- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05807126
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
A Phase I/Ib Study of Anti-CD47 Hu5F9-G4 (Magrolimab) in Combination With Olaparib in Patients With BRCA1/2-Mutant Tumors
Study Overview
Status
Conditions
Detailed Description
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
Enrollment (Estimated)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
California
-
Costa Mesa, California, United States, 92627
- UC Irvine Health Cancer Center-Newport
-
Orange, California, United States, 92868
- UC Irvine Health/Chao Family Comprehensive Cancer Center
-
-
New York
-
Bronx, New York, United States, 10461
- Montefiore Medical Center-Einstein Campus
-
Bronx, New York, United States, 10467
- Montefiore Medical Center - Moses Campus
-
-
Pennsylvania
-
Pittsburgh, Pennsylvania, United States, 15232
- University of Pittsburgh Cancer Institute (UPCI)
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
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
- Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
- Hemoglobin (Hgb) >= 9 g/dL
- Patients infected with human immunodeficiency virus (HIV) who are on effective anti-retroviral therapy with undetectable viral load within 6 months may be eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients with prior brain metastasis that was treated with evidence of resolution or stable disease for 6 months are eligible. Patients are required to be stable and fully tapered off steroids for at least >= 1 month
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
- Women of child-bearing potential, and men who are sexually active and their partner who may become pregnant, must use contraception during treatment and at least for 6 months (women) and 4 months (men) after the last dose of magrolimab and olaparib. Breastfeeding is not allowed during treatment and for one month after receiving the last dose of therapy
- Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (magrolimab, olaparib)
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.
|
Undergo collection of blood samples
Other Names:
Undergo MRI
Other Names:
Undergo CT
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Undergo biopsies
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Tumor macrophage infiltrate (Dose Expansion)
Time Frame: Baseline and cycle 2 days 1-7
|
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)
Time Frame: Baseline and cycle 2 days 1-7
|
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
|
Maximum tolerated dose (MTD) of olaparib with magrolimab (Dose Escalation)
Time Frame: Up to 28 days after the beginning of the treatment cycle
|
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)
Time Frame: Baseline and cycle 2 days 1-7
|
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)
Time Frame: Up to 28 days after the beginning of the treatment cycle
|
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)
Time Frame: Up to 30 days after the last administration
|
Adverse events will be scored by CTCAE v5.0 and tabulated.
|
Up to 30 days after the last administration
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Tumor genomic markers
Time Frame: Up to 36 months
|
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.
|
Up to 36 months
|
Olaparib and magrolimab trough and potentially area under the curve
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
|
Descriptive data will be reported and compared with historical controls.
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Objective response rate (ORR)
Time Frame: Up to 36 months
|
Treatment response will be assessed for all patients based on Response Evaluation Criteria in Solid Tumors version 1.1: complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD).
ORR is defined as the addition of CR and PR.
The probability of ORR will be estimated with exact 95% binomial confidence intervals.
Clinical benefit rate is defined as the addition of CR, PR and SD.
|
Up to 36 months
|
Peripheral blood cytokines and immune cell populations
Time Frame: Pre, C2D1, C3D1, C5D1, and at progression, assessed up to 36 months
|
Peripheral blood cytokines assessed by Luminex or MesoScale Discovery assays.
Immune cell populations assessed by multicolor flow cytometry.
Cytokine levels and immune cell population levels will be followed through treatment and may be compared with a non-parametric paired test, at a significance level (alpha) of 0.05.
|
Pre, C2D1, C3D1, C5D1, and at progression, assessed up to 36 months
|
Circulating tumor (ct)DNA assessment of BRCA and other genes
Time Frame: Baseline, C3D1, and at progression, assessed up to 36 months
|
Will include genes such as RAD51C, RAD51D, and PALB2 over time.
DDR gene expression will be followed through treatment and may be compared descriptively.
|
Baseline, C3D1, and at progression, assessed up to 36 months
|
Drug exposure and response and/or toxicity
Time Frame: Up to 36 months
|
Will correlate drug exposure with response and/or toxicity with pharmacodynamics (biological endpoints, toxicity and efficacy) and analyzed using nonparametric statistics.
|
Up to 36 months
|
Progression free survival (PFS)
Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 36 months
|
Will be assessed using the Kaplan-Meier method, along with 95% confidence regions.
|
Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 36 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Haider S Mahdi, University of Pittsburgh Cancer Institute LAO
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms
- Urogenital Neoplasms
- Neoplasms by Site
- Genital Neoplasms, Male
- Prostatic Diseases
- Urogenital Diseases
- Male Urogenital Diseases
- Genital Diseases, Male
- Genital Diseases
- Prostatic Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Olaparib
- Poly(ADP-ribose) Polymerase Inhibitors
- Magrolimab
Other Study ID Numbers
- NCI-2023-02710 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- UM1CA186690 (U.S. NIH Grant/Contract)
- 10551 (Other Identifier: CTEP)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Anatomic Stage IV Breast Cancer AJCC v8
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Active, not recruitingAnatomic Stage I Breast Cancer AJCC v8 | Anatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic... and other conditionsUnited States
-
M.D. Anderson Cancer CenterActive, not recruitingAnatomic Stage I Breast Cancer AJCC v8 | Anatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic... and other conditionsUnited States
-
Ohio State University Comprehensive Cancer CenterRecruitingAnatomic Stage I Breast Cancer AJCC v8 | Anatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic... and other conditionsUnited States
-
Jonsson Comprehensive Cancer CenterNovartis; Seagen Inc.RecruitingAnatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic Stage IIIA Breast Cancer AJCC v8 | Anatomic Stage IIIB Breast Cancer AJCC v8 | Anatomic Stage IIIC Breast Cancer AJCC... and other conditionsUnited States
-
Ohio State University Comprehensive Cancer CenterRecruitingAnatomic Stage I Breast Cancer AJCC v8 | Anatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic... and other conditionsUnited States
-
Ohio State University Comprehensive Cancer CenterNational Cancer Institute (NCI)WithdrawnAnatomic Stage I Breast Cancer AJCC v8 | Anatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic... and other conditions
-
Ohio State University Comprehensive Cancer CenterNational Cancer Institute (NCI)RecruitingAnatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic Stage IIIA Breast Cancer AJCC v8 | Anatomic Stage IIIB Breast Cancer AJCC... and other conditionsUnited States
-
Mayo ClinicNational Cancer Institute (NCI)Active, not recruitingAnatomic Stage I Breast Cancer AJCC v8 | Anatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic... and other conditionsUnited States
-
M.D. Anderson Cancer CenterActive, not recruitingAnatomic Stage I Breast Cancer AJCC v8 | Anatomic Stage IA Breast Cancer AJCC v8 | Anatomic Stage IB Breast Cancer AJCC v8 | Anatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic... and other conditionsUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)CompletedAnatomic Stage II Breast Cancer AJCC v8 | Anatomic Stage IIA Breast Cancer AJCC v8 | Anatomic Stage IIB Breast Cancer AJCC v8 | Anatomic Stage III Breast Cancer AJCC v8 | Anatomic Stage IIIA Breast Cancer AJCC v8 | Anatomic Stage IIIB Breast Cancer AJCC v8 | Anatomic Stage IIIC Breast Cancer AJCC... and other conditionsUnited States
Clinical Trials on Biospecimen Collection
-
LLS PedAL Initiative, LLCNational Cancer Institute (NCI); Children's Oncology GroupRecruitingAcute Myeloid Leukemia | Juvenile Myelomonocytic Leukemia | Acute Lymphoblastic Leukemia | Myelodysplastic Syndrome | Myeloid Leukemia Associated With Down Syndrome | Mixed Phenotype Acute Leukemia | Acute Myeloid Leukemia Post Cytotoxic Therapy | Myelodysplastic Syndrome Post Cytotoxic TherapyUnited States, Canada, Australia, Puerto Rico, New Zealand
-
Thomas Jefferson UniversityNational Cancer Institute (NCI)Active, not recruiting
-
Ohio State University Comprehensive Cancer CenterGuardant Health, Inc.RecruitingColorectal CarcinomaUnited States
-
Mayo ClinicNational Cancer Institute (NCI)RecruitingMetastatic Renal Cell Carcinoma | Stage IV Renal Cell Cancer AJCC v8United States
-
Mayo ClinicNational Cancer Institute (NCI)RecruitingBreast Adenocarcinoma | HER2-Positive Breast CarcinomaUnited States
-
National Cancer Institute (NCI)Active, not recruitingAnatomic Stage III Breast Cancer AJCC v8 | Anatomic Stage IIIA Breast Cancer AJCC v8 | Anatomic Stage IIIB Breast Cancer AJCC v8 | Anatomic Stage IIIC Breast Cancer AJCC v8 | Prognostic Stage III Breast Cancer AJCC v8 | Prognostic Stage IIIA Breast Cancer AJCC v8 | Prognostic Stage IIIB Breast... and other conditionsUnited States, Puerto Rico
-
Thomas Jefferson UniversityRecruitingMalignant Solid Neoplasm | GlioblastomaUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI); National Institute of General Medical Sciences...Recruiting
-
Ohio State University Comprehensive Cancer CenterRecruitingCancerUnited States
-
M.D. Anderson Cancer CenterActive, not recruitingMetastatic Rectal Adenocarcinoma | Stage III Rectal Cancer AJCC v8 | Stage IIIA Rectal Cancer AJCC v8 | Stage IIIB Rectal Cancer AJCC v8 | Stage IIIC Rectal Cancer AJCC v8 | Stage IV Rectal Cancer AJCC v8 | Stage IVA Rectal Cancer AJCC v8 | Stage IVB Rectal Cancer AJCC v8 | Stage IVC Rectal Cancer AJCC... and other conditionsUnited States