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

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; 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

Intervention: alvocidib (Drug); daunorubicin hydrochloride (Drug); mitoxantrone hydrochloride (Drug); cytarabine (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
B. Smith, Principal Investigator, Affiliation: Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center


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.

Clinical Details

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)

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Complete response rate

Secondary outcome:

Incidence of toxicities, characterized as percentages by treatment and grade

Disease-free survival

Overall survival

Progression-free survival

Proportion of patients with minimal residual disease

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.


Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.


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


- 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

Locations and Contacts

Mayo Clinic in Arizona, Scottsdale, Arizona 85259, United States

Mayo Clinic Scottsdale-Phoenix, Scottsdale, Arizona 85259, United States

Moffitt Cancer Center, Tampa, Florida 33612, United States

Blood and Marrow Transplant Group of Georgia, Atlanta, Georgia 30342, United States

University of Chicago, Chicago, Illinois 60637, United States

Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21287, United States

University of Maryland/Greenebaum Cancer Center, Baltimore, Maryland 21201, United States

Mayo Clinic, Rochester, Minnesota 55905, United States

University of North Carolina, Chapel Hill, North Carolina 27599, United States

Medical University of South Carolina, Charleston, South Carolina 29425, United States

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States

Baylor University Medical Center, Dallas, Texas 75246, United States

Baylor All Saints Medical Center at Fort Worth, Fort Worth, Texas 76104, United States

Virginia Commonwealth University, Richmond, Virginia 23298, United States

Additional Information

Starting date: April 2011
Last updated: October 10, 2014

Page last updated: August 23, 2015

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