Home Blog of Signal Transduction DNA Damage/DNA Repair ATM/ATR Ceralasertib (AZD6738), an oral ATR kinase inhibitor, in combination with carboplatin in patients with advanced solid tumors: a Phase I study

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Ceralasertib (AZD6738), an oral ATR kinase inhibitor, in combination with carboplatin in patients with advanced solid tumors: a Phase I study

Purpose: This study reports the safety, tolerability, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers.

Patients and methods: Eligible patients (n=36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg BID to 60 mg QD) in 21-day cycles. Sequential and concurrent combination dosing schedules were assessed.

Results: Two ceralasertib MTD dose schedules, 20 mg BID on days 4-13 and 40 mg BID on days 1-2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (CTCAE grade {greater than or equal to}3) were anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities of grade 4 thrombocytopenia (n=2; including one grade 4 platelet count decreased) and a combination of grade 4 thrombocytopenia and grade 3 neutropenia occurred in three patients. Ceralasertib was quickly absorbed (tmax ~1 hour), with a terminal plasma half-life of 8-11 hours. Upregulation of pRAD50, indicative of ATM activation, was observed in tumor biopsies during ceralasertib treatment. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed RECIST v1.1 partial responses. Eighteen of 34 (53%) response-evaluable patients had RECIST v1.1 stable disease.

Conclusions: The RP2D for ceralasertib plus carboplatin was established as ceralasertib 40 mg QD on days 1-2 administered with carboplatin AUC5 every 3 weeks, with pharmacokinetic and pharmacodynamic studies confirming pharmacodynamic modulation and preliminary evidence of antitumor activity observed.

Related Products

Cat.No. Product Name Information
S7693 Ceralasertib (AZD6738) Ceralasertib (AZD6738) is an orally active, and selective ATR kinase inhibitor with IC50 of 1 nM. Phase 1/2.

Related Targets

ATM/ATR