Cardiac Safety Study of Entinostat in Men and Women With Advanced Solid Tumors

A Phase 1 Cardiac Safety Study of Entinostat in Men and Women With Advanced Solid Tumors

The purpose of this study is to evaluate the effect of entinostat on heart rate and other electrocardiogram (ECG) parameters. This study will also evaluate the safety and tolerability of entinostat, as well as pharmacokinetic and pharmacodynamic parameters.

Study Overview

• Status: Completed
• Conditions: Neoplasms; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Endocrine Gland Neoplasms; Breast Neoplasms; Breast Diseases; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Bronchial Neoplasms; Solid Tumors; Renal Neoplasm
• Intervention / Treatment: Drug: Entinostat; Drug: Placebo

Detailed Description

This is a single center, randomized, placebo-controlled, single dosing schedule, double-blinded study to evaluate the effect of entinostat as compared to placebo on the electrical activity of the heart in patients with advanced solid tumors. Thirty patients will be randomized in a 1:1 ratio to receive either entinostat or placebo. Study treatment will be blinded to patients and the Investigator. ECG analysts will be blinded to the patient, visit, and treatment allocation. Patients will be on study up to 30 days following study drug administration. Total study duration is expected to be 9 months. After completing this study and at the discretion of the Investigator, patients may elect to enroll into a separate continuation study (SNDX-275-0141).

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • The START Center for Cancer Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of a solid tumor malignancy that is not responsive to standard therapy(ies) or for which there is no approved therapy
• Patients must have acceptable laboratory requirements
• Left ventricular ejection fraction as measured by echocardiogram or multiple-gated acquisition scan that is above the institutional lower level of normal or greater than 50%
• Has experienced resolution of toxic effect(s) of the most recent prior chemotherapy and/or prior surgical and radiation treatment
• Must be able to understand and give written informed consent and comply with study procedures

Exclusion Criteria:

• If the patient has brain metastasis, they must have stable neurologic status without the use of steroids or on a stable or decreasing dose of steroids
• Presence of clinically significant gastrointestinal abnormalities that may affect the absorption of study treatments
• A medical condition that precludes adequate study treatment compliance or assessment, or increases patient risk in the opinion of the Investigator
• Patient has a concomitant cardiovascular issue that precludes adequate study treatment compliance or increases patient risk
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study
• Prior anti-cancer monoclonal antibody within 4 weeks prior to baseline
• Currently enrolled in another investigational study
• Has disease that is suitable for approved therapy administered with curative intent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Entinostat; Participants received a single oral supratherapeutic dose of 15 mg entinostat under fasted conditions.	Drug: Entinostat; Single, supratherapeutic dose of entinostat given orally.; Other Names: MS-275; SNDX-275
Placebo Comparator: Placebo; Participants received a single dose of placebo-matching entinostat under fasted conditions.	Drug: Placebo; Single dose of placebo-matching entinostat (containing inactive ingredients matching the appearance of the active product).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Heart Rate (HR)	Heart rate measured in beats per minute (bpm).	Baseline (pre-dose) through 24 hours post-dose
Change from Baseline in Electrocardiogram Procedures	Change from baseline in QT interval corrected for heart rate (Qtc), PR interval (PR) and QRS complex (QRS).	Baseline (pre-dose) through 24 hours post-dose
Change from Baseline in T-Cell Morphology		Baseline (pre-dose) through 24 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Treatment-emergent Adverse Events (TEAES) and Serious Adverse Events (SAEs)	An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A TEAE is an AE that occurs after the first dose of study drug. A SAE is defined as any AE that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage.	First dose through 30 days post-dose or through resolution of acute toxicities (Up to 31 days)
Number of Participants with Clinically Significant Abnormalities in Laboratory Values Reported as a TEAE	Standard safety laboratory tests included Chemistry, Hematology. Any hematologic or clinical chemistry abnormality considered by the investigator to be clinically significant was reported as a TEAE.	Baseline (pre-dose) through 14 days post-dose or 30 day safety follow-up visit (if applicable)
Change from Baseline in Vital Signs	Vital signs included temperature, pulse, blood pressure, and respiration rate	Baseline (pre-dose) through 14 days post-dose or 30 day safety follow-up visit (if applicable)
Change from Baseline in ECG Values	A 12-lead continuous ECG recording (via a Holter) was recorded on Day 1 for 25 hours. Safety ECGs were read and interpreted by the Investigator on-site for the purpose of safety monitoring and were transmitted electronically to the central ECG laboratory for clinical interpretation by a cardiologist	Baseline ()pre-dose through 14 days post-dose or 30 day safety follow-up visit (if applicable)
Change from Baseline in QTc		Pre-dose through 24 hours post-dose
Cmax (Maximum Plasma Concentration) of Entinostat when given as a Single Supratherapeutic Dose		Pre-dose and multiple time-points through 24 hours post-dose and 14 days post-dose
Tmax (Time of Maximum Plasma Concentration) of Entinostat when given as a Single Supratherapeutic Dose		Pre-dose and multiple time-points through 24 hours post-dose and 14 days post-dose
AUC0-24 (Area under the Plasma Concentration-time Curve from Time Zero to 24 hours) of Entinostat when given as a Single Supratherapeutic Dose		Pre-dose and multiple time-points through 24 hours post-dose and 14 days post-dose
AUC0-t (Area under the Plasma Concentration-time Curve from Time Zero to the Last Measurable Concentration) of Entinostat when given as a Single Supratherapeutic Dose		Pre-dose and multiple time-points through 24 hours post-dose and 14 days post-dose
AUC0-inf (Area under the Plasma Concentration-time Curve from 0-time Extrapolated to Infinity) of Entinostat when given as a Single Supratherapeutic Dose		Pre-dose and multiple time-points through 24 hours post-dose and 14 days post-dose
t1/2 (Elimination Half-life and Apparent Plasma Terminal Phase Elimination Rate Constant) of Entinostat when given as a Single Supratherapeutic Dose		Pre-dose and multiple time-points through 24 hours post-dose and 14 days post-dose
λz (Terminal Elimination Rate Constant) of Entinostat when given as a Single Supratherapeutic Dose		Pre-dose and multiple time-points through 24 hours post-dose and 14 days post-dose

Other Outcome Measures

Outcome Measure	Time Frame
Changes in Immune Regulatory Cells after a Single Dose of Entinostat, when given at a Supratherapeutic Dose, Relative to Placebo Control	Pre-dose through 14 days post-dose
Variability and Changes in Protein Lysine Acetylation in Peripheral Blood Cells after a Single Dose of Entinostat, when given at a Supratherapeutic Dose and Examine the Underlying Biological Variation	Pre-dose through 14 days post-dose

Collaborators and Investigators

• Sponsor: Syndax Pharmaceuticals
• Investigators: Study Director: Michael Meyers, MD, PhD, Syndax Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2016
• Primary Completion (Actual): March 13, 2017
• Study Completion (Actual): March 13, 2017

Study Registration Dates

• First Submitted: August 20, 2016
• First Submitted That Met QC Criteria: September 7, 2016
• First Posted (Estimate): September 13, 2016

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 21, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: solid tumor; entinostat; Histone Deacetylase Inhibitors
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Respiratory Tract Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Endocrine System Diseases; Gastrointestinal Diseases; Bronchial Diseases; Carcinoma, Bronchogenic; Neoplasms; Kidney Neoplasms; Breast Neoplasms; Lung Diseases; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Gastrointestinal Neoplasms; Digestive System Neoplasms; Breast Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Endocrine Gland Neoplasms; Thoracic Neoplasms; Bronchial Neoplasms; Respiratory Tract Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Entinostat
• Other Study ID Numbers: SNDX-275-0140

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will be reviewed throughout the study by the sponsor, Contract Research Organization (CRO) assisting with Serious Adverse Event (SAE) management, and routine monitoring to safeguard the interests of trial patients and to assess the safety of the interventions administered during the trial.