Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes (AZA-PLUS)
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.
|MDS||Drug: Azacitidine Drug: Azacitidine associated with Valproic acid Drug: Azacitidine associated with Lenalidomide Drug: Azacitidine associated with Idarubicine||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||Randomized Phase II Trial Seeking the Most Promising Drug Association With Azacitidine- in Higher Risk Myelodysplastic Syndromes|
- Remission, complete, partial or medullary after 6 cycles [ Time Frame: 6 months ]Achievement of remission, complete, partial or medullary, according to the IWG 2006 criteria39 (see section 10 below) after 6 cycles
- Stable disease with hematological improvement [ Time Frame: 3 and 6 months ]Achievement of stable disease with hematological improvement (HI), according to IWG 2006 criteria after 3 and 6 cycles
- Duration of response [ Time Frame: within 3 years ]Duration of response
- Progression to acute myeloid leukemia [ Time Frame: 3 years ]
- Overall survival [ Time Frame: 3 years ]
- Number of adverse events [ Time Frame: 3 years ]Number of adverse events
|Study Start Date:||June 2011|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||January 2018 (Final data collection date for primary outcome measure)|
|Active Comparator: Azacitidine alone||
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
|Experimental: Azacitidine +Valproic acid||
Drug: Azacitidine associated with Valproic acid
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)
|Experimental: Azacitidine +Lenalidomide||
Drug: Azacitidine associated with Lenalidomide
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)
|Experimental: Azacitidine + Idarubicine||
Drug: Azacitidine associated with Idarubicine
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)
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01342692
|Contact: Pierre Fenaux, MD, PhD||33(1)firstname.lastname@example.org|
|Bobigny, France, 93009|
|Contact: Pierre Fenaux, MD, PhD 33(1)48957050 email@example.com|
|Principal Investigator: Pierre Fenaux, MD, PhD|
|Principal Investigator:||Pierre Fenaux, MD, PhD||Assistance Publique - Hôpitaux de Paris|