Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
Department of Public Health Sciences, University of Chicago, Chicago, Illinois.
Clin Cancer Res. 2020 Jan 1;26(1):18-24. doi: 10.1158/1078-0432.CCR-19-1483. Epub 2019 Sep 26.
5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with genotype-guided dosing of irinotecan.
Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. , and patients received initial irinotecan doses of 180, 135, and 90 mg/m, respectively. 5-FU 2,400 mg/m over 46 hours, leucovorin 400 mg/m, and nab-paclitaxel 125 mg/m were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ≤35% in each genotype group. DLTs were monitored using a sequential procedure.
Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) patients, 1 of 19 (5%) patients, and 0 of 7 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks.
FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and or genotypes. Too few patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.
5-氟尿嘧啶（5-FU）/亚叶酸钙、伊立替康和纳米紫杉醇均为胃肠道癌症的有效药物；联合用药 FOLFIRABRAX 此前尚未进行评估。尿苷二磷酸葡萄糖醛酸转移酶 1A1（UGT1A1）可清除伊立替康的活性代谢物 SN-38。*多态性降低 UGT1A1 酶活性，易导致毒性。我们进行了一项试验，以评估 FOLFIRABRAX 联合伊立替康基因指导剂量给药的安全性和耐受性。
未经治疗的晚期胃肠道癌患者每 14 天接受 FOLFIRABRAX 联合预防性培非格司亭治疗。*患者分别接受初始伊立替康剂量 180、135 和 90mg/m2。5-FU 2400mg/m2 输注 46 小时，亚叶酸钙 400mg/m2，纳米紫杉醇 125mg/m2。如果每个基因型组的第 1 周期剂量限制性毒性（DLT）率≤35%，则认为剂量可耐受。采用序贯程序监测 DLT。
50 例患者入组，其中胰腺 30 例，胆道 9 例，胃食管 6 例，其他 5 例。23 例患者中有 5 例（22%）、19 例患者中有 1 例（5%）和 7 例*患者中无 1 例发生 DLT。DLT 均为 3 级：腹泻（3 例）、恶心（2 例）和发热性中性粒细胞减少症（1 例）。总缓解率为 31%。胰腺、胃食管和胆道癌的缓解率分别为 34%、50%和 11%。18 例（36%）患者接受了至少 24 周的治疗。
FOLFIRABRAX 联合伊立替康基因指导剂量给药在携带或基因型的晚期胃肠道癌患者中是可耐受的。入组的*患者太少，无法得出明确的结果。多个肿瘤类型均有应答。
