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NIH/NCI 367: Predictive Biomarkers to Improve 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

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

 

Summary

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 individual patient’s, or a cohort of patients’ sensitivities or radiation sensitivity of tumors. 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 as well as sensitivities of tumors to radiation. 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 or predict the sensitivity/response of a tumor may allow customization of treatment or delivery of suitable alternative treatment. However, discovery, development, and validation of predictive biomarkers of individual and tumor radiation hypersensitivity are challenging. The challenges include 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. Differences in radiation sensitivity of tumors may allow modification of dose to the tumor to minimize normal tissue damage, or maximize tumor cell killing, or may also allow the use of radiation effect modulators to achieve better therapeutic outcome. However, spatial and temporal heterogeneity in tumor characteristics is an important paradigm in the development of tumor radiation sensitivity predictive tests.

 

Project Goals

The goal of this contract topic is to develop a simple cost effective test that can be used by clinicians to personalize radiation/chemoradiotherapy treatment regimens.  This contract solicitation seeks to identify, develop, and validate a simple, cost-effective test to rapidly assess inter-individual differences in radiation sensitivity of an individual patient’s tumor to radiation therapy and/or predict early and late complications among cancer patients prior to starting radiation therapy. The test developed in response to this solicitation may evaluate normal tissue to predict radiation-therapy related toxicities in specific patient populations, or be developed to predict heightened responsiveness to radiation-therapy.  

Treatment decisions for personalized approach to radiotherapy should take into account the likelihood of a severe adverse event due to damage of normal tissue as well as a predicted sensitivity of the patient’s individual tumor.  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. Similarly, a predictive biomarker of tumor radiation sensitivity allows, in advance of treatment, an indication of sensitivity or resistance to radiation treatment by a specific tumor type and subtype. 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 test that may allow personalization of radiation therapy with curative intent.

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 should be (i) able to predict heterogeneity of radiation responses among a specific group of patients or tumors 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. All applications must include a biological hypothesis and rationale for the selected patient population and indication (e.g. developing biomarkers to indicate mucositis in a patient population with a biological signature that may predispose them to mucositis).

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. NCI’s Program Directors may be invited by the awardees to participate in the pre-IDE discussions with FDA. 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.

Activities and deliverables include the following:

  • Discovery and early development
  • Demonstrate biomarker prevalence and utility
  • 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
  • Demonstrate feasibility
  • Preclinical development and technical validity
  • 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
  • Illustrate the performance of the biomarker(s) with receiver operating characteristic (ROC) data
  • Demonstrate suitability of the test for use in the clinic, including kinetics of biomarker, if transient.
  • Determine the effect of confounders, such as any induction or concurrent chemotherapy regimens.
  • Provide defined metrics for measurements of success
  • Deliver the SOP of the working test or assay to NCI. 
  • Benchmark the technology against quantitative milestones proposed by offers to measure success
  • 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.

Activities and deliverables include the following:

  • Provide a schedule of proposed meetings with FDA regarding approval
  • Early-trial development
  • Retrospective tests using archived, frozen samples from past clinical trials, or prospective trials using fresh human samples.
  • Full development
  • Demonstrate clinical utility
  • Demonstrate clinical validity in a large prospective randomized clinical trial

 

 

Posted: August 1, 2016