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

An Open-label, Randomized, 2-period, 2-sequence Study to Evaluate the Single-dose Pharmacokinetics of Milademetan When Administered Alone or Concomitantly With Itraconazole or Posaconazole in Healthy Subjects

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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics
• Intervention / Treatment: Drug: Milademetan; Drug: Itraconazole; Drug: Posaconazole

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75247
      • Covance Clinical Research Unit, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Healthy participants with no clinically significant medical history or physical examination findings and who also meet all protocol-defined inclusion and exclusion criteria summarized as follows:

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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:

  1. safety and well-being of the participant or offspring
  2. safety of study staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Milademetan alone (A); 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 100 mg capsule for oral administration; Other Names: Experimental product; DS-3032; CYP3A4 Substrate
Other: Milademetan with itraconazole (AB); 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; Milademetan 100 mg capsule for oral administration; Other Names: Experimental product; DS-3032; CYP3A4 Substrate; Drug: Itraconazole; Itraconazole (200 mg) oral solution (20 mL of 10 mg/mL); Other Names: CYP3A4 Inhibitor
Other: Milademetan with posaconazole (AC); 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; Milademetan 100 mg capsule for oral administration; Other Names: Experimental product; DS-3032; CYP3A4 Substrate; Drug: Posaconazole; Posaconazole (200 mg) oral suspension (5 mL of 40 mg/mL); Other Names: CYP3A4 Inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to reach maximum plasma concentration (Tmax) 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 from time 0 to the time of last measurable concentration (AUC0-t) for milademetan	Categories: alone (A), in sequence AB, in sequence AC	within 168 hours postdose
Terminal elimination half-life (t½) of milademetan	Categories: alone (A), in sequence AB, in sequence AC	within 168 hours postdose
Apparent total body clearance (CL/F) of milademetan	Categories: alone (A), in sequence AB, in sequence AC	within 168 hours postdose
Apparent volume of distribution (Vz/F)	Categories: alone (A), in sequence AB, in sequence AC	within 168 hours postdose

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2018
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: July 30, 2018
• First Submitted That Met QC Criteria: July 30, 2018
• First Posted (Actual): August 3, 2018

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole; Itraconazole; Cytochrome P-450 CYP3A Inhibitors
• Other Study ID Numbers: DS3032-A-U107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No