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Development of Radiation Modulators for Use During Radiotherapy


Summary Radiotherapy is employed in the treatment of over half of all cancer patients. Many of those patients suffer adverse effects during and/or after treatment. Additionally, tumors recur in approximately half the patients treated with curative intent. Enhancing specific tumor killing and minimizing normal tissue damage from radiotherapy would improve tumor control and patient quality of life. An ideal intervention would both enhance radiation effects in tumors and protect the normal tissues. Radiosensitizers are agents that are intended to enhance tumor cell killing while having a minimal effect on normal tissues. Recently, two new radiation sensitization drugs have proven clinically effective: Temozolomide treatment with radiotherapy for glioblastoma and Cetuximab treatment combined with radiation for head and neck squamous cell cancers. There is significant potential for further development of novel radiosensitizing agents. Conventionally, radioprotectors are defined as agents given before radiation exposure to prevent or reduce damage to normal tissues, while mitigators refer to those agents given during or after a patient’s prescribed course of radiation therapy to prevent or reduce imminent damage to normal tissues. Both radioprotectors and mitigators are also being developed as potential countermeasures against radiological terrorism and several have shown promise in pre-clinical testing. In order for these to be developed and useful in clinical radiation therapy applications, it is imperative to demonstrate that they do not protect cancer cells. The importance of developing agents that sensitize tumor cells, protect or mitigate radiation-induced damage in normal tissue, improve survival, quality of life, and palliative care in cancer patients was emphasized in a recent NCI workshop on Advanced Radiation Therapeutics - Radiation Injury Mitigation held on January 25th 2010 (Movsas B, et al. Decreasing the adverse effects of cancer therapy: National Cancer Institute guidance for the clinical development of radiation injury mitigators. Clin Cancer Res. 2011 Jan 15;17(2):222-8. Epub 2010 Nov 3. PMID: 21047979), and in a workshop on Radiation Resistance in Cancer Therapy: Its Molecular Bases and Role of the Microenvironment on its Expression held Sept 1-3, 2010. Prior workshops have dealt with sensitization, protection, or radiation effects assessment (Colevas AD, et al. Radiation Modifier Working Group of the National Cancer Institute. Development of investigational radiation modifiers. J Natl Cancer Inst. 2003 May 7;95(9):646-51. Review. PMID:12734315; Stone HB, et al. Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003. Radiat Res. 2004 Dec;162(6):711-28. PMID: 1554812.) This contract topic encourages the development of innovative and promising radioprotectors, mitigators, or sensitizers that either selectively protect normal tissues (but not tumors) against ionizing radiation or selectively sensitize tumors, thereby increasing the therapeutic ratio of radiation. Proposals for radiation modulators are solicited that include preclinical and/or early phase clinical studies demonstrating safety, efficacy, dose, schedule, pharmacokinetics (PK), pharmacodynamics (PD), and metabolism. Proposals should also demonstrate a clear understanding of regulatory requirements, and should include a regulatory plan including key steps such as a pre-IND meeting with FDA, submission of an investigational new drug (IND) application, approval of clinical trial design, and ultimately drug registration. Project Goals The goal is to stimulate collaborations among academic institutions, small businesses, and contract research organizations in order to promote the rapid development of innovative radioresponse modifiers that will decrease normal tissue injury and/or enhance tumor killing, thereby improving radiotherapy outcomes. The long-term goal is to enable small businesses to fully develop, license, and/or market radioresponse modifiers for clinical use. The contract proposal must describe: Phase I • A quantitative estimate of the patient population that will benefit from the availability of such radioresponse modifiers. • A plan for generating evidence that the proposed compound(s) protects at least one relevant normal tissue from radiation-induced injury, and/or sensitizes at least two relevant tumor models. • Either: 1. A plan for generating evidence that the proposed radioprotector(s)/mitigator(s) does not significantly protect cancer cells, OR 2. A plan for generating evidence that the proposed radiosensitizer(s) does not significantly sensitize normal cells and tissues. • The plans must include the methodologies proposed to evaluate the preferential effects on normal tissues or tumors by the compound(s) in vivo (including appropriate biomarkers and endpoints as determined during early interactions with the FDA). • Determination of the optimal dose and schedule in vivo based upon preclinical pharmacodynamic and pharmacokinetic studies. • Statistical validation of the proposed study endpoints including where appropriate, power calculations and rationale for proposed sample sizes. Phase II • The approach to early-phase human trials designed to take into account relevant molecular pathways and targets, and aim to gather pharmacodynamic and pharmacokinetic data to confirm the compound’s observed behavior in animal studies. The approach and experiments to assess the safety and efficacy of the compound(s) in early-phase human trials employing, as appropriate, physician-reported endpoints as well as patient-reported outcomes. Deliverables Phase I may include primarily preclinical studies. Phase II or Fast-Track proposals must contain a section entitled "Regulatory Plan" detailing plans for early involvement of the FDA. There should be a description of how the applicant plans on meeting the requirements to: 1) define suitable biomarkers and endpoints, 2) file IND and 3) design and perform phase 0-2 clinical trials in preparation for product transition to phase 3 clinical trials by groups such as the Radiation Therapy Oncology Group ( Where cooperation of other partners is critical for implementation of the proposed methodology, the applicant should provide evidence of such cooperation (through partnering arrangement, letters of support, etc.). The following deliverables may be required depending on a compound’s maturity in the developmental pipeline: Phase I • Selection and approval of cell line panels for in vitro testing • Demonstration of drug solubility and uptake using cultured normal and transformed cells • Study design for determining clonogenic survival or approved alternative tailored to the mechanism of each tested compound • Clonogenic survival data or approved alternative validating lack of drug toxicity in normal cells, efficacy and specificity of radioprotection for normal cells and/or efficacy and specificity of radiosensitization for tumor cells • Preliminary evidence for lack of in vivo toxicity in normal cells or organisms • Documentation providing a top-level description of the protocols and the testing results should be provided to NCI as part of the Phase I progress report Phase II For advanced pre-clinical work: • Design of NCI and Institutional Animal Care and Use Committee (IACUC)-approved in vivo experimentation plan including statistical validation of experimental design, and sample size determination including power calculations • Selection and approval of tumor cell panel and normal tissues for in vitro testing • Demonstration of bioavailability PK and PD in rodent model • For radiation protectors/mitigators: demonstration by physiologic testing and histological assessment that irradiated normal tissues are spared over a 6-month period • Demonstration of effects (sensitization or lack of protection as appropriate) on tumors using in vivo radiation regrowth delay assays • Collection of data validating lack of drug toxicity, efficacy, and specificity for normal cells over tumor cells in the case of radiation protectors/mitigators • Documentation of the testing protocol and testing results should be provided to NCI as part of the Phase II progress report for pre-clinical studies For proposals advancing to early-phase human trials: • Identify GMP drug source • Obtain IND approval • Provide evidence of established clinical collaboration • Submit protocol for IRB approval • Define suitable clinical endpoints and patient-oriented outcomes
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