Preclinical data suggest that combining a checkpoint inhibition with immunomodulatory derivative can increase anticancer response. We designed a dose-escalation study using a 3 + 3 design to determine the safety, maximum tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting toxicities (DLT) of the anti–CTLA-4 antibody ipilimumab (1.5–3 mg/kg intravenously every 28 days × 4) and lenalidomide (10–25 mg orally daily for 21 of 28 days until disease progression or unacceptable toxicity) in advanced cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma, 4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per immune-related response criteria (−79% to −2%) including a PR (−79% for 7.2+ months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling, a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of the patients achieving a PR demonstrated intermediate mutation burden. In conclusion, combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671–6. ©2017 AACR.

中文翻译：

---

抗 CTLA-4 抗体伊匹单抗和来那度胺在晚期癌症患者中的 1 期剂量递增研究

临床前数据表明，将检查点抑制与免疫调节衍生物相结合可以增加抗癌反应。我们设计了一项使用 3 + 3 设计的剂量递增研究，以确定抗 CTLA-4 抗体易普利姆玛的安全性、最大耐受剂量 (MTD) 或推荐的 II 期剂量 (R2PD) 和剂量限制性毒性 (DLT)。在晚期癌症中，每 28 天静脉注射 1.5–3 mg/kg × 4）和来那度胺（28 天中的 21 天，每天口服 10–25 mg，直至疾病进展或出现不可接受的毒性）。共招募了 36 名患者（霍奇金淋巴瘤，7 名；黑色素瘤，5 名；平滑肌肉瘤，4 名；肾癌，3 名；甲状腺癌，3 名；其他癌症，14 名；先前治疗的中位数为 3 次）。尚未达到 MTD，ipilimumab 3 mg/kg 和来那度胺 25 mg 已被宣布为 R2PD。DLT 为 (G) 3 级皮疹（3 名患者）和 G3 胰腺炎（1 名患者）。除 DLT 之外的 G3/4 药物相关毒性为 G3 贫血（5 名患者）、G3 血栓栓塞（2 名患者）、G3 血小板减少症、G3 皮疹、G3 垂体功能减退症、G3 肺炎、G3 转氨酶和 G4 垂体功能减退症（均发生在 1 位患者中）。根据免疫相关反应标准，8 名患者的肿瘤缩小（-79% 至 -2%），包括在难治性霍奇金淋巴瘤中达到 PR（-79% 持续 7.2 个月以上）。使用全面的基因组分析，评估了 17 名患者的总突变负荷（突变/Mb），其中一名达到 PR 的患者证明了中等突变负荷。总之，易普利姆玛和来那度胺的组合耐受性良好，并在难治性霍奇金淋巴瘤和其他晚期癌症患者中显示出初步的活性信号。摩尔癌症治疗; 17(3); 671-6。©2017 AACR。