MO-TRANS update: A randomized, double-blind, placebo-controlled, multi-center phase III study of mocravimod (MOC) as maintenance treatment in AML patients undergoing allogeneic hematopoietic cell transplantation

Abstract

Abstract Background Allogeneic hematopoietic cell transplantation (allo-HCT) is an increasingly important curative option in adults with high-risk acute myeloid leukemia (AML). Disease relapse remains the commonest cause of transplant failure and innovative strategies with the potential to reduce the risk of disease recurrence are required. Accumulating evidence demonstrates the presence of a potent GVL effect in patients allografted for AML and post-transplant maintenance strategies have the potential to improve survival in this patient population. Mocravimod (MOC), a sphingosine-1-phosphate receptor (S1PR) modulator, has demonstrated a dual mechanism of action: enhancing graft-versus-leukemia (GvL) effects while mitigating graft-versus-host disease (GvHD) by sequestering alloreactive T-cells in lymphoid tissues without impairing cytotoxic function. A previous Phase Ib/IIa study exploring the feasibility of MOC maintenance post-transplant (NCT01830010) demonstrated both excellent tolerability of MOC post-transplant and suggested improved survival compared with matched historical controls (Dertschnig S. et al., 2023). Based on these data, the MO-TRANS phase 3 study (NCT05429632) is evaluating the efficacy and safety of MOC as an adjunctive and maintenance therapy post-allo-HCT in patients with AML. Study Design and Methods This is a global, multicenter, randomized, double-blind, placebo-controlled phase 3 trial. A total of 366 adult patients (18–75 years) with high or intermediate risk (ELN 2022) AML in first complete remission (CR) or any patient in second CR will be randomized 1:1:1 to receive placebo, 1mg MOC, or 3mg MOC orally once daily for up to 12 cycles on top of standard of care GvHD prophylaxis. Stratification factors include remission status (CR1 versus CR2) and pre-transplant MRD status (MRDpos versus MRDneg). Eligible patients are planned to undergo allo-HCT using peripheral blood stem cells from a related or unrelated donor with no more than 1 antigen mismatch or haploidentical donors with a transplant conditioning intensity (TCI) score ≥1.5 using tacrolimus (TAC)-based GvHD-prophylaxis. Use of ATG, alemtuzumab, cyclosporine A (CsA), and abatacept is excluded; other GvHD prophylaxis agents such as post-transplant cyclophosphamide (PTCy) are permitted. Patients with CsA-based GvHD-prophylaxis will no longer be enrolled due to a higher-than-expected rate of macular edema in the CsA stratum. The randomization to the stratum using CsA was discontinued accordingly. Patients with known risk factors for macular edema, such as diabetes mellitus and history of uveitis will also be excluded. All patients that have already been randomized will continue the study and be analyzed. MOC treatment begins two days prior to the start of conditioning. The primary endpoint is relapse-free survival (RFS); secondary endpoints include overall survival (OS) and the incidence of acute and chronic GVHD. The study is currently open and actively enrolling in the following countries: USA, Argentina, Brazil, France, Germany, Israel, Italy, Japan, Poland, Romania, Spain, Switzerland, Taiwan, and the UK. As of July 21, 2025, 101 patients have been randomized, and 100 patients have received blinded study treatment, 47 stratified by CsA-based-GvHD prophylaxis and 53 stratified by TAC. This study will enroll approximately 366 patients globally. Conclusions Relapse remains the primary cause of treatment failure in AML patients undergoing allo-HCT, ultimately resulting in shorter OS. There is an unmet medical need to maintain CR after allo-HCT, especially in AML patients with high risk factors or previous relapse. The MO-TRANS study aims to validate the therapeutic potential of MOC in reducing relapse and GvHD in patients allografted for AML.