A Pilot Study to Test the Feasibility and Immunologic Impact of Sipuleucel-T (Provenge) Administered With or Without Anti-PD-1 mAb (CT-011) and Low Dose Cyclophosphamide in Men With Advanced Castrate-Resistant Prostate Cancer
- 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
- 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
- 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
- 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.
- 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
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 .
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine feasibility of Provenge plus low-dose Cyclophosphamide as well as the immune efficacy of Provenge alone versus Provenge plus low-dose Cyclophosphamide and anti PD1 monoclonal antibodies (CT011) on the change in specific immune response...
Samir N. Khleif, MD
Georgia Regents University
United States: Food and Drug Administration
|Georgia Health Sciences University||Augusta, Georgia 30912|