A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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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 two blood-based next-generation sequencing (NGS) circulating tumor DNA (ctDNA) assays.

Official Title
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A Phase II/III Multicenter Study Evaluating the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Patients With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Somatic Mutations Detected in Blood (B-FAST: Blood-First Assay Screening Trial)

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Alectinib
* Drug: Atezolizumab
* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: Entrectinib
* Drug: Cobimetinib
* Drug: Vemurafenib
* Drug: Bevacizumab
* Drug: GDC-6036
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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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 human immunodeficiency virus (HIV) positivity or autoimmune deficiency syndrome (AIDS)-related illness 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: Alectinib 600 Milligrams (mg)<br>This cohort includes participants with anaplastic lymphoma kinase (ALK) positive NSCLC. Participants will receive alectinib 600 mg orally twice in a day (BID) until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort A is complete. | Drug: Alectinib<br>* 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.<br>* Other names: RO5424802;|
| Experimental: Cohort B: Dose Finding Phase (DFP) Alectinib<br>This cohort includes participants with rearranged during transfection (RET) positive NSCLC. Participants may receive alectinib 900 or 1200 mg orally BID until disease progression, unacceptable toxicity, withdrawal of consent or death if the recommended phase 2 dose (RP2D) is not established in any other clinical study. Participants may receive 750 mg or 600 mg, if it is unsafe to pursue the higher starting dose. Enrollment to Cohort B is complete. | Drug: Alectinib<br>* 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.<br>* Other names: RO5424802;|
| Experimental: Cohort B: Dose Expansion Phase (DEP) Alectinib<br>This cohort includes participants with RET positive NSCLC. Participants will receive alectinib at the RP2D established in the DFP of Cohort B or a separate clinical study. Participants will continue receiving study treatment until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort B is complete. | Drug: Alectinib<br>* 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.<br>* Other names: RO5424802;|
| Experimental: Cohort C: Atezolizumab 1200 mg<br>This cohort includes participants with bTMB positive NSCLC. Participants will receive atezolizumab at a dose of 1200 mg administered by IV infusion every 21 days (Q21D) until disease progression, loss of clinical benefit, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort C is complete. | Drug: Atezolizumab<br>* 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).<br>* Other names: RO5541267;|
| Active Comparator: Cohort C: Pemetrexed, Cisplatin or Carboplatin<br>This cohort includes participants with bTMB positive, non-squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Carboplatin at a dose of area under the concentration-time curve (AUC) of 5 or 6 IV or cisplatin at a dose of 75 milligrams per meter square (mg/m^2) IV on Day 1 of each cycle combined with pemetrexed at a dose of 500 mg/m^2 IV on Day 1 of each cycle. Pemetrexed may be continued as maintenance therapy every 21 days (Q21D) as per local standard of care. Enrollment to Cohort C is complete. | Drug: Pemetrexed<br>* Participants will receive pemetrexed 500 mg/m^2 IV infusion on Day 1 Q21D.<br>Drug: Cisplatin<br>* Participants will receive cisplatin 75 mg/m^2 IV on Day 1 Q21D.<br>Drug: Carboplatin<br>* Participants will receive carboplatin of AUC 5 or 6 IV on Day 1 Q21D.<br>|
| Active Comparator: Cohort C: Gemcitabine, Cisplatin or Carboplatin<br>This cohort includes participants with bTMB positive, squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of every cycle and cisplatin 75 mg/m^2 IV on Day 1 Q21D or gemcitabine 1000 mg/m^2 IV on Days 1 and 8 of every cycle and carboplatin AUC 5 IV on Day 1 Q21D. Enrollment to Cohort C is complete. | Drug: Cisplatin<br>* Participants will receive cisplatin 75 mg/m^2 IV on Day 1 Q21D.<br>Drug: Carboplatin<br>* Participants will receive carboplatin of AUC 5 or 6 IV on Day 1 Q21D.<br>Drug: Gemcitabine<br>* Participants will receive gemcitabine 1000 or 1250 mg/m^2 on Days 1 and 8 of every cycle (1 Cycle=21 days).<br>|
| Experimental: Cohort D: Entrectinib 600 Milligrams (mg)<br>This cohort includes participants with c-ros oncogene 1 positive (ROS1+) NSCLC. Participants will receive entrectinib 600 mg orally once a day (QD) until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort D is complete. | Drug: Entrectinib<br>* Participants will receive entrectinib 600 mg orally QD.<br>* Other names: RO7102122;|
| Experimental: Cohort E: Atezolizumab, Vemurafenib, and Cobimetinib<br>This cohort includes participants with BRAF V600 mutation. Participants will receive: atezolizumab 1680 mg IV Q4W after the run-in period; cobimetinib 60 mg orally (PO) QD on Days 1-21 of each cycle during the run-in and triple-combination periods; and vemurafenib 960 mg PO twice daily (BID) on Days 1-21 of the initial run-in period, then 720 mg PO BID on Days 1-22 of the initial run-in period and on Days 1-28 of each cycle during the triple-combination period. Enrollment to Cohort E is complete. | Drug: Atezolizumab<br>* 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).<br>* Other names: RO5541267;Drug: Cobimetinib<br>* Participants will receive 60 mg PO QD on Days 1-21 of the initial run-in and triple-combination periods.<br>* Other names: RO5514041;Drug: Vemurafenib<br>* 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.<br>* Other names: RO5185426;|
| Experimental: Cohort F: Atezolizumab, Bevacizumab, Carboplatin, and Pemetrexed<br>This cohort includes participants with EGFR exon 20+ NSCLC. Participants will receive atezolizumab + bevacizumab + carboplatin + pemetrexed for 4 or 6 induction cycles (cycle = 21 days). After induction therapy, participants will continue maintenance treatment with atezolizumab + bevacizumab + pemetrexed until disease progression, unacceptable toxicity, withdrawal of consent, or death. Enrollment to Cohort F is complete. | Drug: Atezolizumab<br>* 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).<br>* Other names: RO5541267;Drug: Pemetrexed<br>* Participants will receive pemetrexed 500 mg/m^2 IV infusion on Day 1 Q21D.<br>Drug: Carboplatin<br>* Participants will receive carboplatin of AUC 5 or 6 IV on Day 1 Q21D.<br>Drug: Bevacizumab<br>* Participants will receive 15 mg/kg of IV bevacizumab on Day 1 of each 21-day cycle during the induction and maintenance periods.<br>* Other names: RO4876646;|
| Experimental: Cohort G: GDC-6036 or Docetaxel<br>This cohort includes participants with KRAS G12C mutation. Participants will receive GDC-6036 PO QD or IV docetaxel Q3W (75 mg/m^2) until disease progression or unacceptable toxicity | Drug: GDC-6036<br>* Participants will receive GDC-6036 PO QD until disease progression or unacceptable toxicity.<br>* Other names: RO7435846;Drug: Docetaxel<br>* Participants will receive IV docetaxel Q3W (75 mg/m^2) until disease progression or unacceptable toxicity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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: PFS as Determined by Blinded Independent Central Review (BICR) Based on RECIST v1.1 |  | Baseline up to disease progression or death (up to approximately 6 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cohorts: 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, G: 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) | 
| All Cohorts: Overall Survival (OS) |  | Baseline up to approximately 6 years | 
| All Cohorts: 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 | 
| All Cohorts: 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 | 
| All Cohorts: 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: Dose-Finding Phase; DEP: Dose-Expanding Phase. | 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 |  | 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: Objective Response Rate (ORR) as Assessed by the Investigator Based on RECIST v1.1 |  | Baseline up to approximately 6 years | 
| Cohort G: TTCD on the EORTC QLQ-C30 Physical Functioning and Role Functioning Scales |  | Baseline up to approximately 6 years | 
| Cohort G: Proportion of Participants Reporting Clinically Meaningful Deterioration in Fatigue, Chest Pain, Physical and Role Functioning as Measured by the EORTC QLQ-LC13 and QLQ-C30 Questionnaires |  | Cycle 5 (1 cycle = 21 or 28 days) | 
| Cohort G: Change from Baseline in Fatigue, Chest Pain, Physical and Role Functioning as Measured by the EORTC QLQ-LC13 and QLQ-C30 Questionnaires |  | Cycle 5 (1 cycle = 21 or 28 days) | 
| Cohort G: Tolerability of GDC-6036 or Docetaxel as Assessed by the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) |  | Cycles 1-3 (1 cycle = 21 days) | 
| Cohort G: Plasma Concentration of GDC-6036 |  | Cycles 1-5 (1 cycle = 21 days) |