Circulating tumor DNA validity and potential uses in metastatic breast cancer

npj Breast Cancer, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 12, 2024

Abstract Following the first characterization of circulating tumor DNA (ctDNA) in 1990s, recent advances led to its introduction clinics. At present, European Society Of Medical Oncology (ESMO) recommendations endorse ctDNA testing routine clinical practice for genotyping direct molecularly targeted therapies patients with metastatic cancer. In studies on breast cancer, has been utilized treatment tailoring, tracking mechanisms drug resistance, and predicting disease response before imaging. We review available evidence regarding applications

Language: Английский

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Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials

Journal of Clinical Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Over the past 15 years, landscape of early phase clinical trials (EPCTs) has undergone a remarkable expansion in both quantity and intricacy. The proliferation sites, trials, sponsors, contract research organizations surged exponentially, marking significant shift conduct. However, EPCT operations suffer from numerous inefficiencies, such as cumbersome start-up processes, which are particularly critical when drug safety recommended II dose need to be established timely manner. Networks consortia may overcome some these challenges enrolling suitable patients streamlining start-up, distance disease trajectory come into play. In this article, we provide an overview adult oncology across different continents assembled through systematic review literature snowball sampling methodology. We illustrate their scope, structure, funding, achievements. Fifteen were identified including two United States, three Europe, five Asia-Pacific, intercontinental consortia, within private networks. These vary structure government-funded models National Cancer Institute Experimental Therapeutics Clinical Trials charitably funded organizations. play role collaborative research, molecular tumor boards patient-centric biomarker-matched treatments, trial conduct improve timelines cost efficiency. growth activity complexity resulted number globally. By actively engaging with regulatory bodies pharmaceutical organization industries, have opportunity address evolving faced field accelerate translation scientific discoveries practice.

Language: Английский

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Project Optimus, an FDA initiative: Considerations for cancer drug development internationally, from an academic perspective

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: March 3, 2023

Modern cancer therapeutics are increasingly targeted, bringing the promise of new and improved activity, alongside better tolerability. However, while many indeed resulting in dramatic improvements disease control patient survival, short- long-term tolerability has not always accompanied it. The choice dose schedule is often upper range therapeutic window, driven by maximum tolerated (MTD) model previous cytotoxic agents. There increasing recognition that this needs to change, taking a more holistic approach determine optimal for desired biological effects early clinical development. In US, FDA's Oncology Centre Excellence addressing via Project Optimus initiative: aiming reform optimisation studies so they can demonstrate most appropriate selection. Early development will need dose-exposure, -pharmacodynamic, -toxicity -activity relationships, including randomised evaluations Regulatory agencies outside US similarly exploring this. Along with Australia, Brazil, Canada, Israel, Singapore Switzerland, UK participates Orbis, collaborative program FDA accelerate access medicines through coordinated regulatory review. Close alignment be important internationally require changes across industry, academic units small biotech. We discuss our perspective on implications, opportunities, phase oncology trials as uniquely charity-funded drug facility, Drug Development within Cancer Research charity.

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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DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 24(1), P. 19 - 39

Published: Nov. 12, 2024

Language: Английский

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The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development

Annals of Oncology, Journal Year: 2024, Volume and Issue: 35(11), P. 936 - 953

Published: Aug. 25, 2024

Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming potential remain elusive.

Language: Английский

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STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(12)

Published: June 16, 2024

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and Ivy Glioblastoma Atlas, expression was found in myeloid populations perivascular space. The agonist 8803 increased median survival multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% mice were cured. Ex vivo flow cytometry profiling during therapeutic window demonstrated increases trafficking activation, alongside enhancement CD8+ T cell NK effector responses. Treatment with reprogrammed microglia express costimulatory CD80/CD86 iNOS, while decreasing immunosuppressive CD206 arginase. In humanized mice, is epigenetically silenced, activity maintained, further attesting dependency reprogramming. Although combination a STAT3 inhibitor did not enhance activity, addition anti-PD-1 antibodies treatment enhanced blockade-responsive glioma model. summary, as monotherapy demonstrates marked meriting consideration for clinical translation.

Language: Английский

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The multifactorial effect of obesity on the effectiveness and outcomes of cancer therapies

Nature Reviews Endocrinology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

Language: Английский

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Time toxicity associated with early phase clinical trial participation

ESMO Open, Journal Year: 2023, Volume and Issue: 8(6), P. 102046 - 102046

Published: Nov. 16, 2023

Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed dose determination and safety, represent most intensive of all both clinicians patients. We sought to quantify amount patient consumed through EPCT participation.

Language: Английский

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

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2024, Volume and Issue: 13(6), P. 909 - 918

Published: May 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.

Language: Английский

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