Pembrolizumab Combination Study Planned in Prostate Cancer

Advaxis and Merck have entered into a clinical trial collaboration agreement to evaluate the combination of two novel immunotherapies for the treatment of patients with metastatic castration-resistant prostate cancer. Advaxis's Listeria monocytogenes (Lm)-LLO cancer immunotherapy, ADXS-PSA, will be looked at as a single agent and in combination with Merck’s anti-PD-1 humanized antibody pembrolizumab (MK-3475) in the phase I/II collaborative study.

ADXS-PSA has been designed to secrete PSA fused with the immunostimulant LLO inside of antigen-presenting cells, eliciting an immune response. This agent is also constructed to inhibit Treg and MDSC cells, which are thought to add to the immunologic tolerance of prostate cancer.

The study is planned to begin in early 2015. The phase I portion of the trial will aim to establish an appropriate dose regimen for ADXS-PSA alone and in combination with pembrolizumab. As with a standard dose escalation study, Advaxis and Merck hope to enroll about 20-50 patients in this trial, David Mauro, MD, PhD, executive director of Oncology at Merck Research Laboratories, said in an interview. The phase II portion will evaluate the safety and efficacy of the combination.

Robert Petit, PhD, chief scientific officer at Advaxis, said in an interview that pembrolizumab has demonstrated efficacy in many cancers but that it is generally a non-specific inhibitor of immune tolerance. The hope with this combination, Petit said, is to combine the specific targeting of ADXS-PSA to the ability of pembrolizumab to overcome a mechanism of immunologic tolerance.

“Together, not only can we provide the way to take the shield away from the cancer but we can also provide a new crop of soldiers to go after it,” Petit said.

Advaxis will fund the study, Merck will provide pembrolizumab, and the two companies will collaborate to oversee the conduct of the study. The estimated cost of the study was not disclosed.

This will be the first study of pembrolizumab specifically for the treatment of prostate cancer. ADXS-PSA was explored in xenograft models in combination with radiotherapy in 2012.

In the 2012 study, mice with PSA-expressing TPSA23 tumors, a preclinical model of prostate cancer, were treated with ADXS-PSA, radiotherapy, or the combination of the two treatments. The combination showed complete regression of tumors in 60% of mice compared with ≤10% for mice receiving either therapy alone. In subjects that completely regressed following treatment with the combination, tumors did not develop upon rechallenge with tumor cells, suggesting systemic and protective immune memory.

If the combination of ADXS-PSA and pembrolizumab proves to be safe and elicits some PSA or tumor responses, “the companies would look to expand this study and broaden it into a larger population of patients,” Mauro said. “In terms of where it goes beyond that, it’s too preliminary.”

By the end of 2014, Merck anticipates that pembrolizumab will be evaluated in more than 24 clinical trials. The agent is being looked at in more than 30 types of cancer including bladder, colorectal, gastric, head and neck, melanoma, non-small and small cell lung, renal, pancreatic, prostate, triple negative and estrogen-receptor positive HER2-negative breast, gynecologic, and hematologic malignancies. In April 2013, pembrolizumab received a breakthrough therapy designation from the FDA for the treatment of patients with advanced melanoma previously treated with ipilimumab.

Advaxis is also developing ADXS-HPV for cervical, head and neck, and anal cancers, and ADXS-cHER2 for pediatric osteosarcoma.