e16077
背景： Alofanib (RPT835) 是一种一流的变构抑制剂，可诱导 FGFR2 胞外结构域的构象变化。在这里，我们展示了阿洛法尼的 Ib 期临床研究 (RPT835GC1B) 的最终结果。方法：对标准治疗有可测量疾病的转移性胃腺癌患者是合格的。剂量发现部分采用 3+3 设计，从 50 mg/m2 的剂量水平开始，静脉注射，5 天使用，2 天休息。预计有五个剂量水平。主要终点是最大耐受剂量（MTD）。次要终点包括毒性、PK、客观缓解率 (ORR)、总生存期 (OS) 和无进展生存期 (PFS)。结果：21名患者入组。4 (19.1%)、14 (66.7%)、9 (43%)、3 (14.3%) 和 12 (57%) 名患者有 ECOG PS 2、≥2 个转移部位、肝转移、骨转移和 3- 6系既往治疗，分别。尚未达到 MTD，已宣布 350 mg/m2 的剂量为推荐的 II 期剂量。中位随访时间为 13.0 个月，15 名 (71.4%) 患者出现任何级别的治疗相关不良事件 (TRAE)。6 名 (28.6%) 患者发生 3-4 级 TRAE。两名 (9.5%) 患者在注射后立即因 3 级腹泻和 4 级反应而停止治疗。研究中没有与治疗相关的死亡。确定了一项持续时间为 18.53 个月的部分缓解（5.26%）。疾病控制率 (DCR) 为 68.4%，中位疾病稳定持续时间为 4.91 个月。中位 PFS 为 3.63 (95% CI 1.58–5.68) 个月。中位 OS 为 7.0 (3.82–10.18) 个月。6 个月 OS 率为 57.1%。DCR（中位数 10.05 对 5.9 个月）和无骨转移（8.6 对 3.1）患者的 OS 几乎提高了 2 倍。只有一名患者 (4.8%) 出现 FGFR2 扩增（至死亡时间为 7 个月）。PK 参数根据剂量水平呈线性变化，但未发现与疗效相关。表格总结了剂量组中 TRAE 和 DCR 的发生率。结论：阿洛伐尼是可行的，并且在接受过大量治疗的转移性胃癌患者中显示出早期疗效信号。计划进行 2 期随机试验。临床试验资料：NCT04071184。
"点击查看英文标题和摘要"
Alofanib in subsequent therapy for advanced gastric cancer: Final results from the phase Ib clinical trial.
e16077
Background: Alofanib (RPT835) is a first-in-class allosteric inhibitor that induces conformational changes in the extracellular domain of FGFR2. Here, we present the final results of the phase Ib clinical study (RPT835GC1B) of alofanib. Methods: Patients with metastatic gastric adenocarcinoma resistant to standard therapy with measurable disease were eligible. The dose finding part used a 3+3 design, starting with a dose level of 50 mg/m2, intravenously, 5 days on, 2 days off. Five dose levels were foreseen. Primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included toxicity, PK, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: 21 patients were enrolled. 4 (19.1%), 14 (66.7%), 9 (43%), 3 (14.3%), and 12 (57%) patients had ECOG PS 2, ≥2 metastatic sites, liver metastases, bone metastases, and 3-6 lines previous therapy, respectively. The MTD has not been reached and dose of 350 mg/m2 has been declared as recommended phase II dose. With median follow-up of 13.0 months 15 (71.4%) patients had any grade treatment related adverse events (TRAE). Grade 3-4 TRAE occurred in 6 (28.6%) patients. Two (9.5%) patients discontinued treatment due to grade 3 diarrhea and grade 4 reactions immediately after injections. There were no treatment-related deaths in the study. One partial response (5.26%) with a duration of 18.53 months was identified. Disease control rate (DCR) was 68.4% and median duration of stable disease was 4.91 months. Median PFS was 3.63 (95% CI 1.58–5.68) months. Median OS was 7.0 (3.82–10.18) months. 6-month OS rate was 57.1%. OS was almost 2 times better in patients with DCR (median 10.05 vs. 5.9 months) and without bone metastases (8.6 vs. 3.1). Only one patient (4.8%) had FGFR2 amplification (time to death was 7 months). PK parameters linearly changed depending on the dose level, but no correlation with efficacy was found. Table summarizes rate of TRAE and DCR in dose cohorts. Conclusions: Alofanib was feasible and showed early signals of efficacy in heavily-pretreated patients with metastatic gastric cancer. A phase 2 randomized trial is planned. Clinical trial information: NCT04071184.
Dose level.
| 1
50 mg/m2
| 2
100mg/m2
| 3
165mg/m2
| 4
250mg/m2
| 5
350mg/m2
|
|---|
Number of patients
| 3
| 3
| 3
| 3
| 9
| Any TRAE, N (%)
| 2 (66.7) | 2 (66.7) | 3 (100) | 2 (66.7) | 6 (66.7) | Grade 3-4 TRAE, N (%)
| 2 (66.7)
| 0
| 2 (66.7)
| 0
| 2 (22.2)
| DCR, N (%)
| 3 of 3 (100),
including partial response | 2 of 3 (66.7) | 2 of 3 (66.7)
| 2 of 3 (66.7)
| 4 of 7 (57.1) |
|
京公网安备 11010802027423号