Idarubicin Combined to Azacitidine in Int-2 or High Risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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Patients will receive escalating doses of ldarubicin combined to Azacitidine given at the FDA/EMEA approved Schedule and dosing. For the Phase I study : Determine the safety and tolerance of escalating doses of Idarubicin combined to Azacitidine in patients with INT-2 or higher risk MDS. For the phase II study: Primary: Evaluate rate and duration of response (according to IWG 2006 criteria and IWG 2000 criteria) to the combination of Idarubicin and Azacitidine in patients with INT-2 or higher risk MDS

Detailed Description
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Patients will receive ldarubicin combined to Azacitidine. The first 10 patients will receive Idarubicin 5 mg/m2/d on day 8 of each cycle of Azacitidine 75 mg/m2/d CI during 7 days (First Cohort ). Progression or not to the next cohort of 10 patients : Idarubicin 10 mgm2/d on day 8 of each cycle of Azacitidine 75 mg/m2/d CI during 7 days (Second cohort of 10 patients), will be decided after completion of the first cohort, after review of hematological toxicity by an independent safety review committee (SRC). The next 21 patients will be treated either according to the first or second cohort schedule of Idarubicin, after review of hematological toxicity and efficacy by an independent safety review committee (SRC).

Official Title
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A Phase I-II Study of the Efficacy and Safety of Idarubicin Combined to Azacitidine in Int-2 or High Risk Myelodysplastic Syndromes

Conditions
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High Grade Myelodysplastic Syndrome Lesions

Intervention / Treatment
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* Drug: azacitidine and idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of MDS, or CMML with WBC < 13,000/mm3 that meets IPSS criteria for intermediate-2 or high-risk disease, IPSS score ≥1.5 Myocardial function do not contraindicate the use of idarubicin Age ≥ 18 years Performance Status ≤2 according to ECOG. Serum creatinine < 1.5 x ULN and normal levels of electrolytes (serum sodium 136-145 mmol/l, Potassium 3,5-4,5 mmol/l, alkaline Reserve 23-29 mmol/l, , Calcium 2,15-2,5 mmol/l, Phosphore 0,87-1,45 mmol/l) Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) < 1.5 x upper limit of normal (ULN) Serum total bilirubin < 1.5 x ULN. Must be able to adhere to the study visit schedule and other protocol requirements Signed informed consent. Female subjects of childbearing potential must: • Accept effective contraception without interruption throughout the duration of study and up to three months after the end of treatment. Male subjects must Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy and up to three months after the final treatment if their partner is of childbearing potential and has no contraception. Agree to learn the procedures for preservation of sperm Exclusion Criteria: Uncontrolled infection Prior therapy with anthracycline for MDS. Eligible for an allogeneic stem cell transplantation. Prior therapy with demethylating agents within the last 3 months Prior therapy with Hematopoietic growth factor (ESA or G-CSF) agents or cytotoxic agents (oral chemotherapy, low doses AraC) within the last 30 days. Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) Pregnant or lactating females Known HIV-1 positivity Contra-indication to Anthracyclines

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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: azacitidine 75mg/m²/d + idarubicin 5mg/m²/d<br>phase I : palier 1 have 10 patients and palier 2 have to 10 patients. palier 1: Ida 5mg/m²/d (D8) + AZACITIDINE 75mg/m²/d (D1-D7) | Drug: azacitidine and idarubicin<br>* azacitidine:100mg, 75mg/m²/d, during 7days every 28 days (D1-D7). Idarubicin: 5mg/ml, 5mg/m²/d (palier1) or 10mg/m²/d (palier2), D8<br>|
| Experimental: Azacitidine 75mg/m²/d + idarubicin 10mg/m²/d<br>palier 2: Ida 10mg/m²/d (D8)+ Azacitidine 75mg/m²/d (D1-D7) | Drug: azacitidine and idarubicin<br>* azacitidine:100mg, 75mg/m²/d, during 7days every 28 days (D1-D7). Idarubicin: 5mg/ml, 5mg/m²/d (palier1) or 10mg/m²/d (palier2), D8<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determined tolerance and dose limiting toxicities to idarubicin and azacitidine association. |  | After 12 weeks treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| to determined overall response rate and response duration |  | After six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myelodysplastic syndrome, azacitidine, idarubicin