Genomic Profiling of Metastatic Uveal Melanoma

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Metastatic UM patients (n=153) were treated with AEB071 in a Phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1400 mg. First-cycle dose-limiting toxicities (DLTs) were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses > 700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing (NGS) was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM. In conclusion, the protein kinase C inhibitor AEB071 was well tolerated and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of PKC inhibitors with other compounds in metastatic UM.]]>
Inclusion Criteria: Uveal melanoma with biopsy proven metastatic disease Males and females > 18 years of age Consent to biopsy of tumor Measurable disease according to RECIST version 1.1 WHO performance status of < 1 Exclusion Criteria: Patients with abnormal laboratory values as defined by the protocol Patients who are receiving treatment with strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued prior to study entry Patients with impaired cardiac function or clinically significant cardiac diseases as defined by the protocol Patients with another malignancy that was treated within the last three years with the exceptions of localized basal cell carcinoma and cervical carcinoma Patients with impairment of gastrointestinal function or disease Patients with severe systemic infections Patients who are known to be HIV positive and/or have active hepatitis B or C infection Time since last therapy for treatment of underlying malignancy: Cytotoxic chemotherapy: < duration of the most recent cycle of the previous regimen (a minimum of 2 weeks for all) Nitrosurea: < 6 weeks Biologic therapy: < 4 weeks < 5 x PK half-life of a small molecule therapeutic not otherwise defined above Patients having undergone major surgery less than 4 weeks prior to enrollment or have not fully recovered from prior surgery Women of child-bearing potential unless they are using highly effective methods of contraception during the dosing and for at least 36 hours after last dose. Highly effective contraception as defined in the protocol. Patients with primary central nervous system tumors or brain metastases. Pregnant or nursing (lactating) women. ]]>
Study start date 20-Dec-2011 Study completion date 22-May-2019]]>

约50%的葡萄膜黑色素瘤（Uveal Melanoma, UM）患者会发生转移性疾病，目前尚无有效的系统性治疗方案。本研究旨在评估口服蛋白激酶C（Protein Kinase C, PKC）抑制剂AEB071治疗转移性葡萄膜黑色素瘤患者的安全性与有效性，并对转移性肿瘤样本进行基因组谱分析，以期为联合治疗方案的提出提供依据。
本研究为一项I期单臂临床试验，共纳入153例转移性葡萄膜黑色素瘤患者，予以AEB071治疗，患者每日总给药剂量范围为450 mg至1400 mg。13例患者（13%）在第一治疗周期出现剂量限制性毒性（Dose-limiting Toxicities, DLTs），此类毒性多为胃肠道系统不良反应，且与给药剂量相关，多出现在每日剂量＞700 mg的患者中。
研究观察到初步临床活性：3%的患者达到部分缓解，50%的患者疾病稳定（中位持续时间为15周）。研究对89份转移性肿瘤活检样本进行了高深度靶向新一代DNA测序（Next-generation DNA Sequencing, NGS），检测到此前已在葡萄膜黑色素瘤中被报道的突变，包括GNAQ、GNA11、BAP1、SF3B1、PLCB4基因突变，以及8号染色体臂扩增。GNAQ/GNA11基因突变检出频率为93%，与既往报道一致，证实了转移性葡萄膜黑色素瘤中抑制下游效应蛋白PKC存在治疗窗口。
综上，PKC抑制剂AEB071在转移性葡萄膜黑色素瘤患者中耐受性良好，且展现出适度的临床活性；基因组分析结果与既往原发性葡萄膜黑色素瘤的研究报道相符。本研究数据可为PKC抑制剂与其他药物联合治疗转移性葡萄膜黑色素瘤的方案提供参考思路。

### 纳入标准
1. 经活检证实为转移性葡萄膜黑色素瘤的患者；
2. 年龄＞18岁的男性或女性患者；
3. 同意接受肿瘤活检；
4. 符合实体瘤疗效评价标准（Response Evaluation Criteria in Solid Tumors, RECIST）1.1版定义的可测量病灶；
5. 世界卫生组织（WHO）体能状态评分＜1分。

### 排除标准
1. 存在试验方案定义的实验室指标异常的患者；
2. 正在接受细胞色素P450 3A4（Cytochrome P450 3A4, CYP3A4）强诱导剂或抑制剂治疗，且无法在入组前停药的患者；
3. 存在试验方案定义的心脏功能受损或临床意义显著的心脏疾病的患者；
4. 近3年内接受过其他恶性肿瘤治疗的患者（局限性基底细胞癌和宫颈癌除外）；
5. 存在胃肠道功能受损或胃肠道疾病的患者；
6. 存在严重全身性感染的患者；
7. 已知HIV阳性，或合并活动性乙型/丙型肝炎病毒感染的患者；
8. 针对基础恶性肿瘤的末次治疗时间不符合要求者：
- 细胞毒性化疗：末次给药距离入组时间短于前一方案最近一个周期的持续时间（所有患者至少需间隔2周）；
- 亚硝脲类药物治疗：间隔时间＜6周；
- 生物治疗：间隔时间＜4周；
- 未在上述范畴内的小分子治疗药物：间隔时间＜5倍的药物半衰期；
9. 入组前4周内接受过大手术，或尚未从既往手术中完全恢复的患者；
10. 具有生育能力的女性患者，若未在给药期间及末次给药后至少36小时内使用试验方案定义的高效避孕措施；
11. 患有原发性中枢神经系统肿瘤或脑转移瘤的患者；
12. 妊娠或哺乳期（泌乳期）女性患者。

### 研究起止时间
本研究启动日期为2011年12月20日，研究完成日期为2019年5月22日。