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

NCT00469859 | Completed Phase 1 Results DMC

• 3 other identifiers: AAML06P1CDR0000543398COG-AAML06P1
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 21

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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.

Study Arms (2)

Group 1 (Lestaurtinib dose 50 mg/m2

EXPERIMENTAL

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; Drug: idarubicin; Drug: lestaurtinib

Group 2 (Lestaurtinib: Dose 62.5 mg/m2

EXPERIMENTAL

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; Drug: idarubicin; Drug: lestaurtinib

Interventions

cytarabine DRUG

given IV

Also known as: Cytosine arabinoside, Ara-C, Cytosar, NSC #063878

Group 1 (Lestaurtinib dose 50 mg/m2; Group 2 (Lestaurtinib: Dose 62.5 mg/m2

idarubicin DRUG

Given IV

Also known as: Idarubicin HCl, 4-Demethoxydaunorubicin, 4-DMD, DMDR, IdamycinPFS

Group 1 (Lestaurtinib dose 50 mg/m2; Group 2 (Lestaurtinib: Dose 62.5 mg/m2

lestaurtinib DRUG

Given orally

Also known as: benzodiazocin-1-one, IND#76431

Group 1 (Lestaurtinib dose 50 mg/m2; Group 2 (Lestaurtinib: Dose 62.5 mg/m2

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

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)

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Children's Oncology Group: lead
• National Cancer Institute (NCI): collaborator

Study Sites (21)

Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham

Birmingham, Alabama, 35294, United States

Location

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010-2970, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

Children's Memorial Hospital - Chicago

Chicago, Illinois, 60614, United States

Location

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202-5289, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231-2410, United States

Location

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

C.S. Mott Children's Hospital at University of Michigan Medical Center

Ann Arbor, Michigan, 48109-0286, United States

Location

Masonic Cancer Center at University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis

St Louis, Missouri, 63110, United States

Location

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

New York, New York, 10032, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Knight Cancer Institute at Oregon Health and Science University

Portland, Oregon, 97239-3098, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-9786, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232-6838, United States

Location

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

Dallas, Texas, 75390, United States

Location

Baylor University Medical Center - Houston

Houston, Texas, 77030-2399, United States

Location

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, 98105, United States

Location

MeSH Terms

Conditions

Leukemia; Congenital Abnormalities; Leukemia, Myeloid, Acute

Interventions

Cytarabine; Idarubicin; lestaurtinib

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates

Results Point of Contact

• Title: Results Reporting Coordinator
• Organization: Children's Oncology Group

resultsreportingcoordinator@childrensoncologygroup.org

626-447-0064

Study Officials

• Patrick A. Brown, MD

  Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

  STUDY CHAIR

• Donald Small, MD, PhD

  Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 3, 2007
• First Posted: May 7, 2007
• Study Start: June 1, 2007
• Primary Completion: March 1, 2010
• Study Completion: March 1, 2010
• Last Updated: March 15, 2017
• Results First Posted: December 20, 2013

Record last verified: 2017-02

Locations

US (21)