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

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

This phase I trial finds the best dose of PVEK when given together with fludarabine, 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 the FLAG-Ida regimen may be a safe and effective treatment for patients with acute myeloid leukemia and other high-grade myeloid neoplasms.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Myelodysplastic/Myeloproliferative Neoplasm; Mixed Phenotype Acute Leukemia
• Intervention / Treatment: Drug: Cytarabine; Procedure: Biospecimen Collection; Drug: Fludarabine; Procedure: Echocardiography; Procedure: Bone Marrow Biopsy; Drug: Idarubicin; Procedure: Multigated Acquisition Scan; Procedure: Bone Marrow Aspiration; Drug: Granulocyte Colony-Stimulating Factor; Drug: Pivekimab Sunirine

Detailed Description

OUTLINE: This is a dose-escalation study of PVEK.

INDUCTION THERAPY: Patients receive PVEK intravenously (IV) on day 1 or day 1 and 22. Patients also receive G-CSF subcutaneously (SC) on days 0-5, fludarabine IV over 30 minutes on days 1-5, cytarabine IV over 2 hours on days 1-5, and idarubicin IV on days 1-3 in the absence of disease progression or unacceptable toxicity. Patients who still have cancer after the first cycle of study treatment may receive an additional cycle of intensive chemotherapy with PVEK. Patients who achieve a good response (remission) after the first 1 or 2 cycles of study continue to Post-Remission Therapy.

POST-REMISSION THERAPY: Patients receive PVEK IV on day 1 of each cycle and high-dose cytarabine IV every 12 hours on days 1-6 of each cycle. Treatment repeats every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

Patients also 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 5 years.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Mary-Elizabeth Percival; Phone Number: 206-606-1320; Email: mperciva@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Principal Investigator: Mary-Elizabeth Percival
      • Contact: Mary-Elizabeth Percival; Phone Number: 206-606-1320; Email: mperciva@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 count (WBC) > 100,000/μL 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (PVEK, FLAG-Ida); See Detailed Description.

Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Drug: Idarubicin; Given IV; Other Names: 4-Demethoxydaunomycin; 4-DMDR; 4-Demethoxydaunorubicin; Procedure: Multigated Acquisition Scan; Undergo MUGA scan; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspirate; Drug: Granulocyte Colony-Stimulating Factor; Given SC; Other Names: G-CSF; Granulocyte Colony Stimulating Factor; Colony Stimulating Factor 3; Colony-Stimulating Factor (Granulocyte); Colony-Stimulating Factor 3; CSF3; G CSF; Pluripoietin; Drug: Pivekimab Sunirine; Given IV; Other Names: Anti-CD123 ADC IMGN632; Antibody-drug Conjugate IMGN632; CD123-targeted ADC IMGN632; IMGN 632; IMGN-632; IMGN632

What is the study measuring?

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 5 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 5 years
MRD status	MRD will be measured by multiparameter flow cytometry. All positive testing will be considered positive.	Up to 5 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 5 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 5 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 5 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 5 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 5 years

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: ImmunoGen, Inc.
• Investigators: Principal Investigator: Mary-Elizabeth Percival, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: August 18, 2023
• First Submitted That Met QC Criteria: September 5, 2023
• First Posted (Actual): September 13, 2023

Study Record Updates

• Last Update Posted (Actual): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Bone Marrow Diseases; Hematologic Diseases; Neoplasms; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Lenograstim; Fludarabine; Cytarabine; Idarubicin; Immunoconjugates
• Other Study ID Numbers: RG1123378 (Fred Hutch/University of Washington Cancer Consortium); NCI-2023-03572 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); FHIRB0020122 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No