Study of Magrolimab Combination Therapy in Patients With Non-Surgically Removable Locally Advanced or Metastatic Triple-Negative Breast Cancer

Study Overview
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Brief Summary
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The goals of this clinical study are to learn about the safety, tolerability, dosing and effectiveness of magrolimab in combination with nab-paclitaxel or paclitaxel (cohort 1) or with sacituzumab govitecan-hziy (cohort 2) in patients with non-surgically removable locally advanced or metastatic triple-negative breast cancer.

Detailed Description
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The primary objective of this study for the safety run-in cohorts of the study is to evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of magrolimab in combination with nab-paclitaxel or paclitaxel (Safety Run-In Cohort 1), and sacituzumab govitecan (Safety Run-In Cohort 2) in metastatic triple-negative breast cancer (mTNBC). The primary objective of this study for Phase 2 Cohort 1 is to compare the efficacy of magrolimab in combination with nab-paclitaxel or paclitaxel versus nab-paclitaxel or paclitaxel alone, as determined by progression-free survival (PFS) by investigator assessment. The primary objective of this study for Phase 2 Cohort 2 is to evaluate the efficacy of magrolimab in combination with sacituzumab govitecan as determined by confirmed objective response rate (ORR) by investigator assessment.

Official Title
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A Phase 2 Study of Magrolimab Combination Therapy in Patients With Unresectable, Locally Advanced or Metastatic Triple-Negative Breast Cancer

Conditions
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Triple-Negative Breast Cancer

Intervention / Treatment
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* Drug: Magrolimab
* Drug: Nab-Paclitaxel
* Drug: Paclitaxel
* Drug: Sacituzumab Govitecan-hziy


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Adequate performance status, hematologic, renal and liver function. Measurable disease per RECIST v1.1 Cohort 1: Individuals with previously untreated with systemic therapy for unresectable locally advanced or metastatic TNBC that are considered PD-L1 negative (as determined by an approved test according to local regulations). Cohort 2: Individuals with unresectable, locally advanced or metastatic breast cancer with a diagnosis of TNBC who have received at least 1 and no more than 2 prior lines of systemic therapy in the unresectable, locally advanced or metastatic setting. Individuals must have been previously treated with a taxane in any setting. Individuals with tumors that are considered positive for PD-L1 expression (as determined by an approved test according to local regulations) must have received an immune checkpoint inhibitor for a prior-line of treatment for unresectable locally advanced/metastatic TNBC. Key Exclusion Criteria: Positive serum pregnancy test or breastfeeding female. Active CNS disease. Individuals with asymptomatic and stable, treated CNS lesions (who have been off steroids, radiation and/or surgery and/or other CNS-directed therapy for at least 4 weeks) are allowed. RBC transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening. Red blood cell transfusions are permitted during the screening period and prior to enrollment to meet the hemoglobin inclusion criteria. History of hemolytic anemia, autoimmune thrombocytopenia, or Evans syndrome in the last 3 months. Prior treatment with CD47 or signal regulatory protein alpha-targeting agents. Known inherited or acquired bleeding disorders. Cohort 1 only: Disease progression within 6 months following neoadjuvant/adjuvant therapy. Cohort 2 only: Individuals with active chronic inflammatory bowel disease (ulcerative colitis, Crohn disease) and Individuals with a history of bowel obstruction or gastrointestinal perforation within 6 months of enrollment. Individuals who previously received topoisomerase I inhibitors or antibody-drug conjugates containing a topoisomerase inhibitor. High-dose systemic corticosteroids (≥ 20 mg of prednisone or its equivalent) are not allowed within 2 weeks of Cycle 1 Day 1. Have not recovered (ie, ≥ Grade 2 is considered not recovered) from AEs due to a previously administered agent. Note: individuals with any grade of neuropathy, alopecia, hypo- or hyperthyroidism, or other endocrinopathies that are well controlled with hormone replacement are an exception to this criterion and will qualify for the study. Note: if individuals received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-in Cohort 1: Magrolimab + Nab-Paclitaxel or Paclitaxel<br>Participants with untreated unresectable, locally advanced or metastatic TNBC whose tumors are not appropriate for immune checkpoint inhibitor therapy will receive the following: magrolimab in de-escalating doses to establish RP2D nab-paclitaxel or paclitaxel administered according to local guidelines. Each cycle is 28 days. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Nab-Paclitaxel<br>* Administered intravenously<br>* Other names: Abraxane;Drug: Paclitaxel<br>* Administered intravenously<br>* Other names: Taxol®;|
| Experimental: Phase 2 Cohort 1 Arm A: Magrolimab + Nab-Paclitaxel or Paclitaxel<br>Participants with mTNBC will receive the RP2D determined in the Safety Run-in cohort of magrolimab in combination with nab-paclitaxel or paclitaxel administered according to local guidelines. Each cycle is 28 days. Magrolimab will be continued until development of unacceptable toxicity that cannot be clinically managed by dose or schedule modifications. Nab-paclitaxel or paclitaxel will be continued until development of unacceptable toxicity. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Nab-Paclitaxel<br>* Administered intravenously<br>* Other names: Abraxane;Drug: Paclitaxel<br>* Administered intravenously<br>* Other names: Taxol®;|
| Active Comparator: Phase 2 Cohort 1 Arm B: Nab-Paclitaxel or Paclitaxel<br>Participants with mTNBC will receive nab-paclitaxel or paclitaxel administered according to local guidelines. Each cycle is 28 days. Nab-paclitaxel or paclitaxel will be continued until development of unacceptable toxicity. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Nab-Paclitaxel<br>* Administered intravenously<br>* Other names: Abraxane;Drug: Paclitaxel<br>* Administered intravenously<br>* Other names: Taxol®;|
| Experimental: Safety Run-in Cohort 2: Magrolimab + Sacituzumab govitecan<br>Participants with unresectable, locally advanced or metastatic TNBC who have received at least 1 and no more than 2 prior lines of treatment in the unresectable, locally advanced or metastatic setting will receive the following: magrolimab in de-escalating doses to establish RP2D sacituzumab govitecan on Days 1 and 8 Each cycle is 21 days. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously<br>* Other names: Trodelvy®;|
| Experimental: Phase 2 Cohort 2: Magrolimab + Sacituzumab govitecan<br>Participants with mTNBC will receive the RP2D determined in the Safety Run-in cohort of magrolimab in combination with sacituzumab govitecan on Days 1 and 8. Each cycle is 21 days. Magrolimab will be continued until development of unacceptable toxicity that cannot be clinically managed by dose or schedule modifications.sacituzumab govitecan will be continued until development of unacceptable toxicity. | Drug: Magrolimab<br>* Administered intravenously<br>* Other names: GS-4721;Drug: Sacituzumab Govitecan-hziy<br>* Administered intravenously<br>* Other names: Trodelvy®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Run-in Cohorts: Percentage of Participants Experiencing Dose-Limiting Toxicities (DLTs), Adverse Events (AEs), and Laboratory Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE), Version 5.0 |  | First dose date up to 35 months | 
| Phase 2 Cohort 1: PFS as Determined by Investigator Assessment Using RECIST Version 1.1 | PFS is defined as the time from the date of randomization until the earliest date of documented disease progression, as determined by investigator assessment per RECIST version 1.1, or death from any cause, whichever occurs first. | Up to 35 months | 
| Cohort 2 (Safety Run-In Cohort 2 and Phase 2 Cohort 2): Confirmed Objective Response Rate (ORR) as Determined by Investigator Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | The objective response rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. | Up to 35 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 Cohort 1: Confirmed Objective Response Rate (ORR) as Determined by Investigator Assessment | ORR is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR), as measured by RECIST version 1.1, as determined by investigator assessment. | Up to 35 months | 
| Cohort 2 (Safety Run-in Cohort 2 and Phase 2 Cohort 2): PFS as Determined by Investigator Assessment Using RECIST Version 1.1 | PFS is defined as the time from the date of randomization until the earliest date of documented disease progression, as determined by investigator assessment per RECIST version 1.1, or death from any cause, whichever occurs first. | Up to 35 months | 
| Phase 2 Cohort 1 and Cohort 2 (Safety Run-in Cohort 2 and Phase 2 Cohort 2): Duration of Response (DOR) as Determined by Investigator Assessment per RECIST Version 1.1 | DOR is defined as time from first documentation of complete response or partial response to the earliest date of documented disease progression, as determined by investigator assessment per RECIST version 1.1, or death from any cause, whichever occurs first. | Up to 35 months | 
| Phase 2 Cohort 1 and Cohort 2 (Safety Run-in Cohort 2 and Phase 2 Cohort 2): Overall Survival (OS) | OS is defined as time from date of randomization to death from any cause. | Up to 35 months | 
| Phase 2 Cohort 1 and Cohort 2 (Safety Run-in Cohort 2 and Phase 2 Cohort 2): Percentage of Participants Experiencing AEs and Laboratory Abnormalities According to NCI CTCAE, Version 5.0 |  | First dose date up to 35 months | 
| Magrolimab Concentration Versus Time |  | Up to end of treatment (approximately 35 months) | 
| Antidrug Antibodies (ADA) to Magrolimab |  | Up to end of treatment (approximately 35 months) |