A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Participants With Breast Cancer

Study Overview
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Brief Summary
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This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with breast cancer. Cohort 1 will focus on participants with inoperable, locally advanced or metastatic, estrogen receptor (ER)-positive, HER2-negative breast cancer who had disease progression during or following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; e.g., palbociclib, ribociclib, abemaciclib) in the first- or second-line setting. Cohort 2 will focus on inoperable, locally advanced or metastatic, ER-positive, HER2-positive breast cancer with previous progression to standard-of-care anti-HER2 therapies, of which one was a trastuzumab-and-taxane-based systemic therapy (including in the early setting if recurrence occurred within 6 months of finishing adjuvant therapy) and one was a HER2-targeting antibody-drug conjugate (ADC; e.g., ado-trastuzumab emtansine or trastuzumab-deruxtecan) or a HER2-targeting tyrosine kinase inhibitor (TKI; e.g., tucatinib, lapatinib, pyrotinib or neratinib). The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the patient population. During Stage 1, participants in each cohort will be randomly assigned to treatment arms. Participants in the control or experimental arms who experience unacceptable toxicity, disease progression as determined by the investigator according to RECIST v1.1, or loss of clinical benefit as determined by the investigator during Stage 1 will be given the option of receiving a different treatment combination during Stage 2, provided they meet eligibility criteria and a treatment arm is open for enrollment. No Stage 2 treatment is currently available.

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 Breast Cancer (MORPHEUS- BREAST CANCER)

Conditions
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Inoperable, Locally Advanced or Metastatic, ER-positive Breast Cancer

Intervention / Treatment
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* Drug: Giredestrant
* Drug: Abemaciclib
* Drug: Ipatasertib
* Drug: Inavolisib
* Drug: Ribociclib
* Drug: Everolimus
* Drug: Samuraciclib
* Drug: PH FDC SC
* Drug: Palbociclib
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for Cohort 1 (Stage 1 [and Stage 2, only where indicated]): Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Documented estrogen receptor-positive (ER+) tumor Patients for whom endocrine therapy is recommended and treatment with cytotoxic chemotherapy is not indicated at time of entry into the study, as per national or local treatment guidelines Radiologic/objective evidence of recurrence or progression after the most recent systemic therapy for breast cancer Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease (note: at least one line of therapy must have contained a CDK4/6i administered for a minimum of 8 weeks prior to disease progression.) Postmenopausal status for women Life expectancy ≥3 months Availability of a representative tumor specimen that is suitable for biomarker evaluation via central testing Prior fulvestrant therapy is allowed Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1 Stages 1 and 2: Adequate hematologic and end-organ function Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation Inclusion Criteria for Cohort 2 (Stage 1 [and Stage 2, only where indicated]): Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection ER-positive, HER2-positive breast cancer Postmenopausal status for women Life expectancy ≥3 months Willingness to have a representative tumor specimen that is suitable for biomarker evaluation via central testing submitted, if available Prior endocrine therapy in the advanced setting allowed, including fulvestrant if given more than 28 days prior to randomization, but excluding other selective estrogen receptor degraders (SERDs) Stages 1 and 2: Measurable disease (at least one target lesion) according to RECIST v1.1 Stages 1 and 2: Baseline left ventricular ejection fraction (LVEF) ≥50% as measured by ECHO or MUGA scans Stages 1 and 2: Adequate hematologic and end-organ function Stages 1 and 2: Stable anticoagulant regimen for patients receiving therapeutic anticoagulation Inclusion Criteria for Cohorts 1 and 2 (Stage 2): Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity, disease progression as determined by the investigator according to RECIST v1.1, or loss of clinical benefit as determined by the investigator, provided that a Stage 2 slot is available and patient meets eligibility criteria for Stage 2 Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 because of unacceptable toxicity to drugs, disease progression as determined by the investigator according to RECIST v1.1, or loss of clinical benefit as determined by the investigator Exclusion Criteria: General Exclusion Criteria for all Treatment Arms in Stage 1, Cohorts 1 and 2 (unless only applicable to one cohort, as indicated): Prior treatment with any of the protocol-specified study treatments Treatment with investigational therapy within 28 days prior to initiation of study treatment Systemic treatment for breast cancer within 2 weeks of Cycle 1, Day 1 or 5 half-lives of the drug prior to Cycle 1, Day 1 Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to randomization 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 Eligible only for the control arm Prior allogeneic stem cell or solid organ transplantation Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study 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 Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures Uncontrolled tumor-related pain Uncontrolled or symptomatic hypercalcemia Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases History of leptomeningeal disease 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 History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan Active cardiac disease or history of cardiac dysfunction Positive HIV test at screening or at any time prior to screening Active Hepatitis B or Hepatitis C virus infection Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery, including gastric resection, potentially affecting enteral absorption Known allergy or hypersensitivity to any of the study drugs or any of their excipients applicable to one cohort, as indicated): Cohort 1 only: Known HER2-positive breast cancer Cohort 1 only: Concurrent hormone replacement therapy Cohort 1 only: Prior treatment with cytotoxic chemotherapy for metastatic breast cancer (with the exception of single agent capecitabine, which will count as a single line of therapy) Cohort 2 only: Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy Cohort 2 only: Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose of 10 mg/day methylprednisolone equivalent), excluding inhaled steroids Additional Exclusion Criteria for Giredestrant + Abemaciclib Arm and Giredestrant + Abemaciclib + Atezolizumab Arm (Cohort 1, Stage 1): Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy History of major surgical resection involving the stomach or small bowel, or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea History of syncope of cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest Additional Exclusion Criteria for Giredestrant + Ipatasertib Arm (Cohort 1, Stage 1): Prior treatment with an Akt inhibitor Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications Grade ≥2 uncontrolled or untreated hypercholesterolemia or hypertriglyceremia History of Type 1 or Type 2 diabetes mellitus requiring insulin History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion Additional Exclusion Criteria for Giredestrant + Inavolisib Arm (Cohort 1, Stage 1): Prior treatment with any PI3K, Akt, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K/Akt/mTOR pathway Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes Fasting glucose ≥126 mg/dL or ≥7.0 mmol/L and HbA1c ≥5.7% Any concurrent ocular or intraocular condition that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition Active inflammatory or infectious conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye Symptomatic active lung disease, including pneumonitis Inability to confirm biomarker eligibility based on valid results from either central testing of blood or local testing of blood or tumor tissue that documents one of the protocol-defined PIK3CA mutations Additional Exclusion Criteria for Giredestrant + Ribociclib Arm (Cohort 1, Stage 1): Currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting trial treatment Impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments Additional Exclusion Criteria for Giredestrant + Samuraciclib Arm (Cohort 1, Stage 1): Prior treatment with mTOR inhibitor Receipt of systemic corticosteroids (at a dose >10 mg prednisone/day or equivalent) within 14 days before the first dose of samuraciclib Active bleeding diatheses History of hemolytic anemia or marrow aplasia Receipt of a live-virus vaccination within 28 days or less of planned treatment start Additional Exclusion Criteria for Giredestrant + Atezolizumab-Containing Arms (Cohort 1, Stage 1): Active or history of autoimmune disease or immune deficiency Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies Pregnant or breastfeeding, or intending to become pregnant during study treatment or within 5 months for atezolizumab Additional Exclusion Criteria for Giredestrant + PH FDC SC + Abemaciclib Arm (Cohort 2, Stage 1): Interstitial lung disease or severe dyspnea History of major surgical resection involving the stomach or small bowel, preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, or a condition that may significantly alter the absorption of the oral trial treatments History of syncope of cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest Additional Exclusion Criteria for Giredestrant + PH FDC SC + Palbociclib Arm (Cohort 2, Stage 1): History of major surgical resection involving the stomach or small bowel, preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea, or a condition that may significantly alter the absorption of the oral trial treatments Interstitial lung disease or severe dyspnea

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Cohort 1: Giredestrant Monotherapy<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;|
| Experimental: Cohort 1: Giredestrant + Abemaciclib<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Abemaciclib<br>* 150 mg orally twice a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: Verzenio™;|
| Experimental: Cohort 1: Giredestrant + Ipatasertib<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Ipatasertib<br>* 400 mg orally once a day on Days 1-21 of each 28-day cycle until unacceptable toxicity or disease progression<br>* Other names: RG7440;|
| Experimental: Cohort 1: Giredestrant + Inavolisib<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Inavolisib<br>* 9 mg orally once a day during each 28-day cycle until unacceptable toxicity or disease progression<br>* Other names: RG6114;|
| Experimental: Cohort 1: Giredestrant + Ribociclib<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Ribociclib<br>* 600 mg orally once a day on Days 1-21 of each 28-day cycle until unacceptable toxicity or disease progression<br>* Other names: Kisqali®;|
| Experimental: Cohort 1: Giredestrant + Everolimus<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Everolimus<br>* 10 mg orally once a day during each 28-day cycle until unacceptable toxicity or disease progression<br>* Other names: Afinitor®;|
| Experimental: Cohort 1: Giredestrant + Samuraciclib<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Samuraciclib<br>* 360 mg orally once a day during each 28-day cycle until unacceptable toxicity or disease progression<br>* Other names: CT7001;|
| Experimental: Cohort 1: Giredestrant + Atezolizumab<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Atezolizumab<br>* 840 mg by intravenous (IV) infusion on Days 1 and 15 each 28-day cycle.<br>* Other names: RG7446;|
| Experimental: Cohort 1: Giredestrant + Abemaciclib + Atezolizumab<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Abemaciclib<br>* 150 mg orally twice a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: Verzenio™;Drug: Atezolizumab<br>* 840 mg by intravenous (IV) infusion on Days 1 and 15 each 28-day cycle.<br>* Other names: RG7446;|
| Active Comparator: Cohort 2: Giredestrant + PH FDC SC<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: PH FDC SC<br>* On Day 1 of Cycle 1 (1 cycle is 21 days), pertuzumab and trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) will be administered SC as a fixed dose formulation of 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase. On Day 1 of Cycles 2 and beyond, PH FDC SC will be administered SC once every 21 days as a fixed dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase.<br>* Other names: RG6264;|
| Experimental: Cohort 2: Giredestrant + PH FDC SC + Abemaciclib<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: Abemaciclib<br>* 150 mg orally twice a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: Verzenio™;Drug: PH FDC SC<br>* On Day 1 of Cycle 1 (1 cycle is 21 days), pertuzumab and trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) will be administered SC as a fixed dose formulation of 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase. On Day 1 of Cycles 2 and beyond, PH FDC SC will be administered SC once every 21 days as a fixed dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase.<br>* Other names: RG6264;|
| Experimental: Cohort 2: Giredestrant + PH FDC SC + Palbociclib<br> | Drug: Giredestrant<br>* 30 milligrams (mg) orally once a day (during each 28-day cycle or 21-day cycle, depending on the regimen) until unacceptable toxicity or disease progression<br>* Other names: RG6171;Drug: PH FDC SC<br>* On Day 1 of Cycle 1 (1 cycle is 21 days), pertuzumab and trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) will be administered SC as a fixed dose formulation of 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase. On Day 1 of Cycles 2 and beyond, PH FDC SC will be administered SC once every 21 days as a fixed dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase.<br>* Other names: RG6264;Drug: Palbociclib<br>* 125 mg orally once a day on Days 1-21 during each 28-day cycle until unacceptable toxicity or disease progression<br>* Other names: Ibrance®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Objective Response, Defined as a Complete or Partial Response, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) |  | From Baseline until disease progression (up to 6 years) | 
| Number of Participants with Adverse Events, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) |  | From Baseline until 30 days after the last dose of study drug (up to 6 years) | 
| Plasma Concentration of Giredestrant at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 8, and 16 (each cycle is 28 days), and at treatment discontinuation visit (within 30 days after last dose) | 
| Plasma Concentration of Abemaciclib at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycles 2 and 3 (each cycle is 28 days), and at treatment discontinuation visit (within 30 days after last dose) | 
| Plasma Concentration of Ipatasertib at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycles 2 and 3 (each cycle is 28 days) | 
| Plasma Concentration of Inavolisib at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycles 2 and 3 (each cycle is 28 days) | 
| Plasma Concentration of Ribociclib at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycle 2 (each cycle is 28 days) | 
| Blood Concentration of Everolimus at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycle 2 (each cycle is 28 days) | 
| Plasma Concentration of Samuraciclib at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycles 2, 4, 8, and 16 (each cycle is 28 days), and at treatment discontinuation visit (within 30 days after last dose) | 
| Serum Concentration of Pertuzumab in PH FDC SC Treatment Arms at Specified Timepoints |  | Day 1 of Cycles 1 and 4 (each cycle is 21 days), and at treatment discontinuation visit (within 30 days after last dose) | 
| Serum Concentration of Trastuzumab in PH FDC SC Treatment Arms at Specified Timepoints |  | Day 1 of Cycles 1 and 4 (each cycle is 21 days), and at treatment discontinuation visit (within 30 days after last dose) | 
| Plasma Concentration of Palbociclib at Specified Timepoints |  | Days 1 and 15 of Cycle 1; Day 1 of Cycles 2 and 3 (each cycle is 28 days), and at treatment discontinuation visit (within 30 days after last dose) | 
| Serum Concentration of Atezolizumab at Specified Timepoints |  | Days 1 of Cycles 1, 2, 3, 4, 8, 12, and 16 (each cycle is 28 days), and at treatment discontinuation visit (within 30 days after last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1 |  | From randomization to the date of the first recorded occurrence of disease progression or death from any cause, whichever occurs first (up to 6 years) | 
| Disease Control Rate, Defined as the Percentage of Participants with Stable Disease for ≥12 Weeks or a Complete or Partial Response, as Determined by the Investigator According to RECIST v1.1 |  | From Baseline until disease progression (up to 6 years) | 
| Clinical Benefit Rate, Defined as the Percentage of Participants with Stable Disease for ≥24 Weeks or with Confirmed Complete or Partial Response, as Determined by the Investigator According to RECIST v1.1 |  | From Baseline until disease progression (up to 6 years) | 
| Overall Survival |  | From randomization to death from any cause (up to 6 years) | 
| Duration of Response, as Determined by the Investigator According to RECIST v1.1 |  | From first occurrence of a document objective response to the first date of recorded disease progression or death from any cause, whichever occurs first (up to 6 years) |