The Second Mitochondria-Derived Activator of Caspases Mimetic BI 891065 in Patients With Advanced Solid Tumors: Results From Two Phase I Studies.

INTRODUCTION

BI 891065, a second mitochondria-derived activator of caspases mimetic targets the inhibitor of apoptosis (IAP) family member cIAP1. We describe two first-in-human phase 1 trials assessing BI 891065 ± the anti-programmed cell death protein-1 (PD1) antibody, ezabenlimab, in advanced solid tumors.

METHODS

Trials were conducted in the USA (NCT03166631) and Japan (NCT04138823). Dose escalation of BI 891065 monotherapy (part A) and combined with ezabenlimab (part B) was guided by a Bayesian Logistic Regression Model with overdose control. Primary endpoints were maximum tolerated dose (MTD) and number of patients with dose-limiting toxicities (DLTs) in Cycle 1. Other endpoints included objective response (RECIST v 1.1), pharmacokinetics, and changes in peripheral blood mononuclear cell (PBMC) and tumor cIAP1 levels.

RESULTS

Twenty-five patients (USA study) received 5-400 mg daily BI 891065 monotherapy; 12 patients (Japan study) received 100 mg daily, 200 mg daily, or 200 mg twice-daily BI 891065 monotherapy. No DLTs occurred in the USA study; three occurred in the Japan study: grade 3 increased bilirubin (n = 2) and maculopapular rash (n = 1). Neither study reached MTD for monotherapy. Treatment-related adverse events (TRAEs) occurred in 52% and 75% of patients, respectively. BI 891065 plus ezabenlimab combination (USA study part B only) was received by 37 patients (50-400 mg daily, 200 mg twice-daily) plus ezabenlimab (240 mg fixed-dose, Day 1 of 21-day cycles). One DLT occurred (grade 2 pneumonitis). MTD was not reached. TRAEs occurred in 81% of patients. Neither study reported objective responses; 25%-40% and 35% of patients achieved stable disease with BI 891065 monotherapy and the combination, respectively. cIAP1 levels were reduced in PBMCs and biopsies.

CONCLUSIONS

BI 891065 was tolerable in patients with advanced solid tumors, demonstrating target engagement as monotherapy and combined with ezabenlimab. Both studies ended early due to efficacy data that were insufficiently promising to justify continuation.

TRIAL REGISTRATION: NCT03166631, NCT04138823.