A Phase 1b Study of Intravenous Vedolizumab Plus Standard of Care for Graft-Versus-Host Disease Prophylaxis in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies: 6-Month Results

Background

Subjects with lower gastrointestinal (GI) acute graft-versus-host disease (aGvHD) generally respond poorly to therapy, and therefore have increased morbidity and mortality. Vedolizumab, a gut-selective antibody targeting α₄β₇ integrin, is approved for the treatment of inflammatory bowel diseases. Vedolizumab interferes with gut-trafficking of immunocompetent donor T-lymphocytes and may have a role in preventing GI aGvHD. Here we present the 6-month results of a phase 1b study of the safety, tolerability and clinical activity of vedolizumab combined with standard graft-versus-host disease (GvHD) prophylaxis.

Methods

This is an open-label, dose-finding study of the addition of vedolizumab to standard GvHD prophylaxis in adults undergoing hematopoietic stem cell transplantation (HCT). Cohort 1 comprised subjects aged 18-60 years with a hematologic malignancy undergoing human leukocyte antigen (HLA)-matched or 1 locus-mismatched, unrelated-donor myeloablative transplantation. These subjects received intravenous (IV) vedolizumab (75 mg, on days -1, +13 and +42 of HCT). If subjects in cohort 1 experienced no engraftment failures or dose-limiting toxicities (DLTs), then subsequent subjects were enrolled into a dose-expansion cohort of IV vedolizumab 300 mg (cohort 2), following the same schedule. Key inclusion criteria for cohort 2 were myeloablative regimens (subjects aged 18-60 years) or reduced-intensity conditioning regimens (subjects aged 18-75 years), donor-recipient pairs who were HLA-matched or 1-locus mismatched, and subjects receiving peripheral blood- or bone-marrow-derived stem cells. All subjects received standard GvHD prophylaxis (tacrolimus and methotrexate). The primary objective was to identify an efficacious vedolizumab dose with an acceptable safety profile for future studies, using the following primary safety endpoints: frequency of DLTs from day -1 to day 28, and the number of patients experiencing treatment-emergent adverse events (TEAEs) and serious adverse events from administration of the first dose of vedolizumab until 18 weeks after the final dose. Secondary endpoints included time to neutrophil engraftment, cumulative incidence of grade II-IV aGvHD and frequency by maximum severity of aGvHD by modified Glucksberg criteria. Exploratory endpoints included overall survival (OS) and aGvHD-free survival.

Results

In total, 24 subjects were enrolled at 5 centers (3 in cohort 1, then 21 in cohort 2). The median age was 55 years (range 18-72 years). Most subjects underwent an unrelated donor HCT (83%), and all except 1 were HLA-matched (Table 1). At 6 months after HCT, no DLTs were observed in either cohort. All subjects engrafted within 28 days; the median time to neutrophil engraftment was 14 days in cohort 2. All subjects experienced at least 1 TEAE, which was serious in 13 subjects (2 in cohort 1, 11 in cohort 2). TEAEs were considered vedolizumab-related in 2 subjects in cohort 1 and 6 in cohort 2, including 1 subject in cohort 2 who experienced 2 serious TEAEs: hypotension and febrile neutropenia. The most frequent infections were cytomegalovirus (4 cases) and Clostridium difficile colitis (3 cases). No adverse events led to discontinuation of vedolizumab. There were no cases of grade II-IV aGvHD at 6 months after HCT in cohort 1. In cohort 2, 4 subjects (19%) developed grade II-IV aGvHD at 6 months after HCT; 3 (14%) grade II (1 skin only involvement, 2 skin and lower GI involvement) and 1 (5%) grade III (liver, skin and lower GI involvement). All cases of lower GI aGvHD were limited to stage 1 disease. At 6 months after HCT, 1 subject died from disease relapse in cohort 1, and 2 subjects died in cohort 2; 1 from disease relapse and 1 from aGvHD-related complications. Among subjects in cohort 2, 6-month OS and non-relapse mortality were 90% and 5%, respectively, and grade II-IV and grade III-IV aGvHD-free survival were 76% and 90%, respectively (Table 2).

Conclusions

In subjects receiving vedolizumab in addition to standard GvHD prophylaxis, there were no DLTs or engraftment failures at 6 months after HCT, and the TEAEs observed have been as expected in this population. The low cumulative incidences of grade II-IV and grade III-IV aGvHD are promising; there were no cases of lower GI aGvHD greater than stage 1. Intravenous vedolizumab 300 mg added to standard GvHD prophylaxis for the prevention of GI aGvHD merits further study.

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