Hiroyuki Sato

Bio: Hiroyuki Sato is an academic researcher from Pharmaceuticals and Medical Devices Agency. The author has contributed to research in topics: Clinical study design & Cumulative dose. The author has an hindex of 4, co-authored 12 publications receiving 113 citations.

Master protocol trials in oncology: Review and new trial designs.

Abstract: In oncology, next generation sequencing and comprehensive genomic profiling have enabled the detailed classification of tumors using molecular biology. However, it is unrealistic to conduct phase I-III trials according to each sub-population based on patient molecular subtypes. Common protocols that assess the combination of several molecular markers and their targeted therapies by means of multiple sub-studies are required. These protocols are called "master protocols," and are drawing attention as a next-generation clinical trial design. Recently, several reviews of clinical trials based on the master protocol design have been published, but their definitions of these such trials, including basket, umbrella, and platform trials, were not consistent. Concurrently, the acceleration of the development of new statistical designs for master protocol trials has been underway. This article provides an overview of recent reviews for master protocols, including their statistical design methodologies in Oncology. We also introduce several examples of previous and on-going master protocol trials along with their classifications by some recent studies.

A comparative study of adaptive dose-finding designs for phase I oncology trials of combination therapies

Abstract: Little is known about the relative performance of competing model-based dose-finding methods for combination phase I trials. In this study, we focused on five model-based dose-finding methods that have been recently developed. We compared the recommendation rates for true maximum-tolerated dose combinations (MTDCs) and over-dose combinations among these methods under 16 scenarios for 3 × 3, 4 × 4, 2 × 4, and 3 × 5 dose combination matrices. We found that performance of the model-based dose-finding methods varied depending on (1) whether the dose combination matrix is square or not; (2) whether the true MTDCs exist within the same group along the diagonals of the dose combination matrix; and (3) the number of true MTDCs. We discuss the details of the operating characteristics and the advantages and disadvantages of the five methods compared.

An adaptive dose‐finding method using a change‐point model for molecularly targeted agents in phase I trials

Abstract: The paradigm of oncology drug development is expanding from developing cytotoxic agents to developing biological or molecularly targeted agents (MTAs). Although it is common for the efficacy and toxicity of cytotoxic agents to increase monotonically with dose escalation, the efficacy of some MTAs may exhibit non-monotonic patterns in their dose-efficacy relationships. Many adaptive dose-finding approaches in the available literature account for the non-monotonic dose-efficacy behavior by including additional model parameters. In this study, we propose a novel adaptive dose-finding approach based on binary efficacy and toxicity outcomes in phase I trials for monotherapy using an MTA. We develop a dose-efficacy model, the parameters of which are allowed to change in the vicinity of the change point of the dose level, in order to consider the non-monotonic pattern of the dose-efficacy relationship. The change point is obtained as the dose that maximizes the log-likelihood of the assumed dose-efficacy and dose-toxicity models. The dose-finding algorithm is based on the weighted Mahalanobis distance, calculated using the posterior probabilities of efficacy and toxicity outcomes. We compare the operating characteristics between the proposed and existing methods and examine the sensitivity of the proposed method by simulation studies under various scenarios. Copyright © 2016 John Wiley & Sons, Ltd.

Evolving Japanese regulations on companion diagnostics

Abstract: 141 Canada, Ottawa, Ontario, Canada. 3Institute for Bioscience and Biotechnology Research, National Institute of Standards and Technology, Rockville, Maryland, USA. 4Medical Products Agency of Sweden, Uppsala, Sweden. 5US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Biotechnology Products, Silver Spring, Maryland, USA. e-mail: john.marino@nist.gov, yves.aubin@hc-sc.gc.ca or david.keire@fda.hhs.gov

Effect of design specifications in dose‐finding trials for combination therapies in oncology

Abstract: Model-based dose-finding methods for a combination therapy involving two agents in phase I oncology trials typically include four design aspects namely, size of the patient cohort, three-parameter dose-toxicity model, choice of start-up rule, and whether or not to include a restriction on dose-level skipping. The effect of each design aspect on the operating characteristics of the dose-finding method has not been adequately studied. However, some studies compared the performance of rival dose-finding methods using design aspects outlined by the original studies. In this study, we featured the well-known four design aspects and evaluated the impact of each independent effect on the operating characteristics of the dose-finding method including these aspects. We performed simulation studies to examine the effect of these design aspects on the determination of the true maximum tolerated dose combinations as well as exposure to unacceptable toxic dose combinations. The results demonstrated that the selection rates of maximum tolerated dose combinations and UTDCs vary depending on the patient cohort size and restrictions on dose-level skipping However, the three-parameter dose-toxicity models and start-up rules did not affect these parameters. Copyright © 2016 John Wiley & Sons, Ltd.

Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols

Abstract: Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500–90 = 410), and the median study duration was 22.3 (IQR: 74.1–42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835–255 = 1580), and the median study duration was 58.9 (IQR: 101.3–36.9 = 64.4) months. We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

Improving clinical trial outcomes in amyotrophic lateral sclerosis

Abstract: Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.

An overview of precision oncology basket and umbrella trials for clinicians.

Abstract: With advancements in biomarkers and momentum in precision medicine, biomarker-guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine-to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.

Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB)

Abstract: Precision medicine was born with the development of new diagnostic techniques and targeted drugs, yielding better outcomes in cancer care. With the evolution and increasing sensitivity for detecting oncogenic drivers, liquid biopsies (LBs), specifically cell-free DNA (cfDNA) analysis, have been proposed as a minimally-invasive technique for genomic profiling. Ranging from sequencing techniques to PCR-based methods and other more complex strategies, this approach, currently applicable in some solid tumors with robust evidence, is showing promising opportunities in other cancers. However, difficulties in validating their clinical utility exist within limitation at different levels among several techniques, reporting of the results, lack of appropriate clinical trial designs, and unknown economic impact. One of the aims of the ISLB is to create recommendations to develop reliable and sustainable diagnostic, prognostic and predictive tools using LBs. This paper is addressing these objectives, helping the healthcare providers and scientific community to understand the potential of LB.