Cancer clinical trials: know what's available (Proceedings)

Clinical trials are an important part of our profession. Well-designed clinical trials result in good quality data to help veterinarians and pet owners make informed decisions for the treatment of cancer. For many pet owners, the option of participating is often very appealing as this usually means they are receiving cutting edge care with promising new treatments. Many clients enjoy the knowledge that regardless of the outcome for their own pet, the information that they contribute will help treat pets in the future. In addition, some funded clinical trials offer financial incentive to offset the cost of treatment. Although clinical trials often involve additional paperwork and time, sample collection can be done quickly and easily with some advanced planning and little or no cost.

Offering clinical trials in private practice can be an important practice builder as it enhances the reputation of the practice as having the most current treatments and a progressive approach to cancer treatment. Some patients who are screened for clinical trials do not qualify, which then allows a discussion of other available treatments.

Academic institutions often offer clinical trials and sometimes all treatments must be done at the University. Some trials however can be carried out in private or specialty practice. The goal of this talk is to present information on groups currently performing clinical trials across the country. Topics covered will include: a new website for finding clinical trials (www.vetcancertrials.org ), a review of current clinical trials, contact information, owner obligation, eligibility, and what makes each trial exciting. In addition to clinical trials, we will discuss how both general and specialty practitioners from any specialty can contribute to research on behalf of their clients. Although some information will be discussed here, clinical trials open and close frequently; a current listing will be discussed at the time of the meeting.

What is a clinical trial?

A clinical trial is designed to evaluate a novel treatment for a disease or illness. Clinical trials can be phase 0, 1, 2, 3, or 4.

     • Phase 0 trials (new concept in clinical research) involve a small number of patients for proof-of-concept and target validation (pharmacodynamic endpoint).

     • Phase 1 trials are used when a new treatment is proposed but has never been tried in a clinical patient, and the goal is to find the correct dosage and schedule for the treatment. Additionally, phase 1 trials will involve multiple blood samples to determine the pharmacokinetics of the drug.

     • Phase 2 trials are sometimes combined with phase 1 trials. The goal of a phase 2 trial is to determine how effective the new treatment is, once a dosage is established. In cancer clinical trials, a phase 2 trial is intended to determine what types of cancer will respond or how well a given cancer responds to a new therapy.

     • A phase 3 trial compares the new treatment option to standard treatment options to see if it is better than what is currently recommended. Phase 3 and 4 trials will evaluate chronic toxicity.

     • Lastly, a phase 4 trial compares two or more well established treatment regimes in a given group of patients. These are typically performed after FDA approval.

What is comparative oncology?

Comparative oncology is the study of cancer across species. As we learn more about the biology of cancer, similarities and differences across species for a given tumor type are being realized. There are many cancers that behave very similarly in companion animals and people.

For example osteosarcoma, though more common in dogs than man, is strikingly similar between species. In both dogs and people, the following are true:

     • 80-90% stage negative at presentation

     • approximately 90% are high grade, and 75% are aneuploid

     • there are genetic alterations in tumor suppressor genes (such as p53 and Rb)

     • alkaline phosphatase elevations are associated with a worse prognosis

     • large tumor volume warrants a worse prognosis and mandibular location has a better prognosis

     • 90% of dogs and 80% of people develop metastatic disease within 1 yr (dogs) or 2 yrs (people) with surgery as the only treatment

     • metastasis to lung>bone>soft tissue

     • chemotherapy improves outcome (50-60% 1 year survival in dogs and about 80% 5 year survival in people).

Other cancers that serve as excellent models of disease include oral squamous cell carcinoma in cats and head and neck SCC in people, and lymphoma in dogs and non-Hodgkin's lymphoma in people. Companion animals share our environment and represent an outbred species. They have an intact immune system, unlike many laboratory models. Their cancer typically progresses at an accelerated rate as compared to humans, given their more rapid aging process. Since dogs and cats can serve as models of disease for cancer in people, clinical trials can serve a dual purpose: to inform and improve upon the standards of care for animals with cancer, and also to provide proof-of-concept information for therapies destined for use in people.

How to contribute

Why would a pet owner want to enroll in a clinical trial?

Pet owners usually enroll in clinical trials for one of four reasons (or a combination of them):

1. They want to seek treatment that is viewed as being on the cutting edge. Owners realize (or must be informed) that this is a "win big, lose big" philosophy. In other words, they hope that their pet is one that benefits from what will eventually become an exciting and effective new therapy. However, they must realize that a relatively small percentage of dogs or cats benefit from new treatments in early phase trials as the optimal dose, scheduling, and toxicity avoidance are still being discovered.

2. Their pet has failed all other treatments and there is no standard treatment available. Pets should at least have a good performance status to enter clinical trials so despite having a trial available, this still may not be a good choice for pets with comorbid conditions. Additionally, pets that have failed all other therapy will be less likely to respond, in theory. Success, however, can be incredibly meaningful in this patient population especially.

3. Cost of care is subsidized. Since pets live on our disposable income, often cost of care can preclude a pet owner's ability to seek treatment. Trials may be partially or fully subsidized which can significantly reduce the stress to an owner as they are faced with difficult treatment and end-of-life decisions.

4. They want to contribute to the "big picture." Most pet owners realize that their pets will not live forever. For pets that have recurrent or refractory disease, and for which it is likely that they will die of their cancer, there is peace of mind in the knowledge that their life and death will benefit other animals in the future (and possibly people as well).

Why would you refer a pet for consideration for a clinical trial?

It may seem that sending pets elsewhere for treatment would deny the practice the ability to provide care. In fact, most patients that come for clinical trials would have otherwise been euthanized. By referring patients for clinical trials, pet owners see the referring veterinarian as practicing on the cutting edge. Pet owners may or may not pursue a clinical trial, but having been offered the opportunity generates goodwill and helps them know that they truly have been offered all possible treatment options. This engenders a deeper trust and loyalty between the pet owner and the veterinarian. Additionally, many trials require some care to be provided by the referring veterinarian, such as follow up bloodwork.

There are many ways to contribute to clinical trials. Some clinical trials can subsidize treatment for pets while others require only collection of samples or information. By acquiring test kits and forms in advance, referral for trial evaluation or collection of needed data can be done with minimal effort and time. It is very important to recommend and document regular follow up visits and remind owners to leave forwarding information for contact if they should move. If at all possible, it is very helpful to designate one or two people as primary contacts for owners and other veterinarians seeking information. This can also provide job satisfaction for technicians who desire career advancement and the unique opportunity to be responsible for data management.

Dos and don'ts for clinical trial candidates

It is frustrating for the primary care veterinarian, the pet owner, and the oncologist when a pet could have been eligible for a trial, but some avoidable decisions preclude their enrollment. In order to provide the most complete and cutting edge care, it is important for the general practitioner to keep a few helpful hints in mind when treating cancer patients.

DO: keep a current list of clinical trials available at the nearest referral and academic center. Most programs will keep a one-page flyer handy and are happy to fax or mail this to you. Also, discuss standard of care with the owner and include the possibility of investigational trials in your initial discussion. If possible, take a small, incisional biopsy before making treatment decisions. This allows for better treatment planning anyway, and many trials require that the mass be present at the initiation of treatment. If you cut off what you can and leave only microscopic disease, then that will often exclude the patient from trials, and may also impair proper and complete cancer care regardless of any trials. It is also helpful to do some baseline screening. If trials exclude dogs with lung metastasis, especially if your pet owner must travel some distance to consider a trial, then radiographs of the lung would be helpful. They may be repeated at the institution, but at least dogs with obvious metastasis won't make an unnecessary trip. The same is true for basic bloodwork.

DON'T: administer any treatment before you have had a chance to ask about inclusion and exclusion criteria for available trials. If a trial is a possibility, DON'T give prednisone to lymphoma patients if possible. This will exclude dogs from most trials.

Collaborative efforts

Several groups have formed cooperative networks to foster large scale clinical trials for improved case accrual and data collection. The Veterinary Cooperative Oncology Group (VCOG) was founded to allow members to contribute cases to retro- and prospective clinical trials. The author is the current president of VCOG and efforts are underway to restructure the organization. The current goal is to morph this group into the voice of veterinary oncology, with annual projects consisting of consensus statements for the purpose of standardizing clinical trial execution and reporting. Additionally, the group will generate consensus statements that promote a standard of care for cancer treatment practices in general and for specific cancers.

The author also has been developing a searchable clinical trials database since 2006. The database can be accessed through the internet at www.vetcancertrials.org and provides, for example, information about inclusion and exclusion criteria, financial subsidization, and the concept behind each promising new cancer treatment. Pet owners or veterinarians can search using the following criteria: species, cancer type, and location. During the talk we will review the current status and content of the database.

In addition to collaborations among oncologists based on data availability, several regional groups have been developed. Also, Drs. Chand Khanna and Melissa Paoloni are currently managing clinical trials through the Comparative Oncology Trials Consortium (COTC). The COTC was developed by the Comparative Oncology Program within the Center for Cancer Research at the National Cancer Institute. The COTC is dedicated to translational studies evaluating promising new cancer treatments first in animals with spontaneous cancer, for the ultimate goal of treating people with cancer. Currently there are 17 participating academic veterinary institutions across the United States. Trials are initiated at multiple sites to improve accrual of cases and ensure that trials are completed in a timely manner, with strict attention to quality of data collection.

Another collaborative effort among a smaller group of institutions is the Canine Comparative Oncology Genomics Consortium (CCOGC) tissue banking. Blood, tumor, and normal tissue samples are collected in the process of routine cancer treatment and sent to a central repository. This bank of samples will be a powerful tool for cancer study. Details for both the COTC and the CCOGC can be found at the NCI Comparative Oncology Program website http://ccr.cancer.gov/resources/cop/.

Additionally, many areas of the country have established regional cooperative groups for the purpose of conducting uniform, well-constructed clinical trials. These include cooperative groups in New England, the Southwest, as well as the Animal Clinical Investigation trial network (ACI, www.animalci.com/), among others. The Veterinary Cooperative Oncology Group (VCOG) was originally established to organize and monitor prospective clinical trials, but has recently been reorganized by Dr. Selting and others to generate consensus statements on topics such as trial endpoints and chemotherapy safety.