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Phase 2 Study of Brigatinib in Japanese Participants With Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer (NSCLC)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03410108
Recruitment Status : Active, not recruiting
First Posted : January 25, 2018
Results First Posted : December 14, 2021
Last Update Posted : December 14, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this study is to evaluate efficacy and safety of brigatinib in Japanese participants with anaplastic lymphoma kinase (ALK)-positive NSCLC.

Condition or disease Intervention/treatment Phase
ALK-positive Advanced NSCLC Drug: Brigatinib Phase 2

Detailed Description:

The drug being tested in this study is called brigatinib. Brigatinib is being tested in participants with ALK-positive NSCLC in order to evaluate efficacy and safety of oral doses of brigatinib in Japanese participants with ALK-positive NSCLC.

The study will enroll approximately 110 participants. Participants will be enrolled in non-randomized and opened manner:

- Brigatinib 90 mg for the first 7 days, followed by Brigatinib 180 mg of Brigatinib tablets, once daily in a 28-days cycle.

All participants will be asked to take tablets of brigatinib once daily with or without food throughout the study.

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 53 months. Participants will make multiple visits to the clinic during the treatment period, and posttreatment period including a follow-up assessment after last dose of study drug.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-Arm, Multicenter, Phase 2 Study of Brigatinib in Japanese Patients With ALK-Positive Non-Small Cell Lung Cancer (NSCLC)
Actual Study Start Date : January 29, 2018
Actual Primary Completion Date : September 29, 2020
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Brigatinib

Arm Intervention/treatment
Experimental: Brigatinib 90 mg + Brigatinib 180 mg
Brigatinib 90 milligram (mg), tablets, orally, once daily (QD) for first 7 days followed by brigatinib, 180 mg, tablets, orally, QD in Cycle 1 of 28 days followed by brigatinib 180 mg, tablets, orally, QD in Cycle 2 and onward cycles of 28 days until investigator-assessed progressive disease (PD) or intolerable toxicity, withdrawal of consent, or discontinuation for any other reason, whichever comes first up to Cycle 34 of 28-day cycle, until data cut-off date 29 September 2020.
Drug: Brigatinib
Brigatinib tablet




Primary Outcome Measures :
  1. Confirmed Objective Response Rate (ORR) in the Main Cohort of the Refractory Expansion Part [ Time Frame: From the start of study treatment up to confirmed CR or PR (Up to approximately 23 months) ]
    Confirmed ORR: Percentage of participants confirmed to have achieved complete response(CR) or partial response(PR) per Independent Review Committee(IRC) using Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1 after the initiation of study treatment(confirmed ≥4 weeks after initial response). CR(target lesion response): disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. CR(non-target lesion response): disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size(<10 mm short axis) and normalization of tumor marker level. PR(target lesions): at least 30% decrease in sum of the longest diameters(SLD) of target lesions, taking as reference Baseline sum diameters. As pre-specified in the protocol, this outcome measure was assessed and reported data only in the participants with at least 1 line of prior treatment(called as Main Cohort) of the Refractory Expansion Part.

  2. 12 Months Progression-Free Survival (PFS) Rate in the Tyrosine Kinase Inhibitor (TKI) Naïve Expansion Cohort [ Time Frame: From the start of study treatment up to Month 12 ]
    12 months PFS rate was defined as the percentage of the participants who did not have PFS events (PD per IRC using RECIST version 1.1, or death by any cause) at 12 months after the start of study treatment. PD for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm. PD for non-target lesion: unequivocal progression of existing nontarget lesions. Kaplan-Meier method was used for analysis of percentage of participants who achieved PFS of 12 months. As pre-specified in the protocol, this outcome measure was assessed and reported data only in the TKI-Naïve Expansion Cohort (participants with no prior treatment).


Secondary Outcome Measures :
  1. Confirmed ORR as Assessed by an IRC in All Refractory Participants and TKI-Naïve Expansion Cohort [ Time Frame: From the start of study treatment up to confirmed CR or PR till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    Confirmed ORR was defined as percentage of participants who were confirmed to have achieved CR or PR per an IRC using RECIST version 1.1 after initiation of study treatment (confirmed ≥4 weeks after initial response). CR for target lesion response: disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion response: disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size (<10 mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. As pre-specified in the protocol, the data for this outcome measure is reported based on previous treatment as: All Refractory Participants, and TKI-Naive Expansion Cohort.

  2. Confirmed ORR as Assessed by the Investigator in Main Cohort of the Refractory Expansion Part, Safety Evaluation Lead-in Part, and TKI-Naive Expansion Cohort [ Time Frame: From the start of study treatment up to confirmed CR or PR till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    Confirmed ORR was defined as the percentage of the participants who were confirmed to have achieved CR or PR per the investigator using RECIST version 1.1 after the initiation of study treatment (confirmed ≥4 weeks after initial response). CR for target lesion response: disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion response: disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size (<10 mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part and TKI-Naive Expansion Cohort. The Safety Evaluation Lead-in Part was excluded from the analysis.

  3. Duration of Response (DOR) as Assessed by an IRC in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort [ Time Frame: From first dose at 8-week intervals through Cycle 15 (each cycle=28 days) and at 12-week intervals thereafter until disease progression or death, whichever occurs first till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    DOR was assessed by an IRC, per RECIST version 1.1. DOR was defined as the time between the first documentation of objective tumor response (CR or PR) and the first subsequent documentation of objective PD or death due to any cause, whichever occurs first. PD for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm. PD for non-target lesion: unequivocal progression of existing nontarget lesions. Only responders were analyzed for this outcome measure. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  4. Progression-Free Survival (PFS) as Assessed by an IRC in the Main Cohort of the Refractory Expansion Part, and All Refractory Participants [ Time Frame: From the start of the treatment up to disease progression or death due to any cause, whichever comes first till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    PFS was assessed by an IRC, per RECIST version 1.1. PFS was defined as the time from the start of study treatment to the first documentation of objective PD or to death due to any cause, whichever occurs first. PD for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm. PD for non-target lesion: unequivocal progression of existing nontarget lesions. This outcome measure reports the data in refractory participants only and data is reported per cohort separately for Main Cohort of the Refractory Expansion Part, and for All Refractory Participants.

  5. PFS as Assessed by an IRC in the TKI-Naive Expansion Cohort [ Time Frame: From the start of the treatment up to disease progression or death due to any cause, whichever comes first till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    PFS was assessed by an IRC, per RECIST version 1.1. PFS was defined as the time from the start of study treatment to the first documentation of objective PD or to death due to any cause, whichever occurs first. PD for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm. PD for non-target lesion: unequivocal progression of existing nontarget lesions. This outcome measure reports data only in the TKI-Naive Expansion Cohort.

  6. Disease Control Rate (DCR) as Assessed by an IRC in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort [ Time Frame: From the start of the treatment up to confirmed CR or PR or SD till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    DCR was assessed by an IRC, per RECIST version 1.1. DCR: percentage of participants confirmed to have achieved CR or PR or have best overall response of stable disease (SD), for 6 weeks or more after initiation of study drug. CR (target lesion): disappearance of all target lesions. CR (non-target lesions): the nontarget lesion(s) has fully resolved. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. SD (target lesion): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD (target lesion): SLD increased by at least 20% from the smallest value on study, the SLD must also demonstrate an absolute increase of at least 5 mm. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  7. Time to Response as Assessed by an IRC in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort [ Time Frame: From the start of the treatment up to confirmed CR or PR till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    Time to response was assessed by an IRC, per RECIST version 1.1. and was defined as the time interval from the date of the first dose of study treatment until the initial observation of CR or PR for participants with confirmed CR/PR. CR(target lesion response):disappearance of all extranodal target lesions, all pathological lymph nodes must have decreased to <10 mm in short axis. CR(non-target lesion response):disappearance of all extranodal nontarget lesions, all lymph nodes must be nonpathological in size (<10 mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  8. Overall Survival (OS) as Assessed by an IRC in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort [ Time Frame: From the start of the treatment up to death due to any cause till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  9. Intracranial Objective Response Rate (iORR) in Participants With Measurable Central Nervous System (CNS) Metastases at Baseline in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort [ Time Frame: From the start of the treatment up to confirmed CR or PR till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    Confirmed iORR was defined as the percentage of the participants who had achieved confirmed CR or PR in the intracranial CNS per modified RECIST version 1.1 as evaluated by an IRC after the initiation of study treatment. CR for target lesion: disappearance of all target lesions. CR for non-target lesions: the nontarget lesion(s) has fully resolved. PR for target lesion: at least a 30% decrease in SLD of target lesions, taking as reference the Baseline SLD. Additionally, progression of target lesions must not be present. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  10. Duration of Intracranial Response (iDOR) in Participants With Measurable CNS Metastases at Baseline in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-naive Expansion Cohort [ Time Frame: From first dose at 8-week intervals through Cycle 15 (each cycle=28 days) and at 12-week intervals thereafter until intracranial disease progression or death due to any cause till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    iDOR was assessed by an IRC, per modified RECIST version 1.1 and was defined as the time between first documentation of objective intracranial tumor response (CR or PR) and first subsequent documentation of objective intracranial PD or death due to any cause. Participants who had systemic PD without intracranial PD were censored. CR (target lesion): disappearance of all target lesions. CR (non-target lesions):the nontarget lesion(s) has fully resolved. PR (target lesion):at least a 30% decrease in SLD of target lesions, taking as reference Baseline SLD. Progression of target lesions must not be present. CNS PD (target lesions):at least a 20% increase in SLD of target lesions, taking as reference the nadir SLD (or the baseline) and SLD must also demonstrate an absolute increase of ≥5 mm. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  11. Intracranial Progression-free Survival (iPFS) in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort [ Time Frame: From the start of the treatment up to intracranial disease progression or death due to any cause, whichever comes first till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    iPFS was assessed by an IRC, per modified RECIST version 1.1 and was defined as the time from the start of study treatment to the first documentation of objective intracranial PD or death due to any cause, whichever occurred first. The participant who had systemic PD and withdrawn from study without intracranial PD was censored. CNS PD for target lesions: at least a 20% increase in the SLD of target lesions, taking as reference the nadir SLD (or the baseline, if the baseline is the nadir value) and the SLD must also demonstrate an absolute increase of ≥5 mm. PD for non-target lesions: the nontarget site of disease has shown unequivocal progression. As pre-specified in the protocol, this outcome measure was assessed and reports data per cohort in all participants with measurable or not measurable intracranial metastases at Baseline: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  12. Time on Treatment in the Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort [ Time Frame: From the first dose up to last dose of study drug till data cut-off date: 29 September 2020 (Up to approximately 32 months) ]
    Time on treatment was defined as the time interval from the first dose to the last dose of brigatinib. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort: Main Cohort of the Refractory Expansion Part, All Refractory Participants, and TKI-Naive Expansion Cohort.

  13. Change From Baseline in Patient-Reported Outcomes (PROs) of Health-Related Quality of Life (HRQOL) Scores and Symptoms as Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQC30) Subscale Score [ Time Frame: Refractory Expansion Participants: Baseline and Cycle 22 - each cycle was of 28 days; TKI-Naive Participants: Baseline and Cycle 19 - each cycle was of 28 days ]
    EORTC QLQ-C30 contains 30 items - 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a QOL scale. Out of 30, 28 questions had 4 response levels (not at all, a little, quite a bit, and very much); 2 questions for global health status had score of 1 to 7 (very poor to excellent) to evaluate overall health and QOL. Each subscale raw score including global health status was transformed to a total score of 0 to 100. For functional scales, global health status scale, higher scores=better QOL (positive change from Baseline=improvement). For symptom scales, lower scores=better QOL (negative change from Baseline=improvement). As pre-specified in protocol, this outcome measure was assessed and reports data per cohort: Refractory Expansion Participants (including Main Cohort and Sub-Cohort), and TKI-Naive Expansion Cohort.

  14. Change From Baseline in HRQOL Scores and Symptoms of Lung Cancer as Assessed With the EORTC QLQ- Lung Cancer (LC) 13 (QLQ-LC13) Subscale Score [ Time Frame: Refractory Expansion Participants: Baseline and Cycle 22 - each cycle was of 28 days; TKI-Naive Participants: Baseline and Cycle 19 - each cycle was of 28 days ]
    HRQOL scores was assessed with EORTC, its lung cancer module QLQ-LC13. QLQ-LC13 contains 13 questions (4-point scale where 1=Not at all [best] to 4=Very much [worst]) assessing lung cancer-associated symptoms [cough, hemoptysis, dyspnea, and site-specific pain (chest, arm or shoulder, other parts)], treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Subscale score range: 0 to 100. Higher symptom score = greater degree of symptom severity. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort only in the Refractory Expansion Participants (including Main Cohort and Sub-cohort), and TKI-Naive Expansion Cohort.

  15. Number of Participants With Responses to HRQOL Scores and Symptoms of Lung Cancer as Assessed With the EuroQol 5-Dimensional Questionnaire (EQ-5D-5L) Score [ Time Frame: Refractory Expansion Participants: Cycle 22 - each cycle was of 28 days; TKI-Naive Participants: Cycle 19 - each cycle was of 28 days ]
    EQ-5D-5L comprises of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, 5= extremely severe problems. Higher scores indicated greater levels of problems across the five dimensions. As pre-specified in the protocol, this outcome measure assessed and reports data per cohort only in the Refractory Expansion Participants (including Main Cohort and Sub-cohort), and TKI-Naive Expansion Cohort. Number of participants with a particular score at the given timepoint is reported. Only categories with data are reported.

  16. Change From Baseline in HRQOL Scores and Symptoms of Lung Cancer as Assessed With the EuroQol Visual Analogue Scale (EQ VAS) Score [ Time Frame: Refractory Expansion Participants: Baseline and Cycle 22 - each cycle was of 28 days; TKI-Naive Participants: Baseline and Cycle 19 - each cycle was of 28 days ]
    The EQ VAS records the respondent's self-rated health on a 20 centimeter (cm), vertical, visual analogue scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). As pre-specified in the protocol, this outcome measure assessed and reports data per cohort only in the Refractory Expansion Participants (including Main Cohort and Sub-cohort), and TKI-Naive Expansion Cohort.

  17. Cmax: Maximum Observed Plasma Concentration for Brigatinib on Cycle 1 Days 1 and 22 [ Time Frame: Pre-dose and at multiple time points (0.5, 1, 2, 4, 6, 8, 12, 24; up to 24 hrs) post-dose of Cycle 1 Days 1 and 22 (each cycle = 28 days) ]
    As pre-specified in the protocol, this outcome measure was assessed only in the participants with or without prior ALK-TKI treatment called as the Safety Evaluation Lead-in Part.

  18. Tmax: Time of First Occurrence of Cmax for Brigatinib on Cycle 1 Days 1 and 22 [ Time Frame: Pre-dose and at multiple time points (0.5, 1, 2, 4, 6, 8, 12, 24; up to 24 hrs) post-dose of Cycle 1 Days 1 and 22 (each cycle = 28 days) ]
    As pre-specified in the protocol, this outcome measure was assessed only in the participants with or without prior ALK-TKI treatment called as the Safety Evaluation Lead-in Part.

  19. AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib on Cycle 1 Days 1 and 22 [ Time Frame: Pre-dose and at multiple time points (0.5, 1, 2, 4, 6, 8, 12, 24; up to 24 hrs) post-dose of Cycle 1 Days 1 and 22 (each cycle = 28 days) ]
    As pre-specified in the protocol, this outcome measure was assessed only in the participants with or without prior ALK-TKI treatment called as the Safety Evaluation Lead-in Part.



Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female Japanese participants aged >=20 years on the day of consent.
  2. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
  3. Have histologically or cytologically confirmed stage IIIB, stage IIIC (locally advanced or recurrent and not a candidate for definitive multimodality therapy), or stage IV NSCLC.
  4. Have documentation of ALK rearrangement that meets following criteria.

    For the Safety Evaluation Lead-in Part and the Refractory Expansion Part, participants must meet 1 of the following 2 criteria:

    1. Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break Apart fluorescence in situ hybridization (FISH) Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK (D5F3) Companion Diagnostics (CDx) Assay at any time during prior disease course. The sponsor may require an adequate tissue available for central laboratory testing by the Vysis ALK Break Apart FISH test if a documented ALK rearrangement is confirmed by a positive result from the Nichirei Histofine ALK iAEP Kit "ONLY".
    2. Had a documented ALK rearrangement by a different test at any time during prior disease course, and adequate tissue available for central laboratory testing by the Vysis ALK Break Apart FISH test. Central confirmation of ALK rearrangement is not required before enrollment.

    For TKI-naïve Expansion Cohort, participants must meet the following criteria Have documentation of ALK rearrangement by a positive result from Ministry of Health, Labour and Welfare (MHLW) Approved tests (e.g Vysis ALK Break Apart FISH Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK [D5F3] CDx Assay) prior to enrollment, and required to submit sufficient tumor tissue for central laboratory testing upon request of sponsor. Central confirmation of ALK rearrangement is not required before enrollment

  5. The Refractory Expansion Part only: had documented progressive disease (PD) during treatment or within 30 days after discontinuation of treatment with ALK inhibitor.

    • Note 1: The Refractory Expansion Part consists of the Main Cohort and a Sub-cohort based on prior ALK inhibitor treatment. The Main Cohort includes participants who had previously received alectinib (as their only ALK inhibitor) or both crizotinib and alectinib (regardless the sequence of those 2 ALK inhibitors), and a total of 47 participants will be enrolled. Participants with all other sequences of up to 2 prior ALK inhibitor(s) may be included in the Sub-cohort, and the number of participants will be limited to 20.
    • Note 2: Participants who will be included in the Main Cohort of the refractory should have documented PD during treatment or within 30 days after discontinuation of treatment with alectinib.
  6. Have at least 1 measurable (ie, target) lesion per RECIST version 1.1. Note: Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy. Brain lesions may not be used as target lesions if they were 1) previously treated with whole brain radiation therapy (WBRT) within 3 months, or 2) previously treated by stereotactic radiosurgery (SRS) or surgical resection.
  7. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Grade =<1. Note: Treatment-related alopecia is allowed.
  8. Have a life expectancy of >=3 months.
  9. Have adequate organ and hematologic function, as determined by:

    1. Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =<2.5 times the upper limit of the normal range (ULN) (=<5×ULN is acceptable if liver metastases are present).
    2. Total serum bilirubin =<1.5×ULN (<3.0×ULN for participants with Gilbert syndrome).
    3. Serum creatinine <1.5×ULN. For participants with creatinine levels above or equal to 1.5×ULN, the participant is eligible if the estimated creatinine clearance using the Cockcroft-Gault formula is >=30 mL/minute.
    4. Serum lipase =<1.5×ULN and serum amylase =<1.5×ULN.
    5. Absolute neutrophil count (ANC) >=1.5×10^9/Liter (L).
    6. Platelet count >=75×10^9/L.
    7. Hemoglobin >=9 gram (g)/ deciliter (dL).
    8. Percutaneous oxygen saturation (SpO2) >=94% without oxygen support. Participants who need oxygen support are excluded.
  10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of =<2.
  11. Must meet the following criteria:

    1. Female participants who:

      • Are postmenopausal for at least 1 year before the screening visit, OR
      • Are surgically sterile, OR
      • If they are of childbearing potential, agree to practice 1 highly effective non-hormonal method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, OR
      • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, from the time of signing the informed consent through 4 months after that last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    2. Male participants, even if surgically sterilized (ie, status postvasectomy), who:

      • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, OR
      • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant, during the entire study treatment period and through 4 months after that last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
  12. Have the willingness and ability to comply with scheduled visit and study procedures.

Exclusion Criteria:

  1. Previously received the following treatments. The Refractory Expansion Part only: received any prior ALK inhibitor not specified in the protocol.

    TKI-naïve Expansion Cohort only: received any prior TKI including but not limited to ALK inhibitor and vascular endothelial growth factor receptor (VEGFR) TKI.

  2. The Refractory Expansion Part only: received more than 2 prior ALK inhibitors. Note: The Safety Evaluation Lead-in Part allows participants with any line of prior ALK inhibitor which includes treatment-naïve participants; however, ALK inhibitor-naïve participants may be enrolled after the confirmation of first 3 dose-limiting toxicity (DLT) evaluable participants to have no more than 1 DLT during Cycle 1 by investigator's judgement.
  3. The Safety Evaluation Lead-in Part and the Refractory Expansion Part only: received ALK inhibitor within 7 days before the first dose of brigatinib.
  4. Previously received more than 1 regimen (more than 3 regimens in the Safety Evaluation Lead-in part) of systemic anticancer therapy (other than ALK inhibitors) for locally advanced or metastatic disease. Note: A systemic anticancer therapy regimen will be counted if it is administered over at least 1 cycle. A new anticancer agent used as maintenance therapy will be counted as a new regimen unless it was previously used as initial anticancer therapy. Neoadjuvant or adjuvant systemic anticancer therapy will be counted as a prior regimen if completion of (neo) adjuvant therapy occurred <12 months before the first dose of brigatinib.
  5. Treatment with any investigational products within 30 days or 5 half-lives of that investigational agent, whichever is longer, before the first dose of brigatinib.
  6. Received chemotherapy or radiation within 14 days before the first dose of brigatinib, except stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
  7. Received antineoplastic monoclonal antibodies within 30 days before the first dose of brigatinib.
  8. Received systemic treatment with strong inhibitors or strong and moderate inducers of cytochrome P450 (CYP) 3A within 7 days before the first dose of brigatinib.
  9. Had major surgery within 30 days before the first dose of brigatinib. Minor surgical procedures such as venous catheter placement or minimally invasive biopsies are allowed.
  10. Have been diagnosed with another primary malignancy other than NSCLC, except for the following adequately/definitively treated malignancies: nonmelanoma skin cancer, cervical cancer in situ, nonmetastatic prostate cancer; or participant with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
  11. Have symptomatic central nervous system (CNS) metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days before the first dose of brigatinib. Note: If a participant has worsening neurological symptoms or signs due to CNS metastasis, the participant needs to complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids or use of anticonvulsants for symptomatic control) for 7 days before the first dose of brigatinib.
  12. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with asymptomatic leptomeningeal disease and without cord compression are allowed.
  13. Have ongoing or history of interstitial lung disease (ILD) (including interstitial pneumonitis, pneumonitis, radiation pneumonitis, drug-related pneumonitis, organized pneumonia, and pulmonary alveolitis).
  14. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not limited to:

    1. Myocardial infarction within 6 months before the first dose of brigatinib.
    2. Unstable angina within 6 months before the first dose of brigatinib.
    3. Congestive heart failure within 6 months before the first dose of brigatinib.
    4. Uncontrolled atrial arrhythmias despite appropriate medical therapy.
    5. History of ventricular arrhythmia, including history of ventricular tachycardia, ventricular fibrillation, or torsades de pointes. Participants with premature ventricular contractions are allowed.
    6. Cerebrovascular accident or transient ischemic attack within 6 months before the first dose of brigatinib.
  15. Have uncontrolled hypertension. Participants with hypertension should be under treatment at the start of screening and demonstrate adequate control of blood pressure.
  16. Have an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics.
  17. Have a known history of human immunodeficiency virus (HIV) infection. Testing is not required in the absence of history.
  18. Hepatitis B surface antigen (HBsAg) positive, detectable hepatitis B viral load, or detectable hepatitis C virus (HCV) infection viral load. Note: Participants who have positive hepatitis B core antibody (HBcAb) or hepatitis B surface antibody (HBsAb) can be enrolled but must have an undetectable hepatitis B viral load. Participants who have positive HCV antibody can be enrolled but must have an undetectable hepatitis C viral load.
  19. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of brigatinib.
  20. Have a known or suspected hypersensitivity to brigatinib or its excipients.
  21. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period. Note: Female participants who are lactating will be excluded, even if they discontinue breastfeeding.
  22. Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with the evaluation of brigatinib.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03410108


Locations
Show Show 33 study locations
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Study Protocol  [PDF] July 22, 2020
Statistical Analysis Plan  [PDF] July 13, 2020

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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03410108    
Other Study ID Numbers: Brigatinib-2001
U1111-1204-8752 ( Other Identifier: WHO )
JapicCTI-183823 ( Registry Identifier: JapicCTI )
First Posted: January 25, 2018    Key Record Dates
Results First Posted: December 14, 2021
Last Update Posted: December 14, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Takeda:
Drug therapy
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases