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) or complete
remission with incomplete hematologic recovery (CRi) (CR/CRi) (Phase 2 Cohorts 1 and 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 response rate (Phase 2 Cohort 3).
This study consists of 3 safety run-in cohorts;
- Safety Run-in Cohort 1 (Mag + Ven + Aza)
- Safety Run-in Cohort 2 (Mag + MEC)
- Safety Run-in Cohort 3 (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 (Mag + Ven + Aza)
- Phase 2 Cohort 2 (Mag + MEC)
- Phase 2 Cohort 3 (Mag + CC-486)
Cycle length is 28 days for both the Safety Run-in and Phase 2 cohorts.
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
- Male and female individuals 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)]:
- 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 with Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1; or
- ≥ 18 to 74 years of age with at least 1 of the following comorbidities:
- ECOG performance status of 2 or 3
- 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
- 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 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
- 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 relapsed after initial intensive induction 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 > 40%, lack of symptomatic congestive heart failure, or
clinically significant cardiac arrhythmias
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 age 55 years or
older 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
- 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 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 treated basal cell or localized squamous skin carcinomas,
localized prostate cancer, or other malignancies for which Individuals are not on
active anticancer 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
- Known active or chronic hepatitis B or C infection or human immunodeficiency virus
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
