A phase I, open-label, dose-escalation trial of BI 764532, a DLL3/CD3 bispecific antibody, in patients (pts) with small cell lung carcinoma (SCLC) or other neuroendocrine neoplasms expressing DLL3.

Abstract

TPS8588 Background: First-line standard of care for pts with metastatic SCLC and neuroendocrine carcinoma (NEC) is platinum-based chemotherapy ± immunotherapy. While the addition of anti-PD1 antibodies has improved outcomes, nearly all pts relapse and prognosis is poor. There is a major unmet need for additional treatment (tx) options. BI 764532 is a delta-like ligand 3 (DLL3)/CD3 T cell engaging bispecific antibody. DLL3 is expressed on the cell surface of many SCLC and NEC tumors, but not on normal cells. In preclinical studies, BI 764532 induced cytotoxicity of DLL3-positive cells and showed anti-tumor activity in animal models. Methods: NCT04429087 is a first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic SCLC, large cell neuroendocrine lung carcinoma, NEC or small cell carcinoma of any other origin. Pts must have failed on or be ineligible for available standard therapies (including ≥1 line of platinum-based chemotherapy). Tumors must be positive for DLL3 expression (archived tissue/in-study fresh biopsy) according to central review. Pts must have ≥1 evaluable lesion (modified RECIST 1.1) outside of CNS and adequate liver, bone marrow and renal organ function. Main exclusion criteria: previous tx with T cell engagers or DLL3-targeted therapies; persistent toxicity from previous tx that has not resolved to ≤ CTCAE grade 1; immunodeficiency or receiving immunosuppressive therapy ≤7 days, prior anti-cancer therapy ≤3 wks/5 half-life periods or extensive field radiotherapy ≤2 wks of first dose of BI 764532. The main objective of phase Ia is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 764532, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy. The phase Ib objectives, endpoints and design will be specified after availability of phase Ia results. The trial will assess ≤3 dosing regimens: Regimen A (fixed iv dose once every 3 wks); Regimen B1 (fixed iv dose once every wk); Regimen B2 (step-in dose[s] followed by fixed-dose weekly doses; optional). Tx will continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or a maximum tx duration of 36 mos, whichever occurs first. For Phase Ia, ̃160 pts will be screened and 110 pts accrued. As of Feb 2021, pts are being recruited and treated in early dose escalation cohorts. Clinical trial information: NCT04429087.