Abstract 5532: Polymeric albumin-free paclitaxel intraperitoneal therapy demonstrates superior efficacy over nab-paclitaxel intravenous therapy in a mouse model of metastatic ovarian cancer
Authors: Motamed Kouros , Said Neveen 
Published: August 2015

Introduction: The polymeric albumin-free micellar formulation of paclitaxel, Cynviloq™, is being developed as the next generation nanoparticle paclitaxel for treatment of solid tumor indications. Using albumin-bound nab-paclitaxel (nab-PTX) as comparator in in vitro dissolution and mouse PK studies, we recently reported a 10-fold higher nanoparticle stability in serum-free media and a 10-fold increased peritoneal paclitaxel levels for Cynviloq vs. nab-PTX as early as 1 hour post IP administration at 30 mg/kg. Moreover, since antitumor efficacy of nab-PTX after IV and IP administrations was recently shown to be equivalent in a peritoneal metastatic gastric cancer model, we set out to compare the efficacy of IV nab-PTX vs. IP Cynviloq in a peritoneal metastatic model of ovarian cancer.

Methods: Five to six-weeks old athymic female nu+/nu+ mice were injected IP with 2×106 IGROV1 human ovarian cancer cells/100 μL saline. Mice were randomized into five experimental groups and one saline control group (n = 10-13) 7 days post tumor inoculation with the day of injection assigned as Day 0. nab-PTX was administered IV at 15 or 30 mg/kg, whereas Cynviloq was administered IP at 15, 30 and 60 mg/kg/day according to a qdx5 dosing regimen. Tumor-bearing mice were monitored twice weekly up to 12 weeks for weight loss and girth increase. Study endpoints included quantification of intraperitoneal tumor nodule size and number of nodules, incidence and volume of collected ascites as well as overall survival. Statistical analyses performed included Chi square test, ANOVA and unpaired Student's t-test.

Results: Treatments with either IP Cynviloq or IV nab-PTX were well tolerated and significantly (P&lt;0.05) increased the median survival of mice compared to untreated controls. However, analysis of Kaplan-Meier survival curves revealed that IP Cynviloq treatments conferred significant survival advantage over IV nab-PTX at 15 and 30 mg/kg doses (P = 0.0011 and 0.0387, respectively). Cynviloq-treated cohorts also displayed significant (P = 0.0057) dose-dependent survival advantage relative to the nab-PTX-treated cohorts (P = 0.0454). Consistent with these findings, mice treated with 15 and 30 mg/kg IP Cynviloq showed significantly decreased intraperitoneal tumor burden scores (P = 0.014 and 0.025, respectively). However, significant decreases in ascitic fluid volumes were only observed in mice treated with 15 mg/kg IP Cynviloq (P = 0.006).

Conclusions: Collectively, our data strongly supports the notion that compared to IV-administered nab-PTX, IP delivery of Cynviloq results in improved efficacy without any additional toxicity in a metastatic model of ovarian cancer. Hence, further development of IP-administered Cynviloq in the treatment of indications with malignant ascites, including ovarian and gastric cancers, are therefore warranted.

Citation Format: Kouros Motamed, Neveen Said. Polymeric albumin-free paclitaxel intraperitoneal therapy demonstrates superior efficacy over nab-paclitaxel intravenous therapy in a mouse model of metastatic ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5532. doi:10.1158/1538-7445.AM2015-5532