Magrolimab Monotherapy or Magrolimab in Combination With Azacitidine in Participants With Hematological Malignancies

Phase 1TerminatedNCT03248479

Gilead Sciences258 enrolled

Overview

The primary objectives of this study are: * To confirm the safety and tolerability of magrolimab monotherapy in a relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) population, and of magrolimab in combination with azacitidine in previously untreated participants with AML or MDS and participants with R/R AML and MDS * To evaluate the efficacy of magrolimab monotherapy in R/R AML/MDS, and of magrolimab in combination with azacitidine in previously untreated participants with AML/MDS, or R/R AML/MDS as measured by complete remission (CR) rate for participants with AML and higher-risk MDS, and duration of complete response for participants with AML and higher-risk MDS, and duration of CR for participants with AML and higher-risk MDS * To evaluate the safety, tolerability, and efficacy of magrolimab monotherapy or combination with azacitidine in low-risk MDS participants as measured by red blood cell (RBC) transfusion independence rate

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

258

Conditions

Hematological Malignancies

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Meets the criteria below for the appropriate cohort: * Relapsed/Refractory Cohorts: Pathologically confirmed relapsed or refractory (primary refractory and/or relapsed refractory) acute myeloid leukemia (AML) or confirmed intermediate, high, or very high risk myelodysplastic syndromes (MDS) that is relapsed, refractory or intolerant to conventional therapy. * Treatment-naive/Unfit Cohorts: Previously untreated individuals with histological confirmation of AML who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen; or previously untreated individuals with intermediate, high, or very high risk MDS. Prior and concurrent therapy with hydroxyurea, oral etoposide, erythroid and/or myeloid growth factors is allowed. * Rollover Cohort: Individuals on active magrolimab therapy on the Phase 1 AML (SCI-CD47-002; NCT02678338) trial who are deriving clinical benefit by Investigator assessment. * RBC transfusion dependent low risk MDS cohort: Transfusion-dependent MDS individuals who are very low or low risk by Revised International Prognostic Scoring System (IPSS-R) with previous treatment with an erythroid stimulating agent or lenalidomide. * White blood cell (WBC) count ≤ 20 x 10\^3/mcL * Adequate performance status and hematological, liver, and kidney function. Key Exclusion Criteria: * Prior treatment with cluster of differentiation 47 (CD47) or signal regulatory protein alpha (SIRPα) targeting agents (with exception of magrolimab for individuals in the Rollover cohort). * Treatment-naive/Unfit Cohorts Only: Any prior anti-leukemic therapy (excluding hydroxyurea or oral etoposide), prior treatment with hypomethylating agents and/or low dose cytarabine. * Acute promyelocytic leukemia. * Known inherited or acquired bleeding disorders. * Previous allogeneic hematopoietic stem cell transplant within 6 months prior to enrollment, active graft versus host disease (GVHD), or requiring transplant-related immunosuppression. * Clinical suspicion of active central nervous system (CNS) involvement by leukemia. * Known active or chronic hepatitis B or C infection or HIV. * Pregnancy or active breastfeeding. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Locations (27)

City of Hope National Medical Center

Duarte, California, United States

University of California San Diego (UCSD)

La Jolla, California, United States

UCLA Clinical and Translational Research Center (CTRC)

Los Angeles, California, United States

Chao Family Comprehensive Cancer Center - UC Irvine Medical Center

Orange, California, United States

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

Outcomes

Primary Outcomes

Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)

TEAEs were defined as any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and before the first date of new anti-cancer therapy including stem-cell transplant (SCT) and/or any AEs leading to premature discontinuation of study drug.

Time frame: Up to 4 years

Complete Remission (CR) Rate For Participants With AML

The CR rate is the percentage of participants who achieved CR without minimal residual disease (CRMRD-), and CR as per European Leukemia Net (ELN) AML recommendations. CRMRD- per ELN was defined as neutrophils ≥1.0 × 10\^9/L; platelets ≥100 × 10\^9/L and \<5% bone marrow blasts. If studied pretreatment, CR with negativity for a genetic marker by real-time quantitative polymerase chain reaction (RT-qPCR) or similar modality or CR with negativity by multi-color flow cytometry. CR per ELN criteria is defined as neutrophils ≥1.0 × 10\^9/L; platelets ≥100 × 10\^9/L and \<5% bone marrow blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; MRD positive or unknown.

Time frame: Up to 5 years

CR Rate for Participants With MDS

The CR rate was the percentage of MDS participants who achieved CR per International Working Group (IWG) 2006 criteria. CR per IWG criteria is defined as bone marrow ≤5% myeloblasts with normal maturation of all cell lines. Persistent dysplasia will be noted. Peripheral blood should have: Hemoglobin (Hgb) ≥11 g/dL, platelets ≥100 × 10\^9/L, neutrophils ≥1.0 × 10\^9/L and blasts 0%.

Time frame: Up to 5 years

Percentage of Participants With Red Blood Cell (RBC) Transfusion Independence for Participants With Low-Risk MDS

RBC transfusion independence was defined by the lack of RBC transfusions for at least an 8 week consecutive period at any time after starting therapy.

Time frame: Up to 8 weeks

Secondary Outcomes

Serum Concentration for Magrolimab in TN/U AML and TN MDS Participants

Time frame: Predose and/or after 1 hour of infusion (duration 3 hours (± 30 minutes) for 1mg/kg; 2 hours for 15 mg/kg, 30 mg/kg and 60 mg/kg) in Cycles (each cycle of 28 days) 1 to 7, 9, 11, 13, 15, on Days 1, 2, 3, 4, 8, 11, 15, 16, 17, 18, 22, EOT, Safety Follow-up

Percentage of Participants Who Developed Anti-Magrolimab Antibodies

As per the pre-specified analysis, this outcome measure was analyzed based on different dosing regimens and timepoints when magrolimab was given alone and in combination with the azacitidine. Therefore, the data is reported for magrolimab as monotherapy and magrolimab plus azacitidine. Also, the arms are based on the frequency of magrolimab administered: QW, Q2W, QW to Q2W, Q4W, BIW and BIW to QW as applicable in different cohorts.

Time frame: Up to 5 years

Duration of Complete Remission (DCR) in Participants With AML and MDS

For AML participants: The DCR was defined as the time measurement criteria were first met for CR (including morphologic CR, CRMRD-, cytogenetic complete remission (cCR), and molecular complete remission (mCR) until the first date that recurrent disease or death with evidence of no disease recurrence was objectively documented. CR and CRMRD- were defined in outcome measure 2. cCR was defined as complete disappearance of chromosomal abnormality without appearance of new ones. mCR was defined as morphological blast of ≤ 5% and recovery of absolute neutrophil count (ANC), platelets, and hemoglobin from complete blood counts as well as peripheral blast. For MDS participants: The DCR was defined as the time measurement criteria were first met for CR until the first date that recurrent disease or death with evidence of no disease recurrence is objectively documented. Kaplan-Meier (KM) estimates were used in the outcome measure analysis.

Time frame: Up to 5 years

Percentage of MDS Participants With Objective Response Rate (ORR) as Defined by IWG 2006 MDS Response Criteria

ORR was the percentage of participants who achieved CR, partial remission (PR), marrow CR or hematological improvement (HI) prior to initiation of a new anticancer therapy including SCT per IWG 2006 criteria per investigator's evaluation. CR was defined in outcome measure 2. PR was defined as all CR criteria if abnormal before treatment except the bone marrow blasts decreased by 50% over pretreatment but still \> 5% and cellularity and morphology not relevant. Marrow CR is defined as bone marrow ≤5% myeloblasts and decrease by ≥50% over pretreatment, stable disease with any hematological improvement, peripheral blood: if hematological improvement responses, they were noted in addition to marrow CR. Stable Disease: Failure to achieve at least PR, but no evidence of progression for \> 8 weeks. Percentages were rounded off.

Percentage of AML Participants With Objective Response Rate (ORR)

ORR is the percentage of participants who achieve CR, CR with incomplete hematologic (count) recovery (CRi), CR with partial hematologic (count) recovery (CRh), Partial Response (PR), Morphologic Leukemia-Free State (MLFS) prior to initiation of a new anti-cancer therapy including SCT per European Leukemia Net (ELN) AML 2017 recommendations per investigator's evaluation. CR was defined in outcome measure 2. CRi was defined as neutrophils ≥ 1.0 × 10\^9/L or platelets ≥ 100 × 10\^9/L bone marrow blasts \< 5%. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; MRD positive or unknown. CRh was defined in outcome measure 10. PR was defined in outcome measure 8. MLFS was defined as bone marrow blasts \< 5%. Absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required; marrow should not merely be "aplastic"; at least 200 cells should be enumerated or cellularity should be at least 10%.

Time frame: Up to 5 years

Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) for AML Participants

CRh was defined as CR with partial platelet and absolute neutrophil count recovery while on study prior to initiation of any new anti-acute myeloid leukemia (AML) therapy or stem cell transplant (SCT).

Time frame: Up to 5 years

Duration of Response (DOR) for Participants With AML

The DOR was defined as time measurement criteria were met for complete remission (CR) (including morphologic CR, CRMRD-, cytogenetic complete remission (cCR), and molecular complete remission (mCR), incomplete blood count recovery (CRi), partial hematologic recovery (CRh), partial remission (PR), marrow CR, or morphologic leukemia-free state (MLFS), whichever was first recorded, until the first date that recurrent or progressive disease, or death with evidence of no disease magrolimab progression is objectively documented. CR and CRMRD- were defined in outcome measure 2. cCR and mCR were defined in outcome measure 7. Marrow CR and PR were defined in outcome measure 8. CRi and MLFS were defined in outcome measure 9. CRh was defined in outcome measure 10. KM estimates were used in the outcome measure analysis.

Time frame: Up to 5 years

Duration of Response for Participants With MDS

The DOR was measured from the time measurement criteria were first met for objective response as assessed by IWG MDS criteria until the first date that recurrent disease or death with evidence of no disease recurrence is objectively documented. KM estimates were used in the outcome measure analysis.

Time frame: Up to 5 years

Overall Survival (OS) for Participants With AML or MDS

The length of overall survival will be measured from the date of study treatment initiation until the date of death from any cause. KM estimates were used in the outcome measure analysis.

Time frame: Up to 5 years

Progression Free Survival (PFS) for Participants With AML or MDS

The length of PFS is defined as the time from the date of study treatment initiation until the date of documented disease progression (PD) or death from any cause, whichever occurs first. PD for MDS: \<5% blasts: if blasts increase ≥50% to \>5%; 5%-10% blasts: if blasts increase ≥50% to \>10%; 10%-20% blasts: if blasts increase ≥50% to \>20%; 20%-30% blasts: if blasts increase ≥50% to \>30%. Participants with at least 50% decrement from maximum remission/response in granulocytes / platelets or reduction in Hgb by ≥ 2 g/dL or transfusion dependence. PD for AML was defined as any evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in the blood: \> 50% increase in marrow blasts over baseline (a minimum 15% point increase is required in cases with \< 30% blasts at baseline; or persistent marrow blast percentage of \>70% over at least 3 months; without at least a 100% improvement in absolute neutrophil count.

Time frame: Up to 5 years

Relapse Free Survival (RFS) for Participants With AML or MDS

The length of RFS is defined from the first date of attaining a CR (including morphologic CR, CRMRD-, cCR, and mCR) until the date of AML relapse or death from any cause, whichever occurs first.

Time frame: Up to 5 years

Event Free Survival (EFS) for Participants With AML or MDS

For AML, EFS was defined as the time from the date of study treatment initiation until the date of documented disease progression, death from any cause, or treatment failure (defined as failure to achieve CR/CRi/CRh by Cycle 5 Day 1), whichever occurred first. CR/CRi/CRh were defined in outcome measures 2, 9 and 10 respectively. For MDS, EFS was defined as the time from the date of study treatment initiation to transformation to AML or death from any cause, whichever occurred first. Participants who were not observed to have one of these events during the study were censored at their last response assessment date with evidence of no transformation to AML. KM estimates were used in the outcome measure analysis.

Time frame: Up to 5 years

Minimal Residual Disease (MRD) Negative Response Rate

The MRD-negative response rate was defined as the percentage of participants who reach MRD-negative disease status prior to initiation of other new anti-cancer therapy including SCT and achieve a morphologic CR or marrow CR for MDS participants and achieve CR/CRi/CRh/MLFS for AML participants. MRD-negative disease status will be assessed using a multiparameter flow cytometry-based assay performed by a central laboratory. CR/CRi/MLFS/CRh were defined in outcome measures 2, 9, 10 respectively. Marrow CR was defined in outcome measure 8.

Time frame: Up to 5 years