerance to this
           self-antigen, and cause objective response and PSA declines in patients with metastatic
           AIPC.

        -  This strategy also utilizes an antibody to CTLA-4 that may block the normal signals to
           down regulate the immune response following active vaccination.

        -  Anti CTLA-4 antibodies have been associated with autoimmune events that are generally
           manageable and have been associated with clinical response.

      Objectives:

        -  To determine the safety and tolerability of a combination of a fixed dose of vaccine and
           anti-CTLA4, which will be dose escalated.

        -  To evaluate immunologic response (as measured by an increase in PSA specific T-cells
           measured by ELISPOT in HLA-A2+ patients), and clinical response (as measured by RECIST
           and PSA consensus criteria).

      Eligibility:

        -  Must have metastatic androgen insensitive prostate cancer with no bone pain requiring
           narcotics and have had no more prior chemotherapy.

        -  Life expectancy greater than or equal to 6 months. ECOG 0-1

        -  Should have no autoimmune diseases; no evidence of being immunocompromised; no serious
           intercurrent medical illness; no cardiac disease; no prior splenectomy.

        -  No prior treatment with MDX-010 (Ipilimumab).

        -  No brain metastasis, history of seizures, encephalitis, or multiple sclerosis.

        -  No serious hypersensitivity reaction to egg products.

      Design:

        -  This is an open label, phase I safety trial with sequential cohorts of patients all
           receiving a fixed dose of PSA-TRICOM vaccines and sargramostim, with dose escalation of
           MDX-010 (Ipilimumab).

        -  PROSTVAC -V/TRICOM (vaccinia) 2 x 10(8) pfu subcutaneously will be administered as the
           initial priming vaccine on day 1 of cycle 1 only.

        -  PROSTVAC -F/TRICOM (fowlpox) 1 x 10(9) pfu subcutaneously starting on day 15 followed by
           monthly boosting vaccination. Sargramostim 100 mcg per day will be administered
           subcutaneously at the vaccination site on days 1-4 of each vaccine cycle (prime and
           boost).

        -  MDX-010 (Ipilimumab) will be administered, as per the assigned dose level, as a
           90-minute intravenous infusion on the same day as the monthly boosting vaccinations with
           PROSTVAC-F/TRICOM (fowlpox). After 6 courses of MDX-010, patients may receive
           Maintenance dose of MDX-010 every 3 months until there is evidence of disease
           progression or toxicity, for up to an additional 12 months (equivalent to 4 additional
           MDX-010 courses).

        -  Monthly boosting vaccinations with PROSTVAC-F/TRICOM (fowlpox) and sargramostim may then
           continue until patients meet off study criteria.
    

Intervention name(s): PROSTVAC-V/TRICOM; PROSTVAC-F/TRICOM; MDX-010; Sargramostim
Intervention type(s): Biological; Biological; Drug; Drug
Intervention MeSH terms: Metronidazole; Ipilimumab; Sargramostim
Primary purpose: Treatment
Keywords: Monoclonal Antibody; Vaccine; Cytokines; Immunotherapy; Elispot Assay; Prostate Cancer; Metastatic Prostate Cancer