Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Relapsed or Refractory Acute Leukemia

Study Overview
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Brief Summary
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Drugs used in chemotherapy, such as flavopiridol, 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 a new schedule of more than one drug (combination chemotherapy) may kill more cancer cells. This phase I trial is studying the side effects, best dose, and best schedule for flavopiridol when given together with cytarabine and mitoxantrone in treating patients with relapsed or refractory acute leukemia.

Detailed Description
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OBJECTIVES: I. Determine the toxicities of escalating doses of flavopiridol administered by hybrid bolus-infusion schedule and given in timed sequence with cytarabine and mitoxantrone hydrochloride in patients with refractory or relapsed acute leukemia. II. Determine the incidence of clinical response in patients treated with this regimen. OUTLINE: This is a dose-escalation study of flavopiridol. Patients receive flavopiridol IV over 30 minutes on days 1, 2, and 3. Patients receive cytarabine IV continuously over 72 hours beginning on day 6 and mitoxantrone hydrochloride IV over 60-120 minutes on day 9. Treatment repeats every 35-63 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. Serum and bone marrow samples are collected at baseline, during, and after completion of treatment for future studies. Flavopiridol levels are measured at baseline and on days 1-3 for pharmacokinetics.

Official Title
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Phase I Study of a Pharmacologically Derived Hybrid Bolus-Infusion Schedule of Flavopiridol (NSC 649890, IND 46,211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone for Adults With Relapsed and Refractory Acute Leukemias

Conditions
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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), Malignant Neoplasm, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: alvocidib
* Drug: cytarabine
* Drug: mitoxantrone hydrochloride
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed acute myeloid leukemia or acute lymphoblastic leukemia: Relapsed >= 1 time OR refractory disease: Patients who fail primary induction therapy or who relapse after achieving complete remission are eligible if they have received =< 3 prior courses of induction/reinduction therapy Relapsed >= 1 time OR refractory disease Patients who fail primary induction therapy or who relapse after achieving complete remission are eligible if they have received =< 3 prior courses of induction/reinduction therapy No active CNS leukemia ECOG performance status 0-2 AST and ALT =< 5 times upper limit normal (ULN) Alkaline phosphatase =< 5 times ULN Bilirubin =< 2.0 mg/dL Creatinine =< 2.0 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception LVEF >= 45% by MUGA or ECHO No active, uncontrolled infection No other life-threatening illness No mental deficits and/or psychiatric history that would preclude study compliance No active graft-vs-host disease Recovered from all prior therapies At least 24 hours since prior hydroxyurea, steroids, imatinib mesylate, arsenic trioxide, interferon, or leukapheresis for blast count control At least 4 weeks since prior stem cell transplantation (autologous or allogeneic) At least 4 days since prior growth factors At least 3 weeks since prior chemotherapy, except for non-aplasia producing treatments (e.g., low-dose cyclophosphamide, hydroxyurea, interferon, imatinib mesylate, mercaptopurine, thalidomide, azacitidine, or decitabine) No prior flavopiridol No other concurrent chemotherapy, radiotherapy, or immunotherapy No acute promyelocytic leukemia (M3) No hyperleukocytosis with > 50,000 blasts/mm^3

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: Arm I<br>Patients receive flavopiridol IV over 30 minutes on days 1, 2, and 3. Patients receive cytarabine IV continuously over 72 hours beginning on day 6 and mitoxantrone hydrochloride IV over 60-120 minutes on day 9. | 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;Other: pharmacological study<br>* Correlative study<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose determined by dose-limiting toxicities graded according to NCI-CTC version 3.0 |  | Up to 63 days |