CPX-351 or CLAG-M Regimen for the Treatment of Acute Myeloid Leukemia or Other High-Grade Myeloid Neoplasms in Medically Less-Fit Patients

Randomized Phase 2 Trial of CPX-351 (Vyxeos) vs. CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less-Fit Adults With Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

This phase II trial studies how well CPX-351 or the CLAG-M regimen (consisting of the drugs cladribine, cytarabine, G-CSF, and mitoxantrone) works in treating medically less-fit patients with acute myeloid leukemia or other high-grade myeloid neoplasms. Drugs used in chemotherapy, such as CPX-351, cladribine, cytarabine, G-CSF, and mitoxantrone, 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. Giving CPX-351 or the CLAG-M regimen at doses typically used for medically-fit patients with acute myeloid leukemia may work better than reduced doses of CPX-351 in treating medically less-fit patients with acute myeloid leukemia or other high-grade myeloid neoplasms.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Myeloid Neoplasm
• Intervention / Treatment: Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Drug: Cytarabine; Drug: Mitoxantrone; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Biological: Recombinant Granulocyte Colony-Stimulating Factor; Drug: Cladribine

Detailed Description

OUTLINE: Patients are randomized to 1 of 2 arms in a 1:1 fashion. ARM I = CPX-351; ARM II = CLAG-M.

ARM I (INDUCTION): Patients receive CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. Patients who achieve a response other than an MRDneg CR receive a second course of CPX-351 intravenously IV over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity.

ARM I (POST-REMISSION): Patients who achieve a CR or CR with incomplete hematologic recovery (CRi) receive a reduced dose of CPX-351 IV over 90 minutes on days 1, 3, and 5 for up to 4 additional courses in the absence of disease progression or unacceptable toxicity.

ARM II (INDUCTION): Patients receive cladribine IV over 2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5, G-CSF subcutaneously (SC) on days 0-5, and mitoxantrone IV over 60 minutes on days 1-3 in the absence of disease progression or unacceptable toxicity. Patients who achieve a response other than an MRDneg CR receive a second course of cladribine IV over 2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5, G-CSF SC on days 0-5, and mitoxantrone IV over 60 minutes on days 1-3 in the absence of disease progression or unacceptable toxicity.

ARM II (POST-REMISSION): Patients who achieve a CR/CRi receive an intermediate dose of cytarabine IV over 2 hours on days 1-6 for up to 4 additional courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of untreated "high-grade" myeloid neoplasm (>=10% blasts in blood or bone marrow) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2016 World Health Organization (WHO) classification. 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
• Treatment-related mortality (TRM) score >= 13.1 as calculated with simplified model
• The use of hydroxyurea before enrollment is permitted; hydroxyurea should be discontinued prior to start of study treatment. Patients with symptoms/signs of hyperleukocytosis or white blood cells (WBC) > 100,000/uL or with concern for other complications of high tumor burden or leukostasis (e.g. hypoxia, disseminated intravascular coagulation) can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m^2) any time prior to enrollment
• 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 < 2.0 mg/mL unless elevation is thought to be due to hepatic infiltration by neoplastic cells, Gilbert's syndrome, or hemolysis (assessed within 14 days prior to study day 0)
• Left ventricular ejection fraction (LVEF) >= 45%, assessed within 12 months prior to registration, e.g. by multigated acquisition scan (MUGA) scan or echocardiography or another appropriate diagnostic modality
• Women of childbearing potential and men must agree to use adequate contraception beginning at the signing of the consent until at least 4 weeks after the last dose of study drug
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Myeloid blast crisis of chronic myeloid leukemia (CML), unless patient is not considered candidate for tyrosine kinase inhibitor treatment
• Concomitant illness associated with a likely survival of < 1 year
• Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with anti-microbials and/or controlled or stable. Patients with fever thought to be likely secondary to leukemia are eligible
• Known hypersensitivity to any study drug used in this trial
• Pregnancy or active breast feeding
• Concurrent treatment with any other approved or investigational anti-leukemia agent. Treatment with a FLT3-inhibitor for FLT3-mutated AML is permissible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (CPX-351); INDUCTION: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. Patients who achieve a response other than an MRDneg CR receive a second course of CPX-351 intravenously IV over 90 minutes on days 1, 3, and 5 in the absence of disease progression or unacceptable toxicity. POST-REMISSION: Patients who achieve a CR/CRi receive a reduced dose of CPX-351 IV over 90 minutes on days 1, 3, and 5 for up to 4 additional courses in the absence of disease progression or unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Given IV; Other Names: CPX-351; Cytarabine-Daunorubicin Liposome for Injection; Daunorubicin and Cytarabine (Liposomal); Liposomal AraC-Daunorubicin CPX-351; Liposomal Cytarabine-Daunorubicin; Liposome-encapsulated Combination of Daunorubicin and Cytarabine; Vyxeos
Experimental: Arm II (CLAG-M); INDUCTION: Patients receive cladribine IV over 2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5, G-CSF SC on days 0-5, and mitoxantrone IV over 60 minutes on days 1-3 in the absence of disease progression or unacceptable toxicity. Patients who achieve a response other than an MRDneg CR receive a second course of cladribine IV over 2 hours on days 1-5, cytarabine IV over 2 hours on days 1-5, G-CSF SC on days 0-5, and mitoxantrone IV over 60 minutes on days 1-3 in the absence of disease progression or unacceptable toxicity. POST-REMISSION: Patients who achieve a CR/CRi receive an intermediate dose of cytarabine IV over 2 hours on days 1-6 for up to 4 additional courses in the absence of disease progression or unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Drug: Cytarabine; Given IV; Other Names: ARA-cell; Arabine; Arabinofuranosylcytosine; Aracytidine; Beta-Cytosine Arabinoside; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Drug: Mitoxantrone; Given IV; Other Names: Dihydroxyanthracenedione; Mitozantrone; Biological: Recombinant Granulocyte Colony-Stimulating Factor; Given SC; Other Names: rhG-CSF; Recombinant Colony-Stimulating Factor 3; 143011-72-7; Drug: Cladribine; Given IV; Other Names: CdA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; 2-Chlorodeoxyadenosine; 105014; 105014-F; 2-Chloro-2-Deoxyadenosine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-month Overall Survival (OS)	Will evaluate whether CPX-351 or cladribine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and mitoxantrone (CLAG-M), at doses typically used for medically-fit adults with AML, improve 3-month overall survival in medically-unfit adults with AML compared to attenuated dose CPX-351 as used in our previous institutional trial (32 units/m2 per dose).	Up to 3 months from date of start of protocol therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Remission (CR) Rates	Will compare CR rates between the study arms.	Up to 5 years post treatment
MRDneg CR Rates	Will compare MRDneg CR rates between the study arms.	Up to 5 years post treatment
Response Duration	Will compare response duration between the study arms.	Up to 5 years post treatment
Relapse-free Survival	Will compare RFS between the study arms.	Up to 5 years post treatment
Incidence of Adverse Events	Will use the CTCAE (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events) version 5.0 for toxicity and adverse event reporting. Will describe the toxicity profile and infectious complications of each study treatment.	AEs were recorded from the time of first exposure to the therapy (start of the first drug administration infusion on day 1) until 4 weeks after the last dose. All-Cause Mortality was monitored from study start to data cut-off dates 5/27/2020 to 9/18/2025
30-day Mortality Rate	30-day mortality rate from start of treatment	At 30 days
60-day Mortality	60-day mortality rate from start of treatment	At 60 days
Quality of Life (QOL): Questionnaire	QOL of patients will be assessed longitudinally using the European Organization for Research and Treatment of Cancer (EORTC) core QOL questionnaire (QLQ-C30) and the newly developed acute myeloid leukemia-specific QOL instrument. QOL measures for Global Health Status (GHS), Functional Score, and Symptom Score were scored on a 0-100 scale with lower scores indicating worse outcomes.	Up to 5 years post treatment
Patient Use of Medical Resources (e.g. Transfusions)	Electronic medical chart review to enumerate the number of platelet and red blood cell transfusions administered.	Up to 5 years post treatment
Patient Use of Medical Resources (e.g. Transfusions)	Electronic medical chart review to enumerate the number of days spent on IV antimicrobial therapy and the number of days spent in the ICU.	Up to 5 years post treatment

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Jazz Pharmaceuticals
• Investigators: Principal Investigator: Roland Walter, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2020
• Primary Completion (Actual): June 6, 2025
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: December 9, 2019
• First Submitted That Met QC Criteria: December 10, 2019
• First Posted (Actual): December 12, 2019

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: April 22, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Myeloid and Monocytic Leukemia; Other Hematopoietic
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Therapeutics; Dosage Forms; Drug Administration Routes; Drug Therapy; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Nucleosides; Ribonucleosides; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Anthraquinones; Anthrones; Anthracenes; Quinones; Deoxyribonucleosides; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Deoxyadenosines; Membranes, Artificial; Drug Carriers; Biomimetic Materials; Cytarabine; Daunorubicin; Mitoxantrone; Cladribine; Injections; CPX-351; Liposomes; pegylated granulocyte colony-stimulating factor; 2'-chloro-2'-deoxyadenosine
• Other Study ID Numbers: RG1005577; NCI-2019-07640 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10330 (Other Identifier: CTEP)

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