Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

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.

Download Full-text

BIOMARKER AND CLINICAL TRIAL DESIGN SUPPORT FOR DISEASE-MODIFYING THERAPIES: REPORT OF A SURVEY OF THE EU/US: ALZHEIMER’S DISEASE TASK FORCE

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2018.13 ◽

2018 ◽

pp. 1-7

Author(s):

J. Cummings ◽

N. Fox ◽

B. Vellas ◽

P. Aisen ◽

G. Shan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Trial Design ◽

Task Force ◽

Clinical Trial Design ◽

Disease Modification ◽

Disease Modifying Therapies ◽

Disease Modifying ◽

The Eu

BACKGROUND: Disease-modifying therapies are urgently needed for the treatment of Alzheimer’s disease (AD). The European Union/United States (EU/US) Task Force represents a broad range of stakeholders including biopharma industry personnel, academicians, and regulatory authorities. OBJECTIVES: The EU/US Task Force represents a community of knowledgeable individuals who can inform views of evidence supporting disease modification and the development of disease-modifying therapies (DMTs). We queried their attitudes toward clinical trial design and biomarkers in support of DMTs. DESIGN/SETTING/PARTICIANTS: A survey of members of the EU/US Alzheimer’s Disease Task Force was conducted. Ninety-three members (87%) responded. The details were analyzed to understand what clinical trial design and biomarker data support disease modification. MEASUREMENTS/RESULTS/CONCLUSIONS: Task Force members favored the parallel group design compared to delayed start or staggered withdrawal clinical trial designs to support disease modification. Amyloid biomarkers were regarded as providing mild support for disease modification while tau biomarkers were regarded as providing moderate support. Combinations of biomarkers, particularly combinations of tau and neurodegeneration, were regarded as providing moderate to marked support for disease modification and combinations of all three classes of biomarkers were regarded by a majority as providing marked support for disease modification. Task Force members considered that evidence derived from clinical trials and biomarkers supports clinical meaningfulness of an intervention, and when combined with a single clinical trial outcome, nearly all regarded the clinical trial design or biomarker evidence as supportive of disease modification. A minority considered biomarker evidence by itself as indicative of disease modification in prevention trials. Levels of evidence (A,B,C) were constructed based on these observations. CONCLUSION: The survey indicates the view of knowledgeable stakeholders regarding evidence derived from clinical trial design and biomarkers in support of disease modification. Results of this survey can assist in designing clinical trials of DMTs.

Download Full-text

Faculty Opinions recommendation of Effect of removing race from glomerular filtration rate-estimating equations on anticancer drug dosing and eligibility: a retrospective analysis of National Cancer Institute phase 1 clinical trial participants.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.740641646.793588796 ◽

2021 ◽

Author(s):

Carmine Zoccali ◽

Davide Bolignano

Keyword(s):

Clinical Trial ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Retrospective Analysis ◽

National Cancer Institute ◽

Filtration Rate ◽

Phase 1 ◽

Drug Dosing ◽

Phase 1 Clinical Trial ◽

Trial Participants

Download Full-text

MS clinical trial design for the future

Multiple Sclerosis Journal ◽

10.1177/135245859600100623 ◽

1996 ◽

Vol 1 (6) ◽

pp. 393-399

Author(s):

Donald E Goodkin

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Trial Design ◽

Task Force ◽

Imaging Techniques ◽

Clinical Trial Design ◽

Magnetic Imaging ◽

Frequent Relapses ◽

Composite Outcomes ◽

Important Position

The Clinical Outcomes Task Force has been challenged to develop new easily administered composite outcomes that are more sensitive, highly reliable, properly validated, and measure more effectively the broad spectrum of independent dimensions of MS. The Task Force on Use of MRI in MS Clinical Trials has already provided important position statements and recommendations for the use of magnetic imaging technologies in MS clinical trials. It appears mat T1WGd+activity and change in T2W lesion burden will be most useful as outcomes in patients who recently have experienced frequent relapses. It is anticipated that improved composite outcomes and more powerful statistical methods will facilitate improved predictive validity for MR imaging techniques. If we are successful in meeting these challenges, we should be able to conduct future definitive clinical trials more expeditiously and with fewer patients.

Download Full-text

Impact and utility of COLONTOWN, an online CRC patient and caregiver support group in clinical trial design.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.140 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 140-140

Author(s):

Manju George ◽

Jesse Joshua Smith ◽

Eric David Miller ◽

Paul Bernard Romesser ◽

Nancy Seybold

Keyword(s):

Clinical Trial ◽

Support Groups ◽

Trial Design ◽

Task Force ◽

Clinical Trial Design ◽

Patient Perspectives ◽

Lead Author ◽

Cooperative Group ◽

Caregiver Support ◽

Group Feedback

140 Background: Online cancer patient and caregiver support groups have burgeoned in the recent years; many provide critical emotional support and experiential wisdom to newly diagnosed patients. We outline below our experience engaging patients in clinical trial design working with COLONTOWN, a 5000+ member, online colorectal cancer (CRC) patient and caregiver support and educational community. Effective trial design is a complicated and lengthy process that requires input from multiple sources. Complex trial design can be particularly challenging, where opinions are mixed and a clear path forward may not be visible. Informed patient perspectives from support groups can be invaluable in such situations. Methods: Principal Investigators (PIs) for the oligometastatic CRC ERASure trial and the Janus rectal cancer trial worked with the lead author, a patient who is the Scientific Director of COLONTOWN. An interactive survey strategy was adopted and followed to solicit group feedback. COLONTOWN members (n = 70-120) were enthusiastic to participate and share the logic behind poll choices, and their personal experiences. Poll participation led to additional scientific discussion and improved community engagement around the survey questions. Poll data and highlights of the discussion were collected and passed on to study PIs in a de-identified manner. Results: Feedback from COLONTOWN helped PIs gauge patient enthusiasm for trial concepts and provide patient perspective and clarity to controversial questions in study design. This was particularly useful where data to support more than one option was available and the guidance from the NCI Task Force or cooperative group was split. The perspective from COLONTOWN was invaluable and used alongside NCI Task Force and cooperative group feedback to make decisions to move the trial concept forward. Conclusions: Support groups such as COLONTOWN are a versatile, valuable, underutilized and available resource that can be used to tap into patient perspectives during any clinical trial design process. Ideally, when utilized early, structured patient input can provide unique insights to PIs developing clinical trial concepts that could eliminate barriers and shorten the inception part of trial design. Increased awareness and knowledge of trial design support provided by such cancer communities could facilitate the development of patient-friendly trials to promote better accrual.

Download Full-text