4255 Phase I/II trial of post-transplant cyclophosphamide (PTCy), Bortezomib, and sitagliptin for the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoeitic stem cell transplantation. AUTHORS Sherif S Farag, MD, PhD, Michelle Krogsgaard, PhD2, Mohammad Abu Zaid, MD3, A Samer Al-Homsi, MD, MBA4 AFFILIATIONS 1 Community Health Network MD Anderson Cancer Center, Indianapolis, Indiana, United States 2 New York University, New York, New York, United States 3 Community Health Network MD Anderson Cancer Center, Indianapolis, Indiana, United States 4 Northwell Health Cancer Institute, New York, New York, United States ABSTRACT Background and Significance: GvHD is an important complication of allogeneic hematopoietic stem cell transplantation (HSCT). PTCy plus tacrolimus and mycophenolate is an established standard for prophylaxis of GvHD. Calcineurin inhibitors, however, have a narrow therapeutic index, multiple drug interactions requiring frequent drug monitoring, and directly contribute to transplant-related complications. As they are typically administered for 6-9 months after transplant, patient compliance is essential, and they may prevent early introduction of post-transplant interventions aimed at decreasing risk of relapse. Therefore, approaches reducing GvHD and given for a short duration, avoiding the shortcomings of standard agents, may improve outcomes and broaden applicability of HSCT. Our data shows that proteosome inhibitors reduce the maturation and function of dendritic cells (DC) and that the combination of PTCy and proteosome inhibition is superior to each drug alone in rescuing mice from experimental GvHD (BBMT 2017; 23:225-61). Also, PTCy and bortezomib was clinically well-tolerated, resulting in a low level of chronic GVHD (27%) with an incidence of grade 2-4 acute GVHD of 35.9% (BBMT 2017; 23:1651-7). Sitagliptin, a specific inhibitor of dipeptidylpeptidase (DPP)-4, resulted in a low incidence of grades 2-4 acute GvHD (5%) when combined with tacrolimus and sirolimus (NEJM 2021; 2384:11-19). In addition, sitagliptin synergizes with bortezomib to inhibit T-cell activation and proliferation (Blood 2022; 140 Suppl 1:10204). This study evaluates the safety and efficacy of a novel, short, calcineurin-free regimen of sitagliptin, bortezomib, and PTCy (completed by day +14) for prevention of GvHD without increasing the risk of relapse. Study Design and Methods: This is an open-label, multicenter phase I/II trial evaluating safety and efficacy of PTCy, bortezomib, and sitagliptin in preventing of GvHD (NCT07675174). Phase I determines the maximum tolerated doses (MTD) of sitagliptin and bortezomib in combination with PTCy. In the phase II portion, the primary endpoint is 1-year GvHD-free, relapse survival (GRFS). Secondary endpoints include toxicity, times to engraftment, the cumulative incidences of acute and chronic GVHD, non-relapse mortality, and relapse, and overall survival. Key Eligibility: Age ≥18
4255 Phase I/II trial of post-transplant cyclophosphamide (PTCy), Bortezomib, and sitagliptin for the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoeitic stem cell transplantation. AUTHORS Sherif S Farag, MD, PhD, Michelle Krogsgaard, PhD2, Mohammad Abu Zaid, MD3, A Samer Al-Homsi, MD, MBA4 AFFILIATIONS 1 Community Health Network MD Anderson Cancer Center, Indianapolis, Indiana, United States 2 New York University, New York, New York, United States 3 Community Health Network MD Anderson Cancer Center, Indianapolis, Indiana, United States 4 Northwell Health Cancer Institute, New York, New York, United States ABSTRACT Background and Significance: GvHD is an important complication of allogeneic hematopoietic stem cell transplantation (HSCT). PTCy plus tacrolimus and mycophenolate is an established standard for prophylaxis of GvHD. Calcineurin inhibitors, however, have a narrow therapeutic index, multiple drug interactions requiring frequent drug monitoring, and directly contribute to transplant-related complications. As they are typically administered for 6-9 months after transplant, patient compliance is essential, and they may prevent early introduction of post-transplant interventions aimed at decreasing risk of relapse. Therefore, approaches reducing GvHD and given for a short duration, avoiding the shortcomings of standard agents, may improve outcomes and broaden applicability of HSCT. Our data shows that proteosome inhibitors reduce the maturation and function of dendritic cells (DC) and that the combination of PTCy and proteosome inhibition is superior to each drug alone in rescuing mice from experimental GvHD (BBMT 2017; 23:225-61). Also, PTCy and bortezomib was clinically well-tolerated, resulting in a low level of chronic GVHD (27%) with an incidence of grade 2-4 acute GVHD of 35.9% (BBMT 2017; 23:1651-7). Sitagliptin, a specific inhibitor of dipeptidylpeptidase (DPP)-4, resulted in a low incidence of grades 2-4 acute GvHD (5%) when combined with tacrolimus and sirolimus (NEJM 2021; 2384:11-19). In addition, sitagliptin synergizes with bortezomib to inhibit T-cell activation and proliferation (Blood 2022; 140 Suppl 1:10204). This study evaluates the safety and efficacy of a novel, short, calcineurin-free regimen of sitagliptin, bortezomib, and PTCy (completed by day +14) for prevention of GvHD without increasing the risk of relapse. Study Design and Methods: This is an open-label, multicenter phase I/II trial evaluating safety and efficacy of PTCy, bortezomib, and sitagliptin in preventing of GvHD (NCT07675174). Phase I determines the maximum tolerated doses (MTD) of sitagliptin and bortezomib in combination with PTCy. In the phase II portion, the primary endpoint is 1-year GvHD-free, relapse survival (GRFS). Secondary endpoints include toxicity, times to engraftment, the cumulative incidences of acute and chronic GVHD, non-relapse mortality, and relapse, and overall survival. Key Eligibility: Age ≥18
Created using ChatSlide
This project outlines a calcineurin-free strategy to address Graft-versus-Host Disease (GvHD) in hematopoietic stem cell transplantation (HSCT). It includes a Phase I/II trial (NCT07675174) to establish maximum tolerated doses and assess one-year graft rejection-free survival (GRFS) and safety. The expected clinical impact focuses on achieving complete prophylaxis by day +14, monitoring GvHD, relapse, toxicity, and survival, while simplifying post-HSCT care through fewer interactions.