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

NCT ID: NCT00469859

Last Updated: 2017-03-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-06-30
• Study Completion Date: 2010-03-31

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.

Conditions

Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group 1 (Lestaurtinib dose 50 mg/m2

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)

Group Type: EXPERIMENTAL

cytarabine

Intervention Type: DRUG

given IV

idarubicin

Intervention Type: DRUG

Given IV

lestaurtinib

Intervention Type: DRUG

Given orally

Group 2 (Lestaurtinib: Dose 62.5 mg/m2

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)

Group Type: EXPERIMENTAL

cytarabine

Intervention Type: DRUG

given IV

idarubicin

Intervention Type: DRUG

Given IV

lestaurtinib

Intervention Type: DRUG

Given orally

Interventions

cytarabine

given IV

Intervention Type: DRUG

idarubicin

Given IV

Intervention Type: DRUG

lestaurtinib

Given orally

Intervention Type: DRUG

Other Intervention Names

Cytosine arabinoside; Ara-C; Cytosar; NSC #063878; Idarubicin HCl; 4-Demethoxydaunorubicin; 4-DMD; DMDR; IdamycinPFS; benzodiazocin-1-one; IND#76431

Eligibility Criteria

Inclusion Criteria

• 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)

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Children's Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patrick A. Brown, MD

Role: STUDY_CHAIR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Donald Small, MD, PhD

Role: STUDY_CHAIR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

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

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis

St Louis, Missouri, United States

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

New York, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Knight Cancer Institute at Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas

Dallas, Texas, United States

Baylor University Medical Center - Houston

Houston, Texas, United States

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, United States

Countries

United States

Other Identifiers

CDR0000543398

Identifier Type: OTHER

Identifier Source: secondary_id

COG-AAML06P1

Identifier Type: OTHER

Identifier Source: secondary_id

AAML06P1

Identifier Type: -

Identifier Source: org_study_id