A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.
A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.
复制标题
DOI：
10.18632/oncotarget.28403
复制
发表时间：
2023-04-10
期刊：
影响因子：
--
通讯作者：
Mehnert, Janice M
中科院分区：
文献类型：
--
作者：
Spencer, Kristen R;Portal, Daniella E;Aisner, Joseph;Stein, Mark N;Malhotra, Jyoti;Shih, Weichung;Chan, Nancy;Silk, Ann W;Ganesan, Shridar;Goodin, Susan;Gounder, Murugesan;Lin, Hongxia;Li, Jiadong;Cerchio, Robert;Marinaro, Christina;Chen, Suzie;Mehnert, Janice M
背景：代谢型谷氨酸受体 1 (GRM1) 的过度表达与多种癌症的发病机制有关。利鲁唑是一种谷氨酸释放抑制剂，在临床前模型中与多激酶抑制剂索拉非尼联合显示出协同抗肿瘤活性。该 I 期试验确定了利鲁唑联合索拉非尼治疗晚期癌症患者的毒性特征、剂量限制性毒性、最大耐受剂量 (MTD) 以及药代动力学和药效学特性。患者和方法：采用 3+3 剂量递增设计招募难治性实体瘤患者。利鲁唑以 100 mg PO BID 与索拉非尼联合给药，从每天 200 mg PO 开始，并在 28 天的周期内以每个级别 200 mg 的增量逐步递增。每 2 个周期进行一次重新分期评估。结果：35 名患者入组了 4 个剂量水平。 MTD 在剂量水平 3 时公布（利鲁唑：100 mg PO BID；索拉非尼：400 mg AM/200 mg PM）。药代动力学分析没有揭示药物相互作用的明确证据。肿瘤组织分析中 ERK 和 AKT 磷酸化的持续减少，伴随着 GRM1 表达的减少和促凋亡 BIM 的增加，表明该组合的靶点参与。最佳缓解包括 1 名 (2.9%) 具有 KANK4-RAF1 融合的胰腺腺泡细胞癌患者的部分缓解，以及 11 名 (36%) 患者的病情稳定。结论：利鲁唑和索拉非尼联合治疗晚期实体瘤患者安全且耐受。 RAF1 融合患者的部分缓解表明，可能需要在基因组选择的队列中进行进一步探索。
Background: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. Patients and Methods: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. Results: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. Conclusion: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.