Phase Ia dose-escalation trial with the BET protein inhibitor BI 894999 in patients with advanced or metastatic solid tumours
Background:
Bromodomain and extraterminal domain (BET) inhibitors have shown therapeutic potential in both solid tumors and hematologic cancers. BI 894999 is a novel oral BET inhibitor that has exhibited strong antitumor activity in preclinical models.
Patients and Methods:
Study 1367.1 was an open-label, Phase Ia/Ib dose-escalation trial designed to evaluate the safety and efficacy of once-daily BI 894999 in patients with advanced solid tumors. Three dosing schedules were investigated:
Schedule A: 0.2 to 5.0 mg on Days 1–21 of a 21-day cycle
Schedule B: 1.5 to 2.5 mg on Days 1–15 of a 21-day cycle
Schedule C: A loading dose of 5.0, 6.0, or 7.0 mg on Day 1, followed by maintenance doses of 2.5 to 3.5 mg on Days 2–7 and 15–21 of a 28-day cycle
A total of 77 patients were enrolled (ClinicalTrials.gov ID: NCT02516553).
Results:
Grade ≥3 dose-limiting toxicities (DLTs) occurred in 8 of 21 patients (Schedule A), 5 of 25 (Schedule B), and 9 of 31 (Schedule C). Thrombocytopenia was the most common DLT, reported in 28.6%, 4.8%, and 9.7% of patients in Schedules A, B, and C, respectively. Additional DLTs occurring in at least one patient included increased troponin T (13.6%), hypophosphatemia (4.5%), and elevated creatine phosphokinase (3.0%).
Disease control (defined as stable disease or better) was observed in 23.8% (Schedule A), 24.0% (Schedule B), and 29.0% (Schedule C) of patients. Partial responses were achieved in 9.5% and 4.0% of patients in Schedules A and B, respectively, while the best outcome for Schedule C was stable disease.
Conclusion:
The maximum tolerated doses were established as 1.5 mg (Schedule A), 2.5 mg (Schedule B), and a loading dose of 6.0 mg followed by 3.0 mg maintenance (Schedule C).Amredobresib These findings supported the continued clinical evaluation of BI 894999 in a subsequent Phase Ib study.