Study of Association of Arsenic Trioxide (ATO) and Ascorbic Acid in Myelodysplastic Syndromes

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multicenter phase II trial designed to evaluate the safety and activity of the combination of association of arsenic trioxide (ATO) and ascorbic acid in patients with myelodysplastic syndromes

Official Title
-----------------
Phase II Multicenter Study of Association of Arsenic Trioxide (ATO) and Ascorbic Acid in Myelodysplastic Syndromes

Conditions
-----------------
Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: ATO + Ascorbic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients affected by myelodysplastic syndromes, entering in one of the following groups: Myelodysplastic syndromes independent of WHO diagnostic classification (43) and IPSS prognostic score (2), when present at least one of the following abnormalities: 3q26 chromosome rearrangement. High EVI-1 transcript levels. Myelodysplastic syndromes without excess of blasts (non-RAEB patients) at low or intermediate-1 score risk according to the IPSS (2), as a second line treatment option, after a failure to the first line treatment with erythropoietin +/- G-CSF, immunosuppressive therapy, or other initial treatment modality. Non RAEB patients at intermediate-2 or high risk score or RAEB patients at any prognostic score, who are non candidate to treatment with conventional chemotherapy regimens. Presence of one ore more cytopenias characterised by one ore more of the following elements: Transfusions dependence. Hb< 11 gr/dl Platelet count < 50x109/L Absolute neutrophil count < .5x109/L. ECOG Performance status ≤ 2. Aged from 18 to 80. Life expectancy > 4 months. Creatinine level < 1.5 mg/dl. Liver function tests, including ASL-ALT-alkaline phosphatase lower than 3xULN No previous treatment with chemotherapy, growth factors, cytokines or other experimental treatment within 4 weeks of starting treatment. No history of clinically significant cardiac disease, including congestive heart failure. Cytogenetic evaluation available. Sending of both peripheral blood and bone marrow sample to the central laboratory for EVI-1 rearrangement evaluation. Written Informed consent. Exclusion Criteria: Patients affected by myelodysplastic syndromes entering in categories other than those foreseen by inclusion criteria point 1. Absence of cytopenia defined as the contemporarily presence of all the following conditions: a) no transfusion need; b) Hb > 11 gr/dl; c) platelet count > 50x109/L; d) absolute neutrophil count > .5x109/L. All patients that might be candidate to allogenic stem cell transplantation. Patients that might be candidate to a first line immunosuppressive therapy. ECOG Performance status > 2. Age lower than 18 or higher then 80. Life expectancy < 4 months. Creatinine level > 1.5 mg/dl. Liver function tests, including ASL-ALT-alkaline phosphatase higher than 3xULN Treatment with chemotherapy, growth factors, cytokines or other experimental treatment within 4 weeks of starting treatment. Clinically significant cardiac disease, including congestive heart failure, rhythm abnormalities, QT time > 460m/s, or need of anti-arrhythmic drugs. Concurrent co-morbid medical condition which might exclude administration of therapy, as judged by individual investigator. Absence of cytogenetic evaluation. Participation at same time in another study in which investigational drugs are used. Absence of written Informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Loading phase (week 1): ATO 0.3 mg/Kg/die for 5 consecutive days. Subsequent phase (from week 2 to week 16): ATO 0.25 mg/kg twice a week (day 2 and 5 of every week). Ascorbic acid 1000 mg IV within 30 minutes after each arsenic trioxide infusion for 16 consecutive weeks. | Drug: ATO + Ascorbic acid<br>* ATO will be diluted in 250 ml of normal saline solution at a dosage of 0.3 mg/Kg during the first week of therapy and at a dosage of 0.25 mg/Kg during the subsequent weeks (week 2 to 16), and administered intravenously over a 1-2 hour period. The dose of ascorbic acid will be 1000 mg in 100 cc D5W or normal saline solution (NaCl 0.9 %) (protected from light and air) administered as an IV infusion over 15 to 30 minutes. The dosing solution is not to be mixed with any alkaline solution.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TO evaluate the erythroid response rate (major), according to the International Working Group (IWG) criteria (42) after four months of treatment with the association of ATO and ascorbic acid. |  | 16 mounths | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate platelets and granulocyte response according to the International Working Group (IWG) criteria (42) after four months of treatment with the association of ATO and ascorbic acid |  | 16 mounths | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
myelodysplastic syndromes, arsenic trioxide, ascorbic acid