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

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and how well giving alvocidib together with cytarabine and mitoxantrone works 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. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the efficacy and toxicities of flavopiridol (alvocidib) followed by ara-C and mitoxantrone in adults with newly diagnosed acute myelogenous leukemia (AML) with poor-risk features. II. To determine the disease free and overall survival of patients exhibiting a response to treatment with flavopiridol followed by ara-C and mitoxantrone. OUTLINE: 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 1-2 hours on day 9. Beginning 35-63 days after completion of course 1, patients achieving complete or partial remission may receive a second course of treatment as above. Patients age 50 and over with core binding factor acute myeloid leukemia (AML) (e.g., t[8;21], inv[16], or t[16;16]) achieving a complete remission after course 1 of treatment may receive 3-4 courses of consolidation therapy comprising high-dose cytarabine at the discretion of the investigator. After completion of study treatment, patients are followed periodically.

Official Title
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Phase II Study of Alvocidib (NSC 649890, Flavopiridol) in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone for Adults With Newly Diagnosed, Previously Untreated, Poor-Risk Acute Myelogenous Leukemias

Conditions
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Adult Acute Basophilic Leukemia, Adult Acute Eosinophilic Leukemia, 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 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 / Treatment
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* Drug: alvocidib
* Drug: cytarabine
* Drug: mitoxantrone hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults with established, pathologically confirmed diagnoses of newly diagnosed, poor-risk Acute Myeloid Leukemia(AML) including de novo and secondary Acute Myeloid Leukemias but excluding newly diagnosed acute progranulocytic leukemia (APL, M3) will be considered eligible for study ECOG performance status 0-2 Patient must be able to give informed consent Serum creatinine =< 2.0 ALT, AST =< 5 x upper limit of normal Bilirubin =< 2.0 mg/dl Left ventricular ejection fraction >= 45% Newly diagnosed AML, subtypes M0,1,2,4-7 but excluding M3 (APL) with poor-risk features, including: Age > 50 years, or age > 18 years with one or more of the following criteria: Antecedent hematologic disorder including myelodysplasia (MDS)-related AML (MDS/AML) and prior myeloproliferative disorder (MPD) Treatment-related AML AML with trilineage dysplasia (AML-TLD) 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) Exclusion Criteria: Patients who have received hydroxyurea alone or have received non-cytotoxic therapies previously for MDS or MPD (e.g., thalidomide or lenalidomide, interferon, cytokines, low-dose 5-azacytidine, low-dose cytoxan) will be eligible for this trial Any previous treatment with flavopiridol Concomitant chemotherapy, radiation therapy, or immunotherapy Hyperleukocytosis with >= 50,000 blasts/uL; leukapheresis or hydroxyurea may be used immediately prior to study drug administration for cytoreduction; must be stopped 24 hours before first dose of Flavopiridol Acute Progranulocytic Leukemia (APL, M3) Active CNS leukemia Active, uncontrolled infection; patients with infection under active treatment and controlled with antibiotics 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (alvocidib, cytarabine, mitoxantrone hydrochloride)<br>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 1-2 hours on day 9. Beginning 35-63 days after completion of course 1, patients achieving complete or partial remission may receive a second course of treatment as above. Patients age 50 and over with core binding factor acute myeloid leukemia (AML) (e.g., t[8;21], inv[16], or t[16;16]) achieving a complete remission after course 1 of treatment may receive 3-4 courses of consolidation therapy comprising high-dose cytarabine at the discretion of the investigator. | Drug: alvocidib<br>* Given IV<br>* Other names: L-868275;Drug: cytarabine<br>* Given IV<br>* Other names: cytosine arabinoside;Drug: mitoxantrone hydrochloride<br>* Given IV<br>* Other names: Novantrone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response | Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, an Absolute Neutrophil Count of at least 1000/mililiter and a platelet count of 100,000 mililiter, 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. A complete remission must be confirmed 4 to 6 weeks after the initial documentation. If possible, at least one bone marrow biopsy should be performed to confirm the complete remission. | 6 months |