Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Vanderbilt University, Medical Center, Nashville, Tennessee.
Clin Cancer Res. 2020 Oct 15;26(20):5348-5357. doi: 10.1158/1078-0432.CCR-20-0489. Epub 2020 Jul 21.
The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).
Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.
A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (95% CI, 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.
Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.
重组融合蛋白 ipafricept 阻断 Wnt 信号通路，与吉西他滨和 nab-紫杉醇联合使用可导致异种移植物肿瘤消退。这项 Ib 期研究评估了 ipafricept 联合 nab-紫杉醇+吉西他滨在未经治疗的转移性胰腺腺癌（mPDAC）患者中的应用。
起始剂量递增方案为标准剂量 nab-紫杉醇+吉西他滨联合 ipafricept（3.5mg/kg，第 1、15 天）。由于不同的抗 Wnt 药物会导致脆性骨折，因此后续队列中至少有 6 例患者在第 1 天接受了 3 至 5mg/kg 的 ipafricept，并根据需要进行骨标志物监测和预防性双膦酸盐治疗。基于临床前数据，在第 4 队列中评估了序贯给药（第 1 天给予 ipafricept，第 3 天给予 nab-紫杉醇+吉西他滨）。主要研究终点包括安全性、最大耐受剂量、推荐的 II 期剂量、药代动力学、免疫原性、药效学和疗效。
共入组 26 例患者，1 例入组队列 1，7 例入组队列 2-4。ipafricept 相关的任何级别不良反应包括疲劳、恶心、呕吐、厌食和发热。ipafricept 相关≥3 级不良反应包括 2 例天门冬氨酸氨基转移酶升高，1 例恶心、皮疹、呕吐和白细胞减少。未观察到剂量限制性毒性或脆性骨折。9 例患者（34.6%）有部分缓解，12 例（46.2%）最佳缓解为疾病稳定，临床获益率为 81%。中位无进展生存期为 5.9 个月（95%置信区间[CI]：3.4-18.4），中位总生存期为 9.7 个月（95%CI：7.0-14）。由于该治疗方案中与骨骼相关的毒性和对商业可行性的担忧，该研究由研究发起方终止。1 例患者在同情用药下继续接受治疗。
ipafricept 可与 nab-紫杉醇+吉西他滨联合使用，具有良好的耐受性。Wnt 通路仍然是 mPDAC 治疗的一个有价值的靶点。
