Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect

Nature Reviews Clinical Oncology, Journal Year: 2016, Volume and Issue: 13(11), P. 659 - 673

Published: May 17, 2016

Language: Английский

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Dose Finding of Lenvatinib in Subjects With Advanced Hepatocellular Carcinoma Based on Population Pharmacokinetic and Exposure-Response Analyses

The Journal of Clinical Pharmacology, Journal Year: 2017, Volume and Issue: 57(9), P. 1138 - 1147

Published: May 31, 2017

Hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer occurrences worldwide. Lenvatinib, a multikinase inhibitor, was approved in radioiodine-refractory differentiated thyroid cancer. In this phase 2 study (study 202), we aimed identify the lenvatinib optimal dose subjects with advanced HCC Child-Pugh class A. Pooled data from 1 studies healthy adults and mixed tumor types, 202 HCC, were analyzed using population pharmacokinetic approach. The relationship between treatment-emergent adverse events leading withdrawal or reduction during cycle exposure explored by logistic regression analysis. A receiver operating characteristics analysis used investigate best cutoff values body weight high-risk group early modification. final model included body-weight effects on apparent clearance volume. area under plasma concentration–time curve (AUC) at steady state demonstrated an increase AUC as decreased HCC. An exposure–response observed, higher lower resulting earlier drug reduction. 57.8 kg 2430 ng·h/mL, respectively, predict high risk We therefore recommend 12-mg 8-mg starting doses ≥60 <60 kg,

Language: Английский

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Brightline-1: phase II/III trial of the MDM2–p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS

Future Oncology, Journal Year: 2023, Volume and Issue: 19(9), P. 621 - 629

Published: March 1, 2023

Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive associated with poor prognosis. First-line treatment for advanced/metastatic DDLPS systemic chemotherapy, but efficacy and toxicities substantial. Most tumors have amplification of the

Language: Английский

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Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2023, Volume and Issue: 13(5), P. 691 - 709

Published: Nov. 16, 2023

Project Optimus is a US Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, other stakeholders. Although there much promise this initiative, are several challenges that need be addressed, including multidimensionality problem oncology, heterogeneity cancer patients, importance evaluating long-term tolerability beyond dose-limiting toxicities, lack reliable biomarkers for efficacy. Through lens Totality Evidence with mindset model-informed development, we offer insights into by building quantitative knowledge base integrating diverse sources data leveraging modeling tools build evidence dosage considering exposure, disease biology, efficacy, toxicity, factors. We believe rational can achieved improving outcomes maximizing therapeutic benefit while minimizing toxicity.

Language: Английский

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Therapeutic drug monitoring of monoclonal antibodies in inflammatory and malignant disease: Translating TNF‐α experience to oncology

Clinical Pharmacology & Therapeutics, Journal Year: 2015, Volume and Issue: 99(4), P. 419 - 431

Published: Aug. 12, 2015

Lack of response to monoclonal antibodies (mAbs) has been associated with inadequate mAb serum concentrations. Therapeutic drug monitoring (TDM) mAbs the potential guide more effective dosing in individual patients. This review discusses mechanisms responsible for interpatient variability pharmacokinetics, summarizes exposure‐response data used inflammatory and malignant disease, presents current evidence mAb‐TDM provides hurdles required future steps further implementing mAb‐TDM.

Language: Английский

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Accelerating anticancer drug development — opportunities and trade-offs

Nature Reviews Clinical Oncology, Journal Year: 2018, Volume and Issue: 15(12), P. 777 - 786

Published: Oct. 1, 2018

Language: Английский

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Development of a general method for quantifying IgG-based therapeutic monoclonal antibodies in human plasma using protein G purification coupled with a two internal standard calibration strategy using LC-MS/MS

Analytica Chimica Acta, Journal Year: 2018, Volume and Issue: 1019, P. 93 - 102

Published: Feb. 21, 2018

Language: Английский

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The role of nonrandomized trials in the evaluation of oncology drugs

Clinical Pharmacology & Therapeutics, Journal Year: 2015, Volume and Issue: 97(5), P. 502 - 507

Published: Feb. 12, 2015

Although randomized trials provide the most reliable evidence of a drug's safety and efficacy, there are situations where not possible or ethical. In this article we discuss when how single-arm can be used to support full approval oncology drugs. These include in which an unprecedented effect on tumor response is observed setting high unmet medical need, clinical trial patients have been well characterized, enabling target population clearly defined, experience exists sufficient number allow adequate assessment risk:benefit relationship, proper historical context provided for analysis. We also rates might considered predictive long-term outcomes clinically meaningful themselves certain contexts.

Language: Английский

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Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy

Clinical Cancer Research, Journal Year: 2016, Volume and Issue: 22(11), P. 2623 - 2629

Published: May 31, 2016

Selection of the maximum tolerated dose (MTD) as recommended for registration trials based on a dose-escalation trial using variations an MTD/3 + 3 design often occurs in development oncology products. The approach is not optimal and may result doses that are unacceptably toxic many patients reduction/interruptions might have impact effectiveness. Instead approach, authors recommend integrated approach. In this typically adaptive/Bayesian model provides general framework to incorporate make decisions escalation nonclinical data, such animal efficacy toxicity data; clinical including pharmacokinetics/pharmacodynamics dose/exposure-response data safety. To improve dose-ranging trials, model-based estimation, rather than hypothesis testing, should be used maximize integrate information gathered across doses. This identification doses, which can then confirmed trials. Clin Cancer Res; 22(11); 2623-9. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "NEW APPROACHES FOR OPTIMIZING DOSING OF ANTICANCER AGENTS".

Language: Английский

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Challenges and Opportunities in Dose Finding in Oncology and Immuno‐oncology

Clinical and Translational Science, Journal Year: 2018, Volume and Issue: 11(4), P. 345 - 351

Published: Feb. 1, 2018

Today's cancer therapy has made substantial progress. Recent success in immuno-oncology (IO) and combination therapies provide opportunities to enhance activity the broader population with less drug resistance.1-3 However, these advances also raise challenges oncology development. At 2017 American Society of Clinical Pharmacology Therapeutics (ASCPT) Annual Meeting, issues were addressed a symposium case studies illustrating opportunities. The presentations discussion are summarized this review. It been increasingly acknowledged that conventional maximum tolerated dose (MTD) approach used development may not be ideal, improving selection is needed.4, 5 Historically, MTD dominated dose-finding paradigm. Its origin lies cytotoxic agents based on underlying assumption higher dose, greater likelihood efficacy toxicity.6, 7 Dose-limiting toxicities (DLTs) predefined phase I escalation trials and, DLT criteria, escalated until reached. Over recent decades, variety novel molecular modalities target immune have become available challenged traditional MTD-based Using as only for late-stage could major contributor failures past paradigms, especially since it results large number reductions or discontinuations due toxicity.8 Therefore, finding right schedule best balances risk benefit direction shift toward. Despite need improve oncology, highly challenging heterogeneity disease, complexity biology, high variability response, narrow therapeutic window, resistance, limitation study design severity urgency deliver effective treatments patients. Moreover, clinical clearly defined by phases well controlled. Depending novelty mechanism, level medical promising anticancer new agent, evolve grow into registration trial. For example, first-in-human (FIH) trail IO pembrolizumab, monoclonal antibody blocking interaction between programmed cell death-1 (PD-1) receptor its ligands, served primary evidence supporting initial accelerated approval use melanoma.9 On other hand, such an opportunity seamless present challenges. instance, data sets complex (as they designed meet needs) insufficiently powered when analyzed using analysis tools. raised additional difficulty translate from preclinical models surrogate molecules, systems their multifaceted impacts tumors, tumors microenvironment. Hence, identifying develop approaches tackle key ASCPT 2014 paradigm was expectations discussed.10 During we reviewed what accomplished at symposium: "Finding Right Dose Patients Oncology Immuno-oncology: Are We There Yet How Have Quantitative Pharmacology, Translational Precision Medicine Been Utilized?".11 shared our experience commentary perspectives pharmaceutical industry, practice, regulatory authority. utilizing modeling simulation (M&S) during both early- late-phase advocated. Multidisciplinary collaboration integrates quantitative experimental sciences translational precision medicine emphasized. New advances, methods applications broad spectrum therapy, discussed. Current defining targeted include failing find optimal consequence, continues postmarketing trials. An example cabozantinib, which approved US Food Drug Administration (FDA) metastatic medullary thyroid (MTC) 140 mg administered daily. encountered 79% patients pivotal III resulted 16% discontinuing toxicity. Subsequent revised formulation, conducted much lower 60 mg.12, 13 Roda et al. reported prevalent 34 recently agents.14 Seven required more than 50% This presents challenge where Many still exist, tolerable therapies, whether able identify toxicity agents, optimization dosing schedules combinations. In determination, "3+3" widely trial but offer design. review published articles 181 evaluable trials, 96% them utilized variation.15 More options, model-based Bayesian approaches, considered explored should evaluated totality many factors, including scientific basis, end points, sample size, type, speed, feasibility operation. addition, effort needed educate teams utility different designs development.16 Another lack full characterization chronic toxicity, typical determination methodologies reflect Cycle 1 misrepresent safety profile chronically over multiple cycles, long-term events occur later 1. Additionally, treatment interruptions continue happen beyond 1.17 some delayed assessment always feasible. result identification requires reduced doses subsequent cycles toxicities, resulting unable derive meaningful treatment.16 Approaches Ib expansion cohort can better inform recommended II (RP2D).14 proposal includes 12–20 longer observations (at least two cycles), 30% Jardim supported view appropriate reflective inadequate I.18 Some paradigms emerging worthy consideration gaining efficiency When exposure demonstrated added patients, within-patient strategies incorporated part development, allowing individualized maximal highest possible. Such adopted successfully implemented axitinib, tyrosine kinase inhibitor vascular endothelial growth factor (VEGFR)-1, VEGFR-2, VEGFR-3.19 Wages Tait described conducting I/II account efficacy. 20 method proposed bivariate extension continual reassessment (CRM), combining features CRM order restricted inference. Trial Design (CTD) Task Force National Cancer Institute (NCI) Investigational Steering Committee selecting regimens biological pharmacological rationale data, taking potential pharmacokinetic (PK) pharmacodynamic (PD) interactions.21 Alternative controls leveraging mathematical suggested. exercise very balancing act while keeping manageable. A impediment optimized availability levels II/III studies, assessed. limit ability conduct robust exposure–response (ER) analyses help arriving dose(s) regimen. Recognizing challenge, establishing range rather studying single current RP2D paradigm, recommended.22 attempts testing one level/regimen maximize IO.23, 24 Due life-threatening nature often interpretation challenging. offers integrating sources biomarkers, response competitors. multidisciplinary Research Development. Used proactively properly, M&S powerful tool quantitatively Different (Figure 1). Along learning confirming development,25 continuously modified time next stage Data across molecules integrated build platform models, disease progression, prediction outcome early literature meta-analysis, system pharmacology (QSP) acting same pathway indication. Prior investigational (IND) entering focuses FIH projection predicting efficacious biologically humans. PK/PD, physiologically-based PK (PBPK), QSP models. Preclinical competitor if available, early-phase (phase I/II), informs (RDE) RP2D. evaluate ER relationship characterize course interpatient variability, biomarkers correlate modulation. PK/PD leveraged. III/IV), further window effects intrinsic extrinsic index (CUI), confirm justify selected, properties label. Population PK, ER, progression incorporate all available. PBPK support characterization. approach(es) selected address question(s) hand. Even though areas, impact evolving. Reviewing application (NDA) biologic license (BLA) documents revealed decision varies. axitinib titration schemes sponsor accepted FDA.19 cases, justification show no apparent relationship. examples vismodegib (a hedgehog inhibitor)26 trametinib (an mitogen-activated extracellular signal regulated 2 (MEK1 MEK2)).27 Although limited trial, provides insights low within given level, thus justifying label requirement (PMR) issued optimize dose. vandetanib, inhibitors (TKI) inhibits VEGF against epidermal (EGFR) oncogenic RET kinase. MTD, explore alternative and/or reduce maintain efficacy.28 To effectively select implementing critical. so sufficient collected allow registration. limitations size patient stage, inconclusive stage. efforts obtain biomarker starting would require research strategic plan. Collecting particularly important drugs because disguised pseudo-progression. While typically drive strategy, nonclinical leveraged One WNT974, small-molecule Porcupine investigation, biomarker, RDE selection.29 Briefly, AXIN2, target-engagement dysgeusia, most common adverse event. Based analyses, estimated. then predict profiles regimens. By estimated predicted regimen phase. ABL001, breakpoint cluster region-abelson (BCR-ABL), myeloid leukemia (CML).30, 31 mRNA (%) BCR-ABL correlates CML semiphysiological model developed describe kinetics BCR-ABL. average ABL001 concentration stable derived parameters model. simulated above threshold ≥95% As described, collecting critical Proactive communicating collaborating team important, strategy methodology collect modeling. fast pace potentially prioritized performed real-time fashion timely compounds cellular permeability, comparing vivo unbound vs. potency above, minimal steady state WNT974 IC50s vitro proliferation assays after correction protein binding. small membrane permeability biologics, tissue distribution site action consider. general, translation IO. factors considered, difference biology immunology, expression, disposition. designing on, thoroughly analyzing necessary enablers applied population, fulfil adjustment needs subgroups, factors. Analyses generally focus outcomes points events. established times projects indication, mechanism (MOA), therapy. Atezolizumab, human targets ligand (PD-L1), contributed IMvigor 210 atezolizumab 1,200 once every 3 weeks (Q3W) platinum-treated locally advanced urothelial carcinoma showed statistically significant exposure–efficacy objective rate (ORR), exposure–safety Grade 3–5 special interest (AESI).32 suggested improved expected Q3W, doses, caveat 210. Collectively labeled Q3W. Similar nonsmall-cell lung (NSCLC) open-label randomized-controlled (POPLAR study).33 Longitudinal tumor estimate inhibition (TGI) metrics sum longest diameters (SLD) lesions per Response Evaluation Criteria Solid Tumors (RECIST). framework TGI (such time-to-tumor-growth (TTG), constant (KG), Week 8 change baseline) predictor overall survival (OS) shown several types MOA.34 dynamics appears MOAs. patterns diverse, responses, even increase burden appearance before regression (pseudo-progression).35 lead efficacy, exemplified OS separation late times. applicability POPLAR docetaxel pretreated NSCLC.33, 36 study, arm crossed about 25 weeks, shrinkage docetaxel-treated slower on-treatment KG atezolizumab-treated multivariate parametric linking baseline characteristics (albumin sites) developed. hazard ratio (HR) POPLAR, subpopulations varying PD-L1 expression levels, suggesting validity Tumor dynamic KG) strong point being validated developments led options types. evolvement leads necessity behooves us community work solutions, despite rapidly changing landscape options. Working collectively industry academia challenges, FDA Office Hematology products along Association (AACR) series three workshops (DFWs) IO.37-39 laid groundwork molecule introducing adaptive investigation beneficial antitumor opposed systematic relationships ad-hoc fulfill requirements submission.40 first DFW (DFW-1) May 2015 purpose interdisciplinary forum discuss practices inhibitors.37 academia, personnel. presented understanding dose–response benefit–risk decision-making. successful showcasing prospective active cross-functional throughout take-home messages DFW-1 there increased importance communications, looking implications revisit/retest signals emerge. clear message conference does open designs.41 workshop followed second one, held June 2016.38 broadened products, focused primarily DFW-2 acceptable effect (MABEL) occupancy (RO) choose molecules. Strategies intrapatient "n" cohorts minimize anticipated active.42 These bound ranges ensure safe minimizing doses/patients spectrum, expectation activity. relationships. third dose-optimizing (DFW-3) July Washington DC chemotherapy, checkpoint (ICIs).39 Biomarkers aid define DFW-3. DFWs offered invaluable experts agencies disciplines advancement today's evolving therapies. Collaborations affiliations move forward. type collective intelligence crucial faster smarter bring certain areas optimization. doing encounter having exposure. who withdraw (and hence little benefit) likely exposure, reductions. disparity confound relationship, showing Consideration assessing any differences lowest groups confounding truly observed categorized. imperative biases problematic biologics tested. Change clearance (CL) uncovered nivolumab, necessitating dose.23 Recently, "false positive" acknowledged. Various analysis, incorporating case–control comparison, time-varying CL, TGI.23, 34, 43-45 optimization, test studies. ranging relevance ORR progression-free (PFS)). III) ethical considerations speed earlier access. depend prior molecule. Development predictive ORR, PFS, observed/predicted metrics) OS) way bridging gap phases, Finding hot topic apply benefit. Application PD surrogates immensely points.46, 47 Clearly, teamwork, siloed-approach individual pieces puzzle whole picture. each function responsible generating group sole ownership data. collaborate bigger goal optimizing believe adoption regarding innovative analytical clinical, pharmacologic, appropriate, information guide Y.J., A.S. J.Y.J, wrote article. D.M.H. G.K. content receives funding Institutes Health P30 CA008748. views those authors do necessarily represent position government. annual meeting, Dr. Kim employee FDA; however, publication he employed Y.J. stock shareholder Novartis. J.Y.J. Roche/Genentech. A.S Takeda. consulting advisory role Atara Biotheapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, NIH CA008748, Puma Biotechnology, Loxo. federal conflicts meeting article preparation.

Language: Английский

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