Effect of Rifampin and Efavirenz on the Pharmacokinetics of Fedratinib in Healthy Adult Subjects

NCT03983239 | Completed Phase 1 FDA Drug

• 2 other identifiers: FEDR-CP-002U1111-1233-7946
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This is a 2-part study to evaluate the effect of multiple doses of rifampin or efavirenz on the PK, safety, and tolerability of single doses of fedratinib in healthy subjects. Each study part will consist of a nonrandomized, fixed-sequence, open-label design. The study parts can be run in any order or in parallel. Subjects may participate in one part only. For each part, subjects will participate as follows:

• Screening
• Treatment period (includes baseline)
• Follow-up telephone call (4 days \[± 2 days\] after discharge) During the study, blood samples will be collected at prespecified times for PK. Subject safety will be monitored throughout the study.

Conditions

Healthy Volunteers

Keywords

Healthy Subject; Fedratinib; Rifampin; Efavirenz; Drug Interaction

Outcome Measures

Primary Outcomes (7)

• Fedratinib Pharmacokinetic - Cmax

  Maximum observed plasma concentration

  Up to approximately 8 days.

• Fedratinib Pharmacokinetic - Tmax

  Time to maximum observed plasma concentration

  Up to approximately 8 days.

• Fedratinib Pharmacokinetic - AUC0-t

  Area under the curve from time zero to the last quantifiable concentration

  Up to approximately 8 days.

• Fedratinib Pharmacokinetic - AUC0-∞

  Area under the curve from time zero extrapolated to infinity

  Up to approximately 8 days.

• Fedratinib Pharmacokinetic - t1/2

  Terminal elimination half-life

  Up to approximately 8 days.

• Fedratinib Pharmacokinetic - CL/F

  Apparent total plasma clearance when dosed orally

  Up to approximately 8 days.

• Fedratinib Pharmacokinetic - Vz/F

  Apparent total volume of distribution when dosed orally

  Up to approximately 8 days.

Secondary Outcomes (1)

• Adverse Events (AEs)

  From enrollment until at least 30 days after completion of study treatment

Study Arms (2)

Fedratinib plus Rifampin

EXPERIMENTAL

A single dose of fedratinib on Day 1. On Days 9 through 18, once-daily (QD) doses of rifampin. On Day 17, a single dose of fedratinib will be concomitantly administered with rifampin.

Drug: Fedratinib; Drug: Rifampin; Drug: Efavirenz

Fedratinib plus Efavirenz

EXPERIMENTAL

A single dose of fedratinib on Day 1. On Days 9 through 18, once-daily (QD) doses of efavirenz. On Day 17, a single dose of fedratinib will be concomitantly administered with efavirenz.

Drug: Fedratinib; Drug: Rifampin; Drug: Efavirenz

Interventions

Fedratinib DRUG

Fedratinib

Fedratinib plus Efavirenz; Fedratinib plus Rifampin

Rifampin DRUG

Rifampin

Fedratinib plus Efavirenz; Fedratinib plus Rifampin

Efavirenz DRUG

Efavirenz

Fedratinib plus Efavirenz; Fedratinib plus Rifampin

Eligibility Criteria

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

You may qualify if:

• Subjects must satisfy the following criteria to be enrolled in the study:
• Subject must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted.
• Subject must be willing and able to communicate with the investigator and to adhere to the study visit schedule and other protocol requirements.
• Subject must be a male or female of any race from ≥ 18 and ≤ 65 years of age at the time of signing the informed Consent Form (ICF).
• Female subjects NOT of childbearing potential must:
• a. Have been surgically sterilized (hysterectomy or bilateral oophorectomy; proper documentation required) at least 6 months before Screening, or postmenopausal (defined as 24 consecutive months without menses before Screening, with a follicle-stimulating hormone \[FSH\] level in the post-menopausal range according to the laboratory used at Screening).
• Females of childbearing potential (FCBP) must:
• Have a negative pregnancy test as verified by the investigator at Screening and Baseline (prior to starting study treatment). She must agree to ongoing pregnancy testing during the course of the study, as applicable, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
• Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis, as applicable, and source documented) or agree to use, and be able to comply with, any one of the following highly effective contraception methods without interruption, beginning at least 14 days prior to starting investigational product (IP), during the study treatment, and for at least 30 days after the last dose of IP:
• Intrauterine device (IUD; non-hormonal only); tubal ligation; or a partner with a vasectomy. The chosen form of birth control must be effective by the time the subject receives the first dose of IP.
• Male subjects must:
• a. Practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis, as applicable, and source documented) or agree to use a barrier method of birth control (condoms not made from natural \[animal\] membrane \[latex condoms are recommended\]) during sexual contact with a pregnant female or FCBP while receiving study treatment, during any dose interruptions, and for at least 30 days after the last dose of IP, even if he has undergone a successful vasectomy.
• Must have a body mass index (BMI) ≥ 18 and ≤ 33 kg/m2 at screening.
• Must be healthy, as determined by the investigator on the basis of medical history, physical examination (PE), clinical laboratory test results, vital signs, and 12-lead ECG at screening and check-in (Day -1), as applicable:
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin must be at or below the upper limit of the reference range, on or before check-in (Day -1). Other clinical laboratory results must be either within normal range or deemed not clinically significant by the investigator. Any out of range lab tests may be repeated up to one time during the screening period and up to one time at check-in per Investigator discretion to confirm eligibility.

You may not qualify if:

• The presence of any of the following will exclude a subject from enrollment:
• History (ie, within 3 years) of any clinically significant neurological, GI, hepatic, renal, respiratory, cardiovascular, metabolic, endocrine, hematological, dermatological, psychological, or other major disorders as determined by the investigator.
• Any condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if he or she were to participate in the study or confounds the ability to interpret data from the study (congenital nonhemolytic hyperbilirubinemia \[eg, Gilbert's syndrome\] is not acceptable).
• Subject has prior history of Wernicke's Encephalopathy (WE).
• Subject has thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard.
• Subject has active tuberculosis or another disease caused by mycobacteria.
• Use of any prescribed systemic or topical medication, including vaccines, within 30 days of the first dose administration (with the exception of any odansetron administered for purposes of this study).
• Use of any nonprescribed systemic or topical medication (including vitamin/mineral supplements and herbal medicines) within 14 days of the first dose administration (with the exception of acetaminophen up to 2 grams/day for no more than 3 consecutive days to treat minor illness or headache \[per Investigator judgment\]).
• Exposure to an investigational drug (new chemical entity) within 30 days preceding the first dose administration or 5 half-lives of that investigational drug, if known (whichever is longer).
• Presence of any surgical or medical conditions possibly affecting drug absorption, distribution, metabolism, and excretion (eg, bariatric procedure). Appendectomy and cholecystectomy are acceptable.
• Donated blood or plasma within 8 weeks before the first dose administration.
• History of drug abuse (as defined by the current version of the Diagnostic and Statistical Manual \[DSM\]) within 2 years before dosing or positive drug screening test reflecting consumption of illicit drugs.
• History of alcohol abuse (as defined by the current version of the DSM) within 2 years before dosing or positive alcohol screen.
• Known to have serum hepatitis; known to be a carrier of the hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), or hepatitis C antibody (HCV Ab); have a positive result to the test for hepatitis B or hepatitis C virus at screening or have a positive result to the test for human immunodeficiency virus (HIV) antibodies at screening. Subjects whose results are compatible with prior immunization (including natural and vaccination) against hepatitis B may be included at the discretion of the investigator.
• Use of tobacco- or nicotine-containing products within 3 months prior to check-in.

Sponsors & Collaborators

• Celgene: lead
• Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation: collaborator

Study Sites (1)

Covance Clinical Research Unit Inc - Dallas

Dallas, Texas, 75247, United States

Location

Related Publications (1)

• Ogasawara K, Kam J, Thomas M, Liu L, Liu M, Xue Y, Surapaneni S, Carayannopoulos LN, Zhou S, Palmisano M, Krishna G. Effects of strong and moderate CYP3A4 inducers on the pharmacokinetics of fedratinib in healthy adult participants. Cancer Chemother Pharmacol. 2021 Sep;88(3):369-377. doi: 10.1007/s00280-021-04292-4. Epub 2021 May 21.

  PMID: 34019108 DERIVED

MeSH Terms

Interventions

fedratinib; Rifampin; efavirenz

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Leon Carayannopoulos, MD

  Celgene

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: June 3, 2019
• First Posted: June 12, 2019
• Study Start: June 21, 2019
• Primary Completion: November 2, 2019
• Study Completion: November 6, 2019
• Last Updated: August 21, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: See Plan Description
• Access Criteria: See Plan Description

Locations

US (1)