In this trial, the investigators will test the combination of escalating doses of chemotherapy (starting at relatively low dose) with lenalidomide in intermediate-2-or high risk MDS and AML with del 5 q31. It is hoped that this combined therapy will further increase response rate in intermediate-2-or high risk MDS and AML with del 5 q31, without major toxicity in comparison to historical results obtained with chemotherapy alone in the same subset of patients.
Patients will receive lenalidomide combined to DNR- AraC chemotherapy. The first 31 patients will receive DNR 45 mg/m2/d, during 3 days, and AraC 200mg/m2/d CI during 7 days. Progression or not to the next cohort DNR 60 mgm2/d x3d and AraC 200mg/m2d x7d , or on the contrary reduction to the lower cohort DNR 30 mgm2/d x3d and AraC 200mg/m2d x5d will be decided after inclusion of fixed numbers of patients ,after review of toxicity and efficacy by an independent safety review committee (SRC). Efficacy would be defined as a response rate ≥50%. After inclusion of the first 31 patients, the SRC will choose the cohort dose the last 33 patients will receive, based on toxicity and efficacy criteria. 1. Induction treatment Lenalidomide 10 mg once daily PO during 3 weeks . DNR 30-45-or 60 mg/m2 /d (depending on the cohort during 3 days (IV push)- AraC 200mg/m2/d during 5- 7 or 7 days (continuous infusion)+ G-CSF (lenograstim): 263 ug/d from day 9, until recovery from aplasia (maximum 30 days). Evaluation will be performed after recovery from aplasia, on day 40 at the latest (with marrow aspirate and karyotype). Patients in hematological CR, CRi or marrow CR will proceed to consolidation treatment :Once the cohort dose has been decided by the SRC, a second cohort of 33 patients will be enrolled 2. Consolidation treatment (in patients who achieved CR, Cri, or marrow CR) 6 monthly courses of : DNR (at the daily dose required to achieve CR) day1, combined to AraC 60 mg/m2/12h SC during 5 days will be given. Lenalidomide 10 mg/ d during the first 2 weeks of the course. 3. Maintenance treatment Lenalidomide 10 mg/d 2 weeks every month until relapse (dose reduced if cytopenias) In patients still responding after 52 weeks, the drug will continue to be supplied, and follow up until death will be continued in all patients. SECOND PART OF THE TRIAL AFTER AMENDMENT Treatment schedule of the 2nd Part of the trial In dose level 4, 20 patients will receive lenalidomide 25 mg/d during 21 days combined to DNR- AraC chemotherapy (DNR 60 mgm2/d x3d and AraC 200mg/m2d x7d) during induction. During consolidation, patients will receive Lenalidomide 25 mg/d during 14 days, combined with DNR 60 mgm2/d x1d and AraC 60 mg/m2 x2/d x5d. finally, during maintenance, patients will receive Lenaidomide 25 mg/d x14d every months, until relapse. Progression or not to the next cohort (Lenaidomide 50 mg) will be decided after inclusion of 20 patients, after review of toxicity and efficacy by an independent safety review committee (SRC) (Briefly, given median times to reach ANC and platelets \> 500 and 50000/mm3, respectively of about 27 days in our previous trial with chemotherapy alone (Gardin, Blood), DLT would be defined by having greater than 3 of 10 patients recovering those levels after more than 40 days, or the occurrence of unexpected grade III-IV non hematological toxicity). Efficacy would be defined as a response rate ≥60%. In dose level 5, 20 patients will receive lenalidomide 50 mg/d during 21 days combined to DNR- AraC chemotherapy (DNR 60 mgm2/d x3d and AraC 200mg/m2d x7d) during induction. During consolidation, patients will receive Lenalidomide 50 mg/d during 14 days, combined with DNR 60 mgm2/d x1d and AraC 60 mg/m2 x2/d x5d. finally, during maintenance, patients will receive Lenaidomide 50 mg/d x14d every months, until relapse.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
85
1. Induction treatment Lenalidomide 10 mg once daily PO during 3 weeks . in combination with classical 7+3 chemotherapy. 2. Consolidation treatment 6 monthly courses of : Lenalidomide 10 mg/ d during the first 2 weeks in combination with classical 5+1 consolidation chemotherapy 3. Maintenance treatment Lenalidomide 10 mg/d 2 weeks every month until relapse In absence of toxicity, 20 additionnal patients will be included with lenalidomide dose of 25mg/J, then 20 other additionnals patients with Lenalidomide 50mg/J
CH Angers
Angers, France
hopital Victor Dupouy
Argenteuil, France
Centre Hospitalier de La Cote Basque
Bayonne, France
Hôpital Avicenne
Bobigny, France
CHU Haut-Lévèque
Bordeaux, France
Centre hospitalier de Chambéry
Chambéry, France
CHU de Clermont-Ferrand
Clermont-Ferrand, France
Centre henri Mondor
Créteil, France
Centre Hospitalier du Mans
Le Mans, France
Centre Hospitalier de Lens
Lens, France
...and 15 more locations
Response (CR, mCR and Cri, according to IWG criteria for AML and IWG 2006 criteria for MDS) to the combination of lenalidomide and chemotherapy in adult high and int 2 MDS (IPSS) or AML with deletion 5q[31]
Time frame: At the end of induction
Duration of response
Time frame: At 1 and 2 years
Progression to AML
Time frame: At 1 and 2 years
Survival and safety of the combination of lenalidomide and chemotherapy
Time frame: At 1 and 2 years
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