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

December 16, 2014 updated by: National Cancer Institute (NCI)

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)

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University/Sidney Kimmel Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm I
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.
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Given IV
Other Names:
  • 3-AP
  • OCX-191
Correlative study

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response Rate Including Complete Response, Partial Response, and Hematological Improvement Assessed by Blood Cell Counts, Number of Blasts in Bone Marrow, and Clinical Evaluation
Time Frame: Up to 4 years
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.).
Up to 4 years
Incidence of Grade 3 or 4 Drug-related Non-hematologic Toxicity as Assessed by NCI CTCAE v3.0
Time Frame: Up to 4 years
Up to 4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2006

Primary Completion (Actual)

March 1, 2011

Study Completion (Actual)

March 1, 2011

Study Registration Dates

First Submitted

September 26, 2006

First Submitted That Met QC Criteria

September 26, 2006

First Posted (Estimate)

September 28, 2006

Study Record Updates

Last Update Posted (Estimate)

January 6, 2015

Last Update Submitted That Met QC Criteria

December 16, 2014

Last Verified

June 1, 2014

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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