Camera Silvia, Deleporte Amélie, Bregni Giacomo, Trevisi Elena, Pretta Andrea, Telli Tugba Akin, Polastro Laura, Gombos Andrea, Kayumba Aline, Ameye Lieveke, Piccart-Gebhart Martine, Awada Ahmad, Sclafani Francesco, Hendlisz Alain
Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Data Centre, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Clin Colorectal Cancer. 2020 Dec;19(4):311-318.e1. doi: 10.1016/j.clcc.2020.05.007. Epub 2020 May 29.
Although data from preclinical and clinical studies provide a strong rationale for combining capecitabine with anti-angiogenic agents, clinical development of this fluoropyrimidine in combination with aflibercept has lagged behind other treatments. We conducted a nonrandomized, noncomparative, 2-arm, phase I trial to address this unmet need.
Patients with chemorefractory gastrointestinal and breast cancer were sequentially recruited into a continuous (Arm A, starting dose 1100 mg/m/day) or intermittent (Arm B, 2 weeks on/1 week off, starting dose 1700 mg/m/day) capecitabine dosing arm. Aflibercept was administered at a flat dose of 6 mg/kg every 3 weeks in both arms. A classical 3 + 3, dose-escalation design was used. The primary objective was to establish the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended dose for phase II trials.
Thirty-eight eligible patients were recruited of whom 33 were assessable for DLTs (15 in arm A and 18 in arm B). Fourteen had colorectal cancer, 8 gastric cancer, and 11 breast cancer. DLTs included grade 2 hand-foot syndrome, grade 2 anorexia considered unacceptable by the patient, and grade 3 hypertension. The recommended dose for phase II trials for capecitabine was established at 1300 mg/m/day in Arm A and 2500 mg/m/day in Arm B with treatment-related grade ≥ 3 adverse events occurring in 47% and 50% of patients, respectively. Among 26 assessable patients, the objective response rate was 15.4% in Arm A and 7.7% in Arm B.
Combining capecitabine with aflibercept is feasible and associated with a manageable safety profile and some anti-tumor activity in patients with chemorefractory gastrointestinal and breast cancer.
尽管临床前和临床研究数据为卡培他滨与抗血管生成药物联合使用提供了有力依据，但这种氟嘧啶与阿柏西普联合使用的临床开发落后于其他治疗方法。我们开展了一项非随机、非对照、双臂I期试验，以满足这一未被满足的需求。
对化疗难治性胃肠道癌和乳腺癌患者依次招募进入持续（A组，起始剂量1100mg/m²/天）或间歇（B组，2周用药/1周停药，起始剂量1700mg/m²/天）卡培他滨给药组。两组均每3周给予固定剂量6mg/kg的阿柏西普。采用经典的3+3剂量递增设计。主要目的是确定最大耐受剂量、剂量限制毒性（DLT）以及II期试验的推荐剂量。
共招募了38例符合条件的患者，其中33例可评估DLT（A组15例，B组18例）。14例患有结直肠癌，8例患有胃癌，11例患有乳腺癌。DLT包括2级手足综合征、患者认为不可接受的2级厌食症以及3级高血压。II期试验卡培他滨的推荐剂量确定为A组1300mg/m²/天，B组2500mg/m²/天，分别有47%和50%的患者发生与治疗相关的≥3级不良事件。在26例可评估患者中，A组客观缓解率为15.4%，B组为7.7%。
卡培他滨与阿柏西普联合使用是可行的，对于化疗难治性胃肠道癌和乳腺癌患者，其安全性可控且具有一定的抗肿瘤活性。
