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

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: Sitravatinib; Drug: Warfarin; Drug: Dextromethorphan; Drug: Midazolam; Drug: Digoxin; Drug: Rosuvastatin; Drug: Nivolumab

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Goshen, Indiana, United States, 46526
      • Goshen Health
  • Texas
    • Austin, Texas, United States, 78758
      • NEXT Oncology
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • NEXT Oncology
  • Washington
    • Tacoma, Washington, United States, 98402
      • MultiCare Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Mirati Therapeutics Inc.
• Investigators: Study Director: Curtis Chin, MD, Mirati Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2021
• Primary Completion (Actual): December 22, 2022
• Study Completion (Actual): December 22, 2022

Study Registration Dates

• First Submitted: May 4, 2021
• First Submitted That Met QC Criteria: May 6, 2021
• First Posted (Actual): May 14, 2021

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Antimetabolites; Antineoplastic Agents; Protective Agents; Cardiotonic Agents; Antineoplastic Agents, Immunological; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Respiratory System Agents; Immune Checkpoint Inhibitors; Anticoagulants; Antitussive Agents; Digoxin; Midazolam; Nivolumab; Rosuvastatin Calcium; Dextromethorphan; Warfarin
• Other Study ID Numbers: 516-010

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No