A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate, Midazolam, in Participants With ALK-Positive or ROS1-Positive Solid Tumors

Phase 1

Completed

• Conditions: Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors
• Interventions: Drug: Midazolam; Drug: Brigatinib

• Registration Number: NCT03420742
• Lead Sponsor: Takeda

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 Timeline

• Study First Submitted: 2018-01-29
• Study First Submitted QC: 2018-01-29
• Study First Posted: 2018-02-05
• Study Start: 2019-06-26
• Primary Completion: 2020-03-24
• Study Completion: 2021-04-29
• Status Verified: 2022-04
• Results First Submitted: 2022-04-22
• Results First Submitted QC: 2022-04-22
• Last Update Submitted: 2022-04-22
• Results First Posted: 2023-01-27
• Last Update Posted: 2023-01-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. 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.

2. Eastern cooperative Oncology Group (ECOG) performance status of 0 or 1.

3. Have at least 1 target lesion per response evaluation criteria in solid tumors (RECIST) version 1.1.

4. 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 (<=) 1.

5. Suitable venous access for study-required blood sampling (that is, including PK and laboratory safety tests).

Exclusion Criteria

1. Systemic treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days before enrollment.
2. Prior therapy with brigatinib.
3. Received prior ALK-inhibitor therapy within 7 days before the first dose of study drug.
4. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, before the first dose of study drug.
5. 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.
6. Received antineoplastic monoclonal antibodies within 30 days before the first dose of study drug.
7. 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.
8. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Midazolam 3 mg + Brigatinib 90 mg	Midazolam	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.
Midazolam 3 mg + Brigatinib 90 mg	Brigatinib	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.

Primary Outcome Measures

Name	Time	Method
Part A, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam	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	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	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).

Trial Locations

Locations (14)

Hopital de la Timone; 🇫🇷 Marseille, Provence Alpes COTE D'azur, France

Policlinico Sant'Orsola Malpighi; 🇮🇹 Bologna, Italy

Ospedale San Raffaele; 🇮🇹 Milano, Italy

Azienda Ospedaliero Universitaria di Parma; 🇮🇹 Parma, Italy

Ospedale Santa Maria delle Croci; 🇮🇹 Ravenna, Italy

Hospital Universitario Dexeus; 🇪🇸 Barcelona, Spain

Hospital Universitario Fundacion Jimenez Diaz; 🇪🇸 Madrid, Spain

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Universitario Ramon Y Cajal; 🇪🇸 Madrid, Spain

HM Centro Integral Oncologico Clara Campal; 🇪🇸 Madrid, Spain

Centro di Riferimento Oncologico di Aviano; 🇮🇹 Aviano, Pordenone, Italy

Netherlands Cancer Institute; 🇳🇱 Amsterdam, Noord-holland, Netherlands

Groupe Hospitalier Bichat-Claude Bernard - Hopital Bichat; 🇫🇷 Paris, Ile-de-france, France

Istituto Europeo di Oncologia; 🇮🇹 Milano, Italy