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

描述(申请人提供)：根据癌症地图集，肺癌仍然是全球每年1090万新确诊癌症病例中的主要癌症。肺癌的死亡率比乳腺癌、结肠癌和前列腺癌的死亡率总和还要高。大多数转移性非小细胞肺癌(NSCLC)患者采用以铂为基础的化疗方案。顺铂联合多西紫杉醇是治疗转移性非小细胞肺癌的常用方案之一。虽然这两种药物都是细胞生长的强大破坏者，但对非小细胞肺癌患者来说，这种疗法的阳性治疗应答率仍然很低，从25%到30%。虽然在目前的治疗标准中加入贝伐单抗等新的生物制剂可以改善治疗反应，但接受这种治疗的晚期非小细胞肺癌患者的中位存活率仍然很低，不到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)具有抗增殖和增强细胞毒剂(如紫杉烷、铂类似物)的抗肿瘤作用。我们已经证明，大剂量的骨化三醇和顺铂的给药是可行的，并且与自发性癌症犬的肿瘤完全消退有关。骨化三醇在前列腺癌的临床前和最近的II期临床试验中也显示出与多西紫杉醇的协同作用。根据这些结果和其他研究的支持数据，当骨化三醇与顺铂和多西紫杉醇等药物联合使用时，骨化三醇作为一种有效和耐受性良好的抗肿瘤药物发挥作用，我们推测，将骨化三醇引入非小细胞肺癌患者的治疗方案中，有可能显著改善这些患者的治疗反应。进行这项I/II期临床研究的总体目标将是(1)确定骨化三醇联合顺铂/多西紫杉醇治疗晚期非小细胞肺癌患者的最大耐受量(MTD)和剂量限制毒性(DLT)，(2)评估晚期非小细胞肺癌患者联合应用骨化三醇和顺铂/多西紫杉醇的反应率，(3)评估在MTD静脉注射骨化三醇的药代动力学(PK)，以及(4)评估骨化三醇PK与与骨化三醇崩溃相关的基因特定编码区变化之间的相关性。

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.