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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

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ClinicalTrials.gov Identifier: NCT06034470
Recruitment Status : Recruiting
First Posted : September 13, 2023
Last Update Posted : January 11, 2024
Sponsor:
Collaborator:
ImmunoGen, Inc.
Information provided by (Responsible Party):
Fred Hutchinson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Mixed Phenotype Acute Leukemia Myelodysplastic Syndrome Myelodysplastic/Myeloproliferative Neoplasm Myeloproliferative Neoplasm 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 Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 18, 2023
Estimated Primary Completion Date : December 31, 2026
Estimated Study Completion Date : December 31, 2027


Arm Intervention/treatment
Experimental: Treatment (PVEK, FLAG-Ida)
See Detailed Description.
Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection

Procedure: Bone Marrow Aspiration
Undergo bone marrow aspirate

Procedure: Bone Marrow Biopsy
Undergo bone marrow biopsy
Other Names:
  • Biopsy of Bone Marrow
  • Biopsy, Bone Marrow

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: Echocardiography
Undergo ECHO
Other Name: EC

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Drug: Granulocyte Colony-Stimulating Factor
Given SC
Other Names:
  • Colony Stimulating Factor 3
  • Colony-Stimulating Factor (Granulocyte)
  • Colony-Stimulating Factor 3
  • CSF3
  • G CSF
  • G-CSF
  • Granulocyte Colony Stimulating Factor
  • Pluripoietin

Drug: Idarubicin
Given IV
Other Names:
  • 4-Demethoxydaunomycin
  • 4-Demethoxydaunorubicin
  • 4-DMDR

Procedure: Multigated Acquisition Scan
Undergo MUGA scan
Other Names:
  • Blood Pool Scan
  • Equilibrium Radionuclide Angiography
  • Gated Blood Pool Imaging
  • Gated Heart Pool Scan
  • MUGA
  • MUGA Scan
  • Multi-Gated Acquisition Scan
  • Radionuclide Ventriculogram Scan
  • Radionuclide Ventriculography
  • RNVG
  • SYMA Scanning
  • Synchronized Multigated Acquisition Scanning

Drug: Pivekimab Sunirine
Given IV
Other Names:
  • Anti-CD123 ADC IMGN632
  • Antibody-drug Conjugate IMGN632
  • CD123-targeted ADC IMGN632
  • IMGN 632
  • IMGN-632
  • IMGN632




Primary Outcome Measures :
  1. Incidence of dose-limiting toxicities during cycle 1 [ Time Frame: During cycle 1 (each cycle is 42 days) ]
    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).


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 5 years ]
    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.

  2. Measurable residual disease (MRD) rates [ Time Frame: Up to 5 years ]
    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.

  3. MRD status [ Time Frame: Up to 5 years ]
    MRD will be measured by multiparameter flow cytometry. All positive testing will be considered positive.

  4. Relapse-free survival [ Time Frame: From the date of achievement of remission until the date of hematologic relapse or death from any cause, assessed up to 5 years ]
    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.

  5. Overall survival [ Time Frame: From day 1 of study treatment to the date of death from any cause, up to 5 years ]
    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.

  6. Complete remission rates [ Time Frame: Up to 5 years ]
    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.

  7. Duration of cytopenias [ Time Frame: Up to 5 years ]
    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.

  8. Proportion of patients receiving allogeneic hematopoietic cell transplantation [ Time Frame: Up to 5 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06034470


Contacts
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Contact: Mary-Elizabeth Percival 206-606-1320 mperciva@uw.edu

Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Mary-Elizabeth Percival    206-606-1320    mperciva@uw.edu   
Principal Investigator: Mary-Elizabeth Percival         
Sponsors and Collaborators
Fred Hutchinson Cancer Center
ImmunoGen, Inc.
Investigators
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Principal Investigator: Mary-Elizabeth Percival Fred Hutch/University of Washington Cancer Consortium
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Responsible Party: Fred Hutchinson Cancer Center
ClinicalTrials.gov Identifier: NCT06034470    
Other Study ID Numbers: RG1123378
NCI-2023-03572 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
FHIRB0020122 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: September 13, 2023    Key Record Dates
Last Update Posted: January 11, 2024
Last Verified: January 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Neoplasms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Neoplasms by Histologic Type
Hematologic Diseases
Bone Marrow Diseases
Cytarabine
Fludarabine
Idarubicin
Lenograstim
Immunoconjugates
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors