EFFICACY and SAFETY of the ADDITION of RGI-2001 IV INFUSION to TACROLIMUS and METHOTREXATE for ACUTE GVHD PREVENTION in MYELOABLATIVE HSCT

Document Type

Conference Proceeding

Publication Date

11-9-2023

Publication Title

Bone Marrow Transplant

Keywords

calcineurin inhibitor, glycolipid, methotrexate, mycophenolate mofetil, tacrolimus, abdominal pain, acute graft versus host disease, adult, aged, anemia, clinical article, conference abstract, controlled study, diarrhea, dose calculation, drug combination, drug therapy, female, follow up, gastrointestinal hemorrhage, graft versus host reaction, human, hyperbilirubinemia, incidence, infusion related reaction, intravenous drug administration, leukopenia, liposome, male, nausea, phase 3 clinical trial, prevention, prophylaxis, rash, regulatory T lymphocyte, side effect, single drug dose, stomatitis, survivor, T cell depletion

Abstract

Background: RGI-2001 is a liposomal glycolipid that binds the CD1d receptor of antigen-presenting cells (APC) resulting in activation of invariant natural killer (iNKT) cells. In the context of alloHCT, this interaction results in a cytokine-dependent Treg proliferation with potential modulation of the GvHD pathogenic cascade. Earlier dose-finding studies have shown that a single dose of RGI-2001 given on the day of alloHCT is safe and potentially contributed to prevention of acute GVHD (aGVHD). Methods: RGI-2001-003 is an open-label, multi-center phase 2b study evaluating the efficacy and safety of RGI-2001 when added to a calcineurin inhibitor with methotrexate or mycophenolate mofetil (without T-cell depletion) for the prevention of aGvHD in subjects following myeloablative alloHCT. RGI-2001 was administered in a 30-minute infusion at a dose of 100 ug/kg IV weekly x 6 doses, starting on the day of transplant (Days 0, 7, 14, 21, 28, 35). The primary endpoint of the study is incidence of grades II-IV aGvHD by day 100. Results: A total of 49 subjects treated at 7 U.S. transplant centers were enrolled. Median age was 52 (range 21-65); 27 were male. Donors were 8/8 HLA-matched unrelated (n = 32, 65%) 8/8 HLA-matched related (n = 16, 33%), or 7/8 HLA-matched unrelated (n = 1, 2%). The most common underlying diseases were AML (n = 26, 53%), ALL (n = 11, 22%), and MDS (n = 8, 16%). Graft sources were PBSC (n = 40) or BM (n = 9). Common conditioning regimens were Bu/Flu (83%) and TBI/Cy (12.2%). All subjects received standard tacrolimus/methotrexate for GvHD prophylaxis. One infusion reaction (Grade 2) was reported. Treatmentemergent adverse events (TEAE > 5%) related to RGI-2001 were stomatitis 14%, diarrhea 12%, nausea 12%, abdominal pain 8%, increased bilirubin 8%, ALT enzyme elevation 6%, ALP elevation 6%, and rash 6%. Grade 3 or 4 related TEAE > 2% were stomatitis (6%), anemia (4%), and leukopenia (4%). Per protocol, patients were followed for a maximum of 1 year. The median follow-up of 46 survivors was 363 days (range, 164-365), and 46 of 49 patients had complete follow-up to day 180. Through day 100, there were 10 cases of grades II-IV aGvHD [20.4% (95% CI 10.2-34.3%)], two of which were grades III-IV [(4.1% (0.5-14.0%)]. One subject died at day 102 from aGvHD due to GI bleeding, 2 subjects died without aGvHD (at days 100 and 127). Conclusions: RGI-2001 IV infusion added to the standard-ofcare tacrolimus / methotrexate GvHD prophylaxis shows promising efficacy in the prevention of aGvHD for HLA-matched donors (related or unrelated) with an acceptable safety profile. A phase III study is planned.

Volume

58

First Page

287

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