Lestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia

OBJECTIVES:

Primary

- Determine a safe, tolerable, and biologically active dose of lestaurtinib in
combination with chemotherapy comprising cytarabine and idarubicin in younger patients
with relapsed or refractory FLT3-mutant acute myeloid leukemia.

Secondary

- Determine the overall response rate in patients treated with this regimen.

- Optimize dosing of lestaurtinib based primarily on biologic activity rather than
toxicity.

- Correlate the clinical response to this regimen with the ability to achieve adequate
FLT3 plasma inhibitory activity levels and the in vitro sensitivity of pretreatment
leukemic cells to lestaurtinib in these patients.

- Determine the mechanisms of resistance to lestaurtinib in these patients.

- Assess the feasibility of using rapid central determination of FLT3 mutation status at
study entry to determine induction therapy in future upfront protocols.

OUTLINE: This is a multicenter, dose-finding study of lestaurtinib followed by an efficacy
study.

- Dose-finding phase:

- Course 1: Patients receive cytarabine IV over 2 hours twice daily on days 1-4,
idarubicin IV over 15 minutes on days 2-4, and oral lestaurtinib twice daily on
days 5-28. Patients achieving complete or partial response proceed to course 2.

Cohorts of 6 patients receive escalating doses of lestaurtinib until a tolerable and
biologically active dose (TBAD) is determined. The TBAD is defined as the dose at which no
more than 2 of 6 patients experience DLT and biologic activity is confirmed by plasma
inhibitory activity (PIA) assay.

- Course 2: Patients receive high-dose cytarabine IV over 3 hours twice daily on days 1-4
and oral lestaurtinib (at the dose determined in course 1) twice daily on days 5-28.
Patients achieving complete or partial response proceed to continuation therapy.

- Continuation therapy: Patients receive oral lestaurtinib twice daily on days 1-28.
Treatment repeats every 28 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity.

- Efficacy phase: Once the TBAD is determined, subsequent patients receive treatment
as in course 1 and 2 with lestaurtinib at the TBAD. Patients may also receive
continuation therapy as in the dose-finding phase.

Blood samples are collected periodically during study treatment for pharmacokinetic and PIA
assays.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Diagnosis of acute myeloid leukemia (AML) according to FAB classification

- At least 5% blasts in the bone marrow, with or without extramedullary disease

- In first relapse after induction therapy OR refractory to induction therapy with ≤ 1
attempt at remission induction

- Patients who are in a first relapse > 1 year from their initial diagnosis of AML
are excluded from the dose-finding phase of the study, but are eligible for the
efficacy phase

- First relapse after hematopoietic stem cell transplantation (HSCT) allowed
provided patient has no evidence of active graft-versus-host disease (GVHD) and
is at least 4 months posttransplantation

- Positive for a FLT3 activating mutation (internal tandem duplication or kinase domain
point mutation) using standard polymerase chain reaction-based procedures at any time
in the course of illness

- Treatment-related AML allowed

PATIENT CHARACTERISTICS:

- Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤
16 years of age)

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum
creatinine based on age and gender as follows:

- Creatinine no greater than 0.4 mg/dL (1 month to < 6 months of age)

- Creatinine no greater than 0.5 mg/dL (6 months to < 1 year of age)

- Creatinine no greater than 0.6 mg/dL (1 year to < 2 years of age)

- Creatinine no greater than 0.8 mg/dL (2 years to < 6 years of age)

- Creatinine no greater than 1 mg/dL (6 years to < 10 years of age)

- Creatinine no greater than 1.2 mg/dL (10 years to < 13 years of age)

- Creatinine no greater than 1.4 mg/dL (females) or 1.5 mg/dL (males) (13 years to
< 16 years of age)

- Creatinine no greater than 1.4 mg/dL (females) or 1.7 mg/dL (males) (16 years of
age and over)

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT < 5 times ULN (unless it is related to leukemic involvement)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by
radionuclide angiogram

PRIOR CONCURRENT THERAPY:

- Recovered from all prior therapy

- No prior cumulative anthracycline doses exceeding 450 mg/m^2 daunorubicin equivalents

- Patients who relapse after receiving treatment on protocol COG-AAML03P1 or
COG-AAML0531 (300 mg/m^2 of daunorubicin hydrochloride and 48 mg/m^2 of
mitoxantrone hydrochloride) allowed provided they have not received any
additional anthracyclines

- At least 14 days since prior cytotoxic therapy

- Hydroxyurea allowed to decrease the WBC prior to starting protocol treatment

- No concurrent hydroxyurea

- At least 7 days since prior biologic agents

- At least 14 days since prior monoclonal antibody therapy

- Radiotherapy to chloromas allowed

- Irradiated lesion may not be used to assess tumor response

- No other concurrent chemotherapy, investigational therapy, immunomodulating agents,
or steroids

- Steroids used as an antiemetic allowed

- Prophylactic intrathecal cytarabine allowed

- No concurrent CYP3A4,5 inhibitors, including any of the following:

- Azole antifungals (e.g., fluconazole or voriconazole)

- Cyclosporine

- Erythromycin

- Clarithromycin

- Troleandomycin

- HIV protease inhibitors

- Nefazodone

- No concurrent CYP3A4,5 inducers, including any of the following:

- Carbamazepine

- Dexamethasone

- Rifampin

- Phenobarbital

- Phenytoin

- Hypericum perforatum (St. John's wort)