Determining drug dose in the era of targeted therapies: playing it (un)safe?

Blood Cancer Journal, Journal Year: 2022, Volume and Issue: 12(8)

Published: Aug. 23, 2022

Abstract Targeted therapies against phosphatidylinositol 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and B-cell lymphoma-2 (BCL-2) are approved for chronic lymphocytic leukemia (CLL). Since approval of the first-in-class drugs, next-generation agents have become available continuously under development. While these act on well-characterized molecular targets, this knowledge is only to some extent taken into consideration when determining their dose in phase I trials. For example, BTK occupancy has been assessed dose-finding studies various inhibitors, but minimum doses that result full were not determined. Although targeted a different dose–response relationship than cytotoxic agents, which more effective near maximum tolerated dose, traditional 3 + toxicity-driven trial design remains heavily used era therapies. If pharmacodynamic biomarkers stringently guide selection, recommended II would likely be lower as compared selection. Reduced drug may toxicity, cases severe supported by retrospective demonstrating non-inferior outcomes patients with clinically indicated reductions. Here, we review strategies selection currently select investigational CLL, discuss how our initial clinical experience pointed reductions, intermittent dosing, combinations overcome treatment intolerance resistance.

Language: Английский

---

When Less May Be Enough: Dose Selection Strategies for Immune Checkpoint Inhibitors Focusing on AntiPD-(L)1 Agents

Targeted Oncology, Journal Year: 2022, Volume and Issue: 17(3), P. 253 - 270

Published: May 1, 2022

Language: Английский

---

In Curative Stereotactic Body Radiation Therapy for Prostate Cancer, There Is a High Possibility That 45 Gy in 5 Fractions Will Not Be Tolerated without a Hydrogel Spacer

Published: March 20, 2024

The purpose of this study was to determine the maximum tolerated dose (MTD) for stereotactic body radiation therapy (SBRT) in treatment non-metastatic prostate cancer. This a phase 1 escalation trial conducted Japan. Patients with histologically proven cancer without lymph node or distant metastasis were enrolled. prescribed doses 42.5, 45, 47.5 Gy five fractions. Dose-limiting toxicity (DLT) defined as grade (G) 3+ gastrointestinal genitourinary within 180 days after SBRT completion and 6 plus design used method escalation. A total 16 patients enrolled, 42.5 group 10 45 group. No DLT observed In group, one patient experienced G3 rectal hemorrhage, another had G4 perforation, leading determination MTD. None biochemical recurrence death during follow-up period. We concluded that at 5 fractions could be safely performed, but increased severe toxicity.

Language: Английский

---

In Curative Stereotactic Body Radiation Therapy for Prostate Cancer, There Is a High Possibility That 45 Gy in Five Fractions Will Not Be Tolerated without a Hydrogel Spacer

Cancers, Journal Year: 2024, Volume and Issue: 16(8), P. 1472 - 1472

Published: April 11, 2024

The purpose of this study was to determine the maximum tolerated dose (MTD) for stereotactic body radiation therapy (SBRT) in treatment non-metastatic prostate cancer. This a phase 1 escalation trial conducted Japan. Patients with histologically proven cancer without lymph nodes or distant metastases were enrolled. prescribed doses 42.5, 45, 47.5 Gy five fractions. Dose-limiting toxicity (DLT) defined as grade (G) 3+ gastrointestinal genitourinary within 180 days after SBRT completion, and 6 plus design used method escalation. A total 16 patients enrolled, 42.5 group 10 45 group. No DLT observed In group, one patient experienced G3 rectal hemorrhage, another had G4 perforation, leading determination MTD. None biochemical recurrence death during follow-up period. We concluded that at fractions could be safely performed, but increased severe toxicity.

Language: Английский

---

Convergence Behavior of Optimal Cut-Off Points Derived from Receiver Operating Characteristics Curve Analysis: A Simulation Study

Mathematics, Journal Year: 2022, Volume and Issue: 10(22), P. 4206 - 4206

Published: Nov. 10, 2022

The area under the receiver operating characteristics curve is a popular measure of overall discriminatory power continuous variable used to indicate presence an outcome interest, such as disease or progression. In clinical practice, use cut-off points benchmark values for further treatment planning greatly appreciated, despite loss information that dichotomization implies. Optimal are often derived from fixed sample size studies, and aim this study was investigate convergence behavior optimal with increasing explore heuristic path-based algorithm point determination targets stagnating values. To end, closest-to-(0,1) criterion in analysis used, aimed at deviated less than 1% previous iteration. Such stopped after only few iterations, thereby implicating practicable sizes; however, result was, best, rough estimate unbiased positively negatively biased prevalence 0.5, smaller larger respectively.

Language: Английский

---

A modified Huber loss function for continual reassessment methods in clinical trials

Sequential Analysis, Journal Year: 2024, Volume and Issue: 43(1), P. 28 - 48

Published: Jan. 2, 2024

In dose-finding (DF) trials, methods for discovering an optimal criterion that controls toxicity while demonstrating a potential efficacy have been the subject of statistical research. Although continual reassessment (CRMs) utilized, consensus among practitioners and clinical trial specialists is there always room improvement with CRMs. Within paradigm full-Bayesian method CRMs, we examine performance dose selection algorithms based on family loss functions defined in Huber (The Annals Mathematical Statistics, vol. 35, issue 1, pp. 73–101, 1964), namely, function, special focus modified function (MHLF). Our exploration suggests that, compared to Bayesian interval design (BOIN) (TILF), approach MHLF has able select correct doses fewer average number patients across spectrum escalation schemes such as those seen settings.

Language: Английский

---

Sex as a Biological Variable in Early-Phase Oncology Clinical Trials: Enhancing the Path to Personalised Medicine

Heliyon, Journal Year: 2024, Volume and Issue: 10(12), P. e32597 - e32597

Published: June 1, 2024

Language: Английский

---

PKBOIN‐12: A Bayesian Optimal Interval Phase I/II Design Incorporating Pharmacokinetics Outcomes to Find the Optimal Biological Dose

Pharmaceutical Statistics, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 24, 2024

ABSTRACT Immunotherapies and targeted therapies have gained popularity due to their promising therapeutic effects across multiple treatment areas. The focus of early phase dose‐finding clinical trials has shifted from finding the maximum tolerated dose (MTD) identifying optimal biological (OBD), which aims balance toxicity efficacy outcomes, thus optimizing risk–benefit trade‐off. These often collect pharmacokinetics (PK) outcomes assess drug exposure, shown correlations with but not been utilized in current designs for OBD selection. Moreover, PK are usually available within days after initial treatment, much faster than outcomes. To bridge this gap, we introduce innovative model‐assisted PKBOIN‐12 design, enhances BOIN12 by integrating information into both algorithm final determination process. We further extend TITE‐PKBOIN‐12 address challenges late‐onset Simulation results demonstrate that more effectively identifies allocates a greater number patients it BOIN12. Additionally, decreases probability selecting inefficacious doses as excluding those low exposure. Comprehensive simulation studies sensitivity analysis confirm robustness various scenarios.

Language: Английский

---

Statistical operating characteristics of current early phase dose finding designs with toxicity and efficacy in oncology

Journal of Biopharmaceutical Statistics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 21

Published: Nov. 16, 2024

Traditional phase I dose finding cancer clinical trial designs aim to determine the maximum tolerated (MTD) of investigational cytotoxic agent based on a single toxicity outcome, assuming monotone dose-response relationship. However, this assumption might not always hold for newly emerging therapies such as immuno-oncology and molecularly targeted therapies, making conventional no longer appropriate. To tackle issue, numerous early have been developed identify optimal biological (OBD), which takes both efficacy outcomes into account. In article, we review current model-assisted designs, BOIN-ET, BOIN12, UBI, TEPI-2, PRINTE, STEIN, uTPI OBD compare their operating characteristics. Extensive simulation studies case study using CAR T-cell therapy conducted performance aforementioned under different possible relationship scenarios. The results demonstrate that varies depending particular specific metric considered. Based our practical considerations, BOIN12 outperform other from perspectives.

Language: Английский

---

Overview of model-assisted design for phase I dose-finding trials in oncology

Japanese Journal of Biometrics, Journal Year: 2022, Volume and Issue: 43(1), P. 3 - 36

Published: Jan. 1, 2022

Numerous model-based designs for dose-finding have been proposed to improve the phase I trials (e.g., increasing accuracy identify maximum tolerated dose). However, algorithm-based 3+3 design) are still dominantly used regardless of relatively poor performance due complexity implementation designs. In this review, we introduce model-assisted that simplicity design and similar designs, which promising approaches transcend conventional framework. addition, comprehensively review expansion a complex area such as developments in dual-agent therapies; considerations fast accrual issues or late-onset toxicities would be observed targeted therapies immunotherapies; exploration optimal dose efficacy safety; other toxicity grades historical data).

Language: Английский

---