Phase I Trials Platform in Oncology, CITOHL


The phase I trial unit has acquired a strong experience in application of modeling at different steps of drug development, as shown in some typical examples

Biomarkers Kinetics

    Biomarkers Kinetics : Is it a favorable decrease? Tools to compute modeled kinetic parameters able to inform early on the risk of failure (PSA, hCGres and CA-125) Biomarkers Kinetics

  • K. Dekeister, P-A. Bolze, M. Tod, R. Tod, J. Massardier, J-P. Lotz, T. Hajri, O. Colomban, M. J Seckl, R. Osborne, G. Freyer, F. Golfier, B. You. Validation of an online tool for early prediction of the failure risk in gestational trophoblastic neoplasia patients treated with methotrexate. Cancer Chemother Pharmacol. 2020 Jun 4. Abstract

Innovative phase 1 design:

  • El-Madani M, Colomban O, Tod M, Maillet D, Peron J, Rodriguez-Lafrasse C, Badary O A, Valette P, Lefort T, Cassier P, El-Shenawy S M , El-Demerdash E, Hommel-Fontaine J, Guitton J, Gagnieu M, Ibrahim B Mm, Barrois C, Freyer G, You B. EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib. Future Oncol April 2017, Vol. 13, No. 8, Pages 679-693, DOI 10.2217/fon-2016-0357 Epub 2017 Jan 12. Abstract

  • Hénin E, Meille C, Barbolosi D, You B, Guitton J, Iliadis A, Freyer G. Revisiting dosing regimen using PK/PD modeling: the MODEL1 phase I/II trial of docetaxel plus epirubicin in metastatic breast cancer patients. Breast Cancer Res Treat. 2016 Apr;156(2):331-41. Abstract

  • Meille C, Barbolosi D, Ciccolini J, Freyer G, Iliadis A. Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy. Clin Pharmacokinet. 2016 Mar 5. [Epub ahead of print] Abstract

  • El-Madani M, Hénin E, Lefort T, Tod M, Freyer G, Cassier P, Valette PJ, Rodriguez-Lafrasse C, Berger F, Guitton J, Lachuer J, Slimane K, Barrois C, You B. Multiparameter Phase I trials: a tool for model-based development of targeted agent combinations--example of EVESOR trial. Future Oncol. 2015;11(10):1511-8. Abstract

  • Freyer G, Isambert N, You B, Zanetta S, Falandry C, Favier L, Trillet-Lenoir V, Assadourian S, Soussan-Lazard K, Ziti-Ljajic S, Fumoleau P. Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours. Br J Cancer. 2012 Aug 7;107(4):598-603. Abstract

  • Heudel P, Romestaing P, Barbet N, Falandry C, You B, Glehen O, Freyer G. Capecitabine, irinotecan, oxaliplatin (CAPIRINOX) and concomitant irradiation in advanced rectal cancer: the Lyon R-02-01 phase I trial. Clin Oncol (R Coll Radiol). 2008 Jun;20(5):369-74. Abstract

Innovative tumor growth modelling:

  • Pierrillas PB, Henin E, Ogier J, Kraus-Berthier L, Chenel M, Bouzom F, Tod M. Tumor Growth Inhibition Modelling Based on Receptor Occupancy and Biomarker Activity of a New Bcl-2 Inhibitor in Mice. J Pharmacol Exp Ther. 2018 Dec;367(3):414-424. Abstract

  • Wilson S, Tod M, Ouerdani A, Emde A, Yarden Y, Adda Berkane A, Kassour S, Wei MX, Freyer G, You B, Grenier E, Ribba B. Modeling and predicting optimal treatment scheduling between the antiangiogenic drug sunitinib and irinotecan in preclinical settings. CPT Pharmacometrics Syst Pharmacol. 2015 Dec;4(12):720-7. Abstract

  • Pierrillas PB, Tod M, Amiel M, Chenel M, Henin E. Improvement of Parameter Estimations in Tumor Growth Inhibition Models on Xenografted Animals: a Novel Method to Handle the Interval Censoring Caused by Measurement of Smaller Tumors. AAPS J. 2016 Mar;18(2):404-15. doi: 10.1208/s12248-015-9862-1. Epub 2016 Jan 12. Abstract

  • Sostelly A, Payen L, Guitton J, Di Pietro A, Falson P, Honorat M, Boumendjel A, Gèze A, Freyer G, Tod M. Quantitative evaluation of the combination between cytotoxic drug and efflux transporter inhibitors based on a tumour growth inhibition model. Fundam Clin Pharmacol. 2014 Apr;28(2):161-9. Abstract

  • Lignet F, Benzekry S, Wilson S, Billy F, Saut O, Tod M, You B, Adda Berkane A, Kassour S, Wei MX, Grenier E, Ribba B. Theoretical investigation of the efficacy of antiangiogenic drugs combined to chemotherapy in xenografted mice. J Theor Biol. 2013 Mar 7;320:86-99. Abstract

  • Ribba B, Watkin E, Tod M, Girard P, Grenier E, You B, Giraudo E, Freyer G. A model of vascular tumour growth in mice combining longitudinal tumour size data with histological biomarkers. Eur J Cancer. 2011 Feb;47(3):479-90. Abstract

Innovative biomarker modelling:

  • P. Corbaux, B. You, R. M. Glasspool, N. Yanaihara, A. V. Tinker, K. Lindemann, I. L. Ray-Coquard, M. R. Mirza, F. Subtil, O. Colomban, J. Péron, E. Karamouza, I. McNeish, C. Kelly, T. Kagimura, S. Welch, L.-A. Lewsley, X. Paoletti, A. Cook. Survival and modeled CA-125 KELIM score in ovarian cancer patients in first-line before PARP inhibitor era: a GCIG meta-analysis. European Journal of Cancer, Published:July 04, 2023. Abstract

  • O. Colomban, A. Clamp, A. Cook, I. A McNeish, B. You. Benefit From Fractionated Dose-Dense Chemotherapy in Patients With Poor Prognostic Ovarian Cancer: ICON-8 Trial. JCO Clin Cancer Inform. 2023 Apr;7:e2200188. Abstract

  • A. Puszkiel, B. You, L. Payen, J. Lopez, J. Guitton, P. Rousset, J. Fontaine, J. Péron, D. Maillet, S. Tartas, N. Bonnin, V. Trillet-Lenoir, O. Colomban, D. Augu-Denechere, G. Freyer & M. Tod. A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial. Cancer Chemother Pharmacol (2023).Abstract

  • R. Varnier, A. Puszkiel, M. Tod, S. Calattini, L. Payen, J. Lopez, J. Guitton, V. Schwiertz, J. Fontaine, J. Peron, D. Maillet, S. Tartas, N. Bonnin, O. Colomban, D. Augu-Denechere, G. Freyer & B. You. Clinical results of the EVESOR trial, a multiparameter phase I trial of everolimus and sorafenib combination in solid tumors. Cancer Chemother Pharmacol (2023). Abstract

  • O. Colomban, E-M. Swisher, R. Kristeleit, I. McNeish, R. Shapira-Frommer, S. Goble, K. K. Lin,L. Maloney, G. Freyer, B. You. Mathematical modeling of the early modeled CA-125 longitudinal kinetics (KELIM-PARP) as a pragmatic indicator of rucaparib efficacy in patients with recurrent ovarian carcinoma in ARIEL2 & STUDY 10. eBioMedicine, 2023;89: 104477. Abstract

  • B.You, C. Purdy, L. J. Copeland, E. M. Swisher, M. A. Bookman, G. Fleming, R. Coleman, Leslie M. Randall, K. S. Tewari, B. J. Monk, R. S. Mannel, J. L. Walker, F. Cappuccini, D. Cohn, M. Muzaffar, D. Mutch, A. Wahner-Hendrickson, L. Martin, O. Colomban, and R. A. Burger. Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study. Journal of Clinical Oncology 2022 40:34, 3965-3974. Abstract

  • Robelin P, Tod M, Colomban O, Lachuer J, Ray-Coquard I, Rauglaudre G, Joly F, Chevalier-Place A, Combe P, Lortholary A, Hamizi S, Raban N, Ferron G, Meunier J, Berton-Rigaud D, Alexandre J, Kaminsky MC, Dubot C, Leary A, Malaurie E, You B. Comparative analysis of predictive values of the kinetics of 11 circulating miRNAs and of CA125 in ovarian cancer during first line treatment (a GINECO study). Gynecol Oncol. 2020 Jul 22:S0090-8258(20)33656-8. Abstract

  • Colomban O, Tod M, Peron J, Perren T. J, Leary A, Cook A. D, Sajous C, Freyer G, You B. Bevacizumab for Newly Diagnosed Ovarian Cancers: Best Candidates Among High-Risk Disease Patients (ICON-7). JNCI Cancer Spectr. 2020;4(3):pkaa026. Published 2020 Apr 4. Abstract

  • You B, Robelin P, Tod M, Louvet C, Lotz JP, Abadie-Lacourtoisie S, Fabbro M, Desauw C, Bonichon-Lamichhane N, Kurtz JE, Follana P, Leheurteur M, Del Piano F, Ferron G, DE Rauglaudre G, Ray-Coquard I, Combe P, Chevalier Place A, Joly F, Leary A, Pujade-Lauraine E, Freyer G, Colomban O. CA-125 ELIMination rate constant K (KELIM) Is A Marker Of Chemosensitivity In Patients With Ovarian Cancer: Results from the Phase II CHIVA trial. Clin Cancer Res. 2020 Mar 24. Abstract

  • Colomban O, Tod M, Leary A, Ray-Coquard I, Lortholary A, Hardy-Bessard AC, Pfisterer J, Du Bois A, Kurzeder C, Burges A, Peron J, Freyer G, You B. Early Modeled Longitudinal CA-125 Kinetics and Survival of Ovarian Cancer Patients: A GINECO AGO MRC CTU Study. Clin Cancer Res. 2019 Apr 1. Abstract

  • Ducoulombier S, Golfier F, Colomban O, Benayoun D, Bolze PA, Tod M, You B. Modeling CA-125 During Neoadjuvant Chemotherapy for Predicting Optimal Cytoreduction and Relapse Risk in Ovarian Cancer. Anticancer Res. 2017 Dec;37(12):6879-6886. Abstract

  • de Charry F, Colomban O, You B, Ruffion A, Paparel P, Wilbaux M, Tod M, Freyer G, Perrin P. Identification of Most Aggressive Carcinoma Among Patients Diagnosed With Prostate Cancer Using Mathematical Modeling of Prostate-Specific Antigen Increases. Clin Genitourin Cancer. 2015 Dec 18. Abstract

  • Wilbaux M, Tod M, De Bono J, Lorente D, Mateo J, Freyer G, You B, Hénin E. A Joint Model for the Kinetics of CTC Count and PSA Concentration During Treatment in Metastatic Castration-Resistant Prostate Cancer. CPT Pharmacometrics Syst Pharmacol. 2015 May;4(5):277-85. Abstract

  • Wilbaux M, Hénin E, Oza A, Colomban O, Pujade-Lauraine E, Freyer G, Tod M, You B. Dynamic modeling in ovarian cancer: an original approach linking early changes in modeled longitudinal CA-125 kinetics and survival to help decisions in early drug development. Gynecol Oncol. 2014 Jun;133(3):460-6. Abstract

  • Wilbaux M, Hénin E, Oza A, Colomban O, Pujade-Lauraine E, Freyer G, Tod M, You B. Prediction of tumour response induced by chemotherapy using modelling of CA-125 kinetics in recurrent ovarian cancer patients. Br J Cancer. 2014 Mar 18;110(6):1517-24. doi: 10.1038/bjc.2014.75. Epub 2014 Feb 20. Abstract

  • Almufti R, Wilbaux M, Oza A, Henin E, Freyer G, Tod M, Colomban O, You B. A critical review of the analytical approaches for circulating tumor biomarker kinetics during treatment. Ann Oncol. 2014 Jan;25(1):41-56 Abstract

  • You B, Harvey R, Henin E, Mitchell H, Golfier F, Savage PM, Tod M, Wilbaux M, Freyer G, Seckl MJ. Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements. Br J Cancer. 2013 May 14;108(9):1810-6. Abstract

  • Couder F, Massardier J, You B, Abbas F, Hajri T, Lotz JP, Schott AM, Golfier F. Predictive factors of relapse in low-risk gestational trophoblastic neoplasia patients successfully treated with methotrexate alone. Am J Obstet Gynecol. 2016 Jan 30. Abstract

  • You B, Deng W, Hénin E, Oza A, Osborne R. Validation of the Predictive Value of Modeled Human Chorionic Gonadotrophin Residual Production in Low-Risk Gestational Trophoblastic Neoplasia Patients Treated in NRG Oncology/Gynecologic Oncology Group-174 Phase III Trial. Int J Gynecol Cancer. 2016 Jan;26(1):208-15. Abstract

  • You B, Colomban O, Heywood M, Lee C, Davy M, Reed N, Pignata S, Varsellona N, Emons G, Rehman K, Steffensen KD, Reinthaller A, Pujade-Lauraine E, Oza A. The strong prognostic value of KELIM, a model-based parameter from CA 125 kinetics in ovarian cancer: data from CALYPSO trial (a GINECO-GCIG study). Gynecol Oncol. 2013 Aug;130(2):289-94. Abstract

Physiologycally-based modelling:

  • Pierrillas PB, Henin E, Ball K, Ogier J, Amiel M, Kraus-Berthier L, Chenel M, Bouzom F, Tod M. Prediction of Human Nonlinear Pharmacokinetics of a New Bcl-2 Inhibitor Using PBPK Modeling and Interspecies Extrapolation Strategy. CDrug Metab Dispos. 2019 Jun;47(6):648-656. Abstract

  • Steelandt J, Jean-Bart E, Goutelle S, Tod M. A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child-Pugh Classification. Clin Pharmacokinet. 2015 Dec;54(12):1245-58. Abstract

  • Goutelle S, Tod M. Quantitative methods for prediction of the effect of cytochrome P450 gene polymorphisms on substrate drug exposure. Clin Pharmacokinet. 2015 Mar;54(3):319-20. Abstract

  • Tod M, Nkoud-Mongo C, Gueyffier F. Impact of genetic polymorphism on drug-drug interactions mediated by cytochromes: a general approach. AAPS J. 2013 Oct;15(4):1242-52. doi: 10.1208/s12248-013-9530-2. Epub 2013 Sep 12. Abstract

  • Gérard C, Stocco J, Hulin A, Blanchet B, Verstuyft C, Durand F, Conti F, Duvoux C, Tod M. Determination of the most influential sources of variability in tacrolimus trough blood concentrations in adult liver transplant recipients: a bottom-up approach. AAPS J. 2014 May;16(3):379-91. Abstract

  • Gérard C, Bleyzac N, Girard P, Freyer G, Bertrand Y, Tod M. Links between cyclosporin exposure in tissues and graft-versus-host disease in pediatric bone marrow transplantation: analysis by a PBPK model. Pharm Res. 2011 Mar;28(3):531-9. Abstract

  • Gérard C, Bleyzac N, Girard P, Freyer G, Bertrand Y, Tod M. Influence of dosing schedule on organ exposure to cyclosporin in pediatric hematopoietic stem cell transplantation: analysis with a PBPK model. Abstract

PKPD modelling and categorical data:

  • You B, Salles G, Bachy E, Casasnovas O, Tilly H, Ribrag V, Sebban C, Hénin E, Guitton J, Tod M, Freyer G. Etoposide pharmacokinetics impact the outcomes of lymphoma patients treated with BEAM regimen and ASCT: a multicenter study of the LYmphoma Study Association (LYSA). Cancer Chemother Pharmacol. 2015 Nov;76(5):939-48. Abstract

  • Hénin E, Blanchet B, Boudou-Rouquette P, Thomas-Schoemann A, Freyer G, Vidal M, Goldwasser F, Tod M. Fractionation of daily dose increases the predicted risk of severe sorafenib-induced hand-foot syndrome (HFS). Cancer Chemother Pharmacol. 2014 Feb;73(2):287-97. Abstract

  • Sostelly A, Henin E, Chauvenet L, Hardy-Bessard AC, Jestin-Le Tallec V, Kirsher S, Leyronnas C, Ligeza-Poisson C, Ramdane S, Salavt J, Van-Hult S, Vannetzel JM, Freyer G, Tod M, Falandry C. Can we predict chemo-induced hematotoxicity in elderly patients treated with pegylated liposomal doxorubicin? Results of a population-based model derived from the DOGMES phase II trial of the GINECO. J Geriatr Oncol. 2013 Jan;4(1):48-57. Abstract

  • Paule I, Girard P, Freyer G, Tod M. Pharmacodynamic models for discrete data. Clin Pharmacokinet. 2012 Dec;51(12):767-86 20: Sostelly A, Payen L, Guitton J, Di Pietro A, Falson P, Honorat M, Valdameri G, Geze A, Boumendjel A, Freyer G, Tod M. A template model for studying anticancer drug efflux transporter inhibitors in vitro. Fundam Clin Pharmacol. 2013 Oct;27(5):544-56. Abstract

  • Cotte E, Colomban O, Guitton J, Tranchand B, Bakrin N, Gilly F.N, Glehen O, Tod M. Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure. The Journal of Clinical Pharmacology, 2011;51(1):9-18. Abstract

  • Dartois C, Freyer G, Michallet M, Hénin E, You B, Darlavoix I, Vermot-Desroches C, Tranchand B, Girard P. Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease. Clin Pharmacokinet. 2007;46(5):417-32. Abstract

Optimization and pharmaceutical care:

  • Le Saux O, Bourmaud A, Rioufol C, Colomban O, Guitton J, Schwiertz V, Regnier V, You B, Ranchon F, Maraval-Gaget R, Girard P, Chauvin F, Freyer G, Tod M, Henin E, Trillet-Lenoir V. Over-adherence to capecitabine: a potential safety issue in breast and colorectal cancer patients. Cancer Chemother Pharmacol. 2018 Jun 15. Abstract

  • Bleyzac N, Cuzzubbo D, Rénard C, Garnier N, Dubois V, Domenech C, Goutagny MP, Plesa A, Grardel N, Goutelle S, Janoly-Duménil A, Bertrand Y. Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis. Bone Marrow Transplant. 2016 Jan 25. Abstract

  • Philippe M, Goutelle S, Guitton J, Fonrose X, Bergeron C, Girard P, Bertrand Y, Bleyzac N. Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children. Bone Marrow Transplant. 2016 Jan;51(1):72-8. Abstract

  • Philippe M, Hénin E, Bertrand Y, Plantaz D, Goutelle S, Bleyzac N. Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children. AAPS J. 2015 Sep;17(5):1157-67. Abstract

  • Bourmaud A, Henin E, Tinquaut F, Regnier V, Hamant C, Colomban O, You B, Ranchon F, Guitton J, Girard P, Freyer G, Tod M, Rioufol C, Trillet-Lenoir V, Chauvin F. Adherence to oral anticancer chemotherapy: What influences patients' over or non-adherence? Analysis of the OCTO study through quantitative-qualitative methods. BMC Res Notes. 2015 Jul 4;8:291. Abstract

  • Ranchon F, Vial T, Rioufol C, Hénin E, Falandry C, Freyer G, Trillet-Lenoir V, Le Tourneau C, You B. Concomitant drugs with low risks of drug-drug interactions for use in oncology clinical trials. Crit Rev Oncol Hematol. 2015 May;94(2):189-200. Abstract

  • Dollinger C, Schwiertz V, Sarfati L, Gourc-Berthod C, Guédat MG, Alloux C, Vantard N, Gauthier N, He S, Kiouris E, Caffin AG, Bernard D, Ranchon F, Rioufol C. SIMulation of Medication Error induced by Clinical Trial drug labeling: the SIMME-CT study. Int J Qual Health Care. 2016 Mar 13. Abstract

  • Vantard N, Ranchon F, Schwiertz V, Gourc C, Gauthier N, Guedat MG, He S, Kiouris E, Alloux C, You B, Souquet PJ, Freyer G, Salles G, Trillet-Lenoir V, Rioufol C. EPICC study: evaluation of pharmaceutical intervention in cancer care. J Clin Pharm Ther. 2015 Apr;40(2):196-203. Abstract

  • Sarfati L, Ranchon F, Vantard N, Schwiertz V, Gauthier N, He S, Kiouris E, Gourc-Berthod C, Guédat MG, Alloux C, Gustin MP, You B, Trillet-Lenoir V, Freyer G, Rioufol C. SIMMEON-Prep study: SIMulation of Medication Errors in ONcology: prevention of antineoplastic preparation errors. J Clin Pharm Ther. 2015 Feb;40(1):55-62. Abstract

  • Hénin E, Tod M, Trillet-Lenoir V, Rioufol C, Tranchand B, Girard P. Pharmacokinetically based estimation of patient compliance with oral anticancer chemotherapies: in silico evaluation. Clin Pharmacokinet. 2009;48(6):359-69. Abstract

Innovative Bioanalytics:

  • Le Calvé B, Griveau A, Vindrieux D, Maréchal R, Wiel C, Svrcek M, Gout J, Azzi L, Payen L, Cros J, de la Fouchardière C, Dubus P, Guitton J, Bartholin L, Bachet JB, Bernard D. Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution. Oncotarget. 2016 Apr 1. Abstract

  • Machon C, Bordes C, Cros-Perrial E, Clement Y, Jordheim LP, Lanteri P, Guitton J. Use of designed experiments for the improvement of pre-analytical workflow for the quantification of intracellular nucleotides in cultured cell lines. J Chromatogr A. 2015 Jul 31;1405:116-25. Abstract

  • Machon C, Jordheim LP, Puy JY, Lefebvre I, Dumontet C, Guitton J. Fully validated assay for the quantification of endogenous nucleoside mono- and triphosphates using online extraction coupled with liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2014 May;406(12):2925-41. Abstract

  • Cohen S, Jordheim LP, Megherbi M, Dumontet C, Guitton J. Liquid chromatographic methods for the determination of endogenous nucleotides and nucleotide analogs used in cancer therapy: a review. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Jul 15;878(22):1912-28. Abstract