Ipilimumab and GMCSF Immunotherapy for Prostate Cancer
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Anti-CTLA4 Blockade Alone or Combined With Systemic GM-CSF for Prostate Cancer Immunotherapy|
- To assess for clinical activity by PSA response, of both single agent ipilimumab and the combination of GM-CSF and ipilimumab in chemotherapy-naïve patients with metastatic castrate resistant prostate cancer. [ Time Frame: 12 weeks ]To assess for clinical activity by PSA (prostate-specific antigen) decline of both single agent ipilimumab in chemotherapy-naïve patients with metastatic castrate resistant prostate cancer (CRPC). The primary endpoint is the proportion of treated patients achieving a >30% decline in PSA.
- To evaluate the duration of PSA response and time to PSA progression. To quantify the frequency of immune toxicities. To evaluate T cell activation. To assess for clinical activity by objective response. [ Time Frame: 12 weeks ]
- Assessment of circulating tumor cell (CTC) frequency [ Time Frame: 12 weeks ]To assess whether either treatment can modulate the frequency of circulating tumor cells (CTC). Modulation of the frequency of circulating tumor cells (CTC) will be measured from baseline to Cycle 6/off study visit of treatment.
- Assessment of the antigen specific immune responses induced with treatment [ Time Frame: 12 weeks ]Antigen specific immune responses will be measured by immunoblotting to detect the induction of IgG antibodies and by ELISA and ELISPOT assays to detect antibody and CD4 T cell responses, respectively, against candidate antigens in prostate cancer.
|Study Start Date:||June 2015|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||December 2017 (Final data collection date for primary outcome measure)|
Experimental: Ipilimumab alone
Ipilimumab 3 mg/kg (IV) will be given every 28 days for six cycles (induction) followed by administration once every three months for patients who are not progressing (maintenance).
Ipilimumab 3 mg/kg on day 1 of a 28 day cycle for 6 cycles.
Other Name: CTLA-4 blockade
Experimental: Ipilimumab with GM-CSF
Ipilimumab 3 mg/kg (IV) will be given every 28 days for six cycles (induction) followed by administration once every three months for patients who are not progressing (maintenance). GM-CSF 250 mcg/m2 SQ will be administered on days 1-14 in Cycles 1-6 and then every 3 months for 14 days beginning on the day of ipilimumab administration during the maintenance therapy phase
Ipilimumab 3 mg/kg on day 1 of a 28 day cycle for 6 cycles.
Other Name: CTLA-4 blockadeDrug: GM-CSF
GM-CSF 250 mcg/m2 SQ on days 1-14 for 6 cycles.
Other Name: Sargramostim
Ipilimumab is an antibody (proteins that can find and destroy foreign molecules such as those on bacteria and viruses) against CTLA-4 (a molecule that controls a part of the immune system by shutting it down). It is approved by the U.S. Food and Drug Administration (FDA) to treat patients with late-stage melanoma, skin cancer. The use of ipilimumab in patients with CRPC has not been approved by the FDA.
Some patients in this study will receive GM-CSF along with ipilimumab. In clinical trials, GM-CSF has been safely given to prostate cancer patients in combination with ipilimumab. GM-CSF is not approved by the FDA for use as treatment for prostate cancer. Studies in patients with prostate cancer suggest that GM-CSF may activate the immune system. Since ipilimumab can help keep the immune system from turning off and allow an immune reaction to occur, and GM-CSF can increase the activity of the immune system, it is possible that they may work together to increase the immune response to cancer. The use of ipilimumab in combination with GM-CSF in patients with CRPC has not been approved by the FDA.
It is theorized that if antigen presentation could be improved, the immunostimulatory effects of CTLA-4 blockade could be augmented with improvements in clinical response. To that end, UCSF conducted a phase I clinical trial of ipilimumab in combination with GM-CSF, a cytokine that has been demonstrated to enhance the functional activities of effector cells, including dendritic cells (DC), neutrophils, and monocytes, in chemotherapy-naïve men with CRPC (Protocol 6032).32 Exposure to GM-CSF increases class II MHC expression on dendritic cells and is thought to lead to increased antigen presentation to T cells, stimulating T cell responses, although this mechanism has not been confirmed. We have extensively studied the effects of treatment demonstrating a dose-response relationship in the activation of CD4 and CD8 T cells. Moreover, the expansion of activated (CD25+CD69+) CD4 and CD8 T cells seen with this GM-CSF/ipilimumab combination trial was higher than that seen with GM-CSF or ipilimumab monotherapy seen in our other trials in prostate cancer patients.
We are proposing to conduct a non-comparative randomized phase II study of repetitive dosing of ipilimumab either alone or in combination with GM-CSF in patients with metastatic CRPC. The dosing interval for ipilimumab is based on the prior study which demonstrated drug levels ≥ 10 mg/mL (a minimum level required for CTLA-4 blockade in pre-clinical models) for greater than 28 days. Six doses of ipilimumab were chosen because six doses have been given safely in other trials. Maintenance dosing every three months is empirical, but this dosing frequency is based on discussions with Medarex, Inc. and Bristol-Meyers Squibb and is based on reports indicating the safety and potential efficacy of this maintenance regimen.
This study will use ipilimumab given every 28 days for six cycles (induction) followed by administration once every three months for patients who are not progressing (maintenance). A dosage of 10 mg/kg has been chosen based on the results to date of the phase I study. GM-CSF 250 mcg/m2 SQ will be administered on days 1-14 in Cycles 1-6 and then every 3 months for 14 days beginning on the day of ipilimumab administration during the maintenance therapy phase.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01530984
|United States, California|
|University of California|
|San Francisco, California, United States, 94115|
|Principal Investigator:||Lawrence Fong, MD||University of California, San Francisco|
|Study Chair:||Lawrence Fong, MD||University of California, San Francisco|