scholarly journals Circulating Tumor DNA Reflects Uveal Melanoma Responses to Protein Kinase C Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1740
Author(s):  
John J. Park ◽  
Russell J. Diefenbach ◽  
Natalie Byrne ◽  
Georgina V. Long ◽  
Richard A. Scolyer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Benefit ◽  
Trial Design ◽  
Phase 1 ◽  
Clinical Trial Design ◽  
Roc Curves ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Driver Mutations ◽  
Targeted Next Generation Sequencing

The prognosis for patients with UM is poor, and recent clinical trials have failed to prolong overall survival (OS) of these patients. Over 95% of UM harbor activating driver mutations, and this allows for the investigation of ctDNA. In this study, we investigated the value of ctDNA for adaptive clinical trial design in metastatic UM. Longitudinal plasma samples were analyzed for ctDNA in 17 metastatic UM patients treated with PKCi-based therapy in a phase 1 clinical trial setting. Plasma ctDNA was assessed using digital droplet PCR (ddPCR) and a custom melanoma gene panel for targeted next generation sequencing (NGS). Baseline ctDNA strongly correlated with baseline lactate dehydrogenase (LDH) (p < 0.001) and baseline disease burden (p = 0.002). Early during treatment (EDT) ctDNA accurately predicted patients with clinical benefit to PKCi using receiver operator characteristic (ROC) curves (AUC 0.84, [95% confidence interval 0.65–1.0, p = 0.026]). Longitudinal ctDNA assessment was informative for establishing clinical benefit and detecting disease progression with 7/8 (88%) of patients showing a rise in ctDNA and targeted NGS of ctDNA revealed putative resistance mechanisms prior to radiological progression. The inclusion of longitudinal ctDNA monitoring in metastatic UM can advance adaptive clinical trial design.

Development of Interactive Software for Bayesian Optimal Phase 1 Clinical Trial Design

2005 ◽  
Vol 39 (1) ◽  
pp. 89-98 ◽  
Author(s):  
William F. Rosenberger ◽  
Gerald C. Canfield ◽  
Inna Perevozskaya ◽  
Linda M. Haines ◽  
Petr Hausner
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Phase 1 ◽  
Clinical Trial Design ◽  
Interactive Software ◽  
Phase 1 Clinical Trial

Genomic Analysis of Breast Cancer Heralds a Changing Treatment Paradigm

2014 ◽  
Vol 12 (5S) ◽  
pp. 750-752
Author(s):  
Matthew Ellis
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Molecular Biology ◽  
Trial Design ◽  
Molecular Subtypes ◽  
Clinical Trial Design ◽  
Genomic Analysis ◽  
Driver Mutations ◽  
Annual Conference ◽  
Treatment Paradigm

Deep genomic analysis in breast cancer and the identification of driver mutations will result in treatments based on molecular subtypes and pathways. Mutations not yet familiar to most oncologists will become part of the clinical oncology vernacular. Such discoveries will advance the concept of “biology first, not drug first,” because molecular biology will drive drug development and clinical trial design involving small, molecularly defined subsets of patients, according to a presentation at the NCCN 19th Annual Conference.

scholarly journals Emerging ‘A’ therapies in hemoglobinopathies: agonists, antagonists, antioxidants, and arginine

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 271-275 ◽  
Author(s):  
Elliott Vichinsky
Keyword(s):  
Nitric Oxide ◽  
Clinical Trial ◽  
Trial Design ◽  
Phase 1 ◽  
Clinical Trial Design ◽  
Fetal Hemoglobin ◽  
Cellular Adhesion ◽  
Cell Disease ◽  
The Past ◽  
Novel Drugs

Abstract Sickle cell disease and thalassemia have distinctly different mutations, but both share common complications from a chronic vasculopathy. In the past, fetal hemoglobin–modulating drugs have been the main focus of new therapy, but the increased understanding of the complex pathophysiology of these diseases has led to the development of novel agents targeting multiple pathways that cause vascular injury. This review explores the pathophysiology of hemoglobinopathies and novel drugs that have reached phase 1 and 2 clinical trials. Therapies that alter cellular adhesion to endothelium, inflammation, nitric oxide dysregulation, oxidative injury, altered iron metabolism, and hematopoiesis will be highlighted. To evaluate these therapies optimally, recommendations for improving clinical trial design in hemoglobinopathies are discussed.

scholarly journals Moving Beyond 3+3: The Future of Clinical Trial Design

2021 ◽  
pp. e133-e144
Author(s):  
Razelle Kurzrock ◽  
Chia-Chi Lin ◽  
Tsung-Che Wu ◽  
Brian P. Hobbs ◽  
Roberto Carmagnani Pestana ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Trial Design ◽  
Phase 1 ◽  
Clinical Trial Design ◽  
Simulation Models ◽  
Operating Characteristics ◽  
Dose Selection ◽  
Efficacy Evaluation

Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Yet, the traditional 3+3 design is still the most commonly used. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models, the continued adherence to 3+3 dose-escalation phase I strategies is more likely because these designs perform the best in the real world, pinpointing the correct dose and important side effects with an acceptable degree of precision. Beyond statistical simulations, there are little data to refute the supposed shortcomings ascribed to the 3+3 method. Even so, to address the unique nuances of gene- and immune-targeted compounds, a variety of inventive phase 1 trial designs have been suggested. Strategies for developing these therapies have launched first-in-human studies devised to acquire a breadth of patient data that far exceed the size of a typical phase I design and blur the distinction between dose selection and efficacy evaluation. Recent phase I trials of promising cancer therapies assessed objective tumor response and durability at various doses and schedules as well as incorporated multiple expansion cohorts spanning a variety of histology or biomarker-defined tumor subtypes, sometimes resulting in U.S. Food and Drug Administration approval after phase I. This article reviews recent innovations in phase I design from the perspective of multiple stakeholders and provides recommendations for future trials.

scholarly journals Review of Statistical Methods for Biomarker-Driven Clinical Trials

2019 ◽  
pp. 1-9
Author(s):  
Richard Simon
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Statistical Methods ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Adaptive Methods ◽  
Phase Iii ◽  
Driver Mutations ◽  
New Methods ◽  
Targeted Treatments

The discovery of somatic driver mutations in kinases and receptors has stimulated the development of molecularly targeted treatments that require companion diagnostics and new approaches to clinical development. This article reviews some of the clinical trial designs that have been developed to address these opportunities, including phase II basket and platform trials as well as phase III enrichment and biomarker adaptive designs. It also re-examines some of the conventional wisdom that previously dominated clinical trial design and discusses development and internal validation of a predictive biomarker as a new paradigm for optimizing the intended-use subset for a treatment. Statistical methods now being used in adaptive biomarker-driven clinical trials are reviewed. Some previous paradigms for clinical trial design can limit the development of more effective methods on the basis of prospectively planned adaptive methods, but useful new methods have been developed for analysis of genome-wide data and for the design of adaptively enriched studies. In many cases, the heterogeneity of populations eligible for clinical trials as traditionally defined makes it unlikely that molecularly targeted treatments will be effective for a majority of the eligible patients. New methods for dealing with patient heterogeneity in therapeutic response should be used in the design of phase III clinical trials.

Integrating radiomics into clinical trial design

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jessica J. Waninger ◽  
Michael D. Green ◽  
Catherine Cheze Le Rest ◽  
Benjamin Rosen ◽  
Issam El Naqa
Keyword(s):  
Clinical Trial ◽  
Trial Design ◽  
Clinical Trial Design

scholarly journals X-change symposium: status and future of modern radiation oncology—from technology to biology

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Stefanie Corradini ◽  
Maximilian Niyazi ◽  
Dirk Verellen ◽  
Vincenzo Valentini ◽  
Seán Walsh ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Radiation Oncology ◽  
Trial Design ◽  
Rapid Development ◽  
Clinical Trial Design ◽  
Current Status ◽  
Treatment Modalities ◽  
Special Treatment ◽  
Image Guided Radiotherapy

AbstractFuture radiation oncology encompasses a broad spectrum of topics ranging from modern clinical trial design to treatment and imaging technology and biology. In more detail, the application of hybrid MRI devices in modern image-guided radiotherapy; the emerging field of radiomics; the role of molecular imaging using positron emission tomography and its integration into clinical routine; radiation biology with its future perspectives, the role of molecular signatures in prognostic modelling; as well as special treatment modalities such as brachytherapy or proton beam therapy are areas of rapid development. More clinically, radiation oncology will certainly find an important role in the management of oligometastasis. The treatment spectrum will also be widened by the rational integration of modern systemic targeted or immune therapies into multimodal treatment strategies. All these developments will require a concise rethinking of clinical trial design. This article reviews the current status and the potential developments in the field of radiation oncology as discussed by a panel of European and international experts sharing their vision during the “X-Change” symposium, held in July 2019 in Munich (Germany).

Sign in / Sign up

Export Citation Format

Share Document