Prospective Molecular Profiling of Canine Cancers Provides a Clinically Relevant Comparative Model for Evaluating Personalized Medicine (PMed) Trials.

Background Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting. Methodology A proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type. Conclusions Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (\u3c1 \u3eweek). Clustering data show robust signatures by cancer type but also showed patient-to-patient heterogeneity in drug predictions. This lends further support to the inclusion of a heterogeneous population of dogs with cancer into the preclinical modeling of personalized medicine. Future comparative oncology studies optimizing the delivery of PMed strategies may aid cancer drug development

Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients

On September 14–15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed

The Comparative Oncology Trials Consortium: Using Spontaneously Occurring Cancers in Dogs to Inform the Cancer Drug Development Pathway

Chand Khanna and colleagues describe the work of the Comparative Oncology Trials Consortium (COTC), which provides infrastructure and resources to integrate naturally occurring dog cancer models into the development of new human cancer drugs, devices, and imaging techniques

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs

Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients.This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30 kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy.Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease

Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNFα to Cancer Vasculature

Background: Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings: Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to αV integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5 x 1012 transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance: The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies

The Establishment of the Pfizer-Canine Comparative Oncology and Genomics Consortium Biospecimen Repository

The Canine Comparative Oncology and Genomics Consortium (CCOGC) was formed in 2004 in an effort to capitalize on the generation of a domestic dog genome sequence assembly [1], which created new opportunities to investigate canine cancers at the molecular level [2]. [...

Addendum: Mazcko, C., et al. The Establishment of the Pfizer-Canine Comparative Oncology and Genomics Consortium Biospecimen Repository. Vet. Sci. 2015, 3, 127–130

The authors wish to make the following correction to their paper published in Veterinary Sciences [1]: [...

An idealized view of the opportunity provided by a comparative and integrated oncology drug development path.

<p>This is a theoretical illustration of 100 preclinical agents that may be evaluated by either a conventional or an integrated and comparative drug development path. Data for transition rates and costs of Phase I, II, and III trials are based on published cost estimates <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi2" target="_blank">[3]</a> and reported clinical phase transition probabilities for investigational oncology compounds from the 20 largest firms (by pharmaceutical sales in 2005) from 1993 to 2002 <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi1" target="_blank">[2]</a>,<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Roberts1" target="_blank">[4]</a>. Estimates used to derive a vision of the benefit of an integrated approach to drug development are based, in part, on estimates of transition and approval rates for non-oncology therapeutic areas where informative preclinical models exist <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Adams1" target="_blank">[5]</a>. Relative to the conventional development path, the integrated development path is characterized by improved success early in clinical development and a reduction in drug failures late in clinical development. Conventional oncology drug development results in approximately 40% of eligible agents transitioning from preclinical to Phase I, 75% from Phase I to II, 60% from Phase II to III, and 55% from Phase III to approval <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-DiMasi1" target="_blank">[2]</a>. Therefore, for every 100 preclinical candidates, only ten new drugs will reach the clinic. Of most significance are failures that occur late in the development path (i.e., after Phase II or Phase III evaluation). With an integrated approach, more toxic and ineffective agents may be eliminated prior to Phase I (estimate 30 agents now entering Phase I trials versus 40 in the conventional pipeline). Attrition in Phase I may be minimized (estimated 87.5% success rate) and an additional 30% of drugs may be removed from development prior to Phase II based on comparative studies that demonstrate poor pharmacokinetics, pharmacodynamics, or activity (estimate 18 agents now entering Phase II trials versus 30 in the conventional pipeline). Deprioritization (from above) of these drugs will improve the Phase II success rate (estimate 90%). Data from comparative studies will result in the removal of 20% of remaining drugs prior to Phase III based on lack of efficacy in the adjuvant setting, thereby improving success in Phase III and leading to 90% of Phase III agents receiving FDA approval (compared to 55% in the conventional pipeline). In this model, 12 new drugs out of every 100 preclinical candidates will reach the clinic. Using estimates for Phase I, II, and III trials of US$15.2 million, US$23.5 million, and US86.3 million per trial respectively [3], the total clinical trial expenditures for developing 100 preclinical agents is US2.87 billion using conventional methods. Using the hypothetical improvements described above that result from the integrated approach the clinical costs for development will be US2.03 billion [3]. Factoring in additional costs for comparative studies with this approach of US150,000 for studies conducted in the preclinical setting, US$250,000 for studies conducted before or during Phases I–II human trials and US$1 million for studies conducted before Phases II–III studies, the total cost of development is estimated at US$2.07 billion. The result may be a decrease in average clinical trial costs per approved drug from US$290 million to US$173 million <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000161#pmed.1000161-Adams1" target="_blank">[5]</a>.</p

Consensus recommendations on standardized magnetic resonance imaging protocols for multicenter canine brain tumor clinical trials

The National Cancer Institute Comparative Brain Tumor Consortium, Patient Outcomes Working Group, propose a consensus document in support of standardized magnetic resonance imaging protocols for canine brain tumor clinical trials. The intent of this manuscript is to address the widely acknowledged need to ensure canine brain tumor imaging protocols are relevant and have sufficient equivalency to translate to human studies such that: (1) multi-institutional studies can be performed with minimal inter-institutional variation, and (2) imaging protocols are consistent with human consensus recommendations to permit reliable translation of imaging data to human clinical trials. Consensus recommendations include pre- and postcontrast three-dimensional T1-weighted images, T2-weighted turbo spin echo in all three planes, T2*-weighted gradient recalled echo, T2-weighted fluid attenuated inversion recovery, and diffusion weighted imaging/diffusion tensor imaging in transverse plane; field of view of ≤150 mm; slice thickness of ≤2 mm, matrix ≥ 256 for two-dimensional images, and 150 or 256 for three-dimensional images