Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study.
Date
2021-10-01ICR Author
Author
Yap, TA
Krebs, MG
Postel-Vinay, S
El-Khouiery, A
Soria, J-C
Lopez, J
Berges, A
Cheung, SYA
Irurzun-Arana, I
Goldwin, A
Felicetti, B
Jones, GN
Lau, A
Frewer, P
Pierce, AJ
Clack, G
Stephens, C
Smith, SA
Dean, E
Hollingsworth, SJ
Type
Journal Article
Metadata
Show full item recordAbstract
PURPOSE: This study reports the safety, tolerability, 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 twice daily to 60 mg once daily) in 21-day cycles. Sequential and concurrent combination dosing schedules were assessed. RESULTS: Two ceralasertib MTD dose schedules, 20 mg twice daily on days 4-13 and 40 mg once daily on days 1-2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (Common Terminology Criteria for Adverse Events grade ≥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 3 patients. Ceralasertib was quickly absorbed (tmax ∼1 hour), with a terminal plasma half-life of 8-11 hours. Upregulation of pRAD50, indicative of ataxia telangiectasia mutated (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 once daily 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.
Collections
Subject
Antineoplastic Combined Chemotherapy Protocols
Ataxia Telangiectasia Mutated Proteins
Carboplatin
Humans
Indoles
Maximum Tolerated Dose
Morpholines
Neoplasms
Neutropenia
Nuclear Proteins
Protein Kinase Inhibitors
Pyrimidines
Sulfonamides
Sulfoxides
Thrombocytopenia
Research team
Early Phase Drug Develop
Language
eng
Date accepted
2021-07-19
License start date
2021-10-01
Citation
Clinical Cancer Research, 2021, 27 (19), pp. 5213 - 5224
Publisher
AMER ASSOC CANCER RESEARCH