Institut Gustave Roussy Cancer Campus, Drug Development Department, Villejuif Cedex, France.
Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall D'Hebron University Hospital, and Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Eur J Cancer. 2018 Nov;103:88-97. doi: 10.1016/j.ejca.2018.08.012. Epub 2018 Sep 12.
LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST).
This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS).
Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31-78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6-3.3) for LMS, 1.9 months (0.3-6.1) for GIST and 1.7 months (1.4-2.2) for other STS groups. Median OS was 7.4 months (4.3-non-evaluable [NE]) for LMS, 16.5 months (3.9-16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite.
LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.
LY3039478 是一种口服生物可利用的选择性 Notch 抑制剂。这项 1a/b 期临床试验评估了 LY3039478 在软组织肉瘤（STS）和胃肠道间质瘤（GIST）患者中的安全性、药代动力学和抗肿瘤活性。
这项多部分 1 期试验招募了难治性晚期/转移性 STS 和 GIST、可测量疾病、东部合作肿瘤学组≤1 和基线肿瘤组织的患者。符合条件的患者接受 LY3039478 50mg/75mg，每周 3 次，每 28 天为一个周期，直到疾病进展。安全性评估基于不良事件通用术语标准，版本 4.0。使用实体瘤反应评估标准（RECIST 1.1）和 Choi 标准评估肿瘤反应。主要目标是确认 LY3039478 的推荐 2 期剂量，并记录抗肿瘤活性。次要目标是安全性和毒性、药代动力学（PK）、无进展生存期（PFS）和总生存期（OS）。
共招募了 69 名患者并接受了 LY3039478 治疗（27 名男性，42 名女性；中位年龄 58 岁，范围 31-78 岁）。16/37（43%）有可评估样本的患者 Notch 1 免疫组化阳性。根据 RECIST 1.1，在平滑肌肉瘤（LMS）组（n=29）中，10 名（36%）患者疾病稳定（SD），1 名（4%）患者未确认部分缓解（PR）。在 GIST 组（n=13）中，4 名（31%）患者疾病稳定。在其他 STS 亚型（n=27）中，1 名血管肉瘤患者未确认 PR，6 名（21%）患者疾病稳定。LMS 的中位 PFS 为 1.9 个月（95%置信区间：1.6-3.3），GIST 为 1.9 个月（0.3-6.1），其他 STS 组为 1.7 个月（1.4-2.2）。LMS 的中位 OS 为 7.4 个月（4.3-不可评估[NE]），GIST 为 16.5 个月（3.9-16.5），其他 STS 组为 5.6 个月（3.4-NE）。最常见的不良反应是腹泻、恶心、呕吐和食欲下降。
LY3039478 在 STS 和 GIST 患者中显示出适度的临床活性，且具有可管理的安全性。
