title: Phase I dose escalation study of the PKCι inhibitor aurothiomalate for advanced non-small-cell lung cancer, ovarian cancer, and pancreatic cancer.
abstract: Protein kinase C iota (PKCι) is overexpressed in non-small-cell lung cancer, ovarian, and pancreatic cancers, where it plays a critical role in oncogenesis. The gold compound aurothiomalate (ATM) has been shown to inhibit PKCι signaling and exerts potent antitumor activity in preclinical models. We sought to determine the maximum tolerated dose (MTD) of ATM. We conducted a phase I dose escalation trial of ATM in patients with non-small-cell lung cancer, ovarian or pancreatic cancer. Patients received ATM intramuscularly weekly for three cycles (cycle duration 4 weeks) at 25, 50, or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Blood samples were analyzed for elemental gold levels. Patients were evaluated every 4 weeks for toxicity and every 8 weeks for response. Fifteen patients were enrolled in this study. Six patients were treated at 25 mg, seven at 50 mg, and two at 75 mg. There was one dose-limiting toxicity at 25 mg (hypokalemia), one at 50 mg (urinary tract infection), and none at 75 mg. There were three grade 3 hematologic toxicities. The recommended MTD of ATM is 50 mg. Patients received treatment for a median of two cycles (range 1-3). There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold consistent with linear pharmacokinetics. In summary, this phase I study was successful in identifying ATM 50 mg intramuscularly weekly as the MTD. Future clinical investigations targeting PKCι are currently in progress.
authors: aDepartment of Medical Oncology, Mayo Clinic, Rochester, Minnesota bDepartment of Cancer Biology, Mayo Clinic, Jacksonville, Florida cDepartment of Internal Medicine, Greater Baltimore Medical Center, Baltimore, Maryland dDepartment of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors: Aaron S
authors: AS
authors: Mansfield
authors: Alan P
authors: AP
authors: Fields
authors: Aminah
authors: A
authors: Jatoi
authors: Yingwei
authors: Y
authors: Qi
authors: Alex A
authors: AA
authors: Adjei
authors: Charles
authors: C
authors: Erlichman
authors: Julian R
authors: JR
authors: Molina
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006046:Gold / Q000097:blood; D006052:Gold Sodium Thiomalate / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D007273:Injections, Intramuscular; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000099293:Protein Kinase C-lambda
chemical_list: D000970:Antineoplastic Agents; D006046:Gold; D006052:Gold Sodium Thiomalate; D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda
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