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

Alvocidib, Cytarabine, and Mitoxantrone Hydrochloride or Cytarabine and Daunorubicin Hydrochloride in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
This study is currently recruiting participants.
Verified May 2012 by National Cancer Institute (NCI)

First Received on May 6, 2011.  
Last Updated on May 10, 2012  
History of Changes
Sponsor: Sidney Kimmel Comprehensive Cancer Center
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01349972
  Purpose

RATIONALE: 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 and idarubicin 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.

PURPOSE: This randomized phase II trial is studying how alvocidib, cytarabine, and mitoxantrone hydrochloride work compared to cytarabine and daunorubicin hydrochloride/idarubicin in treating patients with newly diagnosed acute myeloid leukemia.

Condition Intervention Phase
Leukemia Drug: alvocidib
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: idarubicin
Drug: mitoxantrone hydrochloride
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:

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

Primary Outcome Measures:

  • Complete response after one course of induction therapy (FLAM vs 7+3) [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • Toxicity of FLAM vs 7+3 [ Designated as safety issue: Yes ]
  • DFS and OS to FLAM vs 7+3 at 2 years [ Designated as safety issue: No ]
  • MRD after FLAM vs 7+3 [ Designated as safety issue: No ]
  • Correlation between MDR with CR and DFS [ Designated as safety issue: No ]

Estimated Enrollment: 165
Study Start Date: April 2011
Estimated Primary Completion Date: December 2013 (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 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.
Drug: alvocidib

Given IV

Drug: cytarabine

Given IV

Drug: mitoxantrone hydrochloride

Given IV
Active Comparator: Arm II

Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV over 30-60 minutes (or idarubicin IV over 15 minutes) on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride or idarubicin for 2 days.
Drug: cytarabine

Given IV

Drug: daunorubicin hydrochloride

Given IV

Drug: idarubicin

Given IV

Detailed Description:

OBJECTIVES:

Primary

  • 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 (or idarubicin) (ara-C + Daunorubicin) for adults (age 18 to 70) with newly diagnosed, previously untreated, intermediate-risk or poor-risk acute myelogenous leukemia (AML).

Secondary

  • To evaluate and compare the toxicities of FLAM vs 7+3.
  • To compare the 2-year disease-free survival (DFS) and overall survival (OS) in response to FLAM vs 7+3.
  • To detect and compare the presence of minimal-residual disease (MRD) remaining after FLAM vs 7+3.
  • 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 MDS, MPD, t-AML, or severe multi-lineage dysplasia) and/or known adverse cytogenetics, and hyperleukocytosis (WBC ≥ 50,000/mm³). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: 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.
  • Arm II: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin hydrochloride IV over 30-60 minutes (or idarubicin IV over 15 minutes) on days 1-3. Patients who have residual disease on day 14 may receive additional cytarabine for 5 days and daunorubicin hydrochloride (or idarubicin) 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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • All adults with established, pathologically confirmed newly diagnosed acute myeloid leukemia (AML)

    • Adults (≥ 18 years and ≤ 70 years of age) with newly diagnosed AML, subtypes M0, 1, 2, 4-7
    • Excluding newly diagnosed core-binding factor (CBF) AML and acute progranulocytic leukemia (APL, M3)

      • CBF AML 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, fluorescence in situ hybridization (FISH), or molecular testing
  • Subtypes allowed include 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)
  • No active CNS leukemia

PATIENT CHARACTERISTICS:

  • ECOG performance status (PS) 0-3

    • Patients ≥ 65 years old must have had ECOG PS ≤ 2 prior to developing leukemic symptoms
  • Serum creatinine ≤ 2.0 mg/dL
  • ALT/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%
  • No hyperleukocytosis with ≥ 50,000 blasts/μL
  • No active, uncontrolled infection

    • Patients with infection under active treatment and controlled with antibiotics are eligible
  • No presence of other life-threatening illness
  • No patients with mental deficits and/or psychiatric history that preclude them from giving informed consent or from following protocol
  • Not pregnant or nursing
  • No active uncontrolled graft-vs-host disease (GVHD) following allogeneic transplantation for non-AML condition (e.g., MDS, lymphoid malignancy, or aplastic anemia)

    • Patients with GVHD controlled on stable doses of immunosuppressants are eligible

PRIOR CONCURRENT THERAPY:

  • 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
  • No prior alvocidib (flavopiridol)
  • No other concomitant chemotherapy, radiotherapy, or immunotherapy
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01349972

Locations
United States, Arizona
Mayo Clinic Scottsdale Recruiting
Scottsdale, Arizona, United States, 85259-5499
Contact: Clinical Trials Office – All Mayo Clinic Locations     507-538-7623        
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida Recruiting
Tampa, Florida, United States, 33612-9497
Contact: Clinical Trials Office – H. Lee Moffitt Cancer Center and Rese     800-456-7121     canceranswers@moffitt.org    
United States, Georgia
Blood and Marrow Transplant Group of Georgia Recruiting
Atlanta, Georgia, United States, 30342
Contact: Lawrence E. Morris, MD     404-255-1938        
United States, Illinois
Robert H. Lurie Comprehensive Cancer Center at Northwestern University Recruiting
Chicago, Illinois, United States, 60611-3013
Contact: Clinical Trials Office – Robert H. Lurie Comprehensive Cancer     312-695-1301     cancer@northwestern.edu    
Rush Cancer Institute at Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Clinical Trials Office – Rush Cancer Institute at Rush Univers     312-942-5498     clinical_trials@rush.edu    
University of Chicago Cancer Research Center Recruiting
Chicago, Illinois, United States, 60637-1470
Contact: Clinical Trials Office – University of Chicago Cancer Research     773-834-7424        
United States, Maryland
Greenebaum Cancer Center at University of Maryland Medical Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Clinical Trials Office – Greenebaum Cancer Center at Universit     800-888-8823        
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231-2410
Contact: Clinical Trials Office – Sidney Kimmel Comprehensive Cancer Ce     410-955-8804     jhcccro@jhmi.edu    
United States, Minnesota
Masonic Cancer Center at University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Clinical Trials Office – Masonic Cancer Center at University o     612-624-2620        
Mayo Clinic Cancer Center Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Office – All Mayo Clinic Locations     507-538-7623        
United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina – Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599-7295
Contact: Clinical Trials Office – Lineberger Comprehensive Cancer Cente     877-668-0683; 919-966-4432        
United States, South Carolina
Hollings Cancer Center at Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: Clinical Trials Office – Hollings Cancer Center at Medical Uni     843-792-9321        
United States, Tennessee
Vanderbilt-Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232-6838
Contact: Clinical Trials Office – Vanderbilt-Ingram Cancer Center     800-811-8480        
United States, Virginia
Virginia Commonwealth University Massey Cancer Center Recruiting
Richmond, Virginia, United States, 23298-0037
Contact: Clinical Trials Office -Virginia Commonwealth University Masse     804-628-1939        
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Judith E. Karp, MD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:

No publications provided

Responsible Party: Judith E. Karp, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT01349972    
History of Changes
Other Study ID Numbers: CDR0000699421, JHOC-J1101
Study First Received: May 6, 2011
Last Updated: May 10, 2012
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):

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)
secondary acute myeloid leukemia
untreated adult acute myeloid leukemia
acute myeloid leukemia with multilineage dysplasia following myelodysplastic syndrome
adult erythroleukemia (M6a)
adult pure erythroid leukemia (M6b)
adult acute monoblastic leukemia (M5a)
adult acute monocytic leukemia (M5b)
adult acute minimally differentiated myeloid leukemia (M0)

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Flavopiridol
Daunorubicin
Idarubicin
Mitoxantrone
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Growth Inhibitors
Growth Substances
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 21, 2012

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