Abstract C047: A phase Ia/Ib, dose-escalation/expansion study of BI 907828, an MDM2-p53 antagonist, in combination with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in patients with advanced solid tumors
Authors: Tolcher Anthony , Hafez Navid , Yamamoto Noboru , Park Jaehong , Grempler Rolf , Lucarelli Anthony , Vallaster Markus P , Wang Bushi , Hyman David 
Published: March 2020

Abstract
The murine double minute 2 (MDM2) oncogene is the primary negative regulator of the tumor suppressor, tumor protein 53 (TP53). TP53 is either mutated or deleted in human cancers to ablate its pro-apoptotic functions, or its wild-type function is inhibited by high MDM2 levels, contributing to tumor cell proliferation and cancer growth. BI 907828 is a potent MDM2-p53 antagonist that has shown potent anti-tumor activity in preclinical studies. Increasing evidence suggests TP53 also plays a role in the regulation of immune responses. Preclinical data show that the combination of an MDM2-p53 antagonist with anti-PD-1 and anti-LAG3 antibodies produces a synergistic anti-tumor effect in multiple tumor types. This Phase Ia/Ib study aims to determine the safety, recommended phase 2 dose (RP2D), and preliminary anti-tumor activity of BI 907828 in combination with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in a variety of TP53 wild-type cancers. In the Phase Ia (dose escalation) part of the study, patients with a confirmed diagnosis of unresectable, advanced and/or metastatic solid tumors (of any type) irrespective of TP53 mutation status will be enrolled. Patients will receive one dose of BI 907828 every 21 days, at a starting dose of 10 mg orally, in combination with BI 754091 and BI 754111 (fixed doses of 240 mg and 600 mg respectively, intravenously) every 21 days. Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. The primary endpoint is to determine the maximum-tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle. Secondary endpoints include pharmacokinetics and safety. Phase Ia will include approximately 30 evaluable patients. In the Phase Ib (dose expansion) part of the study, patients with previously treated, unresectable, advanced or metastatic tumors that are TP53 wild-type and have at least one measurable target lesion will be enrolled into four expansion cohorts (1: non-small cell lung cancer [NSCLC]; 2: melanoma; 3: well-differentiated/dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma; 4: hepatocellular carcinoma). The recommended dose for expansion (RDE; established in Phase Ia) of BI 907828 will be administered in combination with fixed doses of BI 754091 and BI 754111 every 21 days. In the NSCLC cohort only, patients will be randomized to one of three arms: RDE of BI 907828 in combination with 240 mg fixed dose BI 754091 and 600 mg fixed dose of BI 754111 every 21 days (arm A, 32 patients); 240 mg fixed dose of BI 754091 in combination with 600 mg fixed dose of BI 754111 every 21 days (arm B, 32 patients); RDE of BI 907828 in combination with 240 mg fixed dose of BI 754091 every 21 days (arm C, 16 patients). The primary endpoint is objective response (OR; investigator-assessed, per RECIST 1.1). Secondary endpoints include OR (per iRECIST), disease control (investigator assessed; per RECIST 1.1 and iRECIST), progression-free survival (PFS); PFS rate at 12 and 24 weeks (cohort 3 only) and safety. Phase Ib will include at least 140 evaluable patients (80 patients in cohort 1 and 20 patients each in cohorts 2, 3 and 4).
Citation Format: Anthony Tolcher, Navid Hafez, Noboru Yamamoto, Jaehong Park, Rolf Grempler, Anthony Lucarelli, Markus P Vallaster, Bushi Wang, David Hyman. A phase Ia/Ib, dose-escalation/expansion study of BI 907828, an MDM2-p53 antagonist, in combination with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C047. doi:10.1158/1535-7163.TARG-19-C047