Subgroup-specific dose finding using Bayesian clustering in phase I-II clinical trials

2020 ◽  
Author(s):  
Alexandra Curtis
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Dose Finding ◽  
Bayesian Clustering

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Informed consent in phase I clinical trials: Implications for trends in design.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14077-e14077
Author(s):  
Paul Henry Frankel ◽  
Susan G. Groshen
Keyword(s):  
Clinical Trials ◽  
Informed Consent ◽  
Phase I ◽  
Dose Finding ◽  
Institutional Review Boards ◽  
Severe Toxicity ◽  
Phase I Clinical Trials ◽  
Traditional Use ◽  
Phase I Studies ◽  
Definition Of

e14077 Background: Informed Consent (IC) is a critical aspect of human subjects protection. Institutional Review Boards are tasked with insuring proper IC as one aspect of protecting participants in clinical trials. Phase I trials in oncology present special issues with IC, as often neither the risks nor the benefits are well-known. This has resulted in carefully worded IC templates for Phase I studies based on the traditional use of dose-finding designs that are geared towards finding the “Maximum Tolerated Dose (MTD)”. As the definition of this term varies by study, the implication for patient risk and informed consent are rarely discussed. Methods: We reviewed Phase I designs to present options for improving the informed consent process for Phase I oncology trials. Results: Phase I studies have seen an increase in designs based on work from the early 1990s seeking a dose that results in a targeted percent of patients experiencing a “Dose Limiting Toxicity (DLT)” to define the MTD. The most common definition of a DLT is a treatment-related toxicity that results in a particularly concerning severe toxicity (grade 3 or higher) in the first cycle of therapy and the most common rate targeted (in designs that define toxicity as a goal) is 25%. In that setting, while lower doses may have a lower likelihood of DLT, higher doses or the expansion cohort are likely to have a 25% chance of DLT if the target is pursued. This information is rarely quantitatively communicated in the informed consent. Conclusions: IRBs and investigators should consider communicating through informed consent the quantitative summary of goals of the study and related risk. For example, transparency suggests conveying when the goal (target) of the study is to find the dose where there is a one in four chance of experiencing a severe adverse event in the first cycle.

A Bayesian dose-finding procedure for phase I clinical trials based only on the assumption of monotonicity

2010 ◽  
Vol 29 (17) ◽  
pp. 1808-1824 ◽  
Author(s):  
John Whitehead ◽  
Helene Thygesen ◽  
Anne Whitehead
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Dose Finding ◽  
Phase I Clinical Trials

scholarly journals Adaptive Dose-Finding Studies: A Review of Model-Guided Phase I Clinical Trials

2014 ◽  
Vol 32 (23) ◽  
pp. 2505-2511 ◽  
Author(s):  
Alexia Iasonos ◽  
John O'Quigley
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Dose Escalation ◽  
Late Onset ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Design Parameters ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Trial Duration

Purpose We provide a comprehensive review of adaptive phase I clinical trials in oncology that used a statistical model to guide dose escalation to identify the maximum-tolerated dose (MTD). We describe the clinical setting, practical implications, and safety of such applications, with the aim of understanding how these designs work in practice. Methods We identified 53 phase I trials published between January 2003 and September 2013 that used the continual reassessment method (CRM), CRM using escalation with overdose control, or time-to-event CRM for late-onset toxicities. Study characteristics, design parameters, dose-limiting toxicity (DLT) definition, DLT rate, patient-dose allocation, overdose, underdose, sample size, and trial duration were abstracted from each study. In addition, we examined all studies in terms of safety, and we outlined the reasons why escalations occur and under what circumstances. Results On average, trials accrued 25 to 35 patients over a 2-year period and tested five dose levels. The average DLT rate was 18%, which is lower than in previous reports, whereas all levels above the MTD had an average DLT rate of 36%. On average, 39% of patients were treated at the MTD, and 74% were treated at either the MTD or an adjacent level (one level above or below). Conclusion This review of completed phase I studies confirms the safety and generalizability of model-guided, adaptive dose-escalation designs, and it provides an approach for using, interpreting, and understanding such designs to guide dose escalation in phase I trials.

scholarly journals dfpk: An R-package for Bayesian dose-finding designs using pharmacokinetics (PK) for phase I clinical trials

2018 ◽  
Vol 157 ◽  
pp. 163-177 ◽  
Author(s):  
A. Toumazi ◽  
E. Comets ◽  
C. Alberti ◽  
T. Friede ◽  
F. Lentz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
R Package ◽  
Dose Finding ◽  
Phase I Clinical Trials
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