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Phase 2 Study of Brigatinib in Japanese Patients With 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
Last Update Posted : December 2, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this study is to evaluate efficacy and safety of Brigatinib in Japanese patients 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 patients with ALK-positive NSCLC in order to evaluate efficacy and safety of oral doses of brigatinib in Japanese patients 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.

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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
Estimated Primary Completion Date : August 13, 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
90 mg of Brigatinib tablets, once daily for 7 days, followed by 180 mg of Brigatinib tablets, once daily in a 28-days cycle.
Drug: Brigatinib
Brigatinib tablet




Primary Outcome Measures :
  1. Confirmed Objective Response Rate (ORR) in the Main Cohort of the Refractory Expansion Part [ Time Frame: Up to 23 months ]
    ORR is defined the percentage of the participants who are confirmed to have achieved complete response (CR) or partial response (PR) per an Independent Review Committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 after the initiation of study treatment.

  2. 12 Months Progression-Free Survival (PFS) Rate in the Tyrosine Kinase Inhibitor (TKI) Naïve Expansion Cohort [ Time Frame: Up to 36 months ]
    12 months PFS rate is defined as the percentage of the participants who do not have PFS events (Progression disease [PD] per IRC using RECIST version 1.1, or death by any cause) at 12 months after the start of study treatment.


Secondary Outcome Measures :
  1. Confirmed ORR in the TKI-naïve Expansion Cohort, the Overall Population of the Refractory Expansion Part, and the Safety Evaluation Lead-in Part [ Time Frame: Up to 53 months ]
  2. Duration of Response (DOR) in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Overall Population of the Refractory Expansion Part [ Time Frame: Up to 53 months ]
    DOR will be assessed by an IRC, per RECIST version 1.1. DOR is defined as the time between the first documentation of objective tumor response (CR or PR) and the first subsequent documentation of objective progressive disease (PD) or death due to any cause, whichever occurs first.

  3. Progression-Free Survival (PFS) in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Overall Population of the Refractory Expansion Part [ Time Frame: Up to 53 months ]
    PFS will be assessed by an IRC, per RECIST version 1.1. PFS is 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.

  4. Disease Control Rate (DCR) in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Overall Population of the Refractory Expansion Part [ Time Frame: Up to 53 months ]
    DCR will be assessed by an IRC, per RECIST version 1.1. DCR is defined as the percentage of participants who are confirmed to have achieved CR or PR or have a best overall response of stable disease (SD), per RECIST version 1.1, for 6 weeks or more after initiation of study drug.

  5. Time to Response in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Overall Population of the Refractory Expansion Part [ Time Frame: Up to 53 months ]
    Time to response will be assessed by an IRC, per RECIST version 1.1. Time to response is defined as the time interval from the date of the first dose of study treatment until the initial observation of CR or PR for patients with confirmed CR/PR.

  6. Overall Survival (OS) in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Overall Population of the Refractory Expansion Part [ Time Frame: Up to 53 months ]
    OS is the time from the start of study treatment to the date of death.

  7. Central Nervous System (CNS) Response in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Overall Population of the Refractory Expansion Part [ Time Frame: Up to 53 months ]
    CNS response will be assessed by an IRC, per modified RECIST version 1.1 for assessment of intracranial efficacy (intracranial objective response rate [iORR] and duration of intracranial response [iDOR] in patients who had measurable CNS metastases, and intracranial progression-free survival [iPFS] in all patients). CNS response is defined as the percentage of the participants who have achieved CR or PR in the intracranial CNS per modified RECIST version 1.1 as evaluated by an IRC after the initiation of study treatment.

  8. Time on Treatment in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Overall Population of the Refractory Expansion Part [ Time Frame: Up to 53 months ]
    Time on treatment is the time interval from the first dose to the last dose of Brigatinib.

  9. Confirmed ORR in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Safety Evaluation Lead-in Part [ Time Frame: Up to 53 months ]
    The percentage of participants who are confirmed to have achieved CR or PR per investigator using RECIST version 1.1 after the initiation of study treatment.

  10. Patient-Reported Outcomes (PROs) of Health-Related Quality of Life (HRQOL) Scores and Symptoms of Lung Cancer in the TKI-naïve Expansion Cohort, the Main Cohort of the Refractory Expansion Part, and the Safety Evaluation Lead-in Part [ Time Frame: Up to 53 months ]
    PROs of HRQOL scores and symptoms of lung cancer, assessed with European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, its lung cancer module QLQ-LC13, and the 5-level version of EuroQol 5-dimensional questionnaire (EQ-5D-5L) which are related to patient health, symptoms, and problems. Participants will answer for these questionalries. EORTC-QLQ-C30 contains 28 questions (4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions (7-point scale where 1=Very poor [worst] to 7= Excellent [best]). QLQ-LC13 contains 13 questions (4-point scale where 1=Not at all [best] to 4=Very Much [worst]). EQ-5D-5L consists of 25 checklists on 5 dimensions (Mobility, Self-care, Usual activities, Pain/Discomfort, and Anxiety/Depression) and EQ VAS. EQ VAS records the respondent's self-rated health on a 20 cm, vertical, visual analogue scale ranging from 0 [worst] to 100 [best].

  11. 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 ]
  12. 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 ]
  13. AUC: Area under the Plasma Concentration-Time Curve 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 ]


Information from the National Library of Medicine

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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 patients 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 patient 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, patients must meet 1 of the following 2 criteria:

    1. Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break Apart FISH [fluorescence in situ hybridization] Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK (D5F3) 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, patients must meet the following criteria Have documentation of ALK rearrangement by a positive result from 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 subcohort based on prior ALK inhibitor treatment. The main cohort includes patients 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 patients will be enrolled. Patients with all other sequences of up to 2 prior ALK inhibitor(s) may be included in the subcohort, and the number of patients will be limited to 20.
    • Note 2: Patients 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 patients with Gilbert syndrome).
    3. Serum creatinine <1.5×ULN. For patients with creatinine levels above or equal to 1.5×ULN, the patient 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/L.
    6. Platelet count >=75×10^9/L.
    7. Hemoglobin >=9 g/dL.
    8. Percutaneous oxygen saturation (SpO2) >=94% without oxygen support. Patients 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 patients 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 patient, 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 patients, 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 patient, 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 VEGFR TKI.

  2. The refractory expansion part only: received more than 2 prior ALK inhibitors. Note: The safety evaluation lead-in part allows patients with any line of prior ALK inhibitor which includes treatment-naïve patients; however, ALK inhibitor-naïve patients may be enrolled after the confirmation of first 3 DLT evaluable patients 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 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 patients 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 patient has worsening neurological symptoms or signs due to CNS metastasis, the patient 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). Patients 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. Patients 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. Patients 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 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: Patients 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. Patients 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 patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period. Note: Female patients 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 patient 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: Study Director Takeda
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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
Last Update Posted: December 2, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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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
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