State Key Laboratory of Translational Oncology, Hong Kong, China.
Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China.
Invest New Drugs. 2021 Oct;39(5):1375-1382. doi: 10.1007/s10637-021-01111-8. Epub 2021 Apr 15.
Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC).
This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC.
In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9-6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3-78.0 weeks) vs. 15.14 weeks (95% CI: 13.4-15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes.
PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers.
NCT01092091. Date of registration: March 23, 2010.
聚乙二醇重组人精氨酸酶（PEG-BCT-100）是一种精氨酸耗竭药物。临床前研究表明，由于精氨酸再生酶精氨酸琥珀酸合成酶（ASS）和鸟氨酸转氨甲酰酶（OTC）表达下调，HCC 依赖外源性精氨酸生长。
这是一项评估 PEG-BCT-100 在未经化疗的索拉非尼耐药 HCC 患者中的潜在临床疗效的单臂开放标签 II 期试验。要求对肿瘤活检进行免疫组织化学（IHC）检测 ASS 和 OTC 的表达。每周静脉注射 2.7mg/kg 的 PEG-BCT-100。主要终点是无进展生存期（TTP）；次要终点包括根据 RECIST1.1 评估的影像学反应、无进展生存期（PFS）和总生存期（OS）。治疗结果与肿瘤免疫组化表达的 ASS 和 OTC 相关。
共招募了 27 名患者。中位 TTP 和 PFS 均为 6 周（95%CI，5.9-6.0 周）。疾病控制率（DCR）为 21.7%（5 例稳定疾病）。药物耐受性良好。事后分析表明，精氨酸耗竭持续时间与 OS 相关。对于有可用 IHC 结果的患者，10 例 ASS 阴性肿瘤患者的 OS 为 35 周（95%CI：8.3-78.0 周），而 3 例 ASS 阳性肿瘤患者的 OS 为 15.14 周（95%CI：13.4-15.1 周）；OTC 的表达与治疗结果无关。
PEG-BCT-100 在未经化疗的索拉非尼耐药 HCC 患者中耐受性良好，DCR 中度。ASS 阴性 HCC 的 OS 优势优于 ASS 阳性 HCC。ASS 阴性是 HCC 患者 OS 的潜在生物标志物，可能也是其他 ASS 阴性精氨酸营养缺陷型癌症的潜在生物标志物。
NCT01092091。注册日期：2010 年 3 月 23 日。
