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

Primary Purpose

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
alvocidib
daunorubicin hydrochloride
mitoxantrone hydrochloride
cytarabine
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Mayo Clinic Scottsdale-Phoenix
  • Moffitt Cancer Center
  • Blood and Marrow Transplant Group of Georgia
  • University of Chicago
  • University of Maryland/Greenebaum Cancer Center
  • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
  • Mayo Clinic
  • University of North Carolina
  • Vanderbilt-Ingram Cancer Center
  • Baylor University Medical Center
  • Virginia Commonwealth University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)

Arm II (cytarabine, daunorubicin hydrochloride)

Arm 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.

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.

Outcomes

Primary Outcome Measures

Complete Response Rate
Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/cu mm and a platelet count of 100,000/cu mm, 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. These criteria are taken from Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474

Secondary Outcome Measures

Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
Disease-free Survival
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. Disease-free survival Overall survival was defined from date of randomization to death or last known follow-up. Event free survival was defined as date of randomization to the first occurrence of persistent AML after 1 cycle of induction, relapse or death. Patients were censored for event free survival if they had received non-protocol therapy or a stem cell transplant.
Overall Survival
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
Number of Patients With Minimal Residual Disease
Comparisons of the treatments with respect to MRD will be based on the number of patients with MRD at day 14 after the start of treatment.
Progression-free Survival
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.

Full Information

First Posted
May 6, 2011
Last Updated
July 3, 2017
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01349972
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)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
April 2011 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
172 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (alvocidib, cytarabine, mitoxantrone hydrochloride)
Arm Type
Experimental
Arm 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.
Arm Title
Arm II (cytarabine, daunorubicin hydrochloride)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
alvocidib
Other Intervention Name(s)
FLAVO, flavopiridol, HMR 1275, L-868275
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
daunorubicin hydrochloride
Other Intervention Name(s)
Cerubidin, Cerubidine, daunomycin hydrochloride, daunorubicin, RP-13057
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
mitoxantrone hydrochloride
Other Intervention Name(s)
CL 232315, DHAD, DHAQ
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cytarabine
Other Intervention Name(s)
ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Complete Response Rate
Description
Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an ANC of at least 1000/cu mm and a platelet count of 100,000/cu mm, 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. These criteria are taken from Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-474
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Incidence of Toxicities, Characterized by Number of Events by Treatment and Grade
Description
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
Time Frame
Up to 14 days after completion of study treatment
Title
Disease-free Survival
Description
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated. Disease-free survival Overall survival was defined from date of randomization to death or last known follow-up. Event free survival was defined as date of randomization to the first occurrence of persistent AML after 1 cycle of induction, relapse or death. Patients were censored for event free survival if they had received non-protocol therapy or a stem cell transplant.
Time Frame
Time from randomization until death from any cause or relapse or recurrence, assessed up to 2 years
Title
Overall Survival
Description
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
Time Frame
4 years
Title
Number of Patients With Minimal Residual Disease
Description
Comparisons of the treatments with respect to MRD will be based on the number of patients with MRD at day 14 after the start of treatment.
Time Frame
From study start to 14 days after the start of treatment
Title
Progression-free Survival
Description
Probabilities will be estimated with the Kaplan-Meier estimate. Survival estimates at two years will be estimated.
Time Frame
4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
B. Smith
Organizational Affiliation
Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic Scottsdale-Phoenix
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Blood and Marrow Transplant Group of Georgia
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30342
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Maryland/Greenebaum Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Vanderbilt-Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Baylor University Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26022709
Citation
Zeidner JF, Foster MC, Blackford AL, Litzow MR, Morris LE, Strickland SA, Lancet JE, Bose P, Levy MY, Tibes R, Gojo I, Gocke CD, Rosner GL, Little RF, Wright JJ, Doyle LA, Smith BD, Karp JE. Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia. Haematologica. 2015 Sep;100(9):1172-9. doi: 10.3324/haematol.2015.125849. Epub 2015 May 28.
Results Reference
result
PubMed Identifier
26819054
Citation
Gerber JM, Zeidner JF, Morse S, Blackford AL, Perkins B, Yanagisawa B, Zhang H, Morsberger L, Karp J, Ning Y, Gocke CD, Rosner GL, Smith BD, Jones RJ. Association of acute myeloid leukemia's most immature phenotype with risk groups and outcomes. Haematologica. 2016 May;101(5):607-16. doi: 10.3324/haematol.2015.135194. Epub 2016 Jan 27.
Results Reference
derived
Links:
URL
http://www.ncbi.nlm.nih.gov/m/pubmed/26022709/?i=1&from=zeidner%20jf
Description
Pubmed

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

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