特瑞利木单抗单药或联合度伐利尤单抗治疗日本晚期实体瘤或恶性间皮瘤患者的 I 期研究。
Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma.
机构信息
National Cancer Center Hospital, Tokyo, Japan and Aichi Cancer Center, Nagoya, Japan.
National Hospital Organization Hokkaido Cancer Centre, Sapporo, Japan.
出版信息
Oncologist. 2022 Sep 2;27(9):e703-e722. doi: 10.1093/oncolo/oyac099.
BACKGROUND
The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer.
METHODS
In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given.
RESULTS
In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies.
CONCLUSION
Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347).
背景
本 I 期、开放性试验的主要目的是评估替西木单抗单药治疗和联合度伐单抗治疗日本晚期癌症患者的安全性和耐受性。替西木单抗是一种在临床试验中针对 CTLA-4 的全人源单克隆抗体；度伐单抗是一种针对 PD-L1 的单克隆抗体，用于治疗膀胱癌和肺癌。
方法
在第 1 部分中，替西木单抗 3 或 10 mg/kg 每 4 周（Q4W）给药 6 剂，此后每 12 周给药一次，直至停药（n=8）；随后，41 名恶性胸膜或腹膜间皮瘤（MPM）患者接受替西木单抗 10 mg/kg Q4W 给药 6 剂/Q12W 直至停药。在第 2 部分中，在队列 1（n=4）中，替西木单抗 10 mg/kg（6 剂 Q4W 后 3 剂 Q12W）与度伐单抗 15 mg/kg（13 剂 Q4W）联合给药。在队列 2（n=6）中，替西木单抗 1 mg/kg（4 剂 Q4W）与度伐单抗 20 mg/kg（4 剂 Q4W 后 10 mg/kg Q2W 22 剂）联合给药，而在队列 3（n=6）中，固定剂量替西木单抗 75 mg Q4W 给药 4 剂联合度伐单抗 1500 mg Q4W 给药 13 剂。
结果
在第 1 部分中，替西木单抗 3 或 10 mg/kg（6 剂 Q4W/Q12W 后直至停药）未观察到剂量限制毒性（DLT）。6 名（75%）患者报告了治疗相关不良事件（TRAE）。在 MPM 剂量扩展队列中，38 名（92.7%）患者报告了 TRAE。在第 2 部分中，替西木单抗 10 mg/kg（6 剂 Q4W/Q12W 后 3 剂 Q12W）联合度伐单抗 15 mg/kg（13 剂 Q4W）报告了 1 例 DLT（4 级重症肌无力）。替西木单抗 75 mg（4 剂 Q4W）联合度伐单抗 1500 mg（13 剂 Q4W）报告了 1 例 DLT（4 级高血糖症）。14 名（87.5%）患者报告了 TRAE。替西木单抗表现出低免疫原性；1 名（16.7%）患者产生了抗药物抗体。
结论
替西木单抗 10 mg/kg（Q4W/Q12W）、替西木单抗 1 mg/kg（Q4W）联合度伐单抗 20 mg/kg（Q4W/10 mg/kg Q2W）和固定剂量替西木单抗 75 mg（Q4W）联合度伐单抗 1500 mg（Q4W）是安全且耐受良好的。临床试验标识符：NCT02141347（https://clinicaltrials.gov/ct2/show/NCT02141347）。
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