Non-Small Cell Lung Cancer
Conditions
Brief summary
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.
Interventions
DRUGAlectinib
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.
DRUGAtezolizumab
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).
DRUGPemetrexed
Participants will receive pemetrexed 500 mg/m\^2 IV infusion on Day 1 Q21D.
DRUGCisplatin
Participants will receive cisplatin 75 mg/m\^2 IV on Day 1 Q21D.
DRUGCarboplatin
Participants will receive carboplatin of AUC 5 or 6 IV on Day 1 Q21D.
DRUGGemcitabine
Participants will receive gemcitabine 1000 or 1250 mg/m\^2 on Days 1 and 8 of every cycle (1 Cycle=21 days).
DRUGEntrectinib
Participants will receive entrectinib 600 mg orally QD.
DRUGCobimetinib
Participants will receive 60 mg PO QD on Days 1-21 of the initial run-in and triple-combination periods.
DRUGVemurafenib
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.
DRUGBevacizumab
Participants will receive 15 mg/kg of IV bevacizumab on Day 1 of each 21-day cycle during the induction and maintenance periods.
DRUGDivarasib
Participants will receive divarasib PO QD until disease progression or unacceptable toxicity.
DRUGDocetaxel
Participants will receive IV docetaxel Q3W (75 mg/m\^2) until disease progression or unacceptable toxicity
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of unresectable Stage IIIb not amenable to treatment with combined modality chemoradiation (advanced) or Stage IV (metastatic) NSCLC * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 * Measurable disease * Adequate recovery from most recent systemic or local treatment for cancer * Adequate organ function * Life expectancy greater than or equal to (\>/=) 12 weeks * For female participants of childbearing potential and male participants, willingness to use acceptable methods of contraception
Exclusion criteria
* Inability to swallow oral medication * Women who are pregnant or lactating * Symptomatic, untreated CNS metastases * History of malignancy other than NSCLC within 5 years prior to screening with the exception of malignancies with negligible risk of metastasis or death * Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina * Known active or uncontrolled human immunodeficiency virus (HIV) infection * Either a concurrent condition or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or confounds the ability to interpret data from the study * Inability to comply with other requirements of the protocol
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | 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 | 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 | 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 | 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 | Month 12 |
| Cohort F: Investigator-Assessed Objective Response Rate (ORR) Based on RECIST v1.1 | Baseline up to disease progression or death (up to approximately 6 years) |
| Cohort G: Incidence of Adverse Events (AEs) | Baseline to last dose of study treatment + 30 days or until initiation of new anticancer therapy, whichever occurs first (up to approximately 6 years) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohorts A-F: Duration of Response (DOR) as Assessed by the Investigator Based on RECIST v1.1 | 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 | 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 | 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 | 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 | 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 | 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 | Baseline up to disease progression or death (up to approximately 6 years) | — |
| Cohorts A-F: Overall Survival (OS) | Baseline up to approximately 6 years | — |
| Cohorts A-F: Percentage of Participants with Adverse Events (AEs) | 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) | 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 | 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 | 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) | 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 | 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 | 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 | 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 | 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) | Day 1 to Day 28 of Cycle 1 (cycle length = 28 days) | — |
| Cohort B: Maximum Plasma Concentration (Cmax) of Alectinib | 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) | DFP: Dose-Finding Phase; DEP: Dose-Expanding Phase. |
| Cohort B: Area Under the Concentration-Time Curve from Time Zero to the Last Measurable Concentration (AUC0-last) of Alectinib | 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 | 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 | 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 | 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 | 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 | 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 | Months 6, 12 | — |
| Cohort C: PFS as Assessed by the Investigator based on RECIST v1.1 in bTMB PP2 | Baseline up to disease progression or death (up to approximately 6 years) | — |
| Cohort C: OS in bTMB PP2 | Baseline up to approximately 6 years | — |
| Cohort D: Time to CNS progression as Assessed by the Investigator Based on RECIST v1.1 | 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 | 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 | 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 | Baseline, every 4 weeks until disease progression, up to approximately 6 years | — |
| Cohort D: Mean Plasma Concentration of Entrectinib | 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 | 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 | Month 9 | — |
| Cohort E: TIR as Assessed by IRF | Month 12 | — |
| Cohorts E, F: Serum Concentration of Atezolizumab | 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) | 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) | 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 | Baseline up to approximately 6 years | — |
| Cohort G: Plasma Concentration of Divarasib | Baseline up to approximately 6 years | — |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, France, Germany, Hong Kong, Israel, Italy, Japan, Mexico, New Zealand, Panama, Peru, Poland, Russia, Serbia, Singapore, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed