FIRE-8（AIO-KRK/YMO-0519）试验方案：一项前瞻性、随机、开放标签、多中心 II 期试验，旨在研究替氟尿苷/替匹嘧啶联合帕尼单抗与替氟尿苷/替匹嘧啶联合贝伐珠单抗作为转移性结直肠癌一线治疗的疗效。
Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer.
机构信息
Department of Hematology, Oncology, and Cancer Immunology (CVK/CCM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany.
出版信息
BMC Cancer. 2022 Jul 27;22(1):820. doi: 10.1186/s12885-022-09892-8.
BACKGROUND
Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches.
METHODS
FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled.
DISCUSSION
To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy.
TRIAL REGISTRATION
EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.
背景
转移性结直肠癌（mCRC）患者的初始系统治疗通常基于氟嘧啶（5-氟尿嘧啶[5-FU]或卡培他滨）、奥沙利铂和/或伊立替康联合两种或三种药物化疗方案，联合抗血管内皮生长因子（VEGF）（贝伐珠单抗）或针对 RAS 野生型（WT）肿瘤的抗表皮生长因子受体（EGFR）抗体（panitumumab 或 cetuximab）。不适合强化联合治疗的患者的建议有限，包括氟嘧啶联合贝伐珠单抗或单药抗 EGFR 抗体治疗。三氟尿苷/替匹嘧啶联合单克隆抗体的单化疗方案尚未被批准用于一线治疗。评估三氟尿苷/替匹嘧啶联合贝伐珠单抗在一线治疗 mCRC 患者的 II 期 TASCO 试验和评估三氟尿苷/替匹嘧啶联合 panitumumab 在预处理 mCRC 患者中的 I/II 期 APOLLON 试验的结果表明，这些新的治疗方法具有良好的活性和耐受性。
方法
FIRE-8（NCT05007132）是一项前瞻性、随机、开放标签、多中心 II 期研究，旨在评估三氟尿苷/替匹嘧啶（35mg/m 体表面积[BSA]，每日两次口服，第 1-5 天和第 8-12 天，每 28 天一次）联合抗 EGFR 抗体 panitumumab（6mg/kg 体重，静脉注射，第 1 天和第 15 天，每 28 天一次）[A 组]或（作为对照组）抗 VEGF 抗体 bevacizumab（5mg/kg 体重，静脉注射，第 1 天和第 15 天，每 28 天一次）[B 组]在 RAS WT mCRC 患者中的一线治疗疗效。主要目标是通过 panitumumab 将根据 RECIST 1.1 评估的客观缓解率（ORR）从 30%（对照组）提高至 55%。在 80%的功率和双侧显著性水平为 0.05 的情况下，需要 138 名可评估的患者。考虑到 10%的退出率，将入组 153 名患者。
讨论
据我们所知，这是第一项评估三氟尿苷/替匹嘧啶联合 panitumumab 在 RAS WT mCRC 患者一线治疗中的疗效的 II 期试验。与联合三氟尿苷/替匹嘧啶联合抗 VEGF 抗体相比，联合使用抗 EGFR 抗体可能会导致初始疗效增加。
试验注册
欧盟临床试验注册中心（EudraCT）2019-004223-20.2019 年 10 月 22 日注册，ClinicalTrials.gov NCT05007132.2021 年 8 月 12 日注册。
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