title: Combination of antiangiogenic therapy using the mTOR-inhibitor everolimus and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: a dose-finding study.
abstract: Pancreatic adenocarcinomas are associated with a poor survival prognosis. Besides curative surgical resection, only limited therapies with modest impact are available. New evidence suggests that the mammalian target of rapamycin pathway may be involved in the pathogenesis of neuroendocrine tumors, and breast and renal cell cancer. The phase I study described here was therefore designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of the mammalian target of rapamycin inhibitor everolimus in combination with gemcitabine in patients with advanced pancreatic cancer. Eligible patients had histologically confirmed locally advanced and/or metastatic pancreatic carcinoma and were administered 5 mg everolimus every second day (cohort 1, 2, 3) or 5 mg daily (cohort 4, 5) in combination with escalating low-dose gemcitabine. It was found that if two patients showed DLTs, MTD was reached and gemcitabine dose escalation was stopped at this level. Twenty-seven patients were enrolled in the study (cohort 1: n=3; cohort 2: n=4; cohort 3: n=6; cohort 4: n=7; cohort 5: n=7) and received a maximum 600 mg gemcitabine/week. In cohort 5, two of the six patients experienced DLTs (grade 3 liver toxicity lasting for>7 days). MTD was measured as 400 mg/m/week gemcitabine plus 5 mg/day everolimus. The MTD of a low-dose gemcitabine treatment in combination with everolimus was determined and no new safety concerns were identified in patients with advanced pancreatic cancer.
authors.affiliation: aDepartment of Surgery bDepartment of Internal Medicine III cInstitute of Radiology, LMU, Munich dDepartment of Internal Medicine I, University Ulm, Ulm eBRK Schlossbergklinik, Oberstaufen fNovartis Pharma GmbH, Nürnberg gDepartment of Surgery, University of Magdeburg, Magdeburg, Germany hDepartment of Radiology and Nuclear Medicine, University Basel, Basel, Switzerland.
authors.forename: Mareile
authors.initials: M
authors.lastname: Joka
authors.forename: Stefan
authors.initials: S
authors.lastname: Boeck
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Zech
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.forename: Goetz von
authors.initials: Gv
authors.lastname: Wichert
authors.forename: Thomas
authors.initials: T
authors.lastname: Licht
authors.forename: Annekatrin
authors.initials: A
authors.lastname: Krause
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.forename: Christiane J
authors.initials: CJ
authors.lastname: Bruns
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010179:Pancreas / Q000098:blood supply; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D003841:Deoxycytidine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000093542:Gemcitabine