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

Sponsor

Daiichi Sankyo, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT03614455

Collaborator

(none)

Enrollment

Location

Arms

2.6

Actual Duration (Months)

13.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pharmacokinetics	Drug: Milademetan Drug: Itraconazole Drug: Posaconazole	Early Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

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.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.

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Jul 13, 2018

Actual Primary Completion Date :

Oct 1, 2018

Actual Study Completion Date :

Oct 1, 2018

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Maximum plasma concentration (Cmax) 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]
Categories: alone (A), in sequence AB, in sequence AC
Area under the plasma concentration-time curve extrapolated to infinity (AUCinf) of milademetan [within 168 hours postdose]
Categories: alone (A), in sequence AB, in sequence AC

Secondary Outcome Measures

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]
Categories: alone (A), in sequence AB, in sequence AC
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]
Categories: alone (A), in sequence AB, in sequence AC
Terminal elimination half-life (t½) of milademetan [within 168 hours postdose]
Categories: alone (A), in sequence AB, in sequence AC
Apparent total body clearance (CL/F) of milademetan [within 168 hours postdose]
Categories: alone (A), in sequence AB, in sequence AC
Apparent volume of distribution (Vz/F) [within 168 hours postdose]
Categories: alone (A), in sequence AB, in sequence AC

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance Clinical Research Unit, Inc.	Dallas	Texas	United States	75247

Sponsors and Collaborators

Daiichi Sankyo, Inc.

Investigators

Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Daiichi Sankyo, Inc.

ClinicalTrials.gov Identifier:

NCT03614455

Other Study ID Numbers:

DS3032-A-U107

First Posted:

Aug 3, 2018

Last Update Posted:

Feb 12, 2019

Last Verified:

Nov 1, 2018

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Itraconazole

Posaconazole

Cytochrome P-450 CYP3A Inhibitors

Study Results

No Results Posted as of Feb 12, 2019