Syndax Pharma Starts Phase III Trials for Breast Cancer Drug

The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and Syndax Pharmaceuticals, Inc., announced that they have begun recruiting patients for E2112, a randomized phase III clinical trial of Syndax's entinostat in treatment of patients with advanced breast cancer.

"This trial is designed to determine whether the addition of entinostat to endocrine therapy improves progression-free survival or overall survival in patients with advanced breast cancer," said study lead investigator Roisin M. Connolly, MB, BCh, Assistant Professor of Oncology, Johns Hopkins University, Baltimore, Md. "Furthermore, E2112 is a registration trial, which if successful, could lead to FDA approval of entinostat in combination with exemestane in patients with advanced HR-positive breast cancer."

The trial will evaluate whether the addition of entinostat to endocrine therapy (exemestane) improves progression-free survival and/or overall survival in men and postmenopausal women with hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer who have previously progressed on a nonsteroidal aromatase inhibitor.

E2112 was designed and is being conducted by ECOG-ACRIN under the sponsorship of the National Cancer Institute (NCI). Syndax Pharmaceuticals, the developer of entinostat, is supporting E2112 under a Cooperative Research and Development Agreement with the NCI and a separate agreement with ECOG-ACRIN.

Entinostat, an oral synthetic benzamide derivative that acts by binding to and inhibiting class one histone deacetylase (HDAC), has been designated a Breakthrough Therapy by the Food and Drug Administration when used in combination with exemestane in hormone receptor-positive (HR+) advanced (locally advanced or metastatic) breast cancer.

Entinostat has also been investigated as part of combination therapy in patients with non-small cell lung cancer, acute myeloid leukemia and acute lymphoblastic leukemia. Exemestane (brand name Aromasin) is a steroidal aromatase inhibitor that acts through irreversible binding and inactivation of the aromatase enzyme, resulting in a reduction in circulating estrogen levels.

"ECOG-ACRIN's opening of this phase III study is an important milestone for Syndax and the development of entinostat," said Arlene M. Morris, chief executive officer of Syndax. "Together with ECOG-ACRIN and the NCI, we've designed a rigorous clinical trial capable of examining entinostat's ability to improve clinical outcomes in patients with hormone receptor-positive advanced breast cancer. Because the study is being conducted under a Special Protocol Assessment, Syndax expects that positive data from either of the two primary endpoints, progression-free survival or overall survival, will enable it to submit a New Drug Application to the FDA."

E2112 is trying to meet their goal of 600 patients, and recruitment to the trial will involve participation from the three other network groups of the NCI National Clinical Trials Network that, like ECOG-ACRIN, conduct cancer research in adults.

Aromatase inhibitors, including exemestane, are one of the most commonly prescribed initial treatments in postmenopausal patients with advanced breast cancer. Median progression-free survival in patients with HR+ advanced breast cancer who have previously progressed on a nonsteroidal aromatase inhibitor is approximately three to seven months, thus new approaches are urgently required. Therapeutic strategies that combine endocrine therapies with novel agents aim to improve outcomes for patients by overcoming drug resistance.

A potential mechanism of resistance to endocrine therapy involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of HDAC inhibitors such as entinostat. Because of the frequency of detection of epigenetic alterations in breast cancers, agents that target these changes are of great interest.

"Targeting epigenetic changes, which contribute to drug resistance and are generally thought to be reversible, represents an active area of new drug investigation," said Connolly. "A potentially promising mechanism to overcome resistance to standard therapies may lie in the use of epigenetic modifiers, such as HDAC inhibitors."

A previous phase II study, ENCORE 301, has shown that the addition of entinostat to exemestane, when compared to placebo plus exemestane, resulted in an improvement in both progression-free survival and overall survival, with an acceptable toxicity profile (Yardley J Clin Oncol 2013).
"We hope that the results of E2112 will confirm this benefit, offering a new treatment option for this patient population," said Connolly.

The E2112 trial contains secondary patient-reported outcomes (PRO) endpoints to evaluate differences between arms in treatment toxicities, reduced symptom burden as an indicator of treatment response, and overall health-related quality of life. PRO measures are common in ECOG-ACRIN therapeutic trials due to the scientific aims of its Cancer Control and Outcomes Program, which seeks to increase understanding, from the patient perspective, about how novel therapies impact quality of life.

E2112 investigators are also collaborating with the NCI to validate a new system that ascertains in real time the presence, severity, and interference of symptoms experienced by patients in the trial. The measure is called the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, or PRO-CTCAE.

"The E2112 trial continues the focus of the ECOG-ACRIN Breast Committee to join with our partners at the NCI and in industry to bring new therapies to our patients," said committee chair Kathy D. Miller, MD, Ballve Lantero Scholar in Oncology and Associate Professor, Indiana University, Bloomington, Ind. "E2112 study findings showing a positive treatment effect for entinostat would provide the rationale to evaluate it in the first-line advanced and adjuvant breast cancer settings."