Clinical trials in veterinary oncology are increasing in number and scope. Attributes of the comparative approach are a considerable reason for this increase as they provide a unique opportunity to integrate studies that include dogs with cancer into the development path of new cancer drugs.3, 13, 14, 16-19, 22, 24, 27, 38, 56
These new drugs may be used in dogs with cancer prior to or during their study in human patients. The ability to gather serial biopsies from tumors and repeated fluid collections (serum, plasma, whole blood, urine) from the same patient during exposure to an investigational agent can answer complex questions about how best to use drugs that cannot be answered from tumor measurements alone (). This serial sampling allows for the identification of tumor and surrogate markers of drug activity or target modulation, pharmacodynamics endpoints, which can be uniquely correlated to response in ways that are often not feasible in traditional preclinical rodent studies or in human cancer trials.
Comparative Oncology Focused Clinical Trial Design
Interest from the human cancer drug development industry is based on a need for more reliable ways to evaluate new cancer drugs and the strong similarities established between veterinary and human cancers.57, 58
Because there are no treatment standards for the management of cancer in dogs, there is an added opportunity to provide pet owners and their dogs with access to novel therapeutics earlier in the course of disease and before treatment with conventional chemotherapy as compared to human patients participating in early phase human cancer trials. Beyond the access to new and potentially effective treatments for cancer, most clinical trials involve targeted cancer treatments that are less likely to be associated with side effects than conventional treatment. Furthermore, trials often provide significant financial support to study participants. As such, studies are particularly appealing to populations of clients who would otherwise forego traditional cancer treatments. The naturally shorter life span of our patients also permits the more rapid completion of clinical trials of novel agents that can assess outcome within a 6-18 month window, again impossible in human cancer trials. The benefits of such clinical trials in dogs will include earlier assessment of drug activity and toxicity critical to the design of more informed future veterinary and human clinical trials.
A number of cooperative groups exist to study cancer in dogs. These organizations are made up of veterinary oncologists, surgeons, geneticists, basic scientists and general practitioners who wish to understand the causes of cancer in dogs, seek improved treatments and utilize the dog as a comparative model. The American College of Veterinary Internal Medicine (www.acvim.org
) is the body responsible for training board-certified veterinary specialists in medical oncology; the American College of Veterinary Radiology (www.acvr.org
) trains individuals to become boarded in radiation oncology. The Veterinary Cancer Society (VCS; www.vetcancersociety.org
) founded in 1977 is an organization focused on education and the sharing of scientific knowledge within the veterinary oncology community. VCS along with the Veterinary Co-operative Oncology group (VCOG) have encouraged multi-center collaborative studies that have largely been retrospective in nature. In 2006 the Comparative Oncology and Genomics Consortium (CCOGC; ccr.cancer.gov/resources/cop/scientists/resource_genomics.asp
) Inc., a new not-for-profit entity was established. The CCOGC consists of a broad representation of parties focused on the genetics and biology of cancer naturally in dogs. A primary effort of the CCOGC has been the development of a canine cancer biospecimen repository that can provide materials for large-scale studies of canine cancer biology.
The Comparative Oncology Program (COP; ccr.cancer.gov/resources/cop
) of the National Cancer Institute was developed in 2003 and has established a multi-center collaborative network of academic comparative oncology programs known as the Comparative Oncology Trials Consortium (COTC). The COTC is made up of 14 veterinary teaching hospitals and the goal of this effort is to conduct well-organized and focused clinical trials that provide biologically rich answers to the cancer therapeutic development pathway. These trials emphasize pharmacokinetic and pharmacodynamic endpoints, correlating drug exposure to modulation of tumoral markers and defining their relationship to activity. The first two COTC trials were conducted at seven different institutions. COTC001 involved systemic delivery of a targeted phage carrying the gene for TNF-α, a known potent cytotoxic and antiangiogenic agent, that has been difficult to safely administer in the past. Data from a preliminary study showed that this novel delivery method could effectively target tumor vascular and spare normal organs while identifying a safely tolerable dose. This data was used to design a second study where the agent was given once weekly and its effect on response measured. COTC001 was illustrative of the benefits of the comparative approach as the drug’s target was unique to tumor vascular. Pet dogs with cancer were a necessary model to demonstrate the targeting specificity of this agent within a naturally heterogeneous tumor environment. This model provided the ability to fully evaluate the potential toxicities and efficacy of this drug, which would not have been equally achieved in more traditional research models. Information from this trial is currently directing the development path of this drug for human cancer patients. COTC003 involves the evaluation of Rapamycin in dogs with osteosarcoma, a drug which inhibits an important oncogenic pathway called mTOR that is upregulated in many tumor types. Again the approach in the first phase of study is to define a dose that may be safely administered to dogs that is capable of effectively inhibiting the activated mTOR pathway within the tumor and hopefully correlating to a secondary blood marker of this activity. A follow up study in dogs will measure Rapamycin’s benefit as a treatment for metastatic osteosarcoma. COTC003 provides an example of the benefits of serial tissue sampling allowing for evaluation of a target pathway before and after exposure to a new drug. This type of information is vital to designing more successful second phase treatment trials in canine and human cancer patients and is impossible to uniformly accomplish in trials in man. Also both phases of this study will be complete in less than 1 ½ years, much faster than the comparable human trials with analogues of this drug. This provides an opportunity for early and simultaneous reporting of canine data and subsequent integration of pertinent findings within the ongoing human clinical trials. If effective, this drug holds promise for future development in both species. As illustrated by both of these trials, information provided by COTC studies aims to improve the drug development pathway by answering critical questions in how best to use novel agents for the treatment of cancer in dogs and man.
All of the multi-center efforts described emphasize collaborative science to further integrate comparative oncology into mainstream studies of cancer biology. Most clinical trials are conducted through academic veterinary teaching hospitals or referrals centers, but increasingly include direct involvement from general practitioners. Engaging general practitioners in the conduct of comparative oncology trials is essential to their success. This encourages more robust patient accrual, compliant client participation and more accurate outcome and toxicity reporting.