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

Study Overview
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Brief Summary
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RATIONALE: Lestaurtinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lestaurtinib together with cytarabine and idarubicin may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of lestaurtinib when given together with cytarabine and idarubicin and to see how well they work in treating younger patients with relapsed or refractory acute myeloid leukemia.

Detailed Description
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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.

Official Title
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A Pilot Study of Lestaurtinib (CEP-701) in Combination With Chemotherapy in Young Patients With Relapsed or Refractory FLT3-mutant Acute Myeloid Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: idarubicin
* Drug: lestaurtinib


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 30 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (Lestaurtinib dose 50 mg/m2<br>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 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 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. Continued (see detailed description) | Drug: cytarabine<br>* given IV<br>* Other names: NSC #063878;Drug: idarubicin<br>* Given IV<br>* Other names: IdamycinPFS;Drug: lestaurtinib<br>* Given orally<br>* Other names: IND#76431;|
| Experimental: Group 2 (Lestaurtinib: Dose 62.5 mg/m2<br>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 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 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. Continued (see detailed description) | Drug: cytarabine<br>* given IV<br>* Other names: NSC #063878;Drug: idarubicin<br>* Given IV<br>* Other names: IdamycinPFS;Drug: lestaurtinib<br>* Given orally<br>* Other names: IND#76431;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity | Number of patients with dose-limiting toxicity (DLT) | 28 days | 
| >80% Inhibition of FLT3 Phosphorylation in a Majority of Post-treatment Trough Time Points | FLT3 inhibition is determined in patients receiving lestaurtinib by measuring FLT3 plasma inhibitory activity (PIA). For PIA predictive modeling, a random effects linear regression model will be used to describe the relationship between PIA and Pharmacokinetic (PK) levels for each of the 5 trough plasma samples collected for each patient | Course 1 day 7, day 14, day 21, and day 28. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood acute myeloid leukemia, adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia