A phase I dose escalation trial of BI 2536, a novel Plk1 inhibitor, with standard dose pemetrexed in previously treated advanced or metastatic non-small cell lung cancer (NSCLC)

Abstract

8115 Background: BI 2536 is a novel, highly selective, potent inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression. BI 2536 has demonstrated favorable tolerability and antitumor activity in Phase I trials. We investigated the MTD, safety and PK of BI 2536 in combination with standard dose pemetrexed in patients (pts) with previously treated advanced or metastatic NSCLC. Methods: Eligible pts included stage IIIB/IV NSCLC and ECOG PS 0–2, relapsing after 1st line platinum-based therapy. Pts were treated with 500 mg/m2 pemetrexed and escalating doses of BI 2536 given as a 1h i.v. infusion on Day 1 every three weeks. A standard Phase I 3+3 trial design was used. The primary objective was to determine the MTD of BI 2536 given with pemetrexed. Secondary endpoints were response rate (RECIST), overall safety and PK. AEs were evaluated using NCI-CTCAE v. 3.0. Pts not progressing after 6 cycles of combination therapy were eligible to continue BI 2536 monotherapy until tumor progression. Results: 33 pts were treated at doses from 100–325 mg BI 2536. The MTD was defined at 300 mg BI 2536 after the occurrence of dose limiting toxicities (Grade 3 rash and Grade 4 neutropenia) at 325 mg. The most common drug related AEs were mostly mild to moderate nausea (36%), rash (33%), anorexia (27%), stomatitis (24%) and pruritus (24%). Reversible Grade 3/4 neutropenia occurred in 18% of pts. Other drug related Grade 3 events were rash (n=2), acute renal failure (n=1) and confusion (n=1). There were 2 confirmed durable partial responses; 7 pts were treated for >4 courses. Up to 15 courses of BI 2536 therapy have been administered without cumulative toxicity. The MTD is being confirmed in expanded pt cohorts treated at doses of 200–300 mg. PK analysis showed similar BI 2536 exposure with/without pemetrexed. Pemetrexed exposure was not altered after co-administration of BI 2536. Conclusion: Preliminary results demonstrate that a combination of BI 2536 and pemetrexed has an acceptable safety profile in relapsed NSCLC without any PK interaction. Encouraging antitumor activity was observed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim, Eli Lilly Boehringer Ingelheim Pharma