Department of Medical Oncology, British Columbia Cancer Agency, Vancouver; Department of Urologic Sciences, Vancouver Prostate Center, University of British Columbia, Vancouver, Canada.
University of Washington, Fred Hutchinson Cancer Research Center, Seattle.
Ann Oncol. 2016 Jun;27(6):1116-1122. doi: 10.1093/annonc/mdw068. Epub 2016 Feb 18.
Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer.
Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated.
Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response.
Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway.
NCT00487786.
热休克蛋白 27（Hsp27）是一种伴侣蛋白，通过雄激素受体和其他信号通路调节细胞存活，从而介导癌症进展。Apatorsen（OGX-427）是一种 2'-甲氧基乙基修饰的反义寡核苷酸，可抑制 Hsp27 的表达。本研究评估了晚期癌症患者使用 Apatorsen 的安全性概况和推荐的 II 期剂量。
招募了去势抵抗性前列腺癌（CRPC）、乳腺癌、卵巢癌、肺癌或膀胱癌患者参加这项 I 期剂量递增研究。Apatorsen 每周静脉输注一次，21 天为一个周期，在 5 个剂量水平（200-1000mg）中进行 3 次负荷剂量。评估 Apatorsen 血浆浓度、循环肿瘤细胞（CTC）和 CTC Hsp27 表达以及血清 Hsp27 水平。
共纳入 42 例患者，其中 52%患有 CRPC。患者预处理较多，57%患者有≥3 种既往化疗方案。在负荷剂量/第 1 周期和整个研究期间，分别有 93%（42 例患者中的 40 例）和 100%（42 例患者中的 42 例）的患者出现与治疗相关的不良事件，大多数为 1-2 级，包括寒战、瘙痒、潮红、延长的 APTT、淋巴细胞减少症和贫血。1 例患者在 600mg 剂量水平出现剂量限制性毒性（先前未诊断的脑转移瘤的颅内出血）。未确定最大耐受剂量。Apatorsen 的 Cmax 与剂量呈比例增加。观察到肿瘤标志物的降低和 CTC 的减少，10%的 CRPC 患者的前列腺特异性抗原下降>50%；39 例可评估患者中的 29 例（74%）从基线时的≥5 CTC/7.5ml 降至治疗后的<5 CTC/7.5ml。12 例患者作为最佳反应有稳定的可测量疾病。
在评估的最高剂量（1000mg）下，Apatorsen 可耐受。肿瘤标志物、CTC 和稳定的可测量疾病的变化提示单药活性。正在进行评估 Apatorsen 的 II 期研究。
临床试验.gov 标识符：NCT00487786。
