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4632 Background: Preclinically, HIV Protease Inhibitors (HPIs) radiosensitized tumours with activated PI3-kinase/Akt pathway. We determined the tolerance of nelfinavir with chemoradiation for patients with locally advanced pancreatic cancer (LAPC). METHODS: Patients with histologically proven LAPC were eligible. Oral nelfinavir (2 x 1250 mg) was started 3 days before and continued throughout chemoradiation to 50.4 Gy (boost 59.4 Gy) in 12 patients. Two gemcitabine dose levels (DL) were tested, 6 patients each: 200 mg/m(2) and 300 mg/m(2) on days 1, 8, 22, and 29. MTD was defined as DLT occurring in 1/3 or 2/6 patients. DLT was defined as Grade 4 hematologic toxicity or nonhematologic toxicities of ≥ Grade 3 during treatment or within 4 weeks after completion unless clearly attributable to other clinical causes (e.g. stent occlusion). The MTD was defined as the dose of gemcitabine associated with DLT occurring in 33% of the patients treated at the same DL, and the recommended phase II dose (RPTD) was defined as the DL below the MTD. Cisplatin was administered on the same days at 30 mg/m(2). Phospho-Akt downregulation by nelfinavir was monitored by immunoblotting in patient leukocytes. Restaging PET/CT and CA19-9 levels served to assess response, and responding tumors were resected. RESULTS: Per DL, 5/6 patients received full treatment. Two patients dropped out, one because of clinical depression (DL1) and one with peritoneal metastasis (DL2). Grade 4 toxicities were a transaminase elevation (DL2) due to biliary stent occlusion and acute cholecystitis due to peritoneal metastasis (DL2). Stent occlusions led to DLT grade 3 liver enzyme and bilirubin elevations (2 patients DL1, 1 patient DL2). Grade 3 nausea/vomiting occurred in a DL2 patient and weight loss in a DL1 patient who refused supportive feeding. DL2 was determined as Recommended Phase Two Dose. Secondary complete resection was possible in 6/10 fully treated patients, and one tumor was pathologically sterilized. Partial CT-responses were observed in 5/10 fully treated patients. PET-responses were complete in 5/9, partial in 2/9. No PET-response was seen in 2/9 evaluable patients. CONCLUSIONS: Combined nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with LAPC. [Table: see text].

Type

Journal article

Journal

J Clin Oncol

Publication Date

20/05/2008

Volume

26