Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

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Brief Title

Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Official Title

Randomized Phase II Study Comparing Two Administration Schedules of Flavopiridol (Alvocidib, NSC 649890, IND 46, 211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone Hydrochloride for Adults With Newly Diagnosed, Previously Untreated, Poor Risk Acute Myelogenous Leukemias (AML)

Brief Summary

      This randomized phase II trial is studying two different schedules of alvocidib to compare
      how well they work when given together with cytarabine and mitoxantrone in treating patients
      with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as alvocidib,
      cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells,
      either by killing the cells or by stopping them from dividing. It is not yet known which
      schedule of alvocidib is more effective when given together with cytarabine and mitoxantrone
      in treating patients with acute myeloid leukemia.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the efficacy of two different schedules (bolus vs "hybrid bolus-infusion") of
      alvocidib followed by cytarabine and mitoxantrone hydrochloride in patients with newly
      diagnosed acute myeloid leukemia (AML) with poor-risk features.

      SECONDARY OBJECTIVES:

      I. To compare the toxicities of these regimens. II. To determine the disease-free survival
      and overall survival of patients who demonstrate a response to these regimens.

      III. To compare the pharmacokinetics of alvocidib when administered in two different
      schedules (bolus vs "hybrid bolus-infusion").

      IV. To describe alvocidib-induced alterations in AML blast cell expression of selected target
      mRNA and proteins.

      V. To describe alvocidib-induced alterations in AML blast cell growth kinetic parameters.

      OUTLINE: This is a multicenter study. Patients are stratified according to antecedent
      hematologic disorder of >= 6 months duration prior to transformation to acute myeloid
      leukemia (AML) and any prior antecedent therapy for myelodysplastic syndromes or
      myeloproliferative disorder. Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over
      72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.

      ARM II: Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours
      on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.

      Patients achieving partial or complete response (CR) after the first course of treatment may
      receive a second course of treatment 35-63 days following blood count recovery and/or undergo
      allogeneic bone marrow transplantation. Patients >= 50 years of age with t (8;21), inv (16),
      or t(16;16) AML who achieve CR after the first course of treatment may receive 3-4 courses of
      high-dose cytarabine consolidation therapy.

      Bone marrow and/or blood samples are collected at baseline and periodically during study for
      correlative laboratory studies, including pharmacokinetic studies by liquid chromatography
      and tandem mass spectrometry, analysis of blast cell growth kinetic parameters by flow
      cytometry, and blast cell expression of selected target mRNA and protein by quantitative
      RT-PCR and western blotting.

      After completion of study therapy, patients are followed periodically.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Complete Response

Secondary Outcome

 Number of Participants Experiencing Death From Any Cause Within 60 Days of Starting FLAM

Condition

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome

Intervention

alvocidib

Study Arms / Comparison Groups

 Arm I
Description:  Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.

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

78

Start Date

November 2008

Completion Date

September 2012

Primary Completion Date

November 2010

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed newly diagnosed acute myeloid leukemia (AML) meeting the
             following criteria:

               -  Subtypes M0, M1, M2, M4-7

               -  No acute promyelocytic leukemia (M3)

          -  At least 50 years of age OR >= 18 years of age with >= 1 of the following poor-risk
             disease features:

               -  Antecedent hematologic disorder, including myelodysplastic syndromes
                  (MDS)-related AML or prior myeloproliferative disorder (MPD)

               -  Treatment-related AML, AML with trilineage dysplasia

               -  Myeloid sarcoma, myeloid proliferations related to Down Syndrome, or blastic
                  plasmacytoid dendritic cell neoplasm

               -  AML with trilineage dysplasia

          -  AML with adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q,
             21q, or 17p; t[6;9]; t[9;22]; trisomy 8; trisomy 13, complex karyotypes [>= 3
             unrelated abnormalities]),

          -  No hyperleukocytosis with >= 50,000 blasts/uL (leukapheresis or hydroxyurea allowed
             for cytoreduction immediately prior to the first dose of alvocidib)

          -  No active CNS leukemia

          -  ECOG performance status 0-2

          -  Serum creatinine =< 2.0 mg/dL

          -  ALT/AST =< 5 times upper limit of normal

          -  Bilirubin =< 2.0 mg/dL

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  No active uncontrolled infection

          -  Infection that is under active treatment allowed provided it is controlled with
             antibiotics

          -  No other life-threatening illness

          -  No mental deficits and/or psychiatric history that would preclude giving informed
             consent or following study requirements

          -  At least 24 hours since prior leukapheresis or hydroxyurea for cytoreduction

          -  Prior non-cytotoxic therapies (e.g., thalidomide or lenalidomide, interferon,
             cytokines, low-dose 5-azacytidine, or low-dose cytoxan) for MDS or MPD allowed

          -  Prior chemotherapy or bone marrow/stem cell transplantation for non-AML malignancy
             allowed

          -  No prior alvocidib

          -  No other concurrent chemotherapy, radiotherapy, or immunotherapy

          -  No other concurrent investigational or commercially-available antitumor therapies for
             AML

          -  LVEF >= 45%
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Judith Karp, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00795002

Organization ID

NCI-2009-00298

Secondary IDs

NCI-2009-00298

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Judith Karp, Principal Investigator, Johns Hopkins University/Sidney Kimmel Cancer Center


Verification Date

August 2018