Brigatinib Before Brain Irradiation Trial (B3i Trial)

• ClinicalTrials.gov Identifier: NCT04634110
• Recruitment Status: Terminated
• First Posted: November 18, 2020
• Results First Posted: October 24, 2022
• Last Update Posted: October 24, 2022
• Sponsor: University of Colorado, Denver
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Brain Metastases; Lung Cancer	Drug: Brigatinib	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Brigatinib Before Brain Irradiation Trial (B3i Trial): A Phase II Trial of Brigatinib Alone for Brain Metastases From ALK+ Lung Cancer
• Actual Study Start Date: November 17, 2020
• Actual Primary Completion Date: April 14, 2022
• Actual Study Completion Date: April 14, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Patients with ALK+ NSCLC and brain metastases; Including 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.

Drug: Brigatinib; At day 1, all patients will be started on brigatinib 90 mg daily for 7 days, before escalating to 180 mg daily thereafter as tolerated.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Meet Disease Control Rate (DCR) Criteria of Brain Metastases at 3 Months [ Time Frame: 13-week MRI ±7 days ]
   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 :

1. Time Until Progression With Brigatinib Alone (Part 1) [ Time Frame: up to 24 months ]
   Time until any CNS progressive disease (PD) by RANO-BM criteria and rates at follow up intervals
2. Time Until Progression With Brigatinib Alone (Part 2) [ Time Frame: up to 24 months ]
   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
3. Time Until Progression With Brigatinib Alone (Part 3) [ Time Frame: up to 24 months ]
   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
4. Time Until Progression With Brigatinib Alone (Part 4) [ Time Frame: up to 24 months ]
   Time until progression at any site using RANO-BM for intracranial disease and RECIST for extracranial disease and rates at follow up intervals
5. Overall Survival With a Strategy of Brigatinib Alone [ Time Frame: up to 24 months ]
   Time until death from any cause and rates at follow up intervals
6. Time Until Brain Metastases-Specific Mortality [ Time Frame: up to 24 months ]
   Defined as time to intracranial progression as a component of cause of death and rates at follow up intervals
7. Brain Metastases Objective Response Rates (ORR) With Brigatinib Alone [ Time Frame: up to 24 months ]
   Cumulative rate of best responses individually for complete response (CR), partial response (PR), stable disease (SD), by RANO-BM criteria
8. Time Until the Administration of WBRT With Brigatinib Alone [ Time Frame: up to 24 months ]
   Time until the administration of whole brain-radiotherapy (WBRT) and rates at follow up intervals
9. Longitudinal Changes in Quality of Life With Brigatinib Alone [ Time Frame: up to 24 months ]
   Quality of life will be assessed using standardized QOL metrics (EORTC QLQ C30/BN 20)

Other Outcome Measures:

1. Analysis of Blood at Baseline and at Progression to Correlate With Clinical Outcomes [ Time Frame: up to 24 months ]
   Evaluation of cfDNA at baseline and progression to correlate with clinical outcomes, including incidence of disease recurrence per RANO-BM and RECIST 1.1, survival status by percentage of patients alive at 2 years, and patient rating of quality of life per EORTC QLQ-BN20 and EORTC QLQ-C30 questionnaires.
2. Characterization of Corticosteroid Administration Before and After Brigatinib Initiation [ Time Frame: up to 24 months ]
   Quantification of the agent and dosage of corticosteroids at each study assessment

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

City of Hope

Duarte, California, United States, 91010

United States, Colorado

University of Colorado Hospital

Aurora, Colorado, United States, 80045

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

University of Colorado, Denver

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Chad Rusthoven, MD; University of Colorado, Denver

  Study Documents (Full-Text)

Documents provided by University of Colorado, Denver:

Study Protocol and Statistical Analysis Plan  [PDF] December 29, 2021

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT04634110
• Other Study ID Numbers: 19-2862.cc; P30CA046934 ( U.S. NIH Grant/Contract )
• First Posted: November 18, 2020
• Results First Posted: October 24, 2022
• Last Update Posted: October 24, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases