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338 Predictive Biomarkers of Adverse Reactions to Radiation Treatment

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2–3

Budget (total costs, per award):
Phase I: $300,000 for 9 months;
Phase II: $2,000,000 for 2 years

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

The deadline for receipt of all contract proposals submitted in response to this solicitation is: November 5, 2014 by 4:30 PM ET.


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. Currently, treatment decisions in radiotherapy and radio-chemotherapy are primarily defined by disease stage, tumor location, treatment volume, and patient co-morbidities. However, treatment planning does not take into account individual patient's (or a cohort of patients') sensitivities to radiation. This is an important limitation in personalized care, as there are known variations in individual patients' normal tissue sensitivities to radiation, but treatments are based on population normal tissue complication probabilities. In an era of precision medicine, 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. A biomarker-based test that can predict the risk of developing severe radiotherapy-related complications will allow delivery of suitable alternative treatments. Further, 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 observed in the clinic, the potential need for lengthy, long-term studies for predicting late effects (e.g., predicting risk of fibrosis), and complexities arising from the combination of chemotherapy with radiation.

Several SBIR companies, in partnership with academia, have been working in this field, and some have developed prototype products serving the needs of radiation dose assessment in accidental radiation exposures. Much of this work has been accomplished in response to Requests for Proposals for developing radiation counter-measures (e.g., Biomedical Advanced Research Development Authority (BARDA), and NIAID Centers for Medical Countermeasures for Radiation Injury (CMCR)). The most promising among these technologies can be leveraged by the NCI SBIR program, as they could be quickly and readily translatable to radiation oncology applications for stratifying patients based on their radiation sensitivity. Products coming out of this solicitation may ultimately allow radiation oncologists to determine whether or not certain patients are suitable for treatments involving radiotherapy due to a high degree of normal tissue radiosensitivity.

Project Goals

The goal of this contract topic is to identify, develop, and validate simple and cost-effective biomarker-based test(s) to rapidly assess inter-individual differences in radiation sensitivity, and to predict early and late complications among patients prior to radiation therapy. These predictive biomarker-based test(s) should ideally be: (i) able to predict heterogeneity of radiation responses among patients, (ii) specific to radiation therapy, (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 semi-invasive sampling, (vi) amenable to automation to improve quality control and assurance, (vii) quick in turnaround time between sampling and results (though speed is not as critical as in the countermeasures scenarios), and (viii) cost effective.

This contract topic aims to encourage discovery, development and validation of predictive radiation biomarkers for clinical applications. However, the regulatory pathway to bring biomarkers to market is inherently different than that for drugs, and depends on the clinical setting and intended use. Both the FDA and the Centers for Medicare and Medicaid Services (CMS) through the 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 clinical validation with a locked-down assay before regulatory submission and commercialization. Early interaction with FDA is therefore essential.

The contract proposal must describe:

Phase I:

  • A quantitative estimate of the patient population that will benefit from the availability of the proposed predictive radiation biomarker for the applicable cancer type/organ site.
  • A plan for generating evidence that the proposed biomarker is relevant in the prediction of radiation hyper-sensitivity among patients with cancer, and a logical approach in the developmental pathway to from discovery to the clinic.
  • The plans must have a description of assay characteristics and the effect of known confounders, if any.
  • Level of technological maturity
  • Analytical validation
  • Demonstration of feasibility

Phase II:

  • Must describe the setting and intended use of the predictive biomarker in retrospective or prospective studies using human tissue samples (frozen or fresh)
  • Logical approach to regulatory approval
  • Determination of assay platform and platform migration, if necessary
  • Demonstration of clinical utility and clinical validation
  • A proposed schedule for meeting with the FDA regarding a regulatory submission

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

  • Discovery and early development
  • Demonstrate biomarker prevalence
  • Preliminary data demonstrating feasibility
  • Preclinical development and technical validity
  • Assay characteristics, performance, reproducibility, specificity and sensitivity using frozen samples or retrospective clinical study.
  • Determine the effect of confounders, such as any induction or concurrent chemotherapy regimens

Phase II Activities and Deliverables

  • Early-trial development
    • Retrospective or prospective tests using archived, frozen, or fresh human samples
  • Full development
    • Demonstrate clinical utility
    • Demonstrate clinical validity in a large prospective randomized clinical trial
Updated Date: 
June 24, 2015