Abstract
Background: CPC634 is docetaxel entrapped in core-cross linked polymeric micelles. In preclinical studies, CPC634 demonstrated enhanced pharmacokinetics and improved therapeutic index. This phase I dose escalation study is the first-in-human study with CPC634.Methods: adult patients with advanced solid tumours received CPC634 intravenously either 3-weekly (Q3W) (part 1, dose range 15–100 mg/m2), 2-weekly (Q2W) (part 2, 45 mg/m2) or Q3W with dexamethasone premedication (part 3, 60 mg/m2).Results: thirty-three patients were enrolled. Skin toxicity was dose limiting (DLT) at ≥60 mg/m2 in part 1 and at 45 mg/m2 in part 2 and was the most common CPC634 related grade ≥ 3 adverse event (24%). With dexamethasone premedication no DLTs were observed at 60 mg/m2 Q3W. CPC634 exhibited a dose-proportional pharmacokinetic profile. At 60 mg/m2, the plasma area under the curve was 4067.5 ± 2974.0 ng/h/mL and the peak plasma level 217.3 ± 91.9 ng/mL with a half-life of 39.7 ± 9.4 h for released docetaxel.Conclusion: CPC634 could be administered safely upon pretreatment with dexamethasone. Cumulative skin toxicity was the main DLT. The recommended phase 2 dose was determined at 60 mg/m2 Q3W with dexamethasone premedication.
Highlights
CPC634 is docetaxel entrapped in core-cross linked polymeric micelles
With dexamethasone premedication no dose limiting (DLT) were observed at 60 mg/m2 Q3W
The recommended phase 2 dose was determined at 60 mg/m2 Q3W with dexamethasone premedication
Summary
CPC634 is docetaxel entrapped in core-cross linked polymeric micelles. In preclinical studies, CPC634 demonstrated enhanced pharmacokinetics and improved therapeutic index. Several nanoparticles have been developed that are physical assemblies like liposomes and traditional micelles These physical assemblies are often prone to premature drug release and/or rapid disintegration upon entry into the circulation [7]. This poor pharmacokinetic profile is presumably the reason why most of the current nanoformulations in clinical trials show a comparable toxicity profile to the native drug and only a few show improved efficacy [5,8,9]. CPC634 is a novel nanomedicine consisting of docetaxel covalently entrapped in a stabilized, 65 nm sized core-cross linked polymeric micelles (CCL-PMs) [10,11]. Docetaxel is covalently crosslinked to CCL-PMs via a hydrolysable ester
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