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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
Birmingham, Alabama, United States
Children's Hospital of Orange County
Orange, California, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States
C.S. Mott Children's Hospital at University of Michigan Medical Center
Ann Arbor, Michigan, United States
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States
...and 11 more locations
Dose-limiting Toxicity
Number of patients with dose-limiting toxicity (DLT)
Time frame: 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
Time frame: Course 1 day 7, day 14, day 21, and day 28.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.