Decitabine, Arsenic Trioxide and Ascorbic Acid for Myelodysplastic Syndromes and Acute Myeloid Leukemia - Full Text View

Sponsor:	Washington University School of Medicine
Collaborator:	Cephalon
Information provided by (Responsible Party):	Washington University School of Medicine
ClinicalTrials.gov Identifier:	NCT00671697

Purpose

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

Condition	Intervention	Phase
Myelodysplastic Syndromes and Leukemia, Myeloid, Acute	Drug: Decitabine, Arsenic Trioxide and Ascorbic Acid Drug: Decitabine, Ascorbic Acid, Arsenic Trioxide Drug: Arsenic Trioxide	Phase I

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase I Study of Intravenous Decitabine in Combination With Arsenic Trioxide and Ascorbic Acid in Patients With Myelodysplastic Syndromes and Acute Myeloid Leukemia

Resource links provided by NLM:

MedlinePlus related topics: Acute Myeloid Leukemia Arsenic Leukemia Myelodysplastic Syndromes Vitamin C

Drug Information available for: Ascorbic acid Arsenic trioxide 5-Aza-2'-deoxycytidine

U.S. FDA Resources

Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:

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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To estimate the rate of complete remission (CR) and partial remission (PR) after four cycles of therapy in patients with MDS. [ Time Frame: After every 4 cycles of treatment ] [ Designated as safety issue: No ]
To determine the rate of hematologic improvement [ Time Frame: Weekly ] [ Designated as safety issue: No ]
To determine the rate of transfusion independence [ Time Frame: Weekly ] [ Designated as safety issue: No ]
To determine the time to disease progression to AML [ Time Frame: After every 2 cycles ] [ Designated as safety issue: No ]
To determine the rate of cytogenetic response [ Time Frame: After every 2 cycles ] [ Designated as safety issue: No ]
To determine the rate of overall survival [ Time Frame: Continuous throughout study ] [ Designated as safety issue: No ]
To determine changes in bone marrow vascular density [ Time Frame: at baseline and after 2 and 4 cycles of treatment ] [ Designated as safety issue: No ]
To determine changes in angiogenic mRNA expression. [ Time Frame: at baseline and after 2 and 4 cycles of treatment ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	April 2008
Estimated Study Completion Date:	December 2016
Estimated Primary Completion Date:	December 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 Arsenic Trioxide 0.1mg Arsenic Trioxide	Drug: Decitabine, Arsenic Trioxide and Ascorbic Acid Decitabine 20mg/m2 IV Days 1-5, Ascorbic Acid 1000mg IV Day 1-5, Arsenic Trioxide 0.1 mg/kg Days 1-5, then once weekly for 15 weeks. Other Name: Dacogen, Trisenox and Vitamin C
Experimental: 2 Arsenic Trioxide .02 mg Arsenic Trioxide	Drug: Decitabine, Ascorbic Acid, Arsenic Trioxide Decitabine 20mg/m2 IV Days 1-5, Ascorbic Acid 1000mg IV Day 1-5, Arsenic Trioxide 0.2 mg/kg Days 1-5, then once weekly for 15 weeks. Other Name: Decogen, Trisenox and Vitamin C
Experimental: 3 Arsenic Trioxide .03 mg Arsenic Trioxide	Drug: Arsenic Trioxide Decitabine 20mg/m2 IV Days 1-5, Ascorbic Acid 1000mg IV Day 1-5, Arsenic Trioxide 0.3 mg/kg Days 1-5, then once weekly for 15 weeks. Other Name: Dacogen, Vitamin C and Trisenox

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.

Eligibility

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

Criteria

Inclusion Criteria:

MDS (either de novo or secondary) fitting any of the FAB classifications, MDS. 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 > 60 years
2. Relapsed AML and are not a candidate for cytotoxic chemotherapy.
ECOG performance status of 0-2.
Must give written informed consent indicating their awareness of the investigational nature of this study and its potential hazards.
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).
Serum potassium > 4.0 mEq/L, serum magnesium > 1.8 mg/dL.
Life expectancy of at least 16 weeks.
Women of childbearing age must have a negative serum pregnancy test prior to initiating therapy.
Sexually active women of childbearing potential must use effective birth control during the trial and for at least two months following the trial.
Men must be willing to avoid fathering a new child while receiving therapy with decitabine.
greater than or equal to 18 years, no upper age limit
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:

Known central nervous system (CNS) leukemia.
Previously received greater than or equal to 5 cycles of azacitidine (Vidaza®, Pharmion Corp., Boulder, CO) or decitabine (Dacogen®, MGI Pharma Inc. Bloomington, MN).
QTc > 460 msec.
Known or suspected hypersensitivity to decitabine, arsenic or ascorbic acid.
Receiving any other investigational agents within 30 days of first dose of study drug.
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.
Known positive serology for HIV.
Had radiotherapy within 14 days prior to study enrollment.
Known presence of hepatic tumors.
< 18 years of age
Exclude women who are pregnant or breast feeding.
Known history of glucose-6-phosphate deficiency (G6PD).
Currently taking a Class Ia or Class III antiarrhythmic or other medication causally associated with prolonging QTc (Appendix 11).
Use of aspirin with platelet counts < 50,000/µl.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00671697

Locations

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

Sponsors and Collaborators

Washington University School of Medicine

Cephalon

Investigators

Principal Investigator:

Ravi Vij, M.D.

Washington Univerisity

More Information

Additional Information:

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine This link exits the ClinicalTrials.gov site

This link exits the ClinicalTrials.gov site

No publications provided by Washington University School of Medicine

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Welch JS, Klco JM, Gao F, Procknow E, Uy GL, Stockerl-Goldstein KE, Abboud CN, Westervelt P, DiPersio JF, Hassan A, Cashen AF, Vij R. Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a phase I study. Am J Hematol. 2011 Sep;86(9):796-800. Epub 2011 Aug 3. No abstract available.

Responsible Party:	Washington University School of Medicine
ClinicalTrials.gov Identifier:	NCT00671697 History of Changes
Other Study ID Numbers:	07-0916 / 201011797
Study First Received:	May 1, 2008
Last Updated:	October 25, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Washington University School of Medicine:

MDS
hypomethylating agent
oxidative stress

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Ascorbic Acid
Vitamins
Decitabine

Arsenic trioxide
Antioxidants
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protective Agents
Physiological Effects of Drugs
Micronutrients
Growth Substances
Antimetabolites, Antineoplastic
Antimetabolites
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on February 09, 2012