Background:
* Prostate cancer is the most common cancer and the second leading cause of cancer deaths among males in most Western countries.
* Sipuleucel-T, a recently FDA approved treatment for prostate cancer, is designed to induce an immune response targeted against PAP, an antigen expressed in most prostate cancers. .
* Blockade of PD-1/PD-L1 has been shown to enhance the therapeutic efficacy of peptide cancer vaccines in pre-clinical animal models. CT-011 is a humanized IgG1 kappa recombinant monoclonal antibody against PD-1 receptor that blocks the interaction of PD-L1 with PD-1.
* Preclinical studies demonstrated that CT-011 when administered with low dose cyclophosphamide led to synergistic antitumor effects when combined with HPV16 E749-57 peptide vaccine.
* Given the role CT-011 plays in down-regulating peripheral tolerance and the synergistic relationship it has with cyclophosphamide in doing so, in this study we propose to treat patients with advanced, castrate-resistant disease with CT-011 and low-dose cyclophosphamide as adjuvants in combination with Provenge(Trademark) activated cell vaccine.
Objectives:
* To assess the feasibility of administration of Sipuleucel-T (Provenge(Trademark)) autologous active cellular immunotherapy in combination with low dose cyclophosphamide in men with advanced castrate-resistant (hormone refractory) prostate cancer.
* To determine the immune efficacy of Sipuleucel-T (Provenge(Trademark)) autologous active cellular immunotherapy alone vs. Sipuleucel-T (Provenge(Trademark)) in combination with CT- 011 vs. Sipuleucel-T (Provenge(Trademark)) in combination with low-dose cyclophosphamide and CT-011 on the change in PA2024-specific IFN-? ELISPOT responses in men with advanced, castrate-resistant prostate cancer.
* Secondary objectives will determine the tolerability and toxicities of the combination of low-dose cyclophosphamide/CT-011/ Sipuleucel-T (Provenge(Trademark)) and determine in a preliminary fashion whether this regimen correlates with increased progression-free survival (PFS) and overall survival (OS) in patients and with growth rate in an exploratory fashion.
Eligibility:
* Males greater than or equal to 18 years old with chemotherapy na ve metastatic progressive castrate-resistant prostate cancer defined as progressive disease (two consecutively rising PSA values at a minimum of 1-week intervals (2.0 ng/mL is the minimum starting value for PSA), appearance of one or more new lesions on bone scans, progressive disease by Recist 1.1).
* Must meet minimum organ safety requirements and length of time since prior therapy.
* May not have active infections, autoimmune disease or require immunosuppressive therapies.
Design:
Part 1: Initially the feasibility generating Sipuleucel-T after administration of low dose cyclophosphamide , and will be evaluated using a standard 3 + 3 design for doses of cyclophosphamide 250 mg/m2 or 125 mg/m2. Initially 3 patients will receive cyclophosphamide on day -1 of the first cycle (one day prior to the first infusion of Sipuleucel-T). All patients will receive Sipuleucel-T cell infusion on Day 0. The Sipuleucel-T cell infusion will be repeated every two weeks for a total of three cycles. If Sipuleucel-T active cellular immunotherapy from an apheresis obtained after infusion of cyclophosphamide, which meets the FDA approved Certificate of Analysis (COA) release criteria from Dendreon, cannot be generated, a second apheresis will be performed. Failure of two attempts to generate Sipuleucel-T product after two aphereses at either the 2nd or 3rd scheduled Sipuleucel-T infusion will be considered failure of one patient to meet release criteria .
