Evaluation of NHS-IL12-IL2 Fusion Protein in Tumor-bearing Dogs

Purpose

This is an NIH/NCI-sponsored multisite two-part study that will evaluate the potential efficacy and safety of a combination of 2 cytokines, each of which has shown antineoplastic activity in human and animal protocols, into a single localized, rather than systemic, therapy for canine soft tissue sarcomas, lymphomas, and melanomas. This first study is designed to determine an optimally effective and well-tolerated dose through controlled dose escalation. The second study will use the most effective dose determined by Study 1 to evaluate chronic antitumor activity and tolerance over time.

Background

Interleukin 2 (IL2) is a cytokine that appears to foster long-term anti-tumor immunity and is an approved treatment for human melanoma and renal cancer, but it has shown significant systemic toxicity. Interleukin 12 (IL12), a biologically important regulator of more acute immune responses, has been and is being tested in numerous trials, including some in dogs, but has not yet received approval as a therapeutic agent. Current data from preclinical models in mice suggest that combining IL2 with IL12 yields synergistic effects against cancers and that this combination is promising as a therapeutic agent if toxicity can be controlled or eliminated. To address the problem of systemic toxicity, these cytokines have been attached to NHS, an antibody targeted to necrotic DNA found in the centers of nearly all solid tumors. Mild and predictable adverse effects have been recorded for IL12 linked to NHS and administered IV and intratumorally to dogs with solid tumors in studies at other sites. Client-owned dogs meeting the eligibility criteria will have the NHS-IL12-IL2 fusion protein administered in serial injections directly into easily accessible and measurable tumors in order to locally confine and concentrate the effects of the agent on the lesions. It is further hoped that, in addition to exerting antitumor activity in the injected mass, the treatment will enhance the immune system overall without significant adverse effects.

Eligibility Criteria Study 1

To be considered eligible for this study, prospective dogs must:

  • weigh more than 15 Kg (33 lb)
  • have histologically confirmed lymphoma, melanoma, or soft tissue sarcoma
  • have at least one tumor that is easily accessible and of a suitable size (3-6 cm in length) for serial injections of NHS-IL12-IL2
  • been evaluated as having a favorable performance status (ECOG modified grade 0 or 1) and having no relevant concurrent illnesses, including immune-mediated diseases
  • present with either newly diagnosed or recurrent disease
  • not be receiving radiation or chemotherapy; they must be off such therapy for 3 weeks prior to enrollment
  • be off any medications which may complicate the study; the owner must be willing to list any and all current medications or supplements as they may interfere with the trial drug. NSAIDS may be allowed if the dog has been on them for more than 3 weeks.
  • have owner consent for inclusion in this trial

Trial Treatment Study 1

If, upon examination, the dog meets the eligibility requirements, the owners must complete an Owner Assessment Form of their pet's initial clinical appearance; blood and urine will be sampled and target tumors identified, measured, and imaged by radiography or ultrasound for baseline status. The dog will then receive its first dose of NHS-IL12-IL2 injected directly into the selected tumor (day 0); this will involve an overnight stay for observation, temperature monitoring, and serial blood sampling to monitor the immune response. A second injection will be given 24 hours after the first injection (day 1) and monitored as above for an additional 6 hours before discharge into the owner's care. The owner is required to take their dog's temperature daily for 5 days; a digital thermometer and Owner Assessment forms will be provided for recording daily body temperature (first 5 days) and observations of the dog's behavior or attitude during the 28 day study period.

Dogs must return to OSU weekly for 4 weeks for physical exams, blood/serum analyses, and tumor evaluations; urinalysis and blood coagulation profiles will also be performed at 7 and 14 days post-treatment. At the week 4 examination, radiographs or ultrasound will be performed to redefine disease stage compared to the initial baseline assessment; a tumor biopsy may also be done to assess the tumor tissue viability. Based on this exam, dogs will either be 'off-study' due to progressive disease, or eligible for continued follow up due to stable or responsive disease.

Client Compensation

Costs for NHS-IL12-IL2 are covered by the sponsor (NCI) as are treatments for any adverse events directly attributable to the drug or administration of the drug.

Contact Information

For more information regarding this clinical trial, please contact:

Dr. William Kisseberth
Dr. Cheryl London
Dr. Guillermo Couto
clinicaltrials [at] cvm [dot] osu [dot] edu