222 Lurbinectedin (PM01183): Pharmacokinetics/Pharmacodynamic (PK/PD) Properties in Pancreas, Ovarian and NSCLC Xenografts

Abstract

breast and platinum-resistant/refractory ovarian) clinical evaluation. In vitro studies demonstrate that lurbinectedin causes delayed progression of S phase and cycle arrest in G2M. Also, lurbinectedin was 3−4 time less potent in NER deficient cells whereas it was 100 time more potent in HR deficient cells. The in vivo antitumor activity of lurbinectedin was evaluated in human ovarian carcinoma models, growing subcutaneously (OCX) or in the peritoenal cavity (IPX). Material and Methods: The in vivo pharmacological behavior of lurbinectedin was evaluated in M5076 (murine reticulosarcoma), MN-MCA1 (murine fibrosarcoma), 2 human OCX (HOC 18 and MNB-PTX-1) and 2 IPX (HOC8 and HOC22). Lurbinectedin was given i.v. at 0.2 mg/kg/day on days 0, 7, 14 (q7d×3). The antitumor effect was calculated either by T/C (as a percentage of the change in tumor size for treated [T] and placebo [C]) or by the increase of like span (ILS) (as 100·[(T − C)/C], where ‘T’ and ‘C’ are the median survival time of the treated and placebo); treatment-related anti-metastic activity was also evaluated. Results: In M5076 lurbinectedin was only marginally active (T/C, 73.4%) against the primary tumor whereas in MN-MCA1 demonstrated a good antitumor activity (best T/C 15%). In both tumor models lurbinectedin produced a striking antimetastatic effect (p < 0.001). Lurbinectedin treatment resulted in no antitumor activity in the MNB-PTX-1 model. In animals bearing OCX HOC18 tumors, lurbinectedin treatment induced a strong and long-lasting antitumor effect (minimal T/C, 13% Day 16). Tumor volume were reduced (P < 0.01) compared to placebo on days 10−17. Also, lurbinectedin treatment reduced tumor growth rate: all animals were sacrificed due to tumor volume on Day 63, later than placebo (Day 15). Lurbinectedin treatment of HOC8 IPX xenografts resulted in (P < 0.05) antitumor activity compared to untreated animals (ILS % of 140.0). Eight out of 9 of mice bearing HOC22 IPX tumors and treated with lurbinectedin survived 4 months after the death of the last placebo-treated animal and, then considered as tumor-free. Conclusions: The in vivo antitumor effect of lurbinectedin was demonstrated in a panel of human and murine experimental models, characterized by different behaviors and drug sensitivity.