A Study to Evaluate the Pharmacokinetics of Entinostat in Adult Subjects With Normal and Impaired Renal Function

NCT03192111 | Completed Phase 1 FDA Drug

• 1 other identifier: SNDX-275-0190
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 3

Brief Summary

This purpose of this study is to evaluate the effects of a single dose of entinostat on subjects with varying levels of renal impairment. The primary objective of this study is to evaluate the pharmacokinetics of a single dose of entinostat in adult subjects with mild, moderate and severe renal impairment compared to healthy mean-matched subjects. The secondary objective of this study is to evaluate the safety and tolerability of entinostat in adult subjects with mild, moderate, and severe renal impairment and in healthy mean-matched adult subjects.

Conditions

Renal Impairment; Healthy Volunteer

Keywords

Healthy Volunteers; Mild Renal Impairment; Moderate Renal Impairment; Severe Renal Impairment; Entinostat; Histone Deacetylase Inhibitor; HDAC

Outcome Measures

Primary Outcomes (3)

• To evaluate AUC0-t (area under the concentration-time curve) for entinostat in subjects with varying degrees of renal impairment versus healthy matched subjects.

  AUC0-t will be computed for all subjects

  Pre-dose through Day 22

• To evaluate AUC0-inf (area under the concentration-time curve, from time 0 to infinity) for entinostat in subjects with varying degrees of renal impairment versus healthy matched subjects.

  AUC0-inf will be computed for all subjects

  Pre-dose through Day 22

• To evaluate Cmax (maximum observed concentration) for entinostat in subjects with varying degrees of renal impairment versus healthy matched subjects.

  Cmax will be computed for all subjects

  Pre-dose through Day 22

Secondary Outcomes (1)

• Incidence of Treatment Emergent Adverse Events (safety and tolerability) of entinostat in subjects with varying degrees of renal impairment and healthy mean-matched healthy subjects

  Pre-dose to 14 days after last PK sample

Other Outcomes (6)

• To evaluate AUC%extrap (percent of AUC0-inf extrapolated) for entinostat in subjects with varying degrees of renal impairment versus healthy matched subjects.

  Pre-dose through Day 22

• To evaluate Tmax (time to reach maximum observed concentration) for entinostat in subjects with varying degrees of renal impairment versus healthy matched subjects.

  Pre-dose through Day 22

• To evaluate Kel (apparent terminal elimination rate constant) for entinostat in subjects with varying degrees of renal impairment versus healthy matched subjects.

  Pre-dose through Day 22

Study Arms (4)

Mild Renal Impairment

EXPERIMENTAL

Subjects with mild renal impairment

Drug: Entinostat

Moderate Renal Impairment

EXPERIMENTAL

Subjects with moderate renal impairment

Drug: Entinostat

Severe Renal Impairment

EXPERIMENTAL

Subjects with severe renal impairment

Drug: Entinostat

Healthy Subjects

EXPERIMENTAL

Healthy volunteers mean-matched to the mild, moderate, and severe renal impairment patients

Drug: Entinostat

Interventions

Entinostat DRUG

HDAC (histone deacetylase) inhibitor

Also known as: SNDX-275, MS-275

Healthy Subjects; Mild Renal Impairment; Moderate Renal Impairment; Severe Renal Impairment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Subjects:
• Adult male or female (of non childbearing potential only), at least 18 years of age, at screening.
• BMI ≥ 18.5 to ≤ 40.0 kg/m2, at screening.
• Subject is a non-smoker or moderate smoker (≤ 10 cigarettes/day or the equivalent). Subject must agree to consume no more than 10 cigarettes or equivalent/day from the time of screening and throughout the period of PK sample collection.
• Females must be of non childbearing potential and must have undergone one of the following sterilization procedures, and have official documentation, at least 6 months prior to dosing:
• hysteroscopic sterilization;
• bilateral tubal ligation or bilateral salpingectomy;
• hysterectomy;
• bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status as per PI or designee judgment.
• A non vasectomized, male subject must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond dosing of study drug. (No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to dosing of study drug. A male who has been vasectomized less than 4 months prior to dosing must follow the same restrictions as a non vasectomized male).
• If male, must agree not to donate sperm from dosing until 90 days after dosing of study drug.
• Understands the study procedures in the informed consent form (ICF) and be willing and able to comply with the protocol.
• Mild, Moderate, and Severe Renal Impaired Subjects:
• Baseline health is judged to be stable based on medical history, laboratory profiles, vital signs, or ECGs at screening, as deemed by the PI. Subjects with any clinical laboratory results outside normal ranges may be enrolled if deemed appropriate in the opinion of the PI.
• For subjects with mild RI only: Baseline eGFR 60 89 mL/min/1.73m2, inclusive, based on the MDRD equation at screening defined as follows:

You may not qualify if:

• All Subjects:
• Subject is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.
• History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI or designee.
• History of any illness that, in the opinion of the PI or designee, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
• History or presence of hypersensitivity or idiosyncratic reaction to the study drug or drugs with a benzamide structure (e.g., tiapride, remoxipride, clebropride), related compounds, or inactive ingredients.
• History or presence of any of the following as deemed clinically significant in the opinion of the PI or designee:
• Active cardiovascular disorders (no history of myocardial infarction within 6 months of dosing, no stents or bypass within 6 months of dosing, ≥ Class 2 congestive heart failure).
• Acute or chronic GI conditions (e.g., peptic ulcer, colitis, gastric bypass or equivalent) that would interfere with drug tolerance or absorption; subjects with cholecystectomy or uncomplicated gallbladder for over 1 year of dosing would be allowed.
• Clinically significant infection within 1 month prior to dosing as determined by the PI or designee.
• Female subjects of childbearing potential, pregnant or lactating subjects.
• Positive results for the urine/saliva drug screen or for the urine/breath alcohol screen at screening or check-in unless the positive drug screen is due to prescription drug use and is approved by the PI and Sponsor.
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
• Unable to refrain from or anticipates the use of:
• Any drug known to be metabolized by CYP1A2 or CYP2C8, or to be a strong or moderate inhibitor of P gp or breast cancer resistance protein (BCRP) for 14 days prior to dosing and throughout the study. Use of weak inhibitors may be deemed acceptable following consultation with the Sponsor Medical Monitor and the PI. Appropriate sources will be consulted by the PI or designee to confirm lack of PK/pharmacodynamic interaction with study drug.
• Any medication or substance (including prescription or over-the-counter, including herbal products, natural or herbal supplements) which cannot be discontinued at least 14 days prior to dosing and throughout the study. Subjects who are taking medications for stable diseases for at least \~2 weeks for subjects with severe RI or \~1 month for mild and moderate renal impaired subjects (or 5 half-lives of the compound, whichever is longer) prior to dosing will be allowed to participate in the study at the discretion of the PI and following consultation with the Sponsor Medical Monitor. See Section 10.4.2 for additional details on allowable and prohibited concomitant therapy.

Sponsors & Collaborators

• Syndax Pharmaceuticals: lead

Study Sites (3)

Clinical Pharmacology of Miami

Miami, Florida, 33014, United States

Location

Orlando Clinical Research Center

Orlando, Florida, 32809, United States

Location

New Orleans Center for Clinical Research

Knoxville, Tennessee, 37920, United States

Location

MeSH Terms

Conditions

Renal Insufficiency

Interventions

entinostat

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2017
• First Posted: June 19, 2017
• Study Start: July 27, 2017
• Primary Completion: November 23, 2017
• Study Completion: November 23, 2017
• Last Updated: April 13, 2018

Record last verified: 2018-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)