A Study of Azacitidine in Myelodysplastic Syndrome (MDS) Associated to Systemic Auto-immune and Inflammatory Disorders

Study Overview
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Brief Summary
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This study is a phase II of effcicacy and tolerance of azacitidine in patients with myelodysplatic syndrome and steroid dependent or resistent systemic auto-immune and inflammatory disorders

Detailed Description
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This trial will be a prospective French nationwide study analyzing the effect of treatment with azacitidine in patients with MDS-associated SAID with steroid dependence and/or resistance, and its correlation with possible changes in immunological parameters

Official Title
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A Phase II Study of Efficacy and Tolerance of Azacitidine (AZA) In MDS-associated Steroid Dependent/Refractory Systemic Auto-immune and Inflammatory Disorders (SAID)

Conditions
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MDS, Systemic Autoimmune Diseases

Intervention / Treatment
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* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must understand and voluntarily sign the informed consent form Age 18 years at the time of signing the informed consent form Must be able to adhere to the study visit schedule and other protocol requirements MDS or CMML or AML with 20-30% marrow blasts using 2008 WHO classification, with any of the following characteristics : IPSS intermediate 2 or high, including AML with 20 to 30% marrow blasts and CMML with WBC<13G/L and marrow blasts >10%, IPSS low or int 1 in need of treatment (transfusion dependent anemia resistant to ESAs and/or platelets below 30 G/l or below 50 G/l with bleeding or platelet transfusion requirement, and/or ANC < 0.5 G/l with infectious complications) Documented (by cytogenetic or molecular analysis) MDS /CMML not meeting those criteria, but with at least one significant cytopenia (Hb <10 g/dl, platelets <50G/l, ANC <1 G/l). In this situation, the underlying SAID should be severe and have resisted to a second line treatment (following steroids), if such treatment can be proposed for this particular SAID. Those cases should be discussed prior to inclusion with the trial sponsors complications) SAID-associated with MDS defined according to usual international criteria for each SAID (ie ACR criteria for systemic lupus, Chapel Hill classification for systemic vasculitis, etc…) Steroid dependence and/or resistance of SAID (steroid dependence being defined as the impossibility to decrease steroids during at least 2 months below 15 mg/day; steroid resistance as no response of SAID to at least 1 mg/kg/day of prednisone equivalent during one month) Ineligibility for allogeneic stem cell transplantation during the following 12 months Wash-out at least 6 months since a previous treatement with Lenalidomide No previous use of hypomethylating agents Life expectancy ≥ 6 months Adequate liver function (serum transaminases ≤ 3N) Adequate renal function (creatinine clearance with MDRD formula > 30 ml/min) Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must : Have a negative serum or urine pregnancy test within 2 weeks prior to beginning treatment on this study. Lactating patients are excluded. Agree to use, and to be able to comply with, effective contraception without interruption, 4 weeks before starting study drug throughout the entire duration study drug therapy (including doses interruptions) and for 3 months after the end of the study drug therapy. Male patients must : Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential during the entire period of treatment, even if disruption of treatment and during 3 months after end of treatment. Agree to learn about the procedures for preservation of sperm before starting treatment. Exclusion Criteria: IPSS low and intermediate-1 not meeting the criteria described above Creatinine clearance with MDRD formula < 30 ml/min Serum total bilirubin, or serum transaminases > 3.0 x upper limit of normal (ULN) (except for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS) Known hypersensitivity to the active substance or to any of the excipients of AZA History of severe congestive heart failure, clinically unstable cardiac or pulmonary disease Previous treatment with hypomethylating agents Life-expectancy of less than six months because of another debilitating disease Uncontrolled invasive fungal infection at time of registration or active serious infection not controlled by oral or intravenous antibiotics Known positive for HIV or acute infectious hepatitis, type B or C Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study. Active cancer or prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years Pregnant or lactating females No affiliation to an insurance system

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine 75mg/m²/day<br>Azacitidine 75mg/m²/j subcutaneously daily for 7 days every 4 weeks for a minimum of 6 cycles (unless overt disease progression, especially to Acute Myeloid Leukemia (AML) occure before 6 cycles) Azacitidine will be continued after 6 cycles in patients with hematological response of myelodysplastic syndrome to azacitidine according to IWG2006 criteria by 6 cycles (Complete Response (CR), Partial Response (PR), marrow Complete Response (CRm), stable disease with Hematological Improvment (HI)), for another 6 cycles in patients with complete or partial response of Systemic Auto-Immune Disorders (SAID) after 6 cycles of Azacitidine, even if Myelodysplastic Syndrome remains only stable per IWG2006 criteria | Drug: Azacitidine<br>* Azacitidine at 75mg/m²/j for 7 days.<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate of Myelodysplastic syndrome and systemic autoimmune and inflammatory diseases (SAID) | Overall response rate (including partial and complete response) of systemic autoimmune and inflammatory diseases associated with Myelodysplastic syndrome after 6 cycles of azacitidine | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treament-related adverse events as assessed by CTCAE v4.0 | Number of participants with treament-related adverse events as assessed by CTCAE v4.0 | up to 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Azacitidine, MDS, Systemic auto-immune and inflammatory disorders