Radiation Countermeasures: Interfacing with Clinical Oncology Paul Okunieff, MD CMCR Steering Committee Chair CBARMFI Principal Investigator

OVERVIEW OF PROGRESS SINCE 2005 Can radiation side effects be mitigated? Many new agents and mechanisms (there were none in 2005)Many new agents and mechanisms (there were none in 2005) Improved supportive measures (those used before 2005 might have been detrimental)Improved supportive measures (those used before 2005 might have been detrimental) New industry base (mostly micropharma)New industry base (mostly micropharma) Implications: The harmful effects of therapeutic radiation may be “removed” after the cancer is controlled. Can biodosimetry be used to perform mass screening? Many new technologies for genotoxicity measurementMany new technologies for genotoxicity measurement Many new technologies and biological markers for metabolic responseMany new technologies and biological markers for metabolic response Implications: The immediate response of tumor following might be monitored to assess response and impact of combinations with radiation modifying agents

OVERVIEW OF PROGRESS SINCE 2005 Can radiation side effects be mitigated? Many new agents and mechanisms (there were none in 2005) Improved supportive measures (those used before 2005 might have been detrimental) New industry base (mostly micropharma) Implications: The harmful effects of therapeutic radiation may be “removed” after the cancer is controlled. Can biodosimetry be used to perform mass screening? Many new technologies for genotoxicity measurement Many new technologies and biological markers for metabolic response Implications: The immediate response of tumor following might be monitored to assess response and impact of combinations with radiation modifying agents CMCR and most similar grants and contracts from NIAID and BARDA specifically forbid employing any of the funding they provide for therapeutic testing of cancer patients (with very specific individually approved exceptions). FDA: cancer patients are not considered a model of a radiation bioterror or a nuclear event

FDA Requirements: 1.Mitigation in at least 1 animal model (logically requiring primates) 2.Sufficient benefit to be worthwhile in an animal model for a specific scenario (fallout, ground shine, blast, inhalation, combined injury, dirty bomb…) 3.Proven mechanism of action 4.Similarity of action between species tested and man 5.Safety in an otherwise healthy population 1.Mitigation in at least 1 animal model (logically requiring primates) 2.Sufficient benefit to be worthwhile in an animal model for a specific scenario (fallout, ground shine, blast, inhalation, combined injury, dirty bomb…) 3.Proven mechanism of action 4.Similarity of action between species tested and man 5.Safety in an otherwise healthy population The money spent so far in the CMCR and other NIAID, DARPA, and BARDA objectives have been rewarded by substantial practical progress but no approved agents. Agencies looking for a better partnership with FDA

State of CMCR Drug Development: Organ Specific: The mechanisms leading to acute and late organ dysfunction overlap, but are distinctly different. Different mitigation for different organs: CCOP research Time Dependant: The mechanisms leading to acute organ damage are different than those causing long term progressive damage Different mitigation at different times after exposure: CCOP and Survivorship research Exposure type (eg inhalation): If marrow is not exposed lethal injury can take months or years Time bomb: survivorship research The needed agents are time, dose, radiation type and organ specific

University of Rochester (P Okunieff) This CMCR agent mitigates GI syndrome with survival up to 16 Gy (Control lethal dose (LD 50 ) ≈ 8 Gy). Drug given daily beginning shortly after radiation Curcumin was effective at reduction of cutaneous syndromes but was less effective and potential disadvantageous for GI syndromeCurcumin was effective at reduction of cutaneous syndromes but was less effective and potential disadvantageous for GI syndrome Curcumin is poorly absorbed and varies greatly between individuals and with different dietsCurcumin is poorly absorbed and varies greatly between individuals and with different diets D68 overcomes some of those limitations (absorption and GI)D68 overcomes some of those limitations (absorption and GI) D68 is very relevant to cancer researchD68 is very relevant to cancer research GI toxicity limits our ability to treat many abdominal tumorsGI toxicity limits our ability to treat many abdominal tumors Curcumin is expected to improve tumor response Curcumin is expected to improve tumor response Human experience with agent would help CMCR mission Human experience with agent would help CMCR mission

Pre-radiation 6 months 50 Gy (10 fractions) 7 years h-EsA is another agent that does not appear to deleteriously affect tumor control but powerfully mitigates lung toxicity The implications for improving the safety and therefore the utility of focal lung irradiation is substantial C57BL/6 mouse H-EsA

Range of Devices and Agents being Developed by CMCR: Triage : exposed vs. not-exposed Proteomic Genomic / genotoxicity Metabolomic Simple (dipstick) vs. Advanced technology Dosimetry : Actual physical dose received (whole vs. partial body) Genotoxicity assays Physical chemistry methods (free electrons in teeth, nails) Mitigation : Agents given after exposure that prevent late deaths Example: delayed death due to lung or renal failure Treatment : Agents that reduce severity of existing problems Antibiotics, growth factors, … Epidemiology : Tools to allow long-term evaluation of survivors Critical for agent development and validation but requires useful interventions and technologies as defined above

Range of Devices and Agents that Need to be Developed: Triage : exposed vs. not-exposed Proteomic Genomic / genotoxicity Metabolomic Simple (dipstick) vs. Advanced technology Dosimetry : Actual physical dose received (whole vs. partial body) Genotoxicity assays Physical chemistry methods (free electrons in teeth, nails) Mitigation : Agents given after exposure that prevent late deaths Example: delayed death due to lung or renal failure Treatment : Agents that reduce severity of existing problems Antibiotics, growth factors, … Epidemiology : Tools to allow long-term evaluation of survivors Critical for agent development and validation but requires useful interventions and technologies as defined above All of these have potential correlates with clinical oncology Clinical oncology studies would serve the mission of both cancer research and mitigation research improve access to agents (virtual stockpile) gain comfort and experience with the agents and technologies

Goal of this workshop: We want to be able to say in 2015 that the money spent by the CMCR and other NIAID, DARPA, and BARDA objectives have been rewarded by substantial peacetime medical advancements -- in addition to supplying agents for the Strategic National Stockpile

AFRRI: Armed Forces Radiation Research Institute

Some comments about AFRRI 1.History of excellence in radiation biology, with pioneering work in radiation protectors, growth factor radiomodification, biodosimetry, and combined injury 2.Major impact coordinating national meetings, modeling emergency scenarios, publications for mass casualty events… 3.Probably the best resourced radiobiological lab in the world: Ultra high dose rate CobaltUltra high dose rate Cobalt ReactorReactor Near GLP primate lab geared to do radiobiology studiesNear GLP primate lab geared to do radiobiology studies 4.Recent funding increases for both badly needed infrastructure updates and research 5.However, their mission and resources, like the CMCR, permits little translation of their work for cancer patients 1.History of excellence in radiation biology, with pioneering work in radiation protectors, growth factor radiomodification, biodosimetry, and combined injury 2.Major impact coordinating national meetings, modeling emergency scenarios, publications for mass casualty events… 3.Probably the best resourced radiobiological lab in the world: Ultra high dose rate CobaltUltra high dose rate Cobalt ReactorReactor Near GLP primate lab geared to do radiobiology studiesNear GLP primate lab geared to do radiobiology studies 4.Recent funding increases for both badly needed infrastructure updates and research 5.However, their mission and resources, like the CMCR, permits little translation of their work for cancer patients

Some comments about AFRRI 1.Very interested in collaborations Internal grant program reaches out to CMCR leadership as outside reviewersInternal grant program reaches out to CMCR leadership as outside reviewers Collaborate with civilian researchers on multidisciplinary projectsCollaborate with civilian researchers on multidisciplinary projects Collaborate with national labsCollaborate with national labs 2.Biodosimetry Multi-component assays using routine technologies, hematological and chemistryMulti-component assays using routine technologies, hematological and chemistry 3.Mitigation agent testing and discovery Anti-apoptotic agents, NFKB, AKT, and growth factorsAnti-apoptotic agents, NFKB, AKT, and growth factors Anti-oxidants (Amiphostine)Anti-oxidants (Amiphostine) 1.Very interested in collaborations Internal grant program reaches out to CMCR leadership as outside reviewersInternal grant program reaches out to CMCR leadership as outside reviewers Collaborate with civilian researchers on multidisciplinary projectsCollaborate with civilian researchers on multidisciplinary projects Collaborate with national labsCollaborate with national labs 2.Biodosimetry Multi-component assays using routine technologies, hematological and chemistryMulti-component assays using routine technologies, hematological and chemistry 3.Mitigation agent testing and discovery Anti-apoptotic agents, NFKB, AKT, and growth factorsAnti-apoptotic agents, NFKB, AKT, and growth factors Anti-oxidants (Amiphostine)Anti-oxidants (Amiphostine)

Optimizing future success: 1.Low hanging fruit: agents already know to be safe and already subject to substantial human testing 2.New (creative) agents will have a proposed mechanism: mechanisms component of the animal rule may delay approval, and safety will be unknown 3.Challenge regarding mechanism: mechanism is not a critical part of most FDA approvals (it is supportive data) 1.Low hanging fruit: agents already know to be safe and already subject to substantial human testing 2.New (creative) agents will have a proposed mechanism: mechanisms component of the animal rule may delay approval, and safety will be unknown 3.Challenge regarding mechanism: mechanism is not a critical part of most FDA approvals (it is supportive data) Potential for agents to become better understood and validated if used in a cancer population. The FDA’s acceptance of toxicity is naturally higher in cancer patients than it would be in a healthy population