Piha-Paul S A, Tolcher A W, Vandross A L, Spira A I, Burns M R
The University of Texas MD Anderson Cancer Center, Houston, USA.
NEXT Oncology, San Antonio, USA.
ESMO Open. 2025 Sep 5;10(9):105576. doi: 10.1016/j.esmoop.2025.105576.
Dysregulation of polyamine synthesis has been observed in various cancer cell types. A novel approach to depriving cancer cells of polyamines involves the use of difluoromethylornithine (DFMO) to block polyamine biosynthesis in combination with AMXT 1501, a potent inhibitor of polyamine transport. Preclinical mouse tumor models showed that the combination of AMXT 1501 plus DFMO had strong antitumor activity, together with evidence of a stimulated immune response against tumors.
This was a multicenter phase I, open-label, two-part dose-escalation study, with expansion, to evaluate the safety and preliminary efficacy of oral AMXT 1501 in combination with oral DFMO in patients with advanced solid tumors. In part 1, patients were treated with ascending doses of AMXT 1501 alone for 2 weeks and then in combination with DFMO for an additional 2 weeks. In part 2, AMXT 1501 was dosed with escalating DFMO doses to determine the recommended phase II dose (RP2D), with an expansion cohort to confirm the RP2D. Patients with unresectable, locally advanced, or metastatic solid tumors for which no standard therapy was recognized were eligible.
A total of 56 patients were enrolled and treated (20, 22, and 14 in part 1, part 2, and expansion, respectively). Patients were heavily pretreated; the median number of prior cancer treatments was 10.0. The most common treatment-emergent adverse events (TEAEs) were diarrhea (39.3%), nausea (37.5%), and vomiting (33.9%). There were no grade 4 or 5 TEAEs and no deaths due to TEAEs. Moderate antitumor activity was observed with 2 patients with confirmed responses and 16 patients with stable disease for an overall response rate of 6% and a clinical benefit rate of 49%.
Overall, AMXT 1501 in combination with DFMO was safe and tolerated with evidence of preliminary clinical activity. The RP2D was determined to be AMXT 1501 600 mg twice daily plus DFMO 500 mg.
NCT03536728.
在多种癌细胞类型中均观察到多胺合成失调。一种剥夺癌细胞多胺的新方法是使用二氟甲基鸟氨酸（DFMO）来阻断多胺生物合成，并联合使用强效多胺转运抑制剂AMXT 1501。临床前小鼠肿瘤模型显示，AMXT 1501与DFMO联合使用具有强大的抗肿瘤活性，同时有证据表明对肿瘤的免疫反应受到刺激。
这是一项多中心I期、开放标签、两部分剂量递增研究，并进行扩展，以评估口服AMXT 1501联合口服DFMO治疗晚期实体瘤患者的安全性和初步疗效。在第1部分中，患者先接受递增剂量的AMXT 1501单药治疗2周，然后再联合DFMO治疗2周。在第2部分中，AMXT 1501与递增剂量的DFMO联合给药，以确定推荐的II期剂量（RP2D），并通过一个扩展队列来确认RP2D。符合条件的患者为不可切除、局部晚期或转移性实体瘤患者，且尚无公认的标准治疗方案。
共纳入56例患者并进行治疗（第1部分、第2部分和扩展队列分别为20例、22例和14例）。患者既往接受过大量治疗；既往癌症治疗的中位数为10.0次。最常见的治疗中出现的不良事件（TEAE）为腹泻（39.3%）、恶心（37.5%）和呕吐（33.9%）。没有4级或5级TEAE，也没有因TEAE导致的死亡。观察到中度抗肿瘤活性，2例患者确认有反应，16例患者病情稳定，总缓解率为6%，临床获益率为49%。
总体而言，AMXT 1501联合DFMO是安全且耐受性良好的，并有初步临床活性的证据。确定RP2D为AMXT 1501每日两次600 mg加DFMO 500 mg。
NCT03⑤36728
