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 demonstrated efficacy in solid tumours and haematological malignancies. BI 894999 is a novel oral BET inhibitor that has demonstrated potent antitumour activity in preclinical studies.

PATIENTS AND METHODS

1367.1 was an open-label, Phase Ia/Ib dose-finding study evaluating BI 894999 once daily in patients with advanced solid tumours (Schedule A: 0.2, 0.5, 1.0, 1.5, 2.0, and 5.0 mg, Days 1-21/21-d cycle; Schedule B: 1.5, 2.0, and 2.5 mg, Days 1-15/21-d cycle; Schedule C: loading dose 5.0, 6.0, or 7.0 mg on Day 1 followed by maintenance dose 2.5, 3.0, or 3.5 mg, Days 2-7 and 15-21/28-d cycle); 77 patients were enrolled. NCT02516553.

RESULTS

Grade ≥3 dose-limiting toxicities (DLTs) were reported in 8/21, 5/25, and 9/31 patients for Schedules A, B, and C, respectively. Thrombocytopenia was reported as a DLT in 28.6%, 4.8%, and 9.7% for Schedules A, B, and C, respectively. Other DLTs occurring in ≥1 patient were troponin T increase (13.6%), hypophosphataemia (4.5%), and elevated creatine phosphokinase (3.0%). Disease control was achieved in 23.8%, 24.0%, and 29.0% of patients for Schedules A, B, and C, respectively. A partial response was achieved in 9.5% and 4% of patients with Schedules A and B, respectively. The best response with Schedule C was stable disease.

CONCLUSION

The 1.5, 2.5, and 6.0/3.0 mg doses in Schedules A, B, and C, respectively, were declared as maximum tolerated dose. Based on the strength of these data, BI 894999 was further evaluated in a Phase Ib trial.

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest Patrick Schöffski declares institutional translational research funding for work; an ongoing advisory function; receiving personal honoraria; travel support to attend BET inhibitor-related advisory functions; personal honoraria for educational activities outside of the scope of this paper from Boehringer Ingelheim; consulted/advised for Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Studiecentrum voor Kernenergie, SQZ Biotechnology, Adcendo, PharmaMar, Merck Healthcare KGaA, Medpace; and received research support from CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, and ONA Therapeutics. Jean-Pascal Machiels has consulted/advised for ALX Oncology, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CUE Biopharma, Debiopharm, Incyte Corporation, Innate Pharma, Janssen, Merck Serono, Merck Sharp & Dohme, Nanobiotix, Novartis, Pfizer, Roche; received research funding from Bayer, Janssen, Novartis, Sanofi; and travel, accommodations, and expenses from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, and Pfizer. Sylvie Rottey has received travel grants and advisory/speaker fees from Novartis, Roche, Pfizer, MSD, Bristol Myers Squibb, Ipsen; and received research grants from Roche, MSD. Behbood Sadrolhefazi and Kristell Marzin are employees of Boehringer Ingelheim. Hanny Musa is a former employee of Boehringer Ingelheim. Ahmad Awada has received advisory and speaker fees from Amgen, AstraZeneca, Bayer, Daiichi, EISAI, Genomic Health, Ipsen, LEO Pharma, Lilly, Merck, MSD, Novartis, Pfizer, and Seattle Genetics; received advisory fees from Hengrui, Innate, and Viatris; and received research grants from Bristol Myers Squibb and Roche.