Oxaliplatin-associated hypersensitivity reactions: clinical presentation and management.

Hypersensitivity reactions to cisplatin and carboplatin have been reported in the literature to occur at a rate of 10%-27%. Initial reports of hypersensitivity reactions to oxaliplatin were low; however, more recently, it appears as if the incidence of hypersensitivity reactions to oxaliplatin is similar to that of the earlier generation platinum agents. The degree of the reaction varies from mild flushing to life-threatening anaphylactic responses. After a mild hypersensitivity reaction to oxaliplatin, re-exposing a patient can be considered after administering immunosuppressants (eg, high-dose corticosteroids and histamine antagonists) and/or prolonging the duration of oxaliplatin infusion. In the case of moderate-to-severe reactions to oxaliplatin, re-exposure is usually not considered, and alternative forms of therapy should be explored. However, there are reports of successful desensitization to oxaliplatin, and therefore, re-exposing a patient can be considered after carefully weighing the risks and benefits of additional oxaliplatin therapy.

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

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/m(2)/h. RESULTS: Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m(2)/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m(2)/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.

A phase 1 study of fixed dose rate gemcitabine and irinotecan in patients with advanced pancreatic and biliary cancer.

BACKGROUND: The combination of a fixed dose rate (FDR) infusion of gemcitabine and irinotecan may have a synergistic effect in the treatment of patients with advanced and metastatic pancreatic and biliary cancer. The current study was conducted to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of the combination. METHODS: There were 32 patients with metastatic pancreatic and advanced unresectable/metastatic biliary adenocarcinoma who were entered into this open-label, phase 1 dose escalation trial. Gemcitabine was administered at an FDR of 10 mg/m(2)/minute intravenously (iv). Irinotecan was administered iv over 60 minutes after gemcitabine. Both gemcitabine and irinotecan were given on Days 1 and 8 of a 21-day cycle. RESULTS: The MTD of the combination was gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The DLTs were neutropenia and neutropenic fever. Other DLTs included diarrhea, dehydration, and fatigue. Two patients developed deep venous thrombosis during the treatment. The efficacy of the combination was encouraging, even at the lower dose levels. Of 30 assessable patients, there was 1 complete response, 6 partial responses, and 16 patients with stable disease, with a response rate of 23%, a disease control rate of 76%, a median progression-free survival of 4.7 months, and a median overall survival of 7.0 months. The average number of treatment cycles received was 11. CONCLUSIONS: The recommended doses of the combination for future study are gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The efficacy of the combination is encouraging. Further assessment of the combination with or without biologic agents is suggested.