Background: Canine lymphoma (CL) and hemangiosarcoma (HSA) are aggressive malignancies. Current treatments have limited efficacy, profound toxicity which causes poor quality of life (QoL) in patients. There is strong biological and clinical similarity to human non-Hodgkin lymphoma and human angiosarcoma, which makes dogs an attractive model for translation research. OXC-101 (Karonudib), a dual-function MTH1 inhibitor, induces incorporation of oxidized nucleotides into DNA and inhibits microtubule polymerization and includes the toxicity in cancer cells. OXC-101 is currently being evaluated in two human clinical trials (Phase 1 solid tumors; Phase 1/2 hematologic malignancies) and has received Orphan Drug Designation for acute myeloid leukemia, underscoring its translational relevance. Methods: We conducted an open-label pilot study to assess safety and preliminary efficacy of oral OXC-101 in nine pet dogs with CL (n=6) or HSA (n=3). Dogs received 8-10 mg/kg orally twice daily every other day for up to eight months. Clinical exams, laboratory analyses, and owner feedback were used to monitor safety, response, and quality of life. Results: Eight dogs (five CL, three HSA) completed the evaluable portion; two withdrew for reasons unrelated to treatment. Most CL cases enrolled to trial had relapsed disease after Adriamycin-based chemotherapy. Relapsed CL dogs showed stable disease to partial responses lasting up to five months, with improved quality of life and no evident toxicity. One treatment-naïve stage V CL dog showed rapid lymph node reduction and normalization of liver enzymes within 21 days before voluntary withdrawal. In HSA, two out of three splenectomised dogs remain recurrence-free beyond 150 days with good QoL. In all the enrolled patients, OXC-101 was found to be well tolerated, with no gastrointestinal side effects, no neutropenia/ Thrombocytopenia or any significant biochemical abnormalities. Conclusions: This pilot study shows that OXC-101 is safe and demonstrates early antitumor activity in relapsed CL and post-operative HSA. Given the close parallels between these canine cancers and their human counterparts-and ongoing human trials- these results strongly support further clinical development. OXC-101 may represent a promising new targeted therapy for both veterinary and human oncology.