A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer)

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, and pharmacokinetics of immunotherapy-based treatment combinations in participants with metastatic non-small cell lung cancer (NSCLC). Two cohorts will be enrolled in parallel in this study: Cohort 1 will consist of participants with tumor PD-L1 expression who have received no prior systemic therapy for metastatic NSCLC, and Cohort 2 will consist of participants who experienced disease progression during or following treatment with a platinum-containing regimen and a PD-L1/PD-1 checkpoint inhibitor, given in combination as one line of therapy or as two separate lines of therapy, regardless of PD-L1 expression. In each cohort, eligible participants will initially be assigned to one of several treatment arms (Stage 1). Participants who experience disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment regimen (Stage 2).

Official Title
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A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating The Efficacy And Safety Of Multiple Immunotherapy-Based Treatment Combinations In Patients With Metastatic Non-Small Cell Lung Cancer (Morpheus-Lung)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Cobimetinib
* Drug: RO6958688
* Drug: Docetaxel
* Drug: CPI-444
* Drug: Pemetrexed
* Drug: Carboplatin
* Drug: Gemcitabine
* Drug: Linagliptin
* Drug: Tocilizumab
* Drug: Ipatasertib
* Drug: Bevacizumab
* Drug: Sacituzumab Govitecan
* Other: Radiation
* Drug: Evolocumab
* Drug: Tiragolumab
* Drug: XL092
* Drug: Camonsertib


Participation Criteria
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Eligibility Criteria
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General Inclusion Criteria Eastern Cooperative Oncology Group (ECOG) performance Status of 0 or 1 Life expectancy greater than or equal to 3 months Histologically or cytologically confirmed metastatic, non-squamous or squamous Non-Small Cell Lung Cancer (NSCLC) Measurable disease (at least one target lesion) Adequate hematologic and end-organ function Tumor accessible for biopsy For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating eggs as outlined for each specific treatment arm For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm Inclusion Criteria for Cohort 1 No prior systemic therapy for metastatic NSCLC High tumor PD-L1 expression, defined as Tumor Proportion Score (TPS) or TCs >= 50% or TC3 Inclusion Criteria for Cohort 2 - Disease progression during or following treatment for metastatic or locally advanced, inoperable NSCLC Exclusion Criteria Prior allogeneic stem cell or solid organ transplantation Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases History of leptomeningeal disease Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan History of malignancy other than NSCLC within 2 years prior to screening Active tuberculosis Severe infection within 4 weeks prior to initiation of study treatment

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 |
| --- | --- |
| Active Comparator: Stage 1: Cohort 1: Atezolizumab<br>Participants in the Atezolizumab arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Pemetrexed + Carboplatin or Atezolizumab + Gemcitabine + Carboplatin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>|
| Experimental: Stage 1: Cohort 1: Atezolizumab + Cobimetinib<br>Participants in the Atezolizumab + Cobimetinib arm will receive treatment (cycle length 28 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on 1L treatment, may have the option of receiving Atezolizumab + Pemetrexed + Carboplatin or Atezolizumab + Gemcitabine + Carboplatin treatment, provided they meet the eligibility criteria. Participants who progressed on 2L/3L treatment, may have the option of receiving Atezolizumab + RO6958688, Atezolizumab + Docetaxel or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Cobimetinib<br>* Cobimetinib is administered orally on Days 1-21 of a 28 day cycle.<br>|
| Experimental: Stage 1: Cohort 1: Atezolizumab + RO6958688<br>Participants in the Atezolizumab + RO6958688 arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on 1L treatment, may have the option of receiving Atezolizumab + Pemetrexed + Carboplatin or Atezolizumab + Gemcitabine + Carboplatin treatment, provided they meet the eligibility criteria. Participants who progressed on 2L/3L treatment, may have the option of receiving Atezolizumab + Docetaxel treatment or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: RO6958688<br>* Cycle 1: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle at increasing dosage. Subsequent cycles: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle.<br>Drug: Tocilizumab<br>* Tocilizumab is administered for the management of cytokine-release syndrome in the RO6958688-containing arms.<br>|
| Active Comparator: Stage 1: Cohort 2: Docetaxel<br>Participants in the Docetaxel arm will receive treatment (cycle length 21 days) until unacceptable toxicity or disease progression. Participants who progressed on treatment may have the option of receiving Atezolizumab + RO6958688 or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Docetaxel<br>* Docetaxel is administered by IV on Day 1 of each 21 day cycle.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Cobimetinib<br>Participants in the Atezolizumab + Cobimetinib arm will receive treatment (cycle length 28 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Pemetrexed + Carboplatin, Atezolizumab + Gemcitabine + Carboplatin, Atezolizumab + RO6958688, Atezolizumab + Docetaxel or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Cobimetinib<br>* Cobimetinib is administered orally on Days 1-21 of a 28 day cycle.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + CPI-444<br>Participants in the Atezolizumab + CPI-444 arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on treatment, may have the option of receiving Atezolizumab + RO6958688, Atezolizumab + Docetaxel or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: CPI-444<br>* CPI-444 is administered orally twice daily on Days 1- 21, of a 21 day cycle.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + RO6958688<br>Participants in the Atezolizumab + RO6958688 arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Pemetrexed + Carboplatin, Atezolizumab + Gemcitabine + Carboplatin, Atezolizumab + Docetaxel or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: RO6958688<br>* Cycle 1: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle at increasing dosage. Subsequent cycles: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle.<br>Drug: Tocilizumab<br>* Tocilizumab is administered for the management of cytokine-release syndrome in the RO6958688-containing arms.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Ipatasertib<br>Participants in the Atezolizumab + Ipatasertib arm will receive treatment (cycle length 28 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Docetaxel treatment or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Ipatasertib<br>* Ipatasertib will be administered orally once a day on Days 1-21 of each 28-day cycle.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Docetaxel<br>Participants in Atezolizumab + Docetaxel arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Docetaxel<br>* Docetaxel is administered by IV on Day 1 of each 21 day cycle.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Bevacizumab<br>Participants in Atezolizumab + Bevacizumab arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. Participants who progressed on treatment, may have the option of receiving Atezolizumab + Docetaxel or Atezolizumab + Linagliptin treatment, provided they meet the eligibility criteria. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Bevacizumab<br>* Bevacizumab is administered by IV on Day 1 of each 21-day cycle.<br>|
| Experimental: Stage 2: Cohort 1: Atezolizumab + Pemetrexed + Carboplatin<br>Participants in the Atezolizumab + Pemetrexed + Carboplatin arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Pemetrexed<br>* Pemetrexed is administered by IV on Day 1 of a 21 day cycle.<br>Drug: Carboplatin<br>* Carboplatin is administered by IV on day 1 of the first 4 or 6 cycles out of a 21 day cycle.<br>|
| Experimental: Stage 2: Cohort 1: Atezolizumab + Gemcitabine + Carboplatin<br>Participants in the Atezolizumab + Gemcitabine + Carboplatin arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Carboplatin<br>* Carboplatin is administered by IV on day 1 of the first 4 or 6 cycles out of a 21 day cycle.<br>Drug: Gemcitabine<br>* Gemcitabine is administered by IV on Days 1 and 8 of the first 4 or 6 cycles out of a 21 day cycle.<br>|
| Experimental: Stage 2: Cohort 2: Atezolizumab + RO6958688<br>Participants in the Atezolizumab + RO6958688 arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: RO6958688<br>* Cycle 1: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle at increasing dosage. Subsequent cycles: RO6958688 is administered by IV infusion on Days 1, 8, and 15 of a 21 day cycle.<br>Drug: Tocilizumab<br>* Tocilizumab is administered for the management of cytokine-release syndrome in the RO6958688-containing arms.<br>|
| Experimental: Stage 2: Cohort 2: Atezolizumab + Docetaxel<br>Participants in the Atezolizumab + Docetaxel arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. Participants who have received treatment with Atezolizumab + Docetaxel in Stage 1 will not receive this treatment in Stage 2. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Docetaxel<br>* Docetaxel is administered by IV on Day 1 of each 21 day cycle.<br>|
| Experimental: Stage 2: Cohort 2: Atezolizumab + Linagliptin<br>Participants in the Atezolizumab + Linagliptin arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Linagliptin<br>* Linagliptin is administered orally once daily on Days 1 to 21 out of a 21 day cycle.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Sacituzumab Govitecan<br>Participants in the Atezolizumab + Sacituzumab Govitecan arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Sacituzumab Govitecan<br>* Sacituzumab Govitecan is administered by IV on Day 1 and 8 of each 21-day cycle.<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Bevacizumab + Radiotherapy<br>Participants in the Atezolizumab + Bevacizumab + Radioatherapy arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Bevacizumab<br>* Bevacizumab is administered by IV on Day 1 of each 21-day cycle.<br>Other: Radiation<br>* Radiotherapy up to 21 days<br>|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Evolocumab<br>Participants in the Atezolizumab + Evolocumab arm will receive treatment (cycle length 28 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Evolocumab<br>* Evolocumab is administered subcutaneously at a dose of 140 mg on Days 1 and 15 of each 28-day cycle.<br>|
| Active Comparator: Stage 1: Cohort 1: Atezolizumab + Tiragolumab<br>Participants in the Atezolizumab + Tiragolumab arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Tiragolumab<br>* Tiragolumab is administered on Day 1 of each 21 day cycle.<br>|
| Experimental: Stage 1: Cohort 1: Atezolizumab + Tiragolumab + XL092 (Zanzalintinib)<br>Participants in the Atezolizumab + Tiragolumab + XL092 arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Tiragolumab<br>* Tiragolumab is administered on Day 1 of each 21 day cycle.<br>Drug: XL092<br>* XL092 is administered orally once a day on Day 1 to Day 21 of a 21 day cycle.<br>* Other names: Zanzalintinib;|
| Experimental: Stage 1: Cohort 2: Atezolizumab + Camonsertib<br>Participants in the Atezolizumab + Camonsertib arm will receive treatment (cycle length 21 days) until unacceptable toxicity or loss of clinical benefit. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV on Day 1 of each 21 day cycle or on Days 1 and 15 of each 28 day cycle.<br>Drug: Camonsertib<br>* Camonsertib is administered orally on Days 1-3, Days 8-10 of a 21 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Objective Response |  | Every 6 weeks (starting on Day 1, Cycle 1) for the first 48 weeks and then every 6 or 12 weeks thereafter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) |  | Randomization to the first occurrence of disease progression or death from any cause (up to approximately 7 years) | 
| Overall Survival After Randomization |  | Randomization to death from any cause (up to approximately 7 years) | 
| Percentage of Participants Who Are Alive at Month 6 and at Month 12 |  | Month 6, Month 12 | 
| Duration of Response |  | First occurrence of a documented objective response to disease progression or death (up to approximately 7 years) | 
| Disease Control |  | Randomization to the first occurrence of disease progression or death from any cause (up to approximately 7 years) | 
| Percentage of Participants with Adverse Events |  | Baseline through the end of the study (approximately 7 years) |