Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors.

Autor:	Lim EA; Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York., Bendell JC; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee., Falchook GS; Drug Development Unit, Sarah Cannon Research Institute at HealthONE, Denver, Colorado., Bauer TM; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee., Drake CG; Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York., Choe JH; Duke Cancer Institute, Durham, North Carolina., George DJ; Duke Cancer Institute, Durham, North Carolina., Karlix JL; Sarah Cannon Research Institute, Gainesville, Florida., Ulahannan S; Sarah Cannon Research Institute/Oklahoma University, Oklahoma City, Oklahoma., Sachsenmeier KF; Oncology R&D, AstraZeneca, Boston, Massachusetts., Russell DL; Oncology R&D, AstraZeneca, Boston, Massachusetts., Moorthy G; Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Boston, Massachusetts., Sidders BS; Oncology Biometrics R&D, AstraZeneca, Cambridge, England, United Kingdom., Pilling EA; Oncology Biometrics R&D, AstraZeneca, Cambridge, England, United Kingdom., Chen H; Oncology R&D, AstraZeneca, Boston, Massachusetts., Hattersley MM; Oncology R&D, AstraZeneca, Boston, Massachusetts., Das M; Oncology R&D, AstraZeneca, Gaithersburg, Maryland., Kumar R; Oncology R&D, AstraZeneca, Gaithersburg, Maryland., Pouliot GP; Oncology R&D, AstraZeneca, Boston, Massachusetts., Patel MR; Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, Florida.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Nov 14; Vol. 28 (22), pp. 4871-4884.
DOI:	10.1158/1078-0432.CCR-22-0612
Abstrakt:	Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. Patients and Methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC. Results: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks. Conclusions: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu