A Phase I Trial of Bortezomib and Sorafenib in Advanced Malignant Melanoma

• Published in: The oncologist (Dayton, Ohio) Ohio), 2015-06, Vol.20 (6), p.617-618
• Main Authors: Sullivan, Ryan J., Ibrahim, Nageatte, Lawrence, Donald P., Aldridge, Julie, Giobbie‐Hurder, Anita, Hodi, F. Stephen, Flaherty, Keith T., Conley, Christine, Mier, James W., Atkins, Michael B., McDermott, David F.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib - administration & dosage; Bortezomib - adverse effects; Clinical Trial Results; Disease-Free Survival; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions - physiopathology; Female; Humans; Male; Maximum Tolerated Dose; Melanoma - drug therapy; Melanoma - pathology; Middle Aged; Niacinamide - administration & dosage; Niacinamide - adverse effects; Niacinamide - analogs & derivatives; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - adverse effects
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2015-0105

Lessons Learned This study is a rare example of effective doses of both targeted agents being both administered and tolerated. This combination should not be used in melanoma. Background. Sorafenib and bortezomib affect BCL family member expression. We previously demonstrated that bortezomib augmented sorafenib‐mediated cytotoxicity in melanoma cell lines in vitro. We aimed to combine sorafenib 400 mg b.i.d. with increasing doses of weekly bortezomib. Methods. Patients with metastatic melanoma were enrolled in dose‐escalation cohorts to determine the maximum tolerated dose (MTD) of sorafenib (twice daily) in combination with bortezomib (weekly for 3 of 4 weeks). The MTD was defined as the highest dose level at which less than 33% of patients exhibited a dose‐limiting toxicity (DLT). Efficacy, as measured by 6‐month progression‐free survival and response rate per RECIST, was documented. Results. Eleven patients were enrolled at three dose levels. DLTs (fatigue and rash) were seen in two of three patients at the highest dose level. Five patients were enrolled for sorafenib 400 mg b.i.d. and bortezomib 1.0 mg/m2 weekly for 3 of every 4 weeks; none had DLTs, and this dose level was defined as the MTD. Of 10 evaluable patients, no responses were seen. Two of 11 patients (18%) remained progression free for longer than 6 months. Conclusion. The combination of sorafenib and bortezomib is safe but not active in patients with melanoma. 摘要 背景. 索拉非尼和硼替佐米影响BCL家族成员表达。我们既往的研究显示硼替佐米在体外黑色素瘤细胞系中能增强索拉非尼介导的细胞毒性反应。本研究旨在分析硼替佐米增量（每周1次）联合索拉非尼400 mg（每日2次）的有效性。 方法. 入组转移性黑色素瘤患者作为增量研究队列，以明确索拉非尼（每日2次）联合硼替佐米（每周1次，治疗3周，每4周为1周期）的最大耐受剂量（MTD）。MTD定义为少于33%的患者表现出剂量限制性毒性反应（DLT）的最高剂量水平。按RECIST测量6个月时无进展生存率和缓解率，评估并记录有效性。 结果. 3个剂量水平组共纳入11例患者。最高剂量水平组的3例患者中有2例出现DLT（乏力和皮疹）。5例患者入组索拉非尼400 mg（每日2次）联合硼替佐米1.0 mg/m2（每周1次，治疗3周，每4周为1周期）队列，均未出现DLT，因此该剂量水平定义为MTD。10例可评价患者中未观察到缓解。11例患者中有2例（18%）无进展生存期超过6个月。 结论. 索拉非尼与硼替佐米联合方案在黑色素瘤患者中安全性良好，但未见积极疗效。The Oncologist 2015;20:617–618