Clinical trial NCT04778410: Study of Magrolimab Combinations in Participants With Myeloid Malignancies
Official title: A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Myeloid Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Myeloid Malignancies
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2021-03-03
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: After completion of Safety Run-in cohorts and identification of the RP2D for the specific cohorts, participants may be enrolled to the corresponding Phase 2 cohorts.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical study is to learn more about the safety and dosing of the study drug, magrolimab (Mag), in combination with anti-leukemia therapies in participants with acute myeloid leukemia (AML).

Detailed description: The anti-leukemia therapies are defined as follows:

* Venetoclax (Ven)
* Azacitidine (Aza)
* Mitoxantrone, etoposide, and cytarabine (MEC)

This study consists of 3 safety run-in cohorts;

* Safety Run-in Cohort 1 (1L Unfit AML Mag + Ven + Aza)
* Safety Run-in Cohort 2 (R/R AML Mag + MEC)
* Safety Run-in Cohort 3 (Post-chemo Maintenance Mag + CC-486)

Participants will receive treatment at the assigned dose level for at least 4 cycles in the Safety Run-in cohorts, after which they may continue at the assigned dose level or switch to the RP2D upon agreement between the investigator and the sponsor. After completion of each safety run-in cohort and identification of the RP2D for that cohort, participants may be enrolled into the corresponding Phase 2 cohorts;

* Phase 2 Cohort 1 (1L Unfit AML Mag + Ven + Aza)
* Phase 2 Cohort 2 (R/R AML Mag + MEC)
* Phase 2 Cohort 3 (Post-chemo Maintenance Mag + CC-486)

Cycle length is 28 days for both the Safety Run-in and Phase 2 cohorts.

Note: All cohorts are closed to screening and enrollment.

Eligibility criteria: Key Inclusion Criteria:

All Individuals:

* White blood cell (WBC) count ≤ 20 × 10\^3/microliter (μL) prior to first dose of study treatment. If the individual's WBC count is \> 20 × 10\^3/ μL prior to first dose of study treatment, the individual can be enrolled, assuming all other eligibility criteria are met
* For individuals with prior cardiac history, the hemoglobin must be ≥ 9 grams per deciliter (g/dL) prior to initial dose of study treatment. Transfusions are allowed to meet hemoglobin eligibility
* Adequate liver function
* Adequate renal function
* Individual has provided informed consent
* Individual is willing and able to comply with clinic visits and procedures outlined in the study protocol
* Pretreatment blood cross-match completed
* Males and females of childbearing potential who engage in heterosexual intercourse must agree to use protocol- specified method(s) of contraception
* Individuals must be willing to consent to mandatory pretreatment and on-treatment bone marrow biopsies (trephines), unless not feasible as determined by the investigator and discussed with the sponsor

Safety Run-in Cohort 1 and Phase 2 Cohort 1 (Ineligible (1L) Unfit acute myeloid leukemia (AML) Magrolimab + Venetoclax + Azacitidine):

* Newly diagnosed, previously untreated individuals with histological confirmation of AML by world health organization (WHO) criteria who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age, comorbidity, or other factors. Individuals must be considered ineligible for induction therapy defined by the following:

  * ≥ 75 years of age
  * ≥ 18 to 74 years of age with at least 1 of the following comorbidities:

    * Diffusing capacity of the lung of carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65%
    * Left ventricular ejection fraction (LVEF) ≤ 50%
    * Creatinine clearance (CrCl) \< 45 mL/min calculated by the Cockcroft-Gault formula or measured by 24 hours' urine collection
    * Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy that must be approved by the sponsor medical monitor before study enrollment
* Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3
* Individuals who have not received prior anti-leukemia therapy for AML (excluding hydroxyurea or oral etoposide), hypomethylating agent (HMA), low-dose cytarabine, and/or venetoclax. Individuals with prior myelodysplastic syndrome (MDS) cannot have received a prior HMA, venetoclax, or a chemotherapeutic agent. Other prior MDS therapies, including but not limited to lenalidomide, erythroid-stimulating agents, or similar red blood cell (RBC) -direct therapies, are allowed
* Individuals who have not received strong and/or moderate cytochrome P450 enzyme (CYP) 3A inducers (such as St. John's Wort) within 7 days prior to the initiation of study treatment
* Individuals who have not consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment or are willing to discontinue consumption of these while receiving study drug
* Individuals without malabsorption syndrome or other conditions that preclude enteral route of administration

Safety Run-in Cohort 2 and Phase 2 Cohort 2 (Relapsed/refractory (R/R) AML Magrolimab+Mitoxantrone + Etoposide + Cytarabine (MEC)):

* Individuals with confirmation of AML by WHO criteria who are refractory to or have experienced first relapse after initial intensive chemotherapy. Note: Individuals who are relapsed after or are refractory to more than 1 line of anti-AML treatment are not eligible. Individuals who relapsed after undergoing stem cell transplant may be eligible.
* At least 2 weeks must have elapsed since any prior anti-leukemia agents. Note: Localized non-central nervous system (CNS) radiotherapy, hydroxyurea, and erythroid and/or myeloid growth factors are not criteria for exclusion
* ECOG performance status of 0 to 2
* Individuals with LVEF \> 50%, lack of symptomatic congestive heart failure, or clinically significant cardiac arrhythmias
* Must not have been treated with trastuzumab within 7 months prior to the initiation of study treatment
* Individuals who have not previously received maximum cumulative doses of anthracyclines and anthracenediones
* Individuals without degenerative or toxic encephalopathies.
* Individuals who did not undergo hematopoietic SCT in the past 100 days, are not on immunosuppressive therapy post SCT in the 2 weeks prior to the first dose of study treatment, or have no active clinically significant graft-versus-host disease.

Safety Run-in Cohort 3 and Phase 2 Cohort 3 (Post-chemo Maintenance Magrolimab+CC-486):

* Individuals with histological confirmation of AML by WHO criteria who achieved a complete remission (CR) or CR with incomplete hematologic recovery (CRi) with presence of MRD (MRD positive by flow cytometry assay, defined as ≥ 0.1% detectable MRD) after intensive induction chemotherapy with or without consolidation therapy, prior to starting maintenance therapy for newly diagnosed AML, and who are not candidates for hematopoietic stem cell transplantation (SCT) within 1 year of achievement of initial remission
* ECOG performance status of 0 to 2
* Individuals without malabsorption syndrome or other conditions that preclude enteral route of administration

Key Exclusion Criteria:

* Positive serum pregnancy test
* Breastfeeding female
* Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
* Individuals receiving any live virus vaccine within 4 weeks prior to initiation of study treatments
* Prior treatment with cluster of differentiation 47 (CD47) or signal regulatory protein alpha (SIRPα) -targeting agents
* Current participation in another interventional clinical trial
* Known inherited or acquired bleeding disorders
* Clinical suspicion of or documented active CNS involvement with AML
* Individuals who have acute promyelocytic leukemia
* Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk: benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III-IV
* Second malignancy, except MDS, treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which individuals are not on active anti-cancer therapies and have had no evidence of active malignancy for over 1 year. Previous hormonal therapy with luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are not criteria for exclusion

  * Note: Individuals on maintenance therapy alone who have no evidence of active malignancy for at least ≥ 1 year are eligible.
* Known active or chronic hepatitis B or C infection or human immunodeficiency virus

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Complete Remission (CR) Rate (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Minimal Residual Disease Negative Complete Remission Rate (Cohort 3)
timeFrame: Up to 2 years
measure: Percentage of Participants Experiencing Dose-limiting Toxicities (DLTs) (Safety Run-in Cohorts 1, 2 and 3)
timeFrame: Up to 28 days
measure: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) (Cohorts 1, 2 and 3)
timeFrame: First dose date up to 1.7 years plus 70 days
measure: Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities (Cohorts 1, 2 and 3)
timeFrame: First dose date up to 1.7 years plus 70 days
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Up to 2 years
measure: Complete Remission or Complete Remission With Partial Hematologic Recovery Rate (CR/CRh) (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Duration of Response (DOR) (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Duration of Complete Remission (DCR) (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Duration of CR/CRi (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Duration of CR/CRh (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Event-Free Survival (EFS) (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Relapse-Free Survival (RFS) Rate (Cohort 3)
timeFrame: Up to 2 years
measure: MRD Negative CR/CRi Rate (Cohort 3)
timeFrame: Up to 2 years
measure: Duration of Minimal Residual Disease Negative Complete Remission (Cohort 3)
timeFrame: Up to 2 years
measure: Duration of MRD Negative CR/CRi (Cohort 3)
timeFrame: Up to 2 years
measure: Overall Survival (OS) (Cohorts 1, 2 and 3)
timeFrame: Up to 2 years
measure: Red Blood Cell (RBC) Transfusion Independence Rate (Cohorts 1, 2 and 3)
timeFrame: Up to 2 years
measure: Platelet Transfusion Independence Rate (Cohorts 1, 2 and 3)
timeFrame: Up to 2 years
measure: Plasma Concentration of Magrolimab in Combination With Anti-leukemia Therapy (Cohorts 1, 2 and 3)
timeFrame: Cohort 1: Predose: Days 1, 8, 29, 57, 113, 169, 253 and 337; Cohort 2: Days 1, 8, 29 and 57
measure: Percentage of Participants With Anti-Magrolimab Antibodies (Cohorts 1 and 2)
timeFrame: Up to 2 years
measure: Levels of Anti-Magrolimab Antibodies (Cohorts 1 and 2)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope (City of Hope National Medical Center, City of Hope Medical Center)
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Oklahoma City
country: United States
facility: OU Health, Stephenson Cancer Center
state: Oklahoma
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Milwaukee
country: United States
facility: Froedtert Hospital & the Medical College of Wisconsin
state: Wisconsin
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust, Churchill Hospital
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Mannis GN, Abboud C, Daver NG, Guru Murthy GS, Wang ES, Bradley TJ, et al. Tolerability and Efficacy of Magrolimab Plus Mitoxantrone, Etoposide, and Cytarabine (MEC) in Patients with Acute Myeloid Leukemia (AML) Refractory/Relapsed (R/R) After Induction Chemotherapy (IC). European Hematology Association (EHA) 13-16 June 2024.