This phase I/Ib trial studies the side effects and best dose of Hu5F9-G4 (magrolimab) when given in combination with olaparib for the treatment of patients with breast or castrate-resistant prostate cancer that have spread from where they first started (primary site) to other places in the body (metastatic) or have come back after a period of improvement (recurrent) and have mutations in the BRCA1/2 genes. Magrolimab is a monoclonal antibody with potential anticancer activity and the cability to stimulate the immune system and may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Combination therapy with magrolimab and olaparib may be safe and effective in treating BRCA-mutated metastatic or recurrent breast or castrate-resistant prostate cancer.
PRIMARY OBJECTIVES: I. To evaluate the safety, tolerability, toxicity profile (dose-limiting toxicities \[DLTs\], maximum tolerated doses \[MTDs\]), and phase 2 recommended dose (P2RD) of Hu5F9-G4 (magrolimab) combined with olaparib. II. To evaluate the alteration in the immune microenvironment after combination therapy including alteration of specific immune signatures and pathways related to innate immune response and STING pathway. (Dose expansion) SECONDARY OBJECTIVES: I. To evaluate the status of homologous recombination repair (HR)/DNA damage response (DDR) and other genomic mutations. II. To characterize the pharmacokinetic (PK) profile of olaparib and magrolimab in combination. EXPLORATORY OBJECTIVES: I. To explore the activity of the combination regimen in entire cohort and in the dose expansion cohorts in term of objective response rate (ORR), and progression-free survival (PFS). II. To evaluate the peripheral immune profile. III. To evaluate alterations in the HR/DDR pathway by circulating tumor (ct)DNA. IV. To correlate drug exposure with response and/or toxicity. OUTLINE: This is a dose-escalation study of magrolimab in combination with fixed-dose Olaparib followed by a dose-expansion study. Patients receive magrolimab intravenously (IV) on days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of subsequent cycles. Patients also receive olaparib orally (PO) twice a day (BID) during each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples and computed tomography (CT) and/or magnetic resonance imaging (MRI) throughout the trial. Patients in the dose-expansion portion of the study also undergo tumor biopsies during screening and on study. Patients are followed for 30 days after removal from study treatment, and then followed every 12 months for 36 months or until death whichever comes first.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Undergo biopsies
Undergo collection of blood samples
Undergo CT
Undergo MRI
Given IV
Given PO
UC Irvine Health Cancer Center-Newport
Costa Mesa, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
Montefiore Medical Center-Einstein Campus
The Bronx, New York, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
Maximum tolerated dose (MTD) of olaparib with magrolimab (Dose Escalation)
The MTD is defined as the highest dose level with no more than 1/6 dose-limiting toxicities (DLT). DLT is defined as any grade \>= 3 non-hematologic toxicity despite best supportive care or grade \>= 4 hematologic toxicity per Common Terminology Criteria for Adverse Events version 5.0 attributed as possibly, probably, or definitely related to study drugs during the first cycle of therapy (28 days) lasting more than 7 days.
Time frame: Up to 28 days after the beginning of the treatment cycle
Tumor ribonucleic acid (RNA) sequencing of interferon- gamma (IFN-g) signature, TGF-beta signature, and STING pathway, as well as CD47 expression (Dose Expansion)
Will be compared between tumor tissue using a non-parametric paired test, at a significance level (alpha) of 0.05. This will only be performed in the expansion cohorts.
Time frame: Baseline and cycle 2 days 1-7
Tumor macrophage infiltrate (Dose Expansion)
Will be assessed using multiplex immune imaging and their phenotype (M1/M2 ratio) as well as STING pathway activation (TBK1, IRF3 and IFNB protein expression). Will be compared between tumor tissue using a non-parametric paired test, at a significance level (alpha) of 0.05. This will only be performed in the expansion cohorts.
Time frame: Baseline and cycle 2 days 1-7
Tumor infiltrating immune cells (Dose Expansion)
Will be assessed using multiplex immune imaging. Will be compared between tumor tissue using a non-parametric paired test, at a significance level (alpha) of 0.05. This will only be performed in the expansion cohorts.
Time frame: Baseline and cycle 2 days 1-7
Recommended phase 2 dose (Dose Expansion)
The RP2D determination will include both the DLT period for the MTD, as well as consideration of later cycle DLTs and the overall safety profile..
Time frame: Up to 28 days after the beginning of the treatment cycle
Incidence of adverse events (Dose Expansion)
Adverse events will be scored by CTCAE v5.0 and tabulated.
Time frame: Up to 30 days after the last administration
Tumor genomic markers
Deoxyribonucleic acid (DNA) damage response (DDR) genes including BRCA 1, 2 and other genes such as RAD51C, RAD51D, and PALB, polymorphism status, mutational burden and microsatellite instability (MSI) status will be assessed in available pre-treatment tissue and correlated with immune response by whole exome sequencing.
Time frame: Up to 36 months
Olaparib and magrolimab trough and potentially area under the curve
Descriptive data will be reported and compared with historical controls.
Time frame: Magrolimab: Cycle 1, day 1 (C1D1): Pre-treatment (Pre); C1D8: Pre, after end of infusion, 1 hour after infusion; C1D15: Pre; Olaparib: C1D1, C1D8, C1D15: Pre
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