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Phase I Trial of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir and Chemoradiation for Locally Advanced Pancreatic Cancer

Thomas B. Brunner, Matthias Geiger, Gerhard G. Grabenbauer, Marga Lang-Welzenbach, Tine S. Mantoni, Alexander Cavallaro, Rolf Sauer, Werner Hohenberger, W. Gillies McKenna

From the Departments of Radiation Oncology and Surgery, and Department of Nuclear Medicine, Friedrich-Alexander University of Erlangen-Nuremberg, Nuremberg, Germany; and Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom

Corresponding author: Thomas B. Brunner, MD, Gray Institute of Radiation Oncology and Biology, University of Oxford, Radiobiology Research Institute, Churchill Hospital, Oxford, OX3 7LJ, United Kingdom; e-mail: thomas.brunner{at}rob.ox.ac.uk

Purpose: Preclinically, HIV protease inhibitors radiosensitize tumors with activated PI3-kinase/Akt pathway. We determined the toxicity of nelfinavir chemoradiotherapy in borderline resectable and unresectable pancreatic cancer.

Patients and Methods: Oral nelfinavir (2 x 1,250 mg) was started 3 days before and continued throughout chemoradiotherapy to 50.4 Gy (boost, 59.4 Gy) in 12 patients. Two gemcitabine dose levels (DL) were tested (200 mg/m² and 300 mg/m² on days 1, 8, 22, and 29). Cisplatin was administered on the same days at 30 mg/m². Phospho-Akt downregulation by nelfinavir was monitored by immunoblotting in patient leukocytes. Restaging positron emission tomography (PET)/computed tomography (CT) and CA19-9 levels served to assess response, and responding tumors were resected.

Results: At each DL, five of six patients completed chemoradiotherapy, and two of 12 patients had incomplete chemoradiotherapy because of clinical depression (DL1) and peritoneal metastasis (DL2). Grade 4 toxicities were a transaminase elevation (DL2) as a result of biliary stent occlusion and acute cholecystitis as a result of peritoneal metastasis (DL2). Stent occlusions led to dose-limiting toxicities of grade 3 liver enzyme and bilirubin elevations (two patients at DL1, one patient at DL2). Grade 3 nausea and vomiting occurred in a DL2 patient, and weight loss occurred in a DL1 patient who refused supportive feeding. Secondary complete resection was possible in six of 10 patients with complete chemoradiotherapy, including one tumor with pathologic sterilization. Partial CT responses were observed in five of 10 patients who completed chemoradiotherapy. Of nine patients assessable by PET,responses were complete in five patients and partial patients, and stable disease was observed in two patients.

Conclusion: The combination of nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with pancreatic cancer.

Supported by the University Hospitals of Erlangen and by Grants No. H3RMWX0 from the Medical Research Council (T.B.B., W.G.M.), H3RMGW0 from Cancer Research UK (W.G.M.), and 5PO1-CA-075138 from the National Cancer Institute (T.B.B., W.G.M.). T.B.B. received research funds from F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Both T.B.B. and M.G. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: EudraCT 2006-001766-17.