Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
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Purpose
RATIONALE: 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.
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Leukemia |
Drug: alvocidib Drug: cytarabine Drug: mitoxantrone hydrochloride |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Single Group 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) |
- Complete response [ Time Frame: 1 year ] [ Designated as safety issue: No ]
- Toxicity as assessed by NCI CTCAE v3.0 [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
- Disease-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- Pharmacokinetics [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Blast cell expression of selected target mRNA and proteins [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- Recruitment of remaining blasts into cell cycle [ Time Frame: 1 month ] [ Designated as safety issue: No ]
| Enrollment: | 80 |
| Study Start Date: | November 2008 |
| Primary Completion Date: | July 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
Other Name: flavopiridol
Drug: cytarabine
Given IV
Other Name: ara-C
Drug: mitoxantrone hydrochloride
Given IV
Other Name: novantrone
|
|
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
Other Name: flavopiridol
Drug: cytarabine
Given IV
Other Name: ara-C
Drug: mitoxantrone hydrochloride
Given IV
Other Name: novantrone
|
Detailed Description:
OBJECTIVES:
Primary
- 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
- To compare the toxicities of these regimens.
- To determine the disease-free survival and overall survival of patients who demonstrate a response to these regimens.
- To compare the pharmacokinetics of alvocidib when administered in two different schedules (bolus vs "hybrid bolus-infusion").
- To describe alvocidib-induced alterations in AML blast cell expression of selected target mRNA and proteins.
- 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 21-63 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 |
DISEASE CHARACTERISTICS:
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 myeloid neoplasm (t-AML/t-MDS)
- 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
PATIENT CHARACTERISTICS:
- ECOG performance status 0-2
- Serum creatinine ≤ 2.0 mg/dL
- ALT/AST ≤ 5 times upper limit of normal
- Bilirubin ≤ 2.0 mg/dL
- LVEF ≥ 45%
- 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
PRIOR CONCURRENT THERAPY:
- See Disease Characteristics
- 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
Contacts and Locations| United States, Maryland | |
| Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | |
| Baltimore, Maryland, United States, 21231-2410 | |
| United States, South Carolina | |
| Hollings Cancer Center at Medical University of South Carolina | |
| Charleston, South Carolina, United States, 29425 | |
| United States, Washington | |
| Fred Hutchinson Cancer Research Center | |
| Seattle, Washington, United States, 98109-1024 | |
| Study Chair: | Judith E. Karp, MD | Sidney Kimmel Comprehensive Cancer Center |
More Information
Additional Information:
No publications provided
| Responsible Party: | Michael A. Carducci, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
| ClinicalTrials.gov Identifier: | NCT00795002 History of Changes |
| Other Study ID Numbers: | J0856 CDR0000625222, U01CA070095, P30CA006973, JHOC-J0856 |
| Study First Received: | November 20, 2008 |
| Last Updated: | August 5, 2011 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
|
untreated adult acute myeloid leukemia adult acute myeloid leukemia with 11q23 (MLL) abnormalities 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 minimally differentiated myeloid leukemia (M0) adult acute myeloblastic leukemia without maturation (M1) adult acute myeloblastic leukemia with maturation (M2) |
adult acute myelomonocytic leukemia (M4) adult acute monoblastic leukemia (M5a) adult acute monocytic leukemia (M5b) adult erythroleukemia (M6a) adult pure erythroid leukemia (M6b) adult acute megakaryoblastic leukemia (M7) acute myeloid leukemia with multilineage dysplasia following myelodysplastic syndrome secondary acute myeloid leukemia |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Myeloid, Acute Leukemia, Myeloid Neoplasms by Histologic Type Neoplasms Cytarabine Flavopiridol 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 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 May 19, 2013