MDS-404: Population Pharmacokinetics Modeling and Evaluation of Clinical Efficacy and Safety of Sabatolimab: Dose Selection and Dose-Response Analysis

Abstract

Context: Sabatolimab is an investigational immuno-myeloid therapy targeting TIM-3. The STIMULUS clinical trial program has been designed to evaluate sabatolimab in multiple phase 1–3 trials in patients with MDS and AML. Here, we report PK and clinical data supporting sabatolimab doses being evaluated in the STIMULUS program. Methods: PK was evaluated in patients with advanced solid tumors (NCT02608268), or high/very-high risk MDS, or AML who were ineligible for intensive chemotherapy (NCT03066648). Main Outcome Measures: Total sabatolimab serum concentration was used in population PK modeling to simulate average (Cavg), maximal (Cmax), and trough (Ctrough) concentrations at steady-state. Total serum soluble TIM-3 was measured, and simulation was used to predict membrane-bound TIM-3 occupancy in the bone marrow (BM). PK exposure-response analysis (data cutoff 27 Nov 2019) and assessment of clinical safety/efficacy by dose (data cutoff 25 Jun 2020) were conducted. Results: Sabatolimab PK was similar for patients with solid tumors (n=252) and higher-risk MDS and AML (n=155); no drug–drug interactions were observed for any combinations. Among sabatolimab+HMA regimens, sabatolimab 400 mg Q2W had the highest Ctrough at steady-state, and 800 mg was predicted to be an equivalent Q4W dosing regimen. Both doses had similar steady-state Cavg and similarly high occupancy rates for membrane-bound TIM-3 in the BM (>95% in ≥95% of patients with higher-risk MDS/AML), suggesting similarly high levels of TIM-3 engagement. There was no relationship between steady-state Cmax or Cavg quartiles and the incidence of treatment-related AEs. Exposure-efficacy analysis showed no clear relationship between steady-state Ctrough or Cavg and percent BM blast reduction or clinical benefit (CR/mCR/CRi/PR). Sabatolimab+HMA was safe and well-tolerated, with a low discontinuation rate due to AEs (3.4% [4/116]). Rates of most common grade ≥3 treatment-emergent AEs did not appear to be dose-dependent. Conclusions: Sabatolimab 400 mg Q2W was predicted to have the highest steady-state Ctrough and TIM-3 occupancy rate when combined with HMA; 800 mg was predicted to be an equivalent dosing regimen. No clear relationship was seen between sabatolimab dose or steady-state exposure and safety/efficacy. These results support the clinical development of the sabatolimab 400 mg Q2W and 800 mg Q4W dosing regimens.