Carcinoma, Advanced ALK+ or ROS1+Non-Small-Cell Lung, Neoplasm, Advanced ALK+ or ROS1+Solid Tumors
Conditions
Keywords
Drug therapy, brigatinib, lung cancer, ALK, ROS1
Brief summary
The purpose of this study is to characterize the effect of repeat-dose administration of brigatinib 180 milligram (mg) once daily (QD) on the single-dose pharmacokinetics (PK) of midazolam.
Detailed description
The study will enroll approximately 20 participants to achieve approximately 15 PK-evaluable participants for assessment. This study will consist of 2 parts: Part A of the study will evaluate the effect of repeat-dose administration of brigatinib on the single-dose PK of midazolam. Part B of the study is exploratory and will allow participants to continue brigatinib until disease progression (PD). All participants will receive study drug via the oral route. Participants will be assigned to: Midazolam 3 mg + Brigatinib 90 mg. The overall time to participate in this study is 26 months. Participants will have a 28-day PK cycle in Part A and a maximum of 23 cycles in Part B, and a 30-day follow-up period after end of treatment.
Interventions
DRUGMidazolam
Midazolam syrup.
DRUGBrigatinib
Brigatinib tablets.
Sponsors
Takeda
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Locally advanced or metastatic solid tumors who meet 1 of the following 4 criteria: * With locally advanced or metastatic ALK-positive NSCLC who have progressed on or are intolerant to treatment with at least 1 other ALK inhibitor. * With ALK-positive nonlung solid tumors that are locally advanced or metastatic and for whom no standard, nonexperimental therapy is available. * With locally advanced or metastatic ROS1-positive NSCLC who have progressed on crizotinib therapy or are intolerant to crizotinib, or * With ROS1-positive nonlung solid tumors that are locally advanced or metastatic and for whom no standard, nonexperimental therapy is available. 2. Eastern cooperative Oncology Group (ECOG) performance status of 0 or 1. 3. Have at least 1 target lesion per response evaluation criteria in solid tumors (RECIST) version 1.1. 4. Have recovered from toxicities related to prior anticancer therapy to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 4.03 Grade less than or equal to (\<=) 1. 5. Suitable venous access for study-required blood sampling (that is, including PK and laboratory safety tests).
Exclusion criteria
1. Systemic treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days before enrollment. 2. Prior therapy with brigatinib. 3. Received prior ALK-inhibitor therapy within 7 days before the first dose of study drug. 4. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, before the first dose of study drug. 5. Received chemotherapy or radiation therapy within 14 days before the first dose of study drug, except for stereotactic radiosurgery (SRS) or stereotactic body radiation therapy. 6. Received antineoplastic monoclonal antibodies within 30 days before the first dose of study drug. 7. Had major surgery within 30 days before the first dose of study drug. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed. 8. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity 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) | 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 | 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 | 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) | — |
Countries
France, Italy, Netherlands, Spain
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Parts A and B: All Participants |
|---|---|
| Age, Continuous | 56.0 years STANDARD_DEVIATION 12.08 |
| Estimated Glomerular Filtration Rate (eGFR) | 97.94 mL/min/1.73 m^2 STANDARD_DEVIATION 40.596 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Height | 168.7 centimeter (cm) STANDARD_DEVIATION 9.64 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment Italy | 11 Participants |
| Region of Enrollment Netherlands | 2 Participants |
| Region of Enrollment Spain | 11 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 11 Participants |
| Weight | 73.82 kilogram (kg) STANDARD_DEVIATION 22.415 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 24 |
| other Total, other adverse events | 23 / 24 |
| serious Total, serious adverse events | 17 / 24 |
Outcome results
Primary
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).
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Cycle 1 Day 1: Midazolam Alone | 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 |
| Part A, Cycle 1 Day 21: Midazolam + Brigatinib | Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam | 42.1 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 54.2 |
90% CI: [0.6, 0.915]
Primary
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).
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)
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Cycle 1 Day 1: Midazolam Alone | Part A, Cmax: Maximum Observed Plasma Concentration for Midazolam | 19.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 42.6 |
| Part A, Cycle 1 Day 21: Midazolam + Brigatinib | Part A, Cmax: Maximum Observed Plasma Concentration for Midazolam | 16.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 49.9 |
90% CI: [0.662, 1.06]
Primary
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A, Cycle 1 Day 1: Midazolam Alone | Part A, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam | 0.500 hour |
| Part A, Cycle 1 Day 21: Midazolam + Brigatinib | Part A, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam | 0.500 hour |