Shortening the Timeline of Pediatric Phase I Trials: The Rolling Six Design

Skolnik, Jeffrey; Barrett, Jeffrey S.; Jayaraman, Bhuvana; Patel, Dhaval; Adamson, Peter C.

doi:10.1200/jco.2007.12.7712

Cited by 219 publications

(163 citation statements)

References 15 publications

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“…The case for reduced sample size designs have been long argued with the continued management of the pipeline, necessitating creative but meaningful ways to improve both the efficiency and the productivity of Phase I development. Such improvements have been argued to have a meaningful impact on pediatric drug development (20,29,30). While their focus has been on oncology and on pediatrics, we believe that agile study designs that are based on sound assumptions would still provide meaningful information on the drug candidate, minimizing human exposure, and in a learn/confirm manner, provide impetus for the design of subsequent hypothesis testing clinical study designs.…”

Section: Discussionmentioning

confidence: 99%

“…A newly proposed rolling six design for reducing the time to complete phase I trials in pediatrics has been recently proposed as an alternative to the conventional oncology 3+3 design (20). These investigators have used a discrete event simulation methodology to develop dose escalation/de-escalation and stopping rules based on a priori assumptions of DLT frequencies.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Agile Designs in First-in-Human (FIH) Trials—A Simulation Study

Perlstein

Bolognese

Krishna

et al. 2009

AAPS J

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Abstract. The aim of the investigation was to evaluate alternatives to standard first-in-human (FIH) designs in order to optimize the information gained from such studies by employing novel agile trial designs. Agile designs combine adaptive and flexible elements to enable optimized use of prior information either before and/or during conduct of the study to seamlessly update the study design. A comparison of the traditional 6+2 (active+placebo) subjects per cohort design with alternative, reduced sample size, agile designs was performed by using discrete event simulation. Agile designs were evaluated for specific adverse event models and rates as well as dose-proportional, saturated, and steepaccumulation pharmacokinetic profiles. Alternative, reduced sample size (hereafter referred to as agile) designs are proposed for cases where prior knowledge about pharmacokinetics and/or adverse event relationships are available or appropriately assumed. Additionally, preferred alternatives are proposed for a general case when prior knowledge is limited or unavailable. Within the tested conditions and stated assumptions, some agile designs were found to be as efficient as traditional designs. Thus, simulations demonstrated that the agile design is a robust and feasible approach to FIH clinical trials, with no meaningful loss of relevant information, as it relates to PK and AE assumptions. In some circumstances, applying agile designs may decrease the duration and resources required for Phase I studies, increasing the efficiency of early clinical development. We highlight the value and importance of useful prior information when specifying key assumptions related to safety, tolerability, and PK.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of Agile Designs in First-in-Human (FIH) Trials—A Simulation Study

Perlstein

Bolognese

Krishna

et al. 2009

AAPS J

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“…The dose given is that with estimated toxicity thought closest to the maximum tolerable toxicity [33]. The "rolling six design" allows for accrual of 2 to 6 patients concurrently onto a dose level based on the number of patients enrolled and evaluable, the number having dose-limiting toxicity (DLT), and the number still at risk of developing DLT [34]. This design is intended to shorten the study duration in which there is prior information about the dose range and is useful in pediatric populations.…”

Section: Phase I Clinical Trialsmentioning

confidence: 99%

Clinical Trial Phases

Mahan¹

2014

IJCM

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Developers of drugs, biologicals, and medical devices must ensure product safety, demonstrate medical benefit in people, and mass produce the product. Preclinical development starts before clinical trials and the main goals are to determine safety and effectiveness of the intervention. If preclinical studies show that the therapy is safe and effective, clinical trials are started. Clinical trial phases are steps in the research to determine if an intervention would be beneficial or detrimental to humans and include Phases 0, I, II, III, IV, and V clinical studies. Understanding the basis of clinical trial phases will help researchers plan and implement clinical study protocols and, by doing so, improve the number of therapies coming to market for patients.

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“…Developing drugs for pediatric malignancies also brings with it a number of unique challenges in terms of trial design, potential for disparity in genetics and pathophysiology relative to the adult disease, and what is considered acceptable clinical benefit. Trial design considerations include age-stratified dosing regimens, ageappropriate formulations (Breitkreutz and Boos, 2007), amenable sampling schemes (given the limitations on the number and volume of blood draws), as well as the necessity for flexible enrollment approaches in phase I, such as the rolling six design (Skolnik et al, 2008). The specific oncogenic pathways in adult carcinomas may not be active in the childhood malignancy, although common cellular pathways have emerged (Rossig et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development

Rioux

Waters

2016

Drug Metabolism and Disposition

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Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, ageappropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systemsbased framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

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Shortening the Timeline of Pediatric Phase I Trials: The Rolling Six Design

Abstract: The rolling six design may significantly decrease the duration of pediatric phase I studies without increasing the risk of toxicity. The design will be tested prospectively in upcoming Children's Oncology Group phase I trials.

Cited by 219 publications

References 15 publications

Evaluation of Agile Designs in First-in-Human (FIH) Trials—A Simulation Study

Evaluation of Agile Designs in First-in-Human (FIH) Trials—A Simulation Study

Clinical Trial Phases

Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development

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