Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma.
Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma.
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DOI：
10.1158/1078-0432.ccr-13-0071
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发表时间：
2013-08-01
期刊：
影响因子：
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通讯作者：
Balis FM
中科院分区：
文献类型：
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作者：
Fox E;Widemann BC;Chuk MK;Marcus L;Aikin A;Whitcomb PO;Merino MJ;Lodish M;Dombi E;Steinberg SM;Wells SA;Balis FM
甲状腺髓样癌（MTC）是由RET原癌基因的种系激活突变引起的多发性内分泌肿瘤2型（MEN2）综合征的表现。Vandetanib是一种VEGF和EGF受体抑制剂，可阻断RET酪氨酸激酶活性，并在遗传性MTC成人中具有活性。我们对患有MTC的儿童（5-12岁）和青少年（13-18岁）进行了vandetanib的I/II期试验，以确定推荐剂量并评估抗肿瘤活性。起始剂量为100mg /m2口服，每日1次，连续治疗28天。2个周期后剂量可增至150mg /m2/d。使用RECIST（v1.0）对vandetanib的放射学反应进行量化，通过比较治疗后血清降钙素和癌胚抗原（CEA）水平与基线水平来测量生物标志物反应，并使用患者报告的结果来评估临床获益。16例局部晚期或转移性MTC患者接受vandetanib治疗，中位（范围）27（2-52）个周期。11名患者仍在接受方案治疗。腹泻是主要的剂量限制性毒性。在M918T RET种系突变的受试者（n=15）中，确认的客观部分缓解率为47%（精确95%CI， 21%, 75%）。12名受试者的降钙素和8名受试者的CEA被证实有部分生物标志物反应。采用创新的试验设计并根据靶基因表达选择患者，我们得出结论：vandetanib 100mg /m2/d是一种耐受性良好且高度有效的治疗MEN2B和局部晚期或转移性MTC的儿童和青少年的新疗法。
Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC. We conducted a phase I/II trial of vandetanib for children (5–12 years) and adolescents (13–18 years) with MTC to define a recommended dose and assess anti-tumor activity. The starting dose was 100 mg/m2 administered orally, once daily, continuously for 28 day treatment cycles. The dose could be escalated to 150 mg/m2/d after 2 cycles. Radiographic response to vandetanib was quantified using RECIST(v1.0), biomarker response was measured by comparing post-treatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient reported outcome was used to assess clinical benefit. Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2–52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n=15) the confirmed objective partial response rate was 47% (exact 95%CI, 21%, 75%). Biomarker partial response was confirmed for calcitonin in twelve subjects and for CEA in eight subjects. Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.