Pharmacokinetics (PK) Drug Interaction Study of Milademetan and Itraconazole or Posaconazole in Healthy Participants

NCT03614455 | Completed Early Phase 1 FDA Drug

• 1 other identifier: DS3032-A-U107
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

This will be an open-label, randomized, 3-treatment, 2-period, 2-sequence study in healthy subjects to evaluate the single-dose PK of milademetan when given as monotherapy and when administered with steady-state levels of the strong CYP3A4 inhibitors itraconazole or posaconazole. The duration of the study for each individual subject will be approximately 49 days from the start of Screening through Study Discharge. Subjects will remain in-house for up to 23 days, including 22 overnight stays.

Conditions

Pharmacokinetics

Outcome Measures

Primary Outcomes (2)

• Maximum plasma concentration (Cmax) of milademetan

  Categories: alone (A), in sequence AB, in sequence AC

  pre-dose and then at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose

• Area under the plasma concentration-time curve extrapolated to infinity (AUCinf) of milademetan

  Categories: alone (A), in sequence AB, in sequence AC

  within 168 hours postdose

Secondary Outcomes (5)

• Time to reach maximum plasma concentration (Tmax) of milademetan

  pre-dose and then at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose

• Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t) for milademetan

  within 168 hours postdose

• Terminal elimination half-life (t½) of milademetan

  within 168 hours postdose

• Apparent total body clearance (CL/F) of milademetan

  within 168 hours postdose

• Apparent volume of distribution (Vz/F)

  within 168 hours postdose

Study Arms (3)

Milademetan alone (A)

EXPERIMENTAL

During Period 1, participants receive a single 100 mg milademetan oral dose on Study Day 1, with PK sampling to 168 hours post-dose (during the following 7-day washout period)

Drug: Milademetan

Milademetan with itraconazole (AB)

OTHER

During Period 2, participants receive itraconazole, 200 mg twice daily (BID) on Study day 8 and 200 mg once daily (QD) on Study Days 9 through 20, along with a single 100 mg milademetan dose on Day 14

Drug: Milademetan; Drug: Itraconazole

Milademetan with posaconazole (AC)

OTHER

During Period 2, participants receive 200 mg posaconazole three times daily (TID) on Study Days 8 through 20, along with a single 100 mg milademetan dose on Day 14

Drug: Milademetan; Drug: Posaconazole

Interventions

Milademetan DRUG

Milademetan 100 mg capsule for oral administration

Also known as: Experimental product, DS-3032, CYP3A4 Substrate

Milademetan alone (A); Milademetan with itraconazole (AB); Milademetan with posaconazole (AC)

Itraconazole DRUG

Itraconazole (200 mg) oral solution (20 mL of 10 mg/mL)

Also known as: CYP3A4 Inhibitor

Milademetan with itraconazole (AB)

Posaconazole DRUG

Posaconazole (200 mg) oral suspension (5 mL of 40 mg/mL)

Also known as: CYP3A4 Inhibitor

Milademetan with posaconazole (AC)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may not qualify if:

• Has negative urine test for drugs of abuse, alcohol and tobacco
• If female, is surgically sterile or postmenopausal
• If male, agrees to protocol-defined contraceptive methods
• Has adequate hematologic, hepatic, and renal function as defined by the protocol
• Is able and willing to follow all study procedures
• Has provided a signed informed consent
• Is female who is pregnant or breastfeeding
• Is unable to swallow oral medication
• Is unable to follow study procedures
• Has creatinine clearance \< 90 mL/min at screening
• Is taking or has taken any medications or therapies outside of protocol-defined parameters
• Has history of or a known allergic reaction to azole antifungal agents
• Has any disease or condition that, per protocol or in the opinion of the investigator, might affect:
• safety and well-being of the participant or offspring
• safety of study staff

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (1)

Covance Clinical Research Unit, Inc.

Dallas, Texas, 75247, United States

Location

MeSH Terms

Interventions

milademetan; Itraconazole; Cytochrome P-450 CYP3A Inhibitors; posaconazole

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Cytochrome P-450 Enzyme Inhibitors; Metabolic Side Effects of Drugs and Substances; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Prior to dosing on Day 1 of Treatment Period 1, subjects will be assigned to 1 of 2 sequences (sequences AB or AC), according to a pre-generated randomization scheme.

Study Record Dates

• First Submitted: July 30, 2018
• First Posted: August 3, 2018
• Study Start: July 13, 2018
• Primary Completion: October 1, 2018
• Study Completion: October 1, 2018
• Last Updated: February 12, 2019

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

Locations

US (1)