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Carcinoma, Non-Small-Cell LungPhase 2NCT02094573

A Study to Evaluate the Efficacy of Brigatinib (AP26113) in Participants With Anaplastic Lymphoma Kinase (ALK)-Positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

A Phase 2 study testing Brigatinib in people with Carcinoma, Non-Small-Cell Lung, run by Ariad Pharmaceuticals.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The purpose of this study is to evaluate the efficacy and safety of two different dosing regimens of brigatinib (AP26113) in participants with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma, Non-Small-Cell Lung
What is being tested?
Brigatinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
222 participants
Where
No sites listed yet
Study dates
4 Jun 2014to 27 Feb 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Have histologically or cytologically confirmed locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is anaplastic lymphoma kinase (ALK+).
  • Must meet one of the following two criteria:
  • Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or
  • Have documented ALK positivity by a different test and tissue available for the Vysis® FISH test. Tissue should be derived preferably from a biopsy taken after progression with crizotinib. If such a sample is not available, testing may be performed with archived tumor tissue.
  • Had progressive disease while on crizotinib, as assessed by the investigator or treating physician.
  • Have at least 1 measurable lesion per RECIST v1.1. 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.
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  • Recovered from toxicities related to prior anticancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0) grade ≤2.
  • Are a male or female participants ≥18 years old.
  • Have a life expectancy ≥3 months.
  • Have adequate organ and hematologic function, as determined by:
  • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN; ≤5 x ULN is acceptable if liver metastases are present)
  • Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN for participants with Gilbert syndrome)
  • Serum creatinine ≤1.5 x ULN
  • Serum lipase/amylase ≤1.5 x ULN
  • Absolute neutrophil count (ANC) ≥1500/µL
  • Platelets ≥75000/µL
  • Hemoglobin ≥10 g/dL
  • Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
  • Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.
  • For female participants of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
  • Female and male participants who are fertile must agree to use a highly effective form of contraception with their sexual partners throughout study participation.
  • Must provide a signed and dated informed consent indicating that the participants has been informed of all pertinent aspects of the study, including the potential risks, and is willingly participating.
  • Have the willingness and ability to comply with scheduled visits and study procedures.

Who cannot join

  • Received any prior ALK-targeted TKI other than crizotinib.
  • Received crizotinib within 3 days of the first dose of brigatinib (Day 1, Cycle 1).
  • Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days, except SRS or stereotactic body radiosurgery.
  • Received monoclonal antibodies or had major surgery within 30 days of the first dose of brigatinib (Day 1, Cycle 1).
  • Have been diagnosed with another primary malignancy within the past 3 years (except for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer, which are allowed within 3 years).
  • Have symptomatic CNS metastases that are neurologically unstable or require an increasing dose of corticosteroids.
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  • Have current spinal cord compression.
  • Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
  • Myocardial infarction (MI) within 6 months prior to the first dose of brigatinib
  • Unstable angina within 6 months prior to first dose
  • Congestive heart failure (CHF) within 6 months prior to first dose
  • History of clinically significant (as determined by the treating physician) atrial arrhythmia
  • Any history of ventricular arrhythmia
  • Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose
  • Have a history or the presence of pulmonary interstitial disease or drug-related pneumonitis.
  • Have an ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.
  • Have a known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.
  • Have a history of or active significant gastrointestinal (GI) bleeding within 3 months of the first dose of brigatinib.
  • Have a known or suspected hypersensitivity to brigatinib or its excipients.
  • Have malabsorption syndrome or other GI illness that could affect oral absorption of the study drug.
  • Have any condition or illness that, in the opinion of the investigator, would compromise participants safety or interfere with evaluation of the drug study.
  • Be pregnant or breastfeeding.

About this study

Official title: A Randomized Phase 2 Study of AP26113 in Patients With ALK-positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib

The purpose of this study is to evaluate the efficacy and safety of two different dosing regimens of brigatinib (AP26113) in participants with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib.

Read the detailed description

The drug being tested in this study is called brigatinib (AP26113). Brigatinib was tested to treat people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or were intolerant to crizotinib. This study looked at the efficacy of brigatinib.

The study enrolled 222 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

  • Brigatinib 90 mg
  • Brigatinib 90 mg -180 mg

All participants were asked to take a tablet, orally once daily until disease progression or intolerable toxicity. Participants in Brigatinib 90 mg - 180 mg received 180 mg with a 7-day lead-in at 90 mg.

This multi-center trial was conducted worldwide. The overall time to participate in this study is up to 3 years. Participants will make multiple visits to the clinic, and 3 months after the End-of-Treatment visit. Follow-up is intended to continue for 2 years after the last participants was enrolled into the study.

Being tested
Brigatinib
Keywords
Drug Therapy
Medical subject headings
Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BrigatinibDrug

    Also called AP26113, ALUNBRIG™

    Brigatinib tablets

Study groups in NCT02094573
Study groupRoleWhat they receive
Brigatinib 90 mgExperimentalBrigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).
Receives: Drug: Brigatinib
Brigatinib 90 mg - 180 mgExperimentalBrigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Receives: Drug: Brigatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Confirmed Objective Response Rate (ORR) as Assessed by Investigator

    ORR assessed by the investigator, was defined as percentage of the participants with confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST) v1.1 (confirmed ≥4 weeks after initial response), after initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 97.5% confidence interval was calculated. The treatment regimen was considered to have achieved the primary objective when lower bound of the 97.5% confidence interval for ORR assessed by investigator is greater than 20%.

    Measured: Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)

Secondary outcomes (13)

  1. Confirmed Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC)

    ORR assessed by the IRC, was defined as the percentage of the participants with CR or PR according to RECIST v1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in theSLD of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 95% confidence interval was calculated.

    Measured: Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)

  2. Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Measurable Active Brain Metastases

    Confirmed intracranial CNS ORR was defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

    Measured: Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months

  3. Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants With Only Non-measurable Active Brain Metastases

    Confirmed intracranial CNS ORR is defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after the initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

    Measured: Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months

  4. Intracranial CNS Progression Free Survival (PFS) in Participants With Active Brain Metastases

    Intracranial CNS PFS as evaluated by IRC is defined as the time interval from the date of the first dose of the study drug until the first date at which intracranial CNS disease progression, an increase of 20% or more in the sum of diameters of intracranial CNS target lesions, unequivocal progression of non-target lesions, or the appearance of new lesions in the intracranial CNS, was objectively documented by a scan, or death due to any cause, whichever occurred first. The analysis was based on the Kaplan-Meier (KM) Estimates.

    Measured: Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months

  5. Time to Response

    Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

    Measured: Up to approximately 69 months

  6. Duration of Response

    Duration of response was defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the progressive disease is objectively documented or death. Patients without progressive disease or death were censored at the last valid response assessment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. The analysis was based on the Kaplan-Meier (KM) Estimates.

    Measured: Up to approximately 69 months

  7. Time on Treatment

    Time on treatment was defined as the time from the first to the last dose of study drug. For participants who have not discontinued, time on treatment was censored as of the last dose of the study drug.

    Measured: Up to approximately 69 months

  8. Disease Control Rate (DCR)

    DCR was defined as the percentage of randomized participants who were confirmed to have achieved CR or PR or have a best overall response as stable disease (SD) for 6 weeks or more after initiation of the study drug. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD was defined as at least a 20% increase in the sum of diameters of target lesions.

    Measured: Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)

  9. Progression Free Survival (PFS)

    PFS was defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including Baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). The analysis was based on the Kaplan-Meier (KM) Estimates.

    Measured: Up to approximately 69 months

  10. Overall Survival (OS)

    OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. Intracranial OS was calculated by Kaplan-Meier estimation.

    Measured: Up to approximately 69 months

  11. Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)

    An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug.

    Measured: From first dose of study drug up to 30 days following the last dose of study drug (approximately up to 69 months)

  12. Pre-dose Brigatinib Plasma Concentration

    Measured: Day 1 Cycles 2, 3, 4 and 5 (each Cycle of 28-days) pre-dose

  13. Patient-reported Symptoms Global Health Status/Quality of Life (QoL) Scores

    Patient-reported symptoms global health status/quality of life (QoL) scores were based on questions 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (QLQ-C30). The first 28 questions used 4-point scale (1=not at all,2=a little,3=quite a bit,4=very much) for evaluating 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and last 2 questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Six single-item scales also are included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores for multi-item scales and single-item measures was linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.

    Measured: Baseline and at each 28-day cycle up to end of the study (up to approximately 69 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Mar 2014 (estimated)
  2. Study start4 Jun 2014
  3. Primary completion29 Feb 2016
  4. Study completion27 Feb 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
222 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02094573
Sponsor's protocol ID
AP26113-13-201
Other IDs
2013-002134-21, U1111-1196-8246
Status last verified
Feb 2021
First submitted
18 Mar 2014
Last updated
15 Mar 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Kawata AK, Lenderking WR, Eseyin OR, Kerstein D, Huang J, Huang H, Zhang P, Lin HM. Converting EORTC QLQ-C30 scores to utility scores in the brigatinib ALTA study. J Med Econ. 2019 Sep;22(9):924-935. doi: 10.1080/13696998.2019.1624080. Epub 2019 Jun 25.

    PubMed 31125274

  • Camidge DR, Kim DW, Tiseo M, Langer CJ, Ahn MJ, Shaw AT, Huber RM, Hochmair MJ, Lee DH, Bazhenova LA, Gold KA, Ou SI, West HL, Reichmann W, Haney J, Clackson T, Kerstein D, Gettinger SN. Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials. J Clin Oncol. 2018 Sep 10;36(26):2693-2701. doi: 10.1200/JCO.2017.77.5841. Epub 2018 May 16.

    PubMed 29768119

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Brigatinib in people with Carcinoma, Non-Small-Cell Lung, run by Ariad Pharmaceuticals.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Confirmed Objective Response Rate (ORR) as Assessed by Investigator (time frame: Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02094573, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2021.

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