Abstract CT154: 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

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 H&N cancer; 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-Sørensen, 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.

Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)—validation in two independent cohorts

“…Based on simple marker threshold values from the current study, a prospective phase 2 biomarker-guided study with the cisplatin marker as a companion diagnostic has started. It is enrolling heavily-pretreated breast cancer patients above a specific score to be treated with liposomal cisplatin [ 50 , 51 ]. But could further elaboration on the model for instance combined with known prognostic factors refine the system?…”

Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study

“…The current epirubicin cohort was identified among patients who were screened for participation in a phase 1 trial with liposomal cisplatin (LiPlaCis) [ 19 ].…”

Functionalized liposomes for targeted breast cancer drug delivery

“…A phase I clinical trial for the first cisplatin-encapsulating liposomal formulation with a sPLA 2 -trigger, LiPlaCis®, was performed in advanced and/or refractory solid tumors including prostate, skin, and metastatic breast cancer (NCT01861496). In 2009 trials were halted due to safety issues requiring reformulation [ 353 ], after which the efficacy, dosage, and tolerability of LiPlaCis® continued to be assessed pre-clinically and in phase I/II clinical trials in advanced solid tumors such as head and neck, skin, colorectal, gastric, and breast cancers [ 214 , [354] , [355] , [356] ]. Østrem et al developed a liposomal delivery system optimized for sPLA 2 -triggered drug release by adjusting the fluidity and cholesterol level in the liposomes ( Fig.…”