MO-TRANS: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase III Study of Mocravimod (MOC) As Adjunctive and Maintenance Treatment in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Introduction: In allogeneic hematopoietic cell transplantation (allo-HCT), relapse is one of the major causes of mortality, morbidity, and quality of life impairment. There is an unmet medical need for novel therapies to mitigate this risk. Mocravimod (MOC), a sphingosine-1-phosphate receptor (S1PR) modulator, down regulates the S1PR1 on T-cells and other lymphocytes. This ligand-induced internalization of the S1PR1 renders these cells unresponsive to S1P and deprives them of an obligatory signal to egress from lymphoid organs and thus has been demonstrated to have a dual effect: efficiently sequestering alloreactive donor T-cells within lymphoid organs enabling the eradication of malignant cells through the graft-versus-leukemia (GvL) effect, and restricting T-cell egress to peripheral tissue preventing graft-versus-host-disease (GvHD). S1PR modulation does not interfere with T-cell function, including cytotoxicity, thereby maintaining the anti-leukemia response. The mode of action of mocravimod therefore suggests the decoupling of GvHD from GvL resulting in prevention of GvHD while preserving GvL. Clinical proof of concept was demonstrated by a phase Ib study¹. We aim to evaluate the efficacy and safety of MOC as maintenance treatment in the post-HCT setting in patients with acute myeloid leukemia (AML).

Study Design and Methods: A placebo- controlled design has been chosen for this study to prospectively assess the magnitude of changes in the efficacy and safety that may occur. In this multicenter, global phase III study, 249 participants will be randomized 1:1:1 to receive either MOC 1 mg, MOC 3 mg or placebo, given orally once a day on top of standard of care. Patients are stratified by remission status (complete remission: CR1 vs CR2), the presence of measurable residual disease (MRD positive vs MRD negative), and the type of GvHD prophylaxis used (tacrolimus (TAC) vs cyclosporin A (CsA) based). Adult patients (18-75 years of age) with intermediate or adverse AML based on the European LeukemiaNet (ELN) classification, who are in CR1 or with any risk in CR2, will be included. Participants will undergo allogeneic HCT using peripheral blood stem cells from related or unrelated donors with no more than 1 antigen mismatch or alternatively haploidentical donors. Subjects will receive any conditioning regimen with a transplant conditioning intensity (TCI) score² of ≥1.5. GvHD prophylaxis must be based on TAC or CsA and may include any additional medication except for anti-thymocyte globulin (ATG), alemtuzumab, and abatacept. The use of post-transplant cyclophosphamide is allowed. Treatment with MOC will start 2 days prior to the conditioning treatment and continue in 28-day cycles, for 12 cycles or until relapse, unacceptable toxicity, or consent withdrawal. The primary endpoint is relapse-free survival (RFS). Secondary objectives include overall survival (OS) and occurrence of 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 29, 2024, 88 patients have been randomized. ClinicalTrials.gov identifier NCT05429632.

References: 1 Dertschnig S et al., Transplantation and Cellular Therapy (2023), 29: 41.e1-41e9; 2 Spyridonidis A et al., Bone Marrow Transplantation (2020), 55: 1114-1125