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开发了广泛的治疗分析方法，包括以下内容：抑郁肽、TNP-470、醋酸苯、丁酸苯、他莫昔芬、UCN-01、CAI、沙利度胺、COL-3、苏拉明、美伐兰、厄洛替尼、培立弗辛、SU5416、2ME、MS-275、酮康唑、来那度胺、罗米地辛、AZD2281、吉西他滨、索拉非尼、非那司特、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和葡萄糖糖甙化SN38）、Trk激酶抑制剂AZD7451、波马度胺、奥拉帕尼、索拉非尼、贝利诺他、西地尼、阿比特龙、卡博赞替尼、卡非佐米、咪达唑仑、拉帕替尼、替莫唑胺、perifosine、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，喜树碱的纳米颗粒-药物偶联物）。CPP在I/II期试验中为各种药物提供了PK支持：苏拉明、TNP-470、CAI、UCN-01、多西他赛、黄哌啶醇、沙利度胺、来那度胺、泊马度胺、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、万德他尼、奥拉帕尼、托替康、伊立替康、米特霉素、杜伐单抗、阿比替龙、贝利诺他联合顺铂和依托泊苷、替莫唑胺、7维罗奈尔、selumetinib和免疫毒素LMB-100。在本财政年度，CPP为几项I/II期临床研究提供了PK支持，包括LMB-100在间皮瘤和其他表达间皮素的实体肿瘤患者中的首次人体I期研究；唑替拉西尼联合替莫唑胺治疗复发性高级别星形细胞瘤的I期临床试验来那度胺和放疗治疗小儿胶质瘤的I期研究M6620（一种一流的ATR竞争性抑制剂）和拓扑替康在复发的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的II期研究cabozantinib和docetaxel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：抑郁肽、罗米地辛、索拉非尼、奥拉帕尼、多西他赛联合p-糖蛋白拮抗剂tariquar、TRC105、TRC102、belinostat、米霉素和seviteronel。最近的研究重点是表征NLG207的复合物PK， NLG207是一种强效拓扑异构酶I抑制剂喜树碱（CPT）的纳米颗粒-药物偶联物，以便使用popPK模型更好地描述CPT从纳米颗粒中的释放。NLG207的PK通过结合两个线性双室模型和一阶动力学来描述纳米颗粒结合（共轭）和游离CPT。CPT从纳米颗粒制剂中释放的初始快速清除率为5.71 L/h，在注射结束后4 h，其通过一阶衰减（估计半衰期为0.307 h）降至稳态值0.0988 L/h。游离CPT的肾脏清除率为0.874 L/h。popPK模型证实了共轭CPT的纳米颗粒行为，并对NLG207释放CPT的机理进行了表征。目前的分析为未来的研究提供了坚实的基础，作为正在进行的NLG207临床试验的潜在预测工具。在与博士合作。Mark Ratain和Daniel Goldstein，我们正在评估单克隆抗体免疫检查点抑制剂的硅基延长剂量方案。根据患者对清除率的特定估计，可以模拟最佳替代给药策略，以降低药物和成本负担，同时保持治疗水平，特别是当药物清除率随着时间的推移而降低时。我们假设较长的给药间隔比目前批准的（没有相应的剂量增加）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高于1.5 ug/ml目标浓度的药谷水平来评估。我们也对药物递送和/或药物配方的替代方法感兴趣。恩杂鲁胺（Enzalutamide）是一种成熟的晚期前列腺癌标准治疗药物，其市售配方可能会给一些患者带来不便。我们提出了一项研究来评估液体制剂的生物等效性，以提供一种替代的给药方法。这是一项单剂量、随机、开放标签、双向交叉的先导生物等效性研究，以比较两种口服制剂：四种恩杂鲁胺40毫克液体填充软明胶胶囊（市售），整体给药与160毫克液体恩杂鲁胺（从胶囊中提取），通过口服注射器给药。为了评估生物等效性，患者随机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。该研究未达到预期目标，仅纳入一名患者，因此限制了生物等效性评价。虽然两种配方都表现出良好的耐受性，没有不良事件报告，但耐受性评估问卷显示液体配方的味道令人不快。初步证据表明，在前列腺癌患者中，给予恩杂鲁胺软明胶胶囊提取液与完整胶囊相比，具有相似的药代动力学特征。耐受性可能限制临床应用。CPP参与了几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对3-deazaneplanocin （DZ-Nep）、PV1162、schweinfurthin G、englerin A、aza-englerin、XZ-419、aurora kinase A/B抑制剂SCH-1473759和长效talazoparib前药进行了验证和PK分析。我们进行了schweinfurin G、englerin A和aza-englerin的生物利用度研究。我们与校内和校外研究人员合作，评估各种新型治疗药物在小鼠肿瘤模型和/或非人灵长类动物（NHP）模型中的临床前PK，包括5-氮杂胞苷、培西达替尼、光活化紫杉醇前药和帕比诺他。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，提供临床前PK支持，以研究两类新的englerin A类似物的生物利用度（从坦桑尼亚植物Phyllanthus engleri Pax中提取，基于其高效能和选择性抑制肾癌细胞生长）。第一类类似物在酯上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englerin主体内的七元环的桥头堡进行修饰。用其他更大的取代基取代异丙基得到的化合物显示出与天然产物相当的极好的选择性和效力。选定的化合物还评估了它们对离子通道TRPC4的影响和小鼠静脉毒性，与englerin A相比，这些化合物在两种检测中的效力都较低。