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Workshop Summary
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From page 1... ... Recently, there has been renewed interest in comparative oncology -- the study of naturally developing cancers in animals as models for human disease -- as one way to improve cancer drug development and reduce attrition of investigational agents. Tumors that spontaneously develop in pet dogs and other companion animals as a result of normal aging share many characteristics with human cancers, such as histological appearance, tumor genetics, biological behavior, molecular targets, and therapeutic response. Read the entire page →
From page 2... ... . There is a long history of studying cancer in dogs, and clinical trials for pet patients with cancer can serve as a useful intermediary between traditional preclinical studies and human clinical t rials in the translational research pathway. Read the entire page →
From page 3... ... The opportunities to use data from trials for pet patients to select lead compounds, identify signals of toxicity and efficacy, and help develop dosing regimens for human clinical trials; 3. The way in which data from clinical trials for pet patients are viewed by the U.S. Read the entire page →
From page 4... ... • se clinical trials for pet patients to select the best compound and U to prioritize the most promising combinations to advance in human clinical trials. (Anne Keane, Chand Khanna, Amy LeBlanc, David Vail) Read the entire page →
From page 5... ... Adopt Best Practices for the Ethical Conduct of Clinical Trials for Pet Patients • armonize the consent process for pet patients with the informed H consent process for human clinical trials where possible. Read the entire page →
From page 6... ... However, Carl Barrett of AstraZeneca added a note of optimism based on more recent trends; he said that five oncology agents were approved in the first 5 months of 2015, and there have been more than 30 different targeted therapies approved in the past 10 years. "One Medicine" Concept The "one medicine" concept is a core principle underpinning the inclusion of clinical trials for pet animals in the cancer research continuum, said Matthew Breen from North Carolina State University. Read the entire page →
From page 7... ... Limitations of Traditional Drug Development Preclinical Research Models Only 11 percent of oncology agents that demonstrate efficacy in mouse models are ever approved for humans use, said Beverly Teicher from NCI. One problem with the models, she explained, is that they lack key characteristics of human cancer, such as long latency, natural causation, genomic instability, tumor heterogeneity, and tumor microenvironment characteristics. Read the entire page →
From page 8... ... 8 CLINICAL STUDIES FOR PETS WITH CANCER TABLE 1 Mouse Models in Cancer Research Mouse Model Description Advantages Disadvantages Transplantable Injection • ow cost L • odent tumor cells R syngeneic of cells or • eproducible R • ld tumor cells lines O tumor model explants from • mmunocompetent I • ubcutaneous S the same host implantation species • imited variety L • odent target R • on-immunogenic N • odent host R • ong history/strong L • odent immune R baseline data system • osts readily H • ery quick growth V available • tatistically valid S numbers Human tumor Injection of • H uman tumor cells • ore costly M xenograft human cell • R eproducible • odent stroma R lines, usually • W ide variety • mmunodeficient I subcutaneous • L ong history/strong host baseline data • on-natural tumor N • osts readily H site (subcutaneous) available • ld tumor cell lines O • umor growth T • imited genetic L easily followed diversity • tatistically valid S numbers Disseminated Implanted • imilar to clinical S • C omplex surgery disease models human tumor disease • C ostly xenografts • umor growth in T • R odent stroma tissue of origin of • O ld tumor cell lines primary tumor type • I mmunodeficient • ood variety G host • osts readily H • onreproducibility N available of tumor growth rate • mmunocompetent I • tatistics difficult S host due to low numbers Read the entire page →
From page 9... ... WORKSHOP SUMMARY 9 TABLE 1 Continued Mouse Model Description Advantages Disadvantages "Labeled" Implanted • umor response T • enetically altered G tumor models tumor that can be visualized cell lines carries a with fluorescence or • any clonal lines M foreign luminescence • oor representation P fluorescence • isualization of V of disease protein metastasis • odent stroma R • umor T • mmunodeficient I measurement host • imited variety L • ostly equipment C • osts readily H • tatistics difficult S available due to low numbers Patient-derived Direct • umor cells recently T • arge tumor L xenograft implantation from patient specimen required (PDX) models of a tumor • enetically similar G • low growth S fragment to patient • mmunodeficient I from human • umor T host patients measurement • ouse stroma M • osts readily H • ery costly V available • tatistics difficult S due to low numbers • ot a validated N predictor Genetically Expression of • umor arises in T • imited availability L engineered target or label, desired tissue of hosts mouse models spontaneous • ell-defined lesion, W • imited mutations L carcinogenesis defined mutations not reflective of • mmunocompetent I human disease host • odent tumors R • umor can be T • odent stroma R followed over a • low tumor S long time course development • ery costly V • ariable tumor stage V • umor difficult to T follow • ndpoint is usually E survival • tatistics difficult S due to low numbers SOURCE: Teicher presentation, June 8, 2015. Read the entire page →
From page 10... ... Similarities Between Human Cancers and Naturally Occurring Cancers in Pet Patients Cancer is common in pets, Kastan said. There are more than 170 million pets in the United States (80 million dogs and 90 million cats) Read the entire page →
From page 11... ... Helman concluded that comparative oncology studies in animals with naturally occurring cancers provide important opportunities to expand our understanding of cancer biology and to develop new therapies. He added that the integration of comparative oncology trials into the drug development process should be iterative, with clinical trials for pet patients informing human clinical trials and vice versa. Read the entire page →
From page 12... ... He advocated for an integrated approach to cancer drug development in which clinical trials for pet patients are conducted in parallel with human clinical trials to gain additional insight into drug activity, toxicity, regimen and schedule, biomarkers, and possible combination therapies (Paoloni et al., 2008) (see Figure 1) Read the entire page →
From page 13... ... in 2003 to facilitate such trials, he said, and the COTC has infrastructure and resources in place that can integrate clinical trials for pet patients with naturally occurring cancer into the development of new drugs, devices, and imaging techniques for human cancers. The COTC also has a pharmacodynamics core that provides efficient access to laboratory and investigative platforms for studying the biology of cancer and drug–cancer relationships in pet patients. Read the entire page →
From page 14... ... Khanna also described an example of the "pick the winner" strategy for lead compound selection, in which three novel topoisomerase inhibitors were tested in canine patients with lymphoma. Clinical trials for pet patients can be helpful in distinguishing among multiple compounds in development in order to identify the optimal lead compound for human testing by assess Read the entire page →
From page 15... ... Canine patients require larger doses of drugs than mice, which means that a larger supply of the drug is needed. The drugs used in clinical trials for pet patients do not have to meet good manufacturing practice standards, but the agents used in human clinical trials must meet these Read the entire page →
From page 16... ... . Tanja Zabka, a veterinary pathologist at Genentech, suggested that having a third party interact with regulatory bodies might help in formulating an unbiased approach for integrating clinical trials for pet patients into the development pipeline. Read the entire page →
From page 17... ... Functional experiments suggested that, as with human tumors, this BRAF mutation activates the MAP Kinase signaling pathway. This knowledge might enable the use of canine TCC as a powerful system to evaluate BRAF-targeted therapies or combination therapies, which could enhance the treatment of both human and canine cancers. Read the entire page →
From page 18... ... Genetic data provides crucial information for improving cancer detection, diagnosis, prognosis, intervention, treatment, and prevention. Furthermore, he emphasized, sharing these resources and information is necessary to promote canine cancer research. Read the entire page →
From page 19... ... The CCOGC has also cataloged specimens according to their level of heterogeneity and nucleic acid quality. Breen also described how well-defined specimens from patients with cancer can accelerate cancer research to benefit both pet patients and humans. Read the entire page →
From page 20... ... When whole-genome profiling was performed on a cohort of dogs with bladder cancers, the data showed that three particular chromosomal aberrations were increased, Breen said. Based on these three chromosomal aberrations, a cytogenetic assay with high sensitivity and specificity was developed for identifying the presence of TCC in symptomatic canine patients. Read the entire page →
From page 21... ... One can identify risk factors with as few as about 100 cases and controls, she said. Precision Medicine in Clinical Trials for Pet Patients Jeff Trent from the Translational Genomics Research Institute (TGEN) Read the entire page →
From page 22... ... Trent concluded by saying that genomics-guided drug matching is the best way to study the treatment potential of novel agents for the treatment of cancer in both humans and pet patients. Breen also briefly discussed a collaboration with the COTC that was a proof-of-concept trial to determine the feasibility of collecting a tumor sample from canine patients and generating a prospective molecular profiling report within 1 week (Khanna et al., 2014) Read the entire page →
From page 23... ... , researchers designed clinical trials for canine patients to investigate drug PK and toxicology and to assess therapeutic combinations. The first trial involved the administration of a PAC-1 derivative called sulphonamide PAC-1, or SPAC-1, which required cumbersome 24-hour intravenous infusions, Fan said. Read the entire page →
From page 24... ... No correlation drug exposure between accumulation in tumor tissues and plasma Ibrutinib FDA approved Demonstrated Validation of (Bruton tyrosine for human use efficacy and biomarker test for kinase inhibitor) surrogate use in human trials; endpoint dose modulation Ganetespib Phase III human Determined Proof-of-target for (HSP90 inhibitor) Read the entire page →
From page 25... ... Fan concluded by summarizing the ways in which clinical trials for pet patients can be useful in drug development. In the examples he described, these trials were critical for assessing toxicity and single-agent activity and were necessary for the development of tolerable dosing regimens that could be used to inform the design of trials for human patients. Read the entire page →
From page 26... ... Clinical trials for pet patients also allow the exploration of drug delivery and the assessment of toxicity in a manner that is similar to the process in human trials; it is not possible to do this in mouse models (e.g., comparing infusion versus bolus delivery) , Gustafson said. Read the entire page →
From page 27... ... . Additionally, he said, studies with pet patients enable investigations of potential predictive biomarkers, including the correlations between clinical outcomes and surrogate endpoints. Read the entire page →
From page 28... ... Mutations of the c-kit gene are present in 20 to 40 percent of all canine mast cell tumors, a frequency that is similar to how often activating mutations are present in human gastrointestinal stromal tumors, Thamm said. Clinical trials for canine patients used molecules that were similar to, but not identical with, the lead compound for humans (sunitinib) Read the entire page →
From page 29... ... It would be useful to have a large database of canine cancers so that investigators could understand which cancers could be targeted by investigational drugs, Thamm concluded. IMAGING TECHNOLOGY IN CLINICAL TRIALS FOR PET PATIENTS Challenges and Opportunities in Using PET Imaging in Clinical Trials Peter Choyke from NCI discussed positron emission tomography (PET) Read the entire page →
From page 30... ... However, whether it can be used to effectively measure apoptosis in humans has not been determined. Choyke suggested that this is one example of how PET imaging studies in pet patients could accelerate the development of imaging tracers and drug development. Read the entire page →
From page 31... ... Challenges and Opportunities in Using MRI Imaging in Clinical Trials Functional imaging data from pet patients can help optimize the design of human clinical trials, said Mark Dewhirst from Duke University. He discussed the utility of magnetic resonance imaging (MRI) Read the entire page →
From page 32... ... These kinds of studies could be applied to the investigation of many agents in order to get parallel data for human and pet patients, Dewhirst said. He noted that image data were key to thermal therapy modeling and for establishing the principles for clinical trial quality assurance. Read the entire page →
From page 33... ... Preclinical studies were performed in healthy dogs to assess the likely adverse events before starting phase I clinical trials for canine patients with mast cell tumors. The same PI performed both the preclinical and the phase I studies. Read the entire page →
From page 34... ... However, a slower enrollment would have resulted in fewer pet patients receiving the toxic dose, she said. Finally, London described phase I and II clinical trials for canine patients with lymphoma that were treated with KPT-335, a novel inhibitor of the XPO1 (exportin 1) Read the entire page →
From page 35... ... A focus on tumor biology and drug targets, rather than just looking at istology, is useful in designing clinical trials for pet patients, she said. h LeBlanc detailed a clinical trial for canine patients that administered Read the entire page →
From page 36... ... Clinical trials for pet patients can be useful for carrying out PD studies in naturally occurring cancer, and they can provide access to patients with both treatment-naïve and drugresistant disease, she emphasized. The COTC also provides a connection to a comparative oncology-imaging center with the ability to recruit dogs for imaging studies, she added. Read the entire page →
From page 37... ... CLINICAL TRIAL DESIGN Clinical Trial Designs That Meet the Needs of Pet Patients and Their Owners David Vail from the University of Wisconsin–Madison discussed the design of clinical trials for pet patients. Human patients who enter phase I clinical trials generally have already been treated with standard-of-care therapies, often with three or more different agents, he said. Read the entire page →
From page 38... ... There are strategies that can be used to address some of these concerns, such as owner education and informed consent, treating a very small number of pet patients in the low-dose cohorts, allowing sufficient time for adverse events to occur before escalating the dose, and covering the cost of managing any potential adverse events. Vail said that phase II trials are designed to characterize the clinical and biological activity of investigational agents, such as which tumor types or targets respond to the agent. Read the entire page →
From page 39... ... Best Practices for the Ethical Conduct of Clinical Trials for Pet Patients Rod Page from Colorado State University reported on the outcome of a meeting he helped organize13 in 2014 on the ethical conduct and oversight of clinical trials for pet patients, in which the participants developed a set of best practices for clinical trials for pet patients. He said that the participants at that meeting agreed on the following principles: • Clinical trials must preserve well-being, provide the best supportive care, and provide relief from pain and other distressing symptoms. Read the entire page →
From page 40... ... Page made several suggestions for the post-approval monitoring of trials. This is a new concept for clinical trials in pet patients, he said, and Read the entire page →
From page 41... ... REVIEW OF CORNELL UNIVERSITY COLLEGE OF VETERINARY MEDICINE ACTIVITIES WITH CLIENT OWNED ANIMALS FIGURE 3 Clinical trial approval process at the Cornell University College of Veterinary Medicine. NOTE: CVMRC = clinical veterinary medical research committee; IACUC = institutional animal care and use committee; PI = principal investigator. Read the entire page →
From page 42... ... Page also made several suggestions regarding reporting and publication. He said that improved data management systems should be created, and that it would be helpful to develop a clinical trials registry for pet patients that would be similar to the registry for human clinical trials (www. ClinicalTrials.gov) Read the entire page →
From page 43... ... She also mentioned several ethical considerations that should be discussed before launching a trial, including the appropriateness of delayed conventional therapies, limits on tissue and blood collection, and whether pet patients are likely to benefit from clinical trial research. Olson suggested that pet patients should be considered similar to pediatric patients, noting that both need independent advocates to provide informed consent. Read the entire page →
From page 44... ... Therefore, adverse events from the disease may be mistakenly recorded as adverse effects from the drug, he said. However, he emphasized that any safety signals would be evaluated using the totality of the data and "human clinical data would trump any animal data." Leighton added that FDA has not taken regulatory action, such as a clinical hold or additional monitoring, in response to a safety signal observed in a clinical trial for pet patients. Read the entire page →
From page 45... ... This would be another way to monitor adverse events in these clinical trials, he said. STATUS OF CLINICAL TRIALS FOR PET PATIENTS Wendy Levin from Fate Therapeutics offered some thoughts on incorporating clinical trials for pet patients into oncology drug development. Read the entire page →
From page 46... ... Within an individual drug development company, she said, there are crossfunctional teams that work together to develop a molecule, and there is intense competition among teams for resources. As a result, she said, there is some hesitancy to devoting the time and resources necessary to conduct clinical trials for pet patients. Read the entire page →
From page 47... ... Clinical trials for pet patients can enhance and accelerate drug development efforts by contributing unique information that cannot be obtained from traditional preclinical models or trials for human patients, Keane said. For example, studies with canine cell lines and pet patients with cancers with documented relevance to human cancers could be added to screening panels for all compounds, she said. Read the entire page →
From page 48... ... She also suggested that results from clinical trials for pet patients should be published in human medicine journals and presented at national meetings focused on human medicine to raise awareness of the utility of the model. She also noted that there is some guidance on the best way to translate new cancer treatments from pet patients to human patients (Khanna et al., 2009) Read the entire page →
From page 49... ... Cancer is still a large burden for both human and pet patients, she said, and one that is likely to worsen as the human population ages. "There is a huge need for complementary systems to complement the current structure in cancer research," she said, "and dogs that have naturally occurring cancer or who are at risk for naturally occurring cancer can certainly help." She emphasized that clinical trials for pet patients have been established on a solid foundation of more than 30 years of research through the work of scientists and veterinarians and that the field is well positioned to continue to move forward. Read the entire page →
From page 50... ... This characterization should include complete pathological and clinical behavior characteristics in addition to defining the molecular and genetic events that are important in those cancers, she said. In addition, there is a lack of knowledge among researchers regarding the potential role and value such trials have to offer in translational cancer research, and there are unsubstantiated concerns among drug sponsors that findings from clinical trials for pet patients could adversely affect a new drug application for human use. Read the entire page →
From page 51... ... He said he was encouraged by the strong commitment of the veterinary community to bring together stakeholders from many fields to learn, discuss, and raise awareness of the potential for clinical trials for pet patients and by ongoing campaigns to build public awareness. But, he added, additional investments will be needed to build capacity and facilitate these types of trials. Read the entire page →
From page 52... ... 2009. The Comparative Oncology Trials Consortium: Using spontaneously occurring cancers in dogs to inform the cancer drug development pathway. Read the entire page →
From page 53... ... , from canine tumor model to human clinical development: Where we are? Critical Reviews in Oncology and Hematology 91(1) Read the entire page →
From page 54... ... 2009a. Launching a novel preclinical infrastructure: Comparative Oncology Trials Consortium directed therapeutic targeting of TNFalpha to cancer vasculature. Read the entire page →
From page 55... ... Clinical Cancer Research 15(15) Read the entire page →

From page 1...

... Recently, there has been renewed interest in comparative oncology -- the study of naturally developing cancers in animals as models for human disease -- as one way to improve cancer drug development and reduce attrition of investigational agents. Tumors that spontaneously develop in pet dogs and other companion animals as a result of normal aging share many characteristics with human cancers, such as histological appearance, tumor genetics, biological behavior, molecular targets, and therapeutic response.

Workshop Summary Pages 1-56

Workshop Summary
Pages 1-56