FOLFIRINOX-R 研究设计：FOLFIRINOX 联合regorafenib 作为不可切除 RAS 突变型转移性结直肠癌一线治疗的 I/II 期试验。
FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer.
机构信息
IRCM, Inserm, Université Montpellier, ICM, Montpellier, France.
Department of Medical Oncology, Montpellier Cancer Institute (ICM), Montpellier, France.
出版信息
BMC Cancer. 2021 May 17;21(1):564. doi: 10.1186/s12885-021-08312-7.
BACKGROUND
The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer.
METHODS
FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m, folinic acid 400 mg/m, irinotecan 150-180 mg/m, 5-fluorouracil: 400 mg/m then 2400 mg/m over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle.
DISCUSSION
FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer.
TRIAL REGISTRATION
EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 .
背景
FOLFOXIRI 化疗三联疗法联合抗血管内皮生长因子抗体贝伐珠单抗是治疗转移性结直肠癌的一种选择。在这种情况下，RAS 突变型转移性结直肠癌的治疗效果不如 RAS 野生型转移性结直肠癌。雷戈非尼是一种酪氨酸激酶抑制剂，除了具有抗血管生成作用外，无论 RAS 状态如何，还具有抗增殖活性。本研究旨在研究雷戈非尼联合 FOLFIRINOX（一种使用与 FOLFOXIRI 不同剂量方案的化疗三联疗法）治疗 RAS 突变型转移性结直肠癌患者的安全性和疗效。
方法
FOLFIRINOX-R 是一项前瞻性、多中心、非随机、剂量探索的 1-2 期试验。主要终点是确定最大耐受剂量、推荐的 2 期剂量以及 48 周时疾病控制的患者比例。1 期采用 3+3 设计（12 至 24 例患者入组）。2 期需要 69 例患者，包括 5%的不可评估患者，假设如下，单阶段弗莱明设计，α=5%，β=20%，p0=35%，p1=50%。主要入选标准包括东部肿瘤协作组体力状态评分为 1 分或以下和不可切除的 RAS 突变型转移性结直肠癌，不能进行根治性手术，且既往未接受转移性疾病的治疗。FOLFIRINOX（奥沙利铂 85mg/m2、亚叶酸 400mg/m2、伊立替康 150-180mg/m2、氟尿嘧啶：400mg/m2 然后 2400mg/m2 持续 46 小时）每 14 天给药一次。雷戈非尼（80 至 160mg，按剂量水平）口服，每天一次，在每个周期的第 4 至 10 天给药。
讨论
FOLFIRINOX-R 是第一项评估雷戈非尼联合 FOLFIRINOX 作为 RAS 突变型转移性结直肠癌一线治疗的安全性和疗效的 1/2 期研究。
试验注册
EudraCT：2018-003541-42；ClinicalTrials.gov：NCT03828799。
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