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Defining the Value of a Comparative Approach to Cancer Drug Development Author Manuscript Published OnlineFirst on December 28, 2015; DOI: 10.1158/1078-0432.CCR-15-2347 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Defining the value of a comparative approach to cancer drug development 2 LeBlanc AK, Mazcko C, Khanna C. 3 Comparative Oncology Program, Center for Cancer Research, National Cancer Institute, 4 National Institutes of Health, Bethesda, MD 20892. 5 Short title: Comparative Oncology in Drug Development 6 7 Abstract 8 Comparative oncology as a tool in drug development requires a deeper examination of the 9 value of the approach and examples of where this approach can satisfy unmet needs. This 10 review seeks to demonstrate types of drug development questions that are best answered 11 by the comparative oncology approach. We believe common perceived risks of the 12 comparative approach relate to uncertainty of how regulatory bodies will prioritize or 13 react to data generated from these unique studies conducted in diseased animals, and how 14 these new data will affect ongoing human clinical trials. We contend that it is reasonable to 15 consider these data as potentially informative and valuable to cancer drug development, 16 but as supplementary to conventional preclinical studies and human clinical trials 17 particularly as they relate to the identification of drug-associated adverse events. 18 19 Introduction 20 The study of naturally occurring cancer in companion animals, known as comparative 21 oncology, forms the basis of a translational drug development strategy that primarily 22 includes tumor-bearing pet dogs in clinical trials of novel cancer therapies destined for use 23 in human cancer patients.(1-5) The recognition of spontaneous cancer development in 1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 28, 2015; DOI: 10.1158/1078-0432.CCR-15-2347 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 24 companion animals, and potential for inclusion of such animals in drug development 25 studies, is based upon observations of canine malignancies that share morphologic, 26 histologic and biologic characteristics with human cancers. Dogs’ physical size, amenability 27 to serial biologic sample collections, compressed survival compared to humans, 28 comparable tumor biology, intact immunity and relevant responses to cytotoxic therapies 29 provide clear support to their inclusion as a complementary animal model. (4,5) 30 31 Currently the field of comparative oncology is focused on tumor-bearing dogs as they 32 comprise the majority of those presented to veterinarians for cancer diagnosis and 33 management, which is in turn facilitated by scientific knowledge of malignancies they 34 develop, the collective veterinary clinical experience with anticancer therapies such as 35 chemotherapy and radiation, and availability of basic annotation of the canine genome and 36 immune system. A major milestone was establishment of the National Cancer Institute’s 37 Comparative Oncology Program (NCI-COP) at the National Institutes of Health in 2004. A 38 component of this program is the Comparative Oncology Trials Consortium (NCI-COTC; 39 http://ccr.cancer.gov/resources/cop/COTC.asp), an infrastructure uniting study sponsors, 40 such as pharmaceutical and biotechnology companies, with 21 academic veterinary centers 41 within North America to support multicenter clinical trials of investigational therapeutics, 42 wherein centralized trial support and data management is provided by the NCI.(6,7) This 43 mechanism provides access to a clinical trial infrastructure that delivers trial results in a 44 facile manner, considerate of timelines generally required in drug development strategies. 45 Further, a body of published work now exists to demonstrate the feasibility and 46 applicability of the dog cancer model in drug development to ensure data that is both 2 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 28, 2015; DOI: 10.1158/1078-0432.CCR-15-2347 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 47 scientifically sound and robust, thus supporting inclusion into FDA applications. Although 48 not formal FDA guidance, direction for clinical trial conduct and data reporting exists for 49 drugs evaluated in comparative oncology studies in the pre and post-Investigational New 50 Drug (IND) settings, and has been used effectively by groups actively involved in these 51 efforts. (8) 52 Methods 53 Today’s challenge is how to best capture and convey the value of these studies, given the 54 timeline for drug development and the diversity of data that collectively informs decisions 55 in the development path. Various attempts at defining value have been made, including a 56 financial model that proposes savings of billions of research and development dollars, 57 achieved primarily through the effective design of better phase II human studies.(9) We 58 propose that the value of the comparative approach lies in the answers to critical drug 59 development questions that are not answered in human trials or conventional preclinical 60 models. Herein we present a summary of the types of questions that are best asked and 61 answered by comparative oncology studies (Table 1), along with a discussion of selected 62 studies that generated answers to such questions, thus are demonstrative of the value of 63 the comparative oncology approach. 64 Results 65 Small molecules and the relationship of pharmacokinetics, pharmacodynamics, and clinical 66 assessment of tolerability and efficacy 67 A highly soluble prodrug of ganetespib, STA-1474, was studied in dogs with cancer to 68 establish clinical toxicity, to identify surrogate biomarkers of response and 69 pharmacokinetics between two proposed dosing schedules, and to provide evidence of 3 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 28, 2015; DOI: 10.1158/1078-0432.CCR-15-2347 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 70 biologic activity. This study met all defined objectives, and assisted in devising a dosing 71 strategy to provide prolonged drug exposure to support efficient inhibition of drug target 72 via modulation of a surrogate biomarker in blood (HSP70 upregulation in peripheral blood 73 mononuclear cells (PBMCs)) and tumor levels of c-kit (an HSP90 client protein). 74 Collectively, this data informed the design of human clinical trials of ganetespib and 75 demonstrates the strengths of a naturally-occurring canine model by highlighting the ease 76 of serial biopsy procurement, rapid assessment of differential dose and schedule, and 77 correlative assessment of multiple clinical parameters.(10) In another similar example, an 78 orally-bioavailable XPO1inhibitor verdinexor, a companion agent to a lead human 79 compound KPT-330 (Selinexor, Karyopharm Therapeutics), was studied in tumor-bearing 80 dogs. Based upon profound clinical benefit observed in dogs with non-Hodgkin’s lymphoma 81 (NHL) and the marked similarities between canine and human NHL, the data generated 82 within this study provided critical new information in support of related compounds in 83 humans with hematologic malignancies.(11) Selinexor is currently being evaluated in 84 Phase I and II clinical trials for a variety of human cancers. 85 86 Biomarker validation and optimization of pharmacodynamics (PD) assays within the context 87 of drug exposure in tumor-bearing dogs 88 The irreversible inhibitor of Bruton tyrosine kinase (Btk), ibrutinib, was studied in dogs 89 with B-cell lymphoma to establish tolerability, preliminary efficacy data, and to validate a 90 pharmacodynamic (PD) assay within PBMCs and tumor tissue. Validation of the 91 fluorescently labeled derivative of ibrutinib to monitor occupancy of Btk by the drug has 4 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2015 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 28, 2015; DOI: 10.1158/1078-0432.CCR-15-2347 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 92 led to adoption of this approach as PD readout in subsequent human trials, while also 93 supporting the use of ibrutinib in humans with B cell malignancies.(12,13) 94 Another valuable example is study of hydroxychloroquine, an autophagy inhibitor, given to 95 dogs with NHL. The PD response evaluated in both PBMCs and tumor tissue, obtained via 96 serial peripheral lymph node biopsies, demonstrated that reliance on surrogate PBMC for 97 demonstration of sufficient drug levels for effective autophagy inhibition within tumor 98 tissue cannot always be inferred, thus underscoring the strength of the canine cancer 99 model.(14) 100 101 Immune-modulating agents for cancer therapy 102 A comparative oncology study of an immunocytokine, NHS-IL12, administered 103 subcutaneously to dogs with malignant melanoma was conducted to identify tolerability 104 and immunologic activity of this agent across a range of doses.(15) Pharmacokinetic and 105 pharmacodynamic endpoints, in the form
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