Apriori Prediction of Patient Outcomes: Clinical Translation of Efficacy of An Antibody Drug Conjugate to Human

Abstract

Renu Singh and Patrice Bouchard

Translation of preclinical efficacy of an antibody drug conjugate (ADC) was done to determine dose and dosing regimen for first in human (FIH) study by simulating clinical trial in virtual cancer patients. Clinical trial simulations were done in 50 virtual subjects, systems parameters of PK/PD model were adapted to NSCLC patients for these simulations. It was found that at doses above 1.6 mg/kg Q1W, steady state trough concentrations (Ctrough-ss) were above TSC. The predicted progression free survival (PFS) was approximately 55, 72 and 85% at doses of 0.5, 1 and 2 mg/kg Q1W, while at doses of 1.3, 2.6 and 3.9 mg/kg Q3W survival was predicted to be 50, 65, 80%. Clinical efficacy at high doses and less frequent dosing, wherein average steady state concentrations of conjugated antibody are maintained above TSC was similar to that obtained by maintaining Ctrough-ss at TSC at low dose and more frequent dosing regimen. Therefore, maintaining Ctroughss above the TSC may not be required for improving PFS. A human dose which maintains average steady state concentrations at predicted TSC is sufficient to obtain clinical efficacy and therefore maintaining steady state trough concentrations above TSC may not be desired.

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