Back to resultsLestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Primary Purpose
Leukemia
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
cytarabine
idarubicin
lestaurtinib
Sponsored by
About this trial
This is an interventional treatment trial for Leukemia focused on measuring 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
Eligibility Criteria
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)
Sites / Locations
- Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
- Children's Hospital of Orange County
- Children's National Medical Center
- Winship Cancer Institute of Emory University
- Children's Memorial Hospital - Chicago
- Indiana University Melvin and Bren Simon Cancer Center
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
- C.S. Mott Children's Hospital at University of Michigan Medical Center
- Masonic Cancer Center at University of Minnesota
- Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
- Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
- Cincinnati Children's Hospital Medical Center
- Knight Cancer Institute at Oregon Health and Science University
- Children's Hospital of Philadelphia
- Children's Hospital of Pittsburgh
- St. Jude Children's Research Hospital
- Vanderbilt-Ingram Cancer Center
- Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
- Baylor University Medical Center - Houston
- Children's Hospital and Regional Medical Center - Seattle
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Group 1 (Lestaurtinib dose 50 mg/m2
Group 2 (Lestaurtinib: Dose 62.5 mg/m2
Arm Description
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)
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)
Outcomes
Primary Outcome Measures
Dose-limiting Toxicity
Number of patients with dose-limiting toxicity (DLT)
>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
Secondary Outcome Measures
Full Information
NCT ID
NCT00469859
First Posted
May 3, 2007
Last Updated
February 7, 2017
Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00469859
Brief Title
Lestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official Title
A Pilot Study of Lestaurtinib (CEP-701) in Combination With Chemotherapy in Young Patients With Relapsed or Refractory FLT3-mutant Acute Myeloid Leukemia
Study Type
Interventional
2. Study Status
Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
June 2007 (undefined)
Primary Completion Date
March 2010 (Actual)
Study Completion Date
March 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia
Keywords
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group 1 (Lestaurtinib dose 50 mg/m2
Arm Type
Experimental
Arm Description
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)
Arm Title
Group 2 (Lestaurtinib: Dose 62.5 mg/m2
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
cytarabine
Other Intervention Name(s)
Cytosine arabinoside, Ara-C, Cytosar, NSC #063878
Intervention Description
given IV
Intervention Type
Drug
Intervention Name(s)
idarubicin
Other Intervention Name(s)
Idarubicin HCl, 4-Demethoxydaunorubicin, 4-DMD, DMDR, IdamycinPFS
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
lestaurtinib
Other Intervention Name(s)
benzodiazocin-1-one, IND#76431
Intervention Description
Given orally
Primary Outcome Measure Information:
Title
Dose-limiting Toxicity
Description
Number of patients with dose-limiting toxicity (DLT)
Time Frame
28 days
Title
>80% Inhibition of FLT3 Phosphorylation in a Majority of Post-treatment Trough Time Points
Description
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick A. Brown, MD
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Donald Small, MD, PhD
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Official's Role
Study Chair
Facility Information:
Facility Name
Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Children's Hospital of Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010-2970
Country
United States
Facility Name
Winship Cancer Institute of Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Children's Memorial Hospital - Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Indiana University Melvin and Bren Simon Cancer Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202-5289
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231-2410
Country
United States
Facility Name
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
C.S. Mott Children's Hospital at University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0286
Country
United States
Facility Name
Masonic Cancer Center at University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
Knight Cancer Institute at Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239-3098
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-9786
Country
United States
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Vanderbilt-Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232-6838
Country
United States
Facility Name
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Baylor University Medical Center - Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-2399
Country
United States
Facility Name
Children's Hospital and Regional Medical Center - Seattle
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Lestaurtinib, Cytarabine, and Idarubicin in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
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