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efforts have yielded seminal publications1, 2, 10-13 White Papers14 offering initial recommendations, availability Draft guidance topic.15 We posited that Pharmacology Therapeutics (ASCPT) – as premier professional organization translational optimally positioned host discussion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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Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials

Journal of Clinical Oncology, Journal Year: 2016, Volume and Issue: 34(12), P. 1395 - 1401

Published: March 1, 2016

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on cytotoxic chemotherapy paradigm. Molecularly targeted (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well late-onset and cumulative toxicities. Several approved MTAs been poorly during long-term administration, leading postmarketing optimization studies re-evaluate optimal treatment dose. Using data from completed bortezomib trials, we explore its profile, optimize dose, examine appropriateness designs identifying an dose.We classified captured 481 patients in 14 conducted through National Cancer Institute Therapy Evaluation Program, computed incidence toxicities, compared dose-limiting (DLTs) among groups receiving doses bortezomib.A total 13,008 were captured: 46% patients' first DLTs 88% reductions discontinuations because observed after cycle. Moreover, 1.3 mg/m(2), estimated DLT was > 50%, reduction discontinuation nearly 40%.When considering entire course treatment, exceeds conventional ceiling rate 20% 33%. Retrospective analysis trial provides opportunity MTAs. Future should take into account ensure that a tolerable identified future efficacy comparative trials.

Language: Английский

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Moving Beyond Maximum Tolerated Dose for Targeted Oncology Drugs: Use of Clinical Utility Index to Optimize Venetoclax Dosage in Multiple Myeloma Patients

Clinical Pharmacology & Therapeutics, Journal Year: 2017, Volume and Issue: 102(6), P. 970 - 976

Published: April 17, 2017

Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone previously treated patients multiple myeloma (MM) were performed on a phase Ib dose-ranging study. Logistic regression models utilized to determine relationships, identify subpopulations different responses, optimize the dosage that balanced both efficacy safety. Bortezomib refractory status number prior treatments identified impact response treatment. Higher exposures estimated increase probability achieving very good partial (VGPR) or better through doses 1,200 mg. However, neutropenia (grade ≥3) was at >800 Using clinical utility index, 800 mg daily selected optimally balance VGPR rates MM administered 1-3 lines therapy nonrefractory bortezomib.

Language: Английский

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Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

Cancer Chemotherapy and Pharmacology, Journal Year: 2018, Volume and Issue: 82(1), P. 129 - 138

Published: May 10, 2018

Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that active in the central nervous system (CNS). demonstrated robust efficacy pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final OS safety data to assess dose selection. A semi-parametric Cox proportional hazards model analyzed between individual observed steady-state trough concentrations (Ctrough,ss) combined exposure its major metabolite (M4), baseline covariates (demographics disease characteristics) OS. Univariate logistic regression Ctrough,ss incidence adverse events (AEs: serious Grade ≥ 3). Overall, 92% patients (n = 207/225) had were included analysis. No statistically significant relationship was found following treatment. The only influenced tumor size prior crizotinib treatment duration. Larger shorter both associated with Logistic confirmed no AEs. BID provides systemic exposures at plateau response while maintaining well-tolerated profile. This confirms as recommended global NSCLC.

Language: Английский

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Dose-finding designs for trials of molecularly targeted agents and immunotherapies

Journal of Biopharmaceutical Statistics, Journal Year: 2017, Volume and Issue: 27(3), P. 477 - 494

Published: Feb. 6, 2017

Recently, there has been a surge of early phase trials molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from trial designs that allow inclusion low-grade toxicities, late-onset addition an efficacy endpoint, flexibility in the specification target probability. To study degree adoption these methods, we conducted Web Science search articles published between 2008 2014 describe 1 oncology trials. Trials were categorized based on dose-finding design used type drug studied. Out 1,712 met our criteria, 1,591 (92.9%) utilized rule-based design, 92 (5.4%; range 2.3% 2009 9.7% 2014) model-based or novel design. Over half tested MTA immunotherapy. Among immunotherapy trials, 5.8% 3.9% 8.3% chemotherapy radiotherapy respectively. While percentage using tripled since 2007, continues remain low.

Language: Английский

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