Trial Outcomes & Findings for A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate, Midazolam, in Participants With ALK-Positive or ROS1-Positive Solid Tumors (NCT NCT03420742)
NCT ID: NCT03420742
Last Updated: 2023-01-27
Results Overview
The statistical analysis was calculated via a mixed-effects analysis of variance (ANOVA) fitting terms for treatment (midazolam with or without brigatinib coadministration).
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
24 participants
Primary outcome timeframe
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 posted on
2023-01-27
Participant Flow
Participants took part in the study at 10 investigative sites in the Netherlands, Italy, and Spain from 26 June 2019 to 29 April 2021.
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.
Participant milestones
| Measure |
Parts A and B: All Participants
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.
|
|---|---|
|
Part A (Cycle 1)
STARTED
|
24
|
|
Part A (Cycle 1)
COMPLETED
|
24
|
|
Part A (Cycle 1)
NOT COMPLETED
|
0
|
|
Part B (Cycle 2 to Cycle 20)
STARTED
|
22
|
|
Part B (Cycle 2 to Cycle 20)
COMPLETED
|
22
|
|
Part B (Cycle 2 to Cycle 20)
NOT COMPLETED
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Unit: milliliter per minute per 1.73 square meter (mL/min/1.73 m\^2).
Baseline characteristics by cohort
| Measure |
Parts A and B: All Participants
n=24 Participants
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.
|
|---|---|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
23 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
1 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
2 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
21 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
1 Participants
n=5 Participants
|
|
Age, Continuous
|
56.0 years
STANDARD_DEVIATION 12.08 • n=5 Participants
|
|
Sex: Female, Male
Female
|
13 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
11 Participants
n=5 Participants
|
|
Region of Enrollment
Italy
|
11 Participants
n=5 Participants
|
|
Region of Enrollment
Netherlands
|
2 Participants
n=5 Participants
|
|
Region of Enrollment
Spain
|
11 Participants
n=5 Participants
|
|
Estimated Glomerular Filtration Rate (eGFR)
|
97.94 mL/min/1.73 m^2
STANDARD_DEVIATION 40.596 • n=5 Participants • Unit: milliliter per minute per 1.73 square meter (mL/min/1.73 m\^2).
|
|
Height
|
168.7 centimeter (cm)
STANDARD_DEVIATION 9.64 • n=5 Participants
|
|
Weight
|
73.82 kilogram (kg)
STANDARD_DEVIATION 22.415 • n=5 Participants
|
PRIMARY outcome
Timeframe: 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)Population: 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.
The statistical analysis was calculated via a mixed-effects analysis of variance (ANOVA) fitting terms for treatment (midazolam with or without brigatinib coadministration).
Outcome measures
| Measure |
Part A, Cycle 1 Day 1: Midazolam Alone
n=15 Participants
Midazolam 3 mg, oral solution, once on Day 1 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.
|
Part A, Cycle 1 Day 21: Midazolam + Brigatinib
n=14 Participants
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.
|
|---|---|---|
|
Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam
|
57.2 hour*nanogram per milliliter (h*ng/mL)
Geometric Coefficient of Variation 30.3
|
42.1 hour*nanogram per milliliter (h*ng/mL)
Geometric Coefficient of Variation 54.2
|
PRIMARY outcome
Timeframe: 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)Population: 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.
The statistical analysis was calculated via a mixed-effects ANOVA fitting terms for treatment (midazolam with or without brigatinib coadministration).
Outcome measures
| Measure |
Part A, Cycle 1 Day 1: Midazolam Alone
n=15 Participants
Midazolam 3 mg, oral solution, once on Day 1 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.
|
Part A, Cycle 1 Day 21: Midazolam + Brigatinib
n=15 Participants
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.
|
|---|---|---|
|
Part A, Cmax: Maximum Observed Plasma Concentration for Midazolam
|
19.7 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 42.6
|
16.5 nanogram per milliliter (ng/mL)
Geometric Coefficient of Variation 49.9
|
PRIMARY outcome
Timeframe: 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)Population: 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.
Outcome measures
| Measure |
Part A, Cycle 1 Day 1: Midazolam Alone
n=15 Participants
Midazolam 3 mg, oral solution, once on Day 1 in Treatment Cycle 1 (28-day single treatment cycle) in Part A.
|
Part A, Cycle 1 Day 21: Midazolam + Brigatinib
n=15 Participants
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.
|
|---|---|---|
|
Part A, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam
|
0.500 hour
Interval 0.22 to 1.93
|
0.500 hour
Interval 0.25 to 1.0
|
Adverse Events
Parts A and B: All Participants
Serious events: 17 serious events
Other events: 23 other events
Deaths: 8 deaths
Serious adverse events
| Measure |
Parts A and B: All Participants
n=24 participants at risk
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.
|
|---|---|
|
Hepatobiliary disorders
Bile duct obstruction
|
4.2%
1/24 • 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)
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).
|
|
Infections and infestations
COVID-19
|
4.2%
1/24 • 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)
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).
|
|
Psychiatric disorders
Confusional state
|
4.2%
1/24 • 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)
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).
|
|
General disorders
Disease progression
|
8.3%
2/24 • 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)
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).
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
12.5%
3/24 • 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)
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).
|
|
Renal and urinary disorders
Haematuria
|
4.2%
1/24 • 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)
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).
|
|
Infections and infestations
Infection
|
4.2%
1/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma
|
4.2%
1/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
|
4.2%
1/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to liver
|
4.2%
1/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression
|
4.2%
1/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-small cell lung cancer
|
12.5%
3/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian cancer
|
4.2%
1/24 • 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)
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).
|
|
Gastrointestinal disorders
Pancreatitis
|
4.2%
1/24 • 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)
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).
|
|
Infections and infestations
Pneumonia
|
8.3%
2/24 • 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)
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).
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
4.2%
1/24 • 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)
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).
|
|
Infections and infestations
Respiratory tract infection
|
4.2%
1/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
|
8.3%
2/24 • 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)
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).
|
Other adverse events
| Measure |
Parts A and B: All Participants
n=24 participants at risk
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.
|
|---|---|
|
Gastrointestinal disorders
Abdominal pain
|
12.5%
3/24 • 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)
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).
|
|
Investigations
Alanine aminotransferase increased
|
29.2%
7/24 • 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)
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).
|
|
Investigations
Amylase increased
|
20.8%
5/24 • 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)
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).
|
|
Blood and lymphatic system disorders
Anaemia
|
29.2%
7/24 • 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)
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).
|
|
Investigations
Aspartate aminotransferase increased
|
33.3%
8/24 • 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)
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).
|
|
General disorders
Asthenia
|
12.5%
3/24 • 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)
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).
|
|
Investigations
Blood alkaline phosphatase increased
|
12.5%
3/24 • 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)
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).
|
|
Investigations
Blood cholesterol increased
|
16.7%
4/24 • 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)
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).
|
|
Investigations
Blood creatine phosphokinase increased
|
45.8%
11/24 • 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)
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).
|
|
Investigations
Blood lactate dehydrogenase increased
|
8.3%
2/24 • 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)
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).
|
|
General disorders
Chills
|
8.3%
2/24 • 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)
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).
|
|
Gastrointestinal disorders
Constipation
|
8.3%
2/24 • 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)
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).
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
25.0%
6/24 • 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)
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).
|
|
Metabolism and nutrition disorders
Decreased appetite
|
20.8%
5/24 • 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)
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).
|
|
Gastrointestinal disorders
Diarrhoea
|
37.5%
9/24 • 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)
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).
|
|
Nervous system disorders
Dizziness
|
8.3%
2/24 • 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)
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).
|
|
Gastrointestinal disorders
Dry mouth
|
8.3%
2/24 • 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)
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).
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
33.3%
8/24 • 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)
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).
|
|
General disorders
Fatigue
|
16.7%
4/24 • 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)
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).
|
|
Nervous system disorders
Headache
|
12.5%
3/24 • 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)
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).
|
|
Vascular disorders
Hypertension
|
20.8%
5/24 • 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)
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).
|
|
Metabolism and nutrition disorders
Hypomagnesaemia
|
8.3%
2/24 • 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)
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).
|
|
Investigations
Lipase increased
|
25.0%
6/24 • 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)
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).
|
|
Gastrointestinal disorders
Nausea
|
45.8%
11/24 • 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)
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).
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-small cell lung cancer
|
8.3%
2/24 • 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)
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).
|
|
General disorders
Pyrexia
|
20.8%
5/24 • 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)
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).
|
|
Gastrointestinal disorders
Stomatitis
|
8.3%
2/24 • 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)
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).
|
|
Cardiac disorders
Tachycardia
|
8.3%
2/24 • 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)
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).
|
|
Infections and infestations
Urinary tract infection
|
12.5%
3/24 • 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)
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).
|
|
Gastrointestinal disorders
Vomiting
|
29.2%
7/24 • 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)
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).
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee 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.
- Publication restrictions are in place
Restriction type: OTHER