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


Phase 1
18 Years
N/A
Not Enrolling
Both
Myelodysplastic Syndromes and Leukemia, Myeloid, Acute

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Trial Information

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


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.


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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Time Frame:

4 months after the final patient on the final cohort starts treatment

Safety Issue:

Yes

Principal Investigator

Ravi Vij, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Washington Univerisity

Authority:

United States: Food and Drug Administration

Study ID:

07-0916 / 201011797

NCT ID:

NCT00671697

Start Date:

May 2008

Completion Date:

May 2011

Related Keywords:

  • Myelodysplastic Syndromes and Leukemia, Myeloid, Acute
  • MDS
  • hypomethylating agent
  • oxidative stress
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Washington University St. Louis, Missouri  63110