Preclinical comparison of three indenoisoquinolone candidates in tumor-bearing dogs: a pilot study of topotecan in dogs with lymphoma

Purpose

This is an NIH/NCI-sponsored multisite two-phase open-label, prospective preclinical study that will evaluate the safety and effectiveness of Topotecan and novel Topoisomerase I inhibitors when given to dogs with lymphoma. The first phase is designed to determine an optimally effective and well-tolerated dose through controlled dose escalation. The second phase will be a validation for biological assay development. Anti-cancer activity against canine lymphoma will be assessed in both phases.

Background

Topoisomerase I (topo I), which is highly conserved in eukaryotes, generates single-strand breaks in the DNA backbone, forming cleavage complexes. The complexes are reversible under physiological conditions. Camptothecin and its analogs generate DNA damage by trapping these topo I cleavage complexes and producing lethal double-strand breaks. This class of compounds includes the FDA-approved drugs topotecan and irinotecan. Novel non-camptothecin topo I inhibitors, indenoisoquinolines, are currently in preclinical development as agents with improved bioavailability. The goal is develop an indenoisoquinoline that would overcome some of the limitations associated with camptothecin, while maintaining the specificity and potency of the class. In anticipation of a larger study effort to assess three novel indenoisoquinolines in dogs with lymphoma, a pilot study with a standard agent, Topotecan, is required to establish time lines for sample collection and establish a comparator arm to define dose-response differences among this class of agents.

Topotecan hydrochloride (trade name Hycamtin, GlaxoSmithKline) is the hydrochloride salt of a semisynthetic derivative of camptothecin. Camptothecin is a cytotoxic quinoline-based alkaloid extracted from the Asian tree Camptotheca acuminate. Topotecan is approved by the Food and Drug Administration (FDA) to treat ovarian cancer, small cell lung cancer in patients with advanced disease and in combination with cisplatin to treat refractory or recurrent cervical cancer. Studies in mice and normal dogs have shown Topotecan to be safe. It has yet to be evaluated in the treatment of canine cancers

Inclusion Criteria

  • Histologically confirmed lymphoma (lymphoma may be confirmed by pre-treatment biopsy or cytology)
  • Nodal presentation (stage 2 or greater) with minimal nodes size of 2 cm in the longest dimension
  • Favorable performance status
    • Grade 0 or 1 (Appendix II modified ECOG criteria)
  • Both newly diagnosed dogs and those with recurrent/relapse disease are eligible

Exclusion Criteria

  • Dogs < 10 kg
  • No concurrent chemotherapy or radiation therapy. Dogs must be off of all such therapy for 3 weeks prior to study enrollment.
  • No corticosteroids for 7 days prior to study initiation 
  • Hypercalcemia causing illness
  • Significant co-morbid illness, which includes but is not limited to renal or hepatic failure, history of congestive heart failure or clinical coagulopathy

Study Design/Treatment

If, upon evaluation, the dog meets eligibility criteria, the owner must complete an Owner Assessment Form of their pet's initial clinical appearance. For baseline status, blood and urine will be sampled; target tumors identified, measured, and photographed, thoracic radiographs and/or abdominal ultrasound will be performed, as well as, tumor and skin biopsies. The dog will then receive an intravenous administration of Topotecan (Day 1); this will involve tumor and skin biopsy and serial blood collections. The patient will receive IV Topotecan administration daily for Days 2-5 . On Day 5, a lymph node excision and serial blood collections will be performed on the dog. Subsequently your dog will return weekly (Day 8, 15 and 22) for physical exam, blood draws, urinalysis and tumor measurements.

Dogs will be re-accessed on Day 22 based on clinical response, lab and thoracic radiograph results. Continuance in the study will be based on clinical response to Topotecan. Dogs with stable disease or partial response may continue to receive treatment every 21 days.

Client Compensation

The study covers all costs directly associated with the trial once the dog has been enrolled in the study. Additionally, the study will supply $2,000/event/dog for treatment of any side effects. At the completion of the study, a $1,000 credited will go to the owner's VTH account for additional chemotherapy/treatment for your dog's lymphoma.

Contact Info

For more information on this clinical trial, please contact:

Dr. Bill Kisseberth
E-mail: clinicaltrials [at] cvm [dot] osu [dot] edu
Phone: 614-292- 3551