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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/m(2)/day over weeks 1, 2, 4, and 5 for dose level 1 and 560 mg/m(2)/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 consisting in one case of grade 3 diarrhea and in the other grade 3 GI hemorrhage associated with grade 3 thrombocytopenia and neutropenia. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. Four patients did not complete therapy due to disease progression. One patient on dose level 1 showed a partial response of six months duration. Five patients had stable disease and two patients had progressive disease. K-RAS mutations were found in tumors from three of the four patients evaluated. Farnesylation of the surrogate marker HDJ2 in peripheral blood mononuclear cells was reversibly inhibited during L-778 treatment. In a patient-derived cell line with a K-RASmutation, radiosensitization and reversal of Akt and MAPK activation was noted in the presence of L-778. CONCLUSIONS: The combination of L-778 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization accompanied by reduced Ras effector activation was seen in a patient-derived pancreatic cancer cell line. [Table: see text].


Journal article


J Clin Oncol

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