MO-TRANS: A Phase 2b Placebo-Controlled Study of Mocravimod As Adjunctive and Maintenance Treatment in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplant

Introduction: Mocravimod is a sphingosine 1-phosphate receptor (S1PR) immunomodulator that blocks lymphocyte egress from lymphoid organs via its phosphorylated active metabolite. Allogeneic hematopoietic cell transplant (allo-HCT) is a common treatment in AML, which is indicated as consolidation therapy for intermediate/high risk AML. The therapeutic benefit includes graft-versus-leukemia (GvL) effect of the donor's T cells against the leukemic cells of the patient. One of the major risks of allo-HCT is graft-versus-host disease (GvHD) and is regarded as the off-target effect of the desirable GvL effect, in which the donor T cells respond to and attack normal host cells other than the leukemic cells. The major causes of post-transplant mortality, morbidity and quality of life impairment, remain disease relapse and GvHD.

S1PR modulation does not interfere with T cell cytotoxicity, hence function is maintained, and anti-leukemia response remains potent. Since mocravimod is not immunosuppressive, alloreactive T cells can retain anti-leukemia reactivity to boost GvL while being sequestered in the lymphatic organs and thus not promoting peripheral GvHD. Therefore, treatment with mocravimod as an adjunctive and maintenance therapy to allo-HCT may trigger two positive effects: 1) increase the GvL effect through the eradication of residual malignant cells by alloreactive T cells sequestered in the lymphoid tissues such as lymph nodes, the bone marrow, and the spleen white pulp, and 2) reduce the GvHD because alloreactive T cells are retained in the lymphoid tissues and thus do not migrate into peripheral tissues. Both effects will ultimately result in improving overall survival (OS). Based on the encouraging results of a phase Ib study with mocravimod in the allo-HCT setting, a phase 2b trial is planned.

Study Design and Methods: In this multicenter, double-blind, phase 2b study, approximately 249 pts will be randomized 1:1:1 to receive mocravimod 1mg or mocravimod 3mg or placebo. Patients will be stratified by the complete remission status (CR1 versus CR2), the treatment used for GvHD prophylaxis cyclosporine A (CsA) versus tacrolimus (TAC), and the measurable residual disease (MRD) status (MRD pos versus MRD neg). Key eligibility criteria include age (> 18 years and < 75 years), diagnosis of AML (excluding acute promyelocytic leukemia) with European LeukemiaNet (ELN) high risk disease in CR1, intermediate risk in CR1 if MRD pos, or AML of any risk in CR2. Patients need to be planned to undergo allo-HCT, with either fully matched related or unrelated donor. The planned use of GvHD prophylaxis needs to be either methotrexate (MTX) plus CsA or MTX plus TAC. Treatment in all arms will consist of 28-day cycles with daily administration of either 1mg mocravimod or 3mg mocravimod or placebo. Treatment will start 2 days before conditioning treatment and will be ongoing for 12 cycles or until relapse, unacceptable toxicity, or consent withdrawal. Patients will be observed for overall survival after end of treatment. Primary efficacy endpoint is relapse free survival (RFS), which is calculated as the time from randomization to relapse or death. It will be assessed once 46 events are reached in one mocravimod arm and the placebo arm and will be observed by an unblinded independent data monitoring committee. The first key secondary objective is to assess the effect of mocravimod relative to placebo on Overall Survival (OS). A second key objective is the comparison of the effect on RFS between the second mocravimod arm and the placebo arm and it will be assessed once the primary endpoint analysis timepoint will be reached. The FDA activated the IND #127312 on 22 Apr 2022, and five European Health Authorities approved the study to date: France, the UK, Spain, Switzerland and Germany. Enrollment is expected to begin in Q3, 2022. The ClinicalTrials.gov identifier is NCT05429632.

de Lima:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Malard:Therakos/Mallinckrodt: Honoraria; Sanofi: Honoraria; Astellas: Honoraria; JAZZ pharmaceuticals: Honoraria; Biocodex: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Celgene-BMS: Honoraria. Kueenburg:Priothera: Current Employment. Souquieres:Priothera: Current Employment. Cachat:Priothera: Current Employment. Stylianou:Priothera: Consultancy. Chevallier:Jazz Pharmaceuticals: Honoraria; Abbvie: Honoraria; Pfizer: Research Funding; Incyte: Research Funding; Takeda: Honoraria.