Phase I study of single-agent CC-292, a highly selective Bruton’s tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia
| Autor: | Shuo Ma, James M. Foran, Thomas J. Kipps, Yan Li, Xujie Yu, Jeffrey Marine, Jeff P. Sharman, Jan A. Burger, Marshall T. Schreeder, Wael A. Harb, Paul M. Barr, Janice Gabrilove, Kevin R. Kelly, Jay Mei, Daruka Mahadevan, Thomas P. Miller, Evelyn Barnett, Pilar Nava-Parada, Daniel W. Pierce, Jennifer R. Brown, Monika Miranda, Ada Azaryan, Brian T. Hill |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Chronic lymphocytic leukemia Population Neutropenia Gastroenterology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine immune system diseases hemic and lymphatic diseases Internal medicine medicine Bruton's tyrosine kinase education Online Only Articles Survival rate education.field_of_study biology business.industry Waldenstrom macroglobulinemia Hematology medicine.disease 030104 developmental biology chemistry 030220 oncology & carcinogenesis Ibrutinib Immunology biology.protein Mantle cell lymphoma business |
| Popis: | B-cell receptor (BCR) signaling plays a key role in the pathogenesis of B-cell malignancies, mediating the survival and proliferation of malignant B cells.1,2 Clinical studies have shown that Bruton’s tyrosine kinase (BTK) inhibitors are well tolerated, with promising clinical activity. Ibrutinib has shown 30-month progression-free survival (PFS) of 69% in relapsed chronic lymphocytic leukemia (CLL) patients,3–5 and has substantial activity in mantle cell lymphoma and activated B-cell-type diffuse large B-cell lymphoma.6,7 CC-292 is a highly selective oral small-molecule inhibitor that binds covalently and irreversibly to the same cysteine 481 in BTK as ibrutinib, inhibiting its signaling.8 We report here the results of a phase I study of CC-292 in patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL), B-cell non-Hodgkin lymphoma (B-NHL), and Waldenstrom macroglobulinemia (WM). A total of 113 patients received continuous dosing with CC-292 in 28-day cycles at doses ranging from 125 mg to 1000 mg once daily, and 375 mg and 500 mg twice daily, continuing into dose-expansion cohorts of 750 mg once daily and a preliminary recommended phase II dose (RP2D)-expansion cohort of 500 mg twice daily. Four patients experienced dose-limiting toxicity (DLT) but only one in any treatment cohort. The most frequent grade 3–4 adverse events (AEs) were neutropenia (16%) and thrombocytopenia (8%). The most common non-hematologic treatment-emergent AEs (TEAEs) of any grade were diarrhea (68%) and fatigue (45%). Twice-daily administration of CC-292 was instituted to improve sustained BTK occupancy, and, in fact, did result in more than 90% BTK receptor occupancy at both the 4- and 24-h post-dose time points. Efficacy in the CLL/SLL population (n=84) showed that overall response rate (ORR) in patients receiving twice-daily dosing was 53%; an additional 10% had partial response with lymphocytosis (PR-L). CC-292 was, therefore, well tolerated and achieved high nodal and PR rates in relapsed CLL/SLL patients, but showed less durability than other BTK inhibitors. |
| Databáze: | OpenAIRE |
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