Evaluate the Effect of Entrectinib on the Pharmacokinetics of Midazolam in Cancer Patients

A Phase 1 Study to Evaluate the Potential Pharmacokinetic Interaction Between Entrectinib and Midazolam in Cancer Patients

This is an open-label study in advanced solid tumor patients to determine if entrectinib affects the pharmacokinetics of midazolam and any of its pharmacologically active metabolites.

Study Overview

• Status: Completed
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: Entrectinib; Drug: Midazolam Hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • SCRI-Denver Drug Development Program
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists - Sarasota (North Catttlemen Rd)
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Patients must meet the following criteria in order to be included in the research study:

1. Histologically or cytologically confirmed diagnosis of advanced or metastatic solid tumors that are not responsive to standard therapies or for which there is no effective therapy.
2. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of midazolam administration.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤1.
4. Adequate hematologic, liver and renal function.
5. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

1. Participation in another therapeutic clinical trial within 28 days prior to start of midazolam administration.
2. Prior treatment with entrectinib.
3. Known hypersensitivity or intolerance to midazolam or oral formulation excipients, including allergy to cherries.
4. Any condition (in the past 3 months) that may interfere with the conduct of study assessments or may interfere with the interpretation of study results.
5. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs).
6. Known active infections that may interfere with the conduct of study assessments or may interfere with the interpretation of study results (bacterial, fungal, or viral, including human immunodeficiency virus positive).
7. Other Protocol defined Inclusion/Exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Entrectinib / Midazolam	Drug: Entrectinib; 600 mg oral capsule (fasted and fed); Drug: Midazolam Hydrochloride; 2 mg oral syrup (fasted)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUClast	Area under the concentration-time curve from 0 to the last measurable concentration of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.	4 weeks
AUCinf	Area under the concentration-time curve from 0 to infinity of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.	4 weeks
Cmax	Peak plasma concentration of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.	4 weeks
Tmax	Time of maximum concentration of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.	4 weeks
t1/2	Terminal half-life of midazolam and the pharmacologically active metabolite 1-hydoxymidazolam in the absence or presence of entrectinib.	4 weeks

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2017
• Primary Completion (Actual): July 11, 2018
• Study Completion (Actual): July 11, 2018

Study Registration Dates

• First Submitted: October 27, 2017
• First Submitted That Met QC Criteria: October 31, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Actual): August 21, 2018
• Last Update Submitted That Met QC Criteria: August 17, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Protein Kinase Inhibitors; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Entrectinib
• Other Study ID Numbers: RXDX-101-14; GO40785 (Other Identifier: Hoffman-La Roche)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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