Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors

• Published in: Cancer chemotherapy and pharmacology 2011-02, Vol.67 (2), p.305-314
• Main Authors: Traynor, Anne M, Hewitt, Maureen, Liu, Glenn, Flaherty, Keith T, Clark, Jason, Freedman, Steven J, Scott, Boyd B, Leighton, Ann Marie, Watson, Patricia A, Zhao, Baiteng, O'Dwyer, Peter J, Wilding, George
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Area Under Curve; Aurora kinase; Aurora Kinases; BCR-ABL mutations; Biological and medical sciences; Biological Availability; Cancer Research; Chromosome aberrations; Female; Hematologic Diseases - chemically induced; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Medical genetics; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I; Piperazines - pharmacology; Piperazines - therapeutic use; Piperazines - toxicity; Protein Serine-Threonine Kinases - antagonists & inhibitors; Serine/threonine protein kinases; Treatment Outcome; Tumors; Young Adult
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-010-1318-9

Purpose To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of the 24-h continuous intravenous (CIV) infusion of MK-0457, a novel pan-Aurora kinase inhibitor, in patients with advanced solid tumors and to determine the bioavailability of an oral dose of 100 mg MK-0457. Study design MK-0457 was administered as a 24-h CIV infusion every 21 days. Dose escalation proceeded per toxicity criteria. A 100-mg oral dose was administered to seven patients 48 h prior to the CIV infusion dose of 64 mg/m²/h. Results Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m²/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m²/h. The most common adverse events were nausea, vomiting, diarrhea, and fatigue. Pharmacokinetic analyses revealed that CIV infusion MK-0457 had an estimated mean terminal half-life of approximately 6.6-10.2 h and that end-of-infusion concentrations and mean AUCs were approximately dose proportional. The estimated mean oral bioavailability of MK-0457 was 7.9%. One patient with advanced ovarian cancer attained prolonged stable disease for 11 months. Conclusions MK-0457 was well tolerated in this schedule. Almost half the patients attained stable disease. Further development of this class of agents will likely occur in combination with other anti-cancer treatments.