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

• ClinicalTrials.gov Identifier: NCT03420742
• Recruitment Status: Completed
• First Posted: February 5, 2018
• Results First Posted: January 27, 2023
• Last Update Posted: January 27, 2023
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: January 29, 2018
• First Posted Date: February 5, 2018
• Results First Submitted Date: April 22, 2022
• Results First Posted Date: January 27, 2023
• Last Update Posted Date: January 27, 2023
• Actual Study Start Date: June 26, 2019
• Actual Primary Completion Date: March 24, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2022)

• 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).
• 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) ]

Original Primary Outcome Measures (submitted: January 29, 2018)

• Part A: AUC∞: Area Under the Plasma Concentration-Time Curve from Time 0 to Infinity (AUC∞) for Midazolam [ Time Frame: Days 1 and 21 pre-dose and at multiple time points (up to 24 hours) post-dose ]
• Part A: Cmax: Maximum Observed Plasma Concentration for Midazolam [ Time Frame: Days 1 and 21 pre-dose and at multiple time points (up to 24 hours) post-dose ]
• Part A: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Midazolam [ Time Frame: Days 1 and 21 pre-dose and at multiple time points (up to 24 hours) post-dose ]

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate, Midazolam, in Participants With ALK-Positive or ROS1-Positive Solid Tumors
• Official Title: A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK-Positive or ROS1-Positive Solid Tumors
• 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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors

Intervention

• Drug: Midazolam
  Midazolam syrup.
• Drug: Brigatinib
  Brigatinib tablets.
  Other Name: Alunbrig

Study Arms

Experimental: 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.

Interventions:

• Drug: Midazolam
• Drug: Brigatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 26, 2020): 24
• Original Estimated Enrollment (submitted: January 29, 2018): 20
• Actual Study Completion Date: April 29, 2021
• Actual Primary Completion Date: March 24, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Italy, Netherlands, Spain

Administrative Information

• NCT Number: NCT03420742
• Other Study ID Numbers: Brigatinib-1001; U1111-1203-0166 ( Other Identifier: WHO ); 2018-001624-19 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda
• Original Responsible Party: Ariad Pharmaceuticals
• Current Study Sponsor: Takeda
• Original Study Sponsor: Ariad Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: April 2022