ANTICANCER AGENTS INCORPORATING POLYMER MICELLES UNDER CLINICAL EVALUATION

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Abstract

Tumor-targeted delivery of therapeutic agents is a long-standing pharmacological goal to improve the treatment selectivity and therapeutic index. Most scientists have sought to use ‘active’ receptor-mediated tumor-targeting systems. However, the ‘passive’ targeting afforded by the ‘Enhanced Permeability and Retention (EPR) effect’ provides a versatile and non-saturable approach for tumor-selective delivery. Polymeric micelles are ideally suited to exploit the EPR effect, and have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies.

NK105 is a micellar formulation for paclitaxel (PTX) whose recommended dose (RD) is 150 mg PTX equivalent/m2 administered every 3 weeks, as determined in a phase I trial. Following the phase 1 study, a phase 2 study of NK105 was conducted to evaluate the efficacy and safety of NK105 in patients with advanced gastric cancer after failure of first-line chemotherapy. Eligible patients had measurable disease and one chemotherapeutic regimen except taxane. NK105 (150 mg PTX equivalent/m2) was administered by a 30-min intravenous infusion every 3 weeks without anti-allergic premedication until disease progression, unacceptable toxicity or patient refusal. Fifty-seven patients were enrolled and 56 were evaluable for efficacy. Two complete responses and 12 partial responses were observed for an ORR of 25%. The median PFS and OS were 3.0 and 14.4 months, respectively. Causally related toxicity was mainly mild (grades 1–2) to severe (grades 3–4); other data: neutropenia (64.9%); leukopenia (17.5%); lymphopenia (8.8%); neuropathy-sensory (1.8%); fatigue (3.5%); and stomatitis (1.8%).

NC-6004 consists of PEG and the coordinate complex of Poly(Glu) and CDDP. The mean particle size is ∼20 nm. Rats data revealed that the CDDP 10 mg/kg administration group showed significantly higher concentrations of BUN and creatinine when compared with the NC6004 10 mg/kg administration group. We then conducted a phase 1 study of NC-6004 and found that no renal toxicity occurred with minimum hydration. In addition, GI toxicity was very weak, that is, almost all patient entered in the trial experienced grade 1 or weaker GI toxicity.

At present, a phase 2 study of NC-6004 plus gemcitabin is underway in patients with advanced pancreatic cancer in Taiwan and Singapore.

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