Bayesian Phase I/II Biomarker-Based Dose Finding for Precision Medicine With Molecularly Targeted Agents

Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose–efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website.

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Precision Medicine for Molecularly Targeted Agents and Immunotherapies in Early-Phase Clinical Trials

Translational Oncogenomics ◽

10.4137/tog.s30533 ◽

2015 ◽

Vol Suppl. 1 ◽

pp. 1-11 ◽

Cited By ~ 3

Keyword(s):

Clinical Trials ◽

Precision Medicine ◽

Early Phase ◽

Targeted Agents ◽

Molecularly Targeted Agents ◽

Early Phase Clinical Trials

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Bayesian dose‐finding designs for combination of molecularly targeted agents assuming partial stochastic ordering

Statistics in Medicine ◽

10.1002/sim.6376 ◽

2015 ◽

Vol 34 (5) ◽

pp. 859-875 ◽

Cited By ~ 7

Author(s):

Beibei Guo ◽

Yisheng Li

Keyword(s):

Stochastic Ordering ◽

Dose Finding ◽

Targeted Agents ◽

Molecularly Targeted Agents

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Choice of Starting Dose for Molecularly Targeted Agents Evaluated in First-in-Human Phase I Cancer Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.9606 ◽

2010 ◽

Vol 28 (8) ◽

pp. 1401-1407 ◽

Cited By ~ 38

Author(s):

Christophe Le Tourneau ◽

Anastasios Stathis ◽

Laura Vidal ◽

Malcolm J. Moore ◽

Lillian L. Siu

Keyword(s):

Phase I ◽

Lethal Dose ◽

Maximum Tolerated Dose ◽

Cytotoxic Agents ◽

Phase I Trials ◽

Targeted Agents ◽

Wide Range ◽

Molecularly Targeted Agents ◽

Starting Dose ◽

Dose Levels

Purpose One tenth of the lethal dose to 10% of mice is one of the conventional parameters used to derive a safe starting dose in phase I trials of cytotoxic agents. There is no consensus on which preclinical models and parameters should define the starting dose for molecularly targeted agents. Patients and Methods Reports of 81 first-in-human phase I trials evaluating 60 different molecularly targeted agents administered as monotherapy were reviewed. The maximum-tolerated dose (MTD) was defined as the highest safe dose administered to patients, whereas the maximum-administered dose (MAD) was recorded if the MTD was not reached. Results Fifty-seven of the 81 trials specified the animal model used to determine the starting dose, with 29 (51%) of 57 based on rodent data and 28 (49%) of 57 based on non-rodent data. A wide range of toxicologic parameters was used to select the starting dose. The starting dose exceeded the human MTD in three (3.7%) of 81 trials, and in all three trials, nonhematologic toxicity was dose limiting. The median number of dose levels to reach MTD or MAD from starting dose was five (range, one to 14 dose levels), and the median ratio of MTD or MAD to starting dose was 12 (range, < 1 to 300). Hypothetical doubling of the starting dose appeared to be safe, whereas tripling of the starting dose was unsafe. Conclusion The derivation of starting dose for first-in-human phase I trials of molecularly targeted agents in patients with cancer is safe but is based on diverse practices using a variety of preclinical toxicologic parameters.

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Dose-efficacy relationship for molecularly targeted agents: A literature review of monotherapy phase I cancer clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e13553 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e13553-e13553

Author(s):

Jennifer Arrondeau ◽

Xavier Paoletti ◽

Marie-Paule Sablin ◽

Simona Pop ◽

Christophe Le Tourneau

Keyword(s):

Literature Review ◽

Phase I ◽

Response Rate ◽

Statistical Significance ◽

Maximum Tolerated Dose ◽

Extensive Literature ◽

Phase I Trials ◽

Targeted Agents ◽

Study Results ◽

Molecularly Targeted Agents

e13553 Background: Data regarding the dose-efficacy relationship for molecularly targeted agents (MTAs) are conflicting and all based on institution data. We report the largest study evaluating this relationship based on an extensive literature review of phase I trials of MTAs administered as single agents over the last decade. Methods: Efficacy defined by the occurrence of partial or complete responses was recorded and related to the dose administered expressed as a percentage of the maximum tolerated dose (MTD) or the maximum administered dose (MAD) when the MTD was not reached. Association was estimated using logit model with random intercept to adjust for the study. Results: Hundred and sixty eight phase I trials evaluating 116 MTAs involving 5,668 patients were reviewed. Efficacy was present in 39% of trials, but in only 134 patients (2.3%). Among these 134 patients, the dose at which signs of efficacy occurred was known for 113 patients. Overall, the crude response rate slightly increased from 4% at doses <40% of the MTD/MAD to 6%, 7% and 7% at doses 40-80%, 80-120% and >120%, respectively. However, statistical significance was not reached (p=0.28), whether or not the MTD had been reached. Conclusions: Antitumor activity infrequently occurs in phase I trials of MTAs administered as single agents. Although efficacy seemed to increase with dose, statistical significance was not reached, possibly due to the low response rate and sample size.

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