Abstract C167: KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates antitumor activity in dogs with mast cell tumors
Authors: London Cheryl , Rippy Sarah , Gardner Heather , Kisseberth William , Post Gerald , Janson Neal , Crew Linda , LaVallee Theresa , Gedrich Richard 
Published: May 2016

Abstract
Background: KTN0158 is a novel humanized anti-KIT IgG1 monoclonal antibody that binds canine, feline, non-human primate and human KIT with high affinity. KTN0158 potently inhibits wild-type and some oncogenic variants of KIT in vitro and modulates canine mast cell function and survival in vivo. A clinical trial was conducted in dogs with spontaneous mast cell tumors (MCT) where KIT is known to be widely expressed and where activating mutations in the form of internal tandem duplications (ITDs) in exon 11 are found in 30% of tumors. The purpose of this study was to evaluate the safety, biologic activity and pharmacokinetic/pharmacodynamic (PK/PD) profile associated with KTN0158 administration in dogs with MCT.
Methods: Twelve dogs with measurable MCT were enrolled into this open-label phase 1 dose-escalating clinical trial. Three dose levels and 2 schedules were evaluated (10 or 30 mg/kg given on Day 0 only; 1 or 10 mg/kg given on Days 0 and 21). Serial tumor biopsies and blood samples for PK and PD analysis were collected pre- and post-treatment throughout the study. Dogs were assessed weekly with physical examination and standard laboratory tests (serum chemistries, hematology profiles, and urinalyses) for clinical toxicities and response. Adverse events (AEs) were recorded and graded according to published common terminology criteria for AEs in dogs. Determination of antitumor efficacy was based on objective tumor assessments made according to established RECIST criteria for solid tumors in dogs.
Results: Of the 12 dogs entered in this study, 3 had tumors with exon 11 ITDs and 6 had evidence of metastasis to the local lymph node. All dogs treated with a single dose of KTN0158 at 10 or 30 mg/kg or two doses of KTN0158 at 1 or 10 mg/kg experienced clinical benefit. Partial responses were observed in 5 dogs (n = 1 KIT ITD) and stable disease was observed in 7 dogs (n = 2 KIT ITD). Upon study completion, 11 dogs underwent surgical removal of the MCT with or without extirpation of the draining lymph node. Histopathology failed to identify neoplastic mast cells in tumor samples from 2 dogs (patients 2 and 4) and 3 draining lymph nodes from 3 dogs (patients 2, 3 and 11) classified as metastatic at study entry. The most common adverse events associated with KTN0158 administration were reversible dose-dependent hematologic changes including anemia, neutropenia, and thrombocytopenia, generally occurring 7-14 days post-treatment. Doses of 30 mg/kg KTN0158 resulted in clinically significant toxicities not observed at other dosing levels, including evidence of edema/erythema, grade 4 neutropenia, and grade 3 thrombocytopenia. Evaluation of PK and PD biomarkers is ongoing.
Conclusions: KTN0158 given at 1 and 10 mg/kg demonstrated an acceptable adverse event profile and single agent biologic activity in a relevant spontaneous large animal model of KIT driven malignancy (MCT). The objective responses observed in tumors with and without activating KIT mutation suggest that KTN0158 may provide clinical benefit to patients with GIST and other KIT-driven tumors and human clinical studies are planned.
Citation Format: Cheryl London, Sarah Rippy, Heather Gardner, William Kisseberth, Gerald Post, Neal Janson, Linda Crew, Theresa LaVallee, Richard Gedrich. KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates antitumor activity in dogs with mast cell tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C167.