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

Study Overview
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Brief Summary
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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.

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

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: Entrectinib
* Drug: Midazolam Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet the following criteria in order to be included in the research study: 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. 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. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤1. Adequate hematologic, liver and renal function. 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: Participation in another therapeutic clinical trial within 28 days prior to start of midazolam administration. Prior treatment with entrectinib. Known hypersensitivity or intolerance to midazolam or oral formulation excipients, including allergy to cherries. 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. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 500 milliseconds from ECGs). 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). Other Protocol defined Inclusion/Exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: All patients entering this study will receive midazolam and entrectinib.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Entrectinib / Midazolam<br> | Drug: Entrectinib<br>* 600 mg oral capsule (fasted and fed)<br>Drug: Midazolam Hydrochloride<br>* 2 mg oral syrup (fasted)<br>|

What is the study measuring?
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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 |