A phase II/III, randomized, open-label, multicenter study of BI 907828 compared to doxorubicin in the first-line treatment of patients with advanced dedifferentiated liposarcoma (DDLPS): Brightline-1.
Authors: Schöffski Patrick , Schuetze Scott , Martin Broto Javier , Wagner Andrew J. , Bauer Sebastian , Chen Victoria , Teufel Michael , Lucarelli Anthony , Lahmar Mehdi , Maki Robert G 
Published: June 2022

TPS11586 Background: The standard of care in the first-line treatment of patients (pts) with unresectable/metastatic DDLPS is doxorubicin, despite only moderate efficacy and many associated adverse events (AEs). BI 907828 is a mouse double minute 2 (MDM2)–p53 antagonist that binds to MDM2 and blocks its interaction with p53, leading to p53 stabilization, TP53 target gene induction, cell-cycle arrest and apoptosis in TP53 wild-type tumor cells. In a Phase I study, BI 907828 monotherapy demonstrated a manageable safety profile and preliminary signs of efficacy, particularly in pts with DDLPS (Gounder et al, ESMO 2021). Methods: NCT05218499 is a Phase II/III, randomized, open-label, international, multicenter study (̃125 sites) that aims to evaluate whether BI 907828 is superior to doxorubicin in the first-line treatment of advanced/metastatic DDLPS. In the Phase II part, ≤180 pts will be randomized 1:1:1 to receive BI 907828 30 mg or 45 mg orally every 3 weeks (q3w), or doxorubicin 75 mg/m2 intravenously q3w to a maximum cumulative dose of 450 mg/m2. Main inclusion criteria include: ≥18 years of age; histologically proven advanced/metastatic, unresectable DDLPS; positive MDM2 immunohistochemistry or amplification; ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. Exclusion criteria include a known TP53 gene mutation and prior systemic therapy for liposarcoma. In the experimental arm, treatment will continue until disease progression, unacceptable AEs, or consent withdrawal. Pts who receive doxorubicin may cross-over to receive BI 907828 after confirmed progressive disease. The primary endpoint is progression-free survival (PFS; based on blinded independent central review), defined as the time from randomization to tumor progression (RECIST v1.1) or death from any cause, whichever occurs first. Secondary endpoints are objective response (OR), duration of OR, overall survival, disease control, and pt-reported health-related quality of life. In Phase II, an interim analysis (based on the totality of safety and PK/PD data) will be used to select the optimal BI 907828 dose. Subsequently, an interim futility analysis will be performed after ̃56 PFS events using a log-rank test stratified by the extent of disease (locally advanced vs metastatic). If the selected BI 907828 dose passes the futility boundary, the trial will proceed to Phase III. In the Phase III part, ≥120 additional pts will be randomized 1:1 to receive the selected BI 907828 dose or doxorubicin. The primary PFS analysis will be performed after ̃92 and ̃65 PFS events in pts enrolled before and after the interim futility analysis, respectively, using a weighted inverse normal method combining one-sided p-values from a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05218499.