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Liu H, Ibrahim EIK, Centanni M, Sarr C, Venkatakrishnan K, Friberg LE. Integrated modeling of biomarkers, survival and safety in clinical oncology drug development. Adv Drug Deliv Rev 2025; 216:115476. [PMID: 39577694 DOI: 10.1016/j.addr.2024.115476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/12/2024] [Accepted: 11/15/2024] [Indexed: 11/24/2024]
Abstract
Model-based approaches, including population pharmacokinetic-pharmacodynamic modeling, have become an essential component in the clinical phases of oncology drug development. Over the past two decades, models have evolved to describe the temporal dynamics of biomarkers and tumor size, treatment-related adverse events, and their links to survival. Integrated models, defined here as models that incorporate at least two pharmacodynamic/ outcome variables, are applied to answer drug development questions through simulations, e.g., to support the exploration of alternative dosing strategies and study designs in subgroups of patients or other tumor indications. It is expected that these pharmacometric approaches will be expanded as regulatory authorities place further emphasis on early and individualized dosage optimization and inclusive patient-focused development strategies. This review provides an overview of integrated models in the literature, examples of the considerations that need to be made when applying these advanced pharmacometric approaches, and an outlook on the expected further expansion of model-informed drug development of anticancer drugs.
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Affiliation(s)
- Han Liu
- Department of Pharmacy, Uppsala University, Box 580, 75123, Uppsala, Sweden
| | - Eman I K Ibrahim
- Department of Pharmacy, Uppsala University, Box 580, 75123, Uppsala, Sweden
| | - Maddalena Centanni
- Department of Pharmacy, Uppsala University, Box 580, 75123, Uppsala, Sweden
| | - Céline Sarr
- Pharmetheus AB, Dragarbrunnsgatan 77, 753 19, Uppsala, Sweden
| | | | - Lena E Friberg
- Department of Pharmacy, Uppsala University, Box 580, 75123, Uppsala, Sweden.
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2
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Tosca EM, De Carlo A, Bartolucci R, Fiorentini F, Di Tollo S, Caserini M, Rocchetti M, Bettica P, Magni P. In silico trial for the assessment of givinostat dose adjustment rules based on the management of key hematological parameters in polycythemia vera patients. CPT Pharmacometrics Syst Pharmacol 2024; 13:359-373. [PMID: 38327117 PMCID: PMC10941510 DOI: 10.1002/psp4.13087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 02/09/2024] Open
Abstract
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone-deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight-treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109 /L, WBC ≤10 × 109 /L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles.
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Affiliation(s)
- Elena M. Tosca
- Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, Department of Electrical, Computer and Biomedical EngineeringUniversità degli Studi di PaviaPaviaItaly
| | - Alessandro De Carlo
- Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, Department of Electrical, Computer and Biomedical EngineeringUniversità degli Studi di PaviaPaviaItaly
| | - Roberta Bartolucci
- Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, Department of Electrical, Computer and Biomedical EngineeringUniversità degli Studi di PaviaPaviaItaly
| | | | - Silvia Di Tollo
- Clinical R&D Department, Italfarmaco S.p.ACinisello BalsamoItaly
| | | | | | - Paolo Bettica
- Clinical R&D Department, Italfarmaco S.p.ACinisello BalsamoItaly
| | - Paolo Magni
- Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, Department of Electrical, Computer and Biomedical EngineeringUniversità degli Studi di PaviaPaviaItaly
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3
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Shemesh CS, Chan P, Marchand M, Gonçalves A, Vadhavkar S, Wu B, Li C, Jin JY, Hack SP, Bruno R. Early Decision Making in a Randomized Phase II Trial of Atezolizumab in Biliary Tract Cancer Using a Tumor Growth Inhibition-Survival Modeling Framework. Clin Pharmacol Ther 2023; 114:644-651. [PMID: 37212707 DOI: 10.1002/cpt.2953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 05/09/2023] [Indexed: 05/23/2023]
Abstract
We assess the longitudinal tumor growth inhibition (TGI) metrics and overall survival (OS) predictions applied to patients with advanced biliary tract cancer (BTC) enrolled in IMbrave151 a multicenter randomized phase II, double-blind, placebo-controlled trial evaluating the efficacy and safety of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine. Tumor growth rate (KG) was estimated for patients in IMbrave151. A pre-existing TGI-OS model for patients with hepatocellular carcinoma in IMbrave150 was modified to include available IMbrave151 study covariates and KG estimates and used to simulate IMbrave151 study outcomes. At the interim progression-free survival (PFS) analysis (98 patients, 27 weeks follow-up), clear separation in tumor dynamic profiles with a faster shrinkage rate and slower KG (0.0103 vs. 0.0117 week-1 ; tumor doubling time 67 vs. 59 weeks; KG geometric mean ratio of 0.84) favoring the bevacizumab containing arm was observed. At the first interim analysis for PFS, the simulated OS hazard ratio (HR) 95% prediction interval (PI) of 0.74 (95% PI: 0.58-0.94) offered an early prediction of treatment benefit later confirmed at the final analysis, observed HR of 0.76 based on 159 treated patients and 34 weeks of follow-up. This is the first prospective application of a TGI-OS modeling framework supporting gating of a phase III trial. The findings demonstrate the utility for longitudinal TGI and KG geometric mean ratio as relevant end points in oncology studies to support go/no-go decision making and facilitate interpretation of the IMbrave151 results to support future development efforts for novel therapeutics for patients with advanced BTC.
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Affiliation(s)
- Colby S Shemesh
- Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Phyllis Chan
- Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | | | | | - Shweta Vadhavkar
- Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Benjamin Wu
- Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Chunze Li
- Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Jin Y Jin
- Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA
| | - Stephen P Hack
- Product Development Oncology, Genentech Inc., South San Francisco, California, USA
| | - Rene Bruno
- Clinical Pharmacology, Genentech-Roche, Marseille, France
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Senchukova MA. Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer. World J Gastroenterol 2021; 27:8262-8282. [PMID: 35068869 PMCID: PMC8717017 DOI: 10.3748/wjg.v27.i48.8262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/02/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains a serious oncological problem, ranking third in the structure of mortality from malignant neoplasms. Improving treatment outcomes for this pathology largely depends on understanding the pathogenesis and biological characteristics of GC, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers. It is known that the main cause of death from malignant neoplasms and GC, in particular, is tumor metastasis. Given that angiogenesis is a critical process for tumor growth and metastasis, it is now considered an important marker of disease prognosis and sensitivity to anticancer therapy. In the presented review, modern concepts of the mechanisms of tumor vessel formation and the peculiarities of their morphology are considered; data on numerous factors influencing the formation of tumor microvessels and their role in GC progression are summarized; and various approaches to the classification of tumor vessels, as well as the methods for assessing angiogenesis activity in a tumor, are highlighted. Here, results from studies on the prognostic and predictive significance of tumor microvessels in GC are also discussed, and a new classification of tumor microvessels in GC, based on their morphology and clinical significance, is proposed for consideration.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460021, Russia
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Bornkamp B, Rufibach K, Lin J, Liu Y, Mehrotra DV, Roychoudhury S, Schmidli H, Shentu Y, Wolbers M. Principal stratum strategy: Potential role in drug development. Pharm Stat 2021; 20:737-751. [PMID: 33624407 DOI: 10.1002/pst.2104] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/01/2020] [Accepted: 02/05/2021] [Indexed: 12/12/2022]
Abstract
A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called intercurrent events in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post-hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions.
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Affiliation(s)
- Björn Bornkamp
- Clinical Development and Analytics, Novartis, Basel, Switzerland
| | - Kaspar Rufibach
- Methods, Collaboration, and Outreach Group (MCO), Department of Biostatistics, Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Jianchang Lin
- Statistical & Quantitative Sciences (SQS), Takeda Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Yi Liu
- Nektar Therapeutics, San Francisco, California, USA
| | - Devan V Mehrotra
- Clinical Biostatistics, Merck & Co., Inc., North Wales, Pennsylvania, USA
| | | | - Heinz Schmidli
- Clinical Development and Analytics, Novartis, Basel, Switzerland
| | - Yue Shentu
- Merck & Co., Inc., Rahway, New Jersey, USA
| | - Marcel Wolbers
- Methods, Collaboration, and Outreach Group (MCO), Department of Biostatistics, Hoffmann-La Roche Ltd, Basel, Switzerland
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Alfonso S, Jenner AL, Craig M. Translational approaches to treating dynamical diseases through in silico clinical trials. CHAOS (WOODBURY, N.Y.) 2020; 30:123128. [PMID: 33380031 DOI: 10.1063/5.0019556] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/20/2020] [Indexed: 06/12/2023]
Abstract
The primary goal of drug developers is to establish efficient and effective therapeutic protocols. Multifactorial pathologies, including dynamical diseases and complex disorders, can be difficult to treat, given the high degree of inter- and intra-patient variability and nonlinear physiological relationships. Quantitative approaches combining mechanistic disease modeling and computational strategies are increasingly leveraged to rationalize pre-clinical and clinical studies and to establish effective treatment strategies. The development of clinical trials has led to new computational methods that allow for large clinical data sets to be combined with pharmacokinetic and pharmacodynamic models of diseases. Here, we discuss recent progress using in silico clinical trials to explore treatments for a variety of complex diseases, ultimately demonstrating the immense utility of quantitative methods in drug development and medicine.
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Affiliation(s)
- Sofia Alfonso
- Department of Physiology, McGill University, Montreal, Quebec H3A 0G4, Canada
| | - Adrianne L Jenner
- Department of Mathematics and Statistics, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Morgan Craig
- Department of Physiology, McGill University, Montreal, Quebec H3A 0G4, Canada
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7
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Galectin-1 promotes vasculogenic mimicry in gastric adenocarcinoma via the Hedgehog/GLI signaling pathway. Aging (Albany NY) 2020; 12:21837-21853. [PMID: 33170154 PMCID: PMC7695400 DOI: 10.18632/aging.104000] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022]
Abstract
Background: Galectin-1 (GAL-1), which is encoded by LGALS1, promotes vasculogenic mimicry (VM) in gastric cancer (GC) tissue. However, the underlying mechanism remains unclear. Methods: Immunohistochemical (IHC) and CD34-periodic acid-Schiff (PAS) double staining were used to investigate Glioma-associated oncogene-1(GLI1) expression and VM in paraffin-embedded sections from 127 patients with GC of all tumor stages. LGALS1 or GLI1 were stably transduced into MGC-803 cells and AGS cells, and western blotting, IHC, CD34-PAS double staining and three-dimensional culture in vitro, and tumorigenicity in vivo were used to explore the mechanisms of GAL-1/ GLI1 promotion of VM formation in GC tissues. Results: A significant association between GAL-1 and GLI1 expression was identified by IHC staining, as well as a significant association between GLI1 expression and VM formation. Furthermore, overexpression of LGALS1 enhanced expression of GLI1 in MGC-803 and AGS cells. GLI1 promoted VM formation both in vitro and in vivo. The effects of GLI1 on VM formation were independent of LGALS1. Importantly, the expression of VM-related molecules, such as MMP2, MMP14 and laminin5γ2, was also affected upon GLI1 overexpression or silencing in GC cell lines. Conclusion: GAL-1 promotes VM in GC through the Hh/GLI pathway, which has potential as a novel therapeutic target for treatment of VM in GC.
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Kozłowska E, Vallius T, Hynninen J, Hietanen S, Färkkilä A, Hautaniemi S. Virtual clinical trials identify effective combination therapies in ovarian cancer. Sci Rep 2019; 9:18678. [PMID: 31822719 PMCID: PMC6904444 DOI: 10.1038/s41598-019-55068-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 11/18/2019] [Indexed: 01/06/2023] Open
Abstract
A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.
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Affiliation(s)
- Emilia Kozłowska
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Institute of Automatic Control, Silesian University of Technology, Akademicka 16, 44-100, Gliwice, Poland
| | - Tuulia Vallius
- Department of Oncology and Radiotherapy, Turku University Hospital, University of Turku, Turku, Finland
| | - Johanna Hynninen
- Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland
| | - Sakari Hietanen
- Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland
| | - Anniina Färkkilä
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland. .,Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA. .,Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.
| | - Sampsa Hautaniemi
- Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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9
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Yin A, Moes DJAR, van Hasselt JGC, Swen JJ, Guchelaar HJ. A Review of Mathematical Models for Tumor Dynamics and Treatment Resistance Evolution of Solid Tumors. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2019; 8:720-737. [PMID: 31250989 PMCID: PMC6813171 DOI: 10.1002/psp4.12450] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/17/2019] [Indexed: 12/19/2022]
Abstract
Increasing knowledge of intertumor heterogeneity, intratumor heterogeneity, and cancer evolution has improved the understanding of anticancer treatment resistance. A better characterization of cancer evolution and subsequent use of this knowledge for personalized treatment would increase the chance to overcome cancer treatment resistance. Model‐based approaches may help achieve this goal. In this review, we comprehensively summarized mathematical models of tumor dynamics for solid tumors and of drug resistance evolution. Models displayed by ordinary differential equations, algebraic equations, and partial differential equations for characterizing tumor burden dynamics are introduced and discussed. As for tumor resistance evolution, stochastic and deterministic models are introduced and discussed. The results may facilitate a novel model‐based analysis on anticancer treatment response and the occurrence of resistance, which incorporates both tumor dynamics and resistance evolution. The opportunities of a model‐based approach as discussed in this review can be of great benefit for future optimizing and personalizing anticancer treatment.
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Affiliation(s)
- Anyue Yin
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Network for Personalized Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Network for Personalized Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
| | - Johan G C van Hasselt
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Jesse J Swen
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Network for Personalized Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Network for Personalized Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
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10
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Carusi A, Davies MR, De Grandis G, Escher BI, Hodges G, Leung KMY, Whelan M, Willett C, Ankley GT. Harvesting the promise of AOPs: An assessment and recommendations. THE SCIENCE OF THE TOTAL ENVIRONMENT 2018; 628-629:1542-1556. [PMID: 30045572 PMCID: PMC5888775 DOI: 10.1016/j.scitotenv.2018.02.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/02/2018] [Accepted: 02/02/2018] [Indexed: 05/22/2023]
Abstract
The Adverse Outcome Pathway (AOP) concept is a knowledge assembly and communication tool to facilitate the transparent translation of mechanistic information into outcomes meaningful to the regulatory assessment of chemicals. The AOP framework and associated knowledgebases (KBs) have received significant attention and use in the regulatory toxicology community. However, it is increasingly apparent that the potential stakeholder community for the AOP concept and AOP KBs is broader than scientists and regulators directly involved in chemical safety assessment. In this paper we identify and describe those stakeholders who currently-or in the future-could benefit from the application of the AOP framework and knowledge to specific problems. We also summarize the challenges faced in implementing pathway-based approaches such as the AOP framework in biological sciences, and provide a series of recommendations to meet critical needs to ensure further progression of the framework as a useful, sustainable and dependable tool supporting assessments of both human health and the environment. Although the AOP concept has the potential to significantly impact the organization and interpretation of biological information in a variety of disciplines/applications, this promise can only be fully realized through the active engagement of, and input from multiple stakeholders, requiring multi-pronged substantive long-term planning and strategies.
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Affiliation(s)
- Annamaria Carusi
- Medical Humanities Sheffield, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
| | | | - Giovanni De Grandis
- Science, Technology, Engineering and Public Policy (STEaPP), Boston House, 36-37 Fitzroy Square, London W1T 6EY, UK.
| | - Beate I Escher
- UFZ - Helmholtz Centre for Environmental Research, 04318 Leipzig, Germany; Eberhard Karls University Tübingen, Environmental Toxicology, Centre for Applied Geosciences, 72074 Tübingen, Germany.
| | - Geoff Hodges
- Safety and Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
| | - Kenneth M Y Leung
- The Swire Institute of Marine Science and School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China.
| | - Maurice Whelan
- European Commission, Joint Research Centre (JRC), Ispra, Italy.
| | - Catherine Willett
- The Humane Society of the United States, 700 Professional Drive, Gaithersburg, MD, 20879, USA.
| | - Gerald T Ankley
- US Environmental Protection Agency, 6201 Congdon Blvd, Duluth, MN 55804, USA.
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11
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Mistry HB. On the relationship between tumour growth rate and survival in non-small cell lung cancer. PeerJ 2017; 5:e4111. [PMID: 29201573 PMCID: PMC5712205 DOI: 10.7717/peerj.4111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/09/2017] [Indexed: 01/20/2023] Open
Abstract
A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence, it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. I found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial I found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.
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Affiliation(s)
- Hitesh B Mistry
- Division of Pharmacy, University of Manchester, Manchester, United Kingdom
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12
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Claret L, Han K, Bruno R. Model-Based Estimates of Tumor Growth Inhibition Metrics Are Time-Independent: A Reply to Mistry. CPT Pharmacometrics Syst Pharmacol 2017; 6:225. [PMID: 27997740 PMCID: PMC5397555 DOI: 10.1002/psp4.12163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 12/06/2016] [Indexed: 11/15/2022] Open
Affiliation(s)
- L Claret
- Clinical PharmacologyGenentech/RocheMarseilleFrance
| | - K Han
- Clinical Pharmacology Modeling & SimulationsGlaxoSmithKlinePhiladelphiaPennsylvaniaUSA
| | - R Bruno
- Clinical PharmacologyGenentech/RocheMarseilleFrance
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13
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Mistry HB. Time-Dependent Bias of Tumor Growth Rate and Time to Tumor Regrowth. CPT Pharmacometrics Syst Pharmacol 2016; 5:587. [PMID: 27730754 PMCID: PMC5338270 DOI: 10.1002/psp4.12145] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 10/05/2016] [Indexed: 01/23/2023] Open
Affiliation(s)
- HB Mistry
- Manchester School of PharmacyManchesterUK
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