PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: Refractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 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.
UNASSIGNED: 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%.
UNASSIGNED: 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.
UNASSIGNED: Refractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 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.
UNASSIGNED: 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%.
UNASSIGNED: 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.
摘要：
未经证实：GSK3β丝氨酸/苏氨酸激酶调节代谢和糖原生物合成。GSK3β过表达通过NF-κB和p53凋亡途径促进进展和抵抗。GSK3β通过下调PD-L1和LAG-3检查点并增加NK和T细胞肿瘤杀伤来抑制免疫调节。9-ING-41，一种小分子，选择性GSK3β抑制剂，在化疗耐药的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。
UNASSIGNED：难治性恶性肿瘤（n=162）采用9-ING-41单药治疗（n=65）或与8种细胞毒性方案联合治疗（NCT03678883）。复发性神经胶质瘤（n=18）用9-ING-41IVTIWq21天周期治疗，剂量为3.3、5、9.3、15mg/kg，单药治疗或联合洛莫司汀30mg/m²PO每周q84天周期。首要目标是安全。
未经批准：在所有9个方案中都确认了15mg/kg静脉TIW的RP2D，未发现化疗毒性加重。胶质瘤亚型包括：13个胶质母细胞瘤，2间变性星形细胞瘤,1间变性少突胶质细胞瘤，1星形细胞瘤。中位年龄52（30-69）岁；6名女性，12名男性；ECOG中位数1（0-2）；复发中位数3（1-6）。全部接受前期放疗/替莫唑胺（18/18），加上打捞亚硝基脲(15/18)，贝伐单抗（8/18），TTFelds(6/18),免疫疗法（4/18）。IDH/突变(3/18);1p19q/共缺失(1/18);MGMT/甲基化(1/18)。四人接受9-ING-41单药治疗，14与洛莫司汀并发。没有严重的毒性归因于9-ING-41，只有轻度的视力变化（9/18，50％），或输液反应（4/18，22％）。洛莫司汀相关毒性：G3/4血小板减少症（3/14，21%），G1/2疲惫(4/14，28%)。治疗的中位天数为55天(4-305天);注意到1次部分反应(>50%)。中位OS为5.5（95%CI：2.8-11.4）个月，PFS-6为16.7%。
未经批准：9-ING-41加/减洛莫司汀是安全的，值得在神经胶质瘤患者中进一步研究。
UNASSIGNED：难治性恶性肿瘤（n=162）采用9-ING-41单药治疗（n=65）或与8种细胞毒性方案联合治疗（NCT03678883）。复发性神经胶质瘤（n=18）用9-ING-41IVTIWq21天周期治疗，剂量为3.3、5、9.3、15mg/kg，单药治疗或联合洛莫司汀30mg/m²PO每周q84天周期。首要目标是安全。
未经批准：在所有9个方案中都确认了15mg/kg静脉TIW的RP2D，未发现化疗毒性加重。胶质瘤亚型包括：13个胶质母细胞瘤，2间变性星形细胞瘤,1间变性少突胶质细胞瘤，1星形细胞瘤。中位年龄52（30-69）岁；6名女性，12名男性；ECOG中位数1（0-2）；复发中位数3（1-6）。全部接受前期放疗/替莫唑胺（18/18），加上打捞亚硝基脲(15/18)，贝伐单抗（8/18），TTFelds(6/18),免疫疗法（4/18）。IDH/突变(3/18);1p19q/共缺失(1/18);MGMT/甲基化(1/18)。四人接受9-ING-41单药治疗，14与洛莫司汀并发。没有严重的毒性归因于9-ING-41，只有轻度的视力变化（9/18，50％），或输液反应（4/18，22％）。洛莫司汀相关毒性：G3/4血小板减少症（3/14，21%），G1/2疲惫(4/14，28%)。治疗的中位天数为55天(4-305天);注意到1次部分反应(>50%)。中位OS为5.5（95%CI：2.8-11.4）个月，PFS-6为16.7%。
未经批准：9-ING-41加/减洛莫司汀是安全的，值得在神经胶质瘤患者中进一步研究。
