Clofarabine and Cytarabine in Treating Young Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia
NCT ID: NCT00372619
Last Updated: 2017-06-05
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
74 participants
INTERVENTIONAL
2007-03-31
2012-08-31
Brief Summary
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PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when given together with cytarabine and to see how well they work in treating young patients with refractory or relapsed acute myeloid leukemia or acute lymphoblastic leukemia. (Phase I closed to enrollment as of 09/16/09)
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Detailed Description
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Primary
* To define the overall response rate (complete remission or remission without platelet recovery) in young patients with relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) treated with clofarabine in combination with cytarabine.
Secondary
* To determine the safety profile and tolerability of clofarabine when given in combination with cytarabine in patients with and without prior stem cell transplantation.
* To identify apoptosis specific genes that are important in mediating response to clofarabine and cytarabine.
* To quantitate the level of human equilibrative nucleoside transporter proteins (hENT1 and hENT2) and human concentrative nucleoside transporter proteins (hCNT2 and hCNT3) in blasts of these patients.
* To determine gene expression profiles at study entry and at time of relapse in order to isolate profiles that may predict response and also to complement apoptosis specific protein arrays.
* To perform serial measurements of minimal residual disease (MRD) to provide an objective determination of the effectiveness of this treatment regimen and to correlate with post remission events (relapse, death).
* To perform FLT3/ITD analysis to help determine the prevalence and clinical significance of this somatic mutation in patients with relapsed AML.
OUTLINE: This is a multicenter, phase I, dose-escalation study of clofarabine followed by a phase II study. Patients are stratified according to disease (acute lymphoblastic leukemia \[ALL\] vs acute myeloid leukemia \[AML\]). (Phase I closed to accrual as of 09/16/09)
* Intrathecal CNS prophylaxis (all patients with ALL and at physician's discretion for patients with AML or acute leukemia of ambiguous lineage): Patients receive intrathecal (IT) cytarabine on day 0 of the first course of induction therapy. Patients also receive IT methotrexate on day 1 of the second course of induction therapy and on day 1 of all courses of maintenance therapy.
* Induction therapy:
* Course 1: Patients receive cytarabine IV over 2 hours and clofarabine IV over 2 hours on days 1-5. Patients with ≥ 5% blasts (i.e., M2 or M3 bone marrow) at days 14-21 proceed immediately to course 2 of induction therapy. Patients with \< 5% blasts (i.e., M1 bone marrow) may proceed to course 2 of induction therapy at blood count recovery or at day 42.
* Course 2: Patients receive clofarabine IV over 2 hours followed by cytarabine IV over 2 hours on days 1-5. After the second course of induction therapy, patients with M2 or M3 bone marrow at days 14-21 are removed from the study. Patients with M1 bone marrow proceed to maintenance therapy 14-42 days after the initiation of course 2.
* Maintenance therapy: Patients receive clofarabine and cytarabine as in induction therapy. Treatment repeats every 14-42 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.
Patients may undergo blood and bone marrow sample collection periodically for correlative laboratory studies.
After completion of study therapy, patients are followed periodically for up to 5 years.
PROJECTED ACCRUAL: A total of 87 patients will be accrued for this study.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Clofarabine 40 mg/m² to assess feasibility in ALL patients.
Clofarabine 40 mg/m² to assess feasibility in ALL patients. Patients receive Cycle 1 (14-42 days) Cytarabine IT (aged based dosage 1-1.99 30 mg, 2-2.99 50 mg, ≥ 3 years 70 mg on Day 0, Clofarabine IV (dosage 40 mg/m2/dose) on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Cycle 2 (14-42 days) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 40 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Maintenance cycles 1-10 (14-42 days each) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 40 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5.
clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Clofarabine 40 mg/m² to assess feasibility in AML patients.
Clofarabine 40 mg/m² to assess feasibility in AML patients. Patients receive Cycle 1 (14-42 days) Cytarabine IT (aged based dosage 1-1.99 30 mg, 2-2.99 50 mg, ≥ 3 years 70 mg on Day 0, Clofarabine IV (dosage 40 mg/m2/dose) on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Cycle 2 (14-42 days) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 40 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Maintenance cycles 1-10 (14-42 days each) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 40 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5.
clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Clofarabine 52 mg/m² to assess feasibility in ALL patients.
Clofarabine 52 mg/m² to assess feasibility in ALL patients. Patients receive Cycle 1 (14-42 days) Cytarabine IT (aged based dosage 1-1.99 30 mg, 2-2.99 50 mg, ≥ 3 years 70 mg on Day 0, Clofarabine IV (dosage 52 mg/m2/dose) on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Cycle 2 (14-42 days) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Maintenance cycles 1-10 (14-42 days each) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5.
clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Clofarabine 52 mg/m² to assess efficacy in ALL patients.
Clofarabine 52 mg/m² to assess efficacy in ALL patients. Patients receive Cycle 1 (14-42 days) Cytarabine IT (aged based dosage 1-1.99 30 mg, 2-2.99 50 mg, ≥ 3 years 70 mg on Day 0, Clofarabine IV (dosage 52 mg/m2/dose) on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Cycle 2 (14-42 days) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Maintenance cycles 1-10 (14-42 days each) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5.
clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Clofarabine 52 mg/m² to assess feasibility in AML patients.
Clofarabine 52 mg/m² to assess feasibility in AML patients. Patients receive Cycle 1 (14-42 days) Cytarabine IT (aged based dosage 1-1.99 30 mg, 2-2.99 50 mg, ≥ 3 years 70 mg on Day 0, Clofarabine IV (dosage 52 mg/m2/dose) on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Cycle 2 (14-42 days) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Maintenance cycles 1-10 (14-42 days each) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5.
clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Clofarabine 52 mg/m² to assess efficacy in AML patients
Clofarabine 52 mg/m² to assess efficacy in AML patients. Patients receive Cycle 1 (14-42 days) Cytarabine IT (aged based dosage 1-1.99 30 mg, 2-2.99 50 mg, ≥ 3 years 70 mg on Day 0, Clofarabine IV (dosage 52 mg/m2/dose) on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Cycle 2 (14-42 days) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Maintenance cycles 1-10 (14-42 days each) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5.
clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Clofarabine 52 mg/m² to assess efficacy - ambiguous lineage pt
Clofarabine 52 mg/m² to assess efficacy in acute leukemia of ambiguous lineage patients. Patients receive Cycle 1 (14-42 days) Cytarabine IT (aged based dosage 1-1.99 30 mg, 2-2.99 50 mg, ≥ 3 years 70 mg on Day 0, Clofarabine IV (dosage 52 mg/m2/dose) on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Cycle 2 (14-42 days) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5. Maintenance cycles 1-10 (14-42 days each) Methotrexate IT (age based dosage 1-1.99 8 mg, 2-2.99 10 mg, ≥ 3 12 mg) on day 1, Clofarabine IV 52 mg/m2/dose on days 1-5, and High Dose Cytarabine IV 1000 mg/m2/dose on days 1-5.
clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Interventions
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clofarabine
Given IV for 5 days
cytarabine
Given IV
methotrexate
Given intrathecally or IT age based dosage
laboratory biomarker analysis
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* No CNS 3 involvement (i.e., WBC ≥ 5/μL in the cerebrospinal fluid with blasts present on cytospin)
PATIENT CHARACTERISTICS:
* Karnofsky performance status (PS) 50-100% (\> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age) OR ECOG PS 0-2
* Life expectancy ≥ 8 weeks
* Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min
* Direct bilirubin ≤ 1.5 times upper limit of normal (ULN)
* ALT \< 2.5 times ULN (unless it is related to leukemic involvement)
* Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 45% by gated radionuclide study
* No evidence of dyspnea at rest or exercise intolerance
* Pulse oximetry \> 94% at room air
* Amylase ≤ 1.5 times ULN
* Lipase \< 1.5 times ULN
* No active, uncontrolled grade 3 or 4 infection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for ≥ 3 months after completion of study treatment
* No known hepatitis B or C infection or history of cirrhosis
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* Recovered from all prior therapy\*
* At least 14 days since prior cytotoxic therapy (except hydroxyurea and intrathecal chemotherapy)\*
* At least 7 days since prior biologic agent\*
* At least 14 days since prior monoclonal antibody therapy\*
* No more than 1 prior autologous or allogeneic hematopoietic stem cell transplantation
* No evidence of active graft-vs-host disease
* At least 4 months since transplantation
* No other concurrent chemotherapy or immunomodulating agents
* No other concurrent investigational therapy NOTE: \*Patients who relapse during ALL maintenance therapy do not require a waiting period.
1 Year
30 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
Children's Oncology Group
NETWORK
Responsible Party
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Principal Investigators
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Bassem I. Razzouk, MD
Role: STUDY_CHAIR
St. Vincent Indianapolis Hospital
Todd Cooper, DO
Role: STUDY_CHAIR
University of Alabama at Birmingham
Locations
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UAB Comprehensive Cancer Center
Birmingham, Alabama, United States
Southern California Permanente Medical Group
Downey, California, United States
Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
Long Beach, California, United States
Children's Hospital Central California
Madera, California, United States
Children's Hospital of Orange County
Orange, California, United States
Rady Children's Hospital - San Diego
San Diego, California, United States
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States
Children's Hospital Colorado Center for Cancer and Blood Disorders
Aurora, Colorado, United States
Alfred I. duPont Hospital for Children
Wilmington, Delaware, United States
Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
Washington D.C., District of Columbia, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Lee Cancer Care of Lee Memorial Health System
Fort Myers, Florida, United States
Nemours Children's Clinic
Jacksonville, Florida, United States
Nemours Children's Clinic - Orlando
Orlando, Florida, United States
Nemours Children's Clinic - Pensacola
Pensacola, Florida, United States
St. Joseph's Cancer Institute at St. Joseph's Hospital
Tampa, Florida, United States
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
Atlanta, Georgia, United States
Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
Savannah, Georgia, United States
Cancer Research Center of Hawaii
Honolulu, Hawaii, United States
University of Illinois Cancer Center
Chicago, Illinois, United States
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States
Simmons Cooper Cancer Institute
Springfield, Illinois, United States
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States
St. Vincent Indianapolis Hospital
Indianapolis, Indiana, United States
Kosair Children's Hospital
Louisville, Kentucky, United States
Tulane Cancer Center Office of Clinical Research
Alexandria, Louisiana, United States
CancerCare of Maine at Eastern Maine Medical Center
Bangor, Maine, United States
Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
Baltimore, Maryland, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
UMASS Memorial Cancer Center - University Campus
Worcester, Massachusetts, United States
C.S. Mott Children's Hospital at University of Michigan Medical Center
Ann Arbor, Michigan, United States
Helen DeVos Children's Hospital at Spectrum Health
Grand Rapids, Michigan, United States
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States
Mayo Clinic Cancer Center
Rochester, Minnesota, United States
University of Mississippi Cancer Clinic
Jackson, Mississippi, United States
Ellis Fischel Cancer Center at University of Missouri - Columbia
Columbia, Missouri, United States
Children's Mercy Hospital
Kansas City, Missouri, United States
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
St Louis, Missouri, United States
CCOP - Nevada Cancer Research Foundation
Las Vegas, Nevada, United States
Hackensack University Medical Center Cancer Center
Hackensack, New Jersey, United States
Overlook Hospital
Morristown, New Jersey, United States
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
New Brunswick, New Jersey, United States
Newark Beth Israel Medical Center
Newark, New Jersey, United States
St. Joseph's Hospital and Medical Center
Paterson, New Jersey, United States
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
New York, New York, United States
James P. Wilmot Cancer Center at University of Rochester Medical Center
Rochester, New York, United States
SUNY Upstate Medical University Hospital
Syracuse, New York, United States
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States
Blumenthal Cancer Center at Carolinas Medical Center
Charlotte, North Carolina, United States
Presbyterian Cancer Center at Presbyterian Hospital
Charlotte, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States
Cleveland Clinic Taussig Cancer Center
Cleveland, Ohio, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Dayton Children's - Dayton
Dayton, Ohio, United States
Legacy Emanuel Hospital and Health Center and Children's Hospital
Portland, Oregon, United States
Penn State Children's Hospital
Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
Palmetto Health South Carolina Cancer Center
Columbia, South Carolina, United States
Greenville Hospital Cancer Center
Greenville, South Carolina, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Driscoll Children's Hospital
Corpus Christi, Texas, United States
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
Dallas, Texas, United States
Cook Children's Medical Center - Fort Worth
Fort Worth, Texas, United States
Baylor University Medical Center - Houston
Houston, Texas, United States
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States
Primary Children's Medical Center
Salt Lake City, Utah, United States
Children's Hospital of The King's Daughters
Norfolk, Virginia, United States
Carilion Medical Center for Children at Roanoke Community Hospital
Roanoke, Virginia, United States
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States
Providence Cancer Center at Sacred Heart Medical Center
Spokane, Washington, United States
Marshfield Clinic - Marshfield Center
Marshfield, Wisconsin, United States
Midwest Children's Cancer Center at Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States
CancerCare Manitoba
Winnipeg, Manitoba, Canada
IWK Health Centre
Halifax, Nova Scotia, Canada
Hospital for Sick Children
Toronto, Ontario, Canada
Hopital Sainte Justine
Montreal, Quebec, Canada
Allan Blair Cancer Centre at Pasqua Hospital
Regina, Saskatchewan, Canada
Countries
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Other Identifiers
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CDR0000494654
Identifier Type: OTHER
Identifier Source: secondary_id
NCI-2009-00319
Identifier Type: OTHER
Identifier Source: secondary_id
COG-AAML0523
Identifier Type: OTHER
Identifier Source: secondary_id
AAML0523
Identifier Type: -
Identifier Source: org_study_id
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