COTC007b: Preclinical Comparison of Three Indenoisoquinolines Candidates in Tumor-Bearing Dogs

Purpose

The purpose of this trial evaluating three structurally related chemotherapy drugs is to define their safety, pharmacokinetics, and pharmacodynamic modulation.

Background

Lymphoma is one of the most common cancers in dogs, accounting for 7% to 24% of all canine cancers and having an estimated annual incidence of 13 to 24 cases per 100,000 dogs at risk. Although most dogs with lymphoma respond initially to current chemotherapy drugs, most eventually develop drug resistance. The indenoisoquinolines represent a new class of topoisomerase I inhibitors. This trial is divided into 2 steps: (1) dose escalation, tolerability, pharmacokinetic/pharmacodynamic study and (2) a cohort expansion at the maximally tolerated dose to extend the PK-PD profile of each agent. Study objectives are to distinguish the toxicity profiles of these agents and determine a difference in biological activity if one exists. The results of this study will aid in future design and implementation of trials using these indenoisoquinolines.

Inclusion Criteria

  • Histologically confirmed lymphoma (lymphoma may be confirmed by pre-treatment biopsy or cytology) or soft tissue sarcoma.
    • Lymphoma: Nodal presentation (stage 2 or greater) with minimal nodes size for biopsy of 3 cm in the longest dimension.
    • Soft tissue sarcoma: tumor must be >3 cm longest diameter and amenable to biopsy. Additional lesions can be present but all biopsies will be from same lesion.
  • Favorable performance status Grade 0 or 1 (modified ECOG criteria)
  • Physical examination with weight recorded
  • CBC, serum biochemistry, urinalysis
  • Both newly diagnosed dogs and those with recurrent/relapse disease are eligible
  • Informed owner consent

Enrollment Evaluation

The following are required for enrollment and can be performed at the OSU-VMC < 7 days before drug administration and are at cost to the owner:

  • CBC, serum biochemistry, urinalysis
  • thoracic radiographs

Study Design

Lymphoma cases

  • Pre-treatment tumor biopsy and aspirate
  • Drug (indenoisoquinoline) administration (IV 1 hr infusion) for 5 days
  • Tumor aspirate 2 and 6 hrs post-treatment
  • Tumor biopsy 2, 6 and 24 hrs post-treatment
  • 24-hour serial PK collection, days 1 and 5
  • Blood, plasma and serum collections on Days 3,4,5,8,15,22 and 29
  • Tumor biopsy and aspirate at day 6.
  • Re-evaluated day 8,15,22 and 29
  • Dogs with a complete response (CR) or partial response (PR) may receive additional treatments, dogs with stable disease (SD) or progressive disease (PD) are off-study

Soft tissue sarcoma cases

  • Pre-treatment tumor biopsy and aspirate
  • Drug (indenoisoquinoline) administration (IV 1 hr infusion) for 5 days
  • Tumor aspirate and biopsy 6 hrs post-treatment
  • 24-hour serial PK collection, days 1 and 5
  • Blood, plasma and serum collections on Days 3,4,5,8,15,22 and 29
  • Tumor biopsy and aspirate at day 6.
  • Re-evaluated day 8,15,22 and 29
  • Dogs with a complete response (CR) or partial response (PR) may receive additional treatments, dogs with stable disease (SD) or progressive disease (PD) are off-study

Owner compensation

The study sponsor covers all study associated costs once enrolled in the study as well as provide clients with a $1,000 OSU-CVM account credit for any further veterinary care for their pet.