PK Study to Assess Drug-drug Interaction and QTc Between Sitravatinib and a Cocktail of Substrates

Study Overview
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Brief Summary
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Study 516-010 is an open-label Phase 1, drug-drug interaction and QTc study evaluating the effect of sitravatinib on probe substrates for CYP450 enzymes and BCRP and P-gp transporters.

Detailed Description
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Part 1 of this study is designed to evaluate the potential for drug-drug interactions and QTc effects with sitravatinib monotherapy when administered with probe drugs for specific cytochrome P450 (CYP) enzymes (CYP2C9, CYP2D6, and CYP3A4) and P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters Part 2 allows for patients to continue sitravatinib treatment with the addition of the checkpoint inhibitor Nivolumab.

Official Title
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A Two-cohort, Two-part, Phase 1, Multicenter, Open-label, Fixed-sequence, Drug-Drug Interaction and QTc Assessments of Sitravatinib Followed by Combination Treatment With Nivolumab in Patients With Advanced Solid Malignancies

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Sitravatinib
* Drug: Warfarin
* Drug: Dextromethorphan
* Drug: Midazolam
* Drug: Digoxin
* Drug: Rosuvastatin
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of unresectable advanced/metastatic solid tumor Life expectancy of at least 3 months Adequate bone marrow and organ function Exclusion Criteria: Ongoing medical condition or need for treatment with medication that may affect the PK of study treatments during Part 1 Immunocompromising conditions Impaired heart function Active or prior documented autoimmune disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Two Part, Phase 1 study enrolling patients with advanced tumor types into two cohorts: drug-drug interaction (DDI) and QTc. All patients receive the same anticancer treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort)<br>To evaluate the potential for drug-drug interactions (DDI) with sitravatinib monotherapy. To determine the effect of sitravatinib on the pharmacokinetics (PK) of midazolam (CYP3A4 probe substrate), warfarin (CYP2C9 probe substrate), dextromethorphan (CYP2D6 probe substrate), rosuvastatin (BCRP probe substrate), and digoxin (P-gp probe substrate). | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Warfarin<br>* CYP2C9 probe substrate<br>* Other names: Coumadin;Drug: Dextromethorphan<br>* CYP2D6 probe substrate<br>* Other names: Robitussin;Drug: Midazolam<br>* CYP3A4 probe substrate<br>* Other names: Versed;Drug: Digoxin<br>* P-gp probe substrate<br>* Other names: LANOXICAPS;Drug: Rosuvastatin<br>* BCRP probe substrate<br>* Other names: Crestor;|
| Experimental: Phase 1, Part 1: Sitravatinib monotherapy (QTc cohort)<br>To evaluate the QTc prolongation risk for sitravatinib in patients with advanced/metastatic solid tumors via C-QTc modeling. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;|
| Experimental: Phase 1, Part 2: Combination Therapy (both DDI and QTc cohorts)<br>To evaluate safety and tolerability of Sitravatinib treatment with the addition of the checkpoint inhibitor nivolumab. | Drug: Sitravatinib<br>* Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases<br>* Other names: MGCD516;Drug: Nivolumab<br>* Nivolumab is a programmed death receptor (PD-1) blocking antibody<br>* Other names: OPDIVO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters of probe drugs; AUC from time zero to the last data point (AUC-last) | (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib | Part 1; 1-20 Days | 
| PK parameters of probe drugs; AUC from time zero to infinity (AUC∞) | (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib | Part 1; 1-20 Days | 
| PK parameters of probe drugs; C-max | (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib | Part 1; 1-20 Days | 
| Adverse Events | Characterization of AEs by incidence, severity, timing, seriousness & relationship to study treatment | Through study completion, an average of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma PK parameters of sitravatinib and M10; C-max | C-max | 1-20 Days | 
| Plasma PK parameters of sitravatinib and M10; AUC over the dosing interval (AUC) | AUC over the dosing interval (AUC) | 1-20 Days | 
| Plasma PK parameters of sitravatinib and M10; trough plasma concentration (C-trough) | trough plasma concentration (C-trough) | 1-20 Days | 
| Plasma PK parameters of sitravatinib and M10; time to maximum concentration (t-max) | time to maximum concentration (t-max) | 1-20 Days | 
| Adverse Events | Safety characterized by type, incidence, severity, timing, seriousness & relationship to study treatment of adverse events, and laboratory abnormalities | 1-20 Days | 
| QT/QTc | ECG data | Part 1: Pre-dose to Day 10 (QTc cohort); Part 1: Pre-dose to Day14 (DDI cohort) |