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

NCT04887194 | Completed Phase 1 FDA Drug

• 1 other identifier: 516-010
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 5

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.

Conditions

Advanced Solid Tumor

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (6)

• Plasma PK parameters of sitravatinib and M10; C-max

  1-20 Days

• Plasma PK parameters of sitravatinib and M10; AUC over the dosing interval (AUC)

  1-20 Days

• Plasma PK parameters of sitravatinib and M10; trough plasma concentration (C-trough)

  1-20 Days

• Plasma PK parameters of sitravatinib and M10; time to maximum concentration (t-max)

  1-20 Days

• Adverse Events

  1-20 Days

Study Arms (3)

Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort)

EXPERIMENTAL

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; Drug: Warfarin; Drug: Dextromethorphan; Drug: Midazolam; Drug: Digoxin; Drug: Rosuvastatin

Phase 1, Part 1: Sitravatinib monotherapy (QTc cohort)

EXPERIMENTAL

To evaluate the QTc prolongation risk for sitravatinib in patients with advanced/metastatic solid tumors via C-QTc modeling.

Drug: Sitravatinib

Phase 1, Part 2: Combination Therapy (both DDI and QTc cohorts)

EXPERIMENTAL

To evaluate safety and tolerability of Sitravatinib treatment with the addition of the checkpoint inhibitor nivolumab.

Drug: Sitravatinib; Drug: Nivolumab

Interventions

Sitravatinib DRUG

Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases

Also known as: MGCD516

Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort); Phase 1, Part 1: Sitravatinib monotherapy (QTc cohort); Phase 1, Part 2: Combination Therapy (both DDI and QTc cohorts)

Warfarin DRUG

CYP2C9 probe substrate

Also known as: Coumadin

Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort)

Dextromethorphan DRUG

CYP2D6 probe substrate

Also known as: Robitussin

Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort)

Midazolam DRUG

CYP3A4 probe substrate

Also known as: Versed

Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort)

Digoxin DRUG

P-gp probe substrate

Also known as: LANOXICAPS

Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort)

Rosuvastatin DRUG

BCRP probe substrate

Also known as: Crestor

Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort)

Nivolumab DRUG

Nivolumab is a programmed death receptor (PD-1) blocking antibody

Also known as: OPDIVO

Phase 1, Part 2: Combination Therapy (both DDI and QTc cohorts)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed diagnosis of unresectable advanced/metastatic solid tumor
• Life expectancy of at least 3 months
• Adequate bone marrow and organ function

You may not qualify if:

• 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

Sponsors & Collaborators

• Mirati Therapeutics Inc.: lead

Study Sites (5)

Goshen Health

Goshen, Indiana, 46526, United States

Location

NEXT Oncology

Austin, Texas, 78758, United States

Location

NEXT Oncology

San Antonio, Texas, 78229, United States

Location

NEXT Oncology

Fairfax, Virginia, 22031, United States

Location

MultiCare Health System

Tacoma, Washington, 98402, United States

Location

MeSH Terms

Interventions

sitravatinib; Warfarin; Dextromethorphan; Acetylcysteine; Midazolam; Digoxin; Rosuvastatin Calcium; Nivolumab

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Benzodiazepines; Benzazepines; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Glycosides; Carbohydrates; Sulfonamides; Amides; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Pyrimidines; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins

Study Officials

• Curtis Chin, MD

  Mirati Therapeutics Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 4, 2021
• First Posted: May 14, 2021
• Study Start: April 8, 2021
• Primary Completion: December 22, 2022
• Study Completion: December 22, 2022
• Last Updated: May 8, 2024

Record last verified: 2024-05

Locations

US (5)