Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined with cisplatin or carboplatin in patients with advanced solid tumors.

Abstract

3018^ Background: Volasertib (V) is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk. This phase I study evaluates dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety and pharmacokinetics (PK) of V combined with cisplatin (Cis) or carboplatin (Ca). Methods: Sequential cohorts of patients (pts) received a single 2h infusion of V with Cis (arm A) or Ca (arm B) every 3 wks. Cis and Ca were given for up to 6 cycles (Cy); V was continued until progression or intolerance. MTD was the highest dose at which ≤1/6 pts experienced a DLT in Cy 1. MTD cohorts were expanded to 12 DLT-evaluable pts to further characterize safety. Results: As of January 11 2012, 61 pts (arm A: 30; arm B: 31) were treated. Pt characteristics were (arm A/B): median age 55/58 yrs, male 16/18 pts, ECOG PS 0: 13/14 pts, PS 1: 17/17 pts. Tumors included (pts): non-small cell lung cancer (15); sarcoma (8); colorectal cancer (6); melanoma (4); urothelial cancer (4); other (24). Pts received V + Cis for a median [range] of 3.5 Cy [1-6], V + Ca for 2 Cy [1-6] and V for 3.5 Cy [1-20] in arm A and 2 Cy [1-14] in B. PK analyses are ongoing. MTD was reached at V 300 mg + Cis 100 mg/m2 and V 300 mg + Ca AUC 6. Five partial responses (PR) were seen. 15/30 pts in arm A and 12/31 in B achieved stable disease (SD) or PR. PR or SD for >6 Cy was observed in 6/30 pts and 5/31 pts in arms A and B, respectively. Conclusions: In this phase I study, V in combination with Cis or Ca at full single-agent doses was well tolerated. Furthermore, several objective responses and cases of sustained SD were observed in heavily pretreated pts with advanced solid tumors.[Table: see text]