Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials

Leukemia, Journal Year: 2024, Volume and Issue: 38(3), P. 475 - 481

Published: Jan. 29, 2024

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust durable responses at 45 mg/day in patients CP-CML resistant second-generation TKIs PACE trial. However, cardiovascular toxicities, arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated efficacy safety ponatinib using novel, response-based, dose-reduction strategy whose disease ≥2 who harbor T315I. To assess dose-response relationship effect on ponatinib, we examined outcomes enrolled received ponatinib. A propensity score analysis was used evaluate AOEs across both trials. Survival rates median time achieve ≤1%

Language: Английский

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Interleukin-10 in cancer immunotherapy: from bench to bedside

Trends in cancer, Journal Year: 2023, Volume and Issue: 9(9), P. 716 - 725

Published: June 16, 2023

Language: Английский

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Characterizing Exposure–Response Relationship for Therapeutic Monoclonal Antibodies in Immuno‐Oncology and Beyond: Challenges, Perspectives, and Prospects

Clinical Pharmacology & Therapeutics, Journal Year: 2020, Volume and Issue: 108(6), P. 1156 - 1170

Published: June 19, 2020

Recent data from immuno-oncology clinical studies have shown the exposure-response (E-R) relationship for therapeutic monoclonal antibodies (mAbs) was often confounded by various factors due to complex interplay of patient characteristics, disease, drug exposure, clearance, and treatment response presented challenges in characterization interpretation E-R analysis. To tackle challenges, exposure relationships mAbs oncology are reviewed, a general framework an integrative understanding is proposed. In this framework, baseline factors, envisioned form interconnected triangle, driving underlying three components that compose apparent relationship: exposure-driven E-R, baseline-driven response-driven E-R. Various strategies analysis study design decouple those mitigate confounding effect reviewed their merits limitations, potential roadmap selection these Specifically, metrics based on single-dose pharmacokinetic model can be used while multivariable and/or case control obtained multiple dose levels randomized may account context, importance collecting levels, role prognostic predictive utility clearance at its change over time, future directions discussed.

Language: Английский

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Controlled pharmacokinetic anti-cancer drug concentration profiles lead to growth inhibition of colorectal cancer cells in a microfluidic device

Lab on a Chip, Journal Year: 2020, Volume and Issue: 20(17), P. 3167 - 3178

Published: Jan. 1, 2020

We present a microfluidic device to expose cancer cells dynamic,in vivo-like concentration profile of drug, and quantify efficacy on-chip.

Language: Английский

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Personalised, Rational, Efficacy-Driven Cancer Drug Dosing via an Artificial Intelligence SystEm (PRECISE): A Protocol for the PRECISE CURATE.AI Pilot Clinical Trial

Frontiers in Digital Health, Journal Year: 2021, Volume and Issue: 3

Published: March 12, 2021

Introduction: Oncologists have traditionally administered the maximum tolerated doses of drugs in chemotherapy. However, these toxicity-guided may lead to suboptimal efficacy. CURATE.AI is an indication-agnostic, mechanism-independent and efficacy-driven personalised dosing platform that offer a more optimal solution. While has already been applied variety clinical settings, there are no prior randomised controlled trials (RCTs) on CURATE.AI-guided chemotherapy for solid tumours. Therefore, we aim assess technical logistical feasibility future RCT tumour dosing. We will also collect exploratory data efficacy toxicity, which inform power calculations. Methods analysis: This open-label, single-arm, two-centre, prospective pilot trial, recruiting adults with metastatic tumours raised baseline marker levels who planned palliative-intent, capecitabine-based As small platform, it guide drug each participant based only their own as input data. The primary outcome proportion participants whom successfully provide dosing, judged predefined considerations. Secondary outcomes include timeliness dose recommendations, physician adherence CURATE.AI-recommended doses, clinically significant changes. initially enrol 10 from two hospitals Singapore, perform interim analysis, consider either cohort expansion or RCT. Recruitment began August 2020. trial key precision oncology. Ethics dissemination: National Healthcare Group (NHG) Domain Specific Review Board granted ethical approval this study (DSRB 2020/00334). distribute our findings at scientific conferences publish them peer-reviewed journals. Trial registration number: NCT04522284.

Language: Английский

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Clinical dose rationale of tislelizumab in patients with solid or hematological advanced tumors

Clinical and Translational Science, Journal Year: 2024, Volume and Issue: 17(3)

Published: March 1, 2024

Tislelizumab, an anti-programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first-in-human, dose-finding BGB-A317-001 study (data cutoff [DCO]: August 2017) examined following dosing regimens: 0.5-10 mg/kg every 2 weeks (q2w), 2-5 q2w or q3w, 200 mg q3w. Similar objective response rates (ORRs) were reported 5 q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to modification/discontinuation, immune-mediated AEs, infusion-related reactions) generally comparable across range examined. These results, alongside convenience a fixed dose, formed basis choosing as recommended regimen further use. Pooled exposure-response (E-R) analyses by logistic regression using from (DCO: 2020) three additional I/II studies (DCOs: 2018-2020) showed no statistically significant correlation between pharmacokinetic exposure ORR solid tumor types classical Hodgkin's lymphoma, nor was associated any safety end points evaluated tested. Hence, relatively flat E-R relationship. Overall, totality data, including efficacy, safety, analyses, together relative provided

Language: Английский

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Dose selection of novel anticancer drugs: exposing the gap between selected and required doses

The Lancet Oncology, Journal Year: 2024, Volume and Issue: 25(8), P. e340 - e351

Published: July 29, 2024

Language: Английский

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An exposure–safety analysis to support the dosage of the novel AKT inhibitor capivasertib

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

Published: March 28, 2025

Abstract Purpose This study aimed to evaluate capivasertib exposure–response relationships for clinical safety events support dosage selection. Methods Data from 277 patients with solid tumors participating in three phase 1 studies were analyzed. Capivasertib 80–800 mg was administered as monotherapy orally twice daily (BID) on continuous or intermittent (4 days on, 3 off [4/3] 2 5 [2/5]) schedules. Relationships between exposure related metrics (dose, weekly dose, AUC, AUC PWD , C max and min ) probability of endpoints (adverse event [AE] leading dose discontinuation, AE modification, serious [SAE], grade ≥ 3, 1, diarrhea 2, rash hyperglycemia increased blood glucose > 13.9 mmol/L) evaluated by logistic regression. Results Significant identified all evaluated, except 1. The analysis suggested that most the are driven total exposure, whereas elevations achieved within a dosing interval. experiencing an SAE, lower 480 BID schedule than 320 schedule. Conclusion when suggesting is better tolerated due exposure.

Language: Английский

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Pivotal Dose of Pembrolizumab: A Dose‐Finding Strategy for Immuno‐Oncology

Clinical Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 110(1), P. 200 - 209

Published: Jan. 19, 2021

Despite numerous publications emphasizing the value of dose finding, drug development in oncology is dominated by mindset that higher provides efficacy. Examples finding implemented biopharmaceutical firms can change this mindset. The purpose article to outline a pragmatic selection strategy for immuno-oncology (IO) and other targeted monoclonal antibodies (mAbs). approach was pembrolizumab. Selecting recommended phase II (RP2D) with novel mechanism action often challenging due uncertain relationships between pharmacodynamics measurements clinical end points. Additionally, I efficacy safety data are generally inadequate RP2D IO mAbs. Here, estimated based on (clinical study KN001 A A2) pharmacokinetics as required target saturation, which represents surrogate maximal pharmacological effect antagonist Due limitations associated collecting analyzing tumor biopsies, characterizing intratumoral engagement (TE) challenging. To overcome gap, physiologically-based pharmacokinetic model predict TE. As tumors spatially heterogeneous, TE predicted well-vascularized poorly vascularized regions. impact differences expression, example, interindividual variability cancer type, simulated. Simulations showed 200 mg every 3 weeks achieve ≥ 90% clinically relevant scenarios, resulting recommendation RP2D. Randomized comparison studies (KN001 B2 D) showing similar over fivefold dose/exposure range confirmed pivotal dose.

Language: Английский

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Contemporary dose-escalation methods for early phase studies in the immunotherapeutics era

European Journal of Cancer, Journal Year: 2021, Volume and Issue: 158, P. 85 - 98

Published: Oct. 16, 2021

Language: Английский

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