A phase I trial of the farnesyltransferase and geranylgeranyltransferase-I inhibitor L-778,123 (L-778) and radiotherapy for locally advanced pancreatic cancer

4098 Background: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with RASmutations or Ras activation and produce clinical response in patients with cancer. Treatment with the dual farnesyltransferase and geranylgeranyltransferase-I inhibitor L-778 in combination with radiotherapy has shown tolerability and clinical effects in patients with NSCLC and cancers of the head and neck. Methods: The aim of this study was to determine the maximally tolerated dose of L-778 for patients with locally advanced pancreatic cancer. L-778 was given by continuous I.V. infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1 and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. Results: There were no dose-limiting toxicities (DLTs) observed in eight patients treated on dose level 1. Two of four patients on dose level 2 experienced DLTs consisti...