Queen Elizabeth II Health Sciences Centre, 1278 Tower Road, Room 420, Halifax, Nova Scotia, B3H 2V7, Canada.
Queen Elizabeth II Health Sciences Centre, Room 430, Bethune Building, VG Site, 126 South Park Street, Halifax, Nova Scotia, B3H 2V9, Canada.
J Hematol Oncol. 2018 Sep 24;11(1):122. doi: 10.1186/s13045-018-0661-x.
The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting.
In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria).
As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events.
The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued.
ClinicalTrials.gov, NCT02593760 . Registered November 2, 2015.
JAK 抑制剂（JAKi）芦可替尼是治疗骨髓纤维化（MF）的标准治疗方法，但有些患者没有反应。临床前和临床数据表明，在芦可替尼的基础上加用 Hedgehog 通路抑制剂（HPI）可能会提高反应率。维莫德吉是一种用于治疗局部晚期和转移性基底细胞癌的 HPI。MYLIE 研究评估了在 MF 初治患者中联合使用芦可替尼和维莫德吉的安全性和疗效，并描述了在此环境下维莫德吉的药代动力学（PK）特征。
在这项 Ib 期研究中，10 名中高危原发性或继发性 MF 患者接受了开放标签的维莫德吉（150mg/天口服）和芦可替尼（根据基线血小板计数，15 或 20mg 口服，每日两次）治疗，持续 48 周，或直至停药或退出。整个研究期间采集 PK 样本，与其他患者群体进行比较。24 周时的疗效终点包括脾脏反应（影像学检查体积减少≥35%）和中央及研究者评估的骨髓纤维化改善、症状反应（骨髓增生性肿瘤症状评估总症状评分降低≥50%）和贫血反应（国际骨髓增生性肿瘤研究和治疗工作组修订反应标准）。
截至 2017 年 11 月 17 日，8 名患者完成了 48 周的维莫德吉和芦可替尼治疗；2 名患者提前停药。24 周（±1 周）时，3 名患者经中央审查出现脾脏反应，无患者经中央审查出现骨髓纤维化 1 级改善。5 名患者在 24 周时出现症状反应，无患者出现贫血反应。最常见的不良事件是肌肉痉挛（100%的患者）、脱发（70%）、味觉障碍（50%）、血小板减少（50%）和恶心（40%）；这些事件主要为 1/2 级。3 名患者共发生 6 例严重不良事件。
维莫德吉联合芦可替尼可耐受，未出现新的安全性信号，但没有证据表明维莫德吉联合芦可替尼可改善任何评估的疗效终点。不会进一步评估这种联合治疗。
ClinicalTrials.gov，NCT02593760。于 2015 年 11 月 2 日注册。
