Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Primary Purpose
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
alvocidib
mitoxantrone hydrochloride
cytarabine
pharmacological study
laboratory biomarker analysis
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Eligibility 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%
Sites / Locations
- Johns Hopkins University/Sidney Kimmel Cancer Center
- Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arm I
Arm II
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Complete Response
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
Number of Participants Experiencing Death From Any Cause Within 60 Days of Starting FLAM
Toxicity defined as death from any cause within 60 days of starting FLAM.
Disease-free Survival
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.
Full Information
NCT ID
NCT00795002
First Posted
November 20, 2008
Last Updated
August 3, 2018
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00795002
Brief Title
Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
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)
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
November 2008 (undefined)
Primary Completion Date
November 2010 (Actual)
Study Completion Date
September 2012 (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 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.
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.
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 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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
78 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm I
Arm Type
Experimental
Arm Description
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 Title
Arm II
Arm Type
Experimental
Arm Description
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.
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)
mitoxantrone hydrochloride
Other Intervention Name(s)
CL 232315, DHAD, DHAQ, Novantrone
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
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Complete Response
Description
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.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Number of Participants Experiencing Death From Any Cause Within 60 Days of Starting FLAM
Description
Toxicity defined as death from any cause within 60 days of starting FLAM.
Time Frame
60 days
Title
Disease-free Survival
Description
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.
Time Frame
up to 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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%
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Judith Karp
Organizational Affiliation
Johns Hopkins University/Sidney Kimmel Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
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