Interventional pharmacoeconomics for immune checkpoint inhibitors through alternative dosing strategies

British Journal of Cancer, Год журнала: 2023, Номер 129(9), С. 1389 - 1396

Опубликована: Авг. 4, 2023

Язык: Английский

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Moving the needle for oncology dose optimization: A call for action

CPT Pharmacometrics & Systems Pharmacology, Год журнала: 2024, Номер 13(6), С. 909 - 918

Опубликована: Май 22, 2024

Project Optimus is a major FDA initiative aimed at ensuring dose optimization in oncology drug development, moving away from the maximum tolerated paradigm and prospectively characterizing dose–response for efficacy safety patient-focused maximization of benefit versus risk.1-3 Mitigating toxicities enhancing overall risk therapies necessitates with commitment to evaluation innovative dosing paradigms including individualized approaches, where appropriate. This requires quantitative integration pharmacological mechanism action, efficacy, context associated population variability. The problem cancer pathophysiology, variability sits neatly intersection translational/ precision medicine clinical pharmacology important approach mindset. Forums convened on topic largely engage scientific leaders primarily working research medicine. These include workshops organized by Friends Cancer Research (FOCR),4 American Society Clinical Oncology (ASCO),5, 6 Association (AACR),7, 8 International Pharmacometrics (ISoP)9 partnership US Food Drugs Administration (FDA). Of note, some these efforts have yielded seminal publications1, 2, 10-13 White Papers14 offering initial recommendations, availability Draft guidance topic.15 We posited that Pharmacology Therapeutics (ASCPT) – as premier professional organization translational optimally positioned host discussion opportunities our constituent disciplines (e.g., science, pharmacology, pharmacometrics) synergistically address this multi-disciplinary approach. To end, session was 2023 ASCPT Annual Meeting bringing together representative three journals (CPT), Translational Science (CTS), CPT: Systems (PSP). leaders, at-large representatives medicine, were invited bring forward their opinions participate fireside chat identify needle. enabled engagement broad group experts without requiring primary or affiliation therapeutic area, thereby maximizing diversity opinion, out-of-the-box solutioning, fresh perspectives should help advance us beyond current state. Ahead Meeting, survey launched members meeting attendees get finger pulse Society's membership issues faced provide substrate expert panel. Herein, we present findings survey, review insights gained recommendations communities join forces drive progress. A focused developed sent out February broader session, which consisted six questions relevant (Data S1). open 3 weeks 65 respondents participated survey. not only interested understanding background may influence feedback, but also various approaches challenges modalities. In response question about full time R&D, 58% either engaged had part R&D. suggested feedback diverse backgrounds, intended. Similarly, if strategies other areas are therapies. 86% indeed oncology. Three applied one utility pharmacodynamic (PD) biomarkers, another selection finally study designs focus randomization. 92% responses suggest PD biomarkers least useful. Exposure-response modeling (57%) followed pharmacokinetic (PK)/PD (28%) most preferred selecting doses. 62% did consider randomized dose-ranging necessary optimization, suggesting value application case-by-case leveraging totality evidence optimize (Figure 1). Given area wide range modalities small molecules cell therapies, sought understand level challenge developing each Respondents noted next-generation cytotoxic agents, molecule targeted monoclonal antibodies relatively straightforward many historical examples guide selection. However, antibody-drug conjugates viewed be moderately complex while newer such multi-specific biologics considered very challenging few no 2). From perspective, find right patients swiftly safely possible, buttressed nonclinical data. doesn't always complex. Goldstein et al.16 describe simple concept agents first-in-human setting. suggestions can implemented today. approved doses 25 examined average free concentration steady state (Css) determined similar vitro potency (half-maximal inhibitory (IC50)). Furthermore, authors propose revised trial design therapy cohort expansion initiated less than when there activity Css exceeds threshold informed potency. Ji al.17 case, an inhibitor Porcupine, membrane-bound O-acyltransferase required Wnt secretion. pathway expressed skin tissues; AXIN2 mRNA expression robust sensitive biomarker pathway. predominant issue case dysgeusia. performed integrated PK exposure-response analyses data determine recommended expansion, rather conventional More possible great utility, particularly Weddell al.18 elegant mechanistic model characterizes antibody conjugate (ADC) pharmacokinetics tumor penetration incorporating growth inhibition via ADC binding radially across solid tumors. demonstrates low target expression, payload increased. mechanistically links rates relapse resistance could facilitate optimization. recent example, Susilo al. leveraged systems (QSP) anti-CD20/CD3 T-cell engaging bispecific antibody, mosunetuzumab, account different regimens inter-patient heterogeneity phase I biological determinants dose/exposure-response relationships using novel QSP-derived digital twins approach.19 Approaches nature raise multi-dimensional dimensions dose, patient population, combination partner routinely development. new, development continuing realized. Recent indicate emerging circulating DNA (ctDNA).20, 21 ctDNA, found bloodstream, manifold, detecting diagnosing cancer, guiding tumor-specific treatment, monitoring treatment remission. underlying relationship on-treatment ctDNA dynamics inform definition clinically active represents untapped opportunity. Another innovation has been health technologies proposed multi-domain, capturing functional status, health-related quality life oncology,22 realize promise dosage improved during long-term therapy. ASCPT, pharmacologists, scientists key role collaboration stakeholders. straddles variety stakeholders academics, industry, regulators, others brainstorming consensus formation. For al.,23 reported annual symposium. number observed before Optimus, post-market dose-finding, continued use traditional + designs, lack characterization chronic toxicity, adopting testing more 2/3 trials. fields science yet value-added Cross-stakeholder work expected field increased biomarker-based model-informed solutions finding paper "The Future Trial Design Oncology," Spreafico co-workers Toronto Princess Margaret Centre24 how discovery shifted chemotherapy histology-based targets molecularly immune subsets stratified diagnostic tools. argue classical urgently needs transformed ensure will revolution timely manner. wide-ranging call they patient-centric framework trials, maps journey participant dynamic adaptive continuously technological innovations develop strategies. They conclude success trials based fundamental principles acting locally learn globally treating participants individually collectively." speaks directly opportunity play core new paradigm, particular regard individualization quantitative, integrate knowledge drug, disease, patient. An example QSP, conducted ISoP identified tool utilized developers regimen optimization.25 presented Li al.,26 who II (R2P2D) epcoritamab, CD3×CD20 (bsAb). justified approach, preclinical, PK, biomarker, tumor, dose-escalation I/II trial, basis methods adequately predict bsAbs. Therefore, trimer formation predicted instead actual measures used prediction. Along same lines, Chelliah consortium pharmaceutical companies,27 made conventional, empirical pharmacometrics do fully capitalize all available disease QSP models rational better alternative IO Their proposal "virtual patients" simulated under conditions mimic added aligned earlier-mentioned call-to-action outlined Figure 2 publication,24 future already arrived. Poorly characterized schedule lead provides toxicity additional severe require high rate reductions premature discontinuation result missed drug. remain significant model-based sometimes involve non-static posology, outcome-based adaptation risk.28, 29 offers pivotal reform framework.2, 3, 14, 30-33 By integrating lifecycle, Bayesian learning-and-confirming mindset spectrum, lifecycle 3; top panel) consists building revising collection answer define label. priori consideration pharmacologic inputs elements establishing early access points within open-label design. components improve efficiency enable rapid updates emerge end-to-end utilizes it generated.34-36 predict, interpret, contextualize data, even through simulations outcomes, approximate real-time analysis. both influenced by, influential studies, becomes hypothesis lifecycle. Contemporary evolved utilize model-assisted designs. offer seamless movement cohorts blend escalation evaluation.37, 38 Introducing metrics like pharmacodynamics lower underdosing intrinsic extrinsic factors explain inter-individual reduce bias determination. Several extend dose-toxicity exposure benefit–risk potential drug.39-44 mindset, well-established remains under-utilized It uses program confirm generated.36 (bottom illustrates framework. Expanded larger (to overcome sample size biology impact ability establish signals efficacy) generate preliminarily characterize between exposure, toxicity/tolerability, efficacy. subsequent trial. combined prior collectively defining distributions being informative source quality. probability distribution collected posterior levels desired ratio. When quantity generated high, highly later possibly reducing duration so effective become faster. Maximizing frameworks depend inter-disciplinary alliances pharmacologists statisticians,45 exchange ideas lessons industry regulatory agencies.5 harmonized learnings collaborative interactions further acceptance set precedent programs, ultimately realizing methodologies One main advantages examining non-oncologist translate successful aid enriching holistic toward solving longstanding problems. clear correlate HIV discovery. 1980s, expectancy following AIDS diagnosis approximately year. And 1990s, leading cause death among Americans aged 44. ways, much urgency save lives need therapeutics control epidemic fueled beginning unsophisticated zidovudine initially studied 200 mg q4h, caused anemia neutropenia. fine-tuning eventually led its 300 twice daily. advancements along way infection regarded condition near normal life. Some included deeper continual mechanisms antiretroviral enhanced diagnostics, biomarkers. deployed simultaneously, integrated, advanced methodology urgent public problem. biggest faces now operationalize. No matter proper prospective dose-finding outset, focusing strategy, incredibly beneficial. examples, blood pressure reduction, lowering HbA1c, reduction LDL cholesterol extensively correlated strongly outcomes interest surrogate endpoints. exploration stage critical investment return. R&D explosive advances Drug involves Dose several 4), demanding inter-connected iterative generation Totality Evidence approaching tailored medicines cancers molecular footprints, cannot approached Size Fits Diversity profile immunophenotype considerations patients. Advances sciences informatics enabling deep immunology populations, rapidly applications machine learning artificial intelligence harness multimodal multidimensional represent invaluable platforms requirements. Such elevate fidelity selection, As evident results obligate requirement cases 60% respondents. Indeed, exist integrative confidence anticancer published stories.26, 46-48 substantiated consistency multiple sources mechanism-informed manner simulation.49 critically challenging. pleased note progress publications highlighting translational, therapeutics.50-55 real-life continue refine best practices invite readership cross-sector practitioners submit publication. trust rigorous debate ensue practice, facilitated ASCPT's Networks Communities, go long elevating benefit/ Editorial support provided Dr. Madhuri Shendre, BAMS (Merck Specialties Pvt. Ltd., Bengaluru, India, affiliate Merck KGaA). funding received work. declared competing interests Data S1. Please note: publisher responsible content functionality any supporting information supplied authors. Any queries (other missing content) directed corresponding author article.

Язык: Английский

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Assessing the reporting quality of early phase dose-finding trial protocols: a methodological review

EClinicalMedicine, Год журнала: 2023, Номер 60, С. 102020 - 102020

Опубликована: Май 25, 2023

BackgroundThe paradigm of early phase dose-finding trials has evolved in recent years. Innovative designs and protocols which combine phases I II are becoming more popular health research. However, the quality these trial is unknown due to a lack specific reporting guidelines. Here, we evaluated protocols.MethodsWe conducted cross-sectional study oncology non-oncology posted on ClinicalTrials.gov 2017–2023. A checklist items comprising: 1) original 33-items from SPIRIT 2013 Statement 2) additional unique were used assess quality. The primary endpoint was overall proportion adequately reported items. This registered with PROSPERO (no: CRD42022314572).FindingA total 106 included rule-based 3 + being most design (39.6%). Eleven model-based model-assisted identified only (11/58, 19.0%). 65.1% (95%CI: 63.9–66.3%). each individual item varied substantially (range 9.4%–100%). Oncology showed lower than non-oncology. In multivariable analysis, larger sample sizes industry funding associated higher proportions (all p-values <0.05).InterpretationThe suboptimal (65.1%). There need for improved completeness transparency facilitate rigorous conduct, reproducibility external review.FundingNone.

Язык: Английский

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Encorafenib and Binimetinib: A New Treatment Option for BRAF^V600E-Mutant Non–Small-Cell Lung Cancer

Journal of Clinical Oncology, Год журнала: 2023, Номер 41(21), С. 3679 - 3681

Опубликована: Июнь 4, 2023

Consulting or Advisory Role: Janssen Oncology (Less than $10,000 USD in a single calendar year), Turning Point Therapeutics Sanofi/Aventis GlaxoSmithKline Genentech/Roche Daiichi Sankyo/AstraZeneca Takeda Eisai/H3 Biomedicine G1 Spectrum Pharmaceuticals ($10,000 above year) Research

Язык: Английский

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CONSORT-DEFINE explanation and elaboration: recommendations for enhancing reporting quality and impact of early phase dose-finding clinical trials

EClinicalMedicine, Год журнала: 2025, Номер 79, С. 102987 - 102987

Опубликована: Янв. 1, 2025

SummaryEarly phase dose-finding (EPDF) trials are key in the development of novel therapies, with their findings directly informing subsequent clinical phases and providing valuable insights for reverse translation. Comprehensive transparent reporting these studies is critical accurate interpretation, which may improve expedite therapeutic development. However, quality design characteristics results from EPDF often variable incomplete. The international consensus-based CONSORT-DEFINE (Consolidated Standards Reporting Trials Dose-finding Extension) statement, an extension CONSORT statement randomised trials, was developed to trials. introduced 21 new items modified 19 existing items.This Explanation Elaboration (E&E) document provides important information enhance understanding facilitate implementation checklist. For each or checklist item, we provide a detailed description its rationale supporting evidence, present examples trial reports published peer-reviewed scientific journals. When authors encouraged consult E&E document, together papers, adhere recommendations. Widespread adoption likely thus facilitating peer review such appraisal by researchers, regulators, ethics committee members, funders.FundingThis work further study, funded UK Medical Research Council (MRC)-National Institute Health Care (NIHR) Methodology Programme (MR/T044934/1). Clinical Statistics Unit at Cancer (ICR-CTSU) receives programmatic infrastructure funding (C1491/A25351; CTUQQR-Dec 22/100 004), has contributed accelerating advancement successful completion this work.

Язык: Английский

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SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols

EClinicalMedicine, Год журнала: 2025, Номер 79, С. 102988 - 102988

Опубликована: Янв. 1, 2025

Язык: Английский

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First‐In‐Human Dose Finding Study of Venadaparib (IDX‐1197), a Potent and Selective PARP Inhibitor, in Patients With Advanced Solid Tumors

Cancer Medicine, Год журнала: 2025, Номер 14(4)

Опубликована: Фев. 1, 2025

ABSTRACT Background Venadaparib, a novel poly (ADP‐ribose) polymerase (PARP) inhibitor, has demonstrated high PARP‐1/2 selectivity over other PARP family members and exhibited strong PARP‐trapping activity, effectively inhibiting tumor growth in homologous recombination deficient (HRD) cancer vitro vivo. Methods This phase 1, dose‐finding study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics anticancer efficacy of venadaparib as monotherapy patients with advanced solid tumors that progressed after standard‐of‐care therapy. The employed conventional 3+3 design, doses ranging from 2 mg/d to 240 mg/d. Results Among 32 enrolled patients, most common types were breast (16 patients) ovarian (12 cancers. No dose‐limiting toxicities (DLTs) observed up frequent grade 3 or 4 adverse events anemia (50%), neutropenia (22%) thrombocytopenia (6%). Tumor shrinkage by Response Evaluation Criteria Solid Tumours (RECIST) was at ≥ 40 mg/d, regardless BRCA mutation status.Two partial responses out four receiving reported. Clinical benefit, defined stable disease response, lowest tested dose. Venadaparib 90% PAR inhibitory effect pharmacodynamic analysis 10 based on samples. recommended dose (RP2D) 160 mg once daily. Conclusions Further studies are warranted explore safety combination various agents, well relevant biomarkers. (ClinicalTrials.gov ID: NCT03317743).

Язык: Английский

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Small molecules for Kirsten rat sarcoma viral oncogene homolog mutant cancers: Past, present, and future

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177428 - 177428

Опубликована: Фев. 1, 2025

Язык: Английский

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From Dose-Finding to Dose-Optimization in Early-Phase oncology clinical trials

Cancer Treatment Reviews, Год журнала: 2025, Номер 136, С. 102906 - 102906

Опубликована: Март 4, 2025

Язык: Английский

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BF‐BOIN‐ET: A Backfill Bayesian Optimal Interval Design Using Efficacy and Toxicity Outcomes for Dose Optimization

Pharmaceutical Statistics, Год журнала: 2025, Номер 24(2)

Опубликована: Март 1, 2025

The primary purpose of a dose-finding trial for novel anticancer agents is to identify an optimal dose (OD), defined as the tolerable that has adequate efficacy in unpredictable dose-toxicity and dose-efficacy relationships. FDA project Optimus reforms paradigm optimization recommends trials compare multiple doses generate these additional data at promising levels. backfill helpful settings where drug does not always increase with level. More information available by backfilling patients lower while continues explore higher doses. This paper proposes Bayesian interval design using toxicity outcomes allows be backfilled during prioritizing dose-escalation cohort dose. A simulation study shows proposed design, BF-BOIN-ET advantages compared other designs terms percentage correct OD selection, reducing sample size, shortening duration various realistic settings.

Язык: Английский

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