A Phase II Trial to Evaluate the Efficacy of Fostamatinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Flinn Ian , Bartlett Nancy L. , Blum Kristie A. , Ardeshna Kirit M , LaCasce Ann , Flowers Christopher R. , Shustov Andrei R. , Thress Kenneth , Zheng Fred , Skolnik Jeffery , Friedberg Jonathan W. 
Published: October 2019

Abstract
Background:DLBCL is an aggressive non-Hodgkins lymphoma. While between 50-60% of all patients can be cured with combination chemo-immunotherapy such as R-CHOP, many patients are either refractory to initial treatment, or relapse following remission. Many DLBCL patients exhibit overexpression of components of the B-cell receptor signaling cascade such as spleen tyrosine kinase (Syk), and subsets of DLBCL are particularly reliant on tonic signaling through the B-cell receptor. Fostamatinib is an orally administered Syk inhibitor studied in patients with rheumatoid arthritis, immune thrombocytopenia purpura, solid tumors, and B-cell malignancies. This phase II trial examines the safety and efficacy of fostamatinib in patients with relapsed/refractory DLBCL.
Methods:This study was conducted in the US [ClinicalTrials.gov: NCT01499303] and UK [EudraCT Number: 2011-005371-16]. Eligible patients had measurable DLBCL defined by Cheson, 2007 and progressed following therapy with an anthracycline-based regimen such as R-CHOP. Patients received, or were ineligible for, high-dose chemotherapy with stem-cell rescue in order to enroll in the trial. The trial was originally a 2-arm, randomized, double-blinded trial of fosatamatinib at either 100 mg BID or 200 mg BID. Patients received study drug until disease progression or unacceptable toxicity. Preliminary analysis showed limited efficacy and the protocol was amended to treat all patients at 200 mg BID. Any patient previously randomized was unblinded and given the opportunity to receive 200 mg BID, if previously assigned to the fostamatinib 100 mg BID arm. All newly enrolled patients were assigned to the 200 mg BID arm. Patients underwent response assessment at 8 weeks, and every 12 weeks thereafter. The primary objective was to assess overall response rate (ORR).
Results: Sixty-eight patients were enrolled, 69% male with a median age of 65 yrs (range 29-86 yrs). Adequate tumor tissue was collected for cell of origin analysis for 59 out 68 patients. Thirty four (58%) were of GCB origin, 18 (30%) were ABC of origin and 7 (12%) had an intermediate cell of origin signature. Patients had a median of 3 prior therapies (range 1-8). Forty-seven patients (69%) were dosed with 200 mg fostamatinib BID. An additional 21 patients (31%) received 100 mg fostamatinib BID of which 1 was on study at the time of the amendment receiving 200 mg fostamatinib BID. The most common treatment-related AEs were diarrhea (21% overall, 0% for 100 mg BID, 30% for 200 mg BID), nausea (19% overall, 14% for 100 mg BID, 21% for 200 mg BID), fatigue (18% overall, 14% for 100 mg BID, 19% for 200 mg BID), thrombocytopenia (13% overall, 19% for 100 mg BID, 11% for 200 mg BID), neutropenia (12% overall, 19% for 100 mg BID, 9% for 200 mg BID) and constipation (12% overall, 10% for 100 mg BID, 13% for 200 mg BID). Five patients on 200 mg BID discontinued due to treatment-related AEs (1 each: pneumonitis, pancytopenia, dysphagia, chest discomfort, and lip swelling) and 1 patient on 100 mg BID had their dose reduced due to thrombocytopenia. 18 patients died on study, 16 of disease progression, 1 of intercurrent illness (pneumonia), and 1 on the 200 mg BID arm from a treatment-related AE (pneumonitis). The ORR rate was 3% and clinical benefit (ORR + stable disease) was achieved for 13% of patients. There were 2 patients with objective response (1 CR, 1 PR) and 2 patients with stable disease on the 100 mg BID arm and 0 patients with objective response and 5 patients (11%) with stable disease on the 200 mg BID arm. At the time of data cut off, the clinical response has lasted for a median of 12 weeks (range 4-57 weeks). The cell of origin for pts with clinical benefit was GCB (4 pts), intermediate (4 pts) or unknown (1 pt). None of the patients with clinical benefit were of the ABC phenotype. Six patients with clinical benefit (better than stable disease) were analyzed for mutations in MYD88, CD79A, CD79B, and EZH2 and only 1 patient with a best response of stable disease had identifiable mutations (EZH2, Y646F; MYD88, S219C).
Conclusions: While fostamatinib was generally well tolerated in this patient population, efficacy using this dose and schedule was limited. In addition, there did not appear to be increased activity in patients with the ABC phenotype. A better understanding of which patients will benefit from B-cell receptor signaling blockade based on cell of origin will be important for the further development of BCR inhibitors in DLBCL.

Disclosures
Flinn: AstraZeneca: Research Funding. Thress:AstraZeneca: Employment. Zheng:AstraZeneca: Employment. Skolnik:AstraZeneca: Employment.