A phase IIa/IIb, open-label trial of BI 907828, an MDM2–p53 antagonist, in patients with locally advanced/metastatic biliary tract carcinoma or pancreatic ductal adenocarcinoma: Brightline-2.
Authors: Goyal Lipika , Harding James J. , Ueno Makoto , Lamarca Angela , Macarulla Teresa , Yamamoto Noboru , Hu Joy , Teufel Michael , Maerten Angela , Vogel Arndt , Javle Milind M. 
Published: June 2023

TPS4179 Background: Biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) carry a median survival of one year in the advanced stages, and effective therapies are urgently needed. Mouse double minute 2 (MDM2) is amplified in ~5–6% of cases of BTC and ~1% of PDAC. MDM2, an E3 ubiquitin ligase, is an endogenous negative regulator of p53. Aberrations affecting MDM2 may drive oncogenesis, and indeed, preclinical as well as emerging clinical data suggest blocking MDM2 in TP53 wild-type tumors may be a potential therapeutic strategy. BI 907828 is an MDM2–p53 antagonist that binds to MDM2 and blocks its interaction with p53, thereby restoring p53 function, leading to cell-cycle arrest and apoptosis in TP53 wild-type tumor cells. In ongoing Phase I studies, BI 907828 has demonstrated initial signs of activity in selected advanced/metastatic solid tumors, including BTC and PDAC. Methods: Brightline-2 is a Phase IIa/IIb, open-label, single-arm, multicenter study (~60 sites) that aims to assess the efficacy, safety, and tolerability of BI 907828 monotherapy in patients with locally advanced, unresectable, or metastatic MDM2-amplified, TP53 wild-type BTC (adenocarcinoma histology; Cohort 1; n=~90) or PDAC (Cohort 2; n=~10) [NCT05512377]. Cohorts for other solid tumors may be added via protocol amendment. All patients will receive BI 907828 45mg orally once every 3 weeks. Key inclusion criteria include: ≥18 years of age; locally advanced/metastatic, histologically confirmed unresectable BTC/PDAC; progression or intolerance to standard therapies; local test indicating MDM2 amplification or MDM2 copy number ≥8 and TP53 wild-type (liquid biopsy not permitted); ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. A key exclusion criterion is prior treatment with an MDM2–p53 antagonist. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is objective response rate (ORR; based on blinded central independent review). Secondary endpoints are duration of response, progression-free survival, overall survival, disease control, occurrence of adverse events, and patient-reported health-related quality of life. In Phase IIa, an interim futility analysis will be performed after the initial 30 patients in Cohort 1 have either been followed for ≥12 weeks or have discontinued. If the cohort passes the non-binding interim futility boundary (ORR = 20%), the study will enter Phase IIb, and 60 additional patients will be enrolled onto Cohort 1, totaling 100 patients planned across Cohorts 1 and 2. The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks or until study discontinuation. As of 13 December 2022, 1 patient has been enrolled. Clinical trial information: NCT05512377 .