Fast-Track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 2-4 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 Systemic administration of therapeutic agents for cancer treatment is common practice; however, drug exposure in normal tissues often leads to adverse toxicities thereby limiting the administered dose and treatment efficacy. The use of heat or ultrasound to achieve local activation or release of therapeutic agents has been an active area of research for many years, and approaches involving thermal release of drugs from liposomes has been used in clinical practice. In addition to these approaches, toxicity in off-target tissues might also be avoided if the agent remained encapsulated or inactive until exposed to external radiation within a well-defined target volume. Using external radiation for local drug activation or release may provide unique opportunities and benefits compared to previous strategies. For example, X-rays could be used with nanoscintillators to generate visible photons in vivo, which could then activate photosensitizers for photodynamic therapy (PDT). Such a strategy could extend the range of PDT to deep-seated tumors that are currently intractable with existing PDT. Using external radiation to remotely trigger therapeutic agents could also be used to carefully control the timing of drug release to achieve the appropriate therapeutic drug concentrations within a specific target volume at the right time. Successful treatment using this approach would require delivering safe doses of external radiation to quantitatively control the localized activation or release of the therapeutic agent. Toward achieving these goals, this solicitation is intended to develop combinatory treatment modalities utilizing external ionizing radiation to locally activate or release systemically or intratumorally delivered therapeutics, including high-atomic number elements that emit auger electrons. Remote release triggering mechanisms could include X rays or particle (e.g. proton) beams currently used for radiation therapy of cancer. The goal of this topic is to leverage existing radiation therapy infrastructure that is readily available in many clinical centers. In the future, such therapeutic approaches could be implemented as an addition to the current standard of care involving radiation therapy to achieve improved clinical outcomes. Project Goals This contract solicitation seeks to stimulate research, development, and commercialization of innovative techniques that could synergistically improve the effectiveness of radiation therapy and therapeutic agents or auger emitters to reduce toxicity to normal tissues. Proposals addressing the following technology areas are encouraged: • New treatment strategies • Design, synthesis, and evaluation of innovative therapeutic agents • Development of new drug formulations (e.g., nanoformulations) The short-term goal of the project is to perform feasibility studies for the development and use of combinatory treatment modalities for the treatment of cancer. The long-term goal of the project is to enable small businesses to advance fully developed combinatory treatment modalities to the clinic and eventually to the market. To apply for this topic, offerors should: • Identify or develop an appropriate therapeutic agent that could be activated in vivo by radiation • Develop a drug formulation that could be triggered to release a therapeutic agent by radiation in vivo • Define the mechanism(s) of action for the proposed therapeutic agent • Identify the patient population(s) likely to be impacted by this technology While modification of the radiation delivery device for eventual use with the therapeutic agent in the clinic is acceptable, it must not be the focus of the proposal. Please note that the following are NOT considered appropriate for development under this solicitation: • Development of agents that act as radiation sensitizers • New instrumentation for triggering the release of the therapeutic agent • Combinatory treatment strategies that do not involve the delivery of external radiation Phase I Activities and Deliverables • Demonstrate that the expected release/activation action with a proper amplitude can be induced in vitro and in vivo by safe doses of radiation • Demonstrate (if appropriate) tumor-specific targeting and localization of the therapeutic agent and activation of the therapeutic agent only after exposure to radiation • Carry out a pilot animal pharmacokinetic/pharmacodynamic studies utilizing an appropriate animal model • Significantly characterize the chemistry and purity of the therapeutic agent and chemistry of the reaction Phase II Activities and Deliverables • Demonstrate an improved therapeutic efficacy and improved therapeutic index, assessment of toxicity to normal tissues in vivo • Development of the manufacturing and scale-up scheme • IND-enabling studies carried out in a suitable pre-clinical environment for PK/PD, preclinical efficacy, and safety assessment When appropriate, demonstration of similar or higher efficacy of the proposed strategy when compared to current therapies.