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: 10703095
• 负责人: William Douglas Figg
• 金额: $ 153.78万
• 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/10703095
• 关键词: ABCB1 gene; Adult; Agonist; Antineoplastic Agents; Astrocytoma; Azacitidine; BAY 54-9085; Binding Proteins; Biological; Biological Assay; Biological Availability; Bortezomib; CCR; Camptothecin; Cancer Cell Growth; Carboplatin; Cells; Child; Cisplatin; Clinical Pharmacology; Clinical Research; Clinical Trials Design; Collaborations; Communities; Complex; Concentration measurement; Conduct Clinical Trials; Coupled; Cyclophosphamide; Data; Depsipeptides; Detection; Development; Disseminated Malignant Neoplasm; Dose; Drug Costs; Drug Exposure; Drug Formulations; Drug Interactions; Drug Kinetics; Equation; Erlotinib; Esters; Etoposide; Excretory function; Extramural Activities; Finasteride; Fluorescence; Frequencies; Future; Glioma; Goals; Guidelines; High Pressure Liquid Chromatography; Hodgkin Disease; Imatinib; Immune checkpoint inhibitor; Immunotherapy; Immunotoxins; Interleukin-15; Intervention; Ketoconazole; Laboratories; Liquid substance; Locally Advanced Malignant Neoplasm; MEKs; MS-275; Mathematics; Measures; Melphalan; Mesothelioma; Metabolism; Midazolam; Modeling; Modification; Molecular Target; Monoclonal Antibodies; Mus; Natural Products; Nelfinavir; Nivolumab; Oncology; Oral; Paclitaxel; Patients; Pharmaceutical Economics; 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; Pregnancy; Prodrugs; Program Development; Radiation therapy; Randomized; Randomized Clinical Trials; Recombinants; Recurrence; Refractory; Regimen; Relapse; Renal Cell Carcinoma; Reproducibility; Research Personnel; Rhabdoid Tumor; Route; SU 5416; Sampling; Scheme; Solid Neoplasm; Stress; Suramin; TNP470; Tamoxifen; Tariquidar; Testing; Thalidomide; Therapeutic; Time; Tissues; Topoisomerase-I Inhibitor; Topotecan; Toxic effect; United States National Institutes of Health; Unresectable; Valproic Acid; Visit; Xenograft Model; abiraterone; absorption; analog; analytical method; antagonist; anti-PD-1; aurora kinase A; base; bevacizumab; cancer therapy; chronic graft versus host disease; clinical center; clopidogrel; comparative trial; cost; cytotoxicity; detector; docetaxel; drug clearance; drug development; drug disposition; drug metabolism; first-in-human; flavopiridol; improved; in silico; inhibitor; instrument; intraperitoneal; irinotecan; kinase inhibitor; lapatinib; lenalidomide; mass spectrometer; mesothelin; method development; mucosal melanoma; nanoparticle; nanoparticle drug; nonhuman primate; novel anticancer drug; novel therapeutics; pediatric patients; pembrolizumab; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; phase I trial; phase II trial; pomalidomide; pre-clinical; programs; prospective; simulation; temozolomide; trial comparing; tumor; virtual patient

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, NLG207 (formerly CRLX-101, nanoparticle-drug conjugate of camptothecin), and ONC206. 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; checkpoint inhibitor immunotherapy during pregnancy for relapsed-refractory Hodgkin lymphoma; phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors; phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors. 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. 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. Nivolumab and pembrolizumab, anti-programmed cell death protein 1 monoclonal antibodies, have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach, these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half-lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next, simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that 95% of patients maintained greater than or equal to 1.5 ug/mL at steady state, which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in 95% of patients. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated, showing that 95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50%, thus substantially reducing patient visits (as well as costs), while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing, and ultimately an efficacy-driven comparative trial. 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. We also investigated how dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors. 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 *TRUNCATED*

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，Finastalide，Nelfinavir，Nelfinavir，17-DMAG，Clopidogrel，Hsp90抑制剂PF-04928473，Irinotecan，Irinotecan，Irinotecan（Irinotecan）（其活跃的Sn38和Glucabolite SN38和Gluculite Sn38 an38 in38 in38 an38 in38 in38 in 38 AZD7451, pomalidomide, olaparib, sorafenib, belinostat, cediranib, abiraterone, cabozantinib, carfilzomib, midazolam, lapatinib, temozolomide, perifosine, valproic acid, temozolomide, cyclophosphamide and its 4-hydroxycyclophosphamide metabolite, NLG207（以前为CRLX-101，camptothecin的纳米颗粒 - 药物结合物）和ONC206。 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免疫毒素LMB-100。在当前财政年度，CPP为多项I/II期临床研究提供了PK支持，包括对中皮瘤患者和其他表达间皮素的实体瘤患者的LMB-100 I期研究；复发性高级星形胶质细胞瘤患者的佐替丽氏与替莫唑胺结合的I期试验；神经胶质瘤儿童的Lenalidomide和放射疗法的第一阶段研究； M6620的II期试验（ATR的第一类竞争抑制剂）和复发性SCLC患者中的拓扑转基因；在难治性慢性移植物抗宿主疾病的患者中，核酸胺的第二阶段研究； MCRPC患者的Cabozantinib和多西他赛的I/II期；检查点抑制剂免疫疗法在怀孕期间因复发性炎症性霍奇金淋巴瘤；成人转移性或不可切除的实体瘤患者的重组异二聚体IL-15激动剂的单一药物NIZ985的I阶段研究； 索拉非尼和伊立替康对复发或难治性实体瘤的儿科患者的1阶段研究。多年来，我们对以下化合物进行了人口PK（POPPK）建模：Depsipeptide，Romidepsin，Sorafenib，Olaparib，Docetaxel与P-糖苷拮抗剂野氨基酯，TRC105，TRC102，TRC102，Belinostat，Belinostat，Mithramycin和Seviteron和Severiteron和Severiteron和Seviterel。最近的努力集中在表征NLG207的复杂PK，NLG207是一种有效的拓扑异构酶I抑制剂Camptothecin（CPT）的纳米颗粒 - 药物缀合物，以便更好地描述使用POPPK模型从纳米颗粒中释放的CPT释放。与Drs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基于硅的扩展剂量方案。根据患者特定的清除率估计，可以模拟最佳的替代剂量策略以降低药物和成本负担，但要保持治疗水平，尤其是随着药物的清除随着时间的推移而减少。我们假设比当前批准的时间更长的时间间隔（不相称的剂量增加）将保持疗效。为此，与局部晚期或转移性癌症中的nivolumab或pembrolizumab的扩展间隔给药相比，我们正在协作进行多机构，随机，非效率试验，以研究标准间隔给药的PK。主要目的是评估相对于标准剂量的扩展间隔剂量的非劣效率，如尼伏洛鲁马布和pembrolizumab的药物槽水平高于1.5 ug/ml的药物谷水平评估。 Nivolumab和Pembrolizumab是抗编程的细胞死亡蛋白1单克隆抗体，已彻底改变了肿瘤学，但价格昂贵。使用介入的药物经济学方法，这些药物可以降低频率以降低成本和增加患者的便利性，同时保持疗效。两种药物都是良好的候选者，因为长期寿命长，并且没有剂量与功效关系的证据。 Nivolumab和Pembrolizumab的已建立人群药代动力学模型均用于模拟1000个随机生成的虚拟患者的多种剂量方案的概况。最初对标准剂量方案进行了模拟，以在计算机预测中验证这些剂量。接下来，每3周对Nivolumab 0.3 mg/kg的模拟表明，在稳态下，有95％的患者在稳态下保持大于或等于1.5 ug/ml，这被推断为两种药物的最低有效浓度（MEC）。模拟了两种药物的各种替代剂量方案，以确定哪种治疗方案可以在95％的患者中维持该MEC。每4周的Nivolumab 240 mg的Nivolumab 240毫克的延长剂量方案以及每6周的Pembrolizumab 200 mg的延长剂量，表明95％的患者维持MEC或更高。这些模拟证明了将药物暴露量减少至少50％的潜力，从而大大降低了患者的访问（以及成本），同时保持同等效力。这些模型为正在进行的前瞻性随机临床试验提供了科学理由，将标准间隔固定给药与扩展间隔固定剂量进行比较，并最终是效率驱动的比较试验。 CPP参与了几个临床前药理学项目，以研究药物代谢，PK，药物制剂和生物利用度，以及在药物开发的临床前模型中的疗效，以便为将来的首次首次人类研究提供更准确的给药估算。 CPP已验证了以下化合物的测定法，并进行了PK分析：3-二氮酸胺（DZ-NEP），PV1162，Schweinfurthin G，Englerin A，Aza-Englerin，XZ-Englerin，XZ-419，Aurora激酶A/B抑制剂SCH-14333333459和ARARERARAR和AURIB的AURORA激酶A/B rug。我们已经对Schweinfurthin G，Englerin A和Aza-Englerin进行了生物利用度研究。我们与壁内和外部研究人员合作评估了小鼠肿瘤模型和/或非人类灵长类动物（NHP）模型中各种新型治疗剂的临床前PK，包括5-氮杂丁胺，Pexidartinib，Pexidartinib，可触发paclitaxel prodrug prodrug prodrug prodrug和Panobinostat。我们在粘膜黑色素瘤异种移植模型中评估了Sapanisertib（MTORC1/2抑制剂）和Trametinib（MEK抑制剂）的临床前PK。我们还研究了双重MTORC1/2抑制如何损害细胞防御对非典型teratoid/胸骨类肿瘤中obatoclax诱导的细胞毒性增强的外源性应激的防御措施。 CPP与分子靶标实验室和天然产品分支合作，提供了临床前PK支持，以研究Englerin A的两种类似物的生物利用度（从坦桑尼亚植物Phyllanthus Engleri Pax提取的基于其高效力和抑制肾脏癌细胞生长的基础上）。一类模拟物在酯上进行了修改，以提高稳定性和口服生物利用度，而第二类模拟可以在该化合物的主恩格林体内的七元环的桥头上修改。其他较大的取代基替代异丙基的化合物 *截短 *