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. 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). 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. 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.

Docetaxel entrapped nanoparticle CPC634 is associated with dose-related skin toxicity that resembles conventional docetaxel (Cd)-related skin toxicity. This study compared the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634. In this randomised cross-over study, patients with solid tumours received one cycle of CPC634 and Cd (both at 75 mg/m²). Skin biopsies were taken at baseline and at day 8 of both cycles. Released and total docetaxel (released docetaxel plus entrapped docetaxel) concentrations and histopathological changes in the skin biopsies were evaluated. Twenty patients underwent paired skin biopsies for pharmacokinetic analysis and 10 patients had biopsies available for histopathological assessment. The total skin docetaxel concentration was 369% (95%CI: 229% to 569%, p < 0.001) higher after CPC634 administration compared to Cd while the released docetaxel concentrations were not statistically different (95%CI: −9% to 63%, p = 0.169). The CPC634 released docetaxel concentration in the skin was positively correlated with plasma concentrations (Pearson’s correlation 0.48, p = 0.03). Histopathological examination revealed increased apoptosis, mitotic cells with nuclear atypia, and micronucleation with an enhanced Ki-67 index for both compounds. In conclusion, both CPC634 and Cd treatment result in docetaxel exposure in the skin causing cutaneous anti-mitotic effects such as micronucleation, which could induce an inflammatory reaction leading to skin toxicity.