A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer
A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer
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DOI：
10.1038/bjc.1998.434
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发表时间：
1998-07-01
影响因子：
8.8
通讯作者：
Coombes, RC
中科院分区：
文献类型：
--
作者：
Gulliford, T;English, J;Coombes, RC
临床前研究表明，维生素D类似物EB 1089的降钙活性明显低于其母化合物1，25-二羟基维生素D(1，25(OH)(2)D-3)，并具有显著的抗肿瘤活性。这项I期试验旨在评估该药对晚期癌症患者的降钙性作用。36例晚期乳腺癌和结直肠癌患者给予EB-1089，剂量为0.15~17.0µg·m~(-2)·d~(-1)。连续监测血、尿钙、尿肌酐和血清甲状旁腺激素(PTH)。所有接受17.0mgm(-2)d(-1)治疗的患者均出现高钙血症，停止或减少EB 1089治疗可逆转EB 1089所致的高钙血症。在治疗的前5天，尿钙(P=0.0001)和血清校正钙(P=0.027)与EB-1089剂量呈正相关，而血清甲状旁腺激素(P=0.0001)呈负相关。21名患者接受了为期10至234天的同情治疗。未见完全或部分反应。6名接受治疗90天以上的患者病情稳定。EB 1089耐受性良好，被认为是EB 1089引起的不良反应仅限于对钙代谢的剂量依赖性影响。据估计，这项研究中大多数患者可以耐受的剂量约为7微克米(-2)天(-1)。这些数据支持了之前的工作，即EB 1089的钙化作用明显低于1，25-二羟基维生素D-3。
Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)(2)D-3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 mu g m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 mu g m(-2) day(-1) Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 mu g m(-2) day(-1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D-3.