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

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Brief Title

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

Official Title

Randomized Phase II Trial of Timed Sequential Therapy (TST) With Alvocidib (Flavopiridol), Ara-C and Mitoxantrone (FLAM) vs. "7+3" for Adults Age 70 and Under With Newly Diagnosed Acute Myelogenous Leukemia (AML)

Brief Summary

      This randomized phase II trial is studying how alvocidib, cytarabine, and mitoxantrone
      hydrochloride work compared to cytarabine and daunorubicin hydrochloride in treating patients
      with newly diagnosed acute myeloid leukemia. Alvocidib may stop the growth of cancer cells by
      blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
      cytarabine, mitoxantrone hydrochloride, and daunorubicin hydrochloride 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 whether giving alvocidib, cytarabine, and mitoxantrone
      hydrochloride is more effective than giving cytarabine and daunorubicin hydrochloride in
      treating patients with acute myeloid leukemia.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the rate of complete remission (CR) after 1 course of induction therapy with
      the timed-sequential combination of alvocidib (flavopiridol), cytarabine (cytosine
      arabinoside [ara-C]), and mitoxantrone hydrochloride (FLAM) vs traditional "7+3" cytarabine
      and daunorubicin hydrochloride (ara-C + Daunorubicin) for adults (age 18 to 70) with newly
      diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia
      (AML).

      SECONDARY OBJECTIVES:

      I. To evaluate and compare the toxicities of FLAM vs 7+3. II. To compare the 2-year
      disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.

      III. To detect and compare the presence of minimal-residual disease (MRD) remaining after
      FLAM vs 7+3.

      IV. To determine the expression of ABC transport proteins multidrug resistance 1 (MDR1,
      ABCB1) and breast cancer resistance protein (BCRP, ABCG2) on AML blasts pretreatment and
      correlate the expressions of one or both proteins with CR and DFS in response to FLAM vs 7+3.

      OUTLINE: This is a multicenter study. Patients are stratified according to risk features: age
      (< 50 vs >= 50), secondary AML (pre-existing myelodysplatic syndrome [MDS],
      myeloproliferative diseases [MPD], treatment-related [t]-AML, or severe multi-lineage
      dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (white blood cells [WBC]
      >= 50,000/mm^3). Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive alvocidib intravenously (IV) over 1 hour on days 1-3, cytarabine IV
      over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9.
      Patients who achieve complete or partial response to the first course (completion of all
      doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days
      following blood count recovery, and/or undergo allogeneic bone marrow transplant.

      ARM II: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin
      hydrochloride IV on days 1-3. Patients who have residual disease on day 14 may receive
      additional cytarabine for 5 days and daunorubicin hydrochloride for 2 days. Patients may
      undergo blood and bone marrow collection for correlative studies.

      After completion of study therapy, patients are followed up every 3 months for 2 years, every
      6 months for 5 years, and then annually thereafter.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Complete Response Rate

Secondary Outcome

 Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade

Condition

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome

Intervention

alvocidib

Study Arms / Comparison Groups

 Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)
Description:  Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 1-2 hours on day 9. Patients who achieve complete or partial response to the first course (completion of all doses) may receive a second course of treatment or high-dose cytarabine after 21-63 days following blood count recovery, and/or undergo allogeneic bone marrow transplant.

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

172

Start Date

April 2011

Completion Date

May 2014

Primary Completion Date

May 2014

Eligibility Criteria

        Inclusion Criteria:

          -  All adults with established, pathologically confirmed diagnoses of newly diagnosed AML
             and adults with newly diagnosed AML, excluding newly diagnosed core-binding factor
             (CBF) AMLs and acute progranulocytic leukemia (APL, M3), will be considered eligible
             for study

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-3

               -  Patients >= 65 years of age must have ECOG PS =< 2 prior to developing leukemic
                  symptoms

          -  Serum creatinine ≤ 2.0 mg/dL

          -  Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 5 times upper limit
             of normal (ULN) (unless leukemic infiltration)

          -  Total bilirubin =< 2.0 mg/dL (unless Gilbert disease, hemolysis, or leukemia)

          -  Left ventricular ejection fraction ≥ 45%

          -  Newly diagnosed AML, subtypes M0, 1, 2, 4-7 but excluding M3 (APL), including those
             with the following poor risk features:

               -  Antecedent hematologic disorder including myelodysplasia (MDS)-related AML
                  (MDS/AML) and prior myeloproliferative disorder (MPD)

               -  Treatment-related myeloid neoplasms (t-AML/t-MDS)

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

               -  AML with multilineage dysplasia (AML-MLD)

               -  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; trisomy 21; and complex
                  karyotypes (≥ 3 unrelated abnormalities)

          -  Patients who have received hydroxyurea alone or have received non-cytotoxic therapies
             previously for myelodysplasia (MDS) or myeloproliferative disorder (MPD) (e.g.,
             thalidomide or lenalidomide, interferon, cytokines, 5-azacytidine or decitabine,
             histone deacetylase inhibitors, low-dose cyclophosphamide [cytoxan], tyrosine kinase
             [TK] or dual TK/src inhibitors) will be eligible for this trial

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

        Exclusion Criteria:

          -  Any previous treatment with flavopiridol

          -  Concomitant chemotherapy, radiation therapy, or immunotherapy

          -  Hyperleukocytosis with >= 50,000 blasts/uL; leukopheresis or hydroxyurea may be used
             immediately prior to study drug administration for cytoreduction; must be stopped 24
             hours before first dose of study chemotherapy

          -  CBF AMLs associated with t(8;21) or M4eo subtype (inv[16] or t[16;16]), as diagnosed
             by morphologic criteria, flow cytometric characteristics, and rapid cytogenetics or
             FISH or molecular testing

          -  Acute Progranulocytic Leukemia (APL, M3)

          -  Active central nervous system (CNS) leukemia

          -  Active, uncontrolled infection; patients with infection under active treatment and
             controlled with antibiotics are eligible

          -  Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant for
             non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia); patients with GVHD
             controlled on stable doses of immunosuppressants are eligible

          -  Presence of other life-threatening illness

          -  Patients with mental deficits and/or psychiatric history that preclude them form
             giving informed consent or from following protocol

          -  Pregnant and nursing patients are excluded
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

B. Smith, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01349972

Organization ID

NCI-2011-02587

Secondary IDs

NCI-2011-02587

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

B. Smith, Principal Investigator, Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center


Verification Date

July 2017