VITRAC Therapeutics, LLC (VITRAC) initiated a Phase 1/2 clinical trial of VIC-1911 in combination with sirolimus and post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis in myeloablative allogeneic stem cell transplantation. VIC-1911 is an oral selective Aurora kinase A inhibitor (AURKA).
The trial is being carried out at the University of Minnesota Medical School, Hematology and Transplantation, with Shernan G. Holtan, M.D., the Principal Investigator, and Brian C. Betts, MD. The scientific rationale is based on preclinical work led by Dr. Betts, where AURKA inhibition reduced xenogeneic GVHD in mice and enhanced human regulatory T cell suppression over pathogenic, alloreactive T cells (Betts BC et al. Science Translational Medicine. 2017).
Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk or relapsed/refractory hematologic malignancies. HCT with myeloablative conditioning is currently the standard of care for young, fit patients suitable for HCT. However, GVHD continues to impair survival and contribute to post-transplant morbidity, with 35-50% of transplanted patients diagnosed with this complication. Acute GVHD occurs when donor T cells react against genetically defined proteins on normal host cells. The attack on the host cells can cause an array of symptoms from skin rashes, nausea, vomiting, diarrhea, hepatitis, jaundice, and increase the risk for infection, which typically occur within the first six months post-HCT. Chronic GVHD occurs later in most patients (average of 9-12 months post-HCT) and can lead to scarring and fibrosis of many organs, including the skin and subcutaneous tissues, mucous membranes, lungs, liver, and other organs. The challenge in HCT is to design strategies that reduce the incidence and severity of GVHD without sacrificing graft-versus-tumor effects.
This is a single-arm, Phase 1/2 GVHD prevention trial. The trial is testing the safety and efficacy of a calcineurin inhibitor-free GVHD prophylaxis regimen that includes PTCy, VIC-1911, and sirolimus (PTCy/VIC/SIR). PTCy/VIC/SIR is specifically designed to substantially reduce GVHD, facilitate the full potential of graft-versus-leukemia (GVL) effect, and maximize GVHD-free, relapse-free survival (GRFS). This trial will transplant 8/8 HLA-matched related or unrelated peripheral blood stem cells after myeloablative conditioning with total body irradiation (TBI).
This Phase 1/2 trial will determine the optimal biological dose of VIC-1911 during the Phase 1 portion based on dose limiting toxicities (DLT) for safety and reductions of CD4+, pH3ser10+ T cells for efficacy (phosphorylated histone 3 serine 10 is a biomarker of AURKA activity). The Phase 2 portion will determine both grade II-IV acute GVHD and relapse rates and will be powered to independently test these endpoints for improvement compared with historical results at the University of Minnesota.
“Aurora kinase A is an important resistance mechanism for sirolimus efficacy in GVHD prevention,” said Shernan G. Holtan, M.D. “We hypothesize that the combination of VIC-1911 and sirolimus added to PTCy will ablate CD28 signal transduction, leverage complementary effects on Tregs, and permit the successful omission of a calcineurin inhibitor in GVHD prophylaxis.”
“This is the first clinical trial to use a specific Aurora kinase A inhibitor in GVHD prevention,” said Thomas J. Myers, M.D., Chief Medical Officer of VITRAC Therapeutics. “The trial evaluates a novel GVHD prevention regimen without calcineurin inhibitor toxicities.“
About VITRAC Therapeutics, LLC:: VITRAC is an integrated oncology research and development company with experience developing, managing, and optimizing global pharmaceutical drug development programs from late discovery, translational research, and clinical development through market authorization and post-marketing life-cycle management.