Abstract 4641: Development of modified dosing approaches to achieve specific pharmacokinetic (PK) objectives in the first-in-human phase I clinical trial of IMGN853, a folate receptor α-targeting antibody drug conjugate
Authors: Ponte Jose F. , Running Kelli L. , Kirby Maurice , Chan Julie , Pinkas Jan , O'Leary James J. , Lutz Robert J. 
Published: May 2015

Abstract
IMGN853 is an antibody-drug conjugate (ADC) that binds with high affinity to folate receptor α (FR α). IMGN853 comprises a FR α -binding antibody and the potent maytansinoid, DM4, attached via a disulfide-containing linker. In its first-in-human (FIH) Phase 1 study, 29 patients with epithelial ovarian cancer (n=16), endometrial cancer (n=8), clear cell renal cell carcinoma (n=4), or NSCLC (n=1) were enrolled across seven dose levels ranging from 0.15 to 7.0 mg/kg total body weight (TBW) administered once every three weeks (Q3W). The elimination half-life of IMGN853 was found to be ∼5 days at the higher doses with substantial variability in Cmax and volume of distribution. The occurrence of ocular toxicity was found to have a strong association with high Cmax values (p=0.0004 Fisher exact test) and with high early exposure levels, as measured by area under the curve in the first 24 hours (AUC0-24) (p=0.0001). Additionally, a moderate correlation between weight and Cmax (Pearson r=0.48, p=0.02) was observed.
As a result of these findings, a number of dosing strategies were investigated in an effort to achieve 3 objectives in the study going forward: (1) maximize IMGN853 exposure, (2) keep Cmax and AUC0-24 levels below those associated with ocular toxicity and (3) decrease inter-patient PK variability. Cmax and AUC0-24 values were simulated using alternative formulas for calculating dose using PK data from all patients treated in the 3.3 (n=9), 5.0 (n=10) and 7.0 mg/kg (n=5) FIH dose groups normalized to a 5 mg/kg dose level. These were then compared to Cmax and AUC values from TBW dosing. Four alternate formulas were evaluated: body surface area (BSA), ideal body weight (IBW), lean body weight (LBW) and adjusted ideal body weight (ADJ). Of these four alternate methods, dosing by ADJ resulted in the least total body weight dependence and PK variability compared to the other dosing methods.
Concurrently, a 3-compartment population PK model was developed based on rich and sparse concentration-time profiles of IMGN853 with its Q3W dosing in the clinic. This was used to simulate steady-state exposure to IMGN853 with various dosing schedules, including weekly (QW), every 2 weeks (Q2W), and weekly for 3 weeks in a 4 week cycle (modified weekly). Minimal accumulation between cycles (accumulation index of 1.06) was observed with the modified weekly regimen, while the QW dosing regimen resulted in the highest accumulation (accumulation index of 1.97). Comparing doses that resulted in equivalent Cmax levels, the modified weekly schedule achieved an almost 2-fold increase in overall exposure compared to QW3 dosing, while keeping Cmax levels below those associated with ocular toxicity. An evaluation of the potential benefit of ADJ dosing on a Q3W and a modified weekly schedule is currently ongoing in the Phase 1 clinical trial.
Citation Format: Jose F. Ponte, Kelli L. Running, Maurice Kirby, Julie Chan, Jan Pinkas, James J. O'Leary, Robert J. Lutz. Development of modified dosing approaches to achieve specific pharmacokinetic (PK) objectives in the first-in-human phase I clinical trial of IMGN853, a folate receptor α-targeting antibody drug conjugate. [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 4641. doi:10.1158/1538-7445.AM2014-4641