1722PIn vivo efficacy and enhanced tumour accumulation of liposomal vinorelbine (TLC178) in human sarcoma xenograft mice model

• Published in: Annals of oncology Vol. 30; no. Supplement_5
• Main Authors: Yu, W-N, Tang, J-H, Tsai, Y-C, Wang, H-T
• Format: Journal Article
• Language: English
• Published: Oxford University Press 01.10.2019
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdz283.055

Abstract Background Vinorelbine (VNB) is a member of vinca alkaloid medications and approved for the treatment of non-small cell lung cancer as well as off-label use for metastatic breast cancer over 20 years based upon FDA-approved indication. Several studies have suggested the potential of VNB in treating sarcomas. Liposomal VNB (TLC178) is a novel sustained release liposomal formulation. In the presented studies, TLC178 resulted in enhanced tumor accumulation and greater anti-tumor efficacy than non-liposomal VNB. Methods Mice were subcutaneously inoculated with human sarcoma cell lines (1.5∼4 × 106/mouse) at the dorsal-lateral flank. Treatment was commenced once tumor size reached 150 to 400 mm3 in average. Mice were intravenously (i.v.) injected with test articles by groups. Table:1722PStudy #Cell Type [Cell Density]Initial Tumor Size (mm3)Treatment Group (Dosage)Dosing RegimenPD17060Human Rhabdomyo- sarcoma (RMS) cell line (SJCRH30) [1.5 × 106/mouse]200Saline TLC178 (5 mg/kg) VNB solution (5 mg/kg)TLC178 and VNB were injected at a 4-day interval for three doses.PD17069Human RMS cell line (SJCRH30) [4 × 106/mouse]150Saline TLC178 (7.5 mg/kg) VNB solution (10 mg/kg) + cyclophosphamide (CTX) (19.8 mg/kg)TLC178 and VNB were injected once weekly for two doses while CTX was administrated at 19.8 mg/kg on day 0, 7 and 50 mg/kg on day 8.PD17008Human fibrosarcoma cell line (HT1080) [2.2 × 106/mouse]390D5W TLC178 (5 mg/kg) Doxorubicin (3.4 mg/kg)TLC178 and doxorubicin were injected at a 4-day interval for two doses.PK17066Human RMS cell line (SJCRH30) [2.3 × 106/mouse]150 to 400TLC178 (5 mg/kg) TLC178 (10 mg/kg) VNB solution (10 mg/kg)Single injection*Tumor size was monitored with digital caliper during the study. * Plasma and tumors were collected to determine VNB concentration in bio-distribution study. * Saline or D5W (Dextrose 5% in Water) was used as the control group according to the study design. * VNB solution is vinorelbine injectable solution Results In efficacy studies (Study #PD17060, #PD17069 and #PD17008), TLC178 not only showed better inhibitory effect than that of VNB alone and VNB+CTX treatments in the SJCRH30 RMS xenograft model, but also remarkably suppressed HT1080 human fibrosarcoma compared with doxorubicin, an approved drug for treatment of sarcomas. In a biodistribution study (Study #PK17066), TLC178 yielded larger systemic exposure of total VNB (comprising liposome-encapsulated and unencapsulated VNB), higher local concentration and longer elimination half-life in tumor compared to VNB. Conclusions TLC178 demonstrated improved in vivo systemic VNB PK profile and tumor distribution, which resulted in superior anti-cancer efficacy compared to traditional VNB treatment. Therefore, TLC178 may have potential as a single or combination treatment for sarcomas with decreased dosage and/or frequency, reduced toxicity, and enhanced efficacy. Legal entity responsible for the study Taiwan Liposome Company, Ltd. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.