Food Effects on Milademetan Pharmacokinetics in Healthy Participants

Study Overview
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Brief Summary
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The primary objectives of this trial are: To evaluate the effect of a high-calorie, high-fat meal on the single-dose pharmacokinetics (PK) of milademetan To evaluate the effect of a standard meal on the single-dose PK of milademetan The key secondary objective is to evaluate the safety and tolerability of single-dose milademetan in all treatments. The duration of the study for each individual participant will be approximately 8 weeks from the start of Screening (within 28 days prior to dosing of study drug on Day 1) through the final Follow-up visit or phone call. Participants will remain in the Clinical Research Unit (CRU) from Study Day -2 through Study Day 20 (a total of 22 days and 21 nights). Participants will receive 3 single doses of study drug (at least 1 week apart) over the course of 15 days. At the investigator's discretion, participants may be asked to return to the CRU 14 days (±2 days) after final dose of study drug for a follow-up visit. The end of the study is defined as the date of final follow-up visit of the last subject undergoing the study.

Official Title
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An Open-label, Randomized, 3-period, 3-treatment Crossover Study to Evaluate the Effect of High-fat, High-calorie Food and Standard Food on the Single-dose Pharmacokinetics of Milademetan in Healthy Subjects

Conditions
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Food Effects on Pharmacokinetics

Intervention / Treatment
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* Drug: Milademetan Treatment A
* Drug: Milademetan Treatment B
* Drug: Milademetan Treatment C


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: Crossover Assignment
Interventional Model Description: Participants will be assigned to 1 of 6 treatment sequences (Sequences ABC, ACB, BAC, BCA, CAB, or CBA), according to a pre-generated randomization scheme.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence ABC<br>Participants receive milademetan in a fasted condition (A), then with a high-calorie, high-fat breakfast (B), then with a standard breakfast (C) - with a washout period between treatments. | Drug: Milademetan Treatment A<br>* Treatment A: Single oral dose of milademetan 160 mg capsules under fasted conditions<br>* Other names: Experimental product;Drug: Milademetan Treatment B<br>* Treatment B: Single oral dose of milademetan 160 mg capsules with a high-calorie, high-fat meal<br>* Other names: Experimental product;Drug: Milademetan Treatment C<br>* Treatment C: Single oral dose of milademetan 160 mg capsules with a standard meal.<br>|
| Experimental: Sequence ACB<br>Participants receive milademetan in a fasted condition (A), then with a standard breakfast (C), then with a high-calorie, high-fat breakfast (B) - with a washout period between treatments. | Drug: Milademetan Treatment A<br>* Treatment A: Single oral dose of milademetan 160 mg capsules under fasted conditions<br>* Other names: Experimental product;Drug: Milademetan Treatment B<br>* Treatment B: Single oral dose of milademetan 160 mg capsules with a high-calorie, high-fat meal<br>* Other names: Experimental product;Drug: Milademetan Treatment C<br>* Treatment C: Single oral dose of milademetan 160 mg capsules with a standard meal.<br>|
| Experimental: Sequence BAC<br>Participants receive milademetan with a high-calorie, high-fat breakfast (B), then in a fasted condition (A), then with a standard breakfast (C) - with a washout period between treatments. | Drug: Milademetan Treatment A<br>* Treatment A: Single oral dose of milademetan 160 mg capsules under fasted conditions<br>* Other names: Experimental product;Drug: Milademetan Treatment B<br>* Treatment B: Single oral dose of milademetan 160 mg capsules with a high-calorie, high-fat meal<br>* Other names: Experimental product;Drug: Milademetan Treatment C<br>* Treatment C: Single oral dose of milademetan 160 mg capsules with a standard meal.<br>|
| Experimental: Sequence BCA<br>Participants receive milademetan with a high-calorie, high-fat breakfast (B), then with a standard breakfast (C), then in a fasted condition (A) - with a washout period between treatments. | Drug: Milademetan Treatment A<br>* Treatment A: Single oral dose of milademetan 160 mg capsules under fasted conditions<br>* Other names: Experimental product;Drug: Milademetan Treatment B<br>* Treatment B: Single oral dose of milademetan 160 mg capsules with a high-calorie, high-fat meal<br>* Other names: Experimental product;Drug: Milademetan Treatment C<br>* Treatment C: Single oral dose of milademetan 160 mg capsules with a standard meal.<br>|
| Experimental: Sequence CAB<br>Participants receive milademetan with a standard breakfast (C), then in a fasted condition (A), then with a high-calorie, high-fat breakfast (B) - with a washout period between treatments. | Drug: Milademetan Treatment A<br>* Treatment A: Single oral dose of milademetan 160 mg capsules under fasted conditions<br>* Other names: Experimental product;Drug: Milademetan Treatment B<br>* Treatment B: Single oral dose of milademetan 160 mg capsules with a high-calorie, high-fat meal<br>* Other names: Experimental product;Drug: Milademetan Treatment C<br>* Treatment C: Single oral dose of milademetan 160 mg capsules with a standard meal.<br>|
| Experimental: Sequence CBA<br>Participants receive milademetan with a standard breakfast (C), then with a high-calorie, high-fat breakfast (B), then in a fasted condition (A) - with a washout period between treatments. | Drug: Milademetan Treatment A<br>* Treatment A: Single oral dose of milademetan 160 mg capsules under fasted conditions<br>* Other names: Experimental product;Drug: Milademetan Treatment B<br>* Treatment B: Single oral dose of milademetan 160 mg capsules with a high-calorie, high-fat meal<br>* Other names: Experimental product;Drug: Milademetan Treatment C<br>* Treatment C: Single oral dose of milademetan 160 mg capsules with a standard meal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of milademetan |  | predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours postdose in each treatment period | 
| Area under the plasma concentration-time curve (AUC) extrapolated to infinity (AUCinf) for milademetan |  | within 120 hours postdose in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to teach maximum plasma concentration (Tmax) of milademetan |  | within 120 hours postdose in each treatment period | 
| AUC from time 0 to the time of last measurable concentration (AUClast) for milademetan |  | within 120 hours postdose in each treatment period | 
| Lag time (tlag) for milademetan | Tlag is used to characterize the delay in absorption of orally administered drugs | within 120 hours postdose in each treatment period | 
| Terminal elimination half-life (t½) of milademetan |  | within 120 hours postdose in each treatment period | 
| Apparent total body clearance (CL/F) of milademetan clearance (CL/F), |  | within 120 hours postdose in each treatment period | 
| Apparent volume of distribution (Vz/F) of milademetan |  | within 120 hours postdose in each treatment period |