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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04887194
Recruitment Status : Active, not recruiting
First Posted : May 14, 2021
Last Update Posted : October 10, 2022
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Drug: Sitravatinib Drug: Warfarin Drug: Dextromethorphan Drug: Midazolam Drug: Digoxin Drug: Rosuvastatin Drug: Nivolumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 26, 2021
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


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 Name: MGCD516

Drug: Warfarin
CYP2C9 probe substrate
Other Name: Coumadin

Drug: Dextromethorphan
CYP2D6 probe substrate
Other Name: Robitussin

Drug: Midazolam
CYP3A4 probe substrate
Other Name: Versed

Drug: Digoxin
P-gp probe substrate
Other Name: LANOXICAPS

Drug: Rosuvastatin
BCRP probe substrate
Other Name: 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 Name: 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 Name: MGCD516

Drug: Nivolumab
Nivolumab is a programmed death receptor (PD-1) blocking antibody
Other Name: OPDIVO




Primary Outcome Measures :
  1. PK parameters of probe drugs; AUC from time zero to the last data point (AUC-last) [ Time Frame: 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

  2. PK parameters of probe drugs; AUC from time zero to infinity (AUC∞) [ Time Frame: 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

  3. PK parameters of probe drugs; C-max [ Time Frame: 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

  4. Adverse Events [ Time Frame: Through study completion, an average of 12 months ]
    Characterization of AEs by incidence, severity, timing, seriousness & relationship to study treatment


Secondary Outcome Measures :
  1. Plasma PK parameters of sitravatinib and M10; C-max [ Time Frame: 1-20 Days ]
    C-max

  2. Plasma PK parameters of sitravatinib and M10; AUC over the dosing interval (AUC) [ Time Frame: 1-20 Days ]
    AUC over the dosing interval (AUC)

  3. Plasma PK parameters of sitravatinib and M10; trough plasma concentration (C-trough) [ Time Frame: 1-20 Days ]
    trough plasma concentration (C-trough)

  4. Plasma PK parameters of sitravatinib and M10; time to maximum concentration (t-max) [ Time Frame: 1-20 Days ]
    time to maximum concentration (t-max)

  5. Adverse Events [ Time Frame: 1-20 Days ]
    Safety characterized by type, incidence, severity, timing, seriousness & relationship to study treatment of adverse events, and laboratory abnormalities

  6. QT/QTc [ Time Frame: Part 1: Pre-dose to Day 10 (QTc cohort); Part 1: Pre-dose to Day14 (DDI cohort) ]
    ECG data



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04887194


Locations
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United States, Indiana
Goshen Health
Goshen, Indiana, United States, 46526
United States, Texas
NEXT Oncology
Austin, Texas, United States, 78758
NEXT Oncology
San Antonio, Texas, United States, 78229
United States, Virginia
NEXT Oncology
Fairfax, Virginia, United States, 22031
United States, Washington
MultiCare Health System
Tacoma, Washington, United States, 98402
Sponsors and Collaborators
Mirati Therapeutics Inc.
Investigators
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Study Director: Curtis Chin, MD Mirati Therapeutics Inc.
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Responsible Party: Mirati Therapeutics Inc.
ClinicalTrials.gov Identifier: NCT04887194    
Other Study ID Numbers: 516-010
First Posted: May 14, 2021    Key Record Dates
Last Update Posted: October 10, 2022
Last Verified: October 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Nivolumab
Digoxin
Midazolam
Dextromethorphan
Warfarin
Rosuvastatin Calcium
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Anticoagulants