Exposure-tumour growth inhibition modelling of brigimadlin using phase I solid tumour data to support phase II dose selection.

Abstract

Aims: Brigimadlin (BI 907828) is a potent, oral MDM2-p53 antagonist under clinical investigation for the treatment of advanced solid tumours. A brigimadlin exposure-tumour growth inhibition (E-TGI) model was developed to support the recommended phase II dose (RP2D) selection of brigimadlin in future clinical trials.

Methods: Population modelling was applied to analyse longitudinal tumour size (sum of longest diameters, SLD) data of 151 patients from a phase I trial treated with 5-80 mg brigimadlin every third or fourth week (q3w/q4w). The impact of brigimadlin exposure on tumour shrinkage was assessed and the effects of patient- and tumour-related covariates on model parameters were explored. The final E-TGI model was used to simulate the effect of brigimadlin treatment on longitudinal SLD. The probability of dropout from tumour assessments were characterized via logistic regression and included in simulations to allow for realistic predictions of tumour shrinkage over time.

Results: The E-TGI model adequately characterized the observed SLD data over time. Simulations demonstrated a substantially stronger tumour shrinkage with higher dose, based on the identified exposure-response relationship. For patients with the most common tumour (dedifferentiated liposarcoma) and standard body weight (70 kg) and remaining in the study for 1 year, the median relative change from baseline in tumour size was 0.141%, -4.48%, -10.8% and -17.4%, for treatment with 20, 30, 45 and 60 mg brigimadlin q3w doses, respectively.

Conclusions: The developed E-TGI model predicted that higher doses of brigimadlin resulted in a substantially stronger tumour shrinkage. These results contributed to selecting 45 mg brigimadlin q3w dose as RP2D in subsequent clinical trials.