Lenalidomide and Gemcitabine as First-line Treatment in Patients With Pancreatic Cancer

Pancreatic cancer is characterised by aggressive growth, treatment resistance and an extremely poor prognosis. In subjects with locally advanced or metastatic disease, the median survival is approximately 6 - 11 months and 2 - 6 months, respectively. The currently accepted treatment for this disease in EU is gemcitabine which supplanted treatment with 5-FU after it was shown that median survival duration was marginally improved (4.41 and 5.65 months respectively, p = 0,022). The reported median survival time for subjects treated with single-agent gemcitabine in randomized phase III studies ranged form 4.9 to 7.2 months. Despite these improvements in the treatment of pancreatic cancer, the prognosis remains very poor. Lenalidomide (Revlimid®) belongs to a proprietary class of compounds called immunomodulatory drugs (IMiDs). IMiDshave both immunomodulatory and anti-angiogenic properties which could confer antitumour and antimetastatic effects. Lenalidomide has been demonstrated to possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt phosphorylation response to bFGF.In addition, lenalidomide has a variety of immunomodulatory effects. Gemcitabine (Gemzar®) is a synthetic pyrimidine nucleoside analogue that is used as standard treatment of advanced pancreatic cancer. Beside the cytotoxic activity of gemcitabine, accumulating evidence has indicated that the product promote specific anticancer immune responses that contribute to the therapeutic effects of conventional therapy.Down-regulation in survival rate of pancreatic cell lines has more recently been observed, when treated with lenalidomide and gemcitabine in sub-optimal concentrations.Those data supports a hypothesis of a potential hyper-additive affect of the treatments given in combination. Therefore lenalidomide and gemcitabine should be of major interest to explore for combination therapy. This is a phase I/II open-label, multi-center study. It will consist of a phase I dose-finding part and a phase II part during which subjects will be treated at the MTD established during phase I. Lenalidomide will be administered by a stepwise dose-escalation schedule in the phase I part. Thus, the primary endpoint in the phase I part is to determine the MTD and safety of the regimen lenalidomide and gemcitabine as first-line treatment in subjects with advanced pancreatic cancer.In the phase II part, primary endpoint is to evaluate the immunomodulatory effects of lenalidomide in combination with gemcitabine in the same patient population.