Using Clinical Pharmacology Principles to Develop New Anticancer Therapies

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Over the years, the CPP has developed and validated analytical methods for a wide range of therapeutics that include the following: depsipeptide, tamoxifen, melphalan, erlotinib, perifosine, SU5416, 2ME, MS-275, ketoconazole, lenalidomide, romidepsin, AZD2281, gemicitabine, sorafenib, finasteride, nelfinavir, 17-DMAG, Hsp90 inhibitor PF-04928473, irinotecan (its active metabolite SN38, pomalidomide, olaparib, sorafenib, belinostat, cediranib, abiraterone, cabozantinib, carfilzomib, midazolam, lapatinib, temozolomide, temozolomide, cyclophosphamide, ONC206, and metarrestin (ML-246). The CPP has provided PK support for various numerous compounds agents in phase I/II single agent and combination trials over the years: docetaxel, flavopiridol, thalidomide and its immunomodulatory derivatives (IMiDs), intraperitoneal cisplatin/carboplatin, paclitaxel, imatinib, sorafenib, nelfinavir, bevacizumab, romidepsin, bortezomib, , vandetanib, olaparib, topotecan, irinotecan, mithramycin, durvalumab, abiraterone, belinostat with cisplatin and etoposide, temozolomide, selumetinib, immunotoxin LMB-100, zotiraciclib, berzosertib, NIZ985 (a recombinant heterodimeric IL-15 agonist), cabozantinib, panibinostat, NEO-201, duvelisib, ibrutinib, abemaciclib, combination therapy such as venetoclax, ibrutinib, and lenalidomide, as well as antibody drug conjugates such as sacituzumab govitecan. During the current fiscal year, the CPP provided PK support for several phase I/II clinical studies. We conducted a phase 2 study of single agent ibrutinib for first-line treatment of chronic graft-versus-host disease and evaluated the PK of the drug. We evaluated the PK of vincristine sulfate liposome injection (VSLI), a liposomal formulation of vincristine for relapsed acute lymphoblastic leukemia. We conducted a single arm phase 2 trial of colesevelam, a bile acid binder, for lenalidomide-associated diarrhea in multiple myeloma. Colesevelam treatment was highly effective for treatment of lenalidomide-associated diarrhea. Importantly, the pharmacokinetics of lenalidomide were not affected by concomitant colesevelam treatment. Colesevelam was safe and highly effective for treatment of lenalidomide-associated diarrhea in multiple myeloma and does not reduce the clinical effect of lenalidomide. Over the years, we have conducted population PK (popPK) modeling of the following several compounds including depsipeptide, romidepsin, sorafenib, olaparib, docetaxel combinations belinostat, and mithramycin. We have also performed 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 fixed 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. The trial is currently open and accruing patients. We performed in silico re-optimization of atezolizumab dosing using PopPK simulation and exposure-response simulation. Our prior research demonstrated, via simulation, that an extended-interval dosing regimen (840 mg q6w) following two standard loading doses, maintained efficacy while having a nonsignificant exposure-response relationship with adverse events. In this report, we compare the traditional 30-year-old industry standard NONMEM software, with a free R package, RxODE, and recently developed Pumas software to simulate alternative dosage regimens for atezolizumab, using our previously published article as a benchmark. All three software packages provided comparable exposure metrics. However, Pumas demonstrated significantly higher processing power, resulting in faster processing times of robust data. This report also discusses the advantages and limitations of each software package, aiming to shed light on the cost/-effectiveness of free vs commercially licensed software. This in silico study demonstrated the feasibility of extending the dosing interval of atezolizumab 840 mg to every 6 weeks to maintain clinically effective exposures in the vast majority (>99%) of virtual patients. We next aim to verify this in a clinical trial seeking to validate extended-interval dosing in a personalized approach using therapeutic drug monitoring. 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, and novel androgen receptor antagonists (BG-15a and the pharmacokinetically optimized BG-15n). We collaborate with both intramural and extramural investigators to evaluate the preclinical PK of various novel therapeutics in mouse tumor models, canine and/or non-human primate (NHP) models including 5-azacytidine, pexidartinib, photo-activatable paclitaxel prodrug, panobinostat, sapanisertib, trametinib, and futibatinib. We recently characterized the preclinical PK of indenoisoquinolines (IIQs), a new class of clinical TOP1 inhibitors, in Ewing sarcoma models. We developed a validated LC-MS/MS assay for bioanalysis of plasma concentrations of the novel NAMPT inhibitor OT-82 and characterized its preclinical PK. We also developed and validated an HPLC-MS/MS method for the detection and quantification of AGF94, a novel antifolate, in mouse plasma was developed and validated. Detection and quantification of AGF94 was achieved by multiple reaction monitoring performed by a Sciex QTRAP 5500 mass spectrometer operated in positive electrospray ionization mode. The overall process efficiency was greater than 96% for both the analyte and internal standard. Generally, precision and accuracy of the assay was established, and the assay was utilized to measure preclinical samples from a study using AGF94 in a murine pancreatic cancer model.