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
18 Years
N/A
Both
Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases
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
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.
Inclusion 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
Type of Study:
Interventional
Study Design:
Primary Purpose: Treatment
Principal Investigator
Judith E. Karp, MD
Investigator Role:
Study Chair
Investigator Affiliation:
Sidney Kimmel Comprehensive Cancer Center
Authority:
United States: Federal Government
Study ID:
CDR0000352322, J0357
NCT ID:
NCT00077558
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
Name | Location |
|---|---|
| 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 |
