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3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia

Primary Purpose

Accelerated Phase Chronic Myelogenous Leukemia, Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Blastic Phase Chronic Myelogenous Leukemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
fludarabine phosphate
triapine
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Accelerated Phase Chronic Myelogenous Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Criteria:

  • Not pregnant or nursing

  • Histopathologically confirmed diagnosis of 1 of the following:

    • Myeloproliferative disorders (MPDs) in aggressive phase or transformation
    • CML in accelerated phase or blast crisis
    • Chronic myelomonocytic leukemia in aggressive phase (5-19% bone marrow blasts) or transformation (> 20% bone marrow blasts)

  • Myeloproliferative disorders (MPDs) in aggressive phase or transformation, including the following:

    • Polycythemia vera (PV)
    • Essential thrombocythemia (ET)
    • Myelofibrosis with myeloid metaplasia
    • Hypereosinophilic syndrome
    • Atypical (Philadelphia chromosome negative) chronic myelogenous leukemia (Ph- CML)

  • Patients with aggressive phase MPD (PV, ET, or Ph- CML) must meet ≥ 1 of the following criteria:

    • Marrow blasts > 5%
    • Peripheral blood blasts plus progranulocytes > 10%
    • New onset or increasing myelofibrosis
    • New onset or > 25% increase in hepatomegaly or splenomegaly
    • New onset constitutional symptoms (fever, weight loss, splenic pain, bone pain)
  • Multilineage bone marrow failure
  • Ineligible for established curative regimens, including stem cell transplantation
  • ECOG performance status 0-2
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No chronic toxicity from prior chemotherapy > grade 1
  • No history of severe coronary artery disease
  • Creatinine normal OR creatinine clearance >= 60 mL/min
  • AST and ALT =< 2.5 times normal
  • Bilirubin =< 2.0 mg/dL unless due to leukemia, Gilbert's syndrome, or hemolysis
  • 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
  • No history of allergic reactions attributed to compounds of similar chemical or biological composition to 3-AP (Triapine®) and/or fludarabine phosphate
  • No other life-threatening illness
  • No history of mental deficits and/or psychiatric illness that would preclude study compliance
  • No more than 4 prior induction regimens (3 cytotoxic chemotherapy regimens)
  • At least 3 weeks since prior myelosuppressive cytotoxic agents (6 weeks for mitomycin C or nitrosoureas) and recovered
  • At least 1 week since prior nonmyelosuppressive treatment

  • At least 48 hours since prior noncytotoxic agents for peripheral blood leukemic cell count control, including but not limited to the following:

    • Hydroxyurea
    • Imatinib mesylate
    • Interferon
    • Mercaptopurine
    • Cyclophosphamide
  • At least 2 weeks since prior and no concurrent radiotherapy to treat cancer
  • At least 1 week since prior biologic therapy, including hematopoietic growth factors (e.g., epoetin alfa, darbepoetin alfa, filgrastim [G-CSF], sargramostim [GM-CSF], interleukin-3, or interleukin-11)
  • No other concurrent chemotherapy to treat cancer
  • No concurrent immunotherapy to treat cancer
  • 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)]
  • No active heart disease
  • No concurrent myeloid growth factors
  • No active uncontrolled infection (Infections under active treatment and controlled with antibiotics are allowed)
  • No chronic hepatitis

Sites / Locations

  • Johns Hopkins University/Sidney Kimmel Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

Patients receive 3-AP (Triapine®) IV over 4 hours followed by fludarabine phosphate IV over 30 minutes on days 1-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Response Rate Including Complete Response, Partial Response, and Hematological Improvement Assessed by Blood Cell Counts, Number of Blasts in Bone Marrow, and Clinical Evaluation
Bone marrow aspiration and biopsies were performed prior to treatment, during week 3 of the first cycle, at the time of hematologic recovery from all cycles of therapy (defined as neutrophil count >500/mm3 and platelets >20,000/mm3 independently of transfusion), or at any time that leukemia regrowth was suspected. The overall response rate was defined as complete remission, partial remission, or hematologic improvement, lasting for ≥30 days. Given the different subsets of diseases, standardized response criteria were used for CMML (the Myelodysplastic Syndrome International Working Group criteria),33 CMML transforming to acute myeloid leukemia (standard AML response criteria) , accelerated MPN (Giles et al.), and transformation of MPN to secondary AML (Mascarenhas et al.).
Incidence of Grade 3 or 4 Drug-related Non-hematologic Toxicity as Assessed by NCI CTCAE v3.0

Secondary Outcome Measures

Full Information

First Posted
September 26, 2006
Last Updated
December 16, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00381550
Brief Title
3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia
Official Title
Phase II Trial of Triapine (NSC #663249, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbone) Plus Fludarabine (NSC #312887, Fludarabine Monophosphate) in Adults With Aggressive Myeloproliferative Disorders (MPDs) Including Chronic Myelomonocytic Leukemia (CMML) and Chronic Myelogenous Leukemia in Accelerated Phase (CML-AP) or Blast Crisis (CML-BC)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
August 2006 (undefined)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
March 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase II trial is studying how well giving 3-AP together with fludarabine works in treating patients with myeloproliferative disorders (MPD), chronic myelomonocytic leukemia (CMML), or accelerated phase or blastic phase chronic myelogenous leukemia. Drugs used in chemotherapy, such as 3-AP and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 3-AP may help fludarabine work better by making cancer cells more sensitive to the drug. 3-AP and fludarabine may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving 3-AP together with fludarabine may kill more cancer cells.
Detailed Description
OBJECTIVES: I. Determine the efficacy of 3-AP (Triapine®) followed by fludarabine phosphate in patients with myeloproliferative disorders or chronic myelomonocytic leukemia in aggressive phase or transformation or chronic myelogenous leukemia in accelerated phase or blast crisis. II. Determine the toxicity of this regimen in these patients. III. Determine, preliminarily, the effect of this regimen on circulating leukemic cell genetics in these patients. Outline: This is an open-label study. Patients receive 3-AP (Triapine®) IV over 4 hours followed by fludarabine phosphate IV over 30 minutes on days 1-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow and/or peripheral blood collection at baseline and periodically during study treatment for molecular analysis of Janus kinase 2 (JAK2) mutations, GATA-1 mutations, and expression of the death-inducer-obliterator (Dido) genes on chromosome 20q. After completion of study treatment, patients are followed periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Accelerated Phase Chronic Myelogenous Leukemia, Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Blastic Phase Chronic Myelogenous Leukemia, Chronic Eosinophilic Leukemia, Chronic Myelomonocytic Leukemia, Essential Thrombocythemia, Philadelphia Chromosome Negative Chronic Myelogenous Leukemia, Polycythemia Vera, Primary Myelofibrosis, Relapsing Chronic Myelogenous Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
35 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
Patients receive 3-AP (Triapine®) IV over 4 hours followed by fludarabine phosphate IV over 30 minutes on days 1-5. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
triapine
Other Intervention Name(s)
3-AP, OCX-191
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative study
Primary Outcome Measure Information:
Title
Response Rate Including Complete Response, Partial Response, and Hematological Improvement Assessed by Blood Cell Counts, Number of Blasts in Bone Marrow, and Clinical Evaluation
Description
Bone marrow aspiration and biopsies were performed prior to treatment, during week 3 of the first cycle, at the time of hematologic recovery from all cycles of therapy (defined as neutrophil count >500/mm3 and platelets >20,000/mm3 independently of transfusion), or at any time that leukemia regrowth was suspected. The overall response rate was defined as complete remission, partial remission, or hematologic improvement, lasting for ≥30 days. Given the different subsets of diseases, standardized response criteria were used for CMML (the Myelodysplastic Syndrome International Working Group criteria),33 CMML transforming to acute myeloid leukemia (standard AML response criteria) , accelerated MPN (Giles et al.), and transformation of MPN to secondary AML (Mascarenhas et al.).
Time Frame
Up to 4 years
Title
Incidence of Grade 3 or 4 Drug-related Non-hematologic Toxicity as Assessed by NCI CTCAE v3.0
Time Frame
Up to 4 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Criteria: Not pregnant or nursing Histopathologically confirmed diagnosis of 1 of the following: Myeloproliferative disorders (MPDs) in aggressive phase or transformation CML in accelerated phase or blast crisis Chronic myelomonocytic leukemia in aggressive phase (5-19% bone marrow blasts) or transformation (> 20% bone marrow blasts) Myeloproliferative disorders (MPDs) in aggressive phase or transformation, including the following: Polycythemia vera (PV) Essential thrombocythemia (ET) Myelofibrosis with myeloid metaplasia Hypereosinophilic syndrome Atypical (Philadelphia chromosome negative) chronic myelogenous leukemia (Ph- CML) Patients with aggressive phase MPD (PV, ET, or Ph- CML) must meet ≥ 1 of the following criteria: Marrow blasts > 5% Peripheral blood blasts plus progranulocytes > 10% New onset or increasing myelofibrosis New onset or > 25% increase in hepatomegaly or splenomegaly New onset constitutional symptoms (fever, weight loss, splenic pain, bone pain) Multilineage bone marrow failure Ineligible for established curative regimens, including stem cell transplantation ECOG performance status 0-2 Negative pregnancy test Fertile patients must use effective contraception No chronic toxicity from prior chemotherapy > grade 1 No history of severe coronary artery disease Creatinine normal OR creatinine clearance >= 60 mL/min AST and ALT =< 2.5 times normal Bilirubin =< 2.0 mg/dL unless due to leukemia, Gilbert's syndrome, or hemolysis 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 No history of allergic reactions attributed to compounds of similar chemical or biological composition to 3-AP (Triapine®) and/or fludarabine phosphate No other life-threatening illness No history of mental deficits and/or psychiatric illness that would preclude study compliance No more than 4 prior induction regimens (3 cytotoxic chemotherapy regimens) At least 3 weeks since prior myelosuppressive cytotoxic agents (6 weeks for mitomycin C or nitrosoureas) and recovered At least 1 week since prior nonmyelosuppressive treatment At least 48 hours since prior noncytotoxic agents for peripheral blood leukemic cell count control, including but not limited to the following: Hydroxyurea Imatinib mesylate Interferon Mercaptopurine Cyclophosphamide At least 2 weeks since prior and no concurrent radiotherapy to treat cancer At least 1 week since prior biologic therapy, including hematopoietic growth factors (e.g., epoetin alfa, darbepoetin alfa, filgrastim [G-CSF], sargramostim [GM-CSF], interleukin-3, or interleukin-11) No other concurrent chemotherapy to treat cancer No concurrent immunotherapy to treat cancer 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)] No active heart disease No concurrent myeloid growth factors No active uncontrolled infection (Infections under active treatment and controlled with antibiotics are allowed) No chronic hepatitis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Judith Karp
Organizational Affiliation
Johns Hopkins University/Sidney Kimmel Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University/Sidney Kimmel Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
24362550
Citation
Zeidner JF, Karp JE, Blackford AL, Smith BD, Gojo I, Gore SD, Levis MJ, Carraway HE, Greer JM, Ivy SP, Pratz KW, McDevitt MA. A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms. Haematologica. 2014 Apr;99(4):672-8. doi: 10.3324/haematol.2013.097246. Epub 2013 Dec 20.
Results Reference
result

Learn more about this trial

3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia

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