A Phase I clinical study of cisplatin-incorporated polymeric micelles (NC-6004) in patients with solid tumours

Background: On the basis of preclinical studies of NC-6004, a cisplatin-incorporated micellar formulation, we hypothesised that NC-6004 could show lower toxicity than cisplatin and show greater anti-tumour activity in phase I study. Methods: A total of 17 patients were recruited in a range of advanced solid tumour types. NC-6004 was administered intravenously (i.v.) every 3 weeks. The dose escalation started at 10 mg m −2 and was increased up to 120 mg m −2 according to the accelerated titration method and modified Fibonacci method. Results: One dose-limiting toxicity (DLT) occurred in a patient who was given 90 mg m −2 of NC-6004, otherwise any significant cisplatin-related toxicity was not observed or generally mild toxicity was observed. Despite the implementation of post-hydration and pre-medication regimen, renal impairment and hypersensitivity reactions still developed at 120 mg m −2 , which led to the conclusion that the maximum tolerated dose was 120 mg m −2 , and the recommended dose was 90 mg m −2 , although DLT was not defined as per protocol. Stable disease was observed in seven patients. The maximum concentration and area under the concentration–time curve of ultrafilterable platinum at 120 mg m −2 NC-6004 were 34-fold smaller and 8.5-fold larger, respectively, than those for cisplatin. Conclusion: The delayed and sustained release of cisplatin after i.v. administration contributes to the low toxicity of NC-6004.