Clinical Trials /

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

NCT02921061

Description:

This phase I/II trial studies the side effects and best dose of decitabine when given together with filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly diagnosed, has come back or has not responded to treatment. Drugs used in chemotherapy, such as decitabine, 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. Colony-stimulating factors, such as filgrastim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Decitabine, filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride may work better in treating patients with acute myeloid leukemia and myelodysplastic syndrome.

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

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 9713
  • SECONDARY ID: NCI-2016-01401
  • SECONDARY ID: 9713
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT02921061

Conditions

  • Mixed Phenotype Acute Leukemia
  • Previously Treated Myelodysplastic Syndrome
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory High Risk Myelodysplastic Syndrome
  • Untreated Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Treatment (decitabine, G-CLAM)
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, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (decitabine, G-CLAM)
Decitabine5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, G-CLAM)
FilgrastimFILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimTreatment (decitabine, G-CLAM)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanTreatment (decitabine, G-CLAM)

Purpose

This phase I/II trial studies the side effects and best dose of decitabine when given together with filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly diagnosed, has come back or has not responded to treatment. Drugs used in chemotherapy, such as decitabine, 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. Colony-stimulating factors, such as filgrastim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Decitabine, filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride may work better in treating patients with acute myeloid leukemia and myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Estimate the maximum tolerated dose (MTD) of decitabine when used concomitantly with
      filgrastim, cladribine, cytarabine, and mitoxantrone hydrochloride (G-CLAM) in patients with
      newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

      II. Compare, within the limits of a phase 1/2 study, the rate of complete remission without
      measurable residual disease (minimal residual disease negative [MRDneg] complete remission
      [CR]) with decitabine + G-CLAM at the MTD compared to similar patients treated previously
      with G-CLAM alone.

      SECONDARY OBJECTIVES:

      I. Evaluate, within the limits of a phase 1/2 study, disease response (complete remission,
      overall response rate) relapse-free survival (RFS), event-free survival (EFS), and overall
      survival (OS) in patients with newly-diagnosed AML / high-risk MDS.

      II. Describe, within the limits of a phase 1/2 study, the toxicity profile of the study
      regimen.

      OUTLINE: This is a dose de-escalation study of decitabine.

      INDUCTION: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10. Patients
      also receive filgrastim subcutaneously (SC) on days 0-5, cladribine IV over 2 hours on days
      1-5, cytarabine IV over 2-4 hours on days 1-5, and mitoxantrone hydrochloride IV over 60
      minutes on days 1-3.

      RE-INDUCTION: Patients who do not achieve MRDneg CR after first induction are eligible for
      re-induction. Patients receive the same treatment as during induction except that decitabine
      is omitted.

      CONSOLIDATION THERAPY: Beginning 6 weeks after achieving MRDneg CR or CR/CR with incomplete
      count recovery (CRi) after induction and/or re-induction, patients are eligible to receive
      filgrastim, cladribine, and cytarabine as in Induction. Treatment may be repeated for up to 4
      courses in the absence of disease progression or unacceptable toxicity. Subsequent
      consolidation cycles would be given after recovery from the previous cycle (roughly 4-6
      weeks).

      After completion of study treatment, patients are followed up at for 1 month and every 3
      months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, G-CLAM)ExperimentalCONCURRENT: Patients receive decitabine IV over 1 hour on days 1-10. Patients also receive filgrastim SC on days 0-5, cladribine IV over 2 hours on days 1-5, cytarabine IV over 2-4 hours on days 1-5, and mitoxantrone hydrochloride IV over 60 minutes on days 1-3. Treatment repeats every 10 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Beginning 6 weeks after achieving MRDneg CR or CR/CR with incomplete count recovery (CRi), patients receive decitabine, filgrastim, cladribine, and cytarabine as in Concurrent. Treatment repeats every 10 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
  • Cladribine
  • Cytarabine
  • Decitabine
  • Mitoxantrone Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  For patients with newly diagnosed disease: diagnosis of "high-grade" MDS (>= 10%
             blasts by morphology) 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; for patients with relapsed/refractory disease: prior diagnosis of
             "high-risk" MDS or non-APL AML, with relapsed/refractory disease according to 2003
             recommendations of the International Working Group, requiring first or subsequent
             salvage therapy; patients with mixed phenotype acute leukemia (MPAL) 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

          -  Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT)
             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 =< 9.2 as calculated with simplified model

          -  Should be off any active 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

          -  May have previously received monotherapy with demethylating agents for MDS or AML or
             treatment with a mitoxantrone- or cladribine-based regimen for MDS or AML, including
             G-CLAM, but not demethylating agent as priming for or in combination with chemotherapy

          -  Patients with symptoms/signs of hyperleukocytosis or white blood cells (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

          -  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 registration)

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

          -  Left ventricular ejection fraction >= 45%, assessed within 3 months prior to
             registration, e.g. by multigated 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

          -  Ability to understand and willingness to sign a written 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 24-48 hours

          -  Known hypersensitivity to any study drug

          -  Pregnancy or lactation

          -  Patients may not be receiving any other investigational agents
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determination of Maximum Tolerated Dose (MTD) for decitabine when given together with G-CLAM determined by dose limiting toxicities (DLTs) (Phase I)
Time Frame:Up to 20 days
Safety Issue:
Description:Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. MTD is defined as the highest dose studied in which the incidence of DLT is < 33%.

Secondary Outcome Measures

Measure:Remission (complete remission [CR]/CR with incomplete peripheral blood count recovery [CRi])
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Relapse-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Event-free survival
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated