Using Clinical Pharmacology Principles to Develop New Anticancer Therapies

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

Abstract

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*