Trial Summary

A clinical trial to evaluate a novel anti-cancer therapy is now available. The study is designed into two phases. The initial phase will evaluate the safety of this drug in dogs with any measurable cancer (excluding hemangiosarcoma). The 2^nd phase will evaluate the safety of this drug in dogs with hemangiosarcoma exclusively. No placebo is used.

In both phases, dogs will receive the study drug as daily, oral treatment with evaluations performed once weekly for the first 28 days, then once monthly. Blood sample collection and tumor biopsies are collected throughout the study to assess the metabolism and biological activity of this drug. Dogs with hemangiosarcoma will not receive biopsies.

During the course of the study, dogs will not be allowed any holistic therapy, chemotherapy, or other investigational therapies unless approved by the investigator and the sponsor.

Trial Support and Funding

Study drug, diagnostic tests, and follow-up exams will be paid for by the study sponsor. In the event that side effects are attributed to the study drug, the study will pay for medical management of the side effects.

Trial Eligibility

Client-owned pet dogs that meet the following criteria:

• Histological or cytological diagnosis of cancer - excluding hemangiosarcoma in the first phase of the study;
• Measurable cancer that is amenable to serial biopsy;
• Generally feeling well;
• Prior treatment with chemotherapy accepted but a washout of 21 days is required;
• Prior treatment with non-steroidal anti-inflammatory drugs (NSAID) and prednisone accepted but a 14-day washout is required;
• Prior treatment with radiation therapy is accepted but a 30-day washout is required;
• No prior small molecule inhibitors (i.e. Palladia™);
• No prior immunotherapy (i.e. Melanoma Vaccine);

Trial Participation

The following sites are evaluating patients for participation in this clinical trial:

The Oncology Service
Friendship Hospital for Animals
4105 Brandywine St., NW
Washington, DC 20016
(202) 363-7300

What is Lymphoma?

Lymphoma is the most common malignant cancer treated in veterinary oncology. Lymphoma is a cancer of lymphocytes, which are white blood cells that are part of the immune system and reside in the lymph nodes, bone marrow, and spleen. In most cases, lymphoma is thought of as a disseminated disease where the malignant lymphocytes exist in many tissues throughout the body.

How is Canine Lymphoma Treated?

Multi-agent chemotherapy is the current standard option for treatment of lymphoma. Canine lymphoma is one of the most responsive cancers to chemotherapy. Other treatment options include single-agent chemotherapy or treatment with prednisone alone. Although multi-agent chemotherapy has been shown to significantly prolong the survival time of many animals with lymphoma, there is a need for treatment options that will result in long-term control, and possibly a chance for cure.

Investigational Opportunity for Dogs with Lymphoma

We are currently enrolling dogs in a clinical study using a novel drug called a PAR protein (PARP) inhibitor in combination with conventional chemotherapy agents. This treatment option is being tested to determine if it increases the effectiveness of standard chemotherapy improving long-term survival without adding significant toxicity. PARP is an enzyme that is used by cells to repair DNA damage. This enzyme may be upregulated in cancer cells, allowing the cancer cells to be able to quickly repair DNA damage caused by chemotherapy. This repair activity decreases the effectiveness of chemotherapy and increases chemotherapy resistance. Thus, the goal of using a PARP inhibitor is to potentially diminish this repair and allow chemotherapy to be more effective.

The main goals of this study are to determine an acceptable dose of the PARP inhibitor drug, to determine how the drug is metabolized, determine how effectively it reaches the target tissues (lymph nodes), and to assess the treatment benefit. There are two phases of the study. During the initial (dose-finding) phase, dogs will receive the PARP inhibitor alone. On the first day of the study, dogs will receive a single treatment with the PARP inhibitor. A total of 3 lymph node biopsies and blood samples will be collected over 24 hours. Dogs will then be sent home with the the PARP inhibitor to be administered twice daily for one week.

The second phase of the study involves combining the PARP inhibitor with conventional chemotherapy. While receiving the study drug, dogs will be treated with Vincristine (administered at the clinic once weekly for 3 weeks), Cytoxan (administered by owners in oral form on a 3-4 day regimen starting 4 days after each dose of Vincristine), and Prednisone (administered once daily). The estimated average duration of the study will be 4 weeks. Once the study period is completed, dogs may continue to receive treatment as long as benefit continues.

What Side Effects May Be Seen with this Treatment?

Because the PARP inhibitor is an investigational treatment, the complete side effect profile cannot be predicted. Known side effects of this drug include vomiting and diarrhea. However, other side effects may occur, including life-threatening illness and death. Side effects seen with conventional chemotherapy include vomiting, diarrhea, inflammation of the bladder, and suppression of bone marrow resulting in low white blood cell or platelet counts. The frequency or magnitude of side effects seen with chemotherapy may be worsened when the PARP inhibitor is added to the treatment program.

Is My Dog Eligible for the Study?

To be eligible for the study, a dog must:

• Have a confirmed diagnosis of lymphoma, either by biopsy or fine needle aspirate
• Have enlarged lymph nodes
• Have good overall health
• Not have received chemotherapy in the past 21 days
• Not have received prednisone in the past 21 days
• Not have been treated with radiation therapy in the past 30 days
• Be available for the duration of the study period (28 days)

Owner Responsibilities

Owners are required to keep a log of the time the study drug is given and any adverse effects that are observed. This log will be reviewed by the investigator at each visit. Owners must be able to bring the dog to the clinic for weekly visits (a total of 4-5 after the initial consultation). The study is funded, which means the study will pay for examinations, bloodwork, procedures, treatment and side effects associated with the study protocol. The PARP inhibitor will be provided to owners for 6 months after the completion of the study if they wish to continue treatment. Additional funding is not provided after the first 4 weeks of treatment.

INTRODUCTION
Angiogenesis is essential for cancer progression and metastasis. Inhibition of angiogenesis may be an effective treatment for cancers. The anticancer activity of thalidomide has been demonstrated in early human clinical trials. The objectives of this study are: 1) to determine the safety and efficacy of oral thalidomide against measurable canine cancers, 2) to define an optimal biological dose for thalidomide in dogs, and 3) to define tumor types sensitive to antiangiogenic therapy with thalidomide.

METHODS
This is a single agent, phase I/II clinical study. Entry requirements include measurable and histologically confirmed disease, body weight > 10 kg, no chemotherapy within 10 days of treatment, and informed owner consent. Three escalating dose cohorts (30 cases/cohort) have been defined: 3.3-6.5, 6.6-13, and 13.3-26 mg/kg QD. Physical examinations, CBC, serum biochemistry, and tumor response will be evaluated at day 0 and every 30 days thereafter. Urine and plasma samples collected before and during thalidomide therapy will be assayed for markers of antiangiogenic activity including, basic fibroblast growth factor, vascular endothelial growth factor and interleukin-8.

RESULTS
Six cases to date have been evaluated. All dogs had progressive disease prior to study entry. No side effects to thalidomide have been noted in the first dose cohort.

SD -Stable Disease; PD - Progressive Disease

DISCUSSION
Thalidomide appears be well tolerated in the current dose cohort. No objective tumor responses have been documented at this time. Additional entry of cases with smaller tumor burden may allow antiangiogenic activity to be exerted before disease progression. Surrogate markers of systemic antiangiogenic activity, measured in plasma and urine, may be helpful in defining optimal biologic dose.