Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium

2017 ◽  
Vol 86 ◽  
pp. 275-284
Author(s):  
Francisco Bautista ◽  
Lucas Moreno ◽  
Lynley Marshall ◽  
Andrew D.J. Pearson ◽  
Birgit Geoerger ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Paediatric Oncology ◽  
Phase I Clinical Trials ◽  
Children With Cancer ◽  
Innovative Therapies ◽  
Definition Of

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.

scholarly journals Random-effects meta-analysis for systematic reviews of phase I clinical trials: Rare events and missing data

2016 ◽  
Vol 8 (2) ◽  
pp. 124-135 ◽  
Author(s):  
Mi-Ok Kim ◽  
Xia Wang ◽  
Chunyan Liu ◽  
Kathleen Dorris ◽  
Maryam Fouladi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Missing Data ◽  
Phase I ◽  
Random Effects ◽  
Systematic Reviews ◽  
Rare Events ◽  
Meta Analysis ◽  
Phase I Clinical Trials

scholarly journals Self-Replicating RNA Viruses for RNA Therapeutics

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3310 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Vaccine Development ◽  
Rna Viruses ◽  
Antibody Responses ◽  
Phase Iii ◽  
Phase I Clinical Trials

Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.

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