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A Phase I Multicenter Study of Arsenic Trioxide and Azacitidine in Patients With Myelodysplastic Syndromes

Phase 1
18 Years
Not Enrolling
Leukemia, Myelodysplastic Syndromes

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Trial Information

A Phase I Multicenter Study of Arsenic Trioxide and Azacitidine in Patients With Myelodysplastic Syndromes



- Determine the maximum tolerated dose of azacitidine when given in combination with
arsenic trioxide in patients with myelodysplastic syndromes (MDS). (Phase I)

- Determine the safety and tolerability of this regimen in these patients. (Phase I)

- Determine the major hematologic response (erythroid response) rate in patients with
transfusion-dependent lower-risk MDS treated with this regimen. (Phase II)

- Determine complete and partial remission rates in patients with higher-risk MDS treated
with this regimen. (Phase II)

- Determine the toxicity profile of this regimen in these patients. (Phase I)


- Determine time to disease progression in patients treated with this regimen. (Phase I
and II)

- Determine the overall and progression-free survival of patients treated with this
regimen. (Phase I and II)

OUTLINE: This is an multicenter, open-label, phase I, dose escalation study of azacitidine
followed by a phase II study. Patients enrolled in the phase II portion are stratified
according to baseline International Scoring System score (lower-risk myelodysplastic
syndromes [MDS] vs higher-risk MDS).

- Phase I: Patients receive azacitidine subcutaneously once daily on days 1-5 and arsenic
trioxide IV over 1-4 hours on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity. Patients
with stable disease may receive up to 8 courses of therapy. Patients with responding
disease may continue to receive study therapy until a major response or a complete
remission is achieved.

Cohorts of 3-6 patients receive escalating doses of azacitidine until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.

- Phase II: Patients receive arsenic trioxide as in phase I and azacitidine as in phase I
at one dose level below the MTD determined in phase I.

After the completion of study treatment, patients are followed at 4 weeks and then every
3-12 months for survival.

PROJECTED ACCRUAL: Approximately 3-18 patients will be accrued for the phase I portion of
this study. A total of 60 patients (30 per stratum) will be accrued for the phase II portion
of this study.

Inclusion Criteria:

- Confirmed diagnosis of MDS by standard criteria. Patients within each of the FAB
diagnostic groups of RA, RARS, RAEB, RAEBt, and CMML are eligible. For patients with
lower-risk MDS only: documented red blood cell dependence, defined as the inability
to maintain a hematocrit of > 25% without transfusion support.

- Adequate marrow iron stores

- In patients with serum erythropoietin less than 200 IU/mL at screening, failure to
have responded to a 2 to 3 month trial of recombinant erythropoietin

- Serum creatinine or serum bilirubin < 1.5 times the upper limit of normal; higher
levels are acceptable if ALT levels < 2 x upper limits of normal

- Women of childbearing potential must have a negative serum pregnancy test prior to

- Women of childbearing potential should be advised to avoid becoming pregnant and
should be advised to not father a child while receiving treatment with azacitidine

- Age > 18 years

Exclusion Criteria:

- Treatment with growth factors within the 30 days before first treatment with
ATO/Azacitidine, except that patients with serum erythropoietin < 200 IU/mL who
failed to respond to a trial with EPO are not excluded regardless of the time since
last EPO

- Treatment with cytotoxic or experimental agents within 30 days before first treatment
with ATO/Azacitidine

- Absolute QT interval > 460 msec in the presence of adequate serum potassium and
magnesium values

- Active serious infections that are not controlled by antibiotics

- Pregnant or lactating women

- Inability or unwillingness to comply with the treatment protocol, follow-up, or
research tests

- NYHA Class III or IV heart failure

- Poorly controlled hypertension, diabetes mellitus, or other serious medical or
psychiatric illness that could potentially interfere with the completion of treatment
according to this protocol

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerability as assessed by NCI CTCAE v3.0 (Phase I)

Outcome Time Frame:

Every 28 days upto 8 months

Safety Issue:


Principal Investigator

Gary J. Schiller, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Jonsson Comprehensive Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

February 2007

Completion Date:

Related Keywords:

  • Leukemia
  • Myelodysplastic Syndromes
  • refractory anemia with excess blasts in transformation
  • refractory anemia with excess blasts
  • refractory anemia with ringed sideroblasts
  • refractory anemia
  • chronic myelomonocytic leukemia
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • secondary myelodysplastic syndromes
  • Leukemia
  • Myelodysplastic Syndromes
  • Preleukemia



Jonsson Comprehensive Cancer Center at UCLALos Angeles, California  90095-1781