The following is a summary of “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 ” published in the November 2022 issue of Clinical Cancer by Lim et al.
The purpose of this study is to compare the effectiveness of AZD4635, an adenosine A2A receptor antagonist, either used alone or in combination with durvalumab in treating patients with advanced solid tumors. Patients with relapsed or refractory solid tumors were enrolled in phase Ia (dose escalation), while those with metastatic castration-resistant prostate cancer (mCRPC), colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors were enrolled in phase Ib (dose expansion). Patients were given either 125 mg of durvalumab once daily or 75-200 mg of AZD4635 once daily as monotherapy (AZD4635 75 or 100 mg once daily).
Evaluation of an adenosine gene signature in patients with mCRPC was an experimental objective. Safety was the primary focus. In addition, antitumor efficacy and pharmacokinetics were also studied. As of the 8th of September, 2020, 250 individuals had been treated (AZD4635, n=161; AZD4635 + durvalumab, n=89). DLTs were seen in patients using nanosuspension both as monotherapy (125 mg twice daily; n=2) and in combination with other treatments (75 mg; n=1). Nausea, lethargy, vomiting, decreased appetite, dizziness, and diarrhea were the most common treatment-related side effects. For monotherapy or in combination with durvalumab, the recommended starting dose (RP2D) of the capsule version of AZD4635 was 75 mg once daily.
Exposure was sufficient to cover the target at once-daily dosing of either 100 mg nanosuspension or 75 mg capsule, and the pharmacokinetic profile was dose-proportional. Both tumor responses (2/39) and prostate-specific antigen responses (3/60) were seen in patients with mCRPC treated with monotherapy or combination therapy. The median progression-free survival was longer for those having a high adenosine signature in their blood than for those with a low one. Monotherapy with AZD4635 or combination therapy with it was well tolerated. Responses on the objective scale warrant further combination studies in patients with mCRPC in phase II.
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