吲哚莫德用于晚期恶性肿瘤患者的I期研究。

A phase I study of indoximod in patients with advanced malignancies.

作者信息

Soliman Hatem H, Minton Susan E, Han Hyo Sook, Ismail-Khan Roohi, Neuger Anthony, Khambati Fatema, Noyes David, Lush Richard, Chiappori Alberto A, Roberts John D, Link Charles, Vahanian Nicholas N, Mautino Mario, Streicher Howard, Sullivan Daniel M, Antonia Scott J

机构信息

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.

出版信息

Oncotarget. 2016 Apr 19;7(16):22928-38. doi: 10.18632/oncotarget.8216.

PURPOSE

Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates.

EXPERIMENTAL DESIGN

Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption.

RESULTS

In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 μM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels.

CONCLUSIONS

Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.

目的

吲哚莫德是一种口服的吲哚胺2,3-双加氧酶途径抑制剂，该途径会导致肿瘤介导的免疫抑制。主要终点是晚期实体瘤患者中吲哚莫德的最大耐受剂量（MTD）和毒性。次要终点包括缓解率、药代动力学和免疫相关性。

实验设计

我们的3+3期I期试验包括10个剂量水平（每日一次200、300、400、600和800毫克；每日两次600、800、1200、1600和2000毫克）。纳入标准为可测量的转移性实体恶性肿瘤、年龄≥18岁以及器官/骨髓功能良好。排除标准为化疗在3周内、未治疗的脑转移、自身免疫性疾病或吸收不良。

结果

在48名患者中，每日两次2000毫克时未达到MTD。在每日一次200毫克时，3名先前接受过检查点抑制剂治疗的患者发生了垂体炎。5名患者疾病稳定超过6个月。吲哚莫德血浆AUC和Cmax在1200毫克以上达到平台期。Cmax（每日两次2000毫克时约为12μM）在2.9小时出现，半衰期为10.5小时。C反应蛋白（CRP）水平在多个剂量水平上均升高。