Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
J Clin Oncol. 2012 Nov 20;30(33):4161-7. doi: 10.1200/JCO.2012.42.5223. Epub 2012 Sep 10.
The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma.
Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks.
Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%.
SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.
Janus 激酶 2/信号转导和转录激活因子（JAK2/STAT）通路在血液恶性肿瘤的发病机制中发挥重要作用。我们对一种强效 JAK2 抑制剂 SB1518 在复发淋巴瘤患者中的剂量发现和药代动力学/药效学进行了 I 期研究。
患有复发或难治性霍奇金或非霍奇金淋巴瘤（除伯基特或中枢神经系统淋巴瘤外）的患者入组。患者队列接受 SB1518 每日口服一次，剂量递增，28 天为一周期。在 8 周后评估反应。
34 例患者接受了 100 至 600mg/d 的剂量。未达到最大耐受剂量。治疗耐受性良好，主要为 1 级和 2 级毒性。胃肠道毒性是最常见的与治疗相关的事件。血细胞减少症不常见且程度较轻。在所有剂量下均达到具有药理活性的浓度。第 1 天观察到剂量相关的浓度-时间曲线下面积线性增加，第 15 天无明显蓄积。平均终末半衰期为 1 至 4 天，达峰时间范围为 5 至 9 小时。SB1518 在给药后 4 小时抑制 JAK2 信号，在所有剂量下均可见。大多数患者中，FLT-3 配体（反映 FLT-3 抑制）增加。有 3 例部分缓解（≥300mg/d）和 15 例疾病稳定（SD）患者，大多数缓解持续时间超过 2 个月。7 例 SD 中有 4%至 46%的肿瘤缩小。
SB1518 在复发淋巴瘤中具有令人鼓舞的疗效，为在临床环境中靶向 JAK/STAT 通路治疗淋巴瘤的潜在治疗价值提供了首个原理验证。
