Clinical Studies of Multidrug Resistance Reversal

多药耐药性逆转的临床研究

• 批准号: 7064471
• 负责人: susan bates
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7064471
• 关键词: P glycoprotein; clinical trial phase I; human subject; human therapy evaluation; multidrug resistance; neoplasm /cancer chemotherapy; paclitaxel; patient oriented research; transport inhibitor

The focus of our section's research program is to develop therapeutic strategies aimed at overcoming drug resistance in cancer. Our research has been dedicated to the translation of drug resistance reversal strategies to the clinic. The design of our clinical trials has been enhanced by laboratory support that has allowed us to analyze clinical samples and interpret the clinical trial findings. A significant clinical trial effort has related to the inhibition of P-glycoprotein, an ABC transporter mediating resistance through outward transport of anticancer agents. These studies have been carried out collaboratively with Dr. Tito Fojo and evaluate the hypothesis that Pgp modulation may increase anticancer drug efficacy. In trials carried out across the globe, beginning with the failed first-generation trials that employed agents without sufficient potency, and continuing with the failed second-generation trials centered on valspodar with its accompanying need for anticancer agent dose reduction, there has been much disappointment in this field. Even a multinational randomized trial combining the new agent tariquidar with paclitaxel or vinorelbine closed early for toxicity. It must be stated that there is no convincing proof to date that this strategy will eventually be shown to provide clinical benefit and the resistance reversal paradigm remains a hypothesis. However, the failed earlier strategies do not negate strong evidence supporting continued development of Pgp antagonists.Current studies are evaluating the third generation inhibitor tariquidar (XR9576). In our completed Phase I interaction study with vinorelbine and tariquidar, total inhibition of Pgp-mediated drug efflux was observed in CD56+ cells, with persistence of inhibition for 48 hours after a single intravenous dose of tariquidar. 99mTc-sestamibi imaging was employed as a surrogate for altered drug accumulation in normal and tumor tissues. More than half of the patients had detectable increases in tumor uptake of 99mTc-sestamibi. Our goal in launching a new tariquidar trial was to gather more data regarding the safety of tariquidar in combination with a chemotherapeutic agent and to identify a combination that could be used as a single agent. Docetaxel was chosen as an excellent Pgp substrate with known efficacy that could be benefited by increasing drug accumulation in lung, cervical, or ovarian cancer. In planning an interaction trial of docetaxel with tariquidar, we selected an effective but conservative dose of docetaxel - 75 mg/m2 on a q-3-week schedule. The trial is designed with both pharmacokinetic and pharmacodynamic assays. To examine whether tariquidar interferes with docetaxel clearance, careful pharmacokinetics will be performed on a dose of docetaxel administered with and without tariquidar. To limit the length of time that a patient is treated without the modulator, the pharmacokinetic portion of the study is carried out on two 40 mg/m2 docetaxel doses, one week apart. The order of administration of tariquidar is randomized between the day 1 and day 8 doses. Patients begin therapy with 75 mg/m2 q-3-weeks in combination with tariquidar in the second cycle. In addition to pharmacokinetic analysis, 99mTc-sestamibi studies are performed in each enrolled patient with and without tariquidar, and our laboratory carries out CD56+ rhodamine assays in peripheral mononuclear cells. The trial is open and accruing patients without major toxicity, with 16 patients enrolled to date.Although the 99mTc-sestamibi studies provide good proof-of-concept showing increased radionuclide accumulation following tariquidar, the studies are poorly quantitative because they are planar images and background often overwhelms differences. Led by Peter Herscovitch, the Clinical Center PET department developed a method to label sestamibi with 94mTc for positron emission imaging, promising a more quantitative imaging agent. A clinical trial testing this agent has received IRB approval, with FDA approval pending. We anticipate enrolling patients from Tito Fojo's adrenocortical and renal cell cancer trials, as well as the tariquidar trial described above. It is our hope that the quantitative PET imaging will allow us to better answer the question of how much impact tariquidar can have on patient tumors. It can be argued that tariquidar is the most promising Pgp inhibitor to enter clinical development. Volunteer studies showed its lack of intrinsic toxicity, CD56+ assays suggest durability of Pgp inhibition, and minimal or no inhibition of cytochrome P450 has been detected. Pharmacokinetic interaction studies suggested minimal impact on the clearance of the three anticancer agents tested in combination with tariquidar to date: vinorelbine, doxorubicin, or paclitaxel. However, one concern is the possibility that inhibition of Pgp per se may increase toxicity to Pgp-expressing bone marrow stem cells. This could result in toxicity due to a pharmacodynamic effect without a pharmacokinetic interaction. Thus, the future development of Pgp inhibitors depends upon demonstration of safety as well efficacy. In addition to the tariquidar studies, our laboratory has maintained an interest in drug resistance in other model systems. Several years ago, in collaboration with the NCI's Developmental Therapeutics Program, we identified a number of compounds with selectivity against renal cell caner, based on COMPARE analysis using cytotoxicity data in the 60 cell line panel. These compounds were evaluated in our laboratory and the renal selectivity confirmed. One class of these compounds, the dimethane sulfonates, has been continuously in preclinical development at DTP and are nearing the point at which clinical trials can be considered.

我们部门研究计划的重点是制定旨在克服癌症耐药性的治疗策略。我们的研究致力于将耐药逆转策略转化为临床。实验室支持增强了我们临床试验的设计，使我们能够分析临床样本并解释临床试验结果。一项重要的临床试验工作与 P-糖蛋白的抑制有关，P-糖蛋白是一种 ABC 转运蛋白，通过抗癌药物的向外转运介导耐药性。这些研究是与 Tito Fojo 博士合作进行的，并评估了 Pgp 调节可能提高抗癌药物疗效的假设。在全球范围内进行的试验中，从使用效力不足的药物的失败的第一代试验开始，到以伐斯波达为中心的失败的第二代试验以及随之而来的抗癌药物剂量减少的需要，都令人非常失望在这个领域。即使是一项将新药塔利奎达与紫杉醇或长春瑞滨联合使用的跨国随机试验也因毒性而提前结束。必须指出的是，迄今为止还没有令人信服的证据表明该策略最终将提供临床益处，并且耐药逆转范式仍然是一个假设。然而，早期失败的策略并不能否定支持Pgp拮抗剂继续开发的有力证据。目前的研究正在评估第三代抑制剂tariquidar (XR9576)。在我们完成的长春瑞滨和tariquidar的I期相互作用研究中，在CD56+细胞中观察到Pgp介导的药物流出的完全抑制，单次静脉注射tariquidar后抑制持续48小时。 99mTc-sestamibi 成像被用作正常和肿瘤组织中药物蓄积改变的替代。超过一半的患者的肿瘤对 99mTc-sestamibi 的摄取可检测到增加。我们启动新的 Tariquidar 试验的目标是收集更多有关 Tariquidar 与化疗药物组合的安全性的数据，并确定可用作单一药物的组合。多西紫杉醇被选为一种优秀的 Pgp 底物，其功效已知，可通过增加肺癌、宫颈癌或卵巢癌中的药物积累而受益。在计划多西他赛与塔利奎达的相互作用试验时，我们选择了有效但保守的多西他赛剂量 - 75 mg/m2，每 3 周一次。该试验设计了药代动力学和药效学测定。为了检查塔利奎达是否干扰多西他赛的清除，将对联合和不联合塔利奎达给药的多西他赛剂量进行仔细的药代动力学研究。为了限制患者不使用调节剂治疗的时间长度，该研究的药代动力学部分采用两次 40 mg/m2 多西紫杉醇剂量进行，间隔一周。 Tariquidar 的给药顺序在第 1 天和第 8 天剂量之间是随机的。患者在第二个周期中开始每三周接受 75 mg/m2 与他利奎达联合治疗。除了药代动力学分析外，还在每位入组患者中进行了 99mTc-sestamibi 研究，无论是否使用他利奎达，我们的实验室还在外周单核细胞中进行 CD56+ 罗丹明测定。该试验是开放的，招募的患者没有重大毒性，迄今为止已入组 16 名患者。尽管 99mTc-sestamibi 研究提供了良好的概念验证，显示在 Tariquidar 后放射性核素积累增加，但这些研究的定量性很差，因为它们是平面图像和背景往往会压倒差异。在 Peter Herscovitch 的领导下，临床中心 PET 部门开发了一种用 94mTc 标记 sestamibi 的方法，用于正电子发射成像，有望成为一种更加定量的成像剂。测试该药物的临床试验已获得 IRB 批准，FDA 正在等待批准。我们预计将招募来自 Tito Fojo 的肾上腺皮质和肾细胞癌试验以及上述 tariquidar 试验的患者。我们希望定量 PET 成像能够让我们更好地回答塔利奎达对患者肿瘤有多大影响的问题。可以说，tariquidar 是最有希望进入临床开发的 Pgp 抑制剂。志愿者研究表明其缺乏内在毒性，CD56+ 检测表明 Pgp 抑制具有持久性，并且已检测到细胞色素 P450 的抑制作用极小或没有抑制。药代动力学相互作用研究表明，迄今为止与塔利奎达联合测试的三种抗癌药物（长春瑞滨、阿霉素或紫杉醇）对清除率的影响极小。然而，一个问题是抑制 Pgp 本身可能会增加对表达 Pgp 的骨髓干细胞的毒性。这可能会由于药效学效应而不存在药代动力学相互作用而导致毒性。因此，Pgp 抑制剂的未来发展取决于安全性和有效性的证明。除了 tariquidar 研究之外，我们的实验室还对其他模型系统的耐药性保持着兴趣。几年前，我们与 NCI 的发展治疗计划合作，基于使用 60 个细胞系组中的细胞毒性数据进行的比较分析，确定了许多对肾细胞癌具有选择性的化合物。这些化合物在我们的实验室进行了评估，并证实了肾脏选择性。其中一类化合物，即二甲磺酸盐，已在 DTP 中持续进行临床前开发，并且已接近可以考虑进行临床试验的阶段。