Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study

Purpose: This study evaluated the safety, tolerability, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ceralasertib combined with carboplatin in advanced solid tumors. Exploratory predictive and pharmacodynamic biomarkers were also examined.

Patients and Methods: Thirty-six patients received carboplatin (AUC5) combined with escalating doses of ceralasertib (20 mg twice daily to 60 mg once daily) in 21-day cycles. Sequential and concurrent dosing schedules were tested.

Results:

Two MTD schedules for ceralasertib were identified and well-tolerated with carboplatin: 20 mg twice daily on days 4–13 and 40 mg once daily on days 1–2, with the latter established as the RP2D.

Common grade ≥3 treatment-emergent adverse events included anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities occurred in three patients, including grade 4 thrombocytopenia (n=2) and a combination of grade 4 thrombocytopenia with grade 3 neutropenia.
Pharmacokinetics showed rapid absorption of ceralasertib (tmax ~1 hour) with a terminal half-life of 8–11 hours. Pharmacodynamic studies revealed upregulation of pRAD50, indicating activation of ataxia telangiectasia mutated (ATM) during treatment.

Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed partial responses per RECIST v1.1. Stable disease was observed in 53% (18 of 34) of response-evaluable patients.

Conclusions: The RP2D for ceralasertib in combination with carboplatin was determined to be 40 mg once daily on days 1–2 with carboplatin AUC5 every 3 weeks. Pharmacokinetic and pharmacodynamic analyses confirmed target modulation, and preliminary antitumor activity was observed.