PO.CTP01.02 · 进行中的临床试验
在NCT03643549 IB/II期试验中，通过序贯使用硼替佐米和替莫唑胺抑制26S蛋白酶体，经放大的酪氨酸激酶受体信号转导以利用NF-kB这一机制性靶点，为复发性MGMT阴性GBM带来5个月的延长生存
Inhibiting 26S proteosome with sequential bortezomib and temozolomide garners 5 months prolonged survival in recurrent MGMT -negative GBM through amplified tyrosine kinase receptor signaling to avail NF-kB mechanistic target in NCT03643549 Phase IB/II trial
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤（GBM）是成人中一种难以治疗的原发性脑肿瘤，尤其是对于O⁶-甲基鸟嘌呤DNA甲基转移酶（MGMT）启动子未甲基化（uMGMT）的患者。我们此前证明，在替莫唑胺（TMZ）之前48小时给予蛋白酶体抑制剂硼替佐米（BTZ）可耗竭MGMT蛋白、破坏自噬通量、抑制NF-κB信号，并使uMGMT GBM细胞对化疗增敏。在我们的IB期研究中，TMZ与BTZ联合的剂量递增是安全的，期中分析提示存在潜在临床获益。因此，启动了II期试验的全面招募，以研究临床获益和反应的生物标志物。共入组62例uMGMT启动子的复发性GBM患者，均在放疗后≥12周进展、KPS≥70且有可测量的复发病灶。患者在每个4周周期的第1、4、7天接受BTZ 1.3 mg/m²静脉注射，TMZ从第3天开始口服200 mg/m²，每周5天。不良事件（AE）采用CTCAE分级。临床评估包括NANO、RANO和EQ-5D-5L生活质量评估。采用Kaplan-Meier和Cox回归估计生存概率，以及与在相同参与医院接受治疗的匹配对照（n=118）患者之间的差异。对肿瘤DNA进行全外显子组和RNA测序以识别与反应相关的分子改变。截至2026年1月，在挪威四家大学医院共治疗了62例患者，中位年龄55岁（25-70岁），45例男性、17例女性，中位KPS 90（70-100），NANO 1（0-7）。加用BTZ后的AE仅限于轻度或中度，其中4/7为4级血小板减少，在治疗间歇期间缓解。33例3级AE包括癫痫发作和背痛。整体生活质量良好且在整个治疗期间保持稳定（中位65，范围60-75）。24%（15/62）的患者观察到RANO客观影像学反应。校正分析显示，与uMGMT对照（n=108，以3个月为标志点）12.9个月相比，BORTEM-17患者的OS获益为18.8个月，HR 0.68，95%CI [0.49-0.94]，P=0.008。在校正IDH状态后，BORTEM-17患者（n=55，IDH野生型）的OS为17.9个月，对照（n=108）为12.9个月，HR 0.71，95%CI [0.51-1.06]，P=0.009。总体而言，缓解者的中位OS为23.7个月，其余患者为18.7个月，HR 0.75，95%CI [0.39-1.4]，P=0.005。缓解者在入组后存活9.5个月，而其余患者为5.0个月，HR 0.52，95%CI [0.27-0.99]，P<0.035，中位进展时间为5.1个月对2.3个月，HR 0.45，95%CI [0.23-0.85]，P<0.0001。缓解者保留了更多的受体酪氨酸激酶/NF-κB/PI3K通路成分，表现为EGFR、FGFR3和MAPK11的拷贝数增加，提示对完整RTK信号转导的依赖，从而利用NF-κB（即BTZ的分子靶点）。相比之下，其余队列存在NFKB2、IKKalpha、PTEN和CDKN2的拷贝数缺失，表明NF-κB被消除。RNA测序转录谱分析正在进行中。序贯BTZ+TMZ治疗是安全的，带来临床获益，可能是预后极差的治疗难治性复发患者的一种有效附加治疗。该研究目前正在招募中。ClinicalTrials.gov编号：NCT03643549
查看英文原文 English abstract
Glioblastoma (GBM) is a hard to treat primary brain tumor in adults, especially for patients with unmethylated O 6- methylguanine DNA methyltransferase (u MGMT ) promoter. We previously demonstrated the proteasome inhibitor bortezomib (BTZ) administered 48hrs before temozolomide (TMZ) depletes MGMT protein, disrupts autophagic flux, inhibits NF-κB signaling, and chemosensitizes u MGMT GBM cells. In our phase IB, TMZ dose escalation in combination with BTZ was safe, and interim analysis indicated potential clinical benefit. Thus, full recruitment in phase II trial was launched to investigate clinical benefit and biomarkers for response. 62 recurrent GBM patients with uMGMT promoter, progressing ≥ 12 weeks after radiotherapy, KPS ≥ 70 and with measurable recurrent lesions were enrolled. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, TMZ starting on day 3 with oral at 200mg/m² for 5 days/week. Adverse events (AE) used CTCAE grading. Clinical evaluation included NANO, RANO, and EQ-5D-5L quality of life assessment. Kaplan-Meier and Cox regression were used to estimate survival probabilities and differences between matched control (n=118) patients treated at the same participating hospitals. Whole exome and RNA seq of tumor DNA were conducted to identify response associated molecular changes. Until January 2026,62 patients of median age of 55 (25-70 years), 45 males and 17 females, median KPS 90 (70-100) and NANO 1 (0-7) were treated at four university hospitals in Norway. AEs after addition of BTZ were limited to mild or moderate, where 4/7 were grade 4 thrombocytopenia that resolved during treatment breaks. 33 grade 3 AEs included seizures and backpain. Overall QoL was good and stable throughout the treatment (median 65, range 60-75). RANO objective radiological responses were observed in 24% (15/62) patients. Adjusted analyses showed OS benefit of 18.8 months (mos) for BORTEM-17 patients compared to 12.9 mos for controls with uMGMT (n=108) landmarked at 3 mos, HR0.68, 95%CI[0.49-0.94], P=0.008. Adjusting for IDH status, BORTEM-17 patients (n=55, IDH wt) OS was 17.9 vs. 12.9 mos for controls (n=108) HR0.71, 95%CI[0.51-1.06], P=0.009. Overall, median OS for responders was 23.7 vs. 18.7 mos for rest of patients, HR0.75, 95%CI [0.39-1.4], P=0.005. Responders survived 9.5 mos after recruitment compared to 5.0 mos for rest of patients, HR0.52, 95%CI [0.27-0.99], P<0.035, with median time to progression 5.1 mos vs. 2.3, HR0.45, 95%CI [0.23-0.85], P<0.0001. Responders retained more receptor tyrosine kinase /NF-κB/PI3K pathway components, exemplified by copy-number gains in EGFR, FGFR3, and MAPK11, suggesting dependence on intact RTK signaling, availing NF-κB, that is the molecular target for BTZ. In contrast, rest cohort harbored copy-number loss of NFKB2, IKKalpha, PTEN and CDKN2, indicating NF-κB abrogation. RNA seq transcriptional profiling is ongoing. The sequential BTZ+TMZ therapy is safe, garners clinical benefit and may represent effective additional treatment for treatment refractory recurrent patients with exceptionally poor prognosis. The study is currently recruiting. ClinicalTrials.gov id: NCT03643549
利益披露 Disclosure
D. Goplen, None..
M. A. Rahman, None..
S. Kumar, None..
M. H. Hannisdal, None..
V. Arnesen, None..
A. Waha, None..
L. Oltedal, None..
J. Haasz, None..
J. Brekke, None..
T. S. Solheim, None..
P. Brandal, None..
S. A. Lie, None..
M. Chekenya, None.