A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK-Positive or ROS1-Positive Solid Tumors
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 24
- Locations
- 14
- Primary Endpoint
- Part A, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam
Study Overview
Brief Summary
The purpose of this study is to characterize the effect of repeat-dose administration of brigatinib 180 milligram (mg) once daily (QD) on the single-dose pharmacokinetics (PK) of midazolam.
Detailed Description
The study will enroll approximately 20 participants to achieve approximately 15 PK-evaluable participants for assessment. This study will consist of 2 parts: Part A of the study will evaluate the effect of repeat-dose administration of brigatinib on the single-dose PK of midazolam. Part B of the study is exploratory and will allow participants to continue brigatinib until disease progression (PD). All participants will receive study drug via the oral route. Participants will be assigned to: Midazolam 3 mg + Brigatinib 90 mg.
The overall time to participate in this study is 26 months. Participants will have a 28-day PK cycle in Part A and a maximum of 23 cycles in Part B, and a 30-day follow-up period after end of treatment.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Sequential
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Locally advanced or metastatic solid tumors who meet 1 of the following 4 criteria:
- •With locally advanced or metastatic ALK-positive NSCLC who have progressed on or are intolerant to treatment with at least 1 other ALK inhibitor.
- •With ALK-positive nonlung solid tumors that are locally advanced or metastatic and for whom no standard, nonexperimental therapy is available.
- •With locally advanced or metastatic ROS1-positive NSCLC who have progressed on crizotinib therapy or are intolerant to crizotinib, or
- •With ROS1-positive nonlung solid tumors that are locally advanced or metastatic and for whom no standard, nonexperimental therapy is available.
- •Eastern cooperative Oncology Group (ECOG) performance status of 0 or
- •Have at least 1 target lesion per response evaluation criteria in solid tumors (RECIST) version 1.
- •Have recovered from toxicities related to prior anticancer therapy to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 4.03 Grade less than or equal to (<=)
- •Suitable venous access for study-required blood sampling (that is, including PK and laboratory safety tests).
Exclusion Criteria
- •Systemic treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days before enrollment.
- •Prior therapy with brigatinib.
- •Received prior ALK-inhibitor therapy within 7 days before the first dose of study drug.
- •Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, before the first dose of study drug.
- •Received chemotherapy or radiation therapy within 14 days before the first dose of study drug, except for stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
- •Received antineoplastic monoclonal antibodies within 30 days before the first dose of study drug.
- •Had major surgery within 30 days before the first dose of study drug. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
- •Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.
Arms & Interventions
Midazolam 3 mg + Brigatinib 90 mg
Midazolam 3 mg, orally, once on Day 1, followed by brigatinib 90 mg, orally, once daily on Days 2 to 8, further followed by brigatinib 180 mg, orally, once daily on Days 9 to 28 in Part A Cycle 1 (28 days treatment cycle). Participants escalating to brigatinib 180 mg once daily will also receive midazolam 3 mg, orally, once on Day 21 of Part A Cycle 1. After completion of Part A, participants will continue into Part B. Participants in Part B will receive brigatinib up to 180 mg (or at the highest tolerated dose in Part A), orally, once daily in a 28 day treatment cycle, up to a maximum of 23 cycles or until progression of disease, unacceptable toxicity, or another discontinuation criterion is met.
Intervention: Midazolam (Drug)
Midazolam 3 mg + Brigatinib 90 mg
Midazolam 3 mg, orally, once on Day 1, followed by brigatinib 90 mg, orally, once daily on Days 2 to 8, further followed by brigatinib 180 mg, orally, once daily on Days 9 to 28 in Part A Cycle 1 (28 days treatment cycle). Participants escalating to brigatinib 180 mg once daily will also receive midazolam 3 mg, orally, once on Day 21 of Part A Cycle 1. After completion of Part A, participants will continue into Part B. Participants in Part B will receive brigatinib up to 180 mg (or at the highest tolerated dose in Part A), orally, once daily in a 28 day treatment cycle, up to a maximum of 23 cycles or until progression of disease, unacceptable toxicity, or another discontinuation criterion is met.
Intervention: Brigatinib (Drug)
Outcomes
Primary Outcomes
Part A, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam
Time Frame: Cycle 1, Days 1 (Midazolam alone) and 21 (Midazolam + Brigatinib): pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length is 28 days)
Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam
Time Frame: Cycle 1, Days 1 (Midazolam alone) and 21 (Midazolam + Brigatinib): pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length is 28 days)
The statistical analysis was calculated via a mixed-effects analysis of variance (ANOVA) fitting terms for treatment (midazolam with or without brigatinib coadministration).
Part A, Cmax: Maximum Observed Plasma Concentration for Midazolam
Time Frame: Cycle 1, Days 1 (Midazolam alone) and 21 (Midazolam + Brigatinib): pre-dose and at multiple timepoints (up to 24 hours) post-dose (Cycle length is 28 days)
The statistical analysis was calculated via a mixed-effects ANOVA fitting terms for treatment (midazolam with or without brigatinib coadministration).
Secondary Outcomes
No secondary outcomes reported