PI-071 - HOLISTIC INTEGRATION OF POPULATION PHARMACOKINETICS, PHARMACODYNAMICS AND SAFETY TO DEFINE RECOMMENDED DOSE FOR EXPANSION OF ATR INHIBITOR, M1774: AN ILLUSTRATION OF MODEL-INFORMED EARLY ONCOLOGY DRUG DEVELOPMENT.

J. Mukker¹, P. Diderichsen², I. Gounaris³, Z. Szucs³, J. Bolleddula¹, A. Seithel-Keuth⁴, G. Sessa⁴, G. Locatelli⁴, C. Schaffroth⁴, M. Enderlin⁴, C. Hicking⁴, A. Zutshi¹, N. Terranova⁵, A. Khandelwal⁴, R. Strotmann⁴, L. Benincosa¹, K. Venkatakrishnan¹; ¹EMD Serono, Billerica, MA, USA, ²Certara, Princeton, NJ, USA, ³Merck Serono Ltd., Feltham, United Kingdom, ⁴Merck KGaA, Darmstadt, Germany, ⁵Merck Serono Ltd., Lausanne, Switzerland.

Background: Inhibition of ataxia telangiectasia and Rad3-related (ATR) protein kinase allows cell cycle progression and accumulation of unrepaired DNA damage leading to tumor cell death. We report model-informed selection of the recommended dose for expansion (RDE) of M1774, an orally bioavailable ATR inhibitor.

Methods: A phase I multiple dose study in 55 patients with advanced solid tumors (NCT04170153) was conducted, with dose escalation from 5 mg to 270 mg QD along with BID and intermittent regimens in 21-day cycles. PK, PD, and safety data were quantitatively modeled to enable RDE selection.

Results: M1774 exposure was approximately dose proportional up to 180 mg and slightly more than proportional at higher doses. Maximum tolerated dose was defined as 180 mg QD. Population PK simulations suggested average steady state concentration sufficiently exceeding in vitro pCHK1 IC90 at 130 and 180 mg QD and 180 mg 2 weeks on/1 week off. Exposure-related PD in blood was observed ex vivo [1], with >80% reduction in ɣ-H2AX phosphorylation predicted at doses ≥130 mg, supporting target engagement. Semi-mechanistic PK/PD modeling of cycle 1 and 2 reticulocyte, red blood cell and hemoglobin (Hb) data was used to predict the probability of anemia, which was the most frequently observed adverse event. This suggested that 180 mg 2 weeks on/1 week off allows partial recovery of Hb during multicycle treatment compared to 130 and 180 mg QD. PK was comparable between available Asian (n=5) and Western patients, supporting planning of a future Asia-inclusive strategy.

Conclusion: M1774 180 mg 2 weeks on/1 week off was selected as the RDE to explore efficacy and multi-cycle tolerability in biomarker-selected cohorts. This example demonstrates the utility of a PK/PD modeling framework in early phase oncology drug development.

Yap, T.A., et al. A Phase I study of ATR inhibitor M1774 in patients with solid tumours (DDRiver Solid Tumours 310): Part A1 results. Ann. Oncol. 33, S197-S224 (2022).