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

Sponsor:	Sidney Kimmel Comprehensive Cancer Center
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00077558

Purpose

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.

Condition	Intervention	Phase
Leukemia Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases	Drug: fludarabine phosphate Drug: triapine	Phase I

Study Type:	Interventional
Study Design:	Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic

Drug Information available for: Fludarabine Fludarabine monophosphate 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Study Start Date:

January 2004

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00077558

Locations

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

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center

National Cancer Institute (NCI)

Investigators

Study Chair:

Judith E. Karp, MD

Sidney Kimmel Comprehensive Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

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.

Study ID Numbers:	CDR0000352322, JHOC-J0357, NCI-6255
Study First Received:	February 10, 2004
Last Updated:	July 23, 2008
ClinicalTrials.gov Identifier:	NCT00077558 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

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)

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Vidarabine
Antimetabolites, Antineoplastic
Precancerous Conditions
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Leukemia
Preleukemia
Pathologic Processes
Syndrome
Therapeutic Uses

Disease
Neoplasms by Histologic Type
Hematologic Diseases
Myelodysplastic Syndromes
Myeloproliferative Disorders
Fludarabine monophosphate
Antiviral Agents
Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Fludarabine
Bone Marrow Diseases
Myelodysplastic-Myeloproliferative Diseases

ClinicalTrials.gov processed this record on November 27, 2009