Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid TumorsPhase 1NCT03420742

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

A Phase 1 study testing Midazolam and Brigatinib in people with Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors, run by Takeda at 14 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors
What is being tested?: Midazolam and Brigatinib
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 24 participants
Where: 14 sitesin 4 countries
Study dates: 26 Jun 2019to 29 Apr 2021
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

Show all 9Show fewer

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).

Who cannot join

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.

Trial locations and contacts

14 sites in 4 countries.

Country

City, postcode or hospital

14 sites in 4 countries

Italy6 sites

Centro di Riferimento Oncologico di Aviano
Aviano, Pordenone, 33081
Policlinico Sant'Orsola Malpighi
Bologna, 40138
Ospedale San Raffaele
Milan, 20132
Istituto Europeo di Oncologia
Milan, 20141
Azienda Ospedaliero Universitaria di Parma
Parma, 43126
Ospedale Santa Maria delle Croci
Ravenna, 48121

Other trials in Italy

Spain5 sites

Hospital Universitario Dexeus
Barcelona, 8028
Hospital Universitari Vall d'Hebron
Barcelona, 8035
Hospital Universitario Ramon Y Cajal
Madrid, 28034
Hospital Universitario Fundacion Jimenez Diaz
Madrid, 28040
HM Centro Integral Oncologico Clara Campal
Madrid, 28050

Other trials in Spain

France2 sites

Hopital de la Timone
Marseille, Provence-Alpes-Côte d'Azur Region, 13005
Groupe Hospitalier Bichat-Claude Bernard - Hopital Bichat
Paris, Île-de-France Region, 75018

Other trials in France

Netherlands1 site

Netherlands Cancer Institute
Amsterdam, North Holland, 1066 CX

Other trials in Netherlands

About this study

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

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.

Read the 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.

Conditions: Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors
Being tested: Midazolam, Brigatinib
Keywords: Drug therapy, brigatinib, lung cancer, ALK, ROS1
Medical subject headings: Carcinoma, Neoplasms, Lung Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MidazolamDrug
Midazolam syrup.
BrigatinibDrug
Also called Alunbrig
Brigatinib tablets.

Study groups in NCT03420742
Study group	Role	What they receive
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. Receives: Drug: Midazolam; Drug: Brigatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

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).
Measured: 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).
Measured: 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
Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

26 Jun 201929 Apr 2021

First posted5 Feb 2018
Study start26 Jun 2019
Primary completion24 Mar 2020
Study completion29 Apr 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid TumorsStudies of the same condition, open and under way.
More trials run by TakedaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Other
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Enrolment: 24 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03420742
Sponsor's protocol ID: Brigatinib-1001
Other IDs: U1111-1203-0166, 2018-001624-19, 2018
Status last verified: Apr 2022
First submitted: 29 Jan 2018
Last updated: 27 Jan 2023
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: 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.

Publications

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.
PubMed 36579743

Study at a glance

From the registry record, last updated by the sponsor on 27 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT03420742
Acronym / sponsor ID: Brigatinib-1001
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
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 24 participants (actual)
Lead sponsor: TakedaIndustry (pharma, biotech, devices)
Study start: 26 Jun 2019 (actual)
Primary completion: 24 Mar 2020 (actual)
Study completion: 29 Apr 2021 (actual)
First posted: 5 Feb 2018 (actual)
Results: Posted 27 Jan 2023

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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

Study design

Primary purpose: Other
Allocation: Not applicable
Intervention model: Sequential
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Midazolam 3 mg + Brigatinib 90 mg	Experimental	Drug: Midazolam, Drug: BrigatinibMidazolam 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (9 listed)

Locally advanced or metastatic solid tumors who meet 1 of the following 4 criteria:
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).

Key exclusion criteria (8 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
MidazolamMidazolam syrup.	Drug	Midazolam 3 mg + Brigatinib 90 mg
BrigatinibAlso: AlunbrigBrigatinib tablets.	Drug	Midazolam 3 mg + Brigatinib 90 mg

Primary outcome

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)

Results and safety

Results posted to the registry on 27 Jan 2023, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Parts A and B: All Participants	24	24

Primary outcome: 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). Geometric mean (Geometric Coefficient of Variation). Unit: hour*nanogram per milliliter (h*ng/mL)

Measure	Part A, Cycle 1 Day 1: Midazolam Alone n = 15	Part A, Cycle 1 Day 21: Midazolam + Brigatinib n = 14
Value	57.2 (30.3)	42.1 (54.2)

Part A, Cycle 1 Day 1: Midazolam Alone vs Part A, Cycle 1 Day 21: Midazolam + Brigatinib: Geometric least squares mean ratio: 0.741 (90% CI 0.600 to 0.915)

Population analysed: PK-evaluable population: participants who received protocol-specified regimen during Part A (including brigatinib 180 mg) without dose reductions/interruptions, did not receive any excluded concomitant medications through completion of PK sampling and had sufficient midazolam concentration-time data to estimate PK parameters by noncompartmental analysis methods. As planned, OM was assessed for Part A only. Overall number of participants analyzed were participants who were evaluable for this OM.

Primary outcome: Part A, Cmax: Maximum Observed Plasma Concentration for Midazolam

Measure	Part A, Cycle 1 Day 1: Midazolam Alone n = 15	Part A, Cycle 1 Day 21: Midazolam + Brigatinib n = 15
Value	19.7 (42.6)	16.5 (49.9)

Part A, Cycle 1 Day 1: Midazolam Alone vs Part A, Cycle 1 Day 21: Midazolam + Brigatinib: Geometric least squares mean ratio: 0.836 (90% CI 0.662 to 1.06)

Population analysed: Pharmacokinetic (PK)-evaluable population: participants who received protocol-specified regimen during Part A (including brigatinib 180 mg) without dose reductions/interruptions, did not receive any excluded concomitant medications through completion of PK sampling, and had sufficient midazolam concentration-time data to estimate PK parameters by noncompartmental analysis methods. As planned, this outcome measure (OM) was assessed for Part A only.

Primary outcome: 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). Median (Full Range). Unit: hour

Measure	Part A, Cycle 1 Day 1: Midazolam Alone n = 15	Part A, Cycle 1 Day 21: Midazolam + Brigatinib n = 15
Value	0.500 (0.220 to 1.93)	0.500 (0.250 to 1.00)

Population analysed: PK-evaluable population: participants who received protocol-specified regimen during Part A (including brigatinib 180mg) without dose reductions/interruptions, did not receive any excluded concomitant medications through completion of PK sampling and had sufficient midazolam concentration-time data to estimate PK parameters by noncompartmental analysis methods. As planned, OM was assessed for Part A only.

Adverse events

Time frame: Treatment-emergent adverse events were adverse events (AEs) that started from the first dose of the study drug up to 30 days after the last dose of the study drug (up to Cycle 20 Day 30 ) (Cycle length =28 days). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Parts A and B: All Participants	17 of 24 (70.8%)	23 of 24 (95.8%)	8 of 24

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2023.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 36579743Hanley 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.
Individual participant dataSharing planned: Yes. 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.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Study Director study director

Takeda

14 sites in 4 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in Italy, Spain, France, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Jan 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03420742, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2023.