3-AP Followed By Fludarabine In Treating Patients With Relapsed or Refractory Acute or Chronic Leukemia or High-Risk Myelodysplastic Syndrome

Study Overview
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Brief Summary
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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: This phase I trial is studying the side effects and best dose of fludarabine when given together with 3-AP in treating patients with relapsed or refractory acute leukemia, chronic leukemia, or high-risk myelodysplastic syndrome.

Detailed Description
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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 [MDS] vs chronic lymphocytic leukemia and prolymphocytic leukemia). Patients are assigned to 1 of 2 treatment groups. Group 1 (chronic lymphocytic leukemia or prolymphocytic leukemia): Patients receive 3-AP (Triapine^®) IV over 4 hours and fludarabine IV over 30 minutes on days 1-5. 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. Group 2 (acute leukemias or MDS): Patients receive 3-AP IV continuously over 24 hours on day 1. Beginning within 4 hours after completion of 3-AP, patients receive fludarabine IV over 30 minutes on days 2-6. In both groups, treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 3-34 patients will be accrued for this study.

Official Title
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A Phase I Trial Of Sequential Administration Of Triapine (3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone) Followed By Fludarabine In Adults With Relapsed And Refractory Leukemias And Myelodysplasias

Conditions
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Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Drug: fludarabine phosphate
* Drug: triapine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: fludarabine phosphate|nan|
|Drug: triapine|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, refractory chronic lymphocytic leukemia, recurrent adult acute lymphoblastic leukemia, prolymphocytic leukemia, refractory anemia with excess blasts, chronic myelomonocytic leukemia, recurrent adult acute myeloid leukemia, secondary acute myeloid leukemia, adult acute minimally differentiated myeloid leukemia (M0), adult acute monocytic leukemia (M5b), adult acute erythroid leukemia (M6), adult acute megakaryoblastic leukemia (M7), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute promyelocytic leukemia (M3), adult acute eosinophilic leukemia, adult acute basophilic leukemia, atypical chronic myeloid leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12)