Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study

Abstract

Introduction: A water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK).

Methods: This was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model.

Results: Thirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m². MTD was established as 250 mg/m². Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m² with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration-time curve to infinite time (AUC_inf), respectively.

Conclusion: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (C_max) and AUC_inf showed a tendency to increase linearly with dose within the 150-275 mg/m² dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy.

Trial registration: EudraCT no: 2004-001821-54.

Funding: Oasmia Pharmaceutical AB.

Keywords: Cancer; Dose-finding; First-in-man; Nano-sized micelles; Paclitaxel; Paclitaxel micellar; Pharmacokinetics; XR17.

Fig. 1

Patient disposition. N number of patients, n number of data sets. Of the 34 PK data sets assessed, nine were excluded from the PK evaluation because of the following reasons: missing actual sampling times (n = 1, 175 mg/m²), insufficient data for the PK model (i.e. only 2 post-infusion samples; n = 1, 225 mg/m²), poor fit to the model (n = 2, 225 mg/m², and n = 2, 250 mg/m²) or when PK data sets were assessed repeatedly for the same patient at the same dose level (n = 3, 225 mg/m²)

Fig. 2

Plasma concentration–time curves for total paclitaxel at 1-h infusion of paclitaxel micellar at doses ranging between 90 and 275 mg/m². a Mean concentrations for each dose level on a linear–linear scale, excluding the 90 mg dose (n = 1) since it is outside the clinical dose range and mainly used to assess safety. b Individual (dots) and mean concentrations (continuous line) of data sets included in the PK evaluation, presented per dose level on log-linear scales. n number of data sets

Fig. 3

Relationship between given dose and a mean C_max or b mean AUC_inf after a 1-h infusion for doses between 150 mg/m² and 275 mg/m² of paclitaxel micellar

Fig. 4

Mean C_max of paclitaxel after 0.5-h infusions of paclitaxel micellar (orange squares) and nab-paclitaxel (empty circles, blue triangles) at various dose levels. Nab-paclitaxel data were extracted from six studies compiled by Stage et al. (empty circles; [14]) and one study by Nyman et al. (blue triangles; [15]). Number of patients per dose level of paclitaxel micellar was as follows: N = 2 (150 mg/m²), N = 3 (175 mg/m²), N = 4 (200 mg/m²), N = 4 (225 mg/m²), N = 5 (250 mg/m²), N = 6 (275 mg/m²)