A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer

Study Overview
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Brief Summary
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This is an umbrella study evaluating the efficacy and safety of multiple treatment combinations in participants with metastatic or inoperable locally advanced breast cancer. The study will be performed in two stages. During Stage 1, four cohorts will be enrolled in parallel in this study: Cohort 1 will consist of Programmed death-ligand 1 (PD-L1)-positive participants who have received no prior systemic therapy for metastatic or inoperable locally advanced triple-negative breast cancer (TNBC) (first-line [1L] PD-L1+ cohort). Cohort 2 will consist of participants who had disease progression during or following 1L treatment with chemotherapy for metastatic or inoperable locally-advanced TNBC and have not received cancer immunotherapy (CIT) (second-line [2L] CIT-naive cohort). Cohort 3 will consist of participants with locally-advanced or metastatic HR+, HER2-negative disease with PIK3CA mutation who may or may not have had disease progression during or following previous lines of treatment for metastatic disease (HR+cohort). Cohort 4 will consist of participants with locally-advanced or metastatic HER2+ /HER2-low disease with PIK3CA mutation who had disease progression on standard-of-care therapies (HER2+ /HER2-low cohort). In each cohort, eligible participants will initially be assigned to one of several treatment arms (Stage 1). In addition, participants in the 2L CIT-naïve cohort who experience disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment combination (Stage 2), provided Stage 2 is open for enrollment.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Atezolizumab
* Drug: Ipatasertib
* Drug: SGN-LIV1A
* Drug: Bevacizumab
* Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin)
* Drug: Selicrelumab
* Drug: Tocilizumab
* Drug: Nab-Paclitaxel
* Drug: Sacituzumab Govitecan
* Drug: Abemaciclib
* Drug: Fulvestrant
* Drug: Ribociclib
* Drug: Inavolisib
* Drug: Inavolisib (9 mg)
* Drug: Inavolisib (6 mg)
* Drug: Trastuzumab Deruxtecan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must meet all of the following criteria to qualify for Stage 1 (all cohorts) and to qualify for Stage 2 (2L CIT-naïve cohort): Age >/= 18 years at the time of signing Informed Consent Form ECOG Performance Status of 0 or 1 Able to comply with the study protocol, in the investigator's judgment Metastatic or inoperable locally advanced breast cancer Measurable disease (at least one target lesion) according to RECIST v1.1 Life expectancy >/= 3 months, as determined by the investigator Tumor accessible for biopsy Availability of a representative tumor specimen that is suitable for biomarker analysis via central testing Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from breastfeeding and 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 Metastatic or inoperable locally advanced, histologically documented TNBC No prior systemic treatment for metastatic or inoperable locally advanced TNBC Positive PD-L1 expression, defined as >/= 1% of the tumor area occupied by PD L1-expressing tumor-infiltrating immune cells of any intensity, as determined through use of the U.S. Food and Drug Administration-approved or CE-marked Ventana PD-L1 (SP142) Assay Inclusion criteria for Cohort 2 Metastatic or inoperable locally advanced, histologically documented TNBC Eligible for capecitabine monotherapy Radiologic/objective evidence of recurrence or disease progression after 1L treatment with chemotherapy, for a total of one line of therapy for inoperable locally advanced or metastatic breast cancer Inclusion criteria for Cohort 3 Metastatic or inoperable locally-advanced, histologically documented HR+ breast cancer who had previous lines of treatment for metastatic disease. Fasting glucose < 126 mg/dL or < 7.0 mmol/L and HbA1c </= 6.4% Confirmation of PIK3CA mutation Patients for whom ET (e.g., fulvestrant) is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or local treatments standards Postmenopausal, or premenopausal/perimenopausal status and willing to undergo and maintain treatment with approved LHRH-agonist (also known as gonadotropin-releasing hormone-agonist) therapy for the duration of study Inclusion criteria for Cohort 4 Left ventricular ejection fraction, measured by echocardiogram or radionucleotide ventriculography, greater than 50% Confirmation of HER2+ or HER2-low status Fasting glucose < 126 mg/dL or < 7.0 mmol/L and HbA1c </= 6.4% Confirmation of PIK3CA mutation Exclusion Criteria for Stage 1 Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, CD40 agonists or interleukin-2 (IL-2) or IL-2-like compounds Treatment with investigational therapy within 28 days prior to initiation of study treatment Biologic treatment (e.g., bevacizumab) within 2 weeks prior to initiation of study treatment, or other systemic treatment for TNBC within 2 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment Adverse events from prior anti-cancer therapy that have not resolved to Grade </= 1 or better with the exception of alopecia of any grade and Grade </= 2 peripheral neuropathy Eligibility only for the control arm Exclusion Criteria for Stage 1 (both cohorts) and Stage 2 (2L CIT-naïve cohort) Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Uncontrolled tumor-related pain 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 (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. Active tuberculosis Severe infection within 4 weeks prior to initiation of study treatment Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment Significant cardiovascular disease Prior allogeneic stem cell or solid organ transplantation History of malignancy other than breast cancer within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study Pregnancy or breastfeeding, or intention of becoming pregnant during the study Exclusion Criteria for the 2L CIT-naive cohort, Stage 1 Prior treatment with capecitabine, Treatment with sorivudine or its chemically related analogues, such as brivudine History of severe and unexpected reactions to fluoropyrimidine therapy Known complete absence of dihydropyrimidine dehydrogenase activity Exclusion Criteria for Stage 2 Inability to tolerate atezolizumab during Stage 1 For patients receiving eribulin: congenital long QT syndrome Additional drug-specific exclusion criteria may apply to Stage 1 and 2.

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: Atezolizumab + Nab-Paclitaxel<br>1L PD-L1-positive participants will receive doublet combination treatment with atezolizumab + nab-paclitaxel until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed. | Drug: Atezolizumab<br>* For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: atezolizumab will be administered IV, 840 mg on Days 1 and 15, of each 28-day cycle.<br>Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered by IV, 100 mg/m^2, on Days 1, 8, and 15 of each 28-day cycle.<br>|
| Experimental: Atezolizumab + Nab-Paclitaxel + Tocilizumab<br>1L PD-L1-positive participants will receive combination treatment with atezolizumab plus nab-paclitaxel and tocilizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed. | Drug: Atezolizumab<br>* For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: atezolizumab will be administered IV, 840 mg on Days 1 and 15, of each 28-day cycle.<br>Drug: Tocilizumab<br>* Tocilizumab will be administered IV, 8 mg/kg infusion on Day 1 of each 28 day cycle.<br>Drug: Nab-Paclitaxel<br>* Nab-Paclitaxel will be administered by IV, 100 mg/m^2, on Days 1, 8, and 15 of each 28-day cycle.<br>|
| Experimental: Atezolizumab + Sacituzumab Govitecan<br>1L PD-L1-positive participants will receive doublet combination treatment with atezolizumab plus sacituzumab govitecan until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed. | Drug: Atezolizumab<br>* For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: atezolizumab will be administered IV, 840 mg on Days 1 and 15, of each 28-day cycle.<br>Drug: Sacituzumab Govitecan<br>* Sacituzumab govitecan will be administered by IV, 10 mg/kg, on Days 1 and 8 of each 21-day cycle.<br>|
| Active Comparator: Capecitabine<br>2L CIT-naive participants will receive capecitabine until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1). Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed. | Drug: Capecitabine<br>* Capecitabine will be administered 1250 mg/m^2 orally twice daily on Days 1-14, of each 21 day cycle.<br>|
| Experimental: Atezolizumab + Ipatasertib<br>2L CIT-naive participants will receive doublet combination treatment with atezolizumab + ipatasertib until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed. | Drug: Atezolizumab<br>* For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: atezolizumab will be administered IV, 840 mg on Days 1 and 15, of each 28-day cycle.<br>Drug: Ipatasertib<br>* Ipatasertib will be administered by mouth 400 mg once a day, on Day 1-21 of each 28 day cycle.<br>|
| Experimental: Atezolizumab + SGN-LIV1A<br>2L CIT-naive participants will receive doublet combination treatment with atezolizumab plus SGNLIV1A until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed. | Drug: Atezolizumab<br>* For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: atezolizumab will be administered IV, 840 mg on Days 1 and 15, of each 28-day cycle.<br>Drug: SGN-LIV1A<br>* SGN-LIV1A will be administered IV, 2.5 mg/kg (maximum calculated dose 250 mg), on Day 1 of each 21 day cycle.<br>|
| Experimental: Atezolizumab + Selicrelumab + Bevacizumab<br>2L-CIT-naive participants will receive doublet combination treatment with atezolizumab plus selicrelumab and bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who progressed on treatment may have the option of receiving atezolizumab + chemo, provided they meet the eligibility criteria. Enrollment is closed. | Drug: Atezolizumab<br>* For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: atezolizumab will be administered IV, 840 mg on Days 1 and 15, of each 28-day cycle.<br>Drug: Bevacizumab<br>* Bevacizumab will be administered IV, 10 mg/kg, on Days 1 and 15 of each 28 day cycle.<br>Drug: Selicrelumab<br>* Selicrelumab will be administered by subcutaneous (SC) injection at a fixed dose of 16 mg on Day 1 of Cycles 1 to 4 and every third cycle thereafter (cycle = 28 days).<br>|
| Experimental: Atezolizumab + Chemo (Gemcitabine + Carboplatin or Eribulin)<br>2L CIT-naive participants enrolled in the active comparator arm who experience disease progression per RECIST v1.1 and 2L CIT-naive participants enrolled in an experimental arm who experience loss of clinical benefit as determined by the investigator may receive doublet combination treatment with atezolizumab plus chemotherapy (gemcitabine + carboplatin or eribulin) until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Enrollment is closed. | Drug: Atezolizumab<br>* For Atezolizumab (Atezo) + SGN-LIV1A, Atezo + Sacituzumab Govitecan, or Atezo + Chemo arms: atezolizumab will be administered intravenously (IV), 1200 mg, on Day 1 of each 21-day cycle. For Atezo + Nab-Paclitaxel, Atezo + Selicrelumab + Bevacizumab, Atezo + Ipatasertib, or Atezo + Nab-Paclitaxel + Tocilizumab: atezolizumab will be administered IV, 840 mg on Days 1 and 15, of each 28-day cycle.<br>Drug: Chemotherapy (Gemcitabine + Carboplatin or Eribulin)<br>* Gemcitabine will be administered by IV, 1000 mg/m^2, along with carboplatin, by IV, AUC 2, on Days 1 and 8 of each 21 day cycle. Or Eribulin will be administered by IV, 1.4 mg/m^2 on days 1 and 8 of each 21 day cycle.<br>|
| Experimental: Inavolisib + Abemaciclib + Fulvestrant<br>Hormone receptor-positive (HR+) participants will receive treatment with inavolisib plus abemaciclib plus fulvestrant until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). | Drug: Abemaciclib<br>* Abemaciclib tablets will be administered at a dose of 150 mg twice daily by mouth on Days 1-28 of each cycle (cycle=28 days).<br>Drug: Fulvestrant<br>* Fulvestrant IM injection at a dose of 500 mg will be administered on Days 1 and 15 of Cycle 1, and then on Day 1 of each cycle thereafter (cycle=28 days).<br>Drug: Inavolisib<br>* Inavolisib tablets will be administered at a dose of 9 mg by mouth on Days 1-28 of each cycle (cycle = 28 days).<br>* Other names: GDC-0077, RO7113755;|
| Experimental: Inavolisib + Ribociclib + Fulvestrant<br>Hormone receptor-positive (HR+) participants will receive treatment with inavolisib plus ribociclib plus fulvestrant until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). | Drug: Fulvestrant<br>* Fulvestrant IM injection at a dose of 500 mg will be administered on Days 1 and 15 of Cycle 1, and then on Day 1 of each cycle thereafter (cycle=28 days).<br>Drug: Ribociclib<br>* Ribociclib tablets of 400 mg will be administered by mouth on Days 1-21 of each 28-day cycle.<br>Drug: Inavolisib<br>* Inavolisib tablets will be administered at a dose of 9 mg by mouth on Days 1-28 of each cycle (cycle = 28 days).<br>* Other names: GDC-0077, RO7113755;|
| Experimental: Inavolisib (6 mg) + Trastuzumab Deruxtecan<br>HER2+/HER2-low participants will receive inavolisib (6 mg) + trastuzumab deruxtecan until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1. | Drug: Inavolisib (6 mg)<br>* Inavolisib tablets will be administered at a dose of 6 mg by mouth on Days 1-21 of each cycle (cycle = 21 days).<br>* Other names: GDC-0077, RO7113755;Drug: Trastuzumab Deruxtecan<br>* Trastuzumab Deruxtecan will be administered at a dose of 5.4 mg/kg by IV infusion on Day 1 of each 21-day cycle.<br>|
| Experimental: Inavolisib (9 mg) + Trastuzumab Deruxtecan<br>HER2+/HER2-low participants will receive inavolisib (9 mg) + trastuzumab deruxtecan until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1. | Drug: Inavolisib (9 mg)<br>* Inavolisib tablets will be administered at a dose of 9 mg by mouth on Days 1-21 of each cycle (cycle = 21 days).<br>* Other names: GDC-0077, RO7113755;Drug: Trastuzumab Deruxtecan<br>* Trastuzumab Deruxtecan will be administered at a dose of 5.4 mg/kg by IV infusion on Day 1 of each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) |  | Baseline until disease progression or loss of clinical benefit (approximately 5 years) | 
| Number of Participants With Adverse Events |  | Baseline to end of study (approximately 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) |  | Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5 years) as determined by the investigator according to RECIST v1.1 | 
| Disease Control Rate (DCR) |  | Baseline through end of study (approximately 5 years) | 
| Overall Survival (OS) |  | Randomization to death from any cause, through the end of study (approximately 5 years) | 
| Overall Survival (at specific time-points) |  | 12 and 18 months | 
| Duration of Response (DOR) |  | Randomization until first occurrence of a documented objective response to the first recorded occurrence of disease progression or death from any cause (whichever occurs first), through end of study (approximately 5 years) |