Higher or Lower Dose Cladribine, Cytarabine, and Mitoxantrone in Treating Medically Less Fit Patients With Newly Diagnosed Acute Myeloid Leukemia or Myeloid Neoplasm

• ClinicalTrials.gov Identifier: NCT03012672
• Recruitment Status: Completed
• First Posted: January 6, 2017
• Results First Posted: November 1, 2021
• Last Update Posted: March 8, 2022
• Sponsor: University of Washington
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Anna Halpern, University of Washington

Study Description

Brief Summary:

This randomized pilot trial studies how well higher or lower dose cladribine, cytarabine, and mitoxantrone work in treating medically less fit patients with newly diagnosed acute myeloid leukemia or myeloid neoplasm. Drugs used in chemotherapy, such as cladribine, cytarabine, 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. It is not yet known whether giving cladribine, cytarabine, and mitoxantrone at higher or lower dose may work better in treating patients with newly diagnosed acute myeloid leukemia.

Condition or disease	Intervention/treatment	Phase
Acute Leukemia of Ambiguous Lineage; Acute Myeloid Leukemia; Myeloid Neoplasm	Drug: Cladribine; Drug: Cytarabine; Biological: Granulocyte Colony-Stimulating Factor; Drug: Mitoxantrone Hydrochloride; Other: Quality-of-Life Assessment; Other: Questionnaire Administration	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the feasibility of randomizing medically less fit adults with newly diagnosed acute myeloid leukemia (AML) or analogous myeloid neoplasms to either intensive or non-intensive induction and post remission chemotherapy.

EXPLORATORY OBJECTIVES:

I. To evaluate the attitude of patients and physicians toward randomization and explore reasons for treatment preference.

II. To evaluate whether the ability to assess fitness for intensive chemotherapy can be improved by an augmented treatment-related mortality (TRM) score that includes additional (co-morbidity) factors, and to compare the ability of physicians and the prediction algorithm(s) to assess the likelihood of early death.

III. To compare, within the limits of a pilot study, response, duration of response, and survival between patients receiving intensive and those receiving non-intensive chemotherapy.

IV. To describe the impact of treatment intensity on quality of life of patients undergoing chemotherapy for newly diagnosed AML.

V. To describe the impact of treatment intensity on medical resource utilization and care cost of patients undergoing chemotherapy for newly diagnosed AML.

OUTLINE: Patients agreeable to randomization are randomized to 1 of 2 treatment arms. Patients not agreeable to randomization receive treatment based on their preference.

ARM I (HIGHER-DOSE):

INDUCTION: Patients receive granulocyte colony-stimulating factor (G-CSF) subcutaneously (SC) on days 0-5, higher dose cladribine intravenously (IV) over 2 hours on days 1-5, higher dose cytarabine IV over 2 hours on days 1-5, and higher dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve complete response (CR)/CR with incomplete count recovery (CRi) with up to 2 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II (LOWER-DOSE):

INDUCTION: Patients receive G-CSF SC on days 0-5, lower dose cladribine IV over 2 hours on days 1-5, lower dose cytarabine IV over 1 hour on days 1-5, and lower dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION: Patients who achieve complete response (CR)/CR with incomplete count recovery (CRi) with up to 6 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Impact of Treatment Intensity on Survival, Quality of Life, and Resource Utilization in Medically Less Fit Adults With Acute Myeloid Leukemia and Analogous Myeloid Neoplasms: A Randomized Pilot Study
• Actual Study Start Date: December 30, 2016
• Actual Primary Completion Date: December 10, 2020
• Actual Study Completion Date: February 26, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (higher-dose); INDUCTION: Patients receive G-CSF SC on days 0-5, higher dose cladribine IV over 2 hours on days 1-5, higher dose cytarabine IV over 2 hours on days 1-5, and higher dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients who achieve CR/CRi with up to 2 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.	Drug: Cladribine; Given IV; Other Names: 2-CdA; 2CDA; CdA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; 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; Cytosar-U; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Biological: 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: Mitoxantrone Hydrochloride; Given IV; Other Names: CL 232315; DHAD; DHAQ; Dihydroxyanthracenedione Dihydrochloride; Mitoxantrone Dihydrochloride; Mitoxantroni Hydrochloridum; Mitozantrone Hydrochloride; Mitroxone; Neotalem; Novantrone; Onkotrone; Pralifan; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies
Experimental: Arm II (lower-dose); INDUCTION: Patients receive G-CSF SC on days 0-5, lower dose cladribine IV over 2 hours on days 1-5, lower dose cytarabine IV over 1 hour on days 1-5, and lower dose mitoxantrone IV over 60 minutes on days 1-3. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients who achieve CR/CRi with up to 6 courses of Induction receive G-CSF, cladribine, and cytarabine as in Induction. Courses repeat every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Drug: Cladribine; Given IV; Other Names: 2-CdA; 2CDA; CdA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; 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; Cytosar-U; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Biological: 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: Mitoxantrone Hydrochloride; Given IV; Other Names: CL 232315; DHAD; DHAQ; Dihydroxyanthracenedione Dihydrochloride; Mitoxantrone Dihydrochloride; Mitoxantroni Hydrochloridum; Mitozantrone Hydrochloride; Mitroxone; Neotalem; Novantrone; Onkotrone; Pralifan; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. Feasibility Defined as Proportion of Patients Willing to be Randomized to Either Intensive or Non-intensive Induction and Post Remission Chemotherapy [ Time Frame: At end of enrollment ]
   Randomizing patients to either intensive or non-intensive induction and post remission chemotherapy will be considered feasible if the true proportion of patients willing to be randomized is 60% or higher.

Other Outcome Measures:

1. Event-free Survival [ Time Frame: Up to 5 years ]
   Will be determined by peripheral blood count and bone marrow evaluation and categorized according to criteria recommended by International Working Groups.
2. Medical Complications [ Time Frame: Up to 5 years ]
   Information on medical complications (e.g. need for intensive care unit (ICU) level care, length of ICU stay, neutropenic fever, documented infections, bleeding, reasons for hospitalization) will be collected from the medical records from the University of Washington Medical Center (UWMC) and Seattle Cancer Care Alliance (SCCA).
3. Medical Resource Utilization [ Time Frame: Up to 5 years ]
   Information on use of medical resources (e.g. platelet transfusions; days of IV antimicrobial therapy, total hospital length of stay) will be collected from the medical records from the University of Washington Medical Center (UWMC) and Seattle Cancer Care Alliance (SCCA).
4. Overall Survival [ Time Frame: Up to 5 years ]
   Will be assessed for all patients. Will be determined by peripheral blood count and bone marrow evaluation and categorized according to criteria recommended by International Working Groups.
5. Quality of Life as Measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 [ Time Frame: Up to 12 months ]
   Will be measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. Exploratory, descriptive, and observational methods will be used.
6. Relapse-free Survival [ Time Frame: Up to 5 years ]
   Will be determined by peripheral blood count and bone marrow evaluation and categorized according to criteria recommended by International Working Groups.
7. Response [ Time Frame: Up to 5 years ]
   The differences in anti-leukemic efficacy between patients treated with lower-intensity chemotherapy and those treated with higher-intensity chemotherapy will be estimated. Exploratory, descriptive, and observational methods will be used.
8. Fitness for Intensive Chemotherapy as Measured by a Treatment-related Mortality (TRM) Score That Includes Additional Co-morbidity Factors [ Time Frame: Up to 12 months ]
   The ability of physicians and the prediction algorithm(s) to assess the likelihood of early death will be compared.
9. Duration of Response [ Time Frame: Up to 5 years ]
   Will be evaluated.
10. Care Costs [ Time Frame: Up to 5 years ]
    The costs associated with inpatient and outpatient management will be calculated using electronic billing information from the University of Washington Medical Center (UWMC) and Seattle Cancer Care Alliance (SCCA). Costs will be converted from charges using departmental cost-to-charge ratios. Descriptive information identifying major cost drivers and total/subset costs per phase of treatment will be reported.
11. Attitude of Patients Toward Randomization [ Time Frame: Up to 12 months ]
    Will be determined by a patient preference survey. Exploratory, descriptive, and observational methods will be used.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Diagnosis of untreated "high-grade" myeloid neoplasm (>= 10% myeloid blasts by morphology in bone marrow and/or peripheral blood) 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; patients with acute leukemias of ambiguous lineage are eligible; outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution and cytogenetic/molecular information is available
• 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 leukostasis, white blood cell (WBC) > 100,000/uL, or acute symptoms felt related to their high-grade myeloid neoplasm can be treated with leukapheresis or may receive up to 1 dose of cytarabine (up to 500 mg/m^2) anytime prior to study day 1
• Patients may have received treatment (e.g. azacitidine/decitabine, lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm
• Left ventricular ejection fraction (LVEF) >= 45%, assessed within 3 months prior to registration, e.g. by multigated acquisition (MUGA) scan or echocardiography, or other 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
• Known hypersensitivity to any study drug used in this trial
• Pregnancy or lactation
• Concurrent treatment with any other anti-leukemia agent

Contacts and Locations

Locations

United States, Washington

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States, 98109

Sponsors and Collaborators

University of Washington

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Anna Halpern; Fred Hutch/University of Washington Cancer Consortium

  Study Documents (Full-Text)

Documents provided by Anna Halpern, University of Washington:

Study Protocol and Statistical Analysis Plan  [PDF] July 20, 2021

More Information

• Responsible Party: Anna Halpern, Assistant Professor, Division of Hematology, University of Washington
• ClinicalTrials.gov Identifier: NCT03012672
• Other Study ID Numbers: 9759; NCI-2016-02051 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 9759 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract ); RG9217016 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
• First Posted: January 6, 2017
• Results First Posted: November 1, 2021
• Last Update Posted: March 8, 2022
• Last Verified: February 2022

Additional relevant MeSH terms:

Leukemia; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Cytarabine; 2-chloro-3'-deoxyadenosine; Mitoxantrone; Cladribine; Lenograstim; Sargramostim; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors