Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes

Study Overview
=================
Brief Summary
-----------------
In order to improve the overall survival benefit observed with AZA in higher risk MDS, its combination with other active drugs in MDS must be tested. Among drugs that have demonstrated to be active as a single agent in MDS and have preclinical potential additive or synergistic activity with AZA are Histone deacetylase (HDAC) inhibitors including Valproic acid, Lenalidomide and idarubicin. Phase I studies have already been conducted or are being conducted combining those agents to demethylating agents, showing a low toxicity profile and significant responses in high risk MDS. In this phase II randomized trial, we want to identify the most promising combination of Azacitidine and another drug (among 3 drugs: Valproic acid, Lenalidomide and Idarubicin) in higher risk MDS, by comparison to Azacitidine alone. Of note, based on efficacy and toxicity, one or several combinations may be stopped, and others, previously tested in phase I trials, included after protocol amendment.

Detailed Description
-----------------
The main objective of this phase II randomized trial is to identify, among 3 combinations of Azacitidine and another drug evaluated simultaneously, the most promising combination(s) for the treatment of higher risk MDS (IPSS Int-2 and High) compared to Azacitidine alone. The 3 tested drugs in combination with Azacitidine are: Valproic Acid, Lenalidomide and Idarubicin. The aim of this trial is to identify, in a situation where several potentially interesting drugs tested in combination with AZA exist, the most promising combination(s) based on efficacy compared to azacitidine alone, based on a two-stage design that allows a formal efficacy comparison between the K=3 investigational treatment groups and the control group.

Official Title
-----------------
Randomized Phase II Trial Seeking the Most Promising Drug Association With Azacitidine- in Higher Risk Myelodysplastic Syndromes

Conditions
-----------------
MDS

Intervention / Treatment
-----------------
* Drug: Azacitidine
* Drug: Azacitidine associated with Valproic acid
* Drug: Azacitidine associated with Lenalidomide
* Drug: Azacitidine associated with Idarubicine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age>=18 years Must be able to adhere to the study visit schedule and other protocol requirements Documented diagnosis of MDS, including AREB-t according to FAB classification or CMML (with WBC < 13,000/mm3) that meets IPSS criteria for intermediate-2 or high-risk. Patients should be willing to use adequate contraceptive methods during all the duration of the study Exclusion Criteria: Treatment with AZA or Decitabine in the previous 6 months Previous treatment with any HDAC inhibitor (Sodium valproate, Vorinostat, depsipeptide ou NSC-630176, MS 275, LAQ-824, PXD-101, LBH589, MGCD0103, CRA024781, etc). If Sodium Valproate (Depakine®) was used for seizure, a wash-out period of at least 30 days is required and an appropriate treatment replacement should be performed. Ongoing treatment with corticosteroids exceeding 30mg of prednisone per day. A wash out period of at least 7 days is required. HIV infection Creatinine > 1.5 ULN Serum AST or ALT > 3.0 x upper limit of normal (ULN) Serum total bilirubin > 1.5 mg/dl (except for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS). ≥ grade-2 neuropathy Previous history of Acute myeloblastic leukemia (with marrow blasts>30%) Previous history of allogeneic stem cell transplantation Contra-indication to Anthracyclines: Myocardiopathy, uncontrolled infection, serious renal or hepatic impairment; associated with yellow fever vaccine Known hypersensitivity to the active substance or to any of the excipients of Vidaza®, of valproate, of divalproate, of valpromide, of Lenalidomide, of thalidomide, of idarubicin and/or anthracyclines Patients with a history of severe congestive heart failure, clinically unstable cardiac or pulmonary disease All hepatitis or known personal or familial severe hepatitis, particularly due to drugs Depression with suicidal tendency Use of MILLEPERTUIS, mefloquine No medical insurance in the French Health system 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 Eligibility for allogeneic stem cell transplantation very altered general condition , with WHO performance status of 4, or life expectancy of less than 6 months

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azacitidine alone<br> | Drug: Azacitidine<br>* 6 cycles of Azacitidine 75 mg/m2 subcutaneously daily for 7 days, every 4 weeks The first course will be started on day 1 regardless of the blood count. Subsequent courses will be scheduled every 4 weeks<br>|
| Experimental: Azacitidine +Valproic acid<br> | Drug: Azacitidine associated with Valproic acid<br>* 6 cycles of Azacitidine 75 mg/m2 subcutaneously daily for 7 days, every 4 weeks Valproic Acid (Depakine-Chrono®) (VPA) will be administered concomitantly for a minimum of 6 cycles. - In patients aged 60 years or less: VPA (25 mg/kg twice a day i.e. 50 mg/kg/d) administered orally, daily for 7 days (days 1-7) - In patients older than 60 years: VPA (17.5 mg/kg twice a day i.e. 35 mg/Kg/d) administered orally daily for 7 days (days 1-7)<br>|
| Experimental: Azacitidine +Lenalidomide<br> | Drug: Azacitidine associated with Lenalidomide<br>* 6 cycles of Azacitidine 75 mg/m2 subcutaneously daily for 7 days, every 4 weeks Lenalidomide (Revlimid®) will be administered once daily orally as continuous schedule started on day 1 of Azacitidine. Patients will receive Lenalidomide 10 mg/d, during 14 days (D1 to D14)<br>|
| Experimental: Azacitidine + Idarubicine<br> | Drug: Azacitidine associated with Idarubicine<br>* Azacitidine (Vidaza®) will be administered similarly to group 1 exposed above. Idarubicin (Zavedos®) as the reconstituted solution, will be administered slowly by the intravenous route over 60 minutes at 10 mg/m²of body-surface area on day 8 of Azacitidine or day 10 if azacitidine was administered according to (5-2-2 regimen)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission, complete, partial or medullary after 6 cycles | Achievement of remission, complete, partial or medullary, according to the IWG 2006 criteria39 (see section 10 below) after 6 cycles | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stable disease with hematological improvement | Achievement of stable disease with hematological improvement (HI), according to IWG 2006 criteria after 3 and 6 cycles | 3 and 6 months | 
| Duration of response | Duration of response | within 3 years | 
| Progression to acute myeloid leukemia |  | 3 years | 
| Overall survival |  | 3 years | 
| Number of adverse events | Number of adverse events | 3 years |