Description:
Fast-Track proposals will be accepted Number of anticipated awards: 3-5 Budget (total cost per award):
Phase I: up to $300,000 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
The clinical value of an agent is reflected by both its efficacy and its toxicity. In the chemoprevention space, where agents are administered to a relatively healthy (albeit high-risk) population, the intention is to minimize toxicity. Most chemopreventive agents require administration over long periods of time. This limit on toxicity presents a major challenge in the development of chemopreventive agents with acceptable benefit risk ratios.
Our ability to identify populations at higher risk of developing cancer has significantly improved over the past decade. For example, women with Hereditary Breast and Ovarian Cancer syndrome (HBOC) are at increased risk of developing breast and ovarian cancer, and potentially other cancers (e.g., pancreatic); individuals with Lynch syndrome are at increased risk of developing multiple cancer types including colorectal, endometrial, ovarian, and gastric cancer. We are also able to detect
cancer at earlier stages and often as precancerous lesions. Multiple studies have shown that these individuals at high risk for cancer or with precancerous lesions could benefit from chemoprevention approaches. A small number of chemopreventive agents have found some degree of success in the clinic, including tamoxifen and raloxifene for breast cancer prevention, and aspirin and celecoxib for colorectal cancer prevention. However, the systemic toxicities of these agents have limited their widespread use and acceptability.
Local agent delivery is an important strategy to reduce toxicity of chemopreventive agents, while maintaining clinical benefit. Local delivery of an agent can be performed by a physician or self-administered by an individual, which overcomes some of the access barriers that exist in healthcare. A localized chemoprevention approach is ideal in high risk individuals or individuals with premalignant diseases, as the agent can be applied locally to provide high drug concentrations at specific locations from where early disease would originate, while limiting systemic toxicity.
Project Goals
The goal of this topic is to advance the development and/or application of local delivery devices or formulations for chemoprevention. The technology should be designed for effective delivery of agent to a specific organ while minimizing systemic toxicities. Acceptable toxicities will depend on the agent and target population. Toxicity should not exceed minimal grade 2 local toxicities, while short term local grade 3 toxicity may be acceptable in some populations. The proposed local delivery device/formulation may utilize any technology or agent capable of meeting the goals of this topic. Examples of local administration include topical (for oral, breast, skin or cervical cancers), inhalant (for lung or esophageal cancers), or digestive (for esophageal, stomach, or colorectal cancers). Proposals for development of local delivery devices or formulations via other administration routes or for other cancer types are also encouraged.
The activities that fall within the scope of this contract solicitation include development and application of local delivery formulations or devices. Examples of appropriate activities include pre-clinical toxicity and efficacy studies in appropriate animal models, acceptability studies, and initial first-in-human testing. A local delivery approach for FDA approved chemoprevention agents or for novel chemoprevention agents may also be developed. For novel chemoprevention agents, significant reduction in cancer incidence in suitable cancer prevention animal models should be demonstrated. Phase II clinical trials and beyond are not appropriate for this mechanism; investigators are encouraged to seek support for these studies from alternative NCI programs.
Phase I Activities and Deliverables
Select cancer type(s), organ site(s), chemoprevention agent(s), and method(s) of local delivery with adequate justification.
Demonstrate that the chemoprevention agent is:
o
Stable in local formulation and/or when incorporated with the local delivery device/technology.
o
Released at the organ(s) of interest when incorporated into a local delivery device/technology.
Perform preliminary proof-of-concept of the local delivery approach in a suitable animal model and demonstrate:
o
Accumulation/presence (>90% higher concentration) of the agent at the organ/tissue of interest than in the circulation.
o
At least 90% reduction in agent concentration in the blood compared to systemic delivery / administration.
o
Efficacy of the agent with relevant standard tests based on MOA of the agent (e.g., proliferation assay, apoptosis assay)
o
Significant reduction in toxicity with the local approach compared to systemic administration; relevant organ observed toxicity could be used with appropriate justification
Phase II Activities and Deliverables
For agent(s) (or their metabolites) with known chemoprevention effect when administered systemically (FDA
approved):
o Demonstrate efficacy in suitable animal model(s)
• Perform ADME, bioavailability and efficacy studies of the local delivery approach in suitable animal model(s) and demonstrate:
at least same level of agent concentration at the organ/tissue of interest compared to systemic delivery/administration.
at least 90% higher concentration of the agent in the organ of interest than in the circulation.
at least 90% reduction in agent concentration in the blood compared to systemic delivery/administration.
at least same level of efficacy demonstrated with appropriate standard tests reflecting the MOA of the agent (e.g., proliferation assay, apoptosis assay) compared to systemic delivery/administration.
o
Perform maximum tolerated dose (MTD) and/or biological active dose study and demonstrate superior therapeutic index using local approach compared to systemic administration with adequate justification.
• Toxicity should not exceed minimal grade 2 systemic toxicities while short term local grade 3 toxicity may be acceptable in some populations.
o
IND-enabling studies
•
Develop and execute an appropriate regulatory strategy; schedule pre-IND meeting with the FDA.
•
Perform IND-enabling GLP safety toxicology studies in relevant animal model(s) following FDA guidelines.
For novel (non-FDA approved) chemoprevention agent(s):
o Demonstrate efficacy in suitable animal model(s)
• Perform ADME and bioavailability and efficacy studies of the local delivery approach in suitable animal model(s) and demonstrate:
reduction of oncogenic molecular/cellular characteristics reflecting the MOA of the agent (e.g., proliferation assay, apoptosis assay).
at least 50% reduction in cancer incidence following local administration of the chemoprevention agent in suitable cancer prevention animal model(s).
at least 90% higher concentration of the agent in the organ of interest than in the circulation.
at least 90% reduction in agent concentration in the blood compared to systemic delivery/administration.
o
Perform maximum tolerated dose (MTD) and/or biological active dose study and demonstrate superior therapeutic index using local approach compared to systemic administration with adequate justification.
• Toxicity should not exceed minimal grade 2 systemic toxicities while short term local grade 3 toxicity may be acceptable in some populations.
o
Perform IND-enabling safety toxicology studies in relevant animal model(s) to warrant a type B or type C meeting with the FDA.
For offerors that have completed advanced pre-clinical work, NCI may support pilot human trials.
