RATIONALE: Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth.

PURPOSE: Phase I trial to study the effectiveness of bortezomib in treating young patients who have refractory or recurrent leukemia.

Condition	Treatment or Intervention	Phase
recurrent childhood acute lymphoblastic leukemia childhood chronic myelogenous leukemia recurrent childhood acute myeloid leukemia blastic phase chronic myelogenous leukemia childhood acute promyelocytic leukemia (M3)	Drug: bortezomib  Procedure: enzyme inhibitor therapy	Phase I

OBJECTIVES: Primary

• Determine the maximum tolerated dose and recommended phase II dose of bortezomib in children with refractory or recurrent leukemia.
• Determine the toxic effects of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.

Secondary

• Determine, preliminarily, the antitumor activity of this drug in these patients.
• Determine, preliminarily, the biologic activity of this drug in these patients.

OUTLINE: This is a dose-escalation, open-label, multicenter study.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study within 1.5-36 months.

Ages Eligible for Study:  1 Year   -   21 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed leukemia of 1 of the following types:
• Acute lymphoblastic leukemia
• Acute myeloid leukemia
• Chronic myelogenous leukemia in blast crisis
• Relapsed or refractory disease
• Immunophenotypically confirmed disease, either at initial diagnosis or relapse
• More than 25% blasts in the bone marrow (M3 bone marrow)
• Active extramedullary disease (except leptomeningeal disease) allowed
• No known curative therapy or therapy proven to prolong survival with an acceptable quality of life available

PATIENT CHARACTERISTICS: Age

• 1 to 21

Performance status

• Karnofsky 50-100% (for patients age 11 to 21) OR
• Lansky 50-100% (for patients age 10 and under)

Life expectancy

• Not specified

Hematopoietic

• Platelet count ≥ 20,000/mm^3*
• Hemoglobin ≥ 8.0 g/dL*
• WBC < 20,000/mm^3** (hydroxyurea for cytoreduction allowed)
• No hyperleukocytosis (i.e., WBC > 100,000/mm^3) NOTE: *Transfusion allowed

NOTE: **An exception may be made at the discretion of the investigator

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 5 times ULN
• Albumin ≥ 2 g/dL

Renal

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR
• Creatinine based on age as follows:
• ≤ 0.8 mg/dL for patients age 5 and under
• ≤ 1.0 mg/dL for patients age 6 to 10
• ≤ 1.2 mg/dL for patients age 11 to 15
• ≤ 1.5 mg/dL for patients age 16 to 21

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infection

PRIOR CONCURRENT THERAPY: Biologic therapy

• Recovered from prior immunotherapy
• At least 7 days since prior filgrastim (G-CSF) or sargramostim (GM-CSF)
• At least 7 days since prior biologic agents
• At least 3 months since prior stem cell transplantation or rescue and no evidence of active graft-versus-host disease
• No concurrent prophylactic G-CSF during course 1 of study
• No concurrent immunotherapy
• No concurrent biologic therapy

Chemotherapy

• Recovered from prior chemotherapy
• At least 24 hours since prior hydroxyurea for cytoreduction
• At least 6 weeks since prior nitrosoureas
• No concurrent chemotherapy

Endocrine therapy

• At least 7 days since prior steroids

Radiotherapy

• Recovered from prior radiotherapy
• At least 2 weeks since prior small port local palliative radiotherapy
• At least 3 months since prior total body irradiation, craniospinal irradiation, or irradiation to more than 50% of the pelvis
• At least 6 weeks since other prior substantial bone marrow radiotherapy
• No concurrent radiotherapy

Surgery

• Not specified

Other

• At least 7 days since prior retinoids
• No other concurrent investigational agents
• No other concurrent anticancer agents
• No concurrent anticonvulsant medications known to activate the cytochrome p450 system (e.g., phenytoin, carbamazepine, or phenobarbital)
• Concurrent benzodiazepines and gabapentin are allowed

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States; Recruiting
      Lucile Packard Children's Hospital at Stanford University Medical Center, Palo Alto,  California,  94304,  United States; Recruiting
District of Columbia
      Children's National Medical Center, Washington,  District of Columbia,  20010-2970,  United States; Recruiting
Indiana
      Riley Children Cancer Center at Riley Hospital for Children, Indianapolis,  Indiana,  46202-5225,  United States; Recruiting
Maryland
      Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda,  Maryland,  20892-1182,  United States; Recruiting
Massachusetts
      Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston,  Massachusetts,  02115,  United States; Recruiting
Minnesota
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States; Recruiting
Mississippi
      University of Mississippi Medical Center, Jackson,  Mississippi,  39216-4505,  United States; Recruiting
New York
      Herbert Irving Comprehensive Cancer Center at Columbia University, New York,  New York,  10032,  United States; Recruiting
      SUNY Downstate Medical Center, Brooklyn,  New York,  11203,  United States; Recruiting
Ohio
      Cincinnati Children's Hospital Medical Center, Cincinnati,  Ohio,  45229-3039,  United States; Recruiting
Oregon
      Doernbecher Children's Hospital at Oregon Health & Science University, Portland,  Oregon,  97239-3098,  United States; Recruiting
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States; Recruiting
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213-2583,  United States; Recruiting
Tennessee
      St. Jude Children's Research Hospital, Memphis,  Tennessee,  38105-2794,  United States; Recruiting
Texas
      MBCCOP - South Texas Pediatrics, San Antonio,  Texas,  78229-3900,  United States; Recruiting
      Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas,  Texas,  75390-9063,  United States; Recruiting
      Texas Children's Cancer Center, Houston,  Texas,  77030-2399,  United States; Recruiting
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States; Recruiting
Canada, Ontario
      Hospital for Sick Children, Toronto,  Ontario,  M5G 1X8,  Canada; Recruiting
Canada, Quebec
      Hopital Sainte Justine, Montreal,  Quebec,  H3T 1C5,  Canada; Recruiting

Study chairs or principal investigators

Terzah Marie Horton, MD, PhD,  Study Chair,  Texas Children's Cancer Center   
Lisa Bomgaars, MD,  Texas Children's Cancer Center   

Study ID Numbers:  CDR0000350340; COG-ADVL0317
Record last reviewed:  August 2004
Record first received:  February 10, 2004
ClinicalTrials.gov Identifier:  NCT00077467
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-10-29