Abstract A128: A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies
Authors: Deeken John F. , Weiss Glen J. , Pishvaian Michael J. , Ramanathan Ramesh K. , Hwang Jimmy , Subramaniam Deepa , He Aiwa Ruth , Padiernos Emerson , Cotarla Ion , Lewandowski Karen , Rahman Aquil , Ali Shadid , Marshall John L. 
Published: June 2012

Abstract
Background: Docetaxel is a semi-synthetic microtubule disrupting antineoplastic drug indicated for the treatment of a wide variety of solid tumor malignancies. Past clinical trials have shown a dose-response correlation when used in the treatment of prostate and breast cancer. Common dose limiting toxicities are myelosuppression and neuropathy. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and drug related toxicities, and help overcome multidrug resistance mediated by P-glycoprotein or similar resistant efflux mechanisms. The aims of this phase I study were to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), pharmacokinetics (pK), and clinical response of 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/m2. Drug was infused over 1 hour. Premedication with dexamethasone was not required as it is with standard docetaxel therapy. In patients who experienced infusionrelated reactions pre-medication with steroids, antihistamines, and antipyretics were provided in subsequent cycles. Toxicities were recorded using NCI-CTCAE 3.0, and response was assessed using RECIST criteria. PK samples were drawn during C1 and analyzed using Win NonLin.
Results: Twenty-four patients were treated in total. The total number of cycles each patient received ranged from 1 to 21 (median = 4). Dose escalation proceeded until DLTs were experienced by 2 out of 2 patients at the 132mg/m2 dose level (both Grade 4 neutropenia). When additional patients were treated at the 110 mg/m2 dose, 2 patients experienced Grade 4 neutropenia. The dose level was reduced to 85mg/m2, with one patient experiencing Grade 4 neutropenia at this level. The protocol was amended to allow G-CSF growth factor support and dose re-escalation. An additional 4 patients were treated at 110mg/m2 and none of these patients experienced Grade 4 neutropenia. At this dose level, two patients experiencing Grade 3 fatigue. No patient experienced Grade 3/4 neuropathy, even in two patients treated for 10 and 21 cycles. Two patients experienced Grade 2 neuropathy. Additional toxicities included Grade 3 anemia in three patients. Drug pharmacokinetics followed a two-compartment elimination pattern. Cmax and AUCinf were proportional to dose through the 110mg/m2 dose level with a mean clearance of 28.5L/hr/m2. At the 132mg/m2 dose Cl was 45.4 L/hr/m2. Serum half-lives at the differing dose levels ranged from 15.1 to 22.4 hr. There was no correlation between pK measures and toxicity. One patient had a confirmed partial response (PR) and another had an unconfirmed PR (8%). Eight patients (33%) had prolonged stable disease lasting more than 3 months. One patient continues to have stable disease after 21 cycles.
Conclusion: LE-DT was tolerable with expected toxicities of neutropenia, anemia, and fatigue, but without water retention (edema). Importantly, in this heavily pretreated population no patient experienced clinically significant neuropathy. Clinical benefit (SD+PR) was observed in 41% of the patients. The recommended phase II dose of LE-DT is 110mg/m2 with growth factor support. Phase II studies of LE-DT in prostate and pancreatic cancers are planned.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A128.