This is a phase 2/3, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in combination in participants with unresectable, advanced or metastatic NSCLC determined to harbor oncogenic somatic mutations or positive by tumor mutational burden (TMB) assay as identified by a blood-based next-generation sequencing (NGS) circulating tumor DNA (ctDNA) assay.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,000
Participants will receive 600 mg BID (Cohort A); 900, 1200, or 750 mg BID (Cohort B) or RP2D BID; orally until disease progression, unacceptable toxicity, withdrawal of consent or death.
Participants will receive atezolizumab 1200 mg IV infusion Q21D (Cohorts C and F) or 1680 mg IV infusion Q4W starting on Day 29 (Cohort E).
Participants will receive pemetrexed 500 mg/m\^2 IV infusion on Day 1 Q21D.
Participants will receive cisplatin 75 mg/m\^2 IV on Day 1 Q21D.
Participants will receive carboplatin of AUC 5 or 6 IV on Day 1 Q21D.
Participants will receive gemcitabine 1000 or 1250 mg/m\^2 on Days 1 and 8 of every cycle (1 Cycle=21 days).
Participants will receive entrectinib 600 mg orally QD.
Participants will receive 60 mg PO QD on Days 1-21 of the initial run-in and triple-combination periods.
Participants will receive 960 mg PO BID on Days 1-21 of the initial run-in period, and 720 mg PO BID on Days 22-28 of the initial run-in period and on Days 1-28 of each cycle during the triple-combination period.
Participants will receive 15 mg/kg of IV bevacizumab on Day 1 of each 21-day cycle during the induction and maintenance periods.
Participants will receive divarasib PO QD until disease progression or unacceptable toxicity.
Participants will receive IV docetaxel Q3W (75 mg/m\^2) until disease progression or unacceptable toxicity
UC Davis
Sacramento, California, United States
Rocky Mountain Cancer Center
Denver, Colorado, United States
SCRI Florida Cancer Specialists South
Fort Myers, Florida, United States
Florida Cancer Specialist, North Region
St. Petersburg, Florida, United States
University of Kentucky
Lexington, Kentucky, United States
Cohort A: Percentage of Participants with Confirmed Objective Response as Assessed by the Investigator Based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohort B: Percentage of Participants with Confirmed Objective Response as Assessed by the Investigator Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohort C: Progression Free Survival (PFS) as Assessed by the Investigator Based on RECIST v1.1 in bTMB PP1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohort D: Percentage of Participants with Confirmed Objective Response as Assessed by the Investigator Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohort E: Time in Response (TIR) as Assessed by the Investigator Based on RECIST v1.1
Time frame: Month 12
Cohort F: Investigator-Assessed Objective Response Rate (ORR) Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohort G: Incidence of Adverse Events (AEs)
Time frame: Baseline to last dose of study treatment + 30 days or until initiation of new anticancer therapy, whichever occurs first (up to approximately 6 years)
Cohorts A-F: Duration of Response (DOR) as Assessed by the Investigator Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A, B and D: Percentage of Participants with Clinical Benefit Response as Assessed by the Investigator Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A, B, D, F: PFS as Assessed by the Investigator Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: Duration of Response as Assessed by the Independent Review Facility (IRF) Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A, B and D: Percentage of Participants with Clinical Benefit Response as Assessed by IRF Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: PFS as Assessed by IRF Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: Percentage of Participants with Confirmed Objective Response as Assessed by IRF Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: Overall Survival (OS)
Time frame: Baseline up to approximately 6 years
Cohorts A-F: Percentage of Participants with Adverse Events (AEs)
Time frame: Baseline up to approximately 6 years
Cohorts A, B, D, E, F: Percentage of Participants with Improvement Compared with Baseline in Total Severity Symptom Score as Measured by Symptoms in Lung Cancer (SILC) Scale in Patient-Reported Lung Cancer Symptoms (Cough, Dyspnea and Chest Pain)
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Time to Deterioration in Patient-Reported Lung Cancer Symptoms (Cough, Dyspnea and Chest Pain) as Measured by the SILC Scale
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts C, E, F: Change from Baseline in Patient-Reported Lung Cancer Symptom (Cough, Dyspnea, Chest pain) Score as Measured by the SILC Scale
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Change from Baseline in Health Related Quality of Life (HRQoL) Scores as Measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - C30 (EORTC QLQ-C30)
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A, B, D, E, F: Change from Baseline in HRQoL Scores as Measured by the SILC Scale
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Change from Baseline in Patient Functioning and Symptoms Score as Measured by the EORTC QLQ-C30
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A, B, D, E, F: Change from Baseline in Patient Functioning and Symptoms Score as Measured by the SILC Scale
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Health Status Assessed as an Index Score Using the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
Time frame: Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohort B: Percentage of Participants with Dose-Limiting Toxicities (DLTs)
Time frame: Day 1 to Day 28 of Cycle 1 (cycle length = 28 days)
Cohort B: Maximum Plasma Concentration (Cmax) of Alectinib
DFP: Dose-Finding Phase; DEP: Dose-Expanding Phase.
Time frame: DFP: pre-dose (0 hours [hr]) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Area Under the Concentration-Time Curve from Time Zero to the Last Measurable Concentration (AUC0-last) of Alectinib
Time frame: DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Time to Reach Cmax (Tmax) of Alectinib
Time frame: DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Half-Life (t1/2) of Alectinib
Time frame: DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Metabolite to Parent Exposure Ratio for AUC0-last
Time frame: DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Metabolite to Parent Exposure Ratio for Cmax
Time frame: DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort C: Percentage of Participants with Objective Response as Assessed by the Investigator Based on RECIST v1.1
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohort C: Percentage of Participants Free from Disease Progression as Assessed by the Investigator Based on RECIST v1.1 at Months 6 and 12
Time frame: Months 6, 12
Cohort C: PFS as Assessed by the Investigator based on RECIST v1.1 in bTMB PP2
Time frame: Baseline up to disease progression or death (up to approximately 6 years)
Cohort C: OS in bTMB PP2
Time frame: Baseline up to approximately 6 years
Cohort D: Time to CNS progression as Assessed by the Investigator Based on RECIST v1.1
Time frame: Baseline up to CNS progression (up to approximately 6 years)
Cohort D: Time to CNS progression as Assessed by the IRF Based on RECIST v1.1
Time frame: Baseline up to CNS progression (up to approximately 6 years)
Cohort D: Percentage of Participants who have shown improvement compared with Baseline in patient-reported cognitive function, fatigue, HRQoL, headache and vision disorder per the EORTC QLQ-C30
Time frame: Baseline, every 4 weeks until disease progression, up to approximately 6 years
Cohort D: Percentage of Participants who have shown improvement compared with Baseline in patient-reported cognitive function, fatigue, HRQoL, headache and vision disorder per the EORTC QLQ-BN20
Time frame: Baseline, every 4 weeks until disease progression, up to approximately 6 years
Cohort D: Mean Plasma Concentration of Entrectinib
Time frame: Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days).
Cohort D: Mean Plasma Concentration of Entrectinib Metabolite M5
Time frame: Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days).
Cohort E: TIR as Assessed by the Investigator Based on RECIST v1.1
Time frame: Month 9
Cohort E: TIR as Assessed by IRF
Time frame: Month 12
Cohorts E, F: Serum Concentration of Atezolizumab
Time frame: Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days)
Cohorts E, F: Change from Baseline in Anti-Drug Antibodies (ADAs)
Time frame: Baseline up to approximately 6 years
Cohorts E, F: Time to Confirmed Deterioration (TTCD) in Participant-Reported Lung Cancer Symptoms of Cough, Dyspnea, and Chest Pain, as Measured by the Symptoms in Lung Cancer (SILC)
Time frame: Baseline up to approximately 6 years
Cohorts E, F: Proportion of Participants who Improve Compared with Baseline in Participant-Reported Lung Cancer Symptoms of Cough, Dyspnea, and Chest Pain, as Measured by the SILC
Time frame: Baseline up to approximately 6 years
Cohort G: Plasma Concentration of Divarasib
Time frame: Baseline up to approximately 6 years
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