The first patient has been dosed in a pivotal Phase 2 clinical trial in Japan evaluating entinostat as a therapy for hard-to-treat breast cancers.
Syndax Pharmaceuticals, which developed the therapy, said the trial (NCT03291886) will cover patients with advanced or recurrent hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancers. A pivotal trial is one that is intended to provide evidence for a treatment’s marketing approval. It is usually a Phase 2 or 3 trial.
Under a 2015 licensing agreement, Kyowa Hakko Kirin has exclusive rights to develop and market entinostat in Japan and Korea. So the company is conducting the trial in Japan.
Entinostat is an oral class-1 histone deacetylase inhibitor. It blocks immunosuppressive cells in tumors, including myeloid-derived suppressor cells and regulatory T-cells.
Syndax conducted a Phase 2b clinical trial before the one in Japan. It showed that a combination of entinostat and Pfizer’s approved hormone therapy Aromasin (exemestane) improved the overall survival of patients with HR+ breast cancer.
Syndax is also evaluating the combo in an ongoing Phase 3 clinical trial (NCT02115282) in the United States.
The goal of the latest Phase 2 trial is to see whether entinostat works as well in Japanese as it does in Americans. Some of the trial participants will receive entinostat plus Aromasin and others a placebo plus Aromasin. Kyowa Hakko Kirin hopes to enroll 124 patients in the study.
The primary measure of the combo’s effectiveness in the Japanese trial will be whether it increases patients’ progression-free survival, or the length of time it takes for their cancer to progress. Secondary measures will include patients’ overall survival, overall response rate, and the combo’s safety. Overall response rate is the percentage of patients who respond either fully or partially to a treatment.
Under terms of the licensing agreement, the enrollment of the first patient in Japan led to Kyowa Hakko Kirin making a $5 million milestone payment to Syndax.
“Dosing of the first patient in this pivotal trial marks another important milestone in the entinostat development program,” Dr. Briggs W. Morrison, Syndax’s chief executive officer, said in a press release.”
“We are nearing completion of enrollment of our [U.S.] Phase 3 trial, E2112, comparing entinostat plus exemestane to exemestane monotherapy in advanced HR+, HER2- breast cancer,” Morrison said. “We currently anticipate completion of enrollment in this Phase 3 trial, and release of the progression-free survival analysis” in the first half of 2018. “Through our partnership with Kyowa Hakko Kirin, we are also working to make this promising breast cancer therapy available to patients globally.”
Because entinostat may be able to block immune-suppressive cells in tumors, Syndex is also testing it in combination with FDA-approved PD-1 antagonists in a number of breast cancer.
A PD-1 antagonist prevents immune-cell suppression in cancer. An example is a Phase 1b/2 study (NCT02708680) evaluating a combination of entinostat and Genentech’s Tecentriq (atezolizumab) as a treatment for triple-negative breast cancer.