来自ACTuate 1801研究的恶性胶质瘤亚组：9-ING-41（一种GSK-3β抑制剂）单药治疗或联合化疗用于难治性恶性肿瘤的I/II期研究。
Malignant glioma subset from actuate 1801: Phase I/II study of 9-ING-41, GSK-3β inhibitor, monotherapy or combined with chemotherapy for refractory malignancies.
作者信息
Odia Yazmin, Cavalcante Ludimila, Safran Howard, Powell Steven Francis, Munster Pamela N, Ma Wen Wee, Carneiro Benedito A, Bastos Bruno R, Mikrut Stacy, Mikrut William, Giles Francis J, Sahebjam Solmaz
机构信息
Department of Neuro-Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, Florida, USA.
Actuate Therapeutics, Fort Worth, Texas, USA.
出版信息
Neurooncol Adv. 2022 Feb 7;4(1):vdac012. doi: 10.1093/noajnl/vdac012. eCollection 2022 Jan-Dec.
BACKGROUND
GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating PD-L1 and LAG-3 checkpoints and increasing NK and T-cell tumor killing. 9-ING-41, a small-molecule, selective GSK3β inhibitor, showed preclinical activity in chemo-resistant PDX glioblastoma models, including enhanced lomustine antitumor effect.
METHODS
Refractory malignancies ( = 162) were treated with 9-ING-41 monotherapy ( = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas ( = 18) were treated with 9-ING-41 IV TIW q21day cycles at 3.3, 5, 9.3, 15 mg/kg, as monotherapy or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety.
RESULTS
RP2D of 15 mg/kg IV TIW was confirmed across all 9 regimens, no accentuated chemotherapy toxicity noted. Glioma subtypes included: 13 glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, 1 astrocytoma. Median age 52 (30-69) years; 6 female, 12 male; median ECOG 1 (0-2); median recurrences 3 (1-6). All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). IDH/mutation(3/18); 1p19q/codeletion(1/18); MGMT/methylated(1/18). Four received 9-ING-41 monotherapy, 14 concurrent with lomustine. No severe toxicities were attributed to 9-ING-41, only mild vision changes (9/18, 50%), or infusion reactions (4/18, 22%). Lomustine-related toxicities: G3/4 thrombocytopenia (3/14, 21%), G1/2 fatigue (4/14, 28%). Median days on therapy was 55 (4-305); 1 partial response (>50%) was noted. Median OS was 5.5 (95% CI: 2.8-11.4) months and PFS-6 was 16.7%.
CONCLUSION
9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.
背景
糖原合成酶激酶3β（GSK3β）丝氨酸/苏氨酸激酶调节代谢和糖原生物合成。GSK3β的过表达通过核因子κB（NF-κB）和p53凋亡途径促进肿瘤进展和耐药。GSK3β通过下调程序性死亡受体配体1（PD-L1）和淋巴细胞激活基因3（LAG-3）检查点并增强自然杀伤（NK）细胞和T细胞的肿瘤杀伤作用来抑制免疫调节。9-ING-41是一种小分子、选择性GSK3β抑制剂，在化疗耐药的人源肿瘤异种移植（PDX）胶质母细胞瘤模型中显示出临床前活性，包括增强洛莫司汀的抗肿瘤作用。
方法
对162例难治性恶性肿瘤患者进行了研究，其中65例接受9-ING-41单药治疗，其余97例在先前接受过治疗后联合8种细胞毒性方案进行治疗（NCT03678883）。18例复发性胶质瘤患者接受9-ING-41静脉注射，每3周一次，共3个周期，剂量分别为3.3、5、9.3、15mg/kg，可单药治疗或与洛莫司汀联合使用，洛莫司汀剂量为30mg/m²，口服，每周一次，共3个周期。主要观察指标为安全性。
结果
在所有9种治疗方案中均确定了15mg/kg静脉注射、每3周一次的推荐II期剂量（RP2D），未发现化疗毒性增强。胶质瘤亚型包括：13例胶质母细胞瘤、2例间变性星形细胞瘤、1例间变性少突胶质细胞瘤、1例星形细胞瘤。中位年龄52岁（30 - 69岁）；女性6例，男性12例；中位东部肿瘤协作组（ECOG）体能状态评分为1分（0 - 2分）；中位复发次数为3次（1 - 6次）。所有患者均接受过 upfront 放疗/替莫唑胺（18/18），另外还接受过挽救性亚硝基脲类药物治疗（15/18）、贝伐单抗治疗（8/18）、肿瘤治疗电场（TTFields）治疗（6/18）或免疫治疗（4/18）。异柠檬酸脱氢酶（IDH）/突变（3/18）；1号染色体短臂1区1带/19号染色体长臂（1p19q）/共缺失（1/18）；O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）/甲基化（1/18）。4例患者接受9-ING-41单药治疗，14例患者同时接受洛莫司汀治疗。未发现9-ING-41导致严重毒性反应，仅出现轻度视力改变（9/18，50%）或输液反应（4/18，22%）。洛莫司汀相关毒性反应：3/4级血小板减少（3/14，21%），1/2级疲劳（4/14，28%）。中位治疗天数为55天（4 - 305天）；观察到1例部分缓解（>50%）。中位总生存期（OS）为5.5个月（95%置信区间：2.8 - 11.4个月），无进展生存期6个月（PFS-6）为16.7%。
结论
9-ING-41联合/不联合洛莫司汀治疗安全，值得在胶质瘤患者中进一步研究。
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