RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. 3-AP may help fludarabine kill more cancer cells by making them more sensitive to the drug.

PURPOSE: Phase I trial to study the effectiveness of 3-AP followed by fludarabine in treating patients who have relapsed or refractory acute leukemia, chronic leukemia, or high-risk myelodysplastic syndrome.

Condition	Treatment or Intervention	Phase
acute leukemia adult acute monoblastic and acute monocytic leukemia atypical chronic myeloid leukemia chronic leukemia myelodysplastic and myeloproliferative disease Prolymphocytic Leukemia	Drug: 3-AP  Drug: fludarabine  Procedure: chemosensitization/potentiation  Procedure: chemotherapy	Phase I

OBJECTIVES:

• Determine the feasibility and tolerability of 3-AP (Triapine^® ) followed by fludarabine in patients with relapsed or refractory acute or chronic leukemia or high-risk myelodysplastic syndromes.
• Determine the toxic effects of this regimen in these patients.
• Determine the maximum tolerated dose of this regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of fludarabine. Patients are stratified according to disease (acute leukemias and myelodysplastic syndromes vs chronic lymphocytic leukemia and prolymphocytic leukemia).

Patients receive 3-AP (Triapine^®) IV over 4 hours and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of fludarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 10 additional patients are treated at that dose level.

PROJECTED ACCRUAL: A total of 3-34 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:
• High-risk myelodysplastic syndromes (MDS), including refractory anemia with excess blasts and chronic myelomonocytic leukemia
• International Prognostic Scoring System (IPSS) score at least 1.5 based on the following:
• More than 10% marrow blasts
• Cytopenias in at least 2 lineages
• Adverse cytogenetics
• Acute myeloid leukemia (AML)
• All subtypes, including MDS/AML and treatment-related (secondary) AML
• Acute lymphoblastic leukemia
• Acute progranulocytic leukemia
• Ineligible for arsenic therapy
• Chronic myelogenous leukemia
• Accelerated phase or blastic crisis
• Chronic lymphocytic leukemia
• Prolymphocytic leukemia
• Received or ineligible for established curative regimens, including stem cell transplantation
• Acute and chronic leukemias must be relapsed and/or refractory with progressive disease since last therapy

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• No history of hemolytic anemia grade 2 or greater
• No known glucose-6-phosphate dehydrogenase (G6PD) deficiency
• G6PD screening required for high-risk groups (i.e., patients of African, Asian, or Mediterranean origin/ancestry)

Hepatic

• SGOT and SGPT no greater than 2.5 times normal
• Bilirubin no greater than 2 mg/dL
• No chronic hepatitis

Renal

• Creatinine normal OR
• Creatinine clearance at least 60 mL/min

Cardiovascular

• No active heart disease
• No myocardial infarction within the past 3 months
• No severe coronary artery disease
• No arrhythmias (other than atrial flutter or fibrillation) requiring medication
• No uncontrolled congestive heart failure

Pulmonary

• No dyspnea at rest or with minimal exertion
• No severe pulmonary disease requiring supplemental oxygen

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No neuropathy grade 2 or greater
• No active uncontrolled infection
• Infections under active treatment and controlled by antibiotics are allowed
• No other life-threatening illness
• No psychiatric illness that would preclude study compliance

PRIOR CONCURRENT THERAPY: Biologic therapy

• See Disease Characteristics
• At least 1 week since prior hematopoietic growth factor (e.g., epoetin alfa, filgrastim [G-CSF], sargramostim [GM-CSF], interleukin-3, and interleukin-11)
• No concurrent immunotherapy

Chemotherapy

• Recovered from prior chemotherapy (no greater than grade 1 chronic toxic effects)
• At least 72 hours since prior hydroxyurea
• At least 3 weeks since prior myelosuppressive cytotoxic agents (6 weeks for mitomycin or nitrosoureas)
• No more than 12 prior courses of fludarabine
• No more than 3 prior cytotoxic chemotherapy regimens
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• At least 2 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery

• Not specified

Other

• At least 1 week since prior non-myelosuppressive treatment
• No more than 4 prior induction regimens
• No other concurrent therapy

Georgia
      Blood and Marrow Transplant Group of Georgia, Atlanta,  Georgia,  30342-4777,  United States; Recruiting
Maryland
      Greenebaum Cancer Center at University of Maryland Medical Center, Baltimore,  Maryland,  21201,  United States; Recruiting
      Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore,  Maryland,  21231,  United States; Recruiting
Texas
      University of Texas - MD Anderson Cancer Center, Houston,  Texas,  77030-4095,  United States; Recruiting

Study chairs or principal investigators

Judith E. Karp, MD,  Study Chair,  Sidney Kimmel Cancer Center   

Study ID Numbers:  CDR0000352322; JHOC-J0357; NCI-6255
Record last reviewed:  September 2004
Record first received:  February 10, 2004
ClinicalTrials.gov Identifier:  NCT00077558
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-10-22