Testing the Addition of Immunotherapy With Hu5F9-G4 (Magrolimab) to the Usual PARP Inhibitor, Olaparib for Treatment of Metastatic or Recurrent Breast or Castrate-Resistant Prostate Cancer With BRCA Mutations

NCT05807126 | Withdrawn Phase 1 FDA Drug

• 3 other identifiers: NCI-2023-0271010551UM1CA186690
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Anatomic Stage IV Breast Cancer AJCC v8; Castration-Resistant Prostate Carcinoma; Stage IVB Prostate Cancer AJCC v8

Outcome Measures

Primary Outcomes (6)

• 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.

  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.

  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.

  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.

  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..

  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.

  Up to 30 days after the last administration

Secondary Outcomes (2)

• Tumor genomic markers

  Up to 36 months

• Olaparib and magrolimab trough and potentially area under the curve

  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

Other Outcomes (5)

• Objective response rate (ORR)

  Up to 36 months

• Progression free survival (PFS)

  Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 36 months

• Peripheral blood cytokines and immune cell populations

  Pre, C2D1, C3D1, C5D1, and at progression, assessed up to 36 months

Study Arms (1)

Treatment (magrolimab, olaparib)

EXPERIMENTAL

Patients receive magrolimab IV on days 1, 8, 15 and 22 of cycle 1 and days 1 and 15 of subsequent cycles. Patients also receive olaparib PO 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 CT and/or MRI throughout the trial. Patients in the dose-expansion portion of the study also undergo tumor biopsies during screening and on study.

Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Biological: Magrolimab; Drug: Olaparib

Interventions

Biopsy PROCEDURE

Undergo biopsies

Also known as: BIOPSY_TYPE, Bx

Treatment (magrolimab, olaparib)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (magrolimab, olaparib)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (magrolimab, olaparib)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (magrolimab, olaparib)

Magrolimab BIOLOGICAL

Given IV

Also known as: Hu5F9-G4, ONO-7913

Treatment (magrolimab, olaparib)

Olaparib DRUG

Given PO

Also known as: AZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, Olanib, Olaparix, PARP Inhibitor AZD2281

Treatment (magrolimab, olaparib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Presence of metastatic and/or recurrent solid tumors (therapy naïve or those with prior therapy) with pathogenic BRCA 1/2 mutated cancers where olaparib is indicated as standard of care therapeutic option (not maintenance) as below:
• Metastatic breast cancer:
• Germline - Yes (Y); Somatic - No (N): Must have had prior chemotherapy (chemo) (adjuvant \[adj\], treatment); or if hormone receptor positive (HR+), must have had prior endocrine therapy or deemed inappropriate for endocrine treatment
• Metastatic castrate-resistant prostate cancer (CPRC)
• Germline - Y; Somatic - Y: Treatment after progressive disease on anti-androgens
• BRCA mutation status must be confirmed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory (lab)
• Patients \>= 18 years of age. Because no dosing or adverse event data are currently available on the use of Hu5F9-G4 (magrolimab) in combination with olaparib in patients \< 18 years of age, children are excluded from this study
• Patients may not have had prior PARP inhibitor in the metastatic setting when given for therapeutic purposes. Patients with breast cancer who received adjuvant PARP inhibitor (i) are eligible. Patients who had prior maintenance therapy are eligible.
• At least 4 weeks or 4 prior drug half-lives (whichever is shorter) must have elapsed since completion of the previous systemic therapy
• Expansion Cohort: Willingness and feasibility to undergo pre and post treatment biopsy
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Absolute neutrophil count \>= 1,500/mcL
• Platelets \>= 100,000/mcL
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x institutional ULN

You may not qualify if:

• Previous anti-CD47 therapy
• Concomitant use of strong CYP3A4 inhibitors/inducers can cause clinically significant drug-interactions; thus, study patients who require the use of these CYP enzymes continuously should be excluded. Study patients need to come off 3 eliminated half-lives of moderate CYP3A4 inhibitors and 5 eliminated half-lives of strong CYP3A4 inhibitors
• Patients who require immunosuppressive treatments for comorbidities are not eligible
• Gastrointestinal pathology or history that adversely impacts the ability to take or absorb oral medication
• Inability to comply with the protocol and/or not willing or who will not be available for follow-up assessments
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to magrolimab or other agents used in study
• Patients with uncontrolled intercurrent illness
• Pregnant women are excluded from this study because Hu5F9-G4 (magrolimab) is an anti-CD47 monoclonal antibody agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Hu5F9-G4 (magrolimab), breastfeeding should be discontinued if the mother is treated with Hu5F9-G4 (magrolimab). These potential risks may also apply to other agents used in this study

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (5)

UC Irvine Health Cancer Center-Newport

Costa Mesa, California, 92627, United States

Location

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

Montefiore Medical Center-Einstein Campus

The Bronx, New York, 10461, United States

Location

Montefiore Medical Center - Moses Campus

The Bronx, New York, 10467, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; magrolimab; olaparib

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Haider S Mahdi

  University of Pittsburgh Cancer Institute LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2023
• First Posted: April 11, 2023
• Study Start: March 5, 2024
• Primary Completion (Estimated): December 6, 2026
• Study Completion (Estimated): December 6, 2026
• Last Updated: May 2, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share

Locations

US (5)