Combination Chemotherapy (FLAG-Ida) With Pivekimab Sunirine (PVEK [IMGN632]) for the Treatment of Newly Diagnosed Adverse Risk Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

Study Overview
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Brief Summary
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This phase I clinical trial finds the best dose of pivekimab sunirine (PVEK [IMGN632]) (PVEK) when given together with fludarabine, high-dose cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin, (FLAG-Ida) regimen and studies the effectiveness of this combination therapy in treating patients with newly diagnosed adverse risk acute myeloid leukemia (AML) and other high-grade myeloid neoplasms. PVEK is a monoclonal antibody linked to a chemotherapy drug. PVEK is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD123 receptors, and delivers the chemotherapy drug to kill them. Chemotherapy drugs, such as idarubicin, fludarabine, high-dose cytarabine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. G-CSF helps the bone marrow make more white blood cells in patients with low white blood cell count due to cancer treatment. Giving PVEK with FLAG-Ida regimen may kill more cancer cells than the chemotherapy regimen alone.

Detailed Description
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OUTLINE: This is a phase I, dose-escalation study of PVEK. Patients receive PVEK intravenously (IV) plus G-CSF subcutaneously (SC), fludarabine IV, cytarabine IV, and idarubicin IV on study. Patients undergo bone marrow aspiration and may undergo bone marrow biopsy and blood sample collection throughout the trial. Patients also undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening and as clinically indicated on trial. After completion of study treatment, patients are followed every 3 months for 2 years.

Official Title
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Phase 1 Study of FLAG-Ida With Pivekimab Sunirine (PVEK [IMGN632]) for Adults With Newly Diagnosed Adverse-Risk Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

Conditions
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Acute Myeloid Leukemia, Myeloid Neoplasm

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspiration
* Procedure: Bone Marrow Biopsy
* Drug: Cytarabine
* Procedure: Echocardiography
* Drug: Fludarabine
* Drug: Granulocyte Colony-Stimulating Factor
* Drug: Idarubicin
* Procedure: Multigated Acquisition Scan
* Drug: Pivekimab Sunirine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Diagnosis of untreated AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 5th edition of the World Health Organization (WHO) classification of hematolymphoid tumors. Patients with myelodysplastic, myeloproliferative, or myelodysplastic/myeloproliferative neoplasms and ≥10% blasts in blood and/or bone marrow, are also eligible, as are patients with mixed phenotype acute leukemia (MPAL). Outside diagnostic material is acceptable to establish diagnosis; submission of peripheral blood specimen for flow cytometry performed at the study institution should be considered. Diagnostic material must have been submitted for cytogenetic and/or molecular testing as clinically appropriate Cytogenetically/molecularly adverse-risk disease (European LeukemiaNet [ELN] 2022 criteria) Expression of CD123 on immunophenotypically abnormal blasts, as assessed by local multiparameter flow cytometry. Evaluation of CD123 expression via immunohistochemistry is permissible, for example if flow cytometric assessment is not available Medically fit, as defined by treatment-related mortality (TRM) score =< 13.1 calculated with simplified model The use of hydroxyurea prior to start of study therapy is allowed. Patients with symptoms/signs of hyperleukocytosis, white blood cell (WBC) > 100,000/uL or with concern for other complications of high tumor burden (e.g. disseminated intravascular coagulation) can be treated with leukapheresis prior to start of study therapy Patients may have received low-intensity treatment (e.g. azacitidine/decitabine, lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm (i.e. < 10% blasts in blood and bone marrow) Bilirubin =< 1.5 x institutional upper limit of normal (IULN) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x IULN unless elevation is thought to be due to hepatic infiltration by AML Creatinine clearance ≥60 mL/min Left ventricular ejection fraction >= 45%, assessed by multigated acquisition (MUGA) scan or echocardiography or other appropriate diagnostic modality and no clinical evidence of congestive heart failure Fertile male and female subjects must be willing to use an effective contraceptive method before, during, and for at least 3 months after receiving the investigational agent Provide written informed consent Exclusion Criteria: Diagnosis of blast phase chronic myeloid leukemia (CML) Patients with FLT3-mutated AML Concomitant illness associated with a likely survival of < 1 year Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with antimicrobials, and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired [e.g. known chronic viral hepatitis, human immunodeficiency virus (HIV)]). Patient needs to be clinically stable as defined as being afebrile and hemodynamically stable for 24 hours. Patients with fever thought to be likely secondary to leukemia are eligible Known hypersensitivity to any study drug or prior >= grade 3 hypersensitivity reactions to monoclonal antibodies Confirmed or suspected pregnancy or active breast feeding Treatment with any other investigational anti-leukemia agent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (PVEK, FLAG-Ida)<br>Patients receive PVEK IV plus G-CSF SC, fludarabine IV, cytarabine IV, and idarubicin IV on study. Patients undergo bone marrow aspiration and may undergo bone marrow biopsy and blood sample collection throughout the trial. Patients also undergo ECHO or MUGA scan during screening and as clinically indicated on trial. | Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspirate<br>Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Granulocyte Colony-Stimulating Factor<br>* Given SC<br>* Other names: Pluripoietin;Drug: Idarubicin<br>* Given IV<br>* Other names: 4-DMDR;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA scan<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Pivekimab Sunirine<br>* Given IV<br>* Other names: IMGN632;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities during cycle 1 | Dose-limiting toxicities (DLTs) for trial monitoring are defined as follows: a) Any Grade ≥4 organ toxicity; and b) prolonged severe myelosuppression, as defined by ANC <500/µL and platelet count <25,000/µL, for >42 days after initiation (day 1) of FLAG-Ida chemotherapy in the absence of residual disease (assessed by morphology and flow cytometrically/molecularly/cytogenetically). | During cycle 1 (each cycle is 42 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will be assessed by the NCI CTCAE v.5. Will be analyzed using standard methods for such data: Wilcoxon-rank sum tests for quantitative data; Fisher's exact test for categorical data; Kaplan-Meier, Cox regression, and log-rank tests for time-to-event data. | Up to 2 years | 
| Measurable residual disease (MRD) rates | Will be estimated within the limits of the study with pivekimab sunirine (PVEK) + fludarabine, high-dose cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida) across study cohorts. Will be analyzed using standard methods for such data: Wilcoxon-rank sum tests for quantitative data; Fisher's exact test for categorical data; Kaplan-Meier, Cox regression, and log-rank tests for time-to-event data. | Up to 2 years | 
| MRD status | MRD will be measured by multiparameter flow cytometry. All positive testing will be considered positive. | Up to 2 years | 
| Relapse-free survival | Will be assessed within the limits of the study by the relationship between MRD status after induction therapy and relapse risk/time to relapse. Will be analyzed using standard methods for such data: Wilcoxon-rank sum tests for quantitative data; Fisher's exact test for categorical data; Kaplan-Meier, Cox regression, and log-rank tests for time-to-event data. | From the date of achievement of remission until the date of hematologic relapse or death from any cause, assessed up to 2 years | 
| Overall survival | Will be analyzed using standard methods for such data: Wilcoxon-rank sum tests for quantitative data; Fisher's exact test for categorical data; Kaplan-Meier, Cox regression, and log-rank tests for time-to-event data. | From day 1 of study treatment to the date of death from any cause, up to 2 years | 
| Complete remission rates | Will be analyzed using standard methods for such data: Wilcoxon-rank sum tests for quantitative data; Fisher's exact test for categorical data; Kaplan-Meier, Cox regression, and log-rank tests for time-to-event data. | Up to 2 years | 
| Duration of cytopenias | Will be evaluated by the impact of PVEK dosing regimens on the duration of cytopenias. Will be analyzed using standard methods for such data: Wilcoxon-rank sum tests for quantitative data; Fisher's exact test for categorical data; Kaplan-Meier, Cox regression, and log-rank tests for time-to-event data. | Up to 2 years | 
| Proportion of patients receiving allogeneic hematopoietic cell transplantation | Will be estimated within the limits of the study by the proportion of patients receiving allogeneic HCT in remission with PVEK + FLAG-Ida. Will be analyzed using standard methods for such data: Wilcoxon-rank sum tests for quantitative data; Fisher's exact test for categorical data; Kaplan-Meier, Cox regression, and log-rank tests for time-to-event data. | Up to 2 years |