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.