Abstract 2908: A first-in-human phase I study of SAR650984, a humanized anti-CD38 antibody in patients with CD38+ hematological malignancies: Preliminary PK and PD results of escalation phase
Authors: Ozoux Marie-Laure L. , Guillemin Hélène , Pascual Marie-Hélène H. , Cartot-Cotton Sylvaine , Veyrat-Follet Christine , Valente Delphine , Moulard Maxime , Mauriac Christine , Deslandes Antoine , Semiond Dorothee 
Published: May 2015

Abstract
SAR650984 is a novel humanized monoclonal antibody specifically targeting the CD38. , A phase 1 dose escalation study is being conducted in patients with confirmed CD38+ hematological malignancies to determine safety of SAR650984, to establish the MTD and the biologically active dose, and to characterize the PK and PD after repeated IV administration.
Methods:
The study design was composed of 2 parts. The first one was an accelerated phase with 1 to 3 patients per dose cohort from 0.0001 mg/kg to 0.1 mg/kg and the second phase includes 3 to 7 patients per dose cohort between 0.3 and 20 mg/kg every 2 weeks. An additional 6 patient cohort was added at 10 mg/kg every week.
Results: 34 out of the 39 treated patients were Relapsed Refractory Multiple Myeloma (MM) patients. SAR650984 was well tolerated. Overall Response Rate (CR + PR) for dosing cohorts of ≥1mg/kg is 32% (2 MR, 5 PR, 2 CR of 28).
Pharmacodynamics were evaluated by measuring CD38 density and its occupancy by the drug in bone marrow on cancer cells, using a validated quantitative flow cytometry method. This parameter has been correlated with the dose and exposure levels. Receptor Occupancy (RO) could be detected starting from the 1 mg/kg dose. From 5 mg/kg dose level, preliminary results demonstrated receptor occupancy greater than 70% (maximum observed: 97.7%).
From 0.0001 to 0.01 mg/kg doses, no or limited PK parameters could be calculated. The PK profile was not linear with a decrease in clearance when the dose was increased suggesting target mediated clearance. Based on individual modeling, a moderate to high variability (CV% = 49 to 130%) was observed on estimated systemic total clearance, regardless of the dose group.
At the10 mg/kg Q2W, the shape of the PK profile suggests saturation of the target. All MM patients (N=6) at cycle 1 had SAR650984 plasma trough levels consistently above the 10 µg/ml level which is associated with anti-tumor activity in mouse xenograft studies (Cssmin of the lowest pharmacological active dose). At 20 mg/kg Q2W, in 2/3 MM patients, SAR650984 plasma trough levels from cycle 2 were above the concentration needed to eradicate the tumor (129 µg/mL) in the same animal model, based on the Simeoni et al modelling approach.
These preliminary phase 1 safety and efficacy results are associated with a favorable PK/PD profile and justify the progression of the program to phase 2.
NCT : NCT01084252
Citation Format: Marie-Laure L. Ozoux, Hélène Guillemin, Marie-Hélène H. Pascual, Sylvaine Cartot-Cotton, Christine Veyrat-Follet, Delphine Valente, Maxime Moulard, Christine Mauriac, Antoine Deslandes, Dorothee Semiond. A first-in-human phase I study of SAR650984, a humanized anti-CD38 antibody in patients with CD38+ hematological malignancies: Preliminary PK and PD results of escalation phase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2908. doi:10.1158/1538-7445.AM2014-2908