“ARMY”: First-in-human study of the humanized, defucosylated monoclonal antibody (mAb) MEN1112/OBT357 targeting CD157 antigen, in relapsed or refractory (R/R) acute myeloid leukemia (AML)

Background: Defucosylated mAbs enhance antibody dependent cell-mediated cytotoxicity (ADCC) through an improved affinity for Fc receptors. MEN1112/OBT357 is a humanized, defucosylated mAb targeting Bst1/CD157, a GPI-anchored transmembrane protein highly expressed on blasts of AML patients either at primary diagnosis or relapse. Preclinical findings show that MEN1112/OBT357 has the potential to exert powerful ADCC against AML (Aud et al ASH 2014; Venditti et al ASH 2014). Methods: Multi-center, non-randomized, 3+3 dose escalation/expansion cohort trial of MEN1112/OBT357 intended to recruit approximately 50 adult patients (pts) with R/R AML. Refractory pts must have failed 1 cycle of cytotoxic chemotherapy or hypomethylating agents. A baseline WBC count≤ 10 x 109/L is required (pre-treatment with hydroxyurea is permitted). Main exclusion criteria are acute promyelocytic leukemia, hematopoietic stem cell transplant within 3 months prior to screening and active central nervous system involvement. MEN1112/OBT357 is given intravenously at 5 incremental doses on Days 1, 8, and 15 in a 21-day cycle for a total of 2 cycles; monthly maintenance is allowed in pts achieving clinical benefit. Primary objective is to identify dose limiting toxicities and maximum tolerated dose of MEN1112/OBT357 in pts with R/R AML; secondary objectives include (1) clinical pharmacokinetics, (2) potential immunogenicity, (3) clinical activity (complete-and composite complete remission rate, best response rate, overall survival) in treated pts and (4) its correlation with target expression/saturation, natural killer cells status, ex vivo activity at baseline and clinical/biological AML features. AEs will be graded according to NCI CTCAE v. 4.03 guidelines. Study variables will be presented by dose-cohort and overall using appropriate descriptive statistics. Efficacy will be evaluated in each cohort in pts completing the first cycle and with ≥1 post-cycle assessment using modified IWG 2003 criteria. The individual study duration is 6 months. The enrolment began on December 2014.