Phase I, first-in-human trial of Bruton’s tyrosine kinase inhibitor M7583 in patients with B-cell malignancies

Abstract

M7583 is a potent, highly selective, covalent BTK inhibitor in development. In this phase I, first-in-human, open label, multicenter dose-escalation trial, M7583 was given at 80 mg (three days)/160 mg (full 28-day cycle), then 300 mg/day, 600 mg/day, 900 mg/day, and 300 mg twice daily to 18 patients (median age 63 years) with refractory/resistant, stage III/IV B-cell malignancies who failed prior therapy (NCT02825836). No dose-limiting toxicities were reported. Treatment-emergent adverse events (AEs) occurred in 89% of patients, treatment-related AEs in 78%, and treatment-related grade ≥3 AEs in 17%. Common AEs were diarrhea (33%), fatigue (22%), and vomiting (17%). M7583 was rapidly absorbed and exposure was dose-proportional. BTK occupancy was >95% in the 300 mg twice daily and 900 mg/day cohorts. Objective response rate was 50% and disease control rate 78%, supporting a favorable benefit:risk profile. Fasted doses up to 900 mg once daily and 300 mg twice daily were well tolerated and may be tested in future clinical studies.

Keywords:

• BTK
• M7583
• safety
• efficacy

Acknowledgements

The authors would like to thank patients and their families, investigators, co-investigators, and the study teams at the participating centers and the trial sponsor. Medical writing assistance was provided by Jen Lewis and Helen Swainston, Bioscript Science, Macclesfield, UK and funded by Merck KGaA, Darmstadt, Germany.

Disclosure statement

WJ has served on advisory boards for Acerta and Takeda, and has received research funding from Celgene, AbbVie, Gilead, TG Therapeutics, Janssen, Acerta, Merck KGaA, Darmstadt, Germany, Bengene, Roche, Sandoz–Novartis, and Takeda. SR has received consultancy honoraria from Janssen, Roche, AstraZeneca, Celgene, Pharmacyclics, Gilead, Sunesis, TG Therapeutics, Napp, and Kite, and has received research funding and travel/accommodation expenses from Janssen and Roche. WT has received consultancy honoraria from Roche and Gilead. DT has received grants for meeting attendance from Takeda and Amgen, and has received advisory board honoraria from Novartis. BS is an employee of Merck KGaA, Darmstadt, Germany. JS was an employee of Merck KGaA, Darmstadt, Germany, at the time the work was done. JGG has received honoraria from Genentech/Roche, Abbvie, Acerta, Janssen, Celgene, TG Therapeutics, Kite, Karyopharm, AstraZeneca, Gilead, and Novartis. MD-D has received honoraria from Roche, AbbVie, Acerta, Janssen, and Takeda. PLZ has provided consultancy services for Sanofi, served on advisory boards for Sandoz, served on speaker bureaus/advisory boards for Roche, Celgene, Gilead, Janssen-Cilag, BMS, Kyowa Kirin, Celltrion, Servier, Immune Design, and Portola, and provided consultancy and served on advisory boards/speaker bureaus for Verastem, MSD, Eusapharma.

Data availability statement

Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck KGaA’s Data Sharing Policy. All requests should be submitted in writing to Merck KGaA’s data sharing portal (https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html). When Merck KGaA has a co-research, co-development, or co-marketing or co-promotion agreement, or when the product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck KGaA will endeavor to gain agreement to share data in response to requests.

Additional information

Funding

This work was supported by Merck KGaA, Darmstadt, Germany and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; an affiliate of Merck KGaA, Darmstadt, Germany.