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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

Phase 1
18 Years
Not Enrolling
Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

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Trial Information

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


- 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.

Inclusion Criteria


- 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

- Acute and chronic leukemias must be relapsed and/or refractory with progressive
disease since last therapy



- 18 and over

Performance status

- ECOG 0-2

Life expectancy

- Not specified


- 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)


- SGOT and SGPT no greater than 2.5 times normal

- Bilirubin no greater than 2 mg/dL

- No chronic hepatitis


- Creatinine normal OR

- Creatinine clearance at least 60 mL/min


- 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


- No dyspnea at rest or with minimal exertion

- No severe pulmonary disease requiring supplemental oxygen


- 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


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


- 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


- At least 2 weeks since prior radiotherapy

- No concurrent radiotherapy


- Not specified


- At least 1 week since prior non-myelosuppressive treatment

- No more than 4 prior induction regimens

- No other concurrent therapy

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

Judith E. Karp, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center


United States: Federal Government

Study ID:

CDR0000352322, J0357



Start Date:

January 2004

Completion Date:

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Diseases
  • 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)
  • Leukemia
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases



Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231-2410
M.D. Anderson Cancer Center at University of Texas Houston, Texas  77030
Greenebaum Cancer Center at University of Maryland Medical Center Baltimore, Maryland  21201
Blood and Marrow Transplant Group of Georgia Atlanta, Georgia  30342-1601