Description:
Fast-Track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
Treatment planning for radiation therapy is becoming increasingly complex with the advent of image-guided radiation therapy (IGRT) and charged particle therapy (CPT). Fundamental to treatment planning is dose. The goal of any treatment plan is optimization of dose distribution. In the vast majority of planning this is the physical dose – energy delivery in Joules per kilogram of body mass, or units of Gray (Gy). Simply stated, we engage in creating a complex plan using advanced technology so that we can deliver dose to areas of tumor and avoid delivering dose to areas of normal tissue.
To this end, a large portion of the treatment team’s time and effort is allocated to reproducibly positioning, locating, and contouring key tumor and normal tissue structures, to optimize physical dose distribution. Even upon successful efforts to optimize physical dose delivery, tumor control and toxicity vary. Variation in biologic dose (biologic response to a given physical dose) may make even perfect physical dose delivery systems unable to properly deliver expected therapeutic dose to tumor in the patient. Biologic response and therefore optimal dose prescription may vary in the same patient across time and across location even at the same time. Tools are needed to measure biologic response to delivered physical dose in host systems, ideally that are volumetric – hence our focus on miniature and integrated sensors.
Contemporary engineering and device miniaturization (including nanotechnology) offer many compelling approaches that could enable a new generation of measurement tools to measure biological response directly and/or indirectly. Examples include: nanoparticle systems that self-assemble upon interaction with endogenous biomolecules, nanoparticles that target and allow direct imaging assessment of the tumor and its microenvironment, sensor systems that respond to local cues of biological damage and are excreted for ex vivo assessment, among many others. Standard dosimeters, even implantable dosimeters, cannot address biology in this context. Implantable dosimeters are much larger in scale. For this reason, integrated sensor solutions for measurement of biological response will be the focus of this contract solicitation. These systems can be used alone or in combination and can be utilized both in the body (in vivo) to allow volumetric assessment and extracorporeally (in vitro) to allow rapid, lab-test style measurements.
Project Goals
The purpose of this solicitation is to develop in vivo or in vitro sensor tools to measure biologic response to radiation, specifically, to help to redefine dose from solely the traditional physical dose to include the additional dimension of biological response. The resulting new, multidimensional definition of dose may allow more refined treatment planning and clinical trial development, avoidance of toxicity from overdosing, avoidance of tumor escape from biological under-dosing, and hopefully allow truly personalized medicine to be performed in the combined modality space where chemotherapy, surgery, immunotherapy, and radiation are used in combination to treat patients.
The overarching goal of this solicitation is to produce a toolbox of sensor tools that will be used to improve the outcome for patients with cancer. By developing biologic response measurement tools, it will ultimately be possible to design and interpret biologically optimized treatment. These newly developed sensors are to allow study of the biological effects of radiation and combination therapies. These sensors should facilitate the development and study of precision radiation oncology. The sensors can be used alone, in combination, in the body, or outside of the body. A sensor would report temporal and spatial information about, for example, one biologic pathway, molecule’s activity, or a complex’s formation/function. Ideally, these sensors should be able to generate response via CT or MRI to allow non-invasive dynamic and real-time data collection. As such, the development and evaluation of sensor systems that can measure in a validated fashion biologic response to physical dose from radiation therapy will be preferred. Nanotechnology-based sensors are encouraged.
Overall scope:
Such systems are diverse (e.g. surface chemistries, material properties) as noted in the above examples, and thus this request does not limit the scope of the technical methodologies allowed. The work requested in this announcement includes any type of systems (including but not limited to nanotechnology) that can convey biological information and that can be correlated
with radiation therapy physical dose delivery in treated and untreated human tissue. Thus, sensors should measure biological status in collected liquid or solid samples and/or should evaluate biologic signals in situ that are correlated with tumor control, tumor survival, and toxicity. Mechanisms that involve conjugation and / or chemistry to monitor property changes to nanoparticles (e.g., self-assembly, emission changes, reporter release, etc.) are other examples of methods that fall into the scope of this solicitation. Furthermore, it is desired that sensors be able to be used serially and in combinations in patients before, during, and after treatment. Such biologic response sensors should function with combination therapy (radiation with chemotherapy or other biologic therapy). Sensors that can be imaged via 4D techniques already utilized in radiation therapy are also of particular interest so that spatial biological data can be collected over time to measure spatial changes correlated to treatment. As noted above, mixtures of these agents that can be differentiated via signal characteristics would be of a high priority as well because it may be true that a combination of markers offers unique biologic insights such as toxicity fingerprints or treatment failure fingerprints. Robust combinatorial analysis capabilities of new agents will be a key goal of this project and should be addressed in applications.
Prior to the start of the project a multidisciplinary team must be constructed. This needs to be outlined in submissions for this award. Creation of a multidisciplinary team to design and evaluate the sensor’s design parameters and goals in terms of biology, chemistry, human toxicity, and reporting capabilities is critical. Examples of desired team members will be radiobiologists, imaging scientists, radiation oncologists, chemists, small animal model specialists, and molecular biologists. Failure to outline such a team in the proposal will be considered non-responsive to the FOA.
Projects that may be supported:
Devices/agents that can measure tumor biological change caused by radiation therapy that are injectable or otherwise distributed into in vitro or in vivo models of cancer and normal tissue. Work toward use in humans is of particular interest. The Phase I application must provide a detailed experimental strategy to develop and deliver the biologic response sensor and identify an appropriate cancer biologic signal for the sensor.
Activities not responsive to announcement:
Systems or tools that measure physical dose delivery only. Devices meant to interact with radiation and either potentiate its effects or mitigate its effects. Software solutions to model these effects without actual particle development would also be considered non-responsive.
Phase I Activities and Deliverables
• Development of the sensor to measure biologic response to radiation
• Demonstrate sensor stability in vitro
• Perform in vitro efficacy studies in the relevant cancer cell line(s) and in normal tissue(s): measurement of the target gene/enzyme/other signal
• Establish specificity of the construct and conduct validation studies
• Perform a small in vivo efficacy study in animal model systems to evaluate appropriate correlative endpoints
Activities and deliverables that will be used to evaluate whether the project should continue to be funded for Phase II include:
• Successful measurement of a biologic signal with the construct designed and produced.
• Concordance between known tissue signaling and sensor response (testing for false positive and false negatives).
• Establishment of partnerships for potential validation.
Phase II Activities and Deliverables
• Consultation with FDA regarding development of a regulatory strategy and timeline for an IND submission
• Refinement process development of construction and purification process to allow GMP production
• Demonstrations of sensor use serially in samples at a minimum that are relevant in a pathology/diagnostic capacity but preferably in vivo (properly powered studies)
• Evaluation of tissue with testing in the context of causing toxicity and evaluation of sensor use to predict and/or measure the degree of this toxicity with a goal to taking these agents to clinical use in humans, in vitro and in vivo
• In the first year of the contract, provide the Program and Contract officers with a letter(s) of commercial interest
• In the second year of the contract, provide the Program and Contract officers with a letter(s) of commercial commitment
• By the end of Phase II, submit an IND to FDA
