J. van der Sar

PURPOSE: We studied the safety and tolerability of telatinib, an orally available, small-molecule tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR-2/VEGFR-3), platelet-derived growth factor receptor beta, and c-Kit in combination with capecitabine and irinotecan. EXPERIMENTAL DESIGN: Telatinib twice daily continuously, irinotecan once every 3 weeks, and capecitabine oral twice daily on day 1 to 14 were administered in cycles of 21 days in escalating doses in successive cohorts. Toxicity was evaluated to conform to the Common Terminology Criteria for Adverse Events version 3.0. Pharmacokinetic and (circulating) endothelial (progenitor) cell measurements were done. Tumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty-three patients were included in this phase I trial. Most frequently (>25%) reported adverse events of any grade were vomiting, nausea, fatigue, diarrhea, alopecia, and hand-foot syndrome. A silent myocardial infarction and two cases of decreased left ventricular ejection fraction were reported; both were reversible. Cardiac monitoring of the subsequent patients did not reveal other abnormalities. The study was terminated when the recommended single agent phase II doses of telatinib (900 mg twice daily) and capecitabine/irinotecan was reached. Pharmacokinetic profiles showed no clinically relevant changes upon coadministration of the three drugs. (Circulating) endothelial (progenitor) cell levels stabilized during treatment. Five of 23 patients had partial remission and 9 of 23 patients showed stable disease. CONCLUSIONS: Continuous administration of 900 mg telatinib twice daily can be safely combined with irinotecan (180 mg/m(2)) and capecitabine (1,000 mg/m(2) twice daily, day 1-14) and is the recommended schedule for further phase II studies. Tumor shrinkage and disease stabilization was observed. Cardiac toxicity needs further investigation in following studies.

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