A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.

BACKGROUND: Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.
METHODS: LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m(2) IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis.
RESULTS: Twenty-four patients were treated for 1-30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m(2). Two out of two patients experienced grade 4 neutropenia at the 132 mg/m(2) dose level. When an additional three patients were treated at the expanded 110 mg/m(2) dose level, two experienced grade 4 neutropenia. The 85 mg/m(2) dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m(2) with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8%), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33%) had stable disease lasting more than 3 months, for a clinical benefit rate of 41%.
CONCLUSION: LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41% of the patients. The recommended phase II dose of LE-DT is 85 mg/m(2) without G-CSF or 110 mg/m(2) with G-CSF.