A multicenter phase II study of TSU-68, a novel oral multiple tyrosine kinase inhibitor, in patients with metastatic breast cancer progressing despite prior treatment with an anthracycline-containing regimen and taxane.

PURPOSE: TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor and fibroblast growth factor receptor. TSU-68 demonstrated a strong anti-tumor effect against established human breast cancer xenografts in nude mice without apparent toxicity. We conducted a phase II study to evaluate the efficacy and safety of TSU-68 monotherapy in patients with metastatic breast cancer progressing despite prior treatment with an anthracycline-containing regimen and taxane.
METHODS: TSU-68 was administered daily at a dose of 400 mg twice a day after meals in 20 patients. The primary endpoint was objective overall response rate according to the Response Evaluation Criteria in Solid Tumors guideline version 1.0. Secondary endpoints included clinical benefit rate (complete response, partial response and stable disease lasting for at least 24 weeks), exploratory assessments of change in mRNA levels of biological markers associated with angiogenesis in tumor tissue at the end of Cycle 1, and safety of TSU-68.
RESULTS: Twenty patients were enrolled into the study from October 2002 through April 2003. TSU-68 monotherapy produced objective overall response in none of the patients; however, clinical benefit was seen in 5 % of the patients. The mRNA levels of CD31, Flt-1 and Flk-1/KDR showed a decreasing trend in all 4 patients who provided additional written informed consent for collection of tumor tissue. However, no significant difference was observed in the change in mRNA level due to the small sample size. The most common adverse drug reaction (ADR) was tumor pain (60 %); hematological ADRs rarely occurred, and they were mild in severity. Only one patient experienced grade 2 rash and no patient experienced hypertension. No patients experienced a grade 4 ADR and no episode of death related to the study treatment occurred in the 20 patients.
CONCLUSIONS: TSU-68 monotherapy produced clinical benefit in only 5 % of the patients and did not produce objective overall response; however, the treatment was well tolerated. Further evaluation of the efficacy of TSU-68 will be worthwhile because the mRNA levels of CD31, Flt-1 and Flk-1/KDR decreased in 4 patients.