背景:谷氨酸信号激活肿瘤细胞中的MAPK和PI3K/AKT通路。利鲁唑治疗,一种谷氨酸释放抑制剂,先前已被证明对黑色素瘤患者是安全的,并产生了生物学效应,但没有导致射线照相反应,可能是由于不良的药代动力学特性。因此,我们进行了Ib期试验,以确定利鲁唑前药曲鲁唑(BHV-4157,曲格鲁唑)和PD-1抗体nivolumab联合治疗晚期实体瘤患者的安全性和耐受性.
方法:根据RECIST1.1,晚期或难治性实体瘤和可测量疾病的患者使用半贝叶斯修改的毒性概率间隔剂量递增程序,接受增加剂量的曲鲁唑治疗。曲鲁唑单一疗法口服自我给药,为期14天的导入期,然后每2周继续使用曲鲁唑联合纳武单抗240mgIV。终点包括安全性,药代动力学(PK)和功效。
结果:我们纳入了14例晚期实体瘤患者(黑色素瘤=3,NSCLC=3,肾细胞癌=2,膀胱/尿路上皮癌=2,卵巢癌=1,腺样囊性癌=1,胸膜间皮=1,头颈部癌=1)。11名患者在先前使用PD-1或PD-L1药物治疗后出现癌症进展。患者接受了140至560mg(分)的曲鲁唑每日总剂量。在≥5例患者(>35%)中发生的最常见的治疗相关不良事件(TRAE)是转氨酶和脂肪酶升高。3例患者发生剂量限制性毒性(DLT):(1)3级厌食症,(2)3级疲劳,(3)3级房颤。6名患者以MTD(最大耐受剂量)治疗。没有受试者由于AE而停止治疗。出现一个反应(7%),这是患有PD-1难治性疾病的受试者的部分反应。6个月PFS率为21%。PK数据显示,在所测试的所有剂量组群中,前药曲鲁唑在给药后2小时被有效裂解为利鲁唑。
结论:曲鲁唑和纳武单抗联合用药安全且耐受性良好。测定曲鲁唑的MTD为420mg总日剂量。观察到的抗肿瘤活性,主要是疾病稳定,对PD-1耐药肿瘤患者感兴趣。试验注册ClinicalTrials.gov标识符NCT03229278。
BACKGROUND: Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib
trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors.
METHODS: Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy.
RESULTS: We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested.
CONCLUSIONS: The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors.
Trial Registration ClinicalTrials.gov Identifier NCT03229278.