Decitabine, Arsenic Trioxide and Ascorbic Acid for Myelodysplastic Syndromes and Acute Myeloid Leukemia

May 31, 2013 updated by: Washington University School of Medicine

A Phase I Study of Intravenous Decitabine in Combination With Arsenic Trioxide and Ascorbic Acid in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia

This study is designed to test the combination of decitabine, arsenic trioxide and ascorbic acid in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Myelodysplastic syndromes (MDS) are hematological disorders characterized by ineffective hematopoiesis. DNA hypomethylating agents such as decitabine have been shown to have activity in this disorder by reversing the epigenetic mechanism of gene silencing.

Acute Myeloid Leukemia (AML) is a hematological disorder characterized by ineffective hematopoiesis and malignant expansion of clonal myeloid cells. In elderly patients (≥ 60 years old), MDS commonly precedes the diagnosis of AML. Standard therapy for AML consists of cytotoxic chemotherapy and is often followed with allogeneic stem cell transplantation. Unfortunately, elderly patients are often unable to tolerate such aggressive therapy.

Arsenic has also shown activity in patients with MDS and AML though modulation of apoptosis via increased oxidative stress. In preclinical modes, arsenic activity is related to the production of radical oxygen species that damage mitochondria. Cellular glutathione acts as a cellular antioxidant and can be depleted with the vitamin ascorbic acid which increases intracellular oxidative stress and sensitivity to arsenic trioxide induced apoptosis.

We are studying the combination of decitabine, arsenic trioxide and ascorbic acid, two primary agents and one vitamin all with different mechanisms of action in order to improve the response rate in patients with MDS and AML. This is an open-label, single-arm, single-center, dose escalation Phase I trial of decitabine, arsenic trioxide and ascorbic acid in patients with MDS, either de novo or secondary, fitting any of the FAB classifications and AML.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 1

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

  • United States
    • Missouri
      • St. Louis, Missouri, United States, 63110
        • Washington University

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

Inclusion Criteria:

  1. MDS (either de novo or secondary) fitting any of the FAB classifications or AML defined by FAB classification criteria. Patients with < 5% bone marrow blasts must also meet one of the following criteria:

    1. Symptomatic anemia with either hemoglobin <10.0 g/dL or requiring red blood cell (RBC) transfusion
    2. Thrombocytopenia with a history of two or more platelet counts < 50,000 / µL or a significant hemorrhage requiring platelet transfusions, or
    3. Neutropenia with two or more absolute neutrophil counts < 1,000 /µL.

    AML patients must also have a WBC < 10,000µL and meet one of the following two criteria:

    1. Age greater than or equal to 60 years
    2. Relapsed AML and are not a candidate for cytotoxic chemotherapy.
  2. ECOG performance status of 0-2.
  3. Must give written informed consent indicating their awareness of the investigational nature of this study and its potential hazards.
  4. Adequate renal and hepatic function (creatinine < 1.5x institutional upper limit of normal, total bilirubin ≤ 1.5x institutional upper limit of normal, AST and ALT ≤ 2x institutional upper limit of normal).
  5. Serum potassium > 4.0 mEq/L, serum magnesium > 1.8 mg/dL.
  6. Life expectancy of at least 16 weeks.
  7. Women of childbearing age must have a negative serum pregnancy test prior to initiating therapy.
  8. Sexually active women of childbearing potential must use effective birth control during the trial and for at least two months following the trial.
  9. Men must be willing to avoid fathering a new child while receiving therapy with decitabine.
  10. Greater than or equal to 18 years, no upper age limit
  11. Individuals who are candidates for hematopoietic stem cell transplantation and who meet all other study criteria may participate in the study and receive intravenous decitabine in combination with arsenic trioxide and Ascorbic acid as a treatment prior to transplantation.

Exclusion Criteria:

  1. Known central nervous system (CNS) leukemia.
  2. Previously received greater than or equal to 5 cycles of azacitidine (Vidaza®, Pharmion Corp., Boulder, CO) or decitabine (Dacogen®, MGI Pharma Inc. Bloomington, MN).
  3. QTc > 460 msec.
  4. Known or suspected hypersensitivity to decitabine, arsenic or ascorbic acid.
  5. Receiving any other investigational agents within 30 days of first dose of study drug.
  6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, congestive heart failure of NYHA class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.
  7. Known positive serology for HIV.
  8. Had radiotherapy within 14 days prior to study enrollment.
  9. Known presence of hepatic tumors.
  10. < 18 years of age
  11. Exclude women who are pregnant or breast feeding.
  12. Known history of glucose-6-phosphate deficiency (G6PD).
  13. Currently taking a Class Ia or Class III antiarrhythmic or other medication causally associated with prolonging QTc.
  14. Use of aspirin with platelet counts < 50,000/µl.

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: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Dose Level 1 Arsenic Trioxide & Decitabine

Arsenic trioxide loading dose of 0.1 mg/kg/day IV x 5 days followed by weekly doses of 0.1 mg/kg IV for 15 additional weeks.

Decitabine 20 mg/m2 IV every day on days 1-5 of a 4 weeks cycle for 4 cycles.
Drug: Decitabine
Other Names:
  • Dacogen
Drug: Arsenic Trioxide
Other Names:
  • Dacogen, Vitamin C and Trisenox
EXPERIMENTAL: Dose Level 2 Arsenic Trioxide & Decitabine

Arsenic trioxide loading dose of 0.2 mg/kg/day IV x 5 days followed by weekly doses of 0.2 mg/kg IV for 15 additional weeks.

Decitabine 20 mg/m2 IV every day on days 1-5 of a 4 weeks cycle for 4 cycles.
Drug: Decitabine
Other Names:
  • Dacogen
Drug: Arsenic Trioxide
Other Names:
  • Dacogen, Vitamin C and Trisenox
EXPERIMENTAL: Dose Level 3 Arsenic Trioxide & Decitabine

Arsenic trioxide loading dose of 0.3 mg/kg/day IV x 5 days followed by weekly doses of 0.3 mg/kg IV for 15 additional weeks.

Decitabine 20 mg/m2 IV every day on days 1-5 of a 4 weeks cycle for 4 cycles.
Drug: Decitabine
Other Names:
  • Dacogen
Drug: Arsenic Trioxide
Other Names:
  • Dacogen, Vitamin C and Trisenox

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To define the maximum tolerated dose and dose-limiting toxicities during four cycles of combination decitabine, arsenic trioxide and ascorbic acid in patients with myelodysplastic syndromes (MDS) previously untreated with hypomethylating agents.
Time Frame: 4 months after the final patient on the final cohort starts treatment
4 months after the final patient on the final cohort starts treatment

Secondary Outcome Measures

Outcome Measure
Time Frame
To estimate the rate of complete remission (CR) and partial remission (PR) after four cycles of therapy in patients with MDS.
Time Frame: After 4 cycles of treatment
After 4 cycles of treatment
To determine the rate of hematologic improvement
Time Frame: Weekly through the end of treatment
Weekly through the end of treatment
To determine the rate of transfusion independence
Time Frame: Through completion of treatment
Through completion of treatment
To determine the time to disease progression to AML
Time Frame: Every 4 weeks during treatment and then every 2 months for 2 years after the first dose of study drug
Every 4 weeks during treatment and then every 2 months for 2 years after the first dose of study drug
To determine the rate of cytogenetic response
Time Frame: After every 2 cycles
After every 2 cycles
To determine the rate of overall survival
Time Frame: Every 4 weeks during treatment and then every 2 months for 2 years after the first dose of study drug
Every 4 weeks during treatment and then every 2 months for 2 years after the first dose of study drug
To determine changes in bone marrow vascular density
Time Frame: At baseline, end of cycle 2, end of cycle 4, and end of study
At baseline, end of cycle 2, end of cycle 4, and end of study
To determine changes in angiogenic mRNA expression.
Time Frame: Baseline, end of cycle 2, end of cycle 4, and end of study
Baseline, end of cycle 2, end of cycle 4, and end of study

Collaborators and Investigators

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

Sponsor

Washington University School of Medicine

Collaborators

Cephalon

Investigators

  • Principal Investigator: Ravi Vij, M.D., Washington Univerisity

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.

General Publications

Helpful Links

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

May 1, 2008

Primary Completion (ACTUAL)

January 1, 2010

Study Completion (ACTUAL)

May 1, 2011

Study Registration Dates

First Submitted

May 1, 2008

First Submitted That Met QC Criteria

May 1, 2008

First Posted (ESTIMATE)

May 5, 2008

Study Record Updates

Last Update Posted (ESTIMATE)

June 4, 2013

Last Update Submitted That Met QC Criteria

May 31, 2013

Last Verified

May 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 07-0916 / 201011797

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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