Quantitative systems pharmacology modeling of loncastuximab tesirine combined with mosunetuzumab and glofitamab helps guide dosing for patients with DLBCL

Presented at AACR Annual Meeting 2024. QSP model simulations were used to predict anti-tumor efficacy and guide dosing of the antibody-drug conjugate Loncastuximab tesirine combined with T cell-dependent bispecific antibodies, Mosunetuzumab or Glofitamab for the treatment of B-cell malignancies.

Making drugs from T cells: The quantitative pharmacology of engineered T cell therapeutics

Engineered T cells, particularly CAR T cells, have revolutionized hematological cancer treatment. However, their complexity poses challenges. This research explores how mathematical models, utilizing clinical data, can elucidate relationships between product characteristics, patient physiology, and clinical outcomes, thereby facilitating the development of next-generation cell therapies.

In relapsed or refractory diffuse large B-cell lymphoma, CD19 expression by immunohistochemistry alone is not a predictor of response to loncastuximab tesirine

This study explores Lonca’s efficacy across varying CD19 expression levels, revealing its effectiveness in patients, regardless of low or undetectable CD19 levels by conventional methods. The study integrates quantitative systems pharmacology (QSP) modeling to predict treatment responses, indicating that CD19 expression alone may not predict Lonca’s effectiveness, however, response predictions are improved by considering CD19 surface density.

Integrated Population Pharmacokinetic Analysis of Conjugated and Unconjugated Payload of Patritumab Deruxtecan in Cancer Patients

Presented at ACoP14. Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor (HER3)-targeting antibody-drug conjugate with a topoisomerase I inhibitor payload (DXd). The drug-to-antibody ratio is approximately 8. HER3-DXd is currently being investigated as an anticancer agent in several phase 1-3 clinical studies in breast cancer (BC) and nonsmall cell lung cancer ( NSCLC) patients.

Exposure-Response Analyses of Efficacy and Safety of Patritumab Deruxtecan in Cancer Patients

Presented at ACoP14. ER analyses showed that the 5.6 mg/kg Q3W regimen offers a positive benefit-risk profile with clinically meaningful efficacy and overall manageable and tolerable safety profile. The analyses results support the selection of 5.6 mg/kg Q3W as the recommended dose for further clinical development of HER3-DXd monotherapy.

Exploring the Influence of Bispecific Antibody Mechanisms on In Vitro Dose Response: Insights from an Open-Science Quantitative Systems Pharmacology Model in Julia

Presented at ACoP14. Analysis of the QSP model found that the internalization rate of the target receptors may be an important, yet often underestimated, factor for understanding bsAb efficacy in vitro. Simulations of the model indicated that high rates of receptor turnover can increase model predictions of efficacy, particularly at higher antibody concentrations.

Hands-On Tutorial: Introduction to Immuno-Oncology (IO) Quantitative Systems Pharmacology (QSP) Modeling Using the Open Source Julia Programming Language

ACoP14 pre-meeting workshop. Highlights include exploring Julia as an open source alternative for QSP support of model-informed drug development, gaining insights into IO QSP modeling for antibody drug conjugate (ADCs) and bispecific mAb (bsAb) therapies to drive your own implementations of Project Optimus, and accessing open source Julia versions of two pivotal IO models and parameterizations.

A Clinical Quantitative Systems Pharmacology Framework Describing Loncastuximab Tesirine Distribution and to Explore Patient Outcomes From the LOTIS-2 Clinical Trial in Patients With B-cell Lymphomas

A novel QSP framework integrating PBPK modeling with tumor dynamics was developed using literature and in-house data. By employing a virtual population reflecting patients treated with Lonca, it is possible to evaluate indication, clinical population selection, influence of clinical study covariates, disease phenotypes, and CD19 expression levels on clinical responses

Choice of Hyperparameters for Spike And Slab Prior, with Application to Dose Optimization in Oncology

This poster highlights the use of population pharmacokinetic and exposure-response models with regularized regression using spike and slab priors to optimize dosing for specific patient subpopulations, particularly focusing on the context of valemetostat treatment for Adult T-cell Leukemia / Lymphoma (ATTLL) and Non-Hodgkin’s lymphoma (NHL).

Towards the development of a platform PBPK-QSP model in the Julia programming language for evaluating potential toxicities caused by antibody-drug-conjugate therapies

Antibody-drug conjugates (ADCs) are promising anti-cancer drugs but often cause toxicities in clinical use. This poster presents a new model that predicts toxicities of ADCs, including liver and lung effects for drugs like T-DM1 and T-Dxd, and high hepatotoxicity in CM.

Open-Science Immuno-Oncology QSP Modeling Using Open-Source Julia Solvers

As Julia usage continues to grow within regulated biomedical environments, it is vital to ensure analyses are traceable and reproducible. Conducting analyses in an open-science manner is also critical to expand the adoption of Julia and to facilitate the infrastructure growth of Julia as an accessible ecosystem. A step-by-step model-building example of a classic monoclonal antibody-drug conjugate PBPK/tumor dynamics system illustrates how to develop such a reproducible open-science framework.

A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development

Ana Ruiz-Garcia, Paul Baverel, Dean Bottino, Michael Dolton, Yan Feng, Ignacio González-García, Jaeyeon Kim, Seth Robey, Indrajeet Singh, David Turner, Shu-Pei Wu, Donghua Yin, Di Zhou, Hao Zhu, Peter Bonate. J Pharmacokinet Pharmacodyn. March, 4 2023

Landmark and longitudinal exposure-response analyses for multiple efficacy and safety endpoints to justify the clinical dose of valemetostat for adult T-cell leukemia/lymphoma

Masato Fukae, Kyle Baron, James Rogers, Ramon Garcia, Masaya Tachibana, John Mondick, Takako Shimizu. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster M-026

Simultaneous population pharmacokinetic analysis of total and unbound valemetostat in patients with non Hodgkin lymphoma to quantify the effect of the binding protein, alpha 1 acid glycoprotein

Masato Fukae, Kyle Baron, Masaya Tachibana, John Mondick, Takako Shimizu. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster M-030

Analysis Planning and Interpretation Using Causal Directed Acyclic Graphs: A Case Study in Oncology

James A. Rogers, Hugo Maas, Alejandro Peréz. Poster presented at 2022 American Conference on Pharmacometrics (ACoP13). 30 October – November 2 2022. Poster T-022

Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor (TGCT)

Yin O, Zahir H, French J, Polhamus D, Wang X, Van de Sande M, Tap WD, Gelderblom H, Wagner AJ, Healey JH, Greenberg J, Shuster D, Stacchiotti S. CPT: Pharmacometrics & Systems Pharmacology. 2021101422– 1432. doi:10.1002/psp4.12712

Lorlatinib Exposure-Response Analyses for Safety and Efficacy in a Phase I/II Trial to Support Benefit-Risk Assessment in Non-Small Cell Lung Cancer

Chen J, Ruiz-Garcia A, James LP, et al. Clin Pharmacol Ther. 2021;110(5):1273-1281. doi:10.1002/cpt.2228

Population pharmacokinetic model with time-varying clearance for lorlatinib using pooled data from patients with non-small cell lung cancer and healthy participants

Chen J, Houk B, Pithavala YK, Ruiz-Garcia A. CPT Pharmacometrics Syst Pharmacol. 2021 Feb;10(2):148-160. doi: 10.1002/psp4.12585. Epub 2021 Feb 1.

Improving strategic decision-making with early prediction of survival outcomes in oncology clinical trials

Presentation by Jonathan L. French, Sc.D. at 2020 American Conference on Pharmacometrics (ACoP11) virtual meeting. 11 November 2020.

An evaluation of overall survival in patients with newly diagnosed acute myeloid leukemia and the relationship with glasdegib treatment and exposure

Lin S, Shaik N, Chan G, Cortes JE, Ruiz-Garcia A. Cancer Chemother Pharmacol. 2020 Oct;86(4):451-459. doi: 10.1007/s00280-020-04132-x. Epub 2020 Sep 3.

Phase 1 study to evaluate the effect of the investigational anticancer agent sapanisertib on the QTc interval in patients with advanced solid tumors

Patel, Chirag, Sanjay Goel, Manish R. Patel, Lakshmi Rangachari, Jayson D. Wilbur, Yaping Shou, Karthik Venkatakrishnan, and A. Craig Lockhart. Clinical Pharmacology in Drug Development, June 2020.

Population Pharmacokinetic Analysis for Comparison of Pexidartinib Exposure in Asian and Non-Asian Patients

Chia-Chi Lin, Jun Guo, William D. Tap, Andrew J. Wagner, Silvia Stacchiotti, Jih-Hsiang Lee, Xiaoning Wang, Jia Kang, Hamim Zahir, Shun-ichi Sasaki, Ophelia Yin

Poster presented at the 2019 Connective Tissue Oncology Society annual meeting in Toyko, Japan. 14 Nov 2019

Exposure-Response Analysis of Efficacy and Safety for Pexidartinib in Patients With Tenosynovial Giant Cell Tumor (TGCT)

Ophelia Yin, Jonathan French, Daniel Polhamus, Hamim Zahir, Michiel van de Sande, William D. Tap, Hans Gelderblom, Andrew J. Wagner, Jon Greenberg, Dale Shuster, Silvia Stacchiotti

Poster presented at 2019 American Conference on Pharmacometrics (ACoP10) in Orlando, FL. 23 October 2019.

A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

Eric Burroughs Jordie, Ahmed Elmokadem, Mohammad Azab, and Aram Oganesian

Presented by Eric Jordie at American Conference on Pharmacometrics 2019.

Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients with Tenosynovial Giant Cell Tumor (TGCT) or Other Solid Tumors

Ophelia Yin, Jia Kang, William Knebel, Hamim Zahir, Michiel van de Sande, William D. Tap, Hans Gelderblom, Silvia Stacchiotti, Jon Greenberg, Dale Shuster, Andrew J. Wagner

Poster presented at 2019 American Conference on Pharmacometrics (ACoP10) in Orlando, FL. 21 October 2019.

Pharmacokinetics of trastuzumab emtansine (T-DM1) as a single agent or in combination with pertuzumab in HER2-positive breast cancer patients with recurrent or locally advanced metastatic breast cancer

Lu D, Li C, Riggs M, Polhamus D, French J, Agarwal P, Chen S-C, Vadhavkar S, Patre M, Strasak A, Quartino A, Jin JY, Girish S. Cancer Chemother Pharmacol [Internet]. 2019 May 17. doi: 10.1007/s00280-019-03852-z.

Exposure–response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane

Li C, Wang B, Chen SC, Wada R, Lu D, Wang X, Polhamus D, French J, Vadhavkar S, Strasak A, Smitt M, Joshi A, Samant M, Quartino A, Jin J, Girish S. Cancer Chemotherapy and Pharmacology 80 (6): 1079–90. December 2017.

Modeling methods for analyzing tumor dynamic data from basket trials

Ocampo-Pelland AS, French JL.  Presented at the 8th American Conference on Pharmacometrics (ACoP), Fort Lauderdale, FL, October 2017.

Population pharmacokinetics and exposure–response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens

Chen S-C, Quartino A, Polhamus D, Riggs M, French J, Wang X, Vadhavkar S, Smitt M, Hoersch S, Strasak A, Jin JY, Girish S, and Li C. Br J Clin Pharmacol, 2017 Jul 21.

Population pharmacokinetic modeling of intravenous asparaginase erwinia chrysanthemi: Impact of varied infusion rates on exposure

Zomorodi K, Dumas T, Berry S, Johnston C, and Eller M. 

Population pharmacokinetics (PK) and exposure-response (E-R) analysis of trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) who have received at least two prior regimens of HER2-directed therapy

Chen SC, Quartino AL, Polhamus D, Riggs MM, French JL, Wang X, Vadhavkar S, Smitt M, Hoersch S, Strasak A, Chernyukhin N, Jin JY, Girish S, Li C.  Abstract in Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Cancer Res 2017;77(4 Suppl):Abstract P4-21-26.

Pharmacokinetics (PK) and exposure-response (E-R) analysis of Kadcyla (K) as a single agent or in combination with Perjeta (P) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) who have not received prior chemotherapy for their metastatic disease

Lu D, Li C, Polhamus D, French JL, Riggs MM, Agarwal P, Chen SC, Wang X, Smitt M, Patre M, Strasak A, ChernyukhinN , Quartino AL, Jin JY, Girish S.  Presented at the 7th American Conference on Pharmacometrics (ACoP), Bellevue, WA; October 2016.

Comparisons of multiple exposure-response methodologies in oncology.

Polhamus D, French J, Chen SC, Wang B, Li C, Lu D, Girish S, Jin J, Quartino A.  Presented at the Annual Meeting of the Population Approach Group in Europe (PAGE), Lisboa, June 2016.

A modeling and simulation framework for exposure-response analysis in oncology: comparison and considerations of multiple methodologies

Polhamus D, French J, Chen S-C, Wang B, Li C, Lu D, Girish S, Jin J, Quartino A.  Presented at the 6th American Conference on Pharmacometrics, Arlington, VA; October 2015.

Exposure-response modeling in oncology: technical challenges and proposed solutions

Jonathan French. Presented at the 5th American Conference on Pharmacometrics (ACoP), Las Vegas, NV, October 2014.

PKPD modeling of predictors for adverse effects and overall survival in sunitinib-treated patients with GIST

Hansson EK, Ma G, Amantea MA, French J, Milligan PA, Friberg LE, and Karlsson MO. CPT: Pharmacometrics & Systems Pharmacology. 2013;2(12):e85-. doi:10.1038/psp.2013.62.

PKPD modeling of VEGF, sVEGFR-2, sVEGFR-3, and sKIT as predictors of tumor dynamics and overall survival following sunitinib treatment in GIST

Hansson EK, Amantea MA, Westwood P, Milligan PA, Houk BE, French J, Karlsson MO and Friberg LE. CPT: Pharmacometrics & Systems Pharmacology. 2013;2(11):e84-. doi:10.1038/psp.2013.61

Can methods based on existing models really aid decision making in non-small-cell lung cancer (NSCLC) trials?

Presented at the Annual Meeting of the Population Approach Group Europe (PAGE), Glasgow; June, 2013. Abstract A-06.

Opportunities and challenges of MBMA in oncology

French J. Presented at the 4th American Conference on Pharmacometrics (ACoP), Ft. Lauderdale; May 2013.