Azacitidine and Arsenic Trioxide in Treating Patients With Myelodysplastic Syndromes

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00234000
• Other study ID #: CDR0000442931
• Secondary ID: UCLA-0408087
• Status: Terminated
• Phase: Phase 1
• Start date: February 2007

Study information

• Verified date: August 2012
• Source: Jonsson Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy, such as azacitidine and arsenic trioxide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of azacitidine when given together with arsenic trioxide and to see how well they work in treating patients with myelodysplastic syndromes.

Description:

OBJECTIVES:

Primary

• 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)

Secondary

• 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. primary completion date: February 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 azacitidine/treatment.

• 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

Related Conditions & MeSH terms

• Leukemia
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• arsenic trioxide
Each 28-day treatment cycle will include dosing for 2 days per week of ATO. Subjects will recieve 1 mg/mL each dosing day.
• azacitidine
Each 28-day treatment cycle will include dosing the first five days of cycle with Azacitidine. Cohorts of three to six patients will each receive 25, 50, and 75 mg/m2/d injected subcutaneously.

Locations

Country	Name	City	State
United States	Jonsson Comprehensive Cancer Center at UCLA	Los Angeles	California

Sponsors (3)

Lead Sponsor	Collaborator
Jonsson Comprehensive Cancer Center	Celgene Corporation, CTI BioPharma

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and tolerability as assessed by NCI CTCAE v3.0 (Phase I)		Every 28 days upto 8 months
Secondary	Time to disease progression		Participants are folowed for an average of 1 year after completion of study treatment
Secondary	Overall survival		Participants are followed every 3-12 months for survival