Clinical Trials /

Brigatinib Before Brain Irradiation Trial (B3i Trial)

NCT04634110

Description:

This is a single arm phase II study of brigatinib alone for patients with brain metastases from anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC), who have either not been treated previously with a tyrosine kinase inhibitor (TKI) targeting ALK or who have had prior exposure to crizotinib.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Brigatinib Before Brain Irradiation Trial (B3i Trial)
  • Official Title: Brigatinib Before Brain Irradiation Trial (B3i Trial): A Phase II Trial of Brigatinib Alone for Brain Metastases From ALK+ Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 19-2862.cc
  • SECONDARY ID: P30CA046934
  • NCT ID: NCT04634110

Conditions

  • Brain Metastases
  • Lung Cancer

Interventions

DrugSynonymsArms
BrigatinibPatients with ALK+ NSCLC and brain metastases

Purpose

This is a single arm phase II study of brigatinib alone for patients with brain metastases from anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC), who have either not been treated previously with a tyrosine kinase inhibitor (TKI) targeting ALK or who have had prior exposure to crizotinib.

Detailed Description

      In this single-arm phase II trial, patients with brain metastases from ALK+ NSCLC will be
      treated with brigatinib alone without upfront brain irradiation. Patients will have close
      monitoring with clinical follow up visits and brain magnetic resonance imaging (MRI)
      surveillance, which will maximize safety and allow for early treatment if disease progression
      is observed. If brigatinib alone can demonstrate high rates of CNS disease control, these
      data could support a strategy of upfront brigatinib alone for carefully selected patients
      with brain metastases from ALK+ NSCLC.
    

Trial Arms

NameTypeDescriptionInterventions
Patients with ALK+ NSCLC and brain metastasesExperimentalIncluding patients with brain metastases from ALK (anaplastic lymphoma kinase) positive NSCLC (non-small cell lung cancer), who are either neurologically asymptomatic or who have only mild neurologic symptoms (RTOG [Radiation therapy Oncology Group] acute neurologic morbidity score 0-2) from their brain metastases, who are TKI (tyrosine kinase inhibitor) naïve or who have had prior exposure to crizotinib, but who are naïve to brigatinib and other ALK TKIs including alectinib, lorlatinib, and ceritinib.
  • Brigatinib

Eligibility Criteria

        Inclusion Criteria:

          1. Provision to sign and date the consent form.

          2. Stated willingness to comply with all study procedures and be available for the
             duration of the study.

          3. Ability to take and retain oral medications.

          4. Age ≥18 years.

          5. Patients with ALK+ lung cancer with evidence of ≥1 previously untreated brain
             metastases on brain MRI. Prior therapy (radiation or surgery) for brain metastases is
             allowed. However, patients must have ≥1 previously untreated at the time of
             enrollment.

          6. Patients may be ALK TKI naïve OR have had prior crizotinib therapy.

          7. Patients may be included if they are asymptomatic from their brain metastases
             (RTOG/EORTC grade 0) or if they have mild symptoms from their brain metastases not to
             exceed RTOG/ EORTC grade 1 or 2 (Grade 1: Fully functional status (i.e. able to work)
             with minor neurological findings, no medication needed; Grade 2: Neurological findings
             present sufficient to require home care / nursing assistance may be required /
             medications including steroids/anti-seizure agents may be required) (Cox, James D., et
             al "Toxicity criteria of the radiation therapy oncology group (RTOG) and the European
             organization for research and treatment of cancer (EORTC)." International Journal of
             Radiation Oncology• Biology• Physics 31.5 (1995): 1341-1346).

          8. Neurologically symptomatic patients must not require immediate surgical or radiation
             therapy for their symptoms, as decided by an investigator.

          9. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

         10. Have adequate organ function, as determined by

               -  ALT/AST ≤2.5 × upper limit of normal (ULN); ≤5 × ULN is acceptable if liver
                  metastases are present

               -  Total serum bilirubin ≤1.5 × ULN (<3.0×ULN for patients with Gilbert syndrome)

               -  Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the
                  modification of diet in renal disease (MDRD) equation

               -  Serum lipase/amylase ≤1.5 × ULN

               -  Absolute neutrophil count (ANC) ≥1.5 × 109/L

               -  Platelet count ≥75 × 109/L

               -  Hemoglobin ≥9 g/dL

         11. For females of childbearing potential, have a negative pregnancy test documented prior
             to initiating brigatinib.

         12. For female and male patients who are fertile, agree to use 2 effective methods of
             contraception with their sexual partners from the time of signing the informed consent
             through 4 months after the last dose of study drug, or agree to completely abstain
             from heterosexual intercourse. Brigatinib may decrease effectiveness of hormonal
             contraceptives, therefore, women are recommended to use non-hormonal methods of
             contraception. Highly effective non-hormonal birth control for women of child bearing
             potential with male partners includes:

               -  Sexual abstinence (no sexual intercourse)

               -  Intrauterine device (IUD) or intrauterine system (IUS)

               -  Bilateral tubal ligation (both tubes tied)

               -  Vasectomized partner

         13. Male patients, even if surgically sterilized (i.e., status post-vasectomy) must agree
             to 1 of the following:

               -  Practice effective barrier contraception during the entire study treatment period
                  and through 4 months after the last dose of study drug, or completely abstain
                  from heterosexual intercourse.

        Exclusion Criteria:

          1. Patients who have received prior brigatinib therapy or other CNS-penetrant ALK TKIs,
             including alectinib, lorlatinib, or ceritinib.

          2. RTOG/EORTC Acute CNS symptoms, grade 3 and 4 (Grade 3: Neurological findings requiring
             hospitalization for initial management; Grade 4: Serious neurological impairment that
             includes paralysis, coma, or seizures > 3 per week despite medication /
             hospitalization required).

          3. Currently pregnant, planning a pregnancy during the study period, or breastfeeding.

          4. Have clinically significant, uncontrolled cardiovascular disease per investigator,
             specifically including, but not restricted to:

               1. Myocardial infarction (MI) within 6 months prior to the first dose of study drug

               2. Unstable angina within 6 months prior to first dose of study drug

               3. Clinically significant congestive heart failure (CHF) within 6 months prior to
                  first dose of study drug

               4. History of clinically significant atrial or ventricular arrhythmia (including
                  clinically significant bradyarrhythmia), as determined by the treating physician

               5. Cerebrovascular accident or transient ischemic attack within 6 months prior to
                  first dose of study drug

          5. Have uncontrolled hypertension per the investigator. Patients with persistent
             hypertension of systolic ≥140 or diastolic ≥90 mm Hg should be under treatment on
             study entry to control blood pressure.

          6. Have a history or the presence at baseline of pulmonary interstitial disease,
             drug-related pneumonitis, or radiation pneumonitis.

          7. Have an ongoing or active infection, including, but not limited to, the requirement
             for intravenous (IV) antibiotics.

          8. Have a known history of human immunodeficiency virus (HIV) infection. Testing is not
             required in the absence of history.

          9. Have a known or suspected hypersensitivity to brigatinib or its excipients.

         10. Additional systemic therapies for the treatment of lung cancer may not be taken
             concomitantly with brigatinib (eg, TKIs, immunotherapy, chemotherapy). No washout
             period is required for prior therapy.

         11. Have malabsorption syndrome or other GI illness that could affect oral absorption of
             brigatinib.

         12. Have any condition or illness that, in the opinion of the investigator, would
             compromise patient safety or interfere with the evaluation of brigatinib.

         13. Received systemic treatment with strong cytochrome p-450 (cyp)3a inhibitors, strong
             cyp3a inducers, or moderate cyp3a inducers within 14 days before enrollment.

         14. Had major surgery within 30 days of the first dose of brigatinib. Minor surgical
             procedures such as catheter placement or minimally invasive biopsies are allowed.

         15. Have been diagnosed with another primary malignancy other than NSCLC, except for
             adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively
             treated 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease Control Rate (DCR) of brain metastases at 3 months
Time Frame:13-week MRI ±7 days
Safety Issue:
Description:DCR is defined as complete response (CR), partial response (PR), or stable disease (SD) as defined by the RANO-BM (Response Assessment in Neuro-Oncology Criteria - Brain Metastases) criteria.

Secondary Outcome Measures

Measure:Time until progression with brigatinib alone (part 1)
Time Frame:up to 24 months
Safety Issue:
Description:Time until any CNS progressive disease (PD) by RANO-BM criteria and rates at follow up intervals
Measure:Time until progression with brigatinib alone (part 2)
Time Frame:up to 24 months
Safety Issue:
Description:Time until any local PD (i.e., in brain lesions identified at the time of enrollment) by RANO-BM criteria and rates at follow up intervals
Measure:Time until progression with brigatinib alone (part 3)
Time Frame:up to 24 months
Safety Issue:
Description:Time until any distant brain PD (i.e., new brain lesions that were not present at the time of enrollment) by RANO-BM criteria and rates at follow up intervals
Measure:Time until progression with brigatinib alone (part 4)
Time Frame:up to 24 months
Safety Issue:
Description:Time until progression at any site using RANO-BM for intracranial disease and RECIST for extracranial disease and rates at follow up intervals
Measure:Overall survival with a strategy of brigatinib alone
Time Frame:up to 24 months
Safety Issue:
Description:Time until death from any cause and rates at follow up intervals
Measure:Brain metastases-specific mortality
Time Frame:up to 24 months
Safety Issue:
Description:Defined as time to intracranial progression as a component of cause of death and rates at follow up intervals
Measure:Brain metastases objective response rates (ORR) with brigatinib alone
Time Frame:up to 24 months
Safety Issue:
Description:Cumulative rate of best responses individually for complete response (CR), partial response (PR), stable disease (SD), by RANO-BM criteria
Measure:Time until the administration of WBRT with brigatinib alone
Time Frame:up to 24 months
Safety Issue:
Description:Time until the administration of whole brain-radiotherapy (WBRT) and rates at follow up intervals
Measure:Longitudinal changes in quality of life with brigatinib alone
Time Frame:up to 24 months
Safety Issue:
Description:Quality of life will be assessed using standardized QOL metrics (EORTC QLQ C30/BN 20)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Colorado, Denver

Last Updated

November 18, 2020