ALK Gene Rearrangement, Lung Non-Small Cell Carcinoma, Progressive Disease, ROS1 Gene Rearrangement, Stage IIIB Lung Cancer, Stage IIIC Lung Cancer, Stage IVA Lung Cancer, Stage IVB Lung Cancer, Stage IV Lung Cancer
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of brigatinib in combination with binimetinib in stage IIIB or IV anaplastic lymphoma kinase (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 phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT)/Mitogen-activated protein kinase (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.
Interventions
DRUGBinimetinib
Given PO
DRUGBrigatinib
Given PO
Sponsors
Takeda
Array BioPharma
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * Dose Escalation Phase Only: At least one prior ALK or ROS1 targeted TKI. With progression or intolerance of most recent regimen. * Dose Expansion Phase Only: In addition to the criteria in
Exclusion criteria
# 3, ALK+ patients with no prior chemotherapy, immunotherapy, radiation therapy or other systemic therapy are also allowed. * Measurable or evaluable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria * Age \>= 18 years * Life expectancy of at least 3 months * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Leukocytes \>= 3,000/microliter (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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-Emergent Adverse Events Resulting in Interruption, Reduction, or Delay of study treatment | From treatment initiation through study completion, an average of 1 year | Severity grade will be defined by the NCI CTCAE v5.0. |
| Number of Total Treatment-Emergent Adverse Events (AEs) | From treatment initiation through study completion, an average of 1 year | Treatment Emergent AEs will be defined by the NCI CTCAE v5.0 as AEs newly occuring after the patient has begun study treatment. |
| Number of Treatment-Emergent Adverse Events by Grade | From treatment initiation through study completion, an average of 1 year | Severity grade will be defined by the NCI CTCAE v5.0. |
| Number of Serious Treatment-Emergent Adverse Events by CTCAE v5.0 | From treatment initiation through study completion, an average of 1 year | Severity grade will be defined by the NCI CTCAE v5.0. |
| Number of Treatment-Emergent Adverse Events with an Outcome of Death by CTCAE v5.0 | From treatment initiation through study completion, an average of 1 year | Severity grade will be defined by the NCI CTCAE v5.0. |
| Number of Treatment-Emergent Adverse Events Leading to Discontinuation of Study Treatment | From treatment initiation through study completion, an average of 1 year | Severity grade will be defined by the NCI CTCAE v5.0. |
| Number of Grade 3 or Greater Treatment-Emergent Adverse Events by CTCAE v5.0 | From treatment initiation through study completion, an average of 1 year | Severity grade will be defined by the NCI CTCAE v5.0. |
| Recommended Phase 2 Dose | Up to 12 months | 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 will be used to determine the recommended phase 2 dose for future studies. |
| Number of Participants with Dose Limiting Toxicities | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival (PFS) | Up to 6 months | PFS is measured as the time from start of treatment to time of disease progression at 6 months. Kaplan-Meier method will be used to describe the describe the median PFS with 95% CI. |
| Median Depth of Response Assessed by RECIST v1.1 | 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). |
| Area Under the Plasma Concentration versus Time Curve (AUC) of Brigatinib | 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. |
| Median Overall Survival (OS) | Up to 12 months | Overall Survival is measures as the time from start of treatment to time of death, or lost to follow-up. Kaplan-Meier method will be used to describe the describe the median OS at 12 months with 95% CI. |
| Objective Response Rate (ORR) Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | From treatment initiation through study completion, an average of 1 year | RECIST v1.1 will be used to determine the overall response rate defined as participants with a complete response (CR) or a partial response (PR). Point estimate and 95% exact binomial confidence interval (CI) will be obtained for ORR. |
Countries
United States
Outcome results
None listed