Clinical Trials /

Brigatinib in Treating Patients With ALK and ROS1 Gene Alterations and Locally Advanced or Metastatic Solid Cancers

NCT03868423

Description:

This phase II trial studies how well brigatinib works in treating patients with ALK and ROS1 gene alterations and solid cancers that have spread to nearby tissue and lymph nodes or other places in the body. Brigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Lung Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Brigatinib in Treating Patients With ALK and ROS1 Gene Alterations and Locally Advanced or Metastatic Solid Cancers
  • Official Title: Phase II Study of Brigatinib for Advanced Solid Cancers Harboring Genomic Alterations in ALK (Excluding Lung) and ROS1 Oncogenes

Clinical Trial IDs

  • ORG STUDY ID: OSU-17060
  • SECONDARY ID: NCI-2017-01394
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03868423

Conditions

  • Advanced Malignant Neoplasm
  • ALK Fusion Protein Expression
  • ALK Gene Amplification
  • ALK Gene Mutation
  • Locally Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Malignant Neoplasm in the Central Nervous System
  • Metastatic Malignant Solid Neoplasm
  • ROS1 Fusion Positive
  • ROS1 Gene Amplification
  • ROS1 Gene Mutation

Interventions

DrugSynonymsArms
BrigatinibAlunbrig, AP 26113, AP-26113, AP26113Treatment (brigatinib)

Purpose

This phase II trial studies how well brigatinib works in treating patients with ALK and ROS1 gene alterations and solid cancers that have spread to nearby tissue and lymph nodes or other places in the body. Brigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the overall response rate (ORR) of brigatinib in patients with advanced solid
      tumors harboring genomic alterations in ALK (excluding lung) and ROS1 (all solid tumors).

      SECONDARY OBJECTIVES:

      I. To assess the safety and tolerability of brigatinib in patients with advanced solid tumors
      harboring genomic alterations in ALK (excluding lung) and ROS1 (all solid tumors).

      II. To assess progression free survival (PFS) and overall survival (OS) in patients with
      advanced ALK or ROS1 mutated solid tumors treated with brigatinib.

      III. To assess sensitivity and durability of response to brigatinib in different solid tumor
      types.

      IV. To assess the role of intertumoral and intratumoral heterogeneity in the development of
      resistance to brigatinib.

      V. To identify candidate genomic (including circulating tumor deoxyribonucleic acid [DNA])
      and proteomic biomarkers of tumor sensitivity and resistance to brigatinib using
      high-throughput approaches (exome, transcriptome, reverse phase protein array [RPPA]).

      TERTIARY OBJECTIVES:

      I. Correlation of brigatinib exposure with efficacy and safety. II. Correlation of tumor and
      plasma biomarkers with brigatinib efficacy and safety.

      OUTLINE:

      Patients receive brigatinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 52 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (brigatinib)ExperimentalPatients receive brigatinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Brigatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with histologically or cytologically confirmed diagnosis of locally advanced
             or metastatic solid tumors

          -  Patients must have activating genomic alterations in ALK or ROS1 (mutations, fusions
             or amplifications) by any validated Clinical Laboratory Improvement Act
             (CLIA)-certified molecular testing (fluorescence in situ hybridization [FISH],
             polymerase chain reaction [PCR] or next-generation sequencing [NGS] data are
             acceptable); CLIA validated results from other institutions and commercial diagnostic
             labs (e.g. Foundation Medicine) are also acceptable

          -  Patients with progressive disease on any previous therapy including crizotinib and
             other ALK tyrosine kinase inhibitors (TKIs), chemotherapy or immunotherapy

          -  Patients with locally advanced or metastatic solid tumors who have received no
             previous therapy of any kind (i.e. first-line therapy) are eligible

          -  Patients with brain metastases or metastases elsewhere within the central nervous
             system (CNS) are eligible for study; patients must be neurologically stable and
             asymptomatic

          -  Patients with tumor suitable for biopsy (as assessed by trained specialists in
             interventional radiology) and medically fit to undergo a biopsy or surgical procedure
             will have mandatory pre-treatment tumor biopsy or sampling; however, if patients do
             not have a tumor suitable for biopsy but have another tissue (preferably progressive
             metastatic site) available for molecular evaluation this will be acceptable

          -  Patients with solid tumors must have at least 1 measurable lesion per Response
             Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1; 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

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Life expectancy of greater than 3 months

          -  Patients with multiple malignancies remain eligible

          -  Patients with an inherited cancer syndrome or a medical/family history suggestive of
             an inherited cancer syndrome remain eligible

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and
             through 4 months after the end of treatment; for women of childbearing potential, a
             negative pregnancy test must be documented prior to registration

          -  Absolute neutrophil count >= 1,500/mcL

          -  Hemoglobin >= 10 g/dL

          -  Platelet count >= 75,000/mcL

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert?s syndrome
             (< 5 if metastatic involvement of the liver)

          -  Serum lipase =< 1.5 x ULN

          -  Serum amylase =< 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             institutional ULN

          -  Left ventricular ejection fraction (LVEF) >= 50% by echocardiogram or multi-gated
             acquisition (MUGA)

          -  Normal QT interval on screening electrocardiogram (ECG), defined as QT interval
             corrected of =< 450 ms in males or =< 470 ms in females

          -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault
             formula) >= 60 mL/min OR 24-hour urine creatinine clearance >= 60 mL/min

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients with hematological malignancies

          -  Patients with ALK positive (+) lung cancer

          -  Major surgery (e.g. thoracic, abdominal, vascular, neurosurgery) within 30 days prior
             to registration on study

          -  Pregnant women or mothers who are breastfeeding

          -  Patients who are incarcerated

          -  Patients who have a history or the presence at baseline of pulmonary interstitial
             disease or drug-related pneumonitis, or radiation pneumonitis

          -  Patients who have a known history of human immunodeficiency virus (HIV); testing not
             required in the absence of history

          -  Patients with history of clinically significant bleeding disorder or history of active
             significant gastrointestinal (GI) bleeding within 3 months of first dose of brigatinib

          -  Patients who have malabsorption syndrome or other GI illness or condition that could
             affect oral absorption of the study drug

          -  History of allergic or suspected hypersensitivity reactions attributed to compounds of
             similar chemical or biologic composition to brigatinib

          -  Patients with history of clinically significant atrial arrhythmias (requiring any
             anti-arrhythmic therapy or as determined by the treating physician) or any history of
             ventricular arrhythmias

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

               -  Myocardial infarction (MI) within 6 months prior to first dose of brigatinib

               -  Unstable angina (UA) within 6 months prior to first use

               -  Decompensated congestive heart failure within 6 months prior to first dose

               -  Cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months
                  prior to first dose

          -  Clinically significant, uncontrolled intercurrent illness including, but not limited
             to:

               -  Symptomatic or active infection requiring intravenous (IV) antibiotics

               -  Psychiatric illness and/or social situations that would limit compliance with
                  completion of study requirements

          -  Patients on medications known to be associated with torsades de pointes

          -  Patients who have uncontrolled hypertension; patients with hypertension should be
             under treatment on study entry to control blood pressure

          -  Patients who have received cytotoxic chemotherapy, investigational agents, or
             radiation within 14 days, except stereotactic radiosurgery (SRS) or stereotactic body
             radiosurgery

          -  Patients who have received monoclonal antibodies or had major surgery within 30 days
             of the first dose of brigatinib

          -  Patients who have not recovered (=< Common Terminology Criteria for Adverse Events
             [CTCAE] grade 1) from adverse events (with the exception of alopecia) due to agents
             administered more than 4 weeks earlier

          -  Patients with symptomatic CNS metastases that are neurologically unstable or require
             increasing dose of corticosteroids

          -  Patients with current spinal cord compression
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time Frame:Up to 52 weeks
Safety Issue:
Description:Response for tumors will be assessed using the RECIST 1.1 criteria (using computed tomography scans or calipers by clinical exam) where response will be defined as a partial or complete response. Will be calculated with 95% binomial confidence intervals for the estimate of the proportion of responses.

Secondary Outcome Measures

Measure:Confirmed objective response rate (ORR)
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be assessed by central independent review committee per RECIST version 1.1.
Measure:Time to response
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be evaluated.
Measure:Duration of response
Time Frame:From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 52 weeks
Safety Issue:
Description:Will be evaluated.
Measure:Time on treatment
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be evaluated.
Measure:Disease control rate
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be assessed by RECIST version 1.1.
Measure:Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 52 weeks
Safety Issue:
Description:Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Measure:Overall survival
Time Frame:From treatment initiation to death due to any cause, assessed up to 52 weeks
Safety Issue:
Description:Kaplan-Meier curves will be used to estimate the survival distributions of overall survival.
Measure:Progression-free survival
Time Frame:From the date of study registration to the date of event (ie, death and/or disease progression) or the date of last follow-up if no event has occurred, up to 52 weeks
Safety Issue:
Description:Kaplan-Meier curves will be used to estimate the survival distributions of progression-free survival.
Measure:Clinical benefit rate
Time Frame:6 months
Safety Issue:
Description:Will be calculated by the number of patients who have achieve a response and/or are progression-free and alive at 6 months divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for clinical benefit rate will be calculated.
Measure:Rate of participation of those screened and identified with the eligible genetic alterations
Time Frame:Up to 52 weeks
Safety Issue:
Description:The logistical aspects of the trial will be evaluated and summarized. Disease group-specific outcomes will also be summarized and described, although we will not be powered for any formal evaluation within a disease or histology subset.
Measure:Rate of enrollment of those screened and identified with the eligible genetic alterations
Time Frame:Up to 52 weeks
Safety Issue:
Description:The logistical aspects of the trial will be evaluated and summarized. Disease group-specific outcomes will also be summarized and described, although we will not be powered for any formal evaluation within a disease or histology subset. Genes will be evaluated in aggregate from whole exome and transcriptome sequencing.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sameek Roychowdhury

Last Updated