Mukai Hirofumi, Kogawa Takahiro, Matsubara Nobuaki, Naito Yoichi, Sasaki Masaoki, Hosono Ako
Division of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa City, Chiba Prefecture, 277-8577, Japan.
Invest New Drugs. 2017 Jun;35(3):307-314. doi: 10.1007/s10637-016-0422-z. Epub 2017 Jan 4.
Background K-912 also known as NC-6300 is a novel epirubicin pro-drug conjugate developed using micellar nanoparticle technology. We conducted a first-in-human, Phase 1, open-label, non-randomized dose escalation study to evaluate the safety, tolerability, efficacy, and pharmacokinetics of K-912 administered as monotherapy in patients with advanced or recurrent solid tumors. Methods Patients aged 41 to 72 years with histologically or cytologically confirmed advanced or recurrent malignant solid tumors either refractory to standard therapy or had no other viable treatment options were enrolled. K-912 was administered as a 10-min intravenous infusion every three weeks. Doses were increased in a step-wise manner based on a predetermined series: 15, 30, 60, 80, 100, 130, 170, and 225 mg/m. The appropriateness of doses above 60 mg/m was assessed using a Bayesian continual reassessment model. Treatment-emergent adverse events and tumor response were evaluated according to internationally accepted criteria. Results Nineteen patients were treated with K-912. No additional adverse events expected with anthracyclines were observed. While the number of patients treated at the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) were small, MTD and RP2D were established to be 170 mg/m. Partial response was observed in one patient with breast cancer treated at 100 mg/m, yielding an objective response rate of 5% (1/19). Stable disease was observed in 10 patients. The human pharmacokinetic profile of K-912 was consistent with that observed from nonclinical studies in rats and monkeys. Conclusions This study showed that K-912 was well tolerated in patients with various solid tumors and exhibited less toxicity than conventional epirubicin formulations.
K-912也被称为NC-6300，是一种使用胶束纳米颗粒技术开发的新型表柔比星前药缀合物。我们开展了一项首次人体、1期、开放标签、非随机剂量递增研究，以评估K-912作为单一疗法用于晚期或复发性实体瘤患者时的安全性、耐受性、疗效和药代动力学。方法：纳入年龄在41至72岁之间、经组织学或细胞学确诊为晚期或复发性恶性实体瘤且对标准治疗难治或无其他可行治疗选择的患者。K-912每三周进行一次10分钟的静脉输注给药。剂量根据预定序列逐步增加：15、30、60、80、100、130、170和225mg/m²。使用贝叶斯连续重新评估模型评估60mg/m²以上剂量的适宜性。根据国际公认标准评估治疗中出现的不良事件和肿瘤反应。结果：19例患者接受了K-912治疗。未观察到预期的蒽环类药物额外不良事件。虽然接受最大耐受剂量（MTD）和推荐的2期剂量（RP2D）治疗的患者数量较少，但确定MTD和RP2D为170mg/m²。在一名接受100mg/m²治疗的乳腺癌患者中观察到部分缓解，客观缓解率为5%（1/19）。10例患者病情稳定。K-912的人体药代动力学特征与在大鼠和猴子的非临床研究中观察到的一致。结论：本研究表明，K-912在各种实体瘤患者中耐受性良好，且毒性低于传统表柔比星制剂。
