Anti-CTLA4 Blockade Alone or Combined With Systemic GM-CSF for Prostate Cancer Immunotherapy
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
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
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.
Lawrence Fong, MD
University of California, San Francisco
United States: Food and Drug Administration
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