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

Phase 1

Completed

• Conditions: 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)
• Interventions: Drug: alvocidib; Drug: cytarabine; Drug: mitoxantrone hydrochloride; Other: pharmacological study

• Registration Number: NCT00470197
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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

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.

Study Timeline

• Study Start: 2007-04
• Study First Submitted: 2007-05-03
• Study First Submitted QC: 2007-05-03
• Study First Posted: 2007-05-07
• Primary Completion: 2011-01
• Status Verified: 2013-09
• Last Update Submitted: 2013-09-27
• Last Update Posted: 2013-09-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 35

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	mitoxantrone hydrochloride	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.
Arm I	pharmacological study	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.
Arm I	alvocidib	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.
Arm I	cytarabine	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.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose determined by dose-limiting toxicities graded according to NCI-CTC version 3.0	Up to 63 days

Trial Locations

Locations (2)

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

University of Wisconsin Hospital and Clinics; 🇺🇸 Madison, Wisconsin, United States