Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA
LiPlaCis is a novel liposomal formulation of cisplatin, designed to be specifically degraded by secretory phospholipase A2 (sPLA2) which is over-expressed in tumor tissue. sPLA2 has been shown to be present in a number of different tumor tissues - e.g. prostate, lung, ovarian, breast etc. ( T. Abe 1997 ). Thus, LiPlaCis is intended to improve the therapeutic index due to an improved therapeutic efficacy and possibly also an improved safety and tolerability profile. Objectives: The primary objectives were safety and determination of MTD. Secondary objectives were evaluation of PK, clinical activity, and PD. This included two PoC cohorts to study platinum-DNA adducts in tumor compared to normal tissue following administration of LiPlaCis. Methods: A standard 3+3 design was used to include patients with advanced solid tumors and PS 0-1. LiPlaCis was administered weekly on day 1, day 8 and possibly day 15 every 3 wks. CTCAE v4.03 and RECIST were used to assess safety and tumor activity. Paired tumor and normal tissue biopsies obtained pre-treatment and on day 2 were used to assess sPLA2-IIA protein levels and platinum-DNA adducts (by 32P-postlabeling assay) in two PoC cohorts of 60 and 90 mg LiPlaCis. Results: A total of 16 patients were included at dose levels of 60, 90 and 120 mg. At 120 mg two DLTs were observed and an intermediate dose level of 90 mg Day 1 and 8 and 45 mg Day 15 was explored. After 1 DLT, this dose level was halted and the PoC cohorts were initiated sequentially. The observed DLTs included renal toxicity and infusion reactions. Most frequent AEs of all grades were fatigue, hypomagnesemia and vomiting. The most common (>10%) grade 3-4 AEs were hypomagnesemia, hypokalemia and anemia. Clinical activity was observed in a patient with HN 60 mg (PR), SCC skin;120 mg (PR), BC; 60 mg (SD-ongoing), CRC; 90 mg (SD -18 wks) and gastric cancer; 90 mg (SD-21 wks). In the 60 mg PoC cohort of 3
pts the tumor- to normal tissue ratio of platinum-DNA adducts was from 5.7 to 8.3 fold. Conclusion: MTD has not yet been determined, but ongoing PoC cohorts indicate that LiPlaCis is preferably released in tumor by sPLA2 compared to normal tissue which potentially could improve the therapeutic index of cisplatin.
Citation Format: Ulrik Lassen, Morten Mau-Sorensen, Ulla Hald Buhl, Mogens W. Madsen, Eva Balslev, Dick Pluim, Jan H. M. Schellens, Steen Knudsen, Peter B. Jensen. Phase I dose-escalating PoC study to evaluate the safety and tolerability of LiPlaCis (liposomal cisplatin formulation) in patients with advanced or refractory tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT154.