Phase 2 Trial of Probody-Opdivo Combo Expanding in Advanced Cancers

Phase 2 Trial of Probody-Opdivo Combo Expanding in Advanced Cancers

An ongoing Phase 1/2a trial exploring a type of engineered antibody — the anti-CTLA-4 probody BMS-986249 by CytomX Therapeutics — alone and in combination with Opdivo (nivolumab) in treating advanced solid tumors is expanding to include people with melanoma.

This randomized Phase 2 part of the study (NCT03369223) will assess if a combination of BMS-986249 and Bristol-Myers‘ Opdivo, both immune checkpoint inhibitors, is better than Opdivo alone in melanoma patients whose cancer has spread to distant sites.

Bristol-Myers is leading the trial, which is expected to enroll 375 people across sites in the U.S., Canada, Australia, and Europe.

Immune checkpoint inhibitors are molecules designed to harness the immune system’s ability to fight cancer by blocking signals used by cancer cells use to evade immune attacks. Many such inhibitors are approved to treat various cancers, including the PD-1 inhibitor Opdivo, and the CTLA-4 inhibitor Yervoy (ipilimumab).

But these antibody therapies are sometimes associated an overactive immune system across the body, which can damage tissues and cause other severe side effects.

CytomX is working to develop safer versions of these antibodies — called probodies — which are only active at cancer sites. Probodies are also monoclonal antibodies, but have a masking peptide at their binding site that is only cleaved in the presence of tumor-associated proteases —proteins that break down other proteins.

In this way, these therapies are designed to only assume their fully functional antibody activity at the tumor site and not in healthy tissues.

CytomX’s BMS-986249 is an engineered probody derived from Yervoy, which works as an inhibitor of the protein receptor CTLA-4, stimulating T-cells to remain active and destroy cancer cells.

“CTLA-4 is the prototypical checkpoint target and blocking this mechanism has proven highly effective in the treatment of melanoma and other cancer types,” Sean McCarthy, PhD, president, chief executive officer and chairman of CytomX, said in a press release. “This exciting progress within our alliance with Bristol-Myers Squibb is aimed at the development of anti-CTLA-4 therapies to broaden the reach of this foundational pathway for cancer patients.”

Preclinical results in a mouse tumor model showed that BMS-986249 has similar anti-tumor activity as Yervoy, and depletes tumors of regulatory T cells (Treg) just as well as its parental antibody. (Tregs are immunosuppressive cells, often found in tumors, that prevent the activation of anti-tumor immune cells.)

In addition to the ongoing Phase 1/2 trial — whose expansion resulted in a milestone payment of $10 million from Bristol-Myers to CytomX — Bristol-Myers is conducting a Phase 1/2a trial (NCT03994601) testing a second CytomX’s Yervoy-based probody, BMS-986288, in people with advanced solid tumors. The study is recruiting participants in the U.S. and Canada.

CytomX is also conducting a Phase 2 clinical trial (NCT03993379) testing its anti-PD-L1 probody CX-072 in combination with Yervoy for treating people with relapsed or refractory melanoma.

“This ongoing work by the Bristol-Myers Squibb team complements CytomX’s own work and continued clinical progress with the combination of our anti-PD-L1 Probody, CX-072, with ipilimumab, which will further delineate the potential of our Probody therapeutic platform to deliver differentiated anti-cancer therapies,” McCarthy said.