Ian W Flinn1, Nancy L Bartlett2, Kristie A Blum3, Kirit M Ardeshna4, Ann S LaCasce5, Christopher R Flowers6, Andrei R Shustov7, Kenneth S Thress8, Patrick Mitchell8, Fred Zheng9, Jeffrey M Skolnik9, Jonathan W Friedberg10. 1. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA. Electronic address: iflinn@tnonc.com. 2. Siteman Cancer Center/Washington University School of Medicine, St. Louis, MO, USA. 3. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. 4. Sarah Cannon Research Institute United Kingdom/University College London, London, UK. 5. Dana-Farber Cancer Institute, Boston, MA, USA. 6. Winship Cancer Institute, Atlanta, GA, USA. 7. Seattle Cancer Care Alliance/University of Washington, Seattle, WA, USA. 8. AstraZeneca, Waltham, MA, USA. 9. Formerly at AstraZeneca, Wilmington, DE, USA. 10. University of Rochester Medical Center, Rochester, NY, USA.
Abstract
PURPOSE: To assess the safety and efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGN: Relapsed or refractory DLBCL patients originally received the oral spleen tyrosine kinase inhibitor, fostamatinib in a two-arm, randomised, double-blinded manner at either 100 mg twice a day (BID) or 200 mg BID until disease progression or unacceptable toxicity. The primary objective was to assess the overall response rate (ORR). Preliminary analysis showed limited efficacy and all subsequent patients were treated at 200 mg BID. Previously randomised patients were unblinded and given the opportunity to receive 200 mg BID. RESULTS: Sixty-eight patients were treated (47 at 200 mg BID, 21 at 100 mg BID). Cell of origin analysis showed 58% germinal B-cell (GCB) origin, 30% activated B-cell (ABC) origin and 12% with an intermediate cell of origin signature. The most common treatment-related adverse events of all patients were diarrhoea (21% total, 6% grade 3/4), nausea (19% total, 3% grade 3/4), and, fatigue (18% total, 9% grade 3/4). The ORR rate was 3% across both arms and clinical benefit (≥ stable disease) was achieved for 13% of all patients. The cell of origin for patients with clinical benefit was GCB (4 patients), intermediate (4 patients) or unknown (1 patient). None of the patients with clinical benefit had ABC genotype. CONCLUSIONS: While fostamatinib was generally well tolerated in this patient population, efficacy at these doses and schedule was poor. Unlike data with other B-cell antigen receptor pathway inhibitors, responses were not observed in the ABC genotype.
RCT Entities:
PURPOSE: To assess the safety and efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGN: Relapsed or refractory DLBCL patients originally received the oral spleen tyrosine kinase inhibitor, fostamatinib in a two-arm, randomised, double-blinded manner at either 100 mg twice a day (BID) or 200 mg BID until disease progression or unacceptable toxicity. The primary objective was to assess the overall response rate (ORR). Preliminary analysis showed limited efficacy and all subsequent patients were treated at 200 mg BID. Previously randomised patients were unblinded and given the opportunity to receive 200 mg BID. RESULTS: Sixty-eight patients were treated (47 at 200 mg BID, 21 at 100 mg BID). Cell of origin analysis showed 58% germinal B-cell (GCB) origin, 30% activated B-cell (ABC) origin and 12% with an intermediate cell of origin signature. The most common treatment-related adverse events of all patients were diarrhoea (21% total, 6% grade 3/4), nausea (19% total, 3% grade 3/4), and, fatigue (18% total, 9% grade 3/4). The ORR rate was 3% across both arms and clinical benefit (≥ stable disease) was achieved for 13% of all patients. The cell of origin for patients with clinical benefit was GCB (4 patients), intermediate (4 patients) or unknown (1 patient). None of the patients with clinical benefit had ABC genotype. CONCLUSIONS: While fostamatinib was generally well tolerated in this patient population, efficacy at these doses and schedule was poor. Unlike data with other B-cell antigen receptor pathway inhibitors, responses were not observed in the ABC genotype.
Authors: Ondrej Havranek; Jingda Xu; Stefan Köhrer; Zhiqiang Wang; Lisa Becker; Justin M Comer; Jared Henderson; Wencai Ma; John Man Chun Ma; Jason R Westin; Dipanjan Ghosh; Nicholas Shinners; Luhong Sun; Allen F Yi; Anusha R Karri; Jan A Burger; Tomasz Zal; R Eric Davis Journal: Blood Date: 2017-06-23 Impact factor: 22.113