Clinical benefit in phase I trials of novel molecularly targeted agents: Does dose matter?

Postel-Vinay, S.; Arkenau, H-T.; Ashley, S.; Barriuso, Jorge; Olmos, David; Shaw, Holly; Wright, Morgan; Judson, I.; Bono, Johann S. de; Kaye, SB

doi:10.1200/jco.2008.26.15_suppl.2509

Cited by 22 publications

(29 citation statements)

References 12 publications

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“…3 cohort expansion design that expands an initial cohort of three patients by groups of three until a toxicity rate of 33% is achieved [24]. With MTAs, there is often no correlation between toxicity and clinical effect [25]. Thus, alternative endpoints must be used to determine effective dose levels, such as measures of target inhibition and the measurement of blood levels of the agent under study [26].…”

Section: Phase I Trialsmentioning

confidence: 99%

Clinical trials in the age of personalized medicine

Keating

Cambrosio

2011

J Med Pers

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The paper reviews some of the transformations of cancer clinical trial protocols made necessary by the emergence of molecularly targeted agents. These changes include the creation of a new phase of clinical trials (phase 0) and the alteration of the parameters governing the other three phases. The situation remains unstable: repeated attempts to speed up the development of new drugs have not yet led to a consensus on how to best do so. The new targeted agents raise issues that go beyond the purely technical as changing protocols implicate changes in the organization of translational research.

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Section: Phase I Trialsmentioning

confidence: 99%

Clinical trials in the age of personalized medicine

Keating

Cambrosio

2011

J Med Pers

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“…From an ethical point of view, the risk of severe toxicity must be minimized in these patients who are often treated for tumors that are refractory to standard treatments, and where the clinical benefit from these experimental treatments is usually dismal in this context [17][18][19].…”

Section: Toxicitymentioning

confidence: 99%

“…Numerous authors, as well as the Methodology for the Development of Innovative Cancer Therapies task force, recommend that toxicity remains the primary end point in phase I trials, except in presence of a validated pharmacodynamic biomarker [19,25,31,34,35].…”

Section: Pharmacodynamic Biomarkersmentioning

confidence: 99%

Section: Antitumor Activitymentioning

confidence: 99%

“…Consequently, response rates in these trials are usually low [17][18][19]. As molecularly targeted therapies are thought to sometimes display a cytostatic effect rather than a cytotoxic effect, end points such as progression-free survival and clinical benefit rate, defined as the combination of tumor stabilization rate and objective response rate, have therefore been used more and more frequently [19,42,43]. A recent review of 15 phase I trials of molecularly targeted agents performed at the Royal Marsden Hospital between January 2005 and June 2006 including 135 patients indicated that the clinical benefit defined as the sum of complete responses, partial responses and tumor stabilization of more than 3 months did not depend on the dose of the drug [19].…”

Section: Antitumor Activitymentioning

confidence: 99%

See 2 more Smart Citations

Current challenges for the early clinical development of anticancer drugs in the era of molecularly targeted agents

et al. 2010

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The emergence of molecularly targeted agents in oncology has not only revolutionized the care of cancer patients, but also changed the daily practice of medical oncologists. Molecularly targeted agents indeed often differ from traditional cytotoxic agents by their administration schedules and routes, their toxicity profiles, and/or the assessment of their antitumor activity. In addition, the observation that molecularly targeted agents sometimes have limited antitumor activity as single agents has led clinical investigators to combine molecularly targeted agents together or with cytotoxic agents. We review here the current challenges for the early clinical development of anticancer agents in the era of molecularly targeted agents. We focus on the choice of end points in phase I oncology clinical trials, as well as on the choice of dose escalation methods with an emphasis on available dose escalation methods for molecularly targeted agents and for combination trials.

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A utility approach to individualized optimal dose selection using biomarkers

Taylor

Kong

et al. 2019

Biometrical J

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In many settings, including oncology, increasing the dose of treatment results in both increased efficacy and toxicity. With the increasing availability of validated biomarkers and prediction models, there is the potential for individualized dosing based on patient specific factors. We consider the setting where there is an existing dataset of patients treated with heterogenous doses and including binary efficacy and toxicity outcomes and patient factors such as clinical features and biomarkers. The goal is to analyze the data to estimate an optimal dose for each (future) patient based on their clinical features and biomarkers. We propose an optimal individualized dose finding rule by maximizing utility functions for individual patients while limiting the rate of toxicity. The utility is defined as a weighted combination of efficacy and toxicity probabilities. This approach maximizes overall efficacy at a prespecified constraint on overall toxicity. We model the binary efficacy and toxicity outcomes using logistic regression with dose, biomarkers and dose–biomarker interactions. To incorporate the large number of potential parameters, we use the LASSO method. We additionally constrain the dose effect to be non‐negative for both efficacy and toxicity for all patients. Simulation studies show that the utility approach combined with any of the modeling methods can improve efficacy without increasing toxicity relative to fixed dosing. The proposed methods are illustrated using a dataset of patients with lung cancer treated with radiation therapy.

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Clinical benefit in phase I trials of novel molecularly targeted agents: Does dose matter?

Cited by 22 publications

References 12 publications

Clinical trials in the age of personalized medicine

Clinical trials in the age of personalized medicine

Current challenges for the early clinical development of anticancer drugs in the era of molecularly targeted agents

A utility approach to individualized optimal dose selection using biomarkers

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