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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Metabolic crossroads: unravelling immune cell dynamics in gastrointestinal cancer drug resistance

Cancer Drug Resistance, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Metabolic reprogramming within the tumor microenvironment (TME) plays a critical role in driving drug resistance gastrointestinal cancers (GI), particularly through pathways of fatty acid oxidation and glycolysis. Cancer cells often rewire their metabolism to sustain growth reshape TME, creating conditions such as nutrient depletion, hypoxia, acidity that impair antitumor immune responses. Immune TME also undergo metabolic alterations, frequently adopting immunosuppressive phenotypes promote progression reduce efficacy therapies. The competition for essential nutrients, glucose, between cancer compromises functions effector cells, T cells. Additionally, by-products like lactate kynurenine further suppress activity populations, including regulatory M2 macrophages. Targeting glycolysis presents new opportunities overcome improve therapeutic outcomes GI cancers. Modulating these key has potential reinvigorate exhausted shift toward phenotypes, enhance effectiveness immunotherapies other treatments. Future strategies will require continued research into metabolism, development novel inhibitors, clinical trials evaluating combination Identifying validating biomarkers be crucial patient stratification treatment monitoring. Insights may have broader implications across multiple types, offering avenues improving treatment.

Language: Английский

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TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e010584 - e010584

Published: Feb. 1, 2025

Background M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β PD-(L)1 pathways. Methods This first-in-human, dose-escalation study in patients advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated alone (Part 1A, n=40; 10–2400 mg every 2 weeks, n=32; 2400 3 n=8) or BA 1B, n=18; 300–1600 1200 mg; both intravenous). Primary objectives were safety, tolerability, maximum tolerated dose (MTD) recommended for expansion (RDE). Additional included pharmacokinetics, pharmacodynamics clinical activity ( NCT04457778 ). Results Two dose-limiting toxicities observed: grade adrenal insufficiency 1A: 900 weeks) anemia 1B: 300 mg, only related). MTD was not reached. Overall, median overall survival progression-free 7.6 (95% CI 4.9, 12.0) 1.4 1.3, 1.8) months, respectively. Stable disease as best response observed 13 (32.5%) 5 (27.8%) parts 1A M6223±BA displayed linear pharmacokinetic profile. Anti-TIGIT mode-of-action-related pharmacodynamic effects peripheral blood tumor tissue. RDEs 1600 weeks monotherapy 1600+1200 M6223+BA. Conclusions had manageable safety profile, defined combination therapy. Further evaluation of ongoing the PD-L1 inhibitor avelumab urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530 Trial registration number .

Language: Английский

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Dose Optimization in Oncology Drug Development: An International Consortium for Innovation and Quality in Pharmaceutical Development White Paper

Clinical Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 116(3), P. 531 - 545

Published: May 16, 2024

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality life for patients with cancer. Project Optimus, introduced by U.S. Food Drug Administration, stands as a groundbreaking endeavor to reform dose selection drugs, presenting both opportunities challenges field. To address complex optimization challenges, an Oncology Dose Optimization IQ Working Group was created characterize current practices, provide recommendations improvement, develop toolkit, engage Health Authorities. Historically, cytotoxic chemotherapeutics focused on maximum tolerated dose, paradigm that is less relevant targeted therapies new treatment modalities. A survey conducted this group gathered insights from member companies regarding industry practices in optimization. Given effort multidimensional high failure rates due lack clinically efficacy, advocates case‐by‐case approach inform timing, specific quantitative targets, strategies optimization, depending factors such disease characteristics, patient population, mechanism action, including associated resistance mechanisms, therapeutic index. This white paper highlights evolving nature impact need tailored evidence‐based optimize dosing regimens effectively.

Language: Английский

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Landscape analysis of adverse events and dose intensity for FDA approved oncology small molecules

Cancer Chemotherapy and Pharmacology, Journal Year: 2025, Volume and Issue: 95(1)

Published: Jan. 4, 2025

Language: Английский

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Model‐Informed Selection of the Recommended Phase 2 Dosage for Anti‐TIGIT Immunotherapy Leveraging co‐Expressed PD‐1 Inhibitor Target Engagement

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

Published: Feb. 8, 2025

Refining dose projections requires a deep understanding of drug-target relationships at the site action, which is often challenging to achieve. Here we present case study how one can refine for TIGIT-targeted immunotherapy by leveraging information from well-studied PD-1 pathway since co-expression and TIGIT on immune cells provides unique opportunity extrapolate data target inform dosing strategy other. We develop fit-for-purpose mathematical model that captures experimentally observed relationship between concentration mouse antagonist in plasma engagement within tumor microenvironment (TME). then assess applicability this elucidate drug tiragolumab, an anti-TIGIT antibody, across various doses. This analysis aims our dose-response targeting TIGIT, critical step optimizing therapeutic efficacy, without conducting additional experiments. The approach extended project efficacious doses M6223, another using established model, M6223 clinical PK PD data, as well virtual population analysis. work possible framework refining via quantitative estimation action relationships. Through extrapolating well-characterized pathway, offer method optimization strategies with limited model-informed development.

Language: Английский

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Indication‐Specific Dosing and Dose‐Evaluation Strategies in New Indications for Non‐Oncology Monoclonal Antibodies

The Journal of Clinical Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Abstract Compared to traditional small molecule drugs, monoclonal antibodies (mAbs) often display more complex pharmacokinetic (PK) and pharmacodynamic (PD) properties that may be impacted by disease‐specific factors. For mAbs in non‐oncology indications, where the same drug might used for conditions involving different organ systems and/or having degrees of severity, need indication‐specific dosing tailored dose evaluation strategies is evident. However, a comprehensive analysis on this topic has not been conducted approved therapies. In work, we extracted literature information past 20 years provide exploration new indications. Our included 21 with 50 supplemental approvals Indication‐specific was prevalent, 15 out recommended regimens across two or The majority indications were supported Phase 2 dose‐ranging studies 3 evaluated than one regimen. Importantly, our uncovered relationship between dosing, strategies, system classification original versus indication. We delved into justification supporting including types data modeling approaches considered. Through case studies, highlighted factors influence selection such as target expression levels, disease benefit–risk profile. Lastly, made practical recommendations regarding optimization clinical development multiple

Language: Английский

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Dose Determinations at Drug Approval Reviews: FDA‐Approved Drugs in Past 5 Years

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

Published: Feb. 25, 2025

Drug dose appropriateness is one of the most discussed issues in regulatory reviews. We analyzed determinations during Food and Administration (FDA) drug reviews to determine whether there were changes between proposed approved doses new molecular entities (NMEs), including cases where postmarketing dose‐finding studies requested, explored factors associated with these decisions. Of 218 eligible NMEs 2018 2022, 28 drugs (13%) had modifications or requested additional assessments, 20 which a lower (“downward,” 9.2%) five higher (“upward,” 2.3%). Multinomial logistic regression analysis suggested that products used Accelerated Approval program more likely undergo downward modification (relative risk ratio (RRR) = 5.73). In addition, fact dose/exposure–response relationship was observed for safety, but not efficacy, an increased probability (RRR: 4.27). contrast, use pharmacodynamic biomarkers setting designation Priority Review decreased probabilities change 0.405 0.195, respectively). Infectious disease went through upward than those other therapeutic categories. This study revealed “optimization” occurs FDA's review approval only product characteristics also related process are decisions modify question dose, suggesting considerations presence compelling evidence restrictions data availabilities.

Language: Английский

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Embracing the future of medicine with virtual patients

Drug Discovery Today, Journal Year: 2025, Volume and Issue: unknown, P. 104322 - 104322

Published: March 1, 2025

Language: Английский

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Pharmacology and pharmacokinetics of antibody-drug conjugates, where do we stand?

Cancer Treatment Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102922 - 102922

Published: March 1, 2025

Language: Английский

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