Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK 800 NE 10th Street, OKC, OK 73104, United States of America.
Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK 800 NE 10th Street, OKC, OK 73104, United States of America.
Gynecol Oncol. 2019 Aug;154(2):294-301. doi: 10.1016/j.ygyno.2019.04.001. Epub 2019 Jun 4.
The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P).
Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P).
37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR).
IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.
WNT 通路是上皮性卵巢癌（EOC）的重要致癌驱动因素。首创的重组融合蛋白 ipafricept（IPA）通过结合 Wnt 配体阻断 Wnt 信号。这项 Ib 期试验旨在确定 IPA 联合紫杉烷和铂类治疗（C/P）的最大耐受剂量（MTD）和推荐的 2 期剂量（RPh2）。
剂量递增采用标准的 3+3 设计，在第 1 天静脉注射 IPA，第 1 至 6 周期每 3 周一次，联合 C（AUC=5mg/ml·min）和 P（175mg/m）。为了增强骨骼安全性，试验修订为 IPA 每 3 周 1 天，C/P 每 3 天 1 天的 6 例队列方案（IPA→C/P）。
已有 37 例患者接受治疗；其中 30 例患者在方案修订后接受 q3w IPA（D1）→C/P（D3）（2 和 4mg/kg）治疗。IPA 相关的 TEAEs 发生率≥15%的包括：疲劳（40%）、恶心（35%）、腹泻和食欲下降（各 22%）、味觉障碍（19%）和呕吐（16.2%）。22%的患者报告≥1 次 IPA 相关的≥3 级 TEAEs，最常见的是中性粒细胞减少症（16%）。未观察到剂量限制毒性（DLT）；未达到 MTD。基于骨骼安全性，最大给药剂量为 6mg/kg。总缓解率（ORR）为 75.7%。中位 PFS 为 10.3 个月（95%CI 8.5-14.2），OS 为 33 个月（95%CI 23.4-NR）。
IPA 与序贯 C/P 联合使用具有良好的耐受性。ORR、PFS 和 OS 与历史数据相当，但在有效剂量下该特定 Wnt 抑制剂的骨骼毒性限制了其在 EOC 中的进一步开发。
