Decitabine With GCLAM for Adults With Newly Diagnosed, Relapsed, or Refractory AML or High-Risk MDS

Brief Title

Decitabine With GCLAM for Adults With Newly Diagnosed, Relapsed, or Refractory AML or High-Risk MDS

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)

Brief Summary

      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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants Experiencing Dose Limiting Toxicities (DLTs) at the Maximum Tolerated Dose (MTD) for Decitabine When Given Together With G-CLAM Toxicities (DLTs) (Phase I)

Secondary Outcome

 Number of Participants With Minimal Residual Disease Negative (MRDneg) Complete Remission (Phase II)

Condition

Mixed Phenotype Acute Leukemia

Intervention

Cladribine

Study Arms / Comparison Groups

 Treatment (decitabine, G-CLAM)
Description:  INDUCTION: 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.
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 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).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

28

Start Date

November 17, 2016

Completion Date

October 24, 2018

Primary Completion Date

October 24, 2018

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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Roland Walter, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02921061

Organization ID

9713

Secondary IDs

NCI-2016-01401

Responsible Party

Sponsor

Study Sponsor

Fred Hutchinson Cancer Research Center

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Roland Walter, Principal Investigator, Fred Hutch/University of Washington Cancer Consortium


Verification Date

January 2020