PII-123 - A MODEL-BASED META-ANALYSIS TO ASSESS THE SIMILARITIES AND DIFFERENCES OF CLINICAL SAFETY OF TARGETED-THORIUM-CONJUGATES IN PATIENTS.

C. Wang¹, A. Solms², Y. Zhang¹, B. Ploeger², A. Seelmann², C. Zieschang², H. Hennekes², V. Jardine³, P. Morcos⁴, M. Block⁵; ¹Bayer AG, Wuppertal, Germany, ²Bayer AG, Berlin, Germany, ³Bayer UK, Reading, United Kingdom, ⁴Bayer, Whippany, NJ, USA, ⁵Bayer AG, Leverkusen, Germany.

Background: Targeted alpha therapies (TATs) are developed to specifically deliver alpha-particle radiation to tumors by linking e.g. thorium-227 (TTC) to targeting monoclonal antibodies (mAb). Preclinical and clinical data show, however, myelosuppressive effects. Early assessments of the expected clinical myelosuppression are key to drive informed decision making during and after Phase I studies. Here, we show a meta-analysis applied for different TTCs to assess and compare the clinical myelosuppressive effects.

Methods: Clinical Phase I data from three different TTC’s (CD22/MSLN/PSMA) were used to inform PK/PD models for myelosuppression in patients. A model able to capture the different phases of hematopoiesis as well as the time course of the radiation effect on the neutrophils or thrombocytes was applied. The model-based meta-analysis is used to specifically analyze similarities and differences related to myelosuppression for these TTCs.

Results: CD22-TTC (target on B cells) shows higher myelosuppression, while the effects for MSLN-TTC and PSMA-TTC do not significantly differ for both neutropenia and thrombocytopenia. Based on the population simulations more than 20% of patients are expected to have a Grade 3/4 myelosuppression (neutropenia or thrombocytopenia) at 1.5 MBq (CD22-TTC) and at 3.5 - 4.5 MBq (PSMA/MSLN-TTC), if administered 4 times every 6 weeks.

Conclusion: The meta-analysis presented is based on clinical Phase I data. The representation of the specific processes involved for TTCs allows for an identification of the similarities and differences in myelosuppression of TTC's and can be used to assess the expected range of frequencies for Grade 3/4 myelosuppression at different dose levels and for different schedules. This approach can potentially be also applied to assess myelosuppression of other TATs.