Phase I Evaluation Of Telatinib, A Vegf Receptor Tyrosine Kinase Inhibitor, In Combination With Irinotecan And Capecitabine In Patients With Advanced Solid Tumors

2530 Background: Telatinib is an orally available, small molecule tyrosine kinase domain inhibitor of the VEGFR-2, VEGFR-3, PDGFR-β and c-Kit. We studied the feasibility of telatinib in combination with capecitabine and irinotecan in a phase I study. Methods: Telatinib (cohort 1 and 2: 300 mg bid; cohort 3: 600 mg bid; cohort 4; 900 mg bid continuously, day 1–21), irinotecan (cohort 1; 125 mg/m2 iv and cohort 2,3 and 4; 180 mg/m2 iv on day 1) and capecitabine (1,000 mg/m2 oral twice daily, day 1–14, all cohorts) were administered every three weeks in cohorts of at least 3 patients. Pharmacokinetic measurements were performed. Results: 17 patients (median age 60, range 40–71) with colon (6), gastric (2), pancreatic (1), small cell lung cancer (1) or other solid tumors (7) were included. The most frequently reported adverse events were (CTC grade I/II/III/all %) vomiting (29/18/6/53%), nausea (29/6/12/47%), fatigue (18/17/6/41%), diarhea (24/11/6/41%) and hand foot syndrome (18/23/0/41%). A silent myocardial infarction and a decreased LVEF CTC grade 3 were reported 9 weeks and 16 weeks after start of study treatment. The MTD was not reached at telatinib 900 mg bid, irinotecan 180 mg/m2, capecitabine 1000 mg/m2. The study was terminated when the advised dose of telatinib (900 mg bid), obtained in phase I single agent studies, was reached. Pharmacokinetic (PK) profiles of telatinib, irinotecan/SN 38, and capecitabine/5-FU were obtained on Day 1 of Cycle 1 (chemotherapy, without telatinib), Day 21 of Cycle 1 (telatinib without chemotherapy), and on Day 1 of Cycle 2 (telatinib with concomitant chemotherapy). No clinically relevant changes in exposure to telatinib, irinotecan, SN-38, capecitabine and 5-FU were observed upon coadministration of the 3 drugs. 3 out of 12 patients developed a PR and 6 out of 12 patients showed SD for at least 3 months. Conclusions: Preliminary data show that daily bid telatinib 900 mg can be safely combined with irinotecan (180 mg/m2 ) and capecitabine (1,000 mg/m2 oral twice daily, day 1–14). The observed tumor shrinkage and disease stabilization in various patients indicate preliminary activity of this combination. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer