Clinical trial NCT01420965
Conditions: Prostatic Neoplasms
Keywords: Anti PD-1 Monoclonal Antibody Vaccine Autologous Cellular Immunotherapy Prostate Cancer
Sponsor: Augusta University
Start date: 2012-09-01; Completion date: 2016-12-01
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Sipuleucel-T is a new treatment for advanced stage prostate cancer. It takes cells from a person with prostate cancer and treats them in the laboratory. Then it returns the cells to the person to help the immune system fight the cancer. Sipuleucel-T may be combined with the drug CT-011 to boost its ability to kill cancer cells. The chemotherapy drug cyclophosphamide will also be given, either before or after the cells are collected at the start of the treatment.

Objectives:

\- To test the effectiveness of Sipuleucel-T, CT-011, and cyclophosphamide for prostate cancer.

Eligibility:

\- Men at least 18 years of age who have advanced prostate cancer.

Design:

* Participants will be screened with a medical history, physical exam, blood and urine tests, and imaging studies.
* This study has two parts, with different participants in each part. All participants will be monitored with frequent blood tests and imaging studies.
* Part I:
* Participants will provide cells for the Sipuleucel-T treatment three times. The first time will be 3 days before the chemotherapy. The second time will be 10 days after chemotherapy. The third time will be 24 days after chemotherapy.
* Participants will have one dose of cyclophosphamide the day before the first dose of Sipuleucel-T.
* Participants will have Sipuleucel-T about 3 days after each cell donation.
* Part II:
* Participants will be in three groups: Sipuleucel-T given alone, given with CT-011, or given with both cyclophosphamide and CT-011.
* Participants will provide cells for the Sipuleucel-T treatment three times, as in Part I.
* Participants will have Sipuleucel-T about 3 days after each cell donation, and will receive treatment with the other drugs as directed by the study doctors.

Detailed description:
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 .

Arms: arm 1: Sipuleucel-T autologous active cellular immunotherapy only for 3 cycles (cycle = 14 days) arm 2: Sipuleucel-T for 3 cycles (cycle = 14 days) + CT-011 (3mg/kg) IV infusion delivered over approximately 2 hours, 2 days after each Sipuleucel-T infusion arm 3: Sipuleucel-T for 3 cycles (cycle = 14 days)+ cyclophosphamide (125 or 250mg/m2) IV \[first cycle only\] + CT-011 (3mg/kg) IV infusion delivered over approximately 2 hours, 2 days after each Sipuleucel-T infusion
Interventions: intervention 1: CT-011 (Anti-PD1 Antibody) intervention 2: Sipuleucel-T (Provenge) intervention 3: Cyclophosphamide
Intervention descriptions: intervention 1: Immune Enhancer intervention 2: Vaccine intervention 3: Low dose- Immune Enhancer

Protocol documents: