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

NCT03420742 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: Brigatinib-1001U1111-1203-01662018-001624-19
• Study Type: interventional
• Target: 24
• Locations: 4 countries
• Sites: 14

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.

Conditions

Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors

Keywords

Drug therapy, brigatinib, lung cancer, ALK, ROS1

Outcome Measures

Primary Outcomes (3)

• Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam

  The statistical analysis was calculated via a mixed-effects analysis of variance (ANOVA) fitting terms for treatment (midazolam with or without brigatinib coadministration).

  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, Cmax: Maximum Observed Plasma Concentration for Midazolam

  The statistical analysis was calculated via a mixed-effects ANOVA fitting terms for treatment (midazolam with or without brigatinib coadministration).

  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, 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)

Study Arms (1)

Midazolam 3 mg + Brigatinib 90 mg

EXPERIMENTAL

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.

Drug: Midazolam; Drug: Brigatinib

Interventions

Midazolam DRUG

Midazolam syrup.

Midazolam 3 mg + Brigatinib 90 mg

Brigatinib DRUG

Brigatinib tablets.

Also known as: Alunbrig

Midazolam 3 mg + Brigatinib 90 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 1.
• Have at least 1 target lesion per response evaluation criteria in solid tumors (RECIST) version 1.1.
• 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 (\<=) 1.
• Suitable venous access for study-required blood sampling (that is, including PK and laboratory safety tests).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Takeda: lead

Study Sites (14)

Hopital de la Timone

Marseille, Provence-Alpes-Côte d'Azur Region, 13005, France

Location

Groupe Hospitalier Bichat-Claude Bernard - Hopital Bichat

Paris, Île-de-France Region, 75018, France

Location

Centro di Riferimento Oncologico di Aviano

Aviano, Pordenone, 33081, Italy

Location

Policlinico Sant'Orsola Malpighi

Bologna, 40138, Italy

Location

Ospedale San Raffaele

Milan, 20132, Italy

Location

Istituto Europeo di Oncologia

Milan, 20141, Italy

Location

Azienda Ospedaliero Universitaria di Parma

Parma, 43126, Italy

Location

Ospedale Santa Maria delle Croci

Ravenna, 48121, Italy

Location

Netherlands Cancer Institute

Amsterdam, North Holland, 1066 CX, Netherlands

Location

Hospital Universitario Dexeus

Barcelona, 8028, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 8035, Spain

Location

Hospital Universitario Ramon Y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

HM Centro Integral Oncologico Clara Campal

Madrid, 28050, Spain

Location

Related Publications (1)

• Hanley MJ, D'Arcangelo M, Felip E, Garrido P, Zhu J, Ye M, Vranceanu F, Gupta N. A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK-Positive or ROS1-Positive Solid Tumors. J Clin Pharmacol. 2023 May;63(5):583-592. doi: 10.1002/jcph.2198. Epub 2023 Jan 27.

  PMID: 36579743 DERIVED

MeSH Terms

Conditions

Carcinoma; Neoplasms; Lung Neoplasms

Interventions

Midazolam; brigatinib

Condition Hierarchy (Ancestors)

Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Study Director
• Organization: Takeda

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2018
• First Posted: February 5, 2018
• Study Start: June 26, 2019
• Primary Completion: March 24, 2020
• Study Completion: April 29, 2021
• Last Updated: January 27, 2023
• Results First Posted: January 27, 2023

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

ES (5); NL (1); FR (2); IT (6)