BTK is a key regulator in B-cell receptor-mediated signaling and its inhibition blocks several B-cell functions. Small molecule BTKi have been approved for the treatment of B-cell malignancies, such as resistant/refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström’s macroglobulinemia (WM). M7583 is a potent, highly selective BTKi, under investigation in a two-part, phase I/II trial (NCT02825836) in patients (pts) with refractory/resistant B cell malignancies.
In Part 1 (dose escalation), pts with refractory/resistant B cell malignancies received 28-day cycles of once-daily (QD) M7583, starting at 80 mg for 3 days followed by 160 mg with doses increasing according to an adaptive Bayesian design. Part 2 (dose expansion) will be in pts with diffuse large B cell lymphoma (DLBCL; activated B-cell subtype) or MCL who have failed 1–3 lines of therapy. Safety and tumor response (investigator’s assessment according to Cheson/CLL/Owen criteria) are presented.
As of 27/02/18, in Part 1, 14 pts have been enrolled into the first 4 dose levels (80/160 mg, 300 mg and 600 mg QD and 300 mg twice daily [BID]): 10 men, 4 women; age, 49–80 years; WM (n = 4), MCL (n = 6), marginal zone lymphoma (n = 2), CLL (n = 1), or DLBCL (n = 1). Treatment-emergent adverse events (TEAEs) were mainly mild to moderate in intensity with no dose-limiting toxicities reported. Six pts have had a total of 8 grade ≥3 TEAEs; only 1 TEAE was considered related to treatment (grade 4 neutropenia). One pt had 2 serious TEAEs (chest pain and fever) and 1 pt died (extensive progressive disease, cycle 1). Clinical benefit (stable disease [SD], complete [CR], minor [MR] or partial response [PR]) was observed in 12/14 pts: 6/6 pts who received 160 mg or 300 mg QD (3 PR, 1 MR, 2 SD), 3/5 pts treated with 600 mg QD (1 CR, 1 PR, 1 MR) and 3/3 pts on 300 mg BID (2 PR, 1 SD). Study is ongoing.
M7583 has been well tolerated with evidence of clinical benefit at all the doses investigated. M7583 appears to have a favorable benefit: risk profile.
Clinical trial identification
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Merck KGaA, Darmstadt, Germany.
Provided by Helen Swainston of Bioscript Group, Macclesfield, UK.
W. Jurczak: Advisory board: Sandoz Novartis, Roche, Janssen, Acerta, Abbvie, TG Therapeutics, Teva, Takeda, Spectrum, NovoNordisk, Mundipharma; Research funding: Celgene, Abbvie, Gilead, TG Therapeutics, Janssen, Acerta, Merck, Begene, Pharmacyclics, Pfizer, Roche, Sandoz – Novartis, Takeda, Teva, Servier. S. Rule: Consultancy/honoraria: Janssen, Roche, Astra-Zeneca, Celgene, Pharmacyclics, Gilead, Sunesis, TG Therapeutics, Napp, Kite; Research funding: Janssen, Roche; Travel, accommodation and expenses: Janssen, Roche. W. Townsend: Consultancy/honoraria: Roche, Gilead. B. Sarholz, J. Scheele: Employment: Merck KGaA. J. Gribben: Honoraria: Genentech/Roche, Abbvie, Acerta, Janssen, Celgene, TG Therapeutics, Kite, Karyopharm, AstraZeneca, Gilead, Novartis. P.L. Zinzani: Honoraria: Roche, Celgene, Gilead, J and J, BMS, Karyopharma, Millenium Pharmaceuticals, Bayer, Verastem, Merck, Servier; Advisory committee/board: Roche, Celgene, Gilead, J and J, BMS, Karyopharma, Millenium Pharmaceuticals, Bayer, Verastem, Merck, Servier. All other authors have declared no conflicts of interest.