Study of Magrolimab Combinations in Participants With Myeloid Malignancies

  • Interventional
  • Recruiting
  • NCT04778410
Eligibility Details Visit Clinicaltrials.gov

A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Myeloid Malignancies

The primary objectives of this study are to evaluate the safety, tolerability and to determine the recommended Phase 2 dose (RP2D) of magrolimab (Mag) in combination with the anti-leukemia therapies of venetoclax (Ven) and azacitidine (Aza) (Cohort 1), mitoxantrone, etoposide, and cytarabine (MEC) (Cohort 2) and CC-486 (Cohort 3) respectively in participants with acute myeloid leukemia (AML), to evaluate the efficacy of magrolimab in combination with the anti-leukemia therapies as determined by the rate of complete remission (CR) (Phase 2 Cohorts 1 and 2), and/or complete remission with incomplete hematologic recovery (CRi) (CR/CRi) (Phase 2 Cohort 2) and to evaluate the efficacy of magrolimab in combination with anti-leukemia therapy CC-486 as determined by the minimal residual disease (MRD) negative CR rate (Phase 2 Cohort 3).

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 will be enrolled into the corresponding Phase 2 cohorts;

        - Phase 2 Cohort 1 (1L Unfit UML 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.

Gender
All

Age Group
18 Years and up

Accepting Healthy Volunteers?
No

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 ≥ 9.5 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 AML Mag+Ven+Aza)]:

         - 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

         - 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 Mag+MEC)]:

         - Individuals with histological confirmation of AML by WHO criteria who are refractory to or have experienced first relapse after initial intensive chemotherapy

         - At least 3 weeks must have elapsed since any prior systemic or targeted anti-leukemia agents. NOTE: Localized non-central nervous system (CNS) radiotherapy, hydroxyurea, oral etoposide, 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.

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

         - Individuals with histological confirmation of AML by WHO criteria who achieved a CR or 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-AML therapies and who are in complete remission for over 3 years. 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.

At a Glance

National Government IDNCT04778410

IRB#IRB21-0488

Lead SponsorGilead Sciences

Lead PhysicianRichard Larson

Collaborator(s)N/A

EligibilityAll
18 Years and up
Recruiting