A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients With Myeloid Malignancies
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 54
- 试验地点
- 21
- 主要终点
- Complete Remission (CR) Rate (Cohorts 1 and 2)
研究概览
简要总结
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).
详细描述
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;
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Cohort 1 (1L Unfit AML): Magrolimab + Venetoclax + Azacitidine
Participants with newly diagnosed untreated acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy will receive magrolimab 1 mg/kg on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then every week (QW) x 5 doses; 30 mg/kg every 2 weeks (Q2W) beginning 1 week after the 5 weekly 30 mg/kg dose in every 28-day cycle along with azacitidine and venetoclax first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Magrolimab (Drug)
Cohort 1 (1L Unfit AML): Magrolimab + Venetoclax + Azacitidine
Participants with newly diagnosed untreated acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy will receive magrolimab 1 mg/kg on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then every week (QW) x 5 doses; 30 mg/kg every 2 weeks (Q2W) beginning 1 week after the 5 weekly 30 mg/kg dose in every 28-day cycle along with azacitidine and venetoclax first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Azacitidine (Drug)
Cohort 1 (1L Unfit AML): Magrolimab + Venetoclax + Azacitidine
Participants with newly diagnosed untreated acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy will receive magrolimab 1 mg/kg on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then every week (QW) x 5 doses; 30 mg/kg every 2 weeks (Q2W) beginning 1 week after the 5 weekly 30 mg/kg dose in every 28-day cycle along with azacitidine and venetoclax first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Venetoclax (Drug)
Cohort 2 (R/R AML): Magrolimab + Mitoxantrone + Etoposide + Cytarabine
Participants with relapsed/refractory (RR) AML after intensive induction chemotherapy will receive magrolimab 1 mg/ on Days 1, 4; 15 mg/kg, on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with mitoxantrone + etoposide + cytarabine (MEC) first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Magrolimab (Drug)
Cohort 2 (R/R AML): Magrolimab + Mitoxantrone + Etoposide + Cytarabine
Participants with relapsed/refractory (RR) AML after intensive induction chemotherapy will receive magrolimab 1 mg/ on Days 1, 4; 15 mg/kg, on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with mitoxantrone + etoposide + cytarabine (MEC) first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Mitoxantrone (Drug)
Cohort 2 (R/R AML): Magrolimab + Mitoxantrone + Etoposide + Cytarabine
Participants with relapsed/refractory (RR) AML after intensive induction chemotherapy will receive magrolimab 1 mg/ on Days 1, 4; 15 mg/kg, on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with mitoxantrone + etoposide + cytarabine (MEC) first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Etoposide (Drug)
Cohort 2 (R/R AML): Magrolimab + Mitoxantrone + Etoposide + Cytarabine
Participants with relapsed/refractory (RR) AML after intensive induction chemotherapy will receive magrolimab 1 mg/ on Days 1, 4; 15 mg/kg, on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with mitoxantrone + etoposide + cytarabine (MEC) first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Cytarabine (Drug)
Cohort 3 (Post-Chemo Maintenance): Magrolimab + CC-486
Participants with AML who achieved CR or CRi with MRD positivity following intensive induction chemotherapy will receive magrolimab 1 mg/kg on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with CC-486 as maintenance therapy first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: Magrolimab (Drug)
Cohort 3 (Post-Chemo Maintenance): Magrolimab + CC-486
Participants with AML who achieved CR or CRi with MRD positivity following intensive induction chemotherapy will receive magrolimab 1 mg/kg on Days 1, 4; 15 mg/kg on Day 8; 30 mg/kg on Days 11, 15, and then QW x 5 doses; 30 mg/kg Q2W beginning 1 week after the 5 weekly 30 mg/kg dose along with CC-486 as maintenance therapy first in the Safety Run-in Cohort. Once the safety of recommended dose of magrolimab is confirmed, the participants in Phase 2 Cohort will be enrolled to receive the treatment.
干预措施: CC-486 (Drug)
结局指标
主要结局
Complete Remission (CR) Rate (Cohorts 1 and 2)
时间窗: Up to 2 years
CR rate was the percentage of participants who achieved CR (CR without minimal residual disease (CRMRD-) or complete remission with positive or unknown minimal residual disease (CRMRD+/unk)) as determined by the investigator based on prespecified criteria while on study prior to initiation of any new anti-cancer therapy. CRMRD- and CRMRD+/unk were 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. CRMRD- status as determined using multiparameter flow cytometry with a sensitivity of \< 0.1%. Assessment of leukemia response in participants with acute myeloid leukemia (AML) were conducted based on the European Leukemia Net (ELN) recommendations for AML. Percentages were rounded-off. Clopper-Pearson method was used for outcome measure analysis.
Minimal Residual Disease Negative Complete Remission Rate (Cohort 3)
时间窗: Up to 2 years
The minimal residual disease (MRD) negative CR rate was defined as the percentage of participants who maintain CR as determined by the investigator based on prespecified criteria and reach MRD negative disease status on 2 consecutive bone marrow assessments, as determined using multiparameter flow cytometry with a sensitivity of \< 0.1% while on study prior to initiation of any new anti-AML therapy. Assessment of leukemia response in participants with AML were conducted based on the ELN recommendations for AML. CR was defined in outcome measure #1.
Percentage of Participants Experiencing Dose-limiting Toxicities (DLTs) (Safety Run-in Cohorts 1, 2 and 3)
时间窗: Up to 28 days
DLTs were defined as any Grade 4 or higher hematologic toxicity or Grade 3 or higher nonhematologic toxicity (that had worsened in severity from pretreatment baseline) during the 4-week DLT assessment period and was related to magrolimab or magrolimab combination.
Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) (Cohorts 1, 2 and 3)
时间窗: First dose date up to 1.7 years plus 70 days
TEAEs were defined as any AEs with an onset date on or after the study drug start date and no later than 70 days after the study drug last dosing date or the day before initiation of new anticancer therapy including SCT, whichever comes first. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Percentages were rounded-off.
Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities (Cohorts 1, 2 and 3)
时间窗: First dose date up to 1.7 years plus 70 days
Treatment-emergent laboratory abnormalities were defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study drug plus 70 days or the day before initiation of any new anticancer therapy including SCT, whichever comes first. If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed within the time frame specified above will be considered treatment emergent. Percentages were rounded-off.
次要结局
- Levels of Anti-Magrolimab Antibodies (Cohorts 1 and 2)(Up to 2 years)
- Overall Response Rate (ORR)(Up to 2 years)
- Complete Remission or Complete Remission With Partial Hematologic Recovery Rate (CR/CRh) (Cohorts 1 and 2)(Up to 2 years)
- Duration of Response (DOR) (Cohorts 1 and 2)(Up to 2 years)
- Duration of Complete Remission (DCR) (Cohorts 1 and 2)(Up to 2 years)
- Duration of CR/CRi (Cohorts 1 and 2)(Up to 2 years)
- Duration of CR/CRh (Cohorts 1 and 2)(Up to 2 years)
- Event-Free Survival (EFS) (Cohorts 1 and 2)(Up to 2 years)
- Relapse-Free Survival (RFS) Rate (Cohort 3)(Up to 2 years)
- MRD Negative CR/CRi Rate (Cohort 3)(Up to 2 years)
- Duration of Minimal Residual Disease Negative Complete Remission (Cohort 3)(Up to 2 years)
- Duration of MRD Negative CR/CRi (Cohort 3)(Up to 2 years)
- Overall Survival (OS) (Cohorts 1, 2 and 3)(Up to 2 years)
- Red Blood Cell (RBC) Transfusion Independence Rate (Cohorts 1, 2 and 3)(Up to 2 years)
- Platelet Transfusion Independence Rate (Cohorts 1, 2 and 3)(Up to 2 years)
- Plasma Concentration of Magrolimab in Combination With Anti-leukemia Therapy (Cohorts 1, 2 and 3)(Cohort 1: Predose: Days 1, 8, 29, 57, 113, 169, 253 and 337; Cohort 2: Days 1, 8, 29 and 57)
- Percentage of Participants With Anti-Magrolimab Antibodies (Cohorts 1 and 2)(Up to 2 years)