Exploring New Treatment Options for Cancer Patients

Syndax is developing entinostat as a combination therapy in multiple cancer indications with an initial focus on tumors that have shown sensitivity to immunotherapy. Entinostat is an oral small molecule histone deacetylase, or HDAC inhibitor that has direct effects on both cancer cells and immune regulatory cells, potentially enhancing the body’s immune response to tumors.

Entinostat is currently being evaluated in multiple clinical trials as an immunotherapy in patients with non-small cell lung cancer, or NSCLC, melanoma, ovarian cancer and triple-negative breast cancer, or TNBC, and for use in advanced hormone-receptor positive, or HR+, breast cancer.

  • Entinostat as an Immunotherapy

    Immuno-oncology is an emerging field of cancer medicine that has focused on the development of therapeutic approaches designed to activate the immune system to find and destroy cancer cells. Many tumors have the ability to evade the immune system through direct cellular interactions and recruitment of immuno-suppressive cells to the area surrounding the tumor. One such evasion mechanism is through the expression of proteins known as checkpoint proteins, such as programmed cell death protein ligand 1, or PDL-1, on the cancer cell surface. These checkpoint proteins bind to a corresponding receptor known as programmed cell death protein 1, or PD-1, which is expressed on particular immune cells known as cytotoxic T cells. Through this binding process, cytotoxic T cells are blocked from killing cancer cells. Antibodies known as immune checkpoint inhibitors block the interaction between PD-1 and PDL-1 to restore the ability of cytotoxic T cells to kill cancer cells and have shown significant clinical benefit in treating certain cancers.

    We believe that entinostat acts on a different tumor-evasion mechanism than is targeted by most other immunotherapies in development. Instead of focusing on the interaction between the T cell and the tumor, entinostat has been observed to decrease the population of immuno-suppressive cells known as myeloid-derived suppressor cells, or MDSCs, and regulatory T cells, or Tregs, which localize in the area surrounding the tumor and block T cells from killing cancer cells.

    We believe entinostat, a Class 1-specific histone deacetylase, or HDAC, inhibitor, is the therapy most advanced in development that can directly reduce both the number and activity of MDSCs and Tregs while sparing the cytotoxic T cells. Through blocking the immuno-suppressive effects of MDSCs and Tregs, we believe entinostat has the potential to be used synergistically with therapies such as immune checkpoint inhibitors, resulting in the increased ability of the T cells to attack the tumor.

    ENCORE 601 / KEYNOTE 142

    A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in Combination With Pembrolizumab in Patients With Non-small Cell Lung Cancer, With Expansion Cohorts in Patients With Non-small Cell Lung Cancer and Melanoma. We are working in collaboration with Merck & Co. Inc., or Merck, to study the combination of entinostat with Merck’s immune checkpoint inhibitor, Keytruda® (pembrolizumab), in a Phase 1b/2 clinical trial of up to 178 patients with NSCLC or melanoma. The Phase 1b portion of the clinical trial will evaluate the safety and tolerability of the combination of entinostat and Keytruda and the Phase 2 portion of the clinical trial will assess the efficacy of entinostat combined with Keytruda in patients with either NSCLC or melanoma. Patient enrollment for the Phase 1b portion of the clinical trial was initiated in August 2015.

    ENCORE 602

    A Randomized, Placebo-controlled, Double-blind Phase 2 Study of Atezolizumab With or Without Entinostat in Patients with Metastatic Triple Negative Breast Cancer, with a Phase 1b Lead in Phase. We have established a clinical collaboration with Genentech, Inc. to study the safety and efficacy of entinostat in combination with atezolizumab, an anti-PDL-1 antibody, in patients with triple negative breast cancer, or TNBC. The ENCORE 602 clinical trial is designed as a Phase 1b/2 clinical trial, where the Phase 1b portion will initially evaluate the safety of weekly oral entinostat at a dose of 5 mg administered in combination with 1200 mg of atezolizumab given intravenously every three weeks. Assuming this combination is well tolerated, the Phase 2 portion of the clinical trial will be a randomized, double-blind, placebo-controlled trial. The primary endpoint of the Phase 2 clinical trial will be progression-free survival, or PFS, with response rate, duration of response, time to response and overall survival as secondary end points. Additional exploratory objectives include evaluation of changes in biomarkers in blood and tissue samples collected from patients that may reflect entinostat activity on immune cells. We expect that the enrollment of patients in the ENCORE 602 clinical trial will begin during the first half of 2016 with data expected from the Phase 1b portion in the second half of 2016.

    ENCORE 603

    We have established a clinical trial collaboration with Merck KGaA, Darmstadt, Germany and Pfizer Inc. to study the safety and efficacy of entinostat in combination with avelumab, an investigational anti-PDL-1 antibody, in patients with ovarian cancer. The ENCORE 603 clinical trial is designed as a Phase 1b/2 clinical trial, where the Phase 1b portion will initially evaluate the safety of weekly, oral entinostat with avelumab. If this combination is well tolerated, the Phase 2 portion of the clinical trial will be designed as a randomized, double-blind, placebo-controlled trial. The primary endpoint of the Phase 2 clinical trial will be PFS, with response rate, duration of response, time to response and overall survival as secondary end points. Additional exploratory objectives include evaluation of changes in biomarkers in blood and tissue samples collected from patients that may reflect the effect of entinostat on immune cells. We anticipate that enrollment of patients in the ENCORE 603 clinical trial will begin during the second half of 2016 with data expected from the Phase 1b portion in the first half of 2017.

    J1353

    A Randomized Phase 2 Study of Epigenetic Priming With Azacitidine and Entinostat or Oral Azacitidine Alone Prior to Nivolumab in Subjects With Recurrent Metastatic Non-Small Cell Lung Cancer. This Johns Hopkins University investigator-sponsored Phase 2 clinical trial, funded by Stand Up To Cancer, is currently enrolling up to 90 patients with metastatic NSCLC and is designed to test the ability of epigenetic therapy – a combination of entinostat and Vidaza® (azacitidine) – to enhance the response of NSCLC patients to Opdivo® (nivolumab). We expect proof-of-concept data for this trial will be available from Johns Hopkins University in the second half of 2016.

    NCI-7870

    Phase 1b/2 Study of High Dose Aldesleukin, in Combination With the Histone Deacetylase Inhibitor Entinostat in Patients With Metastatic Renal Cell Carcinoma. This investigator-sponsored Phase 1b/2 clinical trial funded by the National Cancer Institute was designed to determine the safety and efficacy of entinostat combined with Proleukin® (aldesleukin), an approved immune therapy for patients with metastatic renal cell carcinoma. Preliminary results from the completed Phase 1 portion indicated that entinostat may be given safely in combination with Proleukin and indicated that entinostat potentially enhances the response to Proleukin with evidence of causing beneficial changes in certain immune cell functions such as reduction of immune-suppressive Tregs. As of December 2015, the trial has completed enrollment with 47 patients evaluable for safety and 39 evaluable for efficacy. Preliminary results of the entinostat – Proleukin combination in these patients were presented at the American Society of Clinical Oncology – Genitourinary meeting in January 2016. The investigators concluded that the results suggest that entinostat may increase the anti-tumor activity of Proleukin by modulating immunosuppressive cells.

    NCI-9844

    A Phase 1 Study Evaluating Safety, Tolerability, and Preliminary Antitumor Activity of Entinostat and Nivolumab With or Without Ipilimumab in Advanced Solid Tumors. This investigator-sponsored Phase 1 clinical trial, which is being sponsored by the National Cancer Institute, is designed to enroll up to 39 patients to study the safety profile and best dose of entinostat and Opdivo when given together with Yervoy® (ipilmumab) in treating patients with metastatic or unresectable solid tumors or metastatic Human Epidermal Growth Factor Receptor 2 Negative, or HER2-, breast cancer. The trial is expected to begin enrolling patients in the first quarter of 2016.

  • Entinostat in HR+ Breast Cancer

    We are developing entinostat for use in advanced hormone receptor positive, or HR+, breast cancer. Following positive results from our Phase 2b clinical trial, ENCORE 301, entinostat, in combination with Aromasin® (exemestane tablets), was granted breakthrough therapy designation by the U.S. Food and Drug Administration in advanced HR+ breast cancer, an indication for which it is currently being evaluated in a Phase 3 clinical trial.

    E2112

    A Randomized Phase 3 Trial of Endocrine Therapy Plus Entinostat/Placebo in Patients With Hormone Receptor Positive Advanced Breast Cancer. Entinostat is currently being evaluated in a Phase 3 clinical trial in advanced HR+, HER2- breast cancer for which we are providing financial and operational support. Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group, or the ECOG-ACRIN Cancer Research Group, is conducting this clinical trial under sponsorship and funding support from the National Cancer Institute. The Phase 3 clinical trial is designed to determine whether the addition of entinostat to Aromasin improves progression-free survival, overall survival, or both in patients with advanced HR+, HER2- breast cancer who have previously progressed after treatment with standard-of-care hormonal agents. We believe that the submission of the results of the Phase 3 clinical trial, if successful, would be sufficient for regulatory approval of entinostat in the United States.

    ENCORE 301 (Completed)

    A Phase 2, Randomized, Double-Blind, Multicenter Study of Exemestane +/- Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic ER+ Breast Cancer, Progressing on Treatment With a Non-Steroidal AI. We have completed a Phase 2b clinical trial of entinostat in advanced HR+ breast cancer in 130 postmenopausal patients. The trial was a randomized, placebo-controlled clinical trial in which treatment with entinostat was observed to result in a significant advantage to patients when given in addition to Aromasin therapy. Postmenopausal patients with advanced HR+ breast cancer progressing on a non-steroidal aromatase inhibitor were randomly assigned to the combination of Aromasin (25 mg daily) and entinostat (5 mg once per week) or to the combination of Aromasin (25 mg daily) and a placebo. The primary endpoint was PFS, with overall survival as an exploratory endpoint. The trial met the statistical criteria for a positive PFS endpoint using a pre-specified p-value of 0.10 from a one-sided test for statistical significance. The overall survival benefit observed in the entinostat/Aromasin (EE) group was also statistically significant versus the Aromasin/placebo (EP) group.

  • Other Entinostat Clinical Trials

    NCI-8871

    Phase 1 Trastuzumab Cohort Study of Entinostat, Lapatinib and Trastuzumab in Patients With HER2-Positive Metastatic Breast Cancer in Whom Trastuzumab Has Failed.

    NCI-9253

    A Randomized Phase 2 Trial of Cytotoxic Chemotherapy With or Without Epigenetic Priming in Patients With Advanced Non-small Cell Lung Cancer.