Magrolimab, Azacitidine, and Venetoclax for the Treatment of Acute Myeloid Leukemia

Recruitment & Eligibility

Status: Active, not recruiting

Sex: All

Target Recruitment: Not specified

Inclusion Criteria

Inclusion Criteria: - Diagnosis of 1) WHO diagnosis of AML (excluding acute promyelocytic leukemia (APL) - Phase Ib dose finding cohort: Participants aged =18 years old with relapsed/refractory AML are eligible if they are not eligible for potentially curative therapy such as effective salvage therapy or hematopoietic stem cell transplantation or who refuse these options at the time of enrollment. Participants must have received at least one prior therapy for AML. Participants may have received up to 2 prior therapies for AML (i.e. up to salvage 2 status allowed). Eastern Cooperative Oncology Group (ECOG) Performance Status =2 - Phase II (frontline cohort): Participants with newly diagnosed AML who are chemonaive (specified in 4.1.5) who are ineligible for intensive chemotherapy based on EITHER: A. =75 years of age OR B. <75 years of age with at least 1 of the following relevant comorbidities: - Poor performance status (ECOG) score of 2. - Clinically significant heart or lung comorbidities, as reflected by at least 1 of: 1. Left ventricular ejection fraction (LVEF) =50%. 2. Lung diffusing capacity for carbon monoxide (DLCO) =65% of expected. 3. Forced expiratory volume in 1 second (FEV1) =65% of expected. 4. Chronic stable angina or congestive heart failure controlled with medication. 5. Creatinine clearance = 30 mL/min to < 45 ml/min calculated by the Cockcroft-Gault formula or measured by 24 hours' urine collection - Other contraindication(s) to anthracycline therapy (must be documented). - Other comorbidity the investigator judges incompatible with intensive remission induction chemotherapy, which must be documented and approved by the PI. For participants with prior MDS or chronic myelomonocytic leukemia (CMML) or MPN who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML. Participants with MDS or CMML treated with HMA therapies who progress to AML, and have no available therapies or are not candidates for available therapies, will be eligible to be enrolled to the relapsed/refractory cohort at the time of progression to AML. Temporary prior measures such as apheresis, ATRA, steroids while diagnostic work-up of AML is being performed are allowed and not counted as a prior salvage - Phase II (relapsed/refractory prior venetoclax naïve cohort): Participants aged =18 years old with relapsed/refractory AML are eligible if they are not eligible for potentially curative therapy such as effective salvage therapy or hematopoietic stem cell transplantation or who refuse these options at the time of enrollment. Participants must have received at least one prior therapy for AML or at least one prior HMA therapy for MDS/CMML or MPN. Participants may have received up to 2 prior therapies for AML (i.e. up to salvage 2 status allowed). Eastern Cooperative Oncology Group (ECOG) Performance Status =2. Participants must not have received prior venetoclax for MDS or AML. - Phase II (relapsed/refractory prior venetoclax exposed cohort): Participants aged =18 years old with relapsed/refractory AML are eligible if they are not eligible for potentially curative therapy such as effective salvage therapy, targeted therapies, or hematopoietic stem cell transplantation or who refuse these options at the time of enrollment. Participants must have received at least one prior therapy for AML or at least one prior HMA therapy for MDS/CMML or MPN. Participants may have received up to 1 prior therapies for AML (i.e. up to salvage 1 status allowed). Eastern Cooperative Oncology Group (ECOG) Performance Status =2. Participants must have received prior venetoclax for MDS or AML. - Participants with newly diagnosed AML with poor risk karyotype or complex karyotype per ELN2017 and/or TP53 deletions/mutations of any age >/=18 years of age will be eligible for the Phase II (frontline cohort) regardless of eligibility or fitness for intensive chemotherapy - For Phase II (frontline cohort): Participants must be chemonaïve, i.e., not have received any chemotherapy (except hydrea or up to 2 doses of ara-C for transient control of hyperleukocytosis) for AML. They may have received transfusions, hematopoietic growth factors or vitamins for an antecedent hematological disorder (AHD) or for AML. Temporary prior measures such as apheresis, ATRA, steroids or hydrea while diagnostic work-up is being performed are allowed and not counted as a prior salvage. Supportive care therapy for MDS (growth factors, transfusions) will not be considered as prior therapy for MDS/AML and these participants will be enrolled to the frontline cohort of the study if they are otherwise eligible. - In the absence of rapidly progressing disease, the interval from prior treatment to time of initiation of protocol therapy will be at least 2 weeks or at least 5 half-lives (whichever is shorter). The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and will be documented in the protocol eligibility document. The toxicity from prior therapy should have resolved to Grade =1, however alopecia and sensory neuropathy Grade =2 not constituting a safety risk based on investigators judgement is acceptable. The use of chemotherapeutic or anti-leukemic agents is not permitted during the study with the following exceptions: (1) intrathecal (IT) therapy for patients with controlled CNS leukemia at the discretion of the PI. (2) Use of up to 2 doses of cytarabine (up to 2 g/m2 each dose) for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy. Since the effect of most IO-agents, HMA-therapies, venetoclax may be delayed, use of hydroxyurea for patients with rapidly proliferative disease is allowed on study and before the start of study therapy and will not require a washout. These medications will be recorded in the case-report form. - Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS disease is permitted. Participants with a known history of CNS disease or leukemic brain metastasis must have been treated locally, have at least 2 consecutive LPs with no evidence of CNS leukemia at the time of enrollment, and must be clinically stable for at least 4 weeks prior to enrollment and have no ongoing neurological symptoms that in the opinion of the treating physician are related to the CNS disease (sequelae that are a consequence of the treatment of the CNS disease are acceptable). - Serum biochemical values with the following limits: Participants must have adequate renal function as demonstrated by a creatinine clearance (CrCl) = 30 mL/min calculated by the Cockcroft-Gault formula or measured by 24 hours' urine collection. For participants with BMI >23, Adjusted body weight and not Ide

Exclusion Criteria

Not provided

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose of the combination drugs (phase Ib);Response rate (complete remission + complete remission with incomplete count recovery) (phase II);Incidence of adverse events (phase II);Event-free survival (phase II);Duration of response (phase II);Overall survival (phase II)

Secondary Outcome Measures

Name	Time	Method
Change in gene expression (phase II);Change in clinical variables (phase II)

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