Feasibility Study Testing Transcriptional Responses as an Indicator of Individualised Responses to Radiation Effects (RTGene)

October 30, 2018 updated by: Institute of Cancer Research, United Kingdom

Feasibility Study Testing Multi-panel Coding and Non-coding Transcriptional Responses as an Indicator of Individualised Responses to Radiation Effects in Radiation Therapy Patients

Peripheral blood samples will be taken with informed consent from radiotherapy patients undergoing standard radiotherapy at The Royal Marsden before and during treatment for breast, lung, gastrointestinal and genitourinary tumours. Responses from panels of up to 800 coding and non-coding RNAs will be assessed in the samples using the nCounter system. Candidate genes identified by Public Health England, Columbia University and/or in the literature as being specific to radiation responses will be included, together with genes relevant to systemic inflammatory responses, to identify transcriptional responses for a range of doses and exposures on an inter-individual basis. Data will be analysed using existing and new statistical tools focused on count data modelling. The intended outcome is identification of a radiation specific panel of genes to inform individual radiation responses and if the results are favourable, a large scale follow up to this proposed pilot is expected in due course.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Biological markers of radiation exposure play a crucial role in the triage of suspected exposed persons following a radiation accident or incident. They can also estimate individual doses that enable assessment of late radiation effects in affected individuals. In recent years the gene expression assay has been shown to be a sensitive biological marker of radiation exposure with the potential to be used for truly individualised dosimetry. The possibility for this gene expression assay to be used in a large scale mass-casualty scenario has been proposed and tested in a recent intercomparison exercise. Classic cytogenetic techniques, and in particular the gold standard dicentric assay, have two main disadvantages: (1) lack of high-throughput and (2) delays of several days between blood sampling and the availability of results. Although more work needs to be done to further assess its suitability for triage purposes, it is clear that gene expression analysis in blood samples can provide valuable information, as there is a window of time (i.e. 12-48 hours) following radiation exposure where specific radiation-responsive genes have linear dose responses (0-5 Gy). Most work to date has focused on developing sensitive assays for studying gene expression modifications using state of the art technology, i.e. multiplex quantitative, digital polymerase chain reaction (qPCR) and molecular counting systems.

At Public Health England (PHE), recently established technology allows direct counting of nucleic acid molecules (DNA, mRNA, miRNA and lncRNA) without the need for enzymatic reaction or amplification steps hence reducing time for data collection. The system offers multiplexing capacity comparable to microarrays but with greater precision and sensitivity. Another unique advantage of this technology is that there is no need for long, time consuming bioinformatic analyses as the results are obtained as counted number of events. This new gene expression analysis technique has been assessed for radiation biodosimetry applications with promising results. Furthermore, gene expression has shown a high degree of promise as a marker for late effects of radiation, for instance normal tissue reactions following curative radiotherapy for breast cancer. Clinical data suggest that systemic inflammatory responses plays a critical role in the progression of radiation effects: for instance, the neutrophil-to-lymphocyte ratio represents a marker of systemic inflammation pre-treatment and is an independent prognostic factor useful for individual risk assessment in breast cancer patients undergoing radiotherapy. Genes relevant to inflammatory responses are thus interesting candidates for further investigation. Linearity of the transcriptional dose-response for specific radiation-responsive genes in ex vivo exposed human blood samples has recently been demonstrated for the first time, and inter-individual variability in the response after low doses and high doses exposures has been newly assessed. The logical next stage for biological development of the gene expression assay is to validate these new techniques with human blood samples exposed to radiation in vivo.

The use of samples from patients undergoing radiotherapy for validation of techniques has been gaining popularity in recent years. Sophisticated treatment planning for clinical radiotherapy leads to very accurate individual dose calculations that allow for validation of biological estimates of dose. The range of standard radiotherapy schedules chosen for inclusion in this study will provide a wide range of doses for assessment of the gene expression assay alone and in combination with the other cytogenetic assays, to simulate a range of potential exposure scenarios.

Peripheral blood samples will be taken with informed consent from patients undergoing standard radiotherapy before and during treatment for breast, lung, gastrointestinal and genitourinary tumours. Responses from panels of up to 800 coding and non-coding RNAs will be assessed in the samples using the nCounter system. Candidate genes identified by PHE, Columbia and/or in the literature as being specific to radiation responses will be included, together with genes relevant to systemic inflammatory responses, to identify transcriptional responses for a range of doses and exposures on an inter-individual basis. Data will be analysed using existing and new statistical tools focused on count data modelling. The intended outcome is identification of a radiation specific panel of genes to inform individual radiation responses and if the results are favourable, a large scale follow up to this proposed pilot is expected in due course.

Study Type

Observational

Enrollment (Actual)

20

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Patients undergoing radiotherapy for cancer

Description

Inclusion Criteria:

  • Age ≥18 years
  • Requirement for external beam radiotherapy for breast, lung, gastrointestinal or genitourinary tumours
  • Written informed consent

Exclusion Criteria:

  • Previous radiotherapy
  • Concurrent chemotherapy or chemotherapy preceding radiotherapy by less than 4 weeks
  • Concurrent hormone therapy or hormone therapy preceding radiotherapy by less than 4 weeks

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Blood donation during radiotherapy
Participants will be asked to donate a blood sample at 5 time points before and during their radiotherapy
Procedure: Blood donation during radiotherapy
Participants will be asked to donate a blood sample at 5 time points before and during their radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Transcriptional responses as measured by nCounter molecular profiling as biomarker of individual radiation exposure
Time Frame: 3 months after all volunteers have finished radiotherapy and donated blood samples
3 months after all volunteers have finished radiotherapy and donated blood samples

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institute of Cancer Research, United Kingdom

Collaborators

Public Health England

Investigators

  • Principal Investigator: Navita Somaiah, Institute of Cancer Research, United Kingdom

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 12, 2016

Primary Completion (Actual)

July 17, 2018

Study Completion (Actual)

July 17, 2018

Study Registration Dates

First Submitted

May 13, 2016

First Submitted That Met QC Criteria

May 20, 2016

First Posted (Estimate)

May 23, 2016

Study Record Updates

Last Update Posted (Actual)

October 31, 2018

Last Update Submitted That Met QC Criteria

October 30, 2018

Last Verified

October 1, 2018

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • CCR4553

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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