PO.CTP01.01 · 进行中的临床试验

一项评估BXQ-350联合mFOLFOX7和贝伐珠单抗治疗新诊断转移性结直肠癌患者（mCRC）疗效和安全性的Ib/2a期研究：CIPN事件发生率和严重程度较低的证据

A Phase 1b/2a study to evaluate the efficacy and safety of BXQ-350 in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal carcinoma patients (mCRC): Evidence of lower incidence and severity of CIPN events

编号 CT084 展板 15 时间 4/20 09:00–12:00 区域 Section 51 主讲 Reema Patel

分会场 Phase I Clinical Trials in Progress

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作者与单位 Authors & Affiliations

Reema Patel¹, Daniel Flora², Ari Baron³, Davendra Sohal⁴, Saima Sharif⁵, Julie Anne gemmill⁶, Fa Chyi Lee⁷, Gilles H. Tapolsky⁸, Michael Gazda⁸, James Beach⁸, Tariq Arshad⁸

¹University of Kentucky, Lexington, KY,²St Elizabeth Healthcare, Edgewood, KY,³Pacific Hematology, San Francisco, CA,⁴University of Cincinnati, Cincinnati, OH,⁵University of Iowa, Iowa City, IA,⁶Stony Brook University, New York, NY,⁷University of California Irvine, Orange, CA,⁸Bexion Pharmaceuticals, Covington, KY

摘要 Abstract

中文摘要

背景：鞘脂代谢失调在包括mCRC在内的多种癌症类型中很常见，可导致神经节苷脂（GM3）、乳糖神经酰胺（LacCer）、葡萄糖神经酰胺（GluCer）和1-磷酸鞘氨醇（S1P）浓度升高以及神经酰胺（Cer）浓度降低。在mCRC患者中，多项研究表明这些鞘脂浓度升高与更差的预后和不良生存相关。因此，靶向失调的鞘脂代谢并使鞘脂代谢恢复至稳态可能是一种有前景的治疗方法。化疗诱导的周围神经病变（CIPN）是许多抗癌药物相关的重要副作用，在接受奥沙利铂方案的mCRC患者中高度普遍。CIPN可严重影响生活质量（QoL），并可能需要暂停给药、减量或中断。CIPN的病理机制复杂且尚未完全阐明；临床前和临床数据显示存在炎症和免疫参与，以及同样参与癌症进展的鞘脂水平升高。BXQ-350是Saposin C的纳米囊泡，Saposin C是鞘脂代谢的变构激活剂，可影响失调的鞘脂代谢。BXQ-350降低GM3、GluCer和S1P水平，同时也升高神经酰胺水平，促进恢复至稳态。在一项单药1期研究中，BXQ-350安全且耐受性良好（无DLT，无MTD），并显示出活性迹象。在PFS > 6个月的患者中，有4例复发性CRC患者：1例患者PFS约为12个月，2例约为18个月，1例在7年后仍在研究中。此外，一例患者自我报告在给予BXQ-350后其原有的CIPN症状有所改善；这一观察在入组时已确诊CIPN的10例患者中的4例得到证实。方法：BXQ-350正在一项Ib/2a期研究中联合mFOLFOX7和贝伐珠单抗（SoC）用于新诊断mCRC患者进行研究（NCT05322590）。该Ib/2a期是一个安全性剂量递增部分，旨在确定RP2D，探索1.8和2.4 mg/kg BXQ-350联合SoC。主要目的是评估BXQ-350在该联合方案中的安全性和初步疗效。次要目的包括对多种生物标志物的纵向分析，包括鞘脂谱分析。结果：共入组32例可评估患者，全部32例患者已完成SoC治疗方案加BXQ-350。在这32例患者中，21例（66%）存活并处于积极随访中。疾病控制率为91%（30例患者出现SD、PR或CR）。截至2025年9月，ORR为61%，中位PFS为10.6个月。此外，19例（58%）完成了全部12个周期的奥沙利铂给药，28例（85%）至少完成8个周期，仅2例患者因CIPN在第8周期前停止给药。未报告4级CIPN AE，仅报告3例3级CIPN AE，均发生在第12周期后。结论：BXQ-350在该联合方案中安全且耐受性良好。疗效和CIPN结果提示，BXQ-350在联合FOLFOX7+Bev时可能提供临床获益，同时降低CIPN不良事件的发生率和严重程度，从而允许更高累积剂量的奥沙利铂。

查看英文原文 English abstract

Background: Dysregulated sphingolipid metabolism is common to many cancer types, including mCRC, and leads to elevated concentrations of gangliosides (GM3), lactosylceramides (LacCer), glucosylceramides (GluCer) and sphingosine-1-phosphate (S1P) and lower concentration of ceramides (Cer). In mCRC patients, several studies have shown elevated concentrations of these sphingolipids are associated with worse prognosis and poor survival. Therefore, targeting dysregulated sphingolipid metabolism and returning sphingolipid metabolism to homeostasis could be a promising therapeutic approach. Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect associated with many cancer drugs and is highly prevalent in mCRC patients receiving oxaliplatin-based regimens. CIPN can severely impact quality of life (QoL) and may require dose vacation, reduction or interruption. CIPN pathology is complex and not completely understood; preclinical and clinical data have shown inflammatory and immune involvement as well as elevated levels of sphingolipids also involved in cancer progression. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that affects dysregulated sphingolipid metabolism. BXQ-350 lowers GM3, GluCer and S1P levels while it also increases ceramide levels promoting a return to homeostasis. In a single agent Phase 1 study, BXQ-350 was safe and well-tolerated (no DLT, no MTD) and showed signs of activity. Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 7 years. Furthermore, one patient self-reported an improvement of their pre-existing CIPN symptoms after BXQ-350 administration; this observation was confirmed in 4 of 10 patients with established CIPN at the time of enrollment. Method: BXQ-350 is being investigated in a Phase 1b/2a study in combination with mFOLFOX7 and Bevacizumab (SoC) in newly diagnosed mCRC patients (NCT05322590). The Phase 1b/2a is a safety dose escalation part to establish the RP2D exploring 1.8 and 2.4 mg/kg BXQ-350 in combination with SoC. Primary objectives are to assess safety and preliminary efficacy of BXQ-350 in this combination. Secondary objectives include longitudinal analysis of several biomarkers, including sphingolipid profiling. Results: A total of 32 evaluable patients were enrolled, and all 32 patients have completed SoC treatment schedule plus BXQ-350. Amongst these 32 patients, 21(66%) are alive and in active follow-up. The disease control rate was 91% (30 pts had SD, PR or CR). As of September 2025, ORR is 61% and median PFS is 10.6 months. Furthermore, 19 (58%) completed the full 12 Cycles of oxaliplatin dosing, 28 (85%) completed at least 8 Cycles with only 2 patients having dosing halted before Cycle 8 due to CIPN. There were no reported Grade 4 and only 3 reported Grade 3 CIPN AEs, all occurred after Cycle 12. Conclusions: BXQ-350 is safe and well tolerated in the combination. Efficacy and CIPN results suggest that BXQ-350 may provide clinical benefits in combination with FOLFOX7+Bev and reduce, at the same time, incidence and severity of CIPN adverse events allowing for a higher cumulative dose of oxaliplatin

利益披露 Disclosure

R. Patel, None.. D. Flora, None.. A. Baron, None.. D. Sohal, None.. S. Sharif, None.. J. gemmill, None.. F. Lee, None. G. H. Tapolsky, Bexion Pharmaceuticals Employment, Stock, Stock Option, Travel. M. Gazda, Bexion Pharmaceuticals Employment, Stock, Stock Option. J. Beach, Bexion Pharmaceuticals Employment, Stock, Stock Option. T. Arshad, Bexion Pharmaceuticals Employment, Stock, Stock Option, Travel.

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