An Innovative Approach to Optimize First-In-Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T-Cell Engagers: Experience from A Solid Tumor Bispecific T-Cell Engager.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
16 Sep 2024
16 Sep 2024
Historique:
received:
19
03
2024
accepted:
17
08
2024
medline:
17
9
2024
pubmed:
17
9
2024
entrez:
16
9
2024
Statut:
aheadofprint
Résumé
Bispecific T-cell engagers (Bi-TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best-in-class therapeutics for cancer. However, defining the dose and dosing regimen for the first-in-human (FIH) studies of Bi-TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub-therapeutic dosing. Leveraging our in-depth and broad clinical development experience across three generations of Bi-TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half-life extended (HLE) Bi-TCE for gastric cancer. This modified MABEL approach enabled a 10-fold higher starting dose that was deemed safe and well tolerated and saved at least two dose-escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi-TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi-TCEs.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 Amgen. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.
Références
Huehls, A.M., Coupet, T.A. & Sentman, C.L. Bispecific T‐cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290–296 (2015).
Frankel, S.R. & Baeuerle, P.A. Targeting T cells to tumor cells using bispecific antibodies. Curr. Opin. Chem. Biol. 17, 385–392 (2013).
Chandra, F., Zugmaier, G., Velasco, K., Doshi, S., Dutta, S. & Upreti, V.V. Short daily disconnect of blinatumomab continuous intravenous infusion to improve patient quality of life while minimizing impact on exposure and efficacy. Am. Soc. Clin. Pharmacol. Ther. Clin. Pharmacol. Ther 111(S1), S5–S80 (2022).
Wong, H.L. et al. Encouraging pharmacokinetic (PK)/pharmacodynamic (PD) results of subcutaneous (SC) blinatumomab in R/R indolent non‐Hodgkin's lymphoma (I‐NHL) and relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) patients (pts) indicate that patient convenient SC dosing is a viable alternative to continuous intravenous infusion (cIV) dosing. Am. Soc. Clin. Pharmacol. Ther. Clin. Pharmacol. Ther. 111(S1), S79 (2022).
Zhang, X., Lumen, A., Wong, H., Connarn, J., Dutta, S. & Upreti, V.V. A mechanistic physiologically‐based pharmacokinetic platform model to guide adult and pediatric intravenous and subcutaneous dosing for bispecific T cell engagers. Clin. Pharmacol. Ther. 115, 457–467 (2023). https://doi.org/10.1002/cpt.3056.
FDA grants accelerated approval to tarlatamab‐dlle for extensive stage small cell lung cancer. <https://www.fda.gov/drugs/resources‐information‐approved‐drugs/fda‐grants‐accelerated‐approval‐tarlatamab‐dlle‐extensive‐stage‐small‐cell‐lung‐cancer>. Accessed June 16, 2024.
FDA Approves Imdelltra™ (Tarlatamab‐Dlle), the first and only T‐cell engager therapy for the treatment of extensive‐stage small cell lung cancer <https://www.prnewswire.com/news‐releases/fda‐approves‐imdelltra‐tarlatamab‐dlle‐the‐first‐and‐only‐t‐cell‐engager‐therapy‐for‐the‐treatment‐of‐extensive‐stage‐small‐cell‐lung‐cancer‐302148431.html>. Accessed June 16, 2024.
Amgen Inc. Amgen Oncology <https://www.amgenoncology.com/modalities/bite.html>; <https://www.amgenoncology.com/modalities/xmab.html> Accessed June 30, 2023.
Leach, M.W. et al. Strategies and recommendations for using a data‐driven and risk‐based approach in the selection of first‐in‐human starting dose: an international consortium for innovation and quality in pharmaceutical development (IQ) assessment. Clin. Pharmacol. Ther. 109, 1395–1415 (2021).
Suh, H.Y., Peck, C.C., Yu, K.S. & Lee, H. Determination of the starting dose in the first‐in‐human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013. Drug Des. Devel. Ther. 10, 4005–4016 (2016).
Zou, P. et al. Applications of human pharmacokinetic prediction in first‐in‐human dose estimation. AAPS J. 14, 262–281 (2012).
International Council for Harmonization (ICH). S9 Nonclinical Evaluation for Anticancer Pharmaceuticals <https://database.ich.org/sites/default/files/S9_Guideline.pdf>. Accessed Oct 29, 2023.
Saber, H., Gudi, R., Manning, M., Wearne, E. & Leighton, J.K. An FDA oncology analysis of immune activating products and first‐in‐human dose selection. Regul. Toxicol. Pharmacol. 81, 448–456 (2016).
Saber, H., Del Valle, P., Ricks, T.K. & Leighton, J.K. An FDA oncology analysis of CD3 bispecific constructs and first‐in‐human dose selection. Regul. Toxicol. Pharmacol. 90, 144–152 (2017).
Betts, A. & van der Graaf, P.H. Mechanistic quantitative pharmacology strategies for the early clinical development of bispecific antibodies in oncology. Clin. Pharmacol. Ther. 108, 528–541 (2020).
Qi, T., Liao, X. & Cao, Y. Development of bispecific T cell engagers: harnessing quantitative systems pharmacology. Trends Pharmacol. Sci. 44, 880–890 (2023).
Wade, H. Bispecific Landscape <https://www.beacon‐intelligence.com/solutions/bispecific>. Accessed Oct 29, 2023.
Upreti, V.V., Yago, M.R., Kast, J. et al. American society for clinical pharmacology and therapeutics. Clin. Pharmacol. Ther. 109(S1), S5–S88 (2021).
Bailis, J.M. et al. Abstract 3364: preclinical evaluation of BiTE®immune therapy targeting MUC17 or CLDN18.2 for gastric cancer. Cancer Res. 80(16_Supplement), 3364 (2020).
Shah, D.K. & Betts, A.M. Antibody biodistribution coefficients: inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human. MAbs 5, 297–305 (2013).
Claret, L. et al. Model‐based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. J. Clin. Oncol. 27, 4103–4108 (2009).
Ribba, B. et al. A review of mixed‐effects models of tumor growth and effects of anticancer drug treatment used in population analysis. CPT Pharmacometrics Syst. Pharmacol. 3, e113 (2014).
Dudal, S. et al. Application of a MABEL approach for a T‐cell‐bispecific monoclonal antibody: CEA TCB. J. Immunother. 39, 279–289 (2016).
Shen, J., Swift, B., Mamelok, R., Pine, S., Sinclair, J. & Attar, M. Design and conduct considerations for first‐in‐human trials. Clin. Transl. Sci. 12, 6–19 (2019).
Liao, M., Ermakov, S., Kischel, R. et al. Optimization of FIH (First‐in‐Human) starting dose for an HLE‐BiTE® (Half‐life Extended Bispecific T‐cell Engager) molecule for patients with gastric cancer using translational PKPD modeling (2020).