Exposure-tumour growth inhibition modelling of brigimadlin using phase I solid tumour data to support phase II dose
Ida Neldemo1, Kamunkhwala Gausi1, Céline Sarr1
1Pharmetheus AB, Uppsala, Sweden.
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.
Insights
Brigimadlin, an MDM2-p53 antagonist, showed increased tumor shrinkage with higher doses in advanced solid tumors. This exposure-response model supported selecting 45 mg brigimadlin every third week as the recommended phase II dose.
Area of Science:
- Oncology
- Pharmacometrics
- Drug Development
Background:
- Brigimadlin (BI 907828) is an investigational oral MDM2-p53 antagonist for advanced solid tumors.
- Establishing an exposure-response relationship is crucial for optimizing dosing in clinical trials.
Purpose of the Study:
- To develop a brigimadlin exposure-tumor growth inhibition (E-TGI) model.
- To support the selection of the recommended phase II dose (RP2D) for brigimadlin.
Main Methods:
- Population modeling was used to analyze longitudinal tumor size (SLD) data from 151 patients in a Phase I trial.
- The model assessed brigimadlin exposure impact on tumor shrinkage, exploring patient and tumor covariates.
- Logistic regression characterized dropout, enabling realistic tumor shrinkage predictions.
Main Results:
- The E-TGI model accurately described observed tumor size data over time.
- Higher brigimadlin doses led to significantly greater tumor shrinkage, as predicted by the exposure-response relationship.
- For dedifferentiated liposarcoma patients, median tumor size reduction after 1 year ranged from 0.14% (20 mg q3w) to -17.4% (60 mg q3w).
Conclusions:
- The developed E-TGI model confirmed that higher brigimadlin doses enhance tumor shrinkage.
- The findings directly informed the selection of 45 mg brigimadlin every third week (q3w) as the RP2D for future clinical trials.
