A randomized phase III trial in patients with recurrent platinum sensitive ovarian cancer comparing efficacy and safety of paclitaxel micellar and Cremophor EL-paclitaxel.

OBJECTIVE: Paclitaxel micellar was developed to avoid Cremophor-EL (Cr-EL) associated dose limiting toxicity and to allow a shorter infusion time. The efficacy and safety of paclitaxel micellar (+carboplatin) was compared to Cr-EL paclitaxel (+carboplatin) in recurrent platinum-sensitive ovarian, fallopian tube or peritoneal carcinoma. METHODS: This was a multicentre, open-label, randomized phase III trial. Adult patients with recurrent disease was assigned to six 3-week cycles of paclitaxel micellar (250 mg/m2) administered as 1-h infusion or Cr-EL paclitaxel (175 mg/m2) as 3-h infusion. Both arms received carboplatin (AUC 5-6). Primary objective was non-inferiority for progression free survival (PFS) using computed tomography scans. Overall survival (OS) was included as secondary endpoint. RESULTS: Between 2009 and 2013, 789 patients were randomized to receive experimental (N = 397) or control (N = 392) treatment. PFS for paclitaxel micellar was non-inferior to Cr-EL paclitaxel with a hazard ratio of 0.86 (95% CI: 0.72;1.03) in the per protocol population (PP), favouring paclitaxel micellar (non-inferiority margin was 1.2). Non-inferiority of OS was shown in the PP population with a hazard ratio of 0.95 (95% CI: 0.78; 1.16), favouring paclitaxel micellar (non-inferiority margin was 1.185). The most common adverse event was neutropenia (grade ≥ 3); 245 patients (79%) for paclitaxel micellar vs 213 patients (66%) for Cr-EL paclitaxel. The frequency of peripheral sensory neuropathy (any grade) was similar between the arms; 16% for paclitaxel micellar and 20% for Cr-EL paclitaxel. CONCLUSION: Paclitaxel micellar (+ carboplatin) is non-inferior to Cr-EL paclitaxel (+ carboplatin) in terms of PFS and OS in the studied population. It provides a treatment option of a higher paclitaxel dose with a shorter infusion time without mandatory premedication. TRIAL REGISTRATION NUMBER: 2008-002668-32 (EudraCT), NCT00989131 (ClinicalTrials.gov).

Pharmacokinetics of Total and Unbound Paclitaxel After Administration of Paclitaxel Micellar or Nab-Paclitaxel: An Open, Randomized, Cross-Over, Explorative Study in Breast Cancer Patients.

INTRODUCTION: Paclitaxel micellar is a novel formulation of paclitaxel in which retinoic acid derivates solubilize paclitaxel. The aim of the present study was to compare the unbound and total plasma pharmacokinetics of the new formulation with those of nanoparticle albumin-bound (nab)-paclitaxel and to further assess its safety. METHODS: In this open, randomized, cross-over study, 28 female patients with breast cancer were given paclitaxel micellar and nab-paclitaxel as a 1-h intravenous infusion at a dose of 260 mg/m2. Plasma samples were collected during 10 h, which were projected to cover at least 80% of the area to infinite time, AUCinf. Unbound paclitaxel was measured in ultrafiltrate of plasma. Total paclitaxel in plasma was measured after protein precipitation with acetonitrile. Both assays used ultra-performance liquid chromatography (UPLC) followed by MS/MS for drug quantification. The unbound fraction, fu, was calculated as the ratio between the unbound and the total concentration. RESULTS: No difference in fu of paclitaxel between the two formulations was observed. Statistical comparison of AUC0-10h and Cmax of unbound paclitaxel demonstrated that the two formulations met the criteria for bioequivalence. Regarding total paclitaxel levels, Cmax but not AUC0-10h met the criteria. This study supports a safe administration of paclitaxel micellar. CONCLUSION: The two formulations, paclitaxel micellar and nab-paclitaxel, behaved similarly following infusion. Probably, both formulations dissociate immediately in the blood, whereupon released paclitaxel rapidly distributes into tissue. Judged from the bioequivalence demonstrated for unbound paclitaxel, the two formulations are considered clinically equivalent. TRIAL REGISTRATION: EudraCT no.: 2010-019838-27. FUNDING: Oasmia Pharmaceutical AB.

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

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 (AUCinf), respectively. CONCLUSION: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf 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.