An open-label, multicenter, phase I trial of a cremophor-free, polymeric micelle formulation of paclitaxel combined with carboplatin as a first-line treatment for advanced ovarian cancer: a Korean Gynecologic Oncology Group study (KGOG-3016)

Abstract

ObjectiveThis phase I study aimed to determine the maximum tolerated dose (MTD) of Genexol-PM, when combined with carboplatin, as a first-line treatment in patients with advanced ovarian cancer.MethodsThis open-label, multicenter, phase I, dose-escalation study included 18 patients (median age: 59.0 years, range: 40–75 years) diagnosed with advanced epithelial ovarian cancer. All patients had measurable residual disease after debulking surgery. Patients were assigned to groups (n=6 each group) that received different doses of Genexol-PM (220, 260, and 300 mg/m2, once every 3 weeks) and 5 area under the curve (AUC) carboplatin. Safety and efficacy were analyzed for each dose group.ResultsIn this intention-to-treat population, 3 out of 18 patients dropped out of the study: 1 due to dose-limiting toxicity (DLT), 1 due to hypersensitivity, and 1 was lost during follow-up. DLTs were not reported at 220 mg/m2 or 260 mg/m2, but at 300 mg/m2, 1 patient experienced DLT (grade 3 general pain). The MTD of Genexol-PM was not determined, but a dose of 300 mg/m2 or less could be recommended for the phase II study. Most patients (73.9%) with adverse events recovered without sequelae, and no death occurred that was related to the disease or treatment. The best overall response rate was 94.1%.ConclusionGenexol-PM combined with carboplatin was well tolerated as a first-line treatment, and good responses were observed in patients with advanced ovarian cancer. Based on these results, we recommended a dose of 300 mg/m2 or less for a phase II study.

Non-convulsive seizure related to Cremophor EL™-free, polymeric micelle formulation of paclitaxel: a case report

“…A recent open-label, phase 1 trial [ 8 ] was conducted to determine the maximum tolerated dose of Genexol-PM™ when combined with carboplatin as a first-line treatment for advanced ovarian cancer. Dose-limiting toxicities were not reported at 220 mg/m 2 or 260 mg/m 2 , although one patient reported general pain (grade 3, based on National Cancer Institute CTCAE v3.0) at a dose of 300 mg/m 2 .…”

“…In the present case, the patient received 260 mg/m 2 of Genexol-PM™ once every 3 weeks. This dose was assumed to be below the neurotoxic threshold of paclitaxel [ 8 9 ]. However, 4 rounds of chemotherapy were performed prior to seizure occurrence, resulting in a cumulative dose of 1,040 mg/m 2 .…”

Polymeric capsules and micelles as promising carriers of anticancer drugs

“…64 Table 2 summarizes clinical applications of polymeric micelles as carriers of anticancer drugs. Clinical trials with published results have been already performed for formulations with names: Genexol-PM®, [65][66][67][68][69][70][71][72][73][74][75][76] Nanoxel M®, 77 NK 911, 64 NK 105, [78][79][80][81][82] NK 012, 83-87 NC-6004, [88][89][90][91] NC-6300, [92][93][94] BIND-014, [95][96][97] and Sp1049C. [98][99][100] The behavior of polymeric micelles after administration is related to several stress factors acting on these carriers.…”

Safety and Tolerability of Weekly Genexol-PM, a Cremophor-Free Polymeric Micelle Formulation of Paclitaxel, with Carboplatin in Gynecologic Cancer: A Phase I Study

“…To increase the solubility of hydrophobic paclitaxel, paclitaxel has been formulated in a micelle-forming vehicle, Cremophor EL (CrEL) [ 12 ]. However, the addition of CrEL was reported to be associated with hypersensitivity reactions and neurotoxicity [ 13 ]. Even with an appropriate premedication, CrEL-paclitaxel formulations are known to induce mild hypersensitivity reactions in ~44% of patients and grade 3/4 reactions in ~2% of patients [ 14 ].…”