Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	18 and over	NCI	JHOC-J0357 NCI-6255, NCT00077558, 6255

Objectives

1. 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.
2. Determine the toxic effects of this regimen in these patients.
3. Determine the maximum tolerated dose of this regimen in these patients.

Entry 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

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

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

Expected Enrollment

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

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.

Karp JE, Giles FJ, Gojo I, et al.: 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 32 (1): 71-7, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Judith Karp, MD, Protocol chair		Ph: 410-502-7726

Registry Information
Official Title		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
Trial Start Date		2004-01-06
Registered in ClinicalTrials.gov		NCT00077558
Date Submitted to PDQ		2004-01-07
Information Last Verified		2005-11-07
NCI Grant/Contract Number		U01-CA70095, P30-CA06973

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