title: A phase II trial to evaluate the efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
abstract: OBJECTIVE
  To assess the safety and efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
  
  
  METHODS
  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.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA. Electronic address: iflinn@tnonc.com.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Flinn
authors.affiliation: Siteman Cancer Center/Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Bartlett
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.affiliation: Sarah Cannon Research Institute United Kingdom/University College London, London, UK.
authors.forename: Kirit M
authors.initials: KM
authors.lastname: Ardeshna
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Ann S
authors.initials: AS
authors.lastname: LaCasce
authors.affiliation: Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Flowers
authors.affiliation: Seattle Cancer Care Alliance/University of Washington, Seattle, WA, USA.
authors.forename: Andrei R
authors.initials: AR
authors.lastname: Shustov
authors.affiliation: AstraZeneca, Waltham, MA, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Thress
authors.affiliation: AstraZeneca, Waltham, MA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Formerly at AstraZeneca, Wilmington, DE, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Formerly at AstraZeneca, Wilmington, DE, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Skolnik
authors.affiliation: University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Friedberg
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines; D012008:Recurrence; D000072377:Syk Kinase; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib
keywords: B-cell receptor; Clinical trial; DLBCL; Phase II; Syk inhibitor