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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Neoplasms, Neoplasms, Glandular and Epithelial, Neoplasms by Histologic Type, Bronchial Neoplasms, Lung Neoplasms, Respiratory Tract Neoplasms, Thoracic Neoplasms, Digestive System Neoplasms, Endocrine Gland Neoplasms, Carcinoma, Non-Small-Cell Lung, Lung Diseases, Breast Neoplasms, Breast Diseases, Renal Neoplasm, Solid Tumors

Intervention / Treatment
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* Drug: Entinostat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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entinostat, solid tumor, Histone Deacetylase Inhibitors