Prostate Cancer
Conditions
Keywords
GVAX, Ipilimumab, prostate cancer
Brief summary
Ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4, and GVAX have demonstrated anti-tumor activity in prostate cancer. Pre-clinical studies with this combination have demonstrated potent synergy. The purpose of this study is to investigate, using a phase-I 3+3 dose escalation design followed by an expansion cohort, the safety and efficacy of combined treatment with GVAX and ipilimumab in castration-resistant metastatic prostate cancer (CRPC) patients.
Detailed description
A promising immunotherapeutic approach in prostate cancer is whole-cell vaccination. Irradiated allogeneic tumor cells expressing GM-CSF generate a long-lasting and specific anti-tumor immunity in preclinical models. Results from several phase I and II trials showed Prostate GVAX (GVAX) to be well tolerated and suggested improved survival. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a crucial immune checkpoint molecule that down-regulates T-cell activation and proliferation. Ipilimumab, a fully human monoclonal antibody (IgG1) that blocks CTLA-4, promotes antitumor immunity, and has been demonstrated in two phase III trials to improve overall survival in metastatic melanoma patients. Pre-clinical studies of the anti-CTLA-4 antibody in combination with GM-CSF secreting tumor cell vaccines demonstrated a potent synergy. In this phase I study the investigators examine in CRPC patients whether ipilimumab can be safely combined with GVAX. In addition, the investigators will treat an additional 16 patients at a dose level of 3•0 mg/kg to determine the safety profile and antitumor effects of GVAX and ipilimumab in patients with CRPC.
Interventions
DRUGGVAX and ipilimumab
All patients receive a 500 million cell priming dose of granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells (GVAX) intradermally on day 1 followed by bi-weekly intradermal injections of 300 million cells for a 24 week period. The vaccinations are combined with monthly intravenous administrations of ipilimumab. The dose-escalation part of this study will be performed using the standard 3+3 phase-I trial design. Patients will be enrolled in cohorts of three; each cohort will receive an escalating dose of ipilimumab at 0•3, 1•0, 3•0 or 5•0 mg/kg. Sixteen patients will be treated in an expansion cohort with GVAX and 3•0 mg/kg ipilimumab.
Sponsors
Cell Genesys
Medarex
Amsterdam UMC, location VUmc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Males age 18-80 years * Histologic diagnosis of adenocarcinoma of the prostate * Metastatic prostate cancer deemed to be unresponsive or refractory to hormone therapy * Detectable metastases by bone scan, CT scan or MRI * Two consecutive rising PSA values obtained at least two weeks apart and both obtained at least 4-6 weeks after discontinuation of hormone therapy. Second PSA value must be \> 5.0 ng/mL. LHRH agonist should not be discontinued. * Testosterone \< 50 ng/dL. Must have had orchiectomy or is currently receiving an LHRH agonist. * WBC \> 3.0 x 109/L, ANC \> 1.5 x 109/L, hemoglobin \> 6.2 mmol/L, and platelets \> 100 x 109/L * Serum creatinine \< 177 umol/L Bilirubin \< 1.5 times the upper limit of normal AST \< 3 times the upper limit of normal * ECOG performance status 0-2 * Life expectancy of at least 6 months * If sexually active, willing to use barrier contraception during the treatment phase of the protocol * The ability to understand and willingness to sign a written informed consent
Exclusion criteria
* Transitional cell, small cell, neuroendocrine, or squamous cell prostate cancer * Bone pain severe enough to require routine narcotic analgesia use * Clinical evidence of brain metastases or history of brain metastases * Seropositive for HIV, Hepatitis B antigen positive and/or Hepatitis C viremic * Prior chemotherapy or immunotherapy for prostate cancer * Radiation therapy within 4 weeks of the first treatment * Surgery within 4 weeks of the first treatment. Must have recovered from all side effects. * Flutamide within 4 weeks of the first treatment Megesterol acetate (Megace), finasteride (Proscar), bicalutamide (Casodex),nilutamide, aminoglutethimide, ketoconazole or diethylstilbestrol within 6 weeks of the first treatment. * Systemic corticosteroid use within 4 weeks of the first treatment * History of autoimmune disease * History of another malignancy, except for the following: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, adequately treated Stage I or II cancer currently in complete remission or any other cancer that has been in complete remission for at least 5 years
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of patients with adverse events | 7 months |
Secondary
| Measure | Time frame |
|---|---|
| number of patients that have a tumor/PSA response | 7 months |
| number of patients that will develop a tumor-specific (e.g. PSMA, NY-ESO) antibody response as measured by ELISA | 7 months |
| the number of patients that have activated T cells and dendritic cells as measured by FACS | 7 months |
Countries
Netherlands
Outcome results
None listed