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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00795002
First received: November 20, 2008
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Monocytic Leukemia (M5b)
Adult Acute Myeloblastic Leukemia With Maturation (M2)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Acute Myelomonocytic Leukemia (M4)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Drug: alvocidib
Drug: mitoxantrone hydrochloride
Drug: cytarabine
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Complete Response [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Bone marrow showing less than 5% leukemic blasts with normal maturation of all cell lines, an ANC of at least 1000/uL and a platelet count of 100,000/uL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. Repeat marrow confirmation 4-6 weeks following the marrow documenting CR is not required due to the need for continued treatment in CR.


Secondary Outcome Measures:
  • Toxicity [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    as assessed by NCI CTCAE v3.0

  • Disease-free Survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    This will be defined as the time between study entry and the first date that recurrent or progressive disease is objectively documented, or death from any cause occurs.


Enrollment: 70
Study Start Date: November 2008
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: alvocidib
Given IV
Drug: mitoxantrone hydrochloride
Given IV
Drug: cytarabine
Given IV
Other: pharmacological study
Correlative studies
Other: laboratory biomarker analysis
Correlative studies
Experimental: 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.
Drug: alvocidib
Given IV
Drug: mitoxantrone hydrochloride
Given IV
Drug: cytarabine
Given IV
Other: pharmacological study
Correlative studies
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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%
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00795002

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287-8936
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Investigators
Principal Investigator: Judith Karp Johns Hopkins University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00795002     History of Changes
Other Study ID Numbers: NCI-2009-00298, NCI-2009-00298, CDR0000625222, J0856, 8237, U01CA070095
Study First Received: November 20, 2008
Results First Received: January 8, 2013
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Leukemia
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Cytarabine
Flavopiridol
Mitoxantrone
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents

ClinicalTrials.gov processed this record on April 23, 2014