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  • Title: Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer.
    Author: Del Rivero J, Edgerly M, Ward J, Madan RA, Balasubramaniam S, Fojo T, Gramza AW.
    Journal: Oncologist; 2019 Jan; 24(1):16-e14. PubMed ID: 30297385.
    Abstract:
    LESSONS LEARNED: Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early. BACKGROUND: The proto-oncogene RET (REarranged during Transfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC. METHODS: Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. Intrapatient dose escalation was allowed. RESULTS: Twenty-two patients were enrolled and received escalating mg/m2 bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR). CONCLUSION: The MTD of the combination was established as bortezomib, 1.3 mg/m2 IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC. 经验教训 • 口服凡德他尼,每日剂量为 300 mg,并在第 1、4、8 和 11 天静脉注射硼替佐米 1.3 mg/m2,可安全给药。 • 在评估 17 例甲状腺髓样癌患者的预后时,研究员认为联合用药比凡德他尼单药更难给药,而且未必会取得更好的疗效。因此,计划中的 II 期研究提前终止。 摘要 背景。原癌基因 RET(在转染过程中重排)在甲状腺髓样癌 (MTC) 的发病机理中具有重要作用。凡德他尼 (V) 是一种获批用于治疗 MTC 的多靶点酪氨酸激酶抑制剂,其被认为可抑制 MTC 中的 RET。在证明服用硼替佐米 (B) 可降低 RET mRNA 和蛋白质水平的临床前研究的支持下,我们对采用凡德他尼联合硼替佐米治疗晚期实体肿瘤进行了 I 期研究。目的是建立凡德他尼联合硼替佐米的 RP2D (推荐 II 期剂量)方案,该方案预期为 MTC 中靶向 RET 的双重策略。 方法。晚期实体肿瘤患者接受逐步加大的硼替佐米或凡德他尼剂量治疗,以评估每日口服凡德他尼和在 28 天周期内第 1、4、8 和 11 天静脉注射 (IV) 硼替佐米的安全性和耐受性。允许住院期间增加剂量。 结果。有 22 名患者参与试验,逐渐加大的以 mg/m2 为单位的硼替佐米和以 mg 为单位的凡德他尼给药剂量(患者数量),初始剂量数据分别为 1 和 100 (3)、1.3 和 100 (6)、1.3 和 200 (6),以及 1.3 和 300 (7)。患者接受平均四个周期的硼替佐米/凡德他尼(范围是:1‐10)治疗,其中 13 名患者的剂量逐渐加大至 1.3/200,10 名患者逐渐加大至 1.3/300。超过一名患者出现的 G3 毒性,包括高血压 (24%)、疲劳 (19%)、血小板减少 (10%)、腹泻 (10%) 和关节痛 (10%)。未出现与药物相关的 G4/5 毒性。在第 2 个周期内,当硼替佐米/凡德他尼的剂量为 1.3/200 时,出现 G3 血小板减少,此为一种剂量限制性毒性,无需干预即可消除。有 4 例确诊为 MTC (27%) 的患者出现部分缓解 (PR)。 结论。联合用药的 MTD(最大耐受剂量)设定为第 1、4、8 和 11 天硼替佐米 1.3 mg/m2 IV,同时每天口服凡德他尼300 mg。确诊为 MTC 的一例患者观察到 RECIST(实体瘤疗效评价标准)缓解。
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