دورية أكاديمية
Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study.
| العنوان: | 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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| المؤلفون: | 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 |
| المساهمون: | Lopez, Juanita |
| بيانات النشر: | AMER ASSOC CANCER RESEARCH |
| سنة النشر: | 2023 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| مصطلحات موضوعية: | 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 |
| جغرافية الموضوع: | United States |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print; 5224; application/pdf |
| اللغة: | English |
| تدمد: | 1078-0432 1557-3265 |
| العلاقة: | 1078-0432.CCR-21-1032; Clinical Cancer Research, 2021, 27 (19), pp. 5213 - 5224; https://repository.icr.ac.uk/handle/internal/5802Test |
| DOI: | 10.1158/1078-0432.CCR-21-1032 |
| الإتاحة: | https://doi.org/10.1158/1078-0432.CCR-21-1032Test https://repository.icr.ac.uk/handle/internal/5802Test |
| حقوق: | https://creativecommons.org/licenses/by-nc-nd/4.0Test/ |
| رقم الانضمام: | edsbas.DB3BFEAB |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 10780432 15573265 |
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| DOI: | 10.1158/1078-0432.CCR-21-1032 |