Phase II Trial of Pasireotide to Prevent GI Toxicity and Acute Gvhd in Allogeneic HSCT

Abstract

<h3>Background</h3> Gastrointestinal (GI) toxicity and acute graft versus host disease (GVHD) are significant morbidities associated with allogeneic hematopoietic stem cell transplantation (HSCT). The somatostatin analogue Octreotide ameliorates mucosal injury from radiation damage in pre-clinical mouse models. We hypothesized that administration of the longer-acting synthetic somatostatin analogue, Pasireotide, in the peri-transplant period would decrease acute GI toxicity and acute GVHD related to allogeneic HSCT. <h3>Methods</h3> Adult patients who underwent matched allogeneic HSCT with myeloablative conditioning were eligible for this study. Exclusion criteria included severe cardiac and endocrine abnormalities. Pasireotide was administered at 0.9mg twice daily from the day before conditioning began to day +4. The co-primary endpoints were 1) Acute GI toxicity, defined as GI toxicity occurring from the day prior to conditioning to day +30, and 2) Acute GVHD. Results were compared with 50 historical controls matched by Transplant diagnosis, Donor, Graft, GVHD prophylaxis, and Conditioning regimen. <h3>Results</h3> 36 patients were consented for the study, 25 patients received the study drug (5 screen failures, 1 insurance denial, 3 withdrew consent, 1 switched trials, 1 enrolled at an alternate center without available follow-up). There was no difference in Acute GI toxicity, which occurred in all patients in both the Pasireotide and Control groups. Grade 3 or 4 GI toxicity was similar, occurring in 20 patients (80%) in the Pasireotide group and 35 patients (70%) in the Control group. Specific GI toxicities varied in incidence between the Control and Pasireotide study groups (Figure 1), most notable for numerically higher rates of the expected toxicities abdominal pain, bloating, and vomiting in the Pasireotide group. Other common toxicities that occurred in the Pasireotide and Control groups are listed in Figure 1. There was no significant difference in incidence of overall Acute GVHD or Acute GI GVHD (Figure 2). The subset of patients who received Total Body Irradiation (TBI) conditioning had numerically lower Acute GVHD in the Pasireotide group (5/9, 55%) compared to the Control group (16/20, 80%), however this was not statistically significant (Fisher's Exact Test, p=0.21); these patients also had a lower rate of combined upper and lower GI GVHD (3/9, 33% in the Pasireotide group versus 11/20, 55% in the Control group), though this was not statistically significant (Fisher's Exact Test, p=0.43). <h3>Conclusions</h3> In this Phase 2 study, the somatostatin analogue Pasireotide did not decrease GI toxicity in allogeneic HSCT; however, in the subset of patients who received TBI conditioning, there was a numerically (but not statistically) significant decrease in overall and GI Acute GVHD. Further study in a larger cohort of patients undergoing TBI conditioning is warranted.