Using Clinical Pharmacology Principles to Develop New Anticancer Therapies

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和葡萄糖醛酸化SN38）、Trk激酶抑制剂AZD7451、波马度胺、奥拉帕尼、索拉非尼、贝林诺他、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NLG207（以前称为CRLX-101，喜树碱的纳米颗粒-药物偶联物）和ONC206。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期研究卡博赞替尼和多西他赛治疗mCRPC患者的I/II期；妊娠期检查点抑制剂免疫治疗复发难治性霍奇金淋巴瘤单药NIZ985（重组异二聚体IL-15激动剂）用于转移性或不可切除实体瘤成人患者的I期研究；索拉非尼和伊立替康在儿童复发或难治性实体瘤患者中的一期研究。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。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。抗程序性细胞死亡蛋白1单克隆抗体Nivolumab和pembrolizumab已经彻底改变了肿瘤学，但价格昂贵。使用介入性药物经济学方法，可以减少这些药物的使用频率，以降低成本并在保持疗效的同时增加患者的便利性。由于半衰期长，而且没有证据表明剂量与疗效之间存在关系，这两种药物都是较不频繁给药的候选药物。纳武单抗和派姆单抗建立的人群药代动力学模型用于模拟1000名随机生成的虚拟患者的多种给药方案。最初对标准剂量方案进行了模拟，以验证这些计算机预测。接下来，每3周模拟纳武单抗0.3 mg/kg，结果显示95%的患者在稳态下保持大于或等于1.5 ug/mL，这是两种药物的最低有效浓度（MEC）。模拟两种药物的各种替代给药方案，以确定哪种方案可以维持95%的患者的MEC。模拟延长纳武单抗每4周240毫克和每8周480毫克的给药方案以及派姆单抗每6周200毫克的给药方案，显示95%的患者维持MEC或更高。这些模拟表明，有可能减少至少50%的药物暴露，从而大大减少患者就诊（以及成本），同时保持同等疗效。这些模型为一项正在进行的前瞻性随机临床试验提供了科学依据，该试验比较了标准间隔固定给药和延长间隔固定给药，并最终成为一项疗效驱动的比较试验。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。我们还研究了在非典型畸胎瘤/横纹肌样肿瘤中，双重mTORC1/2抑制是如何损害细胞防御外源应激的。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生成化合物*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, 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*