A phase I-II study of oblimersen sodium (G3139, Genasense) in combination with doxorubicin in advanced hepatocellular carcinoma (NCI # 5798)
A phase I-II study of oblimersen sodium (G3139, Genasense) in combination with doxorubicin in advanced hepatocellular carcinoma (NCI # 5798)
复制标题
DOI：
10.1007/s10637-007-9104-1
复制
发表时间：
2008-04-01
影响因子：
3.4
通讯作者：
Moore, M.
中科院分区：
文献类型：
--
作者：
Knox, J. J.;Chen, X. E.;Moore, M.
背景：晚期肝细胞癌（HCC）对大多数标准化疗形式是难治性的，然而对阿霉素的反应是可见的[1-3]。有大量科学证据表明，bcl-2相关的细胞凋亡在肝细胞癌发生、肿瘤进展和化疗耐药性中很重要（综述见[4-6]）。HCC患者肿瘤样本显示bcl-2及其促凋亡相关bax以p-53依赖性方式显著失调（n= 14/15）[7]。HCC细胞系过表达bcl-2，化疗敏感系通过bcl-2途径发生凋亡，并且可以通过用反义寡核苷酸降低bcl-2表达来克服对化疗的抗性[8-10]。bcl-2反义寡核苷酸G3139已显示通过阻断bcl-2合成来增强肿瘤模型中多柔比星的活性[11，12]。这为评价G3139+多柔比星联合治疗HCC提供了依据。通过降低肿瘤bcl-2蛋白水平，HCC可能对阿霉素的凋亡作用敏感，导致更显著或持久的反应。其中G3139在第1 -8天从5 mg/kg递增至7 mg/kg，持续7天连续静脉（iv）输注（CVI），多柔比星从45 mg/kg递增至60 mg/kg。m2静脉推注d5，每28天一次（3个队列）。在II期分析中纳入了以推荐的II期剂量（RP 2D）队列治疗的HCC患者。如果客观缓解率（根据实体瘤缓解评价标准）至少为30%，则设计两阶段II期部分以声明治疗活性，如果<10%，则声明无活性。II期部分的合格患者具有病理学证实的、可测量的、晚期HCC、Childs-Pugh A肝硬化或更好、足够的血液学参数和ECOG PS< 2。肿瘤活检免疫组化相关研究获得在基线和周期1天4同意patients. ResultsTwenty七例患者参加了这项研究，其中19人进行了评估，第二阶段的部分。剂量限制性毒性是在I期组群3中观察到的> 5天的4级中性粒细胞减少症（7 mg/kg的G3139和60 mg/m2的多柔比星）。RP 2D为G3139，7 mg/kg，持续7天CVI（d1-8）+多柔比星，45 mg/m2，静脉推注，d5，每28天一次。在19例患者中，1例不合格，18例可评价毒性，17例可评价反应，接受中位2个周期（范围1，10）。患者特征总结见表1。最常见的毒性是血液学毒性，可归因于G3139加阿霉素和G3139单独。观察到的总体3-4级毒性为：中性粒细胞减少症，67%（中位最低值第24-25天）;淋巴细胞减少症，44%;血小板减少症，6%;转氨酶升高，33%; 1-2级G3139-发热，67%。未观察到反应，试验在第1阶段结束时停止。6例患者（35%）病情稳定，1例患者（患者22）按照方案完成了10个周期。中位至进展时间为1.8个月（95%置信度，1.7-NA），6个月无进展生存期为17.2%（95%置信度，5.3-56.4个月）。19例患者中有18例死亡，中位生存期为5.4个月（2.7-11.6）。对三名患者配对肿瘤活检的相关研究显示，基线时bcl-2表达缺失，但bcl-xl和BAX蛋白中度表达，暴露于G3139后无变化（包括患者#22）。在我们的样本中，bcl-2表达的缺失是在免疫阳性p53的存在下，这与其他报道不同[7]。
BackgroundAdvanced hepatocellular (HCC) is refractory to most standard forms of chemotherapy, however responses to doxorubicin are seen [1–3]. There is a body of scientific evidence suggesting that bcl-2-associated apoptosis is important in hepatocellular carcinogenesis, tumour progression and resistance to chemotherapy (reviewed in [4–6]). HCC patient tumour samples have shown marked dysregulation of bcl-2 and its pro-apoptotic relative bax in a p-53 dependent manner (n= 14/15)[7]. HCC cell lines overexpress bcl-2, chemosensitive lines undergo apoptosis through bcl-2 pathways and resistance to chemotherapy can be overcome by decreasing bcl-2 expression with antisense oligonucleotides [8–10]. The bcl-2 antisense oligonucleotide, G3139, has been shown to enhance the activity of doxorubicin in tumor models by blocking bcl-2 synthesis [11, 12]. This argues for evaluating G3139+ doxorubicin in combination in HCC. By decreasing tumor bcl-2 protein levels, HCC may be sensitized to the apoptotic effects of doxorubicin resulting in more pronounced or durable responses.Materials and methodsAn initial dose-escalation part of the study enrolled patients with advanced solid tumors including HCC, where G3139 was escalated from 5 to 7 mg/kg for 7 days continuous intravenous (iv) infusion (CVI) on d1–8 and doxorubicin was escalated from 45 to 60 mg/m2 iv bolus d5, every 28 days (in three cohorts). HCC patients treated at the recommended phase II dose (RP2D) cohort were included in the phase II analysis. The two-stage phase II portion was designed to declare treatment activity if the objective response rate (by Response Evaluation Criteria in Solid Tumors) was at least 30% and inactive if< 10%. Eligible patients for the phase II portion had pathologically-confirmed, measurable, advanced HCC, Childs-Pugh A cirrhosis or better, adequate hematological parameters and ECOG PS< 2. Tumor biopsies for immunohistochemistry correlative studies were obtained at baseline and cycle 1 day 4 in consenting patients.ResultsTwenty-seven patients were enrolled in this study, 19 of whom were evaluated to the phase II portion. Dose-limiting toxicity was grade 4 neutropenia> 5 days seen in phase I cohort 3 (G3139 at 7 mg/kg and doxorubicin at 60 mg/m 2). RP2D was G3139 at 7 mg/kg for 7 days CVI (d1–8) plus doxorubicin at 45 mg/m 2 iv bolus d5, every 28 days. Of the 19 patients, 1 was ineligible, 18 evaluable for toxicity, 17 evaluable for response, receiving a median of two cycles (range 1, 10). Patient characteristics are summarized in Table 1. Most common toxicities were hematological and could be attributed to both G3139 plus doxorubicin and to G3139 alone. Overall grade 3–4 toxicities seen were: neutropenia, 67%(median nadir day 24–25); lymphopenia, 44%; thrombocytopenia, 6%; transaminitis, 33%; and grade 1–2 G3139-fever, 67%. No responses were seen and the trial was stopped at end of stage 1. Six patients (35%) had stable disease, with one patient (pt) completing ten cycles as per protocol (pt# 22). Median time-to-progression was 1.8 months (95% confidence, 1.7-NA) and 6-month progression-free-survival is 17.2%(95% confidence, 5.3–56.4 months). Eighteen of 19 pts have died with median survival of 5.4 months (2.7–11.6). Correlative studies on three available patients’ paired tumor biopsies showed absent baseline bcl-2 expression but moderate expression of both bcl-xl and BAX protein and with no change after exposure to G3139 (includes pt# 22). In our samples the absence of bcl-2 expression was in the presence of immunopositive p53 which differs from other reports [7].