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

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00077558
First received: February 10, 2004
Last updated: March 9, 2010
Last verified: March 2010

February 10, 2004
March 9, 2010
January 2004
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Complete list of historical versions of study NCT00077558 on ClinicalTrials.gov Archive Site
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3-AP Followed By Fludarabine In Treating Patients With Relapsed or Refractory Acute or Chronic Leukemia or High-Risk Myelodysplastic Syndrome
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

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.

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.

Interventional
Phase 1
Primary Purpose: Treatment
  • Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Diseases
  • Drug: fludarabine phosphate
  • Drug: triapine
Not Provided
Karp JE, Giles FJ, Gojo I, Morris L, Greer J, Johnson B, Thein M, Sznol M, Low J. A phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders. Leuk Res. 2008 Jan;32(1):71-7. Epub 2007 Jul 20.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
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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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00077558
CDR0000352322, J0357, U01CA070095, P30CA006973, JHOC-J0357, NCI-6255
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Sidney Kimmel Comprehensive Cancer Center
National Cancer Institute (NCI)
Study Chair: Judith E. Karp, MD Sidney Kimmel Comprehensive Cancer Center
Sidney Kimmel Comprehensive Cancer Center
March 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP