Syk Inhibition in MItigating Lung Allograft Rejection (SIMILAR): A Trial to Evaluate the Safety and Tolerability of Fostamatinib in Lung Transplant Patients With Donor-Specific Antibodies

Study Description: The overall objective of this study is to assess the clinical safety and tolerability of fostamatinib in lung transplant (LT) patients with positive donor-specific antibodies (DSA). Subjects who test positive for DSA will be identified and approached regarding potential participation in the study. Interested individuals will then be screened for study eligibility. Eligible participants will be randomized in a 1:1 ratio to receive fostamatinib or placebo under blinded conditions. Participants will receive fostamatinib or placebo, first 100 mg orally daily for 2 weeks, then escalate to 100 mg orally twice daily for an additional 2 weeks and then escalate to 150 mg twice daily for an additional 4 weeks. Subjects will be monitored for 28 additional days. The primary outcome is the number of discontinuations of study drug. Secondary outcomes will evaluate other safety parameters, as well as potential clinical and molecular benefits of fostamatinib in the prevention of antibody-mediated rejection (AMR) in DSA+ LT patients. Objectives: Primary Objective: To assess the clinical safety and tolerability of fostamatinib compared to placebo in DSA+ LT patients. Secondary Objectives: To evaluate molecular and clinical benefit of fostamatinib compared to placebo in DSA+ LT patients. Exploratory Objective: To gain additional molecular insight into the mechanism of fostamatinib in DSA+ LT patients. Endpoints: Primary Endpoint: -Incidence and relationship to study drug of the following: -hypertension, neutropenia, diarrhea, increase in LFTs requiring discontinuation of study drug. Secondary Endpoints: * Rate of DSA clearance * Relative change of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) from baseline to Day 56 and from baseline to Day 84 * Number of patients who has discontinued the study drug or placebo without restarting by the end of each dose (Day 14, 28, 56) due to serious adverse events * Incidence of clinical AMR * Number of temporal holds of study drug at different study drug dose. * Number of patients with missed doses of study drug at each study visit. * Number of doses missed at each study drug dose level. * Total number of drug dose by day 56. Exploratory Endpoints: * Adverse events not specified in primary or secondary endpoints: incidence, severity and relationship to study drug * Bronchoalveolar lavage (BAL) neutrophil extracellular trap (NET) production * Plasma tissue-specific cell free (cf)DNA levels at baseline, Day 14, Day 28, Day 42, Day 56, Day 84. * Measure blood concentration of fostamatinib at each dose. This will be measured at the end of the study to prevent unblinding. * Relative change of molecular markers (NETs, interleukin 6, double stranded \[dd\]cfDNA) at baseline, Day 14, Day 28, Day 42, Day 56, and Day 84. * Rate of DSA clearance, relative change of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) from baseline to Day 56 and from baseline to Day 84. * Differential gene expression from RNA sequencing of BAL fluid and PBMCs for drug and placebo * cfDNA, cytokine, and NET at the time of clinical complication