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

• Study Type: Interventional
• 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
• Interventions: Drug: Midazolam; Drug: Brigatinib
• Enrollment: 24

Participant Flow

Recruitment Details

Participants took part in the study at 10 investigative sites in the Netherlands, Italy, and Spain from 26 June 2019 to 29 April 2021.

Pre-assignment Details

Participants with anaplastic lymphoma kinase-positive (ALK-positive) or ROS1-positive solid tumors, including non-small-cell lung cancer (NSCLC) were enrolled in this two-part study to receive midazolam with and without repeated doses of brigatinib in Part A, and further continued treatment with brigatinib at their highest tolerated dose (up to 180 milligram [mg]) in Part B. As planned, combined safety data for Parts A and B were collected and reported.

Arm/Group Title	Parts A and B: All Participants
Arm/Group Description	Midazolam 3 mg, oral solution, once on Day 1, followed by brigatinib 90 mg, tablet, orally, once daily on Days 2 through 8, further followed by dose escalation to brigatinib 180 mg, tablet, orally, once daily on Days 9 through 28 in Treatment Cycle 1 (28-day single treatment cycle) in Part A. Participants also received midazolam 3 mg, oral solution, once on Day 21 in Treatment Cycle 1 in Part A. Participants from Part A may have continued into Part B to receive brigatinib 180 mg or their highest tolerated dose received at the end of Part A, tablet, orally once daily in 28-day treatment cycles from Treatment Cycle 2 up to Treatment Cycle 20, or until PD, intolerable toxicity, or another discontinuation criterion was met.
Period Title: Part A (Cycle 1)
Started	24
Completed	24
Not Completed	0
Period Title: Part B (Cycle 2 to Cycle 20)
Started	22 [1]
Completed	22
Not Completed	0
[1] These were the eligible participants from Part A who had the option to continue their treatment in Part B.

Baseline Characteristics

Arm/Group Title		Parts A and B: All Participants
Arm/Group Description		Midazolam 3 mg, oral solution, once on Day 1, followed by brigatinib 90 mg, tablet, orally, once daily on Days 2 through 8, further followed by dose escalation to brigatinib 180 mg, tablet, orally, once daily on Days 9 through 28 in Treatment Cycle 1 (28-day single treatment cycle) in Part A. Participants also received midazolam 3 mg, oral solution, once on Day 21 in Treatment Cycle 1 in Part A. Participants from Part A may have continued into Part B to receive brigatinib 180 mg or their highest tolerated dose received at the end of Part A, tablet, orally once daily in 28-day treatment cycles from Treatment Cycle 2 up to Treatment Cycle 20, or until PD, intolerable toxicity, or another discontinuation criterion was met.
Overall Number of Baseline Participants		24
Baseline Analysis Population Description		Safety population consisted of all participants who received at least 1 dose of any study drug (brigatinib or midazolam).
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	24 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	23 95.8%
	More than one race	0 0.0%
	Unknown or Not Reported	1 4.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	24 participants
	Hispanic or Latino	2 8.3%
	Not Hispanic or Latino	21 87.5%
	Unknown or Not Reported	1 4.2%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	24 participants
		56.0 (12.08)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	24 participants
	Female	13 54.2%
	Male	11 45.8%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	24 participants
Italy		11 45.8%
Netherlands		2 8.3%
Spain		11 45.8%
Estimated Glomerular Filtration Rate (eGFR) [1]; Mean (Standard Deviation); Unit of measure: mL/min/1.73 m^2
	Number Analyzed	24 participants
		97.94 (40.596)
		[1] Measure Analysis Population Description: Unit: milliliter per minute per 1.73 square meter (mL/min/1.73 m^2).
Height; Mean (Standard Deviation); Unit of measure: Centimeter (cm)
	Number Analyzed	24 participants
		168.7 (9.64)
Weight; Mean (Standard Deviation); Unit of measure: Kilogram (kg)
	Number Analyzed	24 participants
		73.82 (22.415)

Outcome Measures

1. Primary Outcome

Title	Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam
Description	The statistical analysis was calculated via a mixed-effects analysis of variance (ANOVA) fitting terms for treatment (midazolam with or without brigatinib coadministration).
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A, Cycle 1 Day 1: Midazolam Alone	Part A, Cycle 1 Day 21: Midazolam + Brigatinib
Arm/Group Description:	Midazolam 3 mg, oral solution, once on Day 1 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.	Midazolam 3 mg, oral solution, once along with brigatinib 180 mg, tablet, orally, once on Day 21 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.
Overall Number of Participants Analyzed	15	14
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: hour*nanogram per milliliter (h*ng/mL)
	57.2; (30.3%)	42.1; (54.2%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A, Cycle 1 Day 1: Midazolam Alone, Part A, Cycle 1 Day 21: Midazolam + Brigatinib
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Geometric least squares mean ratio
	Estimated Value	0.741
	Confidence Interval	(2-Sided) 90%; 0.600 to 0.915
	Estimation Comments	The ratios of geometric mean were calculated on the basis of the within-participant variance. Participant was treated as a random effect in the model.

2. Primary Outcome

Title	Part A, Cmax: Maximum Observed Plasma Concentration for Midazolam
Description	The statistical analysis was calculated via a mixed-effects ANOVA fitting terms for treatment (midazolam with or without brigatinib coadministration).
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A, Cycle 1 Day 1: Midazolam Alone	Part A, Cycle 1 Day 21: Midazolam + Brigatinib
Arm/Group Description:	Midazolam 3 mg, oral solution, once on Day 1 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.	Midazolam 3 mg, oral solution, once along with brigatinib 180 mg, tablet, orally, once on Day 21 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.
Overall Number of Participants Analyzed	15	15
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: nanogram per milliliter (ng/mL)
	19.7; (42.6%)	16.5; (49.9%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A, Cycle 1 Day 1: Midazolam Alone, Part A, Cycle 1 Day 21: Midazolam + Brigatinib
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Geometric least squares mean ratio
	Estimated Value	0.836
	Confidence Interval	(2-Sided) 90%; 0.662 to 1.06
	Estimation Comments	The ratios of geometric mean were calculated on the basis of the within-participant variance. Participant was treated as a random effect in the model.

3. Primary Outcome

Title	Part A, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam
Description	[Not Specified]
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A, Cycle 1 Day 1: Midazolam Alone	Part A, Cycle 1 Day 21: Midazolam + Brigatinib
Arm/Group Description:	Midazolam 3 mg, oral solution, once on Day 1 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.	Midazolam 3 mg, oral solution, once along with brigatinib 180 mg, tablet, orally, once on Day 21 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.
Overall Number of Participants Analyzed	15	15
Median (Full Range); Unit of Measure: hour
	0.500; (0.220 to 1.93)	0.500; (0.250 to 1.00)

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)
Adverse Event Reporting Description	Primary objective and endpoint was PK. No secondary objectives/endpoints in study. Part B was exploratory and allowed participants to continue brigatinib therapy to receive potential therapeutic benefits until PD. Since treatment with brigatinib was intended to continue without any modification from Part A into Part B (unless dose modifications were required by toxicity/AE /as indicated by study protocol), therefore it was planned to analyze the combined safety data (Parts A and B).
Arm/Group Title	Parts A and B: All Participants
Arm/Group Description	Midazolam 3 mg, oral solution, once on Day 1, followed by brigatinib 90 mg, tablet, orally, once daily on Days 2 through 8, further followed by dose escalation to brigatinib 180 mg, tablet, orally, once daily on Days 9 through 28 in Treatment Cycle 1 (28-day single treatment cycle) in Part A. Participants also received midazolam 3 mg, oral solution, once on Day 21 in Treatment Cycle 1 in Part A. Participants from Part A may have continued into Part B to receive brigatinib 180 mg or their highest tolerated dose received at the end of Part A, tablet, orally once daily in 28-day treatment cycles from Treatment Cycle 2 up to Treatment Cycle 20, or until PD, intolerable toxicity, or another discontinuation criterion was met.
All-Cause Mortality
	Parts A and B: All Participants
	Affected / at Risk (%)
Total	8/24 (33.33%)
Serious Adverse Events
	Parts A and B: All Participants
	Affected / at Risk (%)
Total	17/24 (70.83%)
Gastrointestinal disorders
Pancreatitis † 1	1/24 (4.17%)
General disorders
Disease progression † 1	2/24 (8.33%)
Hepatobiliary disorders
Bile duct obstruction † 1	1/24 (4.17%)
Infections and infestations
COVID-19 † 1	1/24 (4.17%)
Infection † 1	1/24 (4.17%)
Pneumonia † 1	2/24 (8.33%)
Respiratory tract infection † 1	1/24 (4.17%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma † 1	1/24 (4.17%)
Malignant neoplasm progression † 1	1/24 (4.17%)
Metastases to liver † 1	1/24 (4.17%)
Neoplasm progression † 1	1/24 (4.17%)
Non-small cell lung cancer † 1	3/24 (12.50%)
Ovarian cancer † 1	1/24 (4.17%)
Tumour pain † 1	2/24 (8.33%)
Psychiatric disorders
Confusional state † 1	1/24 (4.17%)
Renal and urinary disorders
Haematuria † 1	1/24 (4.17%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	3/24 (12.50%)
Pneumothorax † 1	1/24 (4.17%)
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Parts A and B: All Participants
	Affected / at Risk (%)
Total	23/24 (95.83%)
Blood and lymphatic system disorders
Anaemia † 1	7/24 (29.17%)
Cardiac disorders
Tachycardia † 1	2/24 (8.33%)
Gastrointestinal disorders
Abdominal pain † 1	3/24 (12.50%)
Constipation † 1	2/24 (8.33%)
Diarrhoea † 1	9/24 (37.50%)
Dry mouth † 1	2/24 (8.33%)
Nausea † 1	11/24 (45.83%)
Stomatitis † 1	2/24 (8.33%)
Vomiting † 1	7/24 (29.17%)
General disorders
Asthenia † 1	3/24 (12.50%)
Chills † 1	2/24 (8.33%)
Fatigue † 1	4/24 (16.67%)
Pyrexia † 1	5/24 (20.83%)
Infections and infestations
Urinary tract infection † 1	3/24 (12.50%)
Investigations
Alanine aminotransferase increased † 1	7/24 (29.17%)
Amylase increased † 1	5/24 (20.83%)
Aspartate aminotransferase increased † 1	8/24 (33.33%)
Blood alkaline phosphatase increased † 1	3/24 (12.50%)
Blood cholesterol increased † 1	4/24 (16.67%)
Blood creatine phosphokinase increased † 1	11/24 (45.83%)
Blood lactate dehydrogenase increased † 1	2/24 (8.33%)
Lipase increased † 1	6/24 (25.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	5/24 (20.83%)
Hypomagnesaemia † 1	2/24 (8.33%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-small cell lung cancer † 1	2/24 (8.33%)
Nervous system disorders
Dizziness † 1	2/24 (8.33%)
Headache † 1	3/24 (12.50%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	6/24 (25.00%)
Dyspnoea † 1	8/24 (33.33%)
Vascular disorders
Hypertension † 1	5/24 (20.83%)
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.

Results Point of Contact

• Name/Title: Study Director
• Organization: Takeda
• Phone: +1-877-825-3327
• EMail: TrialDisclosures@takeda.com

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03420742
• Other Study ID Numbers: Brigatinib-1001; U1111-1203-0166 ( Other Identifier: WHO ); 2018-001624-19 ( EudraCT Number )
• First Submitted: January 29, 2018
• First Posted: February 5, 2018
• Results First Submitted: April 22, 2022
• Results First Posted: January 27, 2023
• Last Update Posted: January 27, 2023