Phase I/II Study of Lenalidomide and Gemcitabine as First-line Treatment in Patients With Locally Advanced or Metastatic 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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety (phase I).
In the phase I part of the study, the primary outcome is to determine the MTD and safety of the regimen lenalidomide and gemcitabine in combination. Data from all subjects who receive any study drug will be included in the safety analyses, according to the NCI CTCAE v3.0.
Within the first day after start of treatment until 30 days post the last dose of study drug.
Håkan Mellstedt, Prof.
Karolinska University Hospital
Sweden: Medical Products Agency