近日，正大天晴公示开启《TQB3728片耐受性和药代动力学Ⅰ期临床试验（CTR20201229）》，其中TQB3728为IAP拮抗剂，临床前数据显示其cIAP1 BIR3, cIAP2 BIR3 and XIAP BIR3的IC50值分别为0.7, 11.8, 22.5 nM。
主要目的： 评估TQB3728的安全性和耐受性，确定TQB3728最大耐受剂量（MTD）（如有）、剂量限制性毒性（DLT），为后续研究提供推荐剂量和给药方案。
次要目的： 评估TQB3728口服给药的药代动力学(PK)特征。 评估TQB3728初步抗肿瘤作用。 探究TQB3728对外周血单核细胞中细胞凋亡抑制因子1(cIAP1)蛋白，以及TQB3728对血浆中细胞因子影响的药效动力学(PD)特征。
招募入选标准：经组织学或细胞学确诊的晚期/转移性或难治的实体瘤或淋巴瘤患者，无认可的标准治疗方案或对标准治疗方案无效或不耐受，至少有一个可以进行疗效评估的病灶（实体瘤根据RECIST v1.1标准，淋巴瘤根据Lugano 2014标准）。
国内预计招募25-40人，试验PI为中山大学肿瘤防治中心王树森主任。
TQB3728片剂，规格5mg/片，晨间空腹口服，每周一次。
临床申请提交于2019-11-27；
伦理审查通过于2020-04-01；
临床方案公示于2020-06-19。
| 产品 | 企业 | 临床分期 | 适应症 | 备注 |
| LCL-161 | Novartis | II | 非小细胞肺癌/三阴性乳腺癌/肾细胞癌 | |
| Birinapant | TetraLogic Pharma | II | MDS/CMML/HBV | 有效性不足 |
| ASTX660 | Astex Pharma | I/II | AML/PTCL/CTCL/ATLL | |
| Debio-1143 | Debiopharm | I/II | 胰腺癌/结直肠癌 | 联合PD-1 |
| APG-1387 | 亚盛医药 | I/II | 结直肠癌/鼻咽癌/非小细胞肺癌/HBV | |
| GDC-0917 | Genentech | I | 实体瘤/淋巴瘤 | |
| GDC-0152 | Genentech | I | 实体瘤 | 提前终止 |
| TQB3728 | 正大天晴 | I | 实体瘤/淋巴瘤 |
Abstract 724: Preclinical evaluation of TQB3728, a potent orally active IAP antagonist
- TQB3728 displayed potent biochemical activities for cIAP1 BIR3, cIAP2 BIR3 and XIAP BIR3 with IC50 of 0.7, 11.8 and 22.5 nM, respectively.
- The expected anti-proliferative activities were also observed in both tumor cell lines, with a IC50 of 14.3 Nm for MDA-MB-231, and IC50 of 149.5 nM for EMT6 in the presence of exogenous TNFα (1 ng/ml).
- TQB3728 showed in vivo antitumor activity in the MDA-MB-231 CDX model with 89.8% TGI @30 mpk QD, which is better than LCL-161 (71.9% TGI @30 mpk, QD).
- TQB3728 also showed good antitumor activity in vivo in the Karpas 422 lymphoma CDX model with 112.2% TGI @100 mpk Q3D.
- In EMT6 tumor-bearing mice, the combination of TQB3728 and anti-PD1 antibody significantly regressed the tumor growth (TGI = 106.3%), whereas monotherapies only displayed moderate activities ( 60.6% and 0.4% TGI for anti-PD1 and TQB3728, respectively).
- Western blot analysis of the tumor samples showed that TQB3728 promoted caspase 3 cleavage, indicating that the tumor growth inhibition could be mediated by cell apoptosis signaling.
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