Phase I study of NK105, a nanomicellar paclitaxel formulation, administered on a weekly schedule in patients with solid tumors

Abstract

Previous studies have established the rationale for NK105, a nanomicellar formulation of paclitaxel, administered every 3 weeks. The aim of this phase I study was to determine the recommended dose and pharmacokinetics of weekly administered NK105. NK105 was administered by a 30-min infusion once weekly for three consecutive weeks in each 4-week cycle. In the dose-escalation phase, three to seven patients with solid tumors were enrolled to each of the four dose levels (50–100 mg/m2; n = 16). At a dose level of 100 mg/m2, predefined dose-limiting toxicity (DLT) manifested in only one out of six evaluable patients, whereas a dose delay due to neutropenia during the first course occurred two patients. None of the three patients given 80 mg/m2 had a dose reduction, while a dose delay occurred in two. NK105 exhibited linear pharmacokinetics at doses of 50–100 mg/m2, and approximately 5 % of total paclitaxel was released from micelles. Thus, the recommended dose was set at 80 mg/m2, and an additional 10 advanced breast cancer (ABC) patients were given this dose in the dose-expansion phase. DLT manifested in two patients, and grade ≥ 3 neutropenia was found in eight patients. Among the nine patients who completed the first cycle, four had a dose reduction, mostly because of neutropenia. Of the 10 patients, six achieved partial response (PR), and four achieved stable disease (SD) status. Overall, weekly NK105 was well tolerated and had a desirable antitumor activity profile. Further investigations of NK105 in ABC patients are currently underway.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-016-0381-4) contains supplementary material, which is available to authorized users.

Baker’s Yeast Sensitizes Metastatic Breast Cancer Cells to Paclitaxel In Vitro

“…It induces an apoptotic effect on cancer at high concentrations 33 - 35 and, as a result, its treatment is associated with severe side effects, including gastrointestinal, pulmonary, and neuromuscular toxicities, as well as neutropenia, granulocytopenia, and hypotension. 36 - 38 Therefore, we have focused our research on finding dietary agents that may have the ability to reduce the toxicity of chemotherapy by using lower drug concentrations while maintaining potency against cancer cells. Our recent studies revealed that arabinoxylan rice bran, Biobran/MGN-3, has the ability to sensitize cancer cells to chemotherapy agents daunorubicin 22 and paclitaxel in vitro 23 and in vivo.…”

A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients

“…In a phase I study in solid tumours and breast cancer, all patients who received three or more treatment cycles ( n  = 7) achieved partial response or stable disease in the dose-escalation cohort ( n  = 15), and the overall response rate in the following expansion cohort ( n  = 10) was 60%. 5 In a phase II study evaluating a tri-weekly regimen of NK105 in treated advanced gastric cancer, NK105 (150 mg/m 2 ) had a preferable response rate of 25.0% ( n  = 56), including 2 complete responses. 6 These results suggested the potential of the EPR effect on the mode of action for NK105.…”

Clinical Translation of Self‐Assembled Cancer Nanomedicines

“…For example, more than 90% decrease in the size of the liver metastasis was achieved in a 60‐year‐old patient with pancreatic cancer after treatment with NK105 at a dose level of 150 mg m −2 , and the antitumor response maintained for nearly one year (Figure 2D,E). [ 56 ] In another phase I study report, the recommended dose and pharmacokinetics of weekly administered NK105 was studied in patients with solid tumors, [ 57 ] indicating linear pharmacokinetics at doses of 50–100 mg m −2 , and ≈5% of PTX being released from the micelles. Then, the phase II study of NK105 was performed to evaluate the efficacy and safety of NK105 in 56 patients with advanced or recurrent gastric cancer after failure of first‐line chemotherapy.…”