Using Clinical Pharmacology Principles to Develop New Anticancer Therapies

利用临床药理学原理开发新的抗癌疗法

• 批准号: 10487279
• 负责人: William Douglas Figg
• 金额: $ 129.06万
• 依托单位: DIVISION OF CLINICAL 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/10487279
• 关键词: ABCB1 gene; Adverse event; Antineoplastic Agents; Astrocytoma; Azacitidine; BAY 54-9085; Behavior; Binding Proteins; Biological; Biological Assay; Biological Availability; Bortezomib; CCR; Camptothecin; Cancer Cell Growth; Carboplatin; Child; Cisplatin; Clinical Pharmacology; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Communities; Complex; Concentration measurement; Conduct Clinical Trials; Coupled; Cyclophosphamide; Data; Depsipeptides; Detection; Development; Disseminated Malignant Neoplasm; Dose; Drug Costs; Drug Delivery Systems; Drug Formulations; Drug Interactions; Drug Kinetics; Enrollment; Equation; Erlotinib; Esters; Etoposide; Evaluation; Excretory function; Extramural Activities; Finasteride; Fluorescence; Formulation; Foundations; Frequencies; Future; Gelatin; Glioma; Goals; Guidelines; Half-Life; High Pressure Liquid Chromatography; Imatinib; Immune checkpoint inhibitor; Immunotoxins; Infusion procedures; Intravenous; Ketoconazole; Kinetics; Laboratories; Liquid substance; Locally Advanced Malignant Neoplasm; MEKs; MS-275; Malignant neoplasm of prostate; Mathematics; Measures; Melphalan; Mesothelioma; Metabolism; Methods; Midazolam; Modeling; Modification; Molecular Target; Monoclonal Antibodies; Mus; Natural Products; Nelfinavir; Nivolumab; Oral; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phase I Clinical Trials; Phase I/II Trial; Phase II Clinical Trials; Phenylacetates; Phenylbutyrates; Phyllanthus; Physiological Processes; Plants; Plicamycin; Population; Pre-Clinical Model; Prodrugs; Program Development; Questionnaires; Radiation therapy; Randomized; Recurrence; Refractory; Regimen; Relapse; Renal Cell Carcinoma; Renal clearance function; Reporting; Reproducibility; Research Personnel; Route; SU 5416; Sampling; Scheme; Solid Neoplasm; Suramin; Syringes; TNP470; TRPC4 ion channel; Tamoxifen; Tariquidar; Taste Perception; Testing; Thalidomide; Therapeutic; Therapeutic Equivalency; Time; Tissues; Topoisomerase-I Inhibitor; Topotecan; Toxic effect; United States National Institutes of Health; Valproic Acid; Xenograft Model; abiraterone; absorption; advanced prostate cancer; analog; analytical method; aurora kinase A; base; bevacizumab; cancer therapy; capsule; chronic graft versus host disease; clinical center; clinical practice; clopidogrel; detector; docetaxel; drug clearance; drug development; drug disposition; drug metabolism; first-in-human; flavopiridol; improved; in silico; inhibitor/antagonist; instrument; interest; intraperitoneal; irinotecan; kinase inhibitor; lapatinib; lenalidomide; liquid formulation; mass spectrometer; mesothelin; method development; mucosal melanoma; nanoparticle; nanoparticle drug; nonhuman primate; novel anticancer drug; novel therapeutics; open label; pembrolizumab; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; phase I trial; phase II trial; pomalidomide; pre-clinical; predictive tools; programs; simulation; standard of care; temozolomide; tumor

Over the years, the CPP has developed analytical methods for a wide range of therapeutics that include the following: depsipeptide, TNP-470, phenylacetate, phenylbutyrate, tamoxifen, UCN-01, CAI, thalidomide, COL-3, suramin, melphalan, erlotinib, perifosine, SU5416, 2ME, MS-275, ketoconazole, lenalidomide, romidepsin, AZD2281, gemicitabine, sorafenib, finasteride, nelfinavir, 17-DMAG, clopidogrel, Hsp90 inhibitor PF-04928473, irinotecan (its active metabolite SN38 and glucuronidated SN38), Trk kinase inhibitor AZD7451, pomalidomide, olaparib, sorafenib, belinostat, cediranib, abiraterone, cabozantinib, carfilzomib, midazolam, lapatinib, temozolomide, perifosine, valproic acid, temozolomide, cyclophosphamide and its 4-hydroxycyclophosphamide metabolite, as well as NLG207 (formerly CRLX-101, nanoparticle-drug conjugate of camptothecin). The CPP has provided PK support for various agents in phase I/II trials: suramin, TNP-470, CAI, UCN-01, docetaxel, flavopiridol, thalidomide, lenalidomide, pomalidomide, intraperitoneal cisplatin/carboplatin, paclitaxel, 17-DMAG, imatinib, sorafenib, nelfinavir, bevacizumab, romidepsin, clopidrogrel, bortezomib, TRC-105, vandetanib, olaparib, topotecan, irinotecan, mithramycin, durvalumab, abiraterone, belinostat with cisplatin and etoposide, temozolomide, seviteronel, selumetinib, and immunotoxin LMB-100. During the current fiscal year, the CPP provided PK support for several phase I/II clinical studies, including a first-in-human phase I study of LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin; phase I trial of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas; phase I study of lenalidomide and radiotherapy in children with gliomas; phase II trial of M6620 (a first-in-class competitive inhibitor of ATR) and topotecan in relapsed SCLC patients; phase II study of pomalidomide in patients with refractory chronic graft-versus-host disease; phase I/II of cabozantinib and docetaxel in patients with mCRPC. Over the years, we have conducted population PK (popPK) modeling of the following compounds: depsipeptide, romidepsin, sorafenib, olaparib, docetaxel in combination with the p-glycoprotein antagonist tariquidar, TRC105, TRC102, belinostat, mithramycin and seviteronel. Recent efforts have focused on characterizing the complex PK of NLG207, a nanoparticle-drug conjugate of the potent topoisomerase I inhibitor camptothecin (CPT), in order to better describe CPT release from nanoparticles using a popPK model. The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h, which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h by 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h. The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials. In collaboration with Drs. Mark Ratain and Daniel Goldstein, we're evaluating in silico-based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors. Based on patient-specific estimates for clearance, optimal alternative dosing strategies can be simulated to lower drug and cost burden yet maintain therapeutic levels, especially as the clearance of the drug decreases over time. We hypothesize that longer dosing intervals than those currently approved (without commensurate dose increases) will maintain efficacy. To this end, we are collaborating on a multi-institutional, randomized, non-inferiority trial to investigate the PK of standard interval dosing compared to extended interval dosing of nivolumab or pembrolizumab in locally advanced or metastatic cancers. The primary objective is to assess the noninferiority of extended interval dosing relative to standard dosing, as assessed by drug trough levels above the target concentration of 1.5 ug/ml for both nivolumab and pembrolizumab. We are also interested in alternative methods of drug delivery and/or drug formulations. Enzalutamide is an established standard-of-care treatment for advanced prostate cancer with a commercially available formulation that may be inconvenient for some patients. We proposed a study to evaluate the bioequivalence of a liquid formulation to provide an alternative method of administration. This was a single-dose, randomized, open-label, two-way crossover pilot bioequivalence study to compare two oral formulations of enzalutamide: four enzalutamide 40 mg liquid-filled soft-gelatin capsules (commercially available) administered whole versus enzalutamide 160 mg liquid (extracted from capsules) administered via oral syringe. To assess bioequivalence, patients were randomized to receive a single dose of one formulation, then cross over to receive the alternative formulation following a 42-day washout period. The study did not meet proposed accrual, with only one patient enrolled, thus limiting the bioequivalence evaluation. Although both formulations appeared well tolerated with no adverse events reported, the tolerability assessment questionnaire revealed an unpleasant taste of the liquid formulation. Preliminary evidence suggests a similar pharmacokinetic profile when administering liquid extracted from enzalutamide soft-gelatin capsules compared with intact capsules in patients with prostate cancer. Tolerability may limit use in clinical practice. The CPP participates in several preclinical pharmacology projects in order to study drug metabolism, PK, drug formulation and bioavailability, as well as efficacy in preclinical models of drug development to allow for more accurate dosing estimates for future first-in-human studies. The CPP has validated assays and conducted PK analysis for the following compounds: 3-deazaneplanocin (DZ-Nep), PV1162, schweinfurthin G, englerin A, aza-englerin, XZ-419, aurora kinase A/B inhibitor SCH-1473759, and a long-acting prodrug of talazoparib. We have conducted bioavailability studies for schweinfurthin G, englerin A, and aza-englerin. We collaborate with both intramural and extramural investigators to evaluate the preclinical PK of various novel therapeutics in mouse tumor models and/or non-human primate (NHP) models including 5-azacytidine, pexidartinib, photo-activatable paclitaxel prodrug, and panobinostat. We evaluated the preclinical PK of sapanisertib (mTORC1/2 inhibitor) and trametinib (MEK inhibitor) in mucosal melanoma xenograft models. In collaboration with the Molecular Targets Laboratory and the Natural Products Branch, the CPP provided preclinical PK support to study the bioavailability of two new classes of analogs of englerin A (extracted from the Tanzanian plant Phyllanthus engleri Pax on the basis of its high potency and selectivity for inhibiting renal cancer cell growth). The first class of analogs are modified at the esters to improve stability and oral bioavailability, while the second class of analogs are modified on the bridgehead of the seven-membered ring within the main englerin body of the compound. Replacement of the isopropyl group by other, larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Selected compounds were also evaluated for their effect on the ion channel TRPC4 and for intravenous toxicity in mice, and these had lower potency in both assays compared to englerin A.

多年来，CPP 开发了多种治疗药物的分析方法，包括：缩肽、TNP-470、苯乙酸、苯丁酸、他莫昔芬、UCN-01、CAI、沙利度胺、COL-3、苏拉明、美法仑、厄洛替尼、哌立福辛、SU5416、2ME、MS-275、酮康唑、来那度胺、罗米地辛、AZD2281、吉西他滨、索拉非尼、非那雄胺、奈非那韦、17-DMAG、氯吡格雷、Hsp90抑制剂PF-04928473、伊立替康（其活性代谢物SN38和葡萄糖醛酸化SN38）、Trk激酶抑制剂AZD7451、泊马度胺、奥拉帕尼、索拉非尼、贝林司他、西地尼布​​、阿比特龙、卡博替尼、卡非佐米、咪达唑仑、拉帕替尼、替莫唑胺、哌立福辛、丙戊酸、替莫唑胺、环磷酰胺及其 4-羟基环磷酰胺代谢物，以及 NLG207（以前称为 CRLX-101，纳米颗粒药物缀合物）喜树碱）。 CPP为I/II期试验中的各种药物提供了PK支持：苏拉明、TNP-470、CAI、UCN-01、多西他赛、黄酮吡醇、沙利度胺、来那度胺、泊马度胺、腹腔顺铂/卡铂、紫杉醇、17-DMAG、伊马替尼、索拉非尼、奈非那韦、贝伐珠单抗、罗米地辛、氯吡格雷、硼替佐米、TRC-105、凡德他尼、奥拉帕尼、托泊替康、伊立替康、光神霉素、杜瓦鲁单抗、阿比特龙、贝利司他加顺铂和依托泊苷、替莫唑胺、塞维泰罗、司美替尼和免疫毒素LMB-100。在本财年中，CPP 为多项 I/II 期临床研究提供 PK 支持，包括针对间皮瘤和其他表达间皮素的实体瘤患者进行的 LMB-100 首次人体 I 期研究； zotiraciclib 联合替莫唑胺治疗复发性高级别星形细胞瘤患者的 I 期试验；来那度胺联合放疗治疗儿童胶质瘤的 I 期研究； M6620（一流的 ATR 竞争性抑制剂）和拓扑替康在复发性 SCLC 患者中的 II 期试验；泊马度胺治疗难治性慢性移植物抗宿主病患者的 II 期研究；卡博替尼和多西他赛在 mCRPC 患者中的 I/II 期治疗。多年来，我们对以下化合物进行了群体 PK (popPK) 建模：缩肽、罗米地辛、索拉非尼、奥拉帕尼、多西紫杉醇与 p-糖蛋白拮抗剂塔利奎达、TRC105、TRC102、贝利司他、光神霉素和塞维特罗联合。最近的工作重点是表征 NLG207 的复杂 PK，NLG207 是一种有效的拓扑异构酶 I 抑制剂喜树碱 (CPT) 的纳米颗粒药物缀合物，以便使用 popPK 模型更好地描述纳米颗粒中 CPT 的释放。 NLG207 的 PK 特征是通过将两个线性二室模型与一级动力学相结合来描述纳米颗粒结合（共轭）和游离 CPT。纳米颗粒制剂中 CPT 释放的特征是初始快速清除率为 5.71 L/h，4 小时后通过一级衰减（估计半衰期为 0.307 h）降至稳态值 0.0988 L/h。输液结束。游离 CPT 的肾清除率为 0.874 L/h。 popPK 模型证实了共轭 CPT 的纳米颗粒行为，并从 NLG207 中释放了 CPT 的机械特征。目前的分析为未来的研究奠定了坚实的基础，作为正在进行的 NLG207 临床试验的潜在预测工具。与博士合作。 Mark Ratain 和 Daniel Goldstein，我们正在通过计算机模拟评估单克隆抗体免疫检查点抑制剂的延长给药方案。根据患者特定的清除率估计，可以模拟最佳替代给药策略，以降低药物和成本负担，同时维持治疗水平，特别是当药物清除率随着时间的推移而降低时。我们假设比目前批准的给药间隔更长（没有相应增加剂量）将保持疗效。为此，我们正在合作开展一项多机构、随机、非劣效性试验，以研究纳武单抗或派姆单抗标准间隔给药与延长间隔给药在局部晚期或转移性癌症中的 PK。主要目的是评估延长间隔给药相对于标准给药的非劣效性，通过纳武单抗和派姆单抗的药物谷水平高于 1.5 ug/ml 目标浓度来评估。我们还对药物输送和/或药物配方的替代方法感兴趣。恩杂鲁胺是一种针对晚期前列腺癌的既定标准治疗方法，其市售配方可能对某些患者来说可能不方便。我们提出了一项研究来评估液体制剂的生物等效性，以提供替代的给药方法。这是一项单剂量、随机、开放标签、双向交叉试点生物等效性研究，旨在比较恩杂鲁胺的两种口服制剂：四个恩杂鲁胺 40 毫克液体填充软明胶胶囊（市售）整体给药与恩杂鲁胺 160 毫克液体给药（从胶囊中提取）通过口腔注射器给药。为了评估生物等效性，患者被随机分配接受一种制剂的单剂量，然后在 42 天的洗脱期后交叉接受替代制剂。该研究未达到拟议的应计目标，仅招募了一名患者，从而限制了生物等效性评估。尽管两种制剂似乎都具有良好的耐受性，没有不良事件报告，但耐受性评估问卷显示液体制剂的味道令人不快。初步证据表明，前列腺癌患者服用恩杂鲁胺软明胶胶囊提取的液体与完整胶囊相比，具有相似的药代动力学特征。耐受性可能会限制其在临床实践中的使用。 CPP 参与了多个临床前药理学项目，以研究药物代谢、PK、药物配方和生物利用度以及药物开发临床前模型的功效，以便为未来的首次人体研究提供更准确的剂量估计。 CPP 已对以下化合物进行了验证测定并进行了 PK 分析：3-deazaneplanocin (DZ-Nep)、PV1162、schweinfurthin G、englerin A、aza-englerin、XZ-419、极光激酶 A/B 抑制剂 SCH-1473759 和他拉佐帕尼的长效前药。我们对 schweinfurthin G、englerin A 和 aza-englerin 进行了生物利用度研究。我们与校内和校外研究人员合作，评估各种新型疗法在小鼠肿瘤模型和/或非人灵长类动物 (NHP) 模型中的临床前 PK，包括 5-氮杂胞苷、pexidartinib、光激活紫杉醇前药和帕比司他。我们评估了 sapanisertib（mTORC1/2 抑制剂）和 Trametinib（MEK 抑制剂）在粘膜黑色素瘤异种移植模型中的临床前 PK。 CPP 与分子靶标实验室和天然产物分部合作，提供了临床前 PK 支持，以研究两类新型 englerin A 类似物（从坦桑尼亚植物 Phyllanthus engleri Pax 中提取，因其高效力和选择性）的生物利用度用于抑制肾癌细胞的生长）。第一类类似物在酯处进行修饰以提高稳定性和口服生物利用度，而第二类类似物在化合物的主要恩格勒体内的七元环的桥头上进行修饰。用其他更大的取代基取代异丙基产生的化合物显示出与天然产物相当的优异选择性和效力。还评估了所选化合物对离子通道 TRPC4 的影响以及小鼠体内的静脉毒性，与 englerin A 相比，这些化合物在两项测定中的效力均较低。