PK Study to Assess Drug-drug Interaction and QTc Between Sitravatinib and a Cocktail of Substrates
- Conditions
- Advanced Solid Tumor
- Interventions
- Registration Number
- NCT04887194
- Lead Sponsor
- Mirati Therapeutics Inc.
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
- Confirmed diagnosis of unresectable advanced/metastatic solid tumor
- Life expectancy of at least 3 months
- Adequate bone marrow and organ function
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort) Sitravatinib 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). Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort) Warfarin 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). Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort) Dextromethorphan 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). Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort) Midazolam 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). Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort) Digoxin 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). Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort) Rosuvastatin 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). Phase 1, Part 1: Sitravatinib monotherapy (QTc cohort) Sitravatinib To evaluate the QTc prolongation risk for sitravatinib in patients with advanced/metastatic solid tumors via C-QTc modeling. Phase 1, Part 2: Combination Therapy (both DDI and QTc cohorts) Sitravatinib To evaluate safety and tolerability of Sitravatinib treatment with the addition of the checkpoint inhibitor nivolumab. Phase 1, Part 2: Combination Therapy (both DDI and QTc cohorts) Nivolumab To evaluate safety and tolerability of Sitravatinib treatment with the addition of the checkpoint inhibitor nivolumab.
- Primary Outcome Measures
Name Time Method PK parameters of probe drugs; AUC from time zero to the last data point (AUC-last) Part 1; 1-20 Days (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib
PK parameters of probe drugs; AUC from time zero to infinity (AUC∞) Part 1; 1-20 Days (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib
PK parameters of probe drugs; C-max Part 1; 1-20 Days (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib
Adverse Events Through study completion, an average of 12 months Characterization of AEs by incidence, severity, timing, seriousness \& relationship to study treatment
- Secondary Outcome Measures
Name Time Method Plasma PK parameters of sitravatinib and M10; C-max 1-20 Days C-max
Plasma PK parameters of sitravatinib and M10; AUC over the dosing interval (AUC) 1-20 Days AUC over the dosing interval (AUC)
Plasma PK parameters of sitravatinib and M10; trough plasma concentration (C-trough) 1-20 Days trough plasma concentration (C-trough)
Plasma PK parameters of sitravatinib and M10; time to maximum concentration (t-max) 1-20 Days time to maximum concentration (t-max)
Adverse Events 1-20 Days Safety characterized by type, incidence, severity, timing, seriousness \& relationship to study treatment of adverse events, and laboratory abnormalities
QT/QTc Part 1: Pre-dose to Day 10 (QTc cohort); Part 1: Pre-dose to Day14 (DDI cohort) ECG data
Trial Locations
- Locations (3)
Goshen Health
🇺🇸Goshen, Indiana, United States
MultiCare Health System
🇺🇸Tacoma, Washington, United States
NEXT Oncology
🇺🇸Fairfax, Virginia, United States