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Brigatinib and Binimetinib in Treating Patients With Stage IIIB-IV ALK or ROS1-Rearranged Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT04005144
Recruitment Status : Not yet recruiting
First Posted : July 2, 2019
Last Update Posted : July 2, 2019
Sponsor:
Collaborators:
Takeda
Array BioPharma
Information provided by (Responsible Party):
Caroline McCoach, MD, PhD, University of California, San Francisco

Brief Summary:
This phase I trial studies the side effects and best dose of brigatinib and binimetinib in treating patients with stage IIIB-IV non-small cell lung cancer and a type of gene mutation called a rearrangement in the ALK or ROS1 genes. Brigatinib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
ALK Gene Rearrangement Lung Non-Small Cell Carcinoma Progressive Disease ROS1 Gene Rearrangement Stage IIIB Lung Cancer Stage IIIC Lung Cancer Stage IV Lung Cancer Stage IVA Lung Cancer Stage IVB Lung Cancer Drug: Binimetinib Drug: Brigatinib Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of brigatinib in combination with binimetinib in stage IIIB or IV ALK or ROS1 rearranged non-small cell lung cancer (NSCLC) and the recommended phase 2 dose.

SECONDARY OBJECTIVES:

I. To determine preliminary efficacy of brigatinib in combination with binimetinib in any line of treatment.

II. To characterize the pharmacokinetic parameters of brigatinib in combination with binimetinib.

EXPLORATORY OBJECTIVES:

I. To assess circulating tumor deoxyribonucleic acid (DNA) (ctDNA) utility in evaluating treatment response.

II. To evaluate the blockade of downstream signaling indicating response or resistance to treatment of immunohistochemistry (IHC) for PI3K/AKT/MAPK pathway activity evaluation.

OUTLINE: This a dose-escalation study.

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

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Brigatinib With Binimetinib in Advanced ALK- or ROS1-Rearranged Non-Small Cell Lung Cancer (NSCLC)
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Brigatinib

Arm Intervention/treatment
Experimental: Treatment (brigatinib, binimetinib)
Patients receive brigatinib PO QD and binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162

Drug: Brigatinib
Given PO
Other Names:
  • Alunbrig
  • AP 26113
  • AP-26113
  • AP26113




Primary Outcome Measures :
  1. Recommended Phase 2 Dose of Brigatinib in Combination with Binimetinib [ Time Frame: Up to 12 months ]
    Will be measured by evaluating the number and frequency of adverse events as determined by the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version (v)5.0 by investigator's assessment and to determine the recommended phase 2 dose for future studies.

  2. Number of Participants with Dose Limiting Toxicities [ Time Frame: Up to 28 days ]
    A dose limiting toxicity (DLT) is generally defined as a grade 3 or higher, treatment-related adverse event that is attributable to the study treatment during the first 28 days of therapy (Cycle 1). The dose limiting toxicity will be based on the tolerability observed during cycle 1 of treatment/observation. Adverse events will be assessed by the investigators using NCI-CTCAE v5.0.

  3. Number of All Treatment-Emergent Adverse Events by CTCAE v5.0 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Severity grade will be defined by the NCI CTCAE v5.0.

  4. Number of Treatment-Emergent Adverse Events by CTCAE v5.0 Grade [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Severity grade will be defined by the NCI CTCAE v5.0.

  5. Number of Grade 3 or Greater Treatment-Emergent Adverse Events by CTCAE v5.0 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Severity grade will be defined by the NCI CTCAE v5.0.

  6. Number of Serious Treatment-Emergent Adverse Events by CTCAE v5.0 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Severity grade will be defined by the NCI CTCAE v5.0.

  7. Number of Treatment-Emergent Adverse Events with an Outcome of Death by CTCAE v5.0 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Severity grade will be defined by the NCI CTCAE v5.0.

  8. Number of Treatment-Emergent Adverse Events Leading to Discontinuation of Brigatinib and Binimetinib by CTCAE v5.0 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Severity grade will be defined by the NCI CTCAE v5.0.

  9. Number of Treatment-Emergent Adverse Events Resulting in Interruption, Reduction or Delay of Brigatinib or Binimetinib by CTCAE v5.0 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Severity grade will be defined by the NCI CTCAE v5.0.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Point estimate and 95% exact binomial confidence interval (CI) will be obtained for ORR.

  2. Median Depth of Response Assessed by RECIST v1.1 [ Time Frame: From treatment initiation through study completion, an average of 1 year ]
    Will be defined as maximal reduction in tumor size based on Response Evaluation Criteria in Solid Tumors (RECIST) measurement. Median and inter-quartile range will be used to describe the depth of response (the maximal reduction in tumor size based on RECIST measurement).

  3. Area Under the Plasma Concentration versus Time Curve (AUC) of Brigatinib [ Time Frame: At pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose on days 1 and 15 of cycle 1 ]
    Plasma concentration assessment (pharmacokinetic data) of brigatinib during coadministration with binimetinib will be determined by assay at various timepoints. The assay will be done by Takeda / their designated vendor.

  4. Progression Free Survival (PFS) [ Time Frame: Time from start of treatment to time of disease progression, assessed at 6 months ]
    Kaplan-Meier method will be used to describe the describe PFS at 6 months months with their median and 95% CI.

  5. Overall Survival (OS) [ Time Frame: At 12 months ]
    Kaplan-Meier method will be used to describe the describe OS at 12 months with their median and 95% CI.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Participants must have histologically or cytological confirmed stage IIIB/IV NSCLC
  • Documented ALK-rearrangement (or ROS1- rearrangement) break-apart fluorescence in situ hybridization (FISH) (in >= 15% or tumor cells), or next generation sequencing assay performed on tumor sample or cell free DNA in a Clinical Laboratory Improvement Act (CLIA)-approved laboratory
  • At least one prior ALK or ROS1 targeted tyrosine kinase inhibitor (TKI). With progression or intolerance of most recent regimen
  • Measurable or evaluable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • Life expectancy of at least 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >=1,500/mcL
  • Platelets >= 75,000/mcL
  • Hemoglobin (Hgb) >= 9 gm/dL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 5 x institutional upper limit of normal
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional upper limit of normal if there are liver metastases
  • Creatinine within normal institutional limits OR
  • Creatinine clearance >= 50 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
  • Female participants who:

    • Are postmenopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of the study drugs, or
    • Agree to completely abstain from heterosexual intercourse
  • Male participants, even if surgically sterilized (i.e., status post-vasectomy), who:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of the study drugs, or
    • Agree to completely abstain from heterosexual intercourse
  • Negative pregnancy testing required at screening and cycle 1 day 1 for women of childbearing potential
  • Ability to understand a written informed consent document, and willingness to sign it
  • Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  • Participant is deemed by the investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up)

Exclusion Criteria:

  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 7 days for prior TKI and 14 days for chemotherapy or radiation and 30 days for prior immunotherapy before the first dose of treatment
  • Prior treatment with either study drug as most recent treatment or prior discontinuation of either study drug due to toxicity
  • Known hypersensitivity to any study drug components
  • Known history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis
  • Known history of myositis
  • History of pancreatitis
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease
  • Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:

    • Symptomatic chronic heart failure grade >= 2, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia.
    • Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

      • Myocardial infarction (MI) within 6 months prior to the first dose of brigatinib
      • Unstable angina within 6 months prior to first dose
      • Symptomatic congestive heart failure requiring treatment (New York Heart Association grade >= 2), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality =< 6 months prior to Screening except atrial fibrillation and paroxysmal supraventricular tachycardia
      • Congestive heart failure requiring treatment (New York Heart Association grade >= 2)
      • Left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO)
      • QT interval corrected for heart rate using the Fridericia formula (QTcF) > 480 msec;
      • History of clinically significant atrial arrhythmia
      • Any history of ventricular arrhythmia
      • Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose
  • Uncontrolled hypertension defined as persistent elevation of systolic blood pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg despite current therapy
  • History of chronic inflammatory bowel disease or Crohn?s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) =< 12 months prior to first dose of study treatment
  • Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of binimetinib or brigatinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
  • History of thromboembolic or cerebrovascular events =< 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli
  • Current neuromuscular disorder(s) associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Major surgery =< 3 weeks prior to starting study drugs, or persistent/ongoing side effects of major surgery
  • Pregnant or nursing (lactating) women
  • Other severe, acute, or chronic medical conditions including uncontrolled diabetes mellitus or psychiatric conditions or laboratory abnormalities that, in the opinion of the investigator, may increase the risk associated with study participation or may interfere with ability to participate actively in the study
  • History of another malignancy. Participants with fully resected non-melanoma skin cancer, indolent early stage second malignancies, or who have been disease free for > three years may be eligible following discussion with study principal investigator (PI)
  • Any symptomatic brain metastasis

    • Note: Participants previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for >= 2 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening)
  • Participants receiving any medications or substances that are inhibitors or inducers of CYP3A enzyme(s) and CYP2C8 within 14 days of enrollment are ineligible
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04005144


Contacts
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Contact: Caroline McCoach, MD, PhD 877-827-3222 Cancertrials@ucsf.edu
Contact: Mayra Gonzalez 415-353-7912 Mayra.Gonzalez@ucsf.edu

Locations
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United States, California
University of California, San Francisco Not yet recruiting
San Francisco, California, United States, 94143
Contact: Caroline McCoach, MD, PhD    877-827-3222    Cancertrials@ucsf.edu   
Contact: Mayra Gonzalez    415-353-7912    Mayra.Gonzalez@ucsf.edu   
Principal Investigator: Caroline McCoach, MD, PhD         
Sponsors and Collaborators
University of California, San Francisco
Takeda
Array BioPharma
Investigators
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Principal Investigator: Caroline McCoach, MD, PhD University of California, San Francisco

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Responsible Party: Caroline McCoach, MD, PhD, Assistant Clinical Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04005144     History of Changes
Other Study ID Numbers: 186517
NCI-2019-02315 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: July 2, 2019    Key Record Dates
Last Update Posted: July 2, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Bronchial Neoplasms
Disease Progression
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Disease Attributes
Pathologic Processes