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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pharmacokinetics

Intervention / Treatment
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* Drug: Milademetan
* Drug: Itraconazole
* Drug: Posaconazole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 |