A Pilot Study of Lestaurtinib (CEP-701) in Combination With Chemotherapy in Young Patients With Relapsed or Refractory FLT3-mutant Acute Myeloid Leukemia
- 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.
- Determine the overall response rate in patients treated with this regimen.
- Optimize dosing of lestaurtinib based primarily on biologic activity rather than
- 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
- 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
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.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Tolerable and biologically active dose of lestaurtinib
Patrick A. Brown, MD
Sidney Kimmel Comprehensive Cancer Center
United States: Food and Drug Administration
|Children's Hospital of Philadelphia||Philadelphia, Pennsylvania 19104|
|Vanderbilt-Ingram Cancer Center||Nashville, Tennessee 37232-6838|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins||Baltimore, Maryland 21231-2410|
|Children's Hospital of Orange County||Orange, California 92668|
|Children's National Medical Center||Washington, District of Columbia 20010-2970|
|Children's Hospital of Pittsburgh||Pittsburgh, Pennsylvania 15213|
|Children's Hospital and Regional Medical Center - Seattle||Seattle, Washington 98105|
|Children's Memorial Hospital - Chicago||Chicago, Illinois 60614|
|Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute||Boston, Massachusetts 02115|
|St. Jude Children's Research Hospital||Memphis, Tennessee 38105-2794|
|Winship Cancer Institute of Emory University||Atlanta, Georgia 30322|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas||Dallas, Texas 75390|
|Baylor University Medical Center - Houston||Houston, Texas 77030-2399|
|Indiana University Melvin and Bren Simon Cancer Center||Indianapolis, Indiana 46202-5289|
|C.S. Mott Children's Hospital at University of Michigan Medical Center||Ann Arbor, Michigan 48109-0286|
|Masonic Cancer Center at University of Minnesota||Minneapolis, Minnesota 55455|
|Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis||St. Louis, Missouri 63110|
|Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center||New York, New York 10032|
|Knight Cancer Institute at Oregon Health and Science University||Portland, Oregon 97239-3098|
|Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham||Birmingham, Alabama 35294|