Fostamatinib In Patients Research Articles

Platelet Responses After Tapering and Discontinuation of Fostamatinib in Patients with Immune Thrombocytopenia: A Continuation of the Fostasur Study

Background/objectives: Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor approved for the treatment of adult patients with chronic immune thrombocytopenia (ITP). There is little information about dose tapering and sustained remission after discontinuation in ITP. In this retrospective multicenter study, we evaluated efficacy and safety of fostamatinib in adult patients with ITP before, during, and after tapering/discontinuation (T/D). Methods: T/D was performed on subjects who achieved complete platelet response (CR) with progressive, conditional dose reduction every four weeks. Results: Sixty-one patients were included from 14 reference centers between October 2021 and May 2023. In subjects that completed T/D (n = 9), the median time from treatment initiation to response was 21 days (IQR: 7.5–42), median time from treatment initiation to CR was 28 days (IQR: 28–42), median time from treatment initiation to the start of tapering was 116 days (IQR: 42–140), and duration of tapering was 112.5 days (IQR: 94.5–191). The median platelet count was 232 × 109/L (IQR: 152–345 × 109/L) at tapering and 190 × 109/L (IQR: 142.5–316.5 × 109/L) at discontinuation. With a median follow-up since discontinuation of 263 days (IQR: 247–313 days), only two patients have relapsed (at 63 and 73 days). Fostamatinib was restarted, achieving a new CR. Platelet counts higher than 100 × 109/L in week 12 were the only positive predictive factors for successful tapering and discontinuation. Conclusions: Sustained response in patient with ITP treated with fostamatinib could be developed. The prognostic factors and recommended scheme of tapering still have to be evaluated.

Real-world experience with fostamatinib in patients with immune thrombocytopenia: Results of an observational study (FORTE).

e23289 Background: Immune thrombocytopenia (ITP) is an autoantibody-mediated disease in which platelets are prematurely phagocytosed by Fcg-receptor-bearing macrophages in a spleen tyrosine kinase (SYK)-dependent signaling pathway. Corticosteroids (CS) are used to suppress the immune response, but long-term use carries a heavy burden of toxicity. Subsequent treatments for ITP include fostamatinib, a potent oral SYK inhibitor approved in 2018 based on two randomized, placebo-controlled, phase 3 trials. In trial patients, who received fostamatinib as second-line therapy following CS with or without immunoglobulins (IVIG), 25 of 32 (78%) patients achieved a platelet response of ≥50,000/µL, which was sustained for a median of 83% of treatment days. Here, we report real-world experience with fostamatinib as second-line therapy for ITP from a multi-center, prospective, observational study. Methods: The study (FORTE; NCT04904276) enrolled adult patients with ITP and an insufficient response to prior CS and/or IVIG. Patients were treated according to their clinician’s discretion, and data were collected for up to 12 months at clinic visits. Results: Sixteen patients were enrolled, and 15 were treated. Of the 15, 9 (60%) were female and the median age was 48 years (range, 20-92). 12 (80%) patients had prior CS and 6 (40%) prior IVIG. 7 (47%) patients completed the study and 8 discontinued treatment due to adverse events (4), lack of efficacy (2), and patient decision (2). After initiation of fostamatinib, 93% (14/15) of patients achieved ≥1 platelet count ≥50,000/μL. Median platelet count increased over time from 43,000/μL (IQR 19,000-105,000) at baseline to 167,000/μL (IQR 96,000-180,000) at Month 12. The median cumulative duration of elevated platelet count was 32 weeks (IQR 6.4-49.4). Concomitant CS were used by 7 (47%) patients at baseline, all of whom were able to taper as early as Month 1 and discontinue their dose by Month 3 in 4 patients, Month 6 in 2 patients, and Month 9 in 1 patient. Five patients had ITP-related AEs (4 Grade 1 and 1 Grade 2): gingival bleeding (2), mucosal haemorrhage (2), fatigue (1), contusion (3), headache (1) and epistaxis (1). There were 3 serious AEs in 2 patients: Grade 3 diarrhea in 1 and Grade 2 dyspnea and chills in 1. Overall safety results were consistent with previous studies of fostamatinib. Conclusions: Real world use of fostamatinib as documented in this observational study demonstrated efficacy and safety as second-line therapy for ITP. Fostamatinib allowed successful tapering and discontinuation of CS while maintaining platelet counts above 50,000/μL. Clinical trial information: NCT04904276 .

1141. Phase 3 Trial (in progress) of the SYK Inhibitor Fostamatinib in Patients Hospitalized with COVID-19: Protocol and Study Implementation Updates

Abstract Background Immune dysregulation associated with COVID-19 includes immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Fig 1). Fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor, was approved for immune thrombocytopenia (ITP) in 2018, and the Phase 3 trials showed a lower than expected rate of thrombosis.1 Clinical studies showed a reduction in IL-6 in patients with rheumatoid arthritis.2 The active metabolite of fostamatinib (R406) protected against LPS-induced acute lung injury and thrombosis in mice3,4 and reduced MUC1 in a mouse model of ALI.5 Fostamatinib demonstrated abrogation of the hyperimmune response caused by anti-spike IgG,6 including reduction in hyperactivation of platelets7 and NETosis in neutrophils8 in in vitro studies using plasma from patients with severe COVID-19. A phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo (all received standard of care [SOC]) in 59 hospitalized patients with COVID-19 and demonstrated reduction in mortality, ordinal scale scores, and number of days in the intensive care unit (ICU) as well as meeting the primary endpoint of safety.9 A phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19 is underway. Figure 1.Mechanism of Disease (COVID-19) and Role of SYK inhibition Methods A Phase 3, randomized, double-blind, placebo-controlled, adaptive design, multi-center study (NCT04629703) is underway to evaluate fostamatinib in 308 adult patients hospitalized with COVID-19 and on oxygen without intubation (Fig 2). Patients will receive fostamatinib 150 mg BID or placebo for 14 days; both arms receive SOC. At baseline, the clinical status score (8-point ordinal scale) had to be 5 or 6. Patients ≥ 65 years had to have ≥ 1 risk factor for severe disease and adults < 65 had to have ≥ 3. The primary outcome is days on oxygen (Day 1 to 29). Other endpoints include change in clinical status score, days in the ICU, time to hospital discharge, all-cause mortality, oxygen-free status and safety. Fostamatinib is investigational for COVID-19. Results Blinded data from this trial in progress are as of 2 December 2021. See Fig 3. Conclusion Final results of this Phase 3 trial are anticipated in 2022. Disclosures Lucy Yan, MD, PhD, Rigel Pharmaceuticals: Employee|Rigel Pharmaceuticals: Stocks/Bonds Ziad Mallat, MD, PhD, Rigel Pharmaceuticals: Advisor/Consultant Suzana Margareth Lobo, MD, PhD, Rigel Pharmaceuticals: Grant/Research Support Anuj Malik, MD, MS, Rigel Pharmaceuticals: Grant/Research Support Wolfgang Dummer, MD, PhD, Rigel Pharmaceuticals: Employee|Rigel Pharmaceuticals: Stocks/Bonds.

The Safety and Efficacy of Fostamatinib in Patients with Chronic Immune Thrombocytopenic Purpura Treated in a Real-World Community Hematology Setting

Background: Chronic immune thrombocytopenia (ITP) in adults is a serious autoimmune disease in which platelets are prematurely destroyed, leaving the patient vulnerable to bruising and bleeding. Initial treatment with corticosteroids is intended to suppress the immune response and is effective in many patients but not sustainable. Fostamatinib is an approved therapy for adult patients with ITP who have had an insufficient response to a prior treatment. It is an oral small molecule that targets spleen tyrosine kinase (SYK), which has important roles in cellular proliferation, differentiation, and immune regulation. By blocking SYK, fostamatinib reduces the immune system's destruction of platelets, which allows the platelet (PLT) count to rise, thereby reducing the risk of bleeding in ITP patients. Two placebo-controlled randomized trials demonstrated that fostamatinib was well tolerated and able to induce meaningful platelet responses in heavily pretreated patients, as well as in earlier lines of therapy. The use of fostamatinib in a community hematology setting has not been evaluated. In this study, the real-world utilization and treatment patterns of fostamatinib in patients treated within the QCCA, a network of 17 community hematology clinics across the United States, is presented. Methods: The QCCA network real world database was reviewed for ITP patients who had received fostamatinib over the past 3 years. Data collection consisted of patient demographics, disease characteristics, duration of ITP, existing comorbidities, number and type of prior ITP treatments and PLT count at baseline prior to the start of fostamatinib. All of the information was collected via a standardized data collection form. From the first day until the end of treatment, data were collected on hemoglobin, white blood cells, absolute neutrophil counts, PLT counts, concomitant ITP therapies and the use of rescue IVIG. A meaningful increase in PLTs was defined as achievement of platelet counts ≥ 30 and ≥ 50 x 103/μL over the course of therapy. Results: The medical records of the 46 ITP patients who met the inclusion criteria and received fostamatinib were evaluated. Patients had a median age of 58 years, 65% were female and 35% had a splenectomy. All patients had prior exposure to corticosteroids and the median number of therapies before stating fostamatinib was two. In addition, 65% had received thrombopoietin receptor agonists and rituximab. All patients started therapy at a dose of 100 mg twice daily for a median duration of 2 months (interquartile range [IQR] = 1 to 15) and a mean duration of 6.7 months (95%CI: 3.5 to 9.9). When fostamatinib was started, the median PLT count was 19 x 103/μL (IQR = 3 to 70). From the start of therapy, the maximum increase in the median PLT count was 78 x 103/μL (IQR = 13 to 231), which was achieved after a median of 1.8 months. Over the course of therapy, 31 (67.4%) and 26 (56.5%) of 46 patients achieved or maintained PLT levels ≥ 30 and ≥ 50 x 103/μL respectively. Of note, prior to the start of fostamatinib, 9 and 7 patients respectively, already had PLT levels ≥ 30 and ≥50 x 103/μL. The percent of patients with at least a doubling of their baseline PLT count was 47.8% (95%CI: 32.9 to 63.0%). There were no serious bleeding events reported, and only one patient required the discontinuation of fostamatinib because of adverse events. Among the 46 patients, 16 received concomitant IVIG to increase PLT counts. Conclusions: In this real-world setting, the findings suggest that fostamatinib is safe and effective in patients with chronic ITP who had relapsed or had not responded to one or more prior treatments.

Targeting mucin hypersecretion in COVID-19 therapy.

Targeting mucin hypersecretion in COVID-19 therapy.

The Cardiovascular Risks of Fostamatinib in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Objective: This systematic review and meta-analysis is aimed at assessing the risks of cardiovascular adverse events in patients with rheumatoid arthritis (RA) who have been treated with fostamatinib. Methods: The electronic databases of OVID Medline, OVID EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science were searched to identify studies that reported cardiovascular events or hypertension in RA patients treated with fostamatinib. Two reviewers separately and simultaneously screened the retrieved studies based on study selection criteria, collected data and performed methodological quality assessments. The effect size of meta-analysis was estimated by the Peto odds ratio (OR) or relative risk (RR) with 95% confidence intervals (95%CI). Funnel plot was used to estimate publication bias and sensitivity analysis was performed to test the robustness of the results. Results: A total of 12 trials composed of 5,618 participants with low to moderate risk of bias were included. In comparison to the placebo, the use of fostamatinib was found to elevate the risk of hypertension (RR=3.82, 95%CI 2.88–5.05) but was not associated with the risks of all-cause death (Peto OR=0.16, 95%CI 0.02–1.24), major adverse cardiovascular events (Peto OR=1.24, 95%CI 0.26–5.97), pulmonary heart disease and disease of pulmonary circulation (Peto OR=1.23, 95%CI 0.13–11.87), in addition to other forms of heart disease (Peto OR=1.96, 95%CI 0.72–5.38). Furthermore, sensitivity analysis showed no significant change in effective trends and no publication bias was found. Conclusion: Fostamatinib is associated with increased risk of hypertension; however, no increased risks of cardiovascular events were observed. Further well-planned cohort studies with large study populations and longer follow-up times are needed to elucidate the outcomes. Systematic Review Registration: [PROSPERO], identifier [CRD42020198217].

Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study

Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study

Evaluation of the Oral SYK Inhibitor Fostamatinib in Patients after Allogeneic Transplantation for Chronic Graft-Versus-Host Disease

Our group previously showed that B cells signal aberrantly through the B cell receptor (BCR) in allogeneic hematopoietic stem cell transplant (HCT) patients with active chronic graft-versus-host disease (cGVHD). Preclinical mouse studies have demonstrated the importance of the proximal BCR molecule, spleen tyrosine kinase (SYK), in cGVHD development. Hypothesizing that the oral small molecule SYK inhibitor, fostamatinib, would safely target aberrant BCR-activated B cells in HCT patients, we are conducting a single-center, investigator-initiated phase 1 trial (NCT02611063). Our primary objective is to evaluate the safety and tolerability of fostamatinib in patients early after HCT and in those with refractory active cGVHD. Secondary objectives include assessment of cGVHD manifestations, B cell activation, and immune recovery. Methods: All patients receive HCT treatment per program standards at Duke University. Prophylaxis (P-cGVHD) subjects enroll 80-150 days after HCT and have no evidence of cGVHD. P-cGVHD subjects receive drug for up to 1 year post-transplant (215-285 fostamatinib days). Steroid-refractory cGVHD (SR-cGVHD) subjects enroll with active cGVHD that persists despite systemic high-dose steroids. SR-cGVHD subjects receive drug for up to 365 days total. For all enrollees, modified continual reassessment criteria are used to determine starting dose (100mg daily, 150mg daily, or 100mg twice BID) and any needed dose modifications. We monitor for drug-limiting toxicities (DLTs), adverse events (AEs), and cGVHD manifestations using NIH cGVHD consensus criteria at up to 12 follow-up visits. Results: 15 of a planned 18 total patients have enrolled. In the P-cGVHD group (n=5), of the 4 patients who completed treatment (mean 239 fostamatinib days), 1 patient developed cGVHD while enrolled and 2 patients subsequently developed cGVHD, 4 and 6 weeks after study completion. The fifth P-cGVHD subject discontinued therapy on study day 155 (provider decision to initiate donor lymphocyte infusion for low CD3+ chimerism). In the SR-cGVHD group (n=10), 2 patients completed treatment (mean 365 fostamatinib days); 3 patients withdrew (mean 132 fostamatinib days), for non-cardiac chest pain, progression of cGVHD, and moved away; and 5 patients are actively enrolled (mean 207 fostamatinib days). Both SR-cGVHD patients who completed the study clinically improved while on fostamatinib and requested continuation of drug. A total of 2, 9, and 4 patients have been initiated on 100mg daily, 150mg daily, and 100mg BID, respectively. At the 100mg daily dose, no DLTs were noted. At the 150mg daily dose, 1 patient developed liver function test (LFT) elevation. At the 100mg BID dose, 2 patients developed LFT elevation and 1 patient developed non-cardiac chest pain. One patient required dose adjustment: 100mg BID to 150mg daily, for LFT elevation. Two serious AEs possibly related to fostamatinib occurred: 1 patient developed non-cardiac chest pain and 1 patient developed a deep venous thrombosis. No probably- or definitely-related serious AEs occurred. To assess whether fostamatinib effectively targets aberrantly activated B cells, we examined subjects' whole blood using flow cytometry. When comparing CD19+ B cells on study day 1 versus study day 60 in the SR-cGVHD group (n=7), we found the relative proportion of CD19+CD38+IgDlow plasmablast-like cells was decreased (p=0.03, Fig 1A-B), suggesting fostamatinib 'hit target.' Importantly, in the P-cGVHD group, total lymphocyte and B cell counts did not decrease during day 1 to day 225 (Fig 1C-D), suggesting fostamatinib did not affect immune recovery when given early after HCT. Further investigations with functional assays are underway. Conclusions: This study demonstrates for the first time that fostamatinib is safe and tolerated in HCT recipients both early after transplant and in those with active cGVHD. Importantly, fostamatinib does not appear to hinder lymphocyte or B cell recovery when initiated between days 80-150 after HCT. Additionally, fostamatinib may effectively target aberrantly activated B cells in patients with active SR-cGVHD. Fostamatinib, now FDA-approved for treatment of immune thrombocytopenia, merits a phase 2, randomized controlled trial to assess efficacy as a prophylactic agent against cGVHD. This work was supported by a National Institutes of Health grant, NIH (NHLBI) R01 HL 129061. Fostamatinib was supplied by Rigel. Disclosures Horwitz: Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Gasparetto:BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding.

A Systematic Review and Meta-Analysis of Cardio-Vascular Side Effects with Fostamatinib a Spleen Tyrosine Kinase Inhibitor

Introduction: Spleen tyrosine kinase (Syk), a cytoplasmic tyrosine kinase, is a member of the non-receptor type protein kinase family. Apart from the hematopoietic cells, it is also expressed in the epithelial and endothelial cells. Fostamatinib, a Syk inhibitor, has been proven beneficial in autoimmune disease like rheumatoid arthritis (RA) and immune thrombocytopenia (ITP). Murine models have shown a direct correlation between hypertension and level of R406, the active metabolite of fostamatinib. In this study, we sought to examine the cardiovascular profile of fostamatinib in published and unpublished randomized controlled trials. Methods: A systematic search of Pubmed, Medline and Scopus databases were done from inception till date to identify all phase 2 and 3 clinical trials of fostamatinib in patients with ITP and RA by two independent reviewers. Trials were included if they reported side effects including but not limited to cerebral ischemia or infarction, myocardial ischemia and myocardial infarction, hypertension and cardiac rhythm disorders. 35 trials were retrieved in the initial search which were excluded according to PRISMA (Preferred Reporting Items for Systematic review and Meta-Analyses) guidelines. 11 trials met the eligibility criteria and were included in the final analysis. All statistical analysis was carried out using OpenMetaAnalyst software. Categorical variables from each study are presented as proportions. The proportions from each study were subjected to arcsine transformation and pooled using a random-effects model. This yielded the pooled estimate with 95% confidence intervals. The I2 statistic was used to assess heterogeneity and a value of I2 = 25%-50% was considered mild, 50%-75% as moderate, and > 75% as severe. A P value of <0.05 was considered significant in all cases. Results: 11 trials included in final study had 3941 patients. Cardio-vascular side effects were reported by all trials which ranged from 0.7% to 19.2%. The pooled estimate was 11.7% (8.6%-15.3%, P<0.001 (I2=89.97%)). The most common adverse event reported was hypertension by 10 trials with pooled estimate of 11.1% (8.3%-14.2%, p<0.001(I2=87.27%). The FIT-3 trial reported hypertension as the sole cardiovascular adverse event in 16.7% (n=21) of patients. Other adverse events reported were arrhythmias by 3 trials with incidence of 0.4% (n=11), angina was reported by 5 trials with incidence of 0.8% (n=19). Malignant hypertension was reported in 3 trials with incidence of 0.2%(n=4). 3 trials report heart failure with incidence of 0.3% (n=7). Carotid artery stenosis was observed in only one patient in Oskira 2 trial. Only 2 patients were found to have stroke from all trials, no incidence of aortic stenosis/aneurysm reported. Ventricular fibrillation and peripheral ischemia were observed in one patient respectively and circulatory shock was seen in two patients. Left bundle branch block and pericarditis were also rare side effects observed in only one patient. Conclusion: Our study shows that the use of fostamatinib is significantly associated with cardiovascular side effects, of which hypertension is most significant adverse event. We also recorded a few serious adverse events like hypertensive crises, myocardial infarction, coronary artery disease and congestive heart failure in few patients, but at a very low rate. Larger longitudinal studies are needed to determine the side effect profile of fostamatinib. Disclosures No relevant conflicts of interest to declare.

Real-World Experience with Fostamatinib in Patients with Immune Thrombocytopenia at an Academic Medical Center

Introduction Fostamatinib is a first in its class oral inhibitor of spleen tyrosine kinase (Syk) pathway for treatment of adults with immune thrombocytopenia (ITP) with insufficient response to previous treatment. Choice of treatment for relapsed ITP varies greatly according to clinician and patient preference. It is common for patients to switch between available thrombopoietin (TPO) agonists and now fostamatinib. Titration of these agents is often cumbersome and labor intensive; romiplostim in particular requires weekly visits with lab draws and consumes nurse, pharmacy and provider effort. Here we present real world experience with fostamatinib use in an academic medical center. Methods. We retrospectively identified four patients who were prescribed fostamatinib within the past nine months at Boston Medical Center Health System. All patients had a diagnosis of chronic ITP and were previously treated with corticosteroids, intravenous immunoglobulin (IVIG), and rituximab. With respect to previous TPO receptor use, two of four patients had received both eltrombopag and romiplostim. Patients were started on fostamatinib at a dose of 100 mg by mouth twice daily and titrated up to 150 mg by mouth twice daily if platelet counts were <50 10x9 /L after 4 weeks of therapy. All patients were seen by a pharmacist and provider for initiation of the drug and seen in clinic weekly for the first month on therapy to assess toxicity and efficacy. The duration of follow up for the patients is between 2 and 9 months on therapy. Results. Three of four patients initiated on fostamatinib had a baseline platelet count 100K or greater and the fourth patient had ITP refractory to multiple lines of therapy with a baseline platelet count of 7K at therapy initiation. Three patients sought alternative therapy given side effects from TPO agonists or inconvenience of romiplostim. Three patients had platelets counts >50K at 4 weeks and one patient had a platelet count <30K. Recent platelet counts of the two patients that have been on therapy for 7 and 8 months were 123K and 108K, respectively. The third patient that responded initially discontinued therapy due to lack of stable response. Both of the patients with stable responses were well controlled on previous therapy with romiplostim. One patient required rescue therapy with IVIG and romiplostim due to petechiae 15 days after therapy initiation but continued on therapy thereafter. Two patients that discontinued therapy had platelet counts of 10K and 88K upon discontinuation due to inadequate response and toxicity, respectively. One patient was romiplostim naïve and the other patient had not received romiplostim for four years prior. Two patients developed diarrhea that was managed with loperamide and one led to treatment discontinuation (in combination with insufficient response). One patient experienced hypertension that was managed accordingly. Conclusion. The ideal place in therapy for fostamatinib in ITP therapy is not yet clear. However, the availability as an oral option for patients with refractory disease is appealing. One of our patients required rescue therapy which should be considered when transitioning patients to fostamatinib from TPO agonists. Additionally, side effect management with anti-hypertensives and anti-diarrheal agents may be required to continue therapy. Effectiveness of romiplostim may predict responsiveness to fostamatinib, although additional data are needed. Table Disclosures Shah: Rigel Pharmaceutical: Consultancy, Speakers Bureau. Sarosiek:Acrotech: Research Funding. Sloan:Merck: Other: endpoint review commitee; Abbvie: Other: Endpoint Review Committee; Stemline: Consultancy.

A phase II trial to evaluate the efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

PurposeTo assess the safety and efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Experimental designRelapsed 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. ResultsSixty-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. ConclusionsWhile 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.

Pharmacokinetic Properties of Fostamatinib in Patients With Renal or Hepatic Impairment: Results From 2 Phase I Clinical Studies

PurposePhase III trials of fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis have been completed. Herein, we report the effects of renal and hepatic impairment on the pharmacokinetic (PK) properties of the active metabolite of fostamatinib, R406, in plasma, and on the urinary excretion of R406 and its metabolite N-glucuronide. MethodsTwo Phase I, single-center, open-label clinical trials determined the PK properties and tolerability of fostamatinib in subjects with normal or impaired renal or hepatic function. Twenty-four subjects in the study in renal impairment (8 per group: normal renal function, moderate renal dysfunction, or end-stage renal disease [ESRD]), and 32 subjects in the study in hepatic impairment (8 per group: normal hepatic function or mild, moderate, or severe hepatic impairment) received a single 150-mg dose of fostamatinib. Patients with ESRD in the study in renal impairment participated in 2 treatment periods separated by a ≥1-week washout. In these patients, fostamatinib was administered after dialysis or 2 hours before dialysis. FindingsGeometric mean R406 Cmax and AUC values were less in the combined renally impaired group than in the group with normal renal function; Tmax was similar across groups. However, renal impairment had no apparent effect considered clinically relevant on unbound R406. In patients with ESRD, R406 exposure was less when fostamatinib was administered after compared with before dialysis. Urinary excretion of R406 N-glucuronide was decreased with increasing severity of renal impairment. Renal elimination of R406 was negligible in all groups. Varying degrees of hepatic impairment had no consistent effects on the PK properties of R406. R406 Cmax values were 10% to 15% less in all hepatically impaired groups than in the group with normal hepatic function. AUC and Tmax values were similar between the groups with normal and severely impaired hepatic function; in the groups with mild or moderate hepatic impairment, AUC was less and Tmax was greater. The geometric mean percentage of unbound R406 ranged from 0.64% to 1.95% and was greatest in the group with severe hepatic impairment. The urinary excretion of R406 was minimal. The amount of R406 N-glucuronide excreted in urine was greater in severely hepatically impaired patients. Fostamatinib 150 mg was generally well tolerated. ImplicationsIn these patients, renal or hepatic impairment did not affect exposure to the active metabolite of fostamatinib, R406, to a clinically relevant extent. ClinicalTrials.gov identifiers: NCT01245790 (renal) and NCT01222455 (hepatic).

Abstract 1706: Whole exome sequencing of pre and post treatment diffuse large B cell lymphoma reveals the mutation spectrum of the relapse/refractory patient population

Abstract Our current understanding of the mutation spectrum of relapse/refractory patients is limited. Several published studies describing the mutational landscape of Diffuse Large B cell Lymphoma (DLBCL) have focused, by design, on diagnostic (pre-treatment) biopsies alone, while re-biopsy of patients who are refractory to first line therapy or who relapse on treatment is not standard of care in DLBCL. We have performed whole exome sequencing on 47 post treatment DLBCL core needle biopsies, 8 with matched diagnostic biopsies. Samples were obtained during a phase II trial prior to the start of treatment with the BCR targeted agent fostamatinib (1,2). Patients had progressed following therapy with an anthracycline-based regimen such as R-CHOP and had a median of 3 prior therapies (range 1-8). We compared the whole exome somatic variant and copy number calls from the post treatment and matched pairs to 2 cohorts of primary DLBCL (n = 112) analyzed with the same mutation caller (3,4). The average mutation rate between the pre and post treatment samples (n = 250, 282 respectively) and the paired diagnostic and post treatment biopsies were similar. However, we found that the mutation spectrum between the paired biopsies differed. Known DLBCL hotspot mutations such as MYD88 L265P remained consistent between pre and post treatment biopsies, however novel mutations in known DLBCL targets were found to emerge in the post treatment biopsies. 1. Veldman-Jones, M. et al. Reproducible, quantitative and flexible molecular sub-typing of clinical DLBCL samples using the NanoString nCounter system. Clin Cancer Res (2014) 2. Flinn I, B.N., Blum KA, et al. A Phase II Trial to Evaluate the Efficacy of Fostamatinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). American Society of Hematology (San Francisco, 2014). 3. Zhang, J. et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A 110, 1398-403 (2013). 4. Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 43, 830-7 (2011). Citation Format: Danielle Greenawalt, Kate Byth, Zhongwu Lai, Justin Johnson, Ambar Ahmed, Brian Dougherty, Kenneth Thress, Michael Zinda, Winnie S. Liang, John Carpten, Stephen Fawell, J. Carl Barrett. Whole exome sequencing of pre and post treatment diffuse large B cell lymphoma reveals the mutation spectrum of the relapse/refractory patient population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1706. doi:10.1158/1538-7445.AM2015-1706

A Phase II Trial to Evaluate the Efficacy of Fostamatinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

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.

The effects of the spleen tyrosine kinase inhibitor fostamatinib on ambulatory blood pressure in patients with active rheumatoid arthritis: results of the OSKIRA-ABPM (ambulatory blood pressure monitoring) randomized trial

Clinical trials of fostamatinib in patients with rheumatoid arthritis showed blood pressure (BP) elevation using clinic measurements. The OSKIRA-ambulatory BP monitoring trial assessed the effect of fostamatinib on 24–hour ambulatory systolic BP (SBP) in patients with active rheumatoid arthritis. One hundred thirty–five patients were randomized to fostamatinib 100 mg twice daily (bid; n = 68) or placebo bid (n = 67) for 28 days. Ambulatory, clinic, and home BPs were measured at baseline and after 28 days of therapy. Primary end point was change from baseline in 24–hour mean SBP. Fostamatinib increased 24–hour mean SBP by 2.9 mm Hg (P = .023) and diastolic BP (DBP) by 3.5 mm Hg (P < .001) versus placebo. Clinic/home-measured BPs were similar to those observed with ambulatory BP monitoring. After treatment discontinuation (1 week), clinic BP values returned to baseline levels. Fostamatinib induced elevations in 24–hour mean ambulatory SBP and DBP. BP elevations resolved with fostamatinib discontinuation.

THU0139 Pharmacokinetics of fostamatinib in patients with impaired hepatic function: A phase I study

BackgroundFostamatinib (R788), a spleen tyrosine kinase inhibitor, is currently being developed as an oral therapy for patients with rheumatoid arthritis1. Once administered, fostamatinib is converted to its active moiety, R406....

THU0138 Pharmacokinetics of fostamatinib in patients with impaired renal function: A phase I study

BackgroundFostamatinib (R788), a spleen tyrosine kinase inhibitor, is currently being developed as an oral therapy for patients with rheumatoid arthritis1. In humans, orally administered fostamatinib is converted to the active...

BCR Signaling in Chronic Lymphocytic Leukemia and Related Inhibitors Currently in Clinical Studies

Normal B lymphocytes receive signals from B-cell antigen receptor (BCR) that are triggered by binding of the BCR to an external antigen. Tonic signaling through the BCR provides growth and signals to chronic lymphocytic leukemia (CLL) cells, and plays an important role in the pathogenesis and progression of the disease. Antigen engagement of BCR is followed by intracellular recruitment and activation of BCR-associated kinases including spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk) and phosphatidylinositol 3-kinases (PI3K). Inhibition of signaling pathways downstream of the BCR induces disruption of chemokine-mediated CLL cell migration and cell killing. BCR signal transduction inhibitors represent a promising new strategy for targeted CLL treatment. A number of therapeutic agents have recently been developed with significant activity in CLL. The compounds that are currently investigated in patients with CLL include ibrutinib –inhibitor of Btk, fostamatinib-inhibitor of Syk and idelalisib (GS-1101) –a specific isoform of the PI3K (PI3K) inhibitor. The clinical activity of ibrutinib, GS-1101 and fostamatinib in patients with CLL is associated with marked lymphocytosis due to release of tumor cells from the lymph nodes into the peripheral blood. Further studies are ongoing with single agents and their combinations with other targeted and conventional therapies. This article will review the preclinical rationale of BCR signaling inhibitors in the treatment of CLL, and the clinical evidence supporting the use of these agents in CLL patients.

Inhibition of Spleen Tyrosine Kinase with Fostamatinib Shows Pre-Clinical Activity Against Models of Waldenström Macroglobulinemia

AbstractAbstract 3723 Background:Waldenström macroglobulinemia (WM), a lymphoproliferative disorder with marrow infiltration by lymphoplasmacytic lymphoma cells and production of monoclonal IgM, is characterized clinically by good initial responses to standard therapeutic approaches. However, a minority of patients achieve a complete remission, and most inevitably relapse, indicating a need for validation of new, targeted therapies. Notably, B-cell receptor signaling has been linked to clonal evolution in WM, and Spleen tyrosine kinase (Syk) is over-expressed in primary patient cells. Also, a recent phase I/II study of the Syk inhibitor fostamatinib in patients with a variety of non-Hodgkin lymphomas showed evidence of activity in three patients with WM. These findings supported our central hypothesis, which proposed that Syk could be a rational new target for therapy of WM, which we pursued first with pre-clinical studies. Methods:Studies of fostamatinib were performed using the WM cell line MWCL-1, and the IgM-producing cell line BWCM.1, as well as in primary cells from patients with WM, and in a novel murine xenograft model utilizing MWCL-1 cells. Results:Fostamatinib induced a time- and dose-dependent reduction in viability of MWCL-1 and BWCM.1 cells, with median inhibitory concentrations (IC50) that were in the physiologically relevant range of approximately 0.25 and 1 μM, respectively, at 3 days. Cell cycle analysis showed a decrease in cells at S-phase and at G2/M, while an increase was seen in cells in G1, and in the sub-G1fraction, suggesting induction of apoptosis. Consistent with the possibility that there was activation of type I programmed cell death, increased staining was seen in fostamatinb-treated cells with an antibody to Annexin V. Interestingly, evidence was seen of the induction of type II programmed cell death, or autophagy, as measured by an increase in cells staining with the lysotropic dye acridine orange. At the molecular level, fostamatinib blocked signaling through p44/42 mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), protein kinase B/Akt, and Zeta-chain-associated protein kinase (ZAP)-70/Syk, as judged by a reduction in the phosphorylated forms of these intermediates by Western blotting. Notably, the viability of primary cells isolated from patients with WM was also reduced in association with blockade of p44/42 MAPK. Finally, a novel murine xenograft model was generated by injection of MWCL-1 cells into immunodeficient mice, which developed measurable tumors. When these were treated with fostamatinib, a delay in tumor growth was demonstrable. Conclusions:Targeting Syk with fostamatinib is an attractive strategy against pre-clinical models of WM both in vitro and in vivo. These findings lend further support for translation of fostamatinib to the clinic for patients with relapsed, and possibly even newly diagnosed WM. Disclosures:No relevant conflicts of interest to declare.