Merck & Co. and Syndax Pharmceuticals said today they have begun a clinical trial collaboration to assess the safety and efficacy of combining Syndax’s entinostat, an investigational epigenetic therapy, with Merck’s Keytruda® (pembrolizumab), which won FDA approval last September as the first programmed death receptor-1 (PD-1) inhibitor allowed for use as a drug in the U.S.

Financial terms of the collaboration, to be overseen by a Merck subsidiary, were not disclosed. The companies did say, however, that they plan to launch a Phase Ib/II study to evaluate the combination regimen in patients with either advanced non-small cell lung cancer (NSCLC) or melanoma.

The study is expected to begin enrolling patients in the second half of 2015, Merck and Syndax said. The Phase Ib/II study will be a multi-center, open-label clinical trial to be conducted in two parts: A Phase Ib portion designed to determine the safety and tolerability of entinostat in combination with Keytruda; and a Phase II portion designed to evaluate the efficacy of entinostat combined with Keytruda in patients with advanced NSCLC and melanoma.

The companies said they may extend their collaboration to include a potential Phase III clinical trial, but offered no details.

Entinostat is an oral, highly selective histone deacetylase (HDAC) inhibitor granted Breakthrough Therapy Designation by the FDA in combination with hormone therapy in advanced hormone receptor positive (HR+) breast cancer. The experimental drug is now in Phase III trials for that indication.

In preclinical models, entinostat was shown to enhance the anti-tumor activity of both anti–PD-1 antibodies such as Keytruda, and anti–CTLA-4 antibodies such as Bristol-Myers Squibb’s marketed drug Opdivo, curing more than 80% of the tumor-bearing mice. In contrast, treatment with both anti–PD-1 and anti–CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors.

Following that finding—published last year in Proceedings of the National Academy of Sciences—Syndax retreated from earlier plans for an initial public offering, with the company instead pursuing collaborations with larger pharma partners. In January, Syndax entered into an up-to-$100 million license agreement with Kyowa Hakko Kiring for the exclusive rights to develop and commercialize entinostat in Japan and South Korea (including $25 million upfront).

A humanized monoclonal antibody, Keytruda works by blocking interaction between PD-1 and its receptor ligands, PD-L1 and PD-L2 – thus increasing the immune system’s ability to fight cancer in cells that produce the pigment responsible for color in the skin. Keytruda is indicated for patients with unresectable or metastatic melanoma and disease progression following treatment with ipilimumab and, for patients who are BRAF V600 mutation positive, a BRAF inhibitor.








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