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Filgrastim, Cladribine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

NCT02044796

Description:

This phase I/II trial studies the side effects and best dose of mitoxantrone hydrochloride when given together with filgrastim, cladribine, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndromes that is newly diagnosed, has returned, or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride, 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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Filgrastim, Cladribine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes
  • Official Title: A Phase 1/2 Trial of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS)

Clinical Trial IDs

  • ORG STUDY ID: 2734.00
  • SECONDARY ID: NCI-2013-02465
  • SECONDARY ID: 2734.00
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT02044796

Conditions

  • Acute Biphenotypic Leukemia
  • de Novo Myelodysplastic Syndrome
  • Previously Treated Myelodysplastic Syndrome
  • Recurrent Adult Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Treatment (filgrastim, mitoxantrone, cladribine, cytarabine)
Cytarabine.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-28453Treatment (filgrastim, mitoxantrone, cladribine, cytarabine)
FilgrastimFilgrastim XM02, Filgrastim-sndz, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tbo-filgrastim, Tevagrastim, ZarxioTreatment (filgrastim, mitoxantrone, cladribine, cytarabine)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanTreatment (filgrastim, mitoxantrone, cladribine, cytarabine)

Purpose

This phase I/II trial studies the side effects and best dose of mitoxantrone hydrochloride when given together with filgrastim, cladribine, and cytarabine and to see how well they work in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndromes that is newly diagnosed, has returned, or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride, 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Estimate the maximum tolerated dose (MTD) of dose-intensified mitoxantrone hydrochloride
      (mitoxantrone) as part of the filgrastim (G-CSF), cladribine, cytarabine, mitoxantrone
      hydrochloride (G-CLAM) regimen separately for adults with newly diagnosed acute myeloid
      leukemia (AML) and those with relapsed/refractory AML receiving first or greater salvage
      therapy.

      SECONDARY OBJECTIVES:

      I. To determine, within the limits of a phase 1/2 study, disease response and duration of
      remission separately for patients with newly diagnosed and relapsed/refractory AML.

      II. To describe, within the limits of a phase 1/2 study, the toxicity profile of the study
      regimen separately for patients with newly diagnosed and relapsed/refractory AML.

      OUTLINE: This is a phase I, dose-escalation study of mitoxantrone hydrochloride followed by
      phase II study.

      INDUCTION CHEMOTHERAPY (G-CLAM): Patients receive G-CLAM chemotherapy comprising filgrastim
      subcutaneously (SC) daily on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60
      minutes on days 1-3, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2
      hours daily on days 1-5. Patients achieving complete remission with incomplete peripheral
      blood count recovery (CRi), partial remission, or persistent disease may receive a second
      course of induction chemotherapy. Patients achieving complete remission (CR) or CR with
      incomplete platelet count recovery (CRp) may continue on to Consolidation Chemotherapy.

      CONSOLIDATION CHEMOTHERAPY (G-CLA): Beginning within 6 weeks of achieving CR/CRp/CRi,
      patients receive G-CLA comprising filgrastim SC on days 0-5, cladribine IV over 2 hours daily
      on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Treatment continues for up to
      4 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (filgrastim, mitoxantrone, cladribine, cytarabine)ExperimentalINDUCTION CHEMOTHERAPY (G-CLAM): Patients receive G-CLAM chemotherapy comprising filgrastim SC daily on days 0-5, mitoxantrone hydrochloride IV over 60 minutes on days 1-3, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Patients achieving CRi, partial remission, or persistent disease may receive a second course of induction chemotherapy. Patients achieving CR or CRp may continue on to Consolidation Chemotherapy. CONSOLIDATION CHEMOTHERAPY (G-CLA): Beginning within 6 weeks of achieving CR/CRp/CRi, patients receive G-CLA comprising filgrastim SC on days 0-5, cladribine IV over 2 hours daily on days 1-5, and cytarabine IV over 2 hours daily on days 1-5. Treatment continues for up to 4 courses in the absence of disease progression or unacceptable toxicity.
  • Cladribine
  • Cytarabine
  • Mitoxantrone Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  For patients with newly diagnosed disease: diagnosis of "high-risk" myelodysplastic
             syndrome (MDS) (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL)
             with t(15;17)(q22;q12) or variants according to the 2008 World Health Organization
             (WHO) classification; for patients with relapsed/refractory disease: prior diagnosis
             of "high-risk" MDS or non-APL AML, with relapsed/refractory disease according to
             standard criteria requiring first or subsequent salvage therapy; patients with
             biphenotypic AML are eligible

          -  Outside diagnostic material is acceptable as long as peripheral blood and/or bone
             marrow slides are reviewed at the study institution; flow cytometric analysis of
             peripheral blood and/or bone marrow should be performed according to institutional
             practice guidelines

          -  For patients with relapsed/refractory disease: patients with prior autologous or
             allogeneic hematopoietic cell transplantation (HCT) for MDS/AML are eligible if
             relapse occurs provided symptoms of graft-versus host disease are well controlled with
             stable use of immunosuppressive agents

          -  Treatment-related mortality (TRM) score =< 6.9 as calculated with simplified model

          -  The use of hydroxyurea prior to study registration is allowed; patients with
             symptoms/signs of hyperleukocytosis or white blood cell (WBC) > 100,000/uL can be
             treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500
             mg/m^2/dose) prior to enrollment

          -  For patients with relapsed/refractory disease: patients may have previously received
             chemotherapy with a mitoxantrone- or cladribine-based regimen for MDS or AML; if that
             patient has received G-CLAM before and has been sensitive to this regimen, eligibility
             will be determined on a case-by-case basis by the study principal investigator (PI)

          -  Should be off any active systemic therapy for AML with the exception of hydroxyurea
             for at least 14 days prior to study registration unless patient has rapidly
             progressive disease, and all grade 2-4 non-hematologic toxicities should have resolved

          -  Bilirubin =< 2.5 x institutional upper limit of normal (IULN) unless elevation is
             thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
             (assessed within 14 days prior to study day 0)

          -  Serum creatinine =< 2.0 mg/dL (assessed within 14 days prior to study day 0)

          -  Left ventricular ejection fraction >= 45%, assessed within 3 months prior to study day
             0, e.g. by multi gated acquisition scan (MUGA) scan or echocardiography, or other
             appropriate diagnostic modality and no clinical evidence of congestive heart failure;
             if the patient had anthracycline-based therapy since the most recent cardiac
             assessment, cardiac evaluation should be repeated if there is clinical or radiographic
             suspicion of cardiac dysfunction, or if the previous cardiac assessment was abnormal

          -  Women of childbearing potential and men must agree to use adequate contraception

          -  Provide written informed consent

        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 (e.g. if specific,
             effective therapy is not available/feasible or desired [e.g. 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

          -  Pregnancy or lactation

          -  Treatment with any other investigational agent
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of mitoxantrone, defined as the highest dose studied in which the incidence of dose-limiting toxicity is < 33%, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)
Time Frame:Up to day 45 after start of induction chemotherapy
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall survival rate (Phase II expansion cohort)
Time Frame:12 months
Safety Issue:
Description:In addition to the formal test of 12-month overall survival, the entire survival curve will be estimated using the Kaplan-Meier method. Overall survival of this cohort will be compared to a historical cohort treated with standard of care using Cox regression methods.
Measure:Remission rate (complete remission and complete remission with incomplete platelet count recovery) of this regimen in patients with relapsed/refractory disease (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

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