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

Phase 2

Completed

Conditions: Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
Adult Acute Monoblastic Leukemia (M5a)
Adult Acute Myeloblastic Leukemia Without Maturation (M1)
Adult Pure Erythroid Leukemia (M6b)
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Interventions: Drug: alvocidib
Drug: mitoxantrone hydrochloride
Drug: cytarabine
Other: pharmacological study
Other: laboratory biomarker analysis

Registration Number: NCT00795002

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 78

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%

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I	mitoxantrone hydrochloride	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	laboratory biomarker analysis	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.
Arm I	alvocidib	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 I	laboratory biomarker analysis	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 I	cytarabine	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 I	pharmacological study	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	mitoxantrone hydrochloride	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.
Arm II	pharmacological study	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.
Arm II	cytarabine	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.
Arm II	alvocidib	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.

Primary Outcome Measures

Name	Time	Method
Complete Response	1 year	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

Name	Time	Method
Number of Participants Experiencing Death From Any Cause Within 60 Days of Starting FLAM	60 days	Toxicity defined as death from any cause within 60 days of starting FLAM.
Disease-free Survival	up to 2 years	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.

Trial Locations

Locations (2): Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States