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Poster Discussion session - Haematological malignancies

2586 - Phase I/II, first in human trial with M7583, a Bruton’s tyrosine kinase inhibitor (BTKi), in patients with B cell malignancies

Date

21 Oct 2018

Session

Poster Discussion session - Haematological malignancies

Presenters

Wojceich Jurczak

Citation

Annals of Oncology (2018) 29 (suppl_8): viii359-viii371. 10.1093/annonc/mdy286

Authors

W. Jurczak1, S. Rule2, W. Townsend3, D. Tucker4, B. Sarholz5, J. Scheele6, J. Gribben7, P.L. Zinzani8

Author affiliations

  • 1 Department Of Haematology, Jagiellonian University, 31-007 - Krakow/PL
  • 2 Department Of Haematology, Plymouth University Medical School, PL4 8AA - Plymouth/GB
  • 3 Department Of Haematology, University College London Hospitals NHS Foundation Trust, London/GB
  • 4 Department Of Haematology, Torbay and South Devon NHS Trust, TQ2 7AA - Torquay/GB
  • 5 R&d Global Biostatistics & Epidemiology, Merck KGaA, Darmstadt/DE
  • 6 Global Clinical Development, Merck KGaA, Darmstadt/DE
  • 7 Department Of Haematology, Barts Cancer Institute, Queen Mary University of London, London/GB
  • 8 Institute Of Hematology 'l.e A. Seragnoli', University of Bologna, Bologna/IT
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Resources

Abstract 2586

Background

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.

Methods

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.

Results

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.

Conclusions

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

NCT02825836.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany.

Funding

Merck KGaA, Darmstadt, Germany.

Editorial Acknowledgement

Provided by Helen Swainston of Bioscript Group, Macclesfield, UK.

Disclosure

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.

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