Targeted Therapeutic Approaches for the Treatment of Cancer: The Future Is Bright

Journal of Personalized Medicine, Journal Year: 2025, Volume and Issue: 15(4), P. 141 - 141

Published: April 2, 2025

The last two decades have ushered in unprecedented advancements the treatment of cancer [...]

Language: Английский

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Oncology Dose Optimization: Tailored Approaches to Different Molecular Classes

Clinical Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: April 18, 2025

Oncology dose optimization during the era of chemotherapy focused on identifying maximum tolerated (MTD) for registrational trials, often resulting in significant toxicity. The advent molecular targeted drugs and immunotherapies offers potential to achieve similar efficacy with lower doses fewer side effects, as maximal is reached at below MTD. Recent FDA guidance outlines expectations improving oncology drug development. This review presents a framework tailored by categorizing molecules into four distinct classes based their mechanisms action clinical activities: small molecule therapies antibody‐drug conjugates (Class 1), large antagonists 2), cancer immunotherapy agonists 3), limited or no single‐agent activity 4). Unique considerations each class are discussed, supported illustrative case examples. To enhance robust decision‐making optimize patient resource utilization, we propose using proof gate initiating expansion one multiple levels. emphasizes importance integrating all relevant preclinical data, disease knowledge, measurements highlights essential role quantitative pharmacology statistical modeling optimizing doses.

Language: Английский

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AI in the development of vaccines for emerging and re-emerging diseases

Salud Ciencia y Tecnología, Journal Year: 2025, Volume and Issue: 4

Published: Jan. 15, 2025

Introduction: The integration of artificial intelligence (AI) into vaccine development has revolutionized traditional methodologies, significantly enhancing the speed, precision, and scalability immunological research. Emerging re-emerging infectious diseases, driven by zoonotic spillovers, antimicrobial resistance, global environmental changes, pose substantial challenges. Addressing these requires innovative approaches, with AI playing a pivotal role in advancing solutions.Development: applications vaccinology include antigen detection, adjuvant optimization, immune response simulation. Deep learning algorithms streamline identification immunogenic targets conserved antigens, enabling for highly mutable pathogens such as SARS-CoV-2, HIV, influenza. Case studies demonstrate AI's transformative impact, including its rapid creation mRNA vaccines COVID-19, promising antigens malaria, enhanced efficacy influenza through predictive modeling. However, challenges unequal access to technology, biases data models, ethical concerns regarding genomic privacy persist. Recommendations address barriers increasing diversity, strengthening frameworks, investing infrastructure democratize AI-driven innovations.Conclusions: ability reduce time cost, improve enable personalized immunization strategies positions it cornerstone modern vaccinology. With continued advancements equitable implementation, holds potential reshape development, pandemic preparedness, longstanding public health disparities globally.

Language: Английский

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Barriers to publishing early phase clinical trials: the oncologists’ perspective

The Oncologist, Journal Year: 2025, Volume and Issue: 30(4)

Published: April 1, 2025

Abstract Introduction Findings from early phase studies are not always placed in the public domain. This study aims to explore why many clinical oncology published, as well identify potential barriers investigators encountered publication process. Methods Semi-structured interviews were conducted among with experience studies. Interviews analyzed using reflexive thematic analysis. Results Twenty-one interviewed. The majority worked Europe (n = 13), while other based North America 4), Asia 2) or Oceania 2). We identified three reasons believed publishing trial results was important: (1) there is an ethical and moral responsibility; (2) should be no loss of knowledge society; (3) waste resources. Four main process trials identified: practical (eg, increased complexity number trials/trial sites), insufficient resources money, time human), limited motivation intrinsic investigator prospect return for sponsor), (4) inadequate collaboration different interests between industry partners investigators). Finally, five major stakeholders that can potentially contribute improving process: journal editors, sponsors, investigators, regulatory bodies, (5) society. Investigator suggestions this process, each stakeholder, presented. Conclusions highlights experienced trials. Recognizing acknowledging these crucial devise effective strategies improve sharing

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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Advancements in programmed cell death research in antitumor therapy: a comprehensive overview

APOPTOSIS, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 2, 2024

Language: Английский

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UGT1A1 Testing in Breast Cancer: should it become routine practice in patients treated with antibody-drug conjugates?

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 196, P. 104265 - 104265

Published: Feb. 1, 2024

Language: Английский

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Moving the Needle for Oncology Dose Optimization: A Call for Action

Clinical Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 115(6), P. 1187 - 1197

Published: May 12, 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 response for efficacy safety patient-focused maximization of benefit vs. 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 medicine—is optimally positioned host discussion opportunities our constituent disciplines (e.g., science, pharmacology, pharmacometrics) synergistically address this multidisciplinary approach. To end, session was 2023 ASCPT Annual Meeting bringing together representative three journals Society—Clinical (CPT), Translational Science (CTS), CPT: Systems (PSP). leaders, as at-large representatives 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 solutions, fresh perspectives should help advance us beyond current state. Ahead annual meeting, survey launched members meeting attendees get finger pulse society's membership issues faced provide substrate expert panel. Herein, we present findings review insights gained recommendations communities join forces drive progress. A focused developed sent out February broader session, which consisted six questions relevant (Supplementary Information). open 3 weeks 65 respondents participated survey. not only interested understanding background may influence feedback, but also various approaches challenges modalities. In question about full-time R&D, 58% either engaged had part-time R&D. suggested feedback diverse backgrounds, intended. Similarly, if strategies other areas are therapies. Eighty-six percent indeed oncology. Three applied optimization—one utility pharmacodynamic (PD) biomarkers, another one selection, finally study designs focus randomization. Ninety-two 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 multispecific biologics considered very challenging few no 2). From perspective, find right patients swiftly safely possible, buttressed nonclinical data. does 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 analyses data determine recommended expansion, rather conventional More possible great utility, particularly Weddell al.18 elegant mechanistic model characterizes 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.19 leveraged systems (QSP) anti-CD20/CD3 T-cell engaging bispecific antibody, mosunetuzumab, account different regimens interpatient heterogeneity phase I biological determinants dose/exposure–response relationships using novel QSP-derived digital twins Approaches nature raise multidimensional dimensions dose, patient population, combination partner—a 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 remission. underlying relationship on-treatment ctDNA dynamics inform definition clinically active represents untapped opportunity. Another innovation has been health technologies proposed multidomain, 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 symposium. number observed before Optimus, post-market dose-finding, continued use traditional + designs, lack characterization chronic toxicity, adopting testing more II/III 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-workers24 Toronto Princess Margaret Centre how discovery shifted chemotherapy histology-based targets molecularly immune subsets stratified diagnostic precision 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 selection optimization.25 presented Li al.,26 who II (R2P2D) epcoritamab, CD3xCD20 antibody (bsAb). justified approach, preclinical, PK, biomarker, tumor, dose-escalation part I/II trial, basis methods adequately predict bsAbs. Therefore, trimer formation predicted instead actual measures used prediction. Along same lines, Chelliah27 consortium pharmaceutical companies, 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 al.24 outlined Figure 2 publication, 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 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 interindividual reduce bias determination. Several extend dose-toxicity exposure benefit–risk potential drug.39-44 mindset, well established remains underutilized 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 interdisciplinary 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 nononcologist translate successful aid enriching holistic toward solving longstanding problems. clear correlate HIV discovery. 1980s, expectancy following AIDS diagnosis ~1 year. And 1990s, leading cause death among Americans aged 25–44. ways, much urgency save lives need therapeutics control epidemic fueled beginning unsophisticated dosing—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 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 interconnected 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 represent invaluable platforms requirements. Such elevate fidelity partner As evident results survey, 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/risk Editorial support provided Dr Madhuri Shendre, BAMS (Merck Specialties Pvt. Ltd., Bengaluru, India, affiliate Merck KGaA). editorial co-published journals: & Therapeutics, Pharmacology, Science. 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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Moving the needle for oncology dose optimization: A call for action

Clinical and Translational Science, Journal Year: 2024, Volume and Issue: 17(6)

Published: June 1, 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 vs. 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 mechanisms action, efficacy, context associated population variability. The problem mechanism 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 medicine—is 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 Society—Clinical (CPT), Translational Science (CTS), CPT: Systems (PSP). leaders, as at-large representatives 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 solutions, 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 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-time R&D. suggested diverse backgrounds, intended. Similarly, if strategies other areas are therapies. And 86% indeed oncology. Three applied optimization—one utility pharmacodynamic (PD) biomarkers, another one 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 modalities, such multi-specific biologics considered very challenging few no 2). From perspective, find right patients swiftly safely possible, buttressed nonclinical data. does 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 analyses data determine recommended expansion, rather conventional More possible great utility, particularly Weddell al.18 elegant mechanistic model characterizes 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 multidimensional dimensions dose, patient population, combination partner—a 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 multidomain, 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 2018 reported annual symposium. number observed before Optimus, postmarket dose-finding, continued use traditional + designs, lack characterization chronic toxicity, adopting testing more II/III trials. fields science yet value-added Cross-stakeholder work expected field increased biomarker-based model-informed solutions dose-finding article "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 selection optimization.25 presented Li al.,26 who II (R2P2D) epcoritamab, CD3 × CD20 antibody (bsAb). justified approach, preclinical, PK, biomarker, tumor, dose-escalation part I/II trial, basis methods adequately predict bsAbs. Therefore, trimer formation predicted instead actual measures used prediction. Along same lines, paper Chelliah consortium pharmaceutical companies27 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 al.24 outlined Figure 2 publication, future already arrived. Poorly characterized schedule lead provides toxicity additional severe require high rate reductions, premature discontinuation result missed drug. vs 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 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 1 year. 1990s, leading cause death among Americans aged 25–44. ways, much urgency save lives need therapeutics control epidemic fueled beginning unsophisticated dosing—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 much-improved life. Some included deeper continual antiretroviral enhanced diagnostics, biomarkers. deployed simultaneously, integrated, advanced methodology urgent public problem. biggest faces now operationalize. No matter proper prospective outset, focusing strategy, incredibly beneficial. examples, blood pressure reduction, lowering HbA1c, reduction LDL cholesterol extensively correlated strongly outcomes interest surrogate end points. 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 represent invaluable platforms requirements. Such elevate fidelity partner As evident results survey, 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 Journals 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/risk Editorial support provided Dr. Madhuri Shendre, BAMS (Merck Specialties Pvt. Ltd., Bengaluru, India, affiliate Merck KGaA). 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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Model‐informed Evidence for Clinical Non‐inferiority of Every‐2‐Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer

Clinical Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 116(4), P. 1071 - 1081

Published: Aug. 12, 2024

Cetuximab was initially developed and approved as a first‐line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m 2 Q1W 400 loading dose). An every‐2‐weeks schedule (500 Q2W) recently by several health authorities. Being synchronized chemotherapy, Q2W should improve patients' convenience healthcare resource utilization. Herein, we present evidence of non‐inferiority cetuximab, compared dosing using pharmacometrics modeling clinical trial simulation (CTS). Pooled data from five phase I–III trials 852 KRAS wild‐type mCRC treated or cetuximab were modeled population exposure–tumor size (TS) model linked to overall survival (OS); exposure derived previously established pharmacokinetic model. A semi‐mechanistic TS adapted the Claret incorporated killing rate proportional area under concentration‐time curve over weeks (AUC) Eastern Cooperative Oncology Group (ECOG) status covariate on baseline TS. The OS Weibull hazard ECOG, TS, primary tumor location, predicted percent change at 8 covariates. Model‐based simulations revealed indistinguishable early shrinkage between vs. cetuximab. CTS evaluated (predefined margin 1.25) 1,000 trials, each 2,000 virtual receiving (1:1), demonstrated 94% cases. Taken together, these analyses provide model‐based potential benefits providers.

Language: Английский

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