Clinical Trials /

Brigatinib and Bevacizumab for the Treatment of ALK-Rearranged Locally Advanced, Metastatic, or Recurrent Non-small Cell Lung Cancer

NCT04227028

Description:

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.

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

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Brigatinib and Bevacizumab for the Treatment of ALK-Rearranged Locally Advanced, Metastatic, or Recurrent Non-small Cell Lung Cancer
  • Official Title: Phase Ib Study of Brigatinib Plus Bevacizumab in Patients With ALK-Rearranged Non-Small Cell Lung Cancer (NSCLC) Who Have Previously Progressed on Prior ALK-Directed Therapy

Clinical Trial IDs

  • ORG STUDY ID: NU 19L01
  • SECONDARY ID: STU00211030
  • SECONDARY ID: NU 19L01
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: NCI-2019-08726
  • NCT ID: NCT04227028

Conditions

  • 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

Interventions

DrugSynonymsArms
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab awwb, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar CT-P16, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, BP102, BP102 Biosimilar, HD204, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501Treatment (brigatinib, bevacizumab)
BrigatinibAlunbrig, AP 26113, AP-26113, AP26113Treatment (brigatinib, bevacizumab)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (brigatinib, bevacizumab)ExperimentalPatients receive brigatinib PO QD on days 1-28 of cycle 1 and days 1-21 of subsequent cycles. Patients also receive bevacizumab 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.
  • Bevacizumab
  • Brigatinib

Eligibility Criteria

        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
             of =< 2

          -  Patient life expectancy of more than 12 weeks

          -  Patients must have adequate organ and bone marrow function during screening, as
             defined below:

          -  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

                    -  Note: Female patients who are pregnant, planning a pregnancy, or nursing are
                       not eligible

               -  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

                    -  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

          -  Patients who have an uncontrolled intercurrent illness including, but not limited to
             any of the following, are not 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,

                    -  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

               -  Active uncontrolled infection or severe infectious disease such as severe
                  pneumonia, meningitis, or septicemia,

               -  Known active or chronic viral hepatitis or human immunodeficiency virus (HIV),

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

          -  Patients with any other illness or condition that the treating investigator feels
             would interfere with study compliance or would compromise the patient's safety or
             study endpoints are not eligible

          -  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

          -  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

          -  Patients who have significant, uncontrolled, or active cardiovascular disease,
             specifically including, but not restricted to the following are not eligible:

               -  Myocardial infarction within 6 months before registration

               -  Unstable angina within 6 months before registration

               -  Congestive heart failure within 6 months before registration

               -  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 had a cerebrovascular accident or transient ischemic attack within 6
             months before registration are not eligible

          -  Patients who have uncontrolled hypertension are not eligible

               -  Note: Patients with hypertension per the opinion of the treating investigator
                  should be under treatment on study entry to control blood pressure

          -  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 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 a known or suspected hypersensitivity to brigatinib, or its
             excipients are not eligible

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Within 30 days of treatment discontinuation or prior to start of next treatment
Safety Issue:
Description:Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

Secondary Outcome Measures

Measure:Dose-limiting toxicities
Time Frame:Up to 28 days
Safety Issue:
Description:Will be evaluated in the first 28 days of treatment for the first 6-12 patients in the safety cohort to determine any dose limiting toxicities at this dose.
Measure:Overall response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Will be defined as the overall number of patients with complete response plus partial response and assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. A proportion and exact 95% binomial confidence interval will be calculated.
Measure:Duration of response
Time Frame:From first documentation of clinical benefit from treatment to the time of documentation of progressive disease or death, whichever comes first, assessed up to 3 years
Safety Issue:
Description:Will be analyzed using medians and ranges.
Measure:Progression-free survival (PFS)
Time Frame:From treatment initiation to the time of documented disease progression or death from any cause, whichever comes first, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method. If there is a change of treatment in multiple patients, then a competing risk cumulative incidence for PFS will be calculated using the treatment change as a competing risk.
Measure:Overall survival (OS)
Time Frame:From treatment initiation until death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Northwestern University

Last Updated

January 10, 2020