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), ONC206, and metarrestin (ML-246). 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, immunotoxin LMB-100, zotiraciclib, M6620 (a first-in-class competitive inhibitor of ATR), NIZ985 (a recombinant heterodimeric IL-15 agonist), sorafenib and irinotecan, as well as the combo of cabozantinib and docetaxel for mCRPC patients. During the current fiscal year, the CPP provided PK support for several phase I/II clinical studies, including a phase I trial of panobinostat in children with diffuse intrinsic pontine glioma; a first-in-human phase I clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors; phase II study of duvelisib and ibrutinib combination therapy for chronic lymphocytic leukemia; a phase I trial of sacituzumab govitecan plus berzosertib in advanced 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, seviteronel, and NLG207, a nanoparticle-drug conjugate of the potent topoisomerase I inhibitor camptothecin. 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. 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. We performed in silico re-optimization of atezolizumab dosing using PopPK simulation and exposure-response simulation. 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. 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 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 and canine models. We also investigated how dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors. We also evaluated the preclinical PK of trametinib in the presence or absence of ganitumab in RAS-mutated PAX-fusion negative rhabdomyosarcoma 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. Replacement of the glycolate by other functionalities as well as esterification of the glycolate hydroxyl yielded compounds which displayed excellent selectivity and potency compared with the natural product. TRPC4/5 ion channel experiments with five compounds showed delayed or reduced agonism with TRPC5, at much higher concentrations than englerin A. The same compounds were not detectable in mouse serum after a single oral dose of 12.5 mg/kg. At 100 mg/kg p.o., no toxicity was observed, and blood levels were barely detectable. Intravenous administration led to toxicity but at substantially lower doses than for englerin A.