A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors
A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors
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DOI：
10.1158/1078-0432.ccr-06-1165
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发表时间：
2007-02-15
影响因子：
11.5
通讯作者：
Johnson, Candance S.
中科院分区：
文献类型：
--
作者：
Fakih, Marwan G.;Trump, Donald L.;Johnson, Candance S.
目的：在临床前模型中，骨化三醇和酪氨酸激酶抑制剂吉非替尼是协同作用并调节细胞外信号调节激酶(ERK)和Akt通路。因此，我们进行了骨化三醇和吉非替尼的I期研究，以确定该组合的最大耐受量(MTD)。实验设计：静脉注射骨化三醇。在第1周、第3周和此后每周超过1小时。从第2周(第8天)开始，每日口服固定剂量的吉非替尼250毫克。在MTD被定义之前，三名患者的队列中发生了升级。骨化三醇和吉非替尼的药代动力学研究。通过系列皮肤活检研究表皮生长因子受体(EGFR)途径的药效相互作用。结果：32例患者得到治疗。在接受96微克/周骨化三醇治疗的四名患者中，有两名患者出现了剂量限制性高钙血症。在MTD为74微克/周的骨化三醇剂量水平上，7名患者中有1名出现了剂量限制性高钙血症。骨化三醇剂量与血骨化三醇峰值(C(Max))和全身暴露(AUC)呈线性关系。MTD时平均(+/-SD)血清骨化三醇C(Max)为6.68+/-1.42 ng/mL。吉非替尼治疗可抑制皮肤中EGFR、Akt和Erk的磷酸化。骨化三醇对皮肤EGFR或其下游成分的影响并不一致。联合应用吉非替尼和骨化三醇并不能调节连续肿瘤活检患者的肿瘤EGFR通路。骨化三醇可以安全地与吉非替尼联合使用。在临床前模型中，骨化三醇在MTD为74微克时达到的骨化三醇浓度超过了与抗肿瘤活性相关的体内浓度。
Purpose: In preclinical models, calcitriol and the tyrosine kinase inhibitor gefitinib are synergistic and modulate extracellular signal-regulated kinase (Erk) and Akt pathways. Therefore, we conducted a phase I study of calcitriol and gefitinib to determine the maximum tolerated dose (MTD) of this combination.Experimental Design: Calcitriol was given i.v. over 1 h on weeks 1, 3, and weekly thereafter. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for calcitriol and gefitinib. Serial skin biopsies were done to investigate epidermal growth factor receptor (EGFR) pathway pharmacodynamic interactions.Results: Thirty-two patients were treated. Dose-limiting hypercalcemia was noted in two of four patients receiving 96 mu g/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 mu g/wk calcitriol dose level. The relationship between calcitriol dose and peak serum calcitriol (C(max)) and systemic exposure (AUC) was linear. Mean (+/- SD) serum calcitriol C(max) at the MTD was 6.68 +/- 1.42 ng/mL. Gefitinib treatment inhibited EGFR, Akt, and Erk phosphorylation in the skin. Calcitriol did not have consistent effects on skin EGFR or its downstream elements. The combination of gefitinib and calcitriol did not modulate tumor EGFR pathway in patients with serial tumor biopsies.Conclusions: High doses of weekly i.v. calcitriol can be administered safely in combination with gefitinib. Calcitriol concentrations achieved at the MTD 74 mu g calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.