Optimizing Dosing of Oncology Drugs

Minasian, Lori M.; Rosen, Osnat; Auclair, Daniel; Rahman, Atiqur; Pazdur, Richard; Schilsky, Richard L.

doi:10.1038/clpt.2014.153

Cited by 71 publications

(82 citation statements)

References 14 publications

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“…In addition, frequent postmarketing requirements to study lower doses or alternate regimens are needed to optimize use of the drug (1). Identification of the "right dose" before approval is the goal; however, it is sometimes challenging to conduct adequate dose-ranging trials when the biology of the target is not well understood and/or there is an unmet medical need to make the drug available to patients quickly.…”

Section: Introductionmentioning

confidence: 99%

Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy

Nie¹,

Rubin²,

Mehrotra³

et al. 2016

Clinical Cancer Research

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Selection of the maximum tolerated dose (MTD) as the recommended dose for registration trials based on a doseescalation trial using variations of an MTD/3 þ 3 design often occurs in the development of oncology products. The MTD/3 þ 3 approach is not optimal and may result in recommended doses that are unacceptably toxic for many patients and in dose reduction/interruptions that might have an impact on effectiveness. Instead of the MTD/3 þ 3 approach, the authors recommend an integrated approach. In this approach, typically an adaptive/Bayesian model provides a general framework to incorporate and make decisions for dose escalation based on nonclinical data, such as animal efficacy and toxicity data; clinical data, including pharmacokinetics/pharmacodynamics data; and dose/exposure-response data for efficacy and safety. To improve dose-ranging trials, model-based estimation, rather than hypothesis testing, should be used to maximize and integrate the information gathered across trials and doses. This approach may improve identification of optimal recommended doses, which can then be confirmed in registration trials.

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Section: Introductionmentioning

confidence: 99%

Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy

Nie¹,

Rubin²,

Mehrotra³

et al. 2016

Clinical Cancer Research

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“…The underlying principle stems from the chemotherapy era, where the more drug that is tolerated by the patient, the more efficacy you achieved, but needed to be balanced by safety. With targeted agents, however, it is possible that the exposure–response for safety and efficacy may be separated, and several examples have been presented by academia and regulators on the need for dose optimization on therapeutic proteins in the oncology area 19, 20, 21, 22. This work aims at presenting the exposure–response modeling of safety and efficacy performed with data obtained in squamous NSCLC patients, given gemcitabine‐cisplatin with or without necitumumab 12…”

mentioning

confidence: 99%

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

Cosson

Wallin³

2017

CPT Pharmacometrics Syst. Pharmacol.

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We sought to describe the exposure–response relationship of necitumumab efficacy in squamous non‐small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard. The change in tumor size was characterized using linear growth and first‐order shrinkage. Overall survival was described using a combination of a Weibull function and Gompertz function for the hazard, with dynamic tumor size being a predictor for the hazard. Although body weight resulted in higher clearance and lower exposure, simulations showed that an 800 mg flat dose provided optimal response regardless of body weight.

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“…6 To address the need for better-designed trials, in May 2015, the Food and Drug Administration and the American Association of Cancer Research convened a meeting of researchers entitled, "Dose-finding of Small Molecule Oncology Drugs," to evaluate alternative methods to optimize and improve dose finding for MTAs. Several case studies of MTAs approved at nonoptimal doses were presented at the meeting, indicating that case studies can help better illustrate the aspects of existing oncology drug development methods and designs that can be improved.…”

Section: Introductionmentioning

confidence: 99%

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials

Lee

Backenroth

Cheung

et al. 2016

JCO

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The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to reevaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. Patients and MethodsWe classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. ResultsA total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m 2 , the estimated cumulative incidence of DLT was . 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. ConclusionsWhen considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials.

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Optimizing Dosing of Oncology Drugs

Cited by 71 publications

References 14 publications

Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy

Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials

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