PK Study to Assess Drug-drug Interaction Between Sitravatinib and a P-gp Inducer and an Inhibitor.

Study Overview
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Brief Summary
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A Phase 1 Open-label, Two-cohort, One-sequence Crossover Study to Investigate the Effect of P glycoprotein Inhibitor (Itraconazole) and Inducer (Rifampin) on the Pharmacokinetics, Safety, and Tolerability of Sitravatinib in Healthy Subjects.

Official Title
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A Phase 1 Open-label, Two-cohort, One-sequence Crossover Study to Investigator the Effect of P-glycoprotien Inhibitor (Itraconazole) and Inducer (Rifampin) on the Pharmacokinetics, Safety, and Tolerability of Sitravatinib in Health Subjects

Conditions
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Healthy Adults

Intervention / Treatment
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* Drug: Sitravatinib 50 mg
* Drug: Sitravatinib 100 mg
* Drug: Itraconazole
* Drug: Rifampin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Body mass index between 18.0 and 32.0 kg/m2, inclusive. In good health, determined by no clinically significant findings from medical history, physical examination, 12 lead ECG, vital sign measurements, and clinical laboratory evaluations at screening and/or check-in, as assessed by the investigator (or qualified designee). Females of childbearing potential will not be pregnant or lactating and must have a negative result on an approved pregnancy test at screening and check-in. Females of childbearing potential must agree to use contraception. Male subjects must agree to use contraception. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. Key Exclusion Criteria: Significant history of clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the investigator. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, any components of the IMP, or other substance (not including seasonal allergies), unless approved by the investigator. History of intestinal disease, inflammatory bowel disease, major gastric surgery, or other gastrointestinal conditions (eg, uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study treatment or result in inability to swallow oral medications. (Uncomplicated appendectomy and hernia repair are allowed. Cholecystectomy is not allowed.) History of Gilbert's syndrome or suspicion of Gilbert's syndrome based on elevated total and indirect bilirubin (may be confirmed by repeat). Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to study drug administration on Day 1 of Period 1.

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: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a Phase 1, single-center, open-label, 2-cohort, 1-sequence crossover study to investigate the effect of coadministration of a P glycoprotein (P-gp) inhibitor, itraconazole, (Cohort 1) and a P-gp inducer, rifampin, (Cohort 2) in healthy subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1 Treatment A<br>A single-dose administration of sitravatinib malate 50 mg on Day 1. Day 12, a single dose of sitravatinib malate 50 mg will be will be followed by a 72-hour PK sample collection period. Subjects will be discharged from the CRU on Day 4 after collection of 72-hour postdose PK sample and completion of all required study procedures. | Drug: Sitravatinib 50 mg<br>* 50 mg Sitravatinib on Day 1 (Group 1A)<br>* Other names: MGCD516;|
| Active Comparator: Group 1 Treatment B<br>On Days 9 to 11, itraconazole 200 mg will be administered QD in the morning. On Day 12, a single dose of sitravatinib malate 50 mg will be coadministered with itraconazole. Itraconazole QD dosing will continue on Days 13 to 18 to maintain steady state during the PK sample collection period. | Drug: Itraconazole<br>* Itraconazole QD from Day 9 to Day 18, and Sitravatinib 50 mg at Day 12 (Group 1B)<br>* Other names: Protonix;|
| Active Comparator: Group 2 Treatment A<br>A single-dose administration of sitravatinib malate 100 mg on Day 1 will be followed by a 72-hour PK sample collection period. Subjects will be discharged from the CRU on Day 4 after collection of 72-hour postdose PK sample and completion of all required study procedures. | Drug: Sitravatinib 100 mg<br>* 100 mg Sitravatinib on Day 1 (Group 2A)<br>* Other names: MGCD516;|
| Active Comparator: Group 2 Treatment B<br>On Days 9 to 15, rifampin 600 mg will be administered QD in the morning. On Day 16, a single dose of sitravatinib malate 100 mg will be coadministered with rifampin followed by a 72 hour PK sample collection period. Rifampin QD dosing will continue on Days 17 to 22 to maintain steady state during the PK sample collection period. | Drug: Rifampin<br>* Rifampin QD from Day 9 to Day 22, and Sitravatinib 100 mg at Day 16 (Group 2B)<br>* Other names: Pepcid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Cmax (sitravatinib) | Maximum observed plasma concentration | Up to Day 168 hours after dosing | 
| Pharmacokinetics - AUC∞ (sitravatinib) | Area under the plasma concentration-time curve from time zero extrapolated to infinity | Up to 168 hours after dosing | 
| Pharmacokinetics - AUClast (sitravatinib) | Area under the curve from time zero to the last measured time point | Up to 168 hours after dosing | 
| Pharmacokinetics - tmax (sitravatinib) | Terminal elimination half-life | Up to 168 hours after dosing | 
| Pharmacokinetics - CL/F (sitravatinib) | Apparent total plasma clearance when dosed orally | Up to 168 hours after dosing | 
| Pharmacokinetics - Vz/F (sitravatinib) | Apparent volume of distribution when dosed orally | Up to 168 hours after dosing | 
| Pharmacokinetics - uf (sitravatinib) | Unbound fraction | Up to 168 hours after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Incidence and severity of AEs | Up to 12 weeks from screening |