Clofarabine and Cytarabine in Treating Young Patients With Refractory or Relapsed Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia - Full Text View

Sponsor:	Children's Oncology Group
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00372619

Purpose

RATIONALE: Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

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)

Condition	Intervention	Phase
Leukemia	Drug: clofarabine Drug: cytarabine Drug: methotrexate Other: laboratory biomarker analysis	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment
Official Title:	A Phase I/II Study of CLOLAR® (Clofarabine, IND# 73, 789) in Combination With Cytarabine in Pediatric Patients With Refractory/Relapsed Leukemia

Resource links provided by NLM:

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood

Drug Information available for: Methotrexate Cytarabine hydrochloride Clofarabine Cytarabine

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Maximum tolerated dose of clofarabine in combination with cytarabine (Phase I closed to accrual as of 09/16/09) [ Designated as safety issue: Yes ]
Overall response rate [ Designated as safety issue: No ]

Secondary Outcome Measures:

Safety and tolerability as measured by CTCAE v3.0 [ Designated as safety issue: Yes ]

Estimated Enrollment:	87
Study Start Date:	March 2007
Estimated Primary Completion Date:	November 2010 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

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.

Eligibility

Ages Eligible for Study:	1 Year to 30 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed diagnosis of 1 of the following:
- Acute myeloid leukemia (AML) with ≥ 5% blasts in the bone marrow (M2/M3 bone marrow) with or without extramedullary disease
- Acute lymphoblastic leukemia (ALL) with > 25% blasts in the bone marrow (M3 bone marrow) with or without extramedullary disease
- Acute leukemia of ambiguous lineage with ≥ 5% blasts in the bone marrow (M2/M3 bone marrow) with or without extramedullary disease
Disease must have relapsed after or be refractory to prior induction therapy
- Patients with AML or acute leukemia of ambiguous lineage must be in first relapse OR refractory to first induction therapy with ≤ 1 attempt at remission induction
  - Patients with AML who enroll on the phase I portion of the study must have received prior mitoxantrone hydrochloride and cytarabine for newly diagnosed AML (phase I closed to accrual as of 09/16/09)
- Patients with ALL must be in second or third relapse (≤ 3 prior induction regimens) OR refractory to reinduction in first relapse
  - Patients with ALL refractory to first induction therapy are not eligible
No acute promyelocytic leukemia
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00372619

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Locations

United States, Alabama
UAB Comprehensive Cancer Center
Birmingham, Alabama, United States, 35294
United States, California
Children's Hospital of Orange County
Orange, California, United States, 92868
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202-5289
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
United States, Michigan
C.S. Mott Children's Hospital at University of Michigan Medical Center
Ann Arbor, Michigan, United States, 48109-0286
United States, Minnesota
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, Mississippi
University of Mississippi Cancer Clinic
Jackson, Mississippi, United States, 39216-4505
United States, Missouri
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
St. Louis, Missouri, United States, 63110
United States, New York
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
New York, New York, United States, 10032
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-9786
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232-6838
United States, Texas
Baylor University Medical Center - Houston
Houston, Texas, United States, 77030-2399
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
Dallas, Texas, United States, 75390
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Hopital Sainte Justine
Montreal, Quebec, Canada, H3T 1C5

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

Study Chair:	Bassem I. Razzouk, MD	St. Vincent Indianapolis Hospital
Investigator:	Todd Cooper, DO	University of Alabama at Birmingham

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Children's Oncology Group - Group Chair Office ( Gregory H. Reaman )
Study ID Numbers:	CDR0000494654, COG-AAML0523
Study First Received:	September 6, 2006
Last Updated:	November 4, 2009
ClinicalTrials.gov Identifier:	NCT00372619 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

recurrent childhood acute lymphoblastic leukemia
recurrent childhood acute myeloid leukemia
acute undifferentiated leukemia
adult acute minimally differentiated myeloid leukemia (M0)
childhood acute minimally differentiated myeloid leukemia (M0)
adult acute myeloblastic leukemia without maturation (M1)
childhood acute myeloblastic leukemia without maturation (M1)
adult acute myeloblastic leukemia with maturation (M2)
childhood acute myeloblastic leukemia with maturation (M2)
adult acute myelomonocytic leukemia (M4)
childhood acute myelomonocytic leukemia (M4)

adult acute monoblastic leukemia (M5a)
childhood acute monoblastic leukemia (M5a)
adult acute monocytic leukemia (M5b)
childhood acute monocytic leukemia (M5b)
adult erythroleukemia (M6a)
adult pure erythroid leukemia (M6b)
childhood acute erythroleukemia (M6)
adult acute megakaryoblastic leukemia (M7)
childhood acute megakaryocytic leukemia (M7)
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Leukemia, Lymphoid
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Reproductive Control Agents
Leukemia, Myeloid, Acute
Leukemia
Therapeutic Uses
Abortifacient Agents
Methotrexate
Dermatologic Agents

Nucleic Acid Synthesis Inhibitors
Cytarabine
Clofarabine
Immunoproliferative Disorders
Neoplasms by Histologic Type
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Enzyme Inhibitors
Leukemia, Myeloid
Folic Acid Antagonists
Abortifacient Agents, Nonsteroidal
Antiviral Agents
Immunosuppressive Agents
Pharmacologic Actions
Lymphatic Diseases

ClinicalTrials.gov processed this record on November 25, 2009