A Phase I/II Clinical Trial of Intravenous (I.V.) Calcitriol with Fixed Doses of

固定剂量静脉注射 (I.V.) 骨化三醇的 I/II 期临床试验

• 批准号: 7700525
• 负责人: NITHYA RAMNATH
• 金额: $ 19.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7700525
• 关键词: 25-hydroxycholecalciferol-24-hydroxylase; Affect; Animals; Atlases; Biological; Blood; Breast; CDKN1A gene; Calcitriol; Calcitriol/Dexamethasone; Cancer Patient; Canis familiaris; Caring; Catabolism; Chemotherapy-Oncologic Procedure; Cisplatin; Cisplatin/Docetaxel; Clinical; Clinical Research; Clinical Trials; Code; Colon; Combined Modality Therapy; Cytotoxic agent; DNA Damage; Data; Dexamethasone; Disease; Disease regression; Dose; Dose-Limiting; Drug Combinations; Drug Kinetics; Enrollment; Enzymes; Exhibits; Exons; Genes; Genetic Polymorphism; Genomics; Genus Cola; Goals; Human; Hypercalcemia; In Vitro; Intravenous; Introns; Laboratories; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mus; Non-Small-Cell Lung Carcinoma; Nucleotides; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Platinum; Rate; Reporting; Research; Role; Safety; Sampling; Signal Pathway; Single Nucleotide Polymorphism; Solid Neoplasm; Squamous cell carcinoma; Standards of Weights and Measures; Subgroup; TP53 gene; Taxane Compound; Techniques; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; Vitamin D; analog; antitumor agent; base; bevacizumab; cancer diagnosis; cell growth; cell killing; chemotherapy; cohort; cytotoxic; cytotoxicity; day; docetaxel; improved; in vivo; in vivo Model; mortality; neoplastic cell; oncoprotein p21; pre-clinical; repaired; research study; response; taxane; tumor

DESCRIPTION (provided by applicant): According to the Cancer Atlas, lung cancer remains the major cancer among the 10.9 million new cases of cancer diagnosed annually worldwide. The mortality from lung cancer is greater than the combined mortality for breast, colon and prostate cancer combined. Most patients with metastatic non-small-cell lung cancer (NSCLC) are treated with platinum-based chemotherapy regimens. The drug combination of cisplatin and docetaxel is one of the commonly used regimens in metastatic NSCLC. Although both drugs are powerful disruptors of cell growth, positive therapeutic response rates to this therapy remain low for NSCLC patients, from 25% to 30%. While adding new biologics such as bevacizumab to the current treatment standard can improve treatment response, median survival for advanced NSCLC patients receiving this type of treatment remains low at under 12 months. Research studies have demonstrated that Vitamin D, and it's signaling pathways are important biological targets in cancer therapeutics. In vitro and in vivo calcitriol (1, 25 dihydroxycholcalciferol) is antiproliferative and potentiates the antitumor effects of cytotoxic agents (e.g. taxanes, platinum analogues). We have shown that administration of high doses of calcitriol and cisplatin is feasible and associated with complete tumor regressions in dogs with spontaneous cancers. Calcitriol has also shown to be synergistic with docetaxel both in preclinical as well as in a recent phase II clinical trial in prostate cancer. Based on these results and other supporting data from studies indicating that calcitriol functions as a potent and well tolerated anti-tumor agent when used in combination with drugs likes cisplatin and docetaxel, we hypothesize that introducing calcitriol into treatment regimes for NSCLC patients has the potential to demonstrably improve treatment response for these patients. The overall goals for conducting this phase I/II clinical study will be (1) to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of calcitriol in combination with cisplatin/docetaxel in patients with advanced NSCLC, (2) to assess the response rates of patients with advanced NSCLC to the combination of calcitriol with cisplatin/docetaxel, (3) to evaluate the pharmacokinetics (PK) of administering calcitriol intravenously at the MTD, and (4) to evaluate correlations between calcitriol PK and changes on specific coding regions of the gene associated with calcitriol breakdown.

描述（由申请人提供）：根据癌症地图集，肺癌仍然是全球每年诊断的1090万新癌症病例中的主要癌症。肺癌的死亡率高于乳腺癌、结肠癌和前列腺癌的死亡率之和。大多数转移性非小细胞肺癌（NSCLC）患者接受含铂化疗方案治疗。顺铂和多西他赛联合用药是治疗转移性NSCLC的常用方案之一。虽然这两种药物都是细胞生长的强力干扰剂，但NSCLC患者对这种疗法的积极治疗反应率仍然很低，从25%到30%。虽然在目前的治疗标准中加入新的生物制剂（如贝伐珠单抗）可以改善治疗反应，但接受此类治疗的晚期NSCLC患者的中位生存期仍然较低，低于12个月。研究表明，维生素D及其信号通路是癌症治疗中重要的生物学靶点。在体外和体内，骨化三醇（1，25二羟基胆钙化醇）具有抗增殖作用，并增强细胞毒性药物（例如紫杉烷类、铂类似物）的抗肿瘤作用。我们已经证明，给予高剂量的骨化三醇和顺铂是可行的，并与自发性癌症犬的肿瘤完全消退相关。骨化三醇在前列腺癌的临床前以及最近的II期临床试验中也显示出与多西他赛的协同作用。基于这些结果和来自研究的其他支持数据，这些研究表明，当与顺铂和多西他赛等药物联合使用时，骨化三醇作为一种有效且耐受性良好的抗肿瘤药物，我们假设将骨化三醇引入NSCLC患者的治疗方案中有可能明显改善这些患者的治疗反应。进行该I/II期临床研究的总体目标是（1）确定骨化三醇联合顺铂/多西他赛治疗晚期NSCLC患者的最大耐受剂量（MTD）和剂量限制性毒性（DLT），（2）评估晚期NSCLC患者对骨化三醇联合顺铂/多西他赛的缓解率，（3）评价以MTD静脉内施用骨化三醇的药代动力学（PK），和（4）评价骨化三醇PK与骨化三醇分解相关基因的特定编码区的变化之间的相关性。