The Second Mitochondria-Derived Activator of Caspases Mimetic BI 891065 in Patients With Advanced Solid Tumors:
Manish R Patel1, Erika P Hamilton2, Ben George3
1Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida, USA.
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.
Insights
BI 891065, a novel cancer therapeutic, showed tolerability in advanced solid tumors. Combination therapy with ezabenlimab demonstrated target engagement but lacked promising efficacy for further trials.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- BI 891065 is a second mitochondria-derived activator of caspases mimetic targeting cIAP1.
- Phase 1 trials investigated BI 891065 alone and with the anti-PD1 antibody ezabenlimab in advanced solid tumors.
Purpose of the Study:
- To assess the safety and tolerability of BI 891065 monotherapy and in combination with ezabenlimab.
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs).
- To evaluate preliminary efficacy, pharmacokinetics, and target engagement (cIAP1 levels).
Main Methods:
- Two first-in-human Phase 1 trials (USA: NCT03166631, Japan: NCT04138823) were conducted.
- Dose escalation of BI 891065 monotherapy and combination with ezabenlimab used a Bayesian Logistic Regression Model.
- Primary endpoints included MTD and DLTs; secondary endpoints included objective response, pharmacokinetics, and cIAP1 levels.
Main Results:
- Neither monotherapy nor combination therapy reached MTD.
- DLTs were observed, including increased bilirubin and rash with monotherapy, and pneumonitis with combination therapy.
- Stable disease was achieved in 25%-40% with monotherapy and 35% with combination; objective responses were not reported. cIAP1 levels decreased in PBMCs and tumors.
Conclusions:
- BI 891065 was tolerable in advanced solid tumors, showing target engagement.
- Combination with ezabenlimab was also tolerable, with target engagement observed.
- Both studies were terminated early due to insufficient efficacy data to warrant continuation.
