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Predictive Biomarkers of Adverse Reactions to Radiation Treatment

Radiotherapy is an important definitive and palliative treatment modality for millions of patients with cancer and is used alone or in combination with drug therapy. However, a variety of patient, tumor, and treatment-related factors will influence its outcome. Significant advances in delivery and distribution of dose for radiotherapy have been made over the years. Currently, treatment decisions in radiotherapy/radiochemotherapy are primarily defined by disease stage, tumor location, treatment volume, and patient co-morbidities, together with general guidelines concerning normal tissue tolerance for surrounding organs. However, treatment planning does not take into account an individual patient?s, or a cohort of patients? sensitivities to this important modality of treatment. This is an important limitation in personalized care, as there are known variations in individual patient normal tissue sensitivities to radiation, but treatments are based on population normal tissue complication probabilities. As molecularly targeted therapy is being integrated into radiotherapy and chemotherapy, selecting the ?right type of treatment? is critical to improve outcomes.
A substantial number of patients treated with radiotherapy suffer from severe to life-threatening adverse acute effects as well as debilitating late reactions. Acute side effects (e.g. skin reactions, mucositis, etc.) are often dose limiting, but may be reversible in contrast to the late effects such as fibrosis in the lung, telangiectasia, and atrophy, which are irreversible and progressive. A biomarker-based test that can predict the risk of developing severe radiotherapy-related complications will allow delivery of suitable alternative treatments. Such stratification may also allow dose escalation to the tumor in less sensitive patients. However, discovery, development, and validation of predictive biomarkers of radiation hypersensitivity are challenging, particularly due to a low incidence of normal tissue complications in the clinic, the need for long-term studies for predicting late effects, and the combination of chemotherapy with radiation as standard of care for most tumors.
Project Goals
The goal of this contract topic is to identify, develop, and validate a simple, cost-effective biomarker(s) to rapidly assess inter-individual differences in radiation sensitivity and predict early and late complications among patients with cancer prior to radiation therapy.
A predictive biomarker of individual radiation sensitivity can measure any biological changes in response to absorbed ionizing radiation, which is able to predict imminent normal tissue injury prior to radiotherapy and help determine radiotherapy suitability and outcomes. Radiation biomarkers are an emerging and rapidly developing area of research, with potential applications in predicting individual radiosensitivity, predicting severity of normal tissue injury among patients, assessing and monitoring of tumor response to radiation therapy as well as in estimating dose to accidentally radiation-exposed individuals. The purpose of this contract topic is to develop a radiation biomarker(s) to specifically identify and exclude likely ?over responders? prior to radiotherapy in order to avoid severe complications and to refer them for alternative treatment modalities.
A variety of radiation biomarkers have already been explored or are currently under development at different technology readiness levels (TRLs) at different government agencies and programs. This contract topic intends to leverage on these advances. These assays include but are not limited to (i) fibroblast clonogenic assay, (ii) measurement of DNA damage foci, (iii) damaged base metabolites, (iv) various types of chromosome aberrations studied in different phases of cell cycles, serum biomarkers, gene expression changes, (v) protein and microRNA expression changes, (vi) and genetic tests.
To be of practical value in the clinic, where radiation exposures are well-defined in terms of dose, distribution and timing, and thus quite different from radiation accidents, a predictive radiation biomarker of individual radiation sensitivity should be (i) able to predict heterogeneity of radiation responses among patients in clinic, (ii) specific to radiation, (iii) sensitive, (iv) able to show signal persistence as applicable to radiation therapy or have known time-course kinetics of signal, (v) amenable for non-invasive or minimally-invasive sampling, (vi) amenable to automation to improve quality control and assurance, (vii) have a quick turn-around time between sampling and results (though speed is not as critical as in the countermeasures scenarios), (viii) and be cost effective.
This contract topic aims to encourage the development and validation of predictive radiation biomarkers for clinical applications as described above. Both the FDA and the Centers for Medicare and Medicaid Services (CMS) through Clinical Laboratory Improvement Amendment (CLIA) regulate diagnostic tests. A reasonable predictive radiation biomarker development process for identifying likely ?over-responders? to radiation treatment may involve biomarker discovery, assay design and validation, determination of assay feasibility, assay optimization and harmonization, assessing the assay performance characteristics (reproducibility, sensitivity, specificity etc.), determining the effect of confounders, if any, determination of suitable assay platforms and platform migration as may often be needed, and clinical validation with a locked-down assay before regulatory submission and commercialization. Early pre-IDE interaction with FDA is therefore critical. The following activities and deliverables are applicable to both biomarkers for acute early effects and surrogate endpoints for late effects.
Phase I Activities and Deliverables
Phase I contract proposals must describe (i) a quantitative estimate of the patient population that will benefit from the availability of such predictive radiation biomarkers for the applicable cancer type/organ site, (ii) a plan for generating evidence that the proposed biomarker or biomarkers are relevant in the prediction of radiation hyper-sensitivity among patients with cancer and logical approach in the developmental pathway to clinic from discovery, (iii) a description of assay characteristics including sensitivity and specificity and the effects of known confounders, if any, (iv) level of technological maturity, describing critical technology elements allowing technology readiness assessment by the reviewers, (v) and a description of the proposed regulatory pathway for approval and pre-IDE consultation with FDA. In such meetings with FDA it is expected that the applicant will invite NCI?s participation, where applicable.
 
Activities and deliverables include the following:
?       Discovery and early development
o   Demonstrate biomarker prevalence and utility
o   Develop a working qualitative test correlating the presence or absence of the biomarker(s) with potential outcome or a quantitative assay to assess radiation sensitivity
o   Demonstrate feasibility
?       Preclinical development and technical validity
o   Provide assay characteristics, including but not limited to performance, reproducibility, specificity, and sensitivity data using frozen (or other) samples from past clinical trials, or retrospective clinical studies providing adequate power calculations
o   Illustrate the performance of the biomarker(s) with receiver operating characteristic (ROC) data
o   Demonstrate suitability of the test for use in the clinic, including kinetics of biomarker, if transient.
o   Determine the effect of confounders, such as any induction or concurrent chemotherapy regimens.
o   Provide defined metrics for measurements of success
o   Deliver the SOP of the working test or assay to NCI.
o   Benchmark the technology against quantitative milestones proposed by offers to measure success
o   Provide description of proposed regulatory pathway for approval and pre-IDE consultation with FDA
 
Phase II Activities and Deliverables
Phase II contract proposals must describe (i) the setting and intended use of the predictive biomarker(s) in retrospective or prospective studies using human tissue samples (frozen or fresh), (ii) a logical approach to regulatory approval, (iii) a description of assay platform and platform migration, if necessary, (iv) a demonstration of clinical utility and clinical validation, (v) a proposed schedule for meeting with FDA regulators regarding approval. In such meetings with FDA it is expected that the applicant will invite NCI?s participation, where applicable.
 
Activities and deliverables include the following:
?       Provide a schedule of proposed meetings with FDA regarding approval
?       Early-trial development
o   Retrospective tests using archived, frozen samples from past clinical trials, or prospective trials using fresh human samples.
?       Full development
o   Demonstrate clinical utility
 
o   Demonstrate clinical validity in a large prospective randomized clinical trial 

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