RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. PURPOSE: Phase II trial to study the effectiveness of 506U78 in treating patients with chronic lymphocytic leukemia that has not responded to fludarabine or alkylating agents.

Condition	Treatment or Intervention	Phase
refractory chronic lymphocytic leukemia T-cell chronic lymphocytic leukemia B-cell Chronic Lymphocytic Leukemia	Drug: U78	Phase II

OBJECTIVES: I. Estimate the anticancer efficacy of 506U78 in patients with chronic lymphocytic leukemia who are refractory to fludarabine and alkylator therapy. II. Define the safety (including incidence of infection) of 506U78 in these patients. III. Evaluate the pharmacokinetics of 506U78 and ara-G, and assess the intracellular pharmacokinetics of ara-GTP in patients receiving multiple treatment courses (at M.D. Anderson Cancer Center only). IV. Determine the response rate, time to maximal response, and duration of response of patients treated with this drug. V. Determine two-year survival rate and progression-free survival of patients treated with this drug.

PROTOCOL OUTLINE: This is an open-label, multicenter study. Patients are stratified according to cellular type of disease (B-CLL vs T-CLL). Patients receive 506U78 IV over 2 hours on days 1, 3, and 5. Courses are repeated every 28 days. Treatment continues for a maximum of 8 courses in the absence of disease progression or unacceptable toxicity. Patients are followed at 28 days after the final course and then every 2 months for 2 years until disease progression. Patients with progressive disease are followed for survival every 3 months for 2 years or until death.

PROJECTED ACCRUAL: Approximately 14-100 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically proven refractory B-cell or T-cell chronic lymphocytic leukemia; Evidence of active disease following fludarabine or alkylator therapy
• Must meet one or more of the following criteria for active disease: Minimum of one of the following disease-related symptoms: Weight loss of more than 10% within the previous 6 months; Extreme fatigue (e.g., unable to work or perform usual activities); Fevers greater than 100.5 degrees F for 2 weeks or more without evidence of infection; Night sweats without evidence of infection; Evidence of progressive marrow failure manifested by the development of, or worsening of autoimmune anemia and /or thrombocytopenia that is poorly responsive to corticosteroid therapy; Massive nodes or clusters (e.g., greater than 10 cm in longest diameter) or progressive lymphadenopathy; Progressive lymphocytosis with an increase of greater than 50% over a 2-month period or an anticipated doubling time of less than 6 months
• Ineligible if marked hypogammaglobulinemia or development of monoclonal protein in the absence of the above criteria for active disease
• Must have one of the following resulting from prior fludarabine or alkylator-containing therapy: Disease progression during therapy OR Failure to respond or obtained less than a partial response to therapy OR Disease progression within 6 months of the last course of therapy following and initial response; Failure to respond or disease progression allowed at any time following the final course if alkylator agent was not the most recent therapy
• Must have adequate hepatic and renal function; No liver dysfunction due to organ infiltration by lymphocytes

--Prior/Concurrent Therapy--

• Biologic therapy: No prior bone marrow or peripheral stem cell transplantation; At least 4 weeks since prior biologic therapy and recovered Concurrent growth factors allowed
• Chemotherapy: At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) and recovered; No prior 506U78 therapy; No other concurrent chemotherapy
• Endocrine therapy: No concurrent corticosteroid therapy greater than 10 mg/day of prednisone equivalent; No concurrent corticosteroids as antiemetics; Concurrent hormone replacement therapy or oral contraceptives allowed; Concurrent hydrocortisone as prophylaxis or treatment of transfusion reactions allowed
• Radiotherapy: At least 4 weeks since prior radiotherapy and recovered; No concurrent radiotherapy
• Surgery: Not specified
• Other: No other concurrent anticancer agents

--Patient Characteristics--

• Age: 18 and over
• Performance status: Karnofsky 60-100%
• Life expectancy: At least 12 weeks
• Hematopoietic: Not specified
• Hepatic: Bilirubin no greater than 2 times upper limit of normal
• Renal: Creatinine clearance at least 50 mL/min
• Neurologic: No neurotoxicity of grade 2 or higher Other: Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception during and for up to 28 days after study; No history of seizure disorder; No active infection; No other malignancy within the past 2 years (except adequately treated non- melanomatous skin cancer or carcinoma in situ) that would preclude study; No systemic nonmalignant comorbid disease that would preclude study; No psychological, sociological, or geographical condition that would preclude study

Alabama
      University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham,  Alabama,  35294-3300,  United States
Arizona
      Arizona Cancer Center, Tucson,  Arizona,  85724,  United States
Arkansas
      University of Arkansas for Medical Sciences, Little Rock,  Arkansas,  72205,  United States
California
      Cedars-Sinai Medical Center, Los Angeles,  California,  90048,  United States
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States
      Scripps Clinic, La Jolla,  California,  92037,  United States
      Sidney Kimmel Cancer Center, San Diego,  California,  92121,  United States
Colorado
      Clinical Studies, Ltd., Denver,  Colorado,  80222,  United States
District of Columbia
      Lombardi Cancer Center, Washington,  District of Columbia,  20007,  United States
      Walter Reed Army Medical Center, Washington,  District of Columbia,  20307-5000,  United States
Illinois
      Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago,  Illinois,  60611-3013,  United States
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637-1470,  United States
Iowa
      Holden Comprehensive Cancer Center at The University of Iowa, Iowa City,  Iowa,  52242-1009,  United States
Maryland
      Johns Hopkins Oncology Center, Baltimore,  Maryland,  21231-2410,  United States
      Medicine Branch, Bethesda,  Maryland,  20892,  United States
Missouri
      Washington University School of Medicine, Saint Louis,  Missouri,  63110,  United States
New Jersey
      St. Joseph's Hospital and Medical Center, Paterson,  New Jersey,  07503,  United States
New York
      Long Island Jewish Medical Center, New Hyde Park,  New York,  11040,  United States
Ohio
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States
South Carolina
      Greenville Hospital System, Greenville,  South Carolina,  29605,  United States
Texas
      Physician Reliance Network, Inc., Dallas,  Texas,  75246,  United States
      University of Texas - MD Anderson Cancer Center, Houston,  Texas,  77030-4009,  United States

Study chairs or principal investigators

Tonya M. Peele,  Study Chair,  GlaxoSmithKline   

Study ID Numbers:  CDR0000066719; GW-PGAA2003; CWRU-GLAX-1999; MB-405; NCI-98-C-0164; UCLA-991004701A
Record last reviewed:  March 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00003635
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-16