A Randomised Phase II study comparing the efficacy of 5azacitidine alone versus combination therapy with lenalidomide and 5azacitidine in patients with higher risk myelodysplastic syndromes (MDS) and low marrow blast count acute myeloid leukaemia (AML). (MDS04)

Funding

Commercial sector/Industry,Celgene Pty Ltd

Scientific enquiries

Dr Dr Melita Kenealy

Brief Summary

Lenalidomide and Azacitidine each have clear evidence of efficacy in MDS, and have shown activity in AML. However, not all patients respond so better regimens, including combinations, are required. MDS and AML are heterogeneous diseases, and lenalidomide and azacitidine may target different cellular populations and induce differing clinical responses. Combinations of immunomodulatory drugs and azacitidine have been explored and shown to be feasible. This is an open label, multi-centre, randomise .... Lenalidomide and Azacitidine each have clear evidence of efficacy in MDS, and have shown activity in AML. However, not all patients respond so better regimens, including combinations, are required. MDS and AML are heterogeneous diseases, and lenalidomide and azacitidine may target different cellular populations and induce differing clinical responses. Combinations of immunomodulatory drugs and azacitidine have been explored and shown to be feasible. This is an open label, multi-centre, randomised Phase II study exploring the toxicity and efficacy of the combination of lenalidomide and 5azacitidine compared to 5azacitidine alone. After an initial 2 cycles with 5azacitidine (75mg/m2/day x7days over 9days of a 28 day cycle; 5-2-2 regimen), patients will be randomised 1:1 to either combination 5azacitidine and lenalidomide (5azacitidine 75mg/m2/day x5days of a 28 day cycle + lenalidomide commencing cycle 3 10mg/dayx21days of a 28 day cycle) or 5azacitidine alone (75mg/m2/day x7days over 9days of a 28 day cycle; 5-2-2 regimen) for 12 months to primary endpoint, then all patients may continue 5azacitidine alone until progression or toxicity. Response will be determined by peripheral blood counts, transfusions, bone marrow morphology and cytogenetics, according to IWG criteria. The study also incorporates a correlative laboratory component designed to determine the mechanism of action of 5azacitidine +/- lenalidomide and to determine a baseline profile which may predict those most responsive. These studies will incorporate gene methylation and expression, and enumeration of lymphocyte subsets, natural killer cell function and cytokine profiles.
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Key Inclusion Criteria

Disease diagnosis of either MDS (by World Health Organisation criteria, those with refractory anaemia and Refractory Anaemia with Ringed Sideroblasts to also have at least one clinically significant cytopenia), nonproliferative Chronic Myelomonocytic Leukaemia (CMML) or low marrow blast count AML; Eastern Cooperative Oncology Group (ECOG) 2 or less with life expectancy at least 3 months, adequate contraception and adequate renal and hepatic function, written informed consent.

Key Exclusion Criteria

Prior chemotherapy for MDS or AML except low dose cytarabine or hydroxyurea, any prior demethylating agent or immunomodulatory drug (including thalidomide or lenalidomide), prior diagnosis of cancer except with low risk of recurrence, significant renal, hepatic, cardiac or respiratory disease or severe active infection.