Brigatinib and Bevacizumab for the Treatment of ALK-Rearranged Locally Advanced, Metastatic, or Recurrent NSCLC

  • STATUS
    Recruiting
  • End date
    Nov 1, 2023
  • participants needed
    31
  • sponsor
    City of Hope Medical Center
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Updated on 4 October 2022
See if I qualify
monoclonal antibodies
measurable disease
brigatinib
lipase
lung cancer
gilbert's syndrome
glomerular filtration rate
metastasis
neutrophil count
liver metastasis
tumor cells
monoclonal antibody therapy
bevacizumab
liver metastases
line of therapy
leptomeningeal disease
periodic abstinence
recurrent non-small cell lung cancer
lactational amenorrhea

Summary

This phase Ib trial studies the side effects and best dose of brigatinib and how well it works with bevacizumab in treating patients with ALK-rearranged non-small cell lung cancer that has spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic) or has come back (recurrent). Brigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known if brigatinib and bevacizumab will work better in treating patients with ALK-rearranged non-small cell lung cancer.

Description

PRIMARY OBJECTIVE:

I. To determine toxicity and tolerability, and the maximum tolerated dose (MTD) of brigatinib and bevacizumab in patients with ALK rearranged non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To describe the dose-limiting toxicities of brigatinib in combination with bevacizumab.

II. To estimate overall response rate (ORR) to treatment with brigatinib and bevacizumab.

III. To estimate the duration of response as defined by the time of first documented clinical benefit to the time of progression.

IV. To estimate patient survival by measuring progression free survival (PFS) as defined by the time from treatment initiation to documented disease progression or death from any cause. Overall survival (OS) as defined by the time from treatment initiation until death due to any cause.

EXPLORATORY OBJECTIVES:

I. To identify predictive biomarkers using genetics and tumor immunology-based assessment platforms.

Ia. Analysis with next-generation sequencing (NGS) to identify predictive biomarkers for response using tissue and cerebral spinal fluid (CSF) (optional for patients with brain metastases).

Ib. Tumor tissue will be obtained at baseline, and cell free deoxyribonucleic acid (DNA) (cfDNA)/cell tumor DNA (ctDNA) obtained at baseline and the time of progression or study completion will be evaluated for genomic alterations and biomarkers.

II. Evaluation of central nervous system (CNS) penetration through cerebral spinal fluid (CSF) obtained by lumbar puncture on cycle 2 day 1 (C2D1) (with time matched pharmacokinetic [PK] blood draw), and at progression or study completion for consenting patients (optional).

OUTLINE: This is a dose-escalation study of brigatinib.

Patients receive brigatinib orally (PO) once daily (QD) on days 1-28 of cycle 1 and days 1-21 of subsequent cycles. Patients also receive bevacizumab intravenously (IV) on day 8 of cycle 1 and day 1 of subsequent cycles. Starting cycle 2, cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, 3, 6, 9, and 12 months, then every 6 months for up to 3 years.

Details
Condition Locally Advanced Lung Non-Small Cell Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage III Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Treatment bevacizumab, brigatinib
Clinical Study IdentifierNCT04227028
SponsorCity of Hope Medical Center
Last Modified on4 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Patients must have a histologically documented (either primary or metastatic site) diagnosis of locally advanced, recurrent, or metastatic ALK rearranged non-small cell lung cancer (NSCLC)
Patients must have shown progression on ALK-directed therapy
Note: Patients may have received more than one prior line of therapy, however, at least one of these must be an ALK-directed line of therapy
Patients must have measurable disease as per appropriate guidelines by Response
Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
Patients must have the ability to understand and the willingness to sign a written consent prior to registration in the study
Patients with asymptomatic (as determined by the treating investigator) CNS metastasis are eligible for participation
Note: Patients with leptomeningeal disease are not eligible
Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status
Patient life expectancy of more than 12 weeks
Patients must have adequate organ and bone marrow function during screening, as defined below
of =< 2
Absolute neutrophil count >= 1.5 x 10^9/L
Hemoglobin >= 9 g/dL
Note: Transfusions are permitted (transfusions >= 1 day to registration are allowed)
Platelets >= 75 x 10^(9)/L
Total bilirubin =< 1.5 x upper limit of normal (ULN)
Note: Patients with Gilbert syndrome are exempt
Alanine amino transferase and aspartate aminotransferase =< 2.5 x ULN
Note: =< 5 x ULN is acceptable if liver metastases are present
Serum lipase =< 1.5 x ULN
Creatine kinase (CPK) < 5.0 x ULN
Estimated glomerular filtration rate (eGFR) using the modification of diet in renal disease (MDRD) equation >= 30 mL/min/1.73 m^2
Patients must meet criteria for appropriate contraception, listed as follows
Female patients must meet at least one of the following criteria
Are postmenopausal with last menstrual period at least 1 year before registration, OR
Are surgically sterile, OR
If they are of childbearing potential
Agree to practice 1 highly effective method of non-hormonal contraception and one additional effective (barrier) method at the same time, from the time of signing the informed consent through 180 days after the last dose of study drug, or
Agree to practice true abstinence, when is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. 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.)
Agree not to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug. Agree not to breast-feed for the duration of treatment through 6 months post treatment
Male patients, even if surgically sterilized (i.e. status post-vasectomy), must
Agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, or
Note: Female patients who are pregnant, planning a pregnancy, or nursing are
not eligible
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception. Female and male condoms should not be used together.)
Agree not to donate sperm during the course of this study or within 180 days after receiving their last dose of study drug

Exclusion Criteria

Patients who have had prior systemic anticancer or radiotherapy =< 14 days prior to first dose of brigatinib are not eligible
Patients may not have received any other investigational agents =< 14 days prior to first dose of brigatinib
Patients who have received antineoplastic monoclonal antibodies within 21 days of the first dose of brigatinib, and tyrosine kinase inhibitors (TKIs) within 7 days of the first dose of brigatinib are not eligible
Patients with prior severe infusion reaction to bevacizumab are not eligible
Patients with other coexisting malignancies or malignancies diagnosed within the previous 3 years that per the investigator are at high-risk of relapse within one year are not eligible
Note: Exceptions to this include non-melanoma skin cancer, cervical cancer in-situ, well-differentiated thyroid cancer or prostate cancer. Other cancers that per assessment of the principal investigator (PI) are not prognosis-limiting can be allowed after review by the PI. If there is no evidence of disease for at least 3 years, patients may be eligible
Uncontrolled pulmonary, renal, or hepatic dysfunction
Ongoing or active infection requiring systemic treatment including hepatitis B and hepatitis C
Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection
Patients who have an uncontrolled intercurrent illness including, but not limited to
any of the following, are not eligible
Note: Patients who have isolated positive hepatitis B core antibody (i.e. in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
Known active or chronic viral hepatitis or human immunodeficiency virus (HIV)
Psychiatric illness/social situations that would limit compliance with study requirements
Active uncontrolled infection or severe infectious disease such as severe
Female patients who are pregnant, planning a pregnancy, or nursing or have a positive serum pregnancy test within 7 days prior registration (without subsequent negative vaginal ultrasound) are not eligible
pneumonia, meningitis, or septicemia
Patients who have had major surgery within 30 days of registration, are not eligible
Note: Minor surgical procedures such as catheter placement or minimally invasive biopsies are allowed
Myocardial infarction within 6 months before registration
Patients with any other illness or condition that the treating investigator feels
Unstable angina within 6 months before registration
would interfere with study compliance or would compromise the patient's safety
Congestive heart failure within 6 months before registration
or study endpoints are not eligible
History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician
Any history of clinically significant ventricular arrhythmia
Patients who have uncontrolled hypertension are not eligible
Patients who have significant, uncontrolled, or active cardiovascular disease
Note: Patients with hypertension per the opinion of the treating investigator should be under treatment on study entry to control blood pressure
specifically including, but not restricted to the following are not eligible
Patients who have a history of or the presence at baseline of grade 2 or higher uncontrolled drug related pneumonitis, or radiation pneumonitis are not eligible
Patients who have malabsorption syndrome or other gastrointestinal (GI) illness that could affect oral absorption of brigatinib in the opinion of the treating Investigator are not eligible
Patients with recent history of pulmonary embolism, or untreated deep vein thrombosis in the last 3 months are not eligible
Note: Patients may be eligible if they have received at least 3 months of anticoagulation for a deep vein thrombosis
Patients who have had a cerebrovascular accident or transient ischemic attack within 6
Patients who have received systemic treatment with strong cytochrome P-450 (CYP)3A inhibitors, strong CYP3A inducers or moderate CYP3A inducers within 14 days before registration are not eligible
months before registration are not eligible
Patients who have the presence at baseline of unresolved pulmonary interstitial
disease that is grade 3 or 4 are not eligible
Patients who have a known or suspected hypersensitivity to brigatinib, or its
excipients are not eligible
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monoclonal antibodies
measurable disease
brigatinib
lipase
lung cancer
gilbert's syndrome
glomerular filtration rate
metastasis
neutrophil count
liver metastasis
tumor cells
monoclonal antibody therapy
bevacizumab
liver metastases
line of therapy
leptomeningeal disease
periodic abstinence
recurrent non-small cell lung cancer
lactational amenorrhea

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