Phase I dose-escalation study of E7080, a selective tyrosine kinase inhibitor, administered orally to patients with solid tumors.

Abstract

2540 Background: E7080 is a potent, orally administered, receptor tyrosine kinase inhibitor of KDR, VEGFR1, VEGFR3, FGFR2, and RET. Antiangiogenic and antiproliferative activity were seen in human cancer xenograft models, suggesting that E7080 may be a promising anticancer agent. We report the MTD and DLT determination of E7080 administered in a continuous twice daily (bid) schedule. Methods: Escalating doses of E7080 ranging from 0.1 mg to 12 mg bid were studied in patients (pts) with advanced solid tumors. Tumor assessments were made after every two 28-day cycles, and responses investigator reported. Results: As of December 2009,77 pts (age range 28-85 yrs) have been treated with E7080 in this study for a mean of 6 cycles (range 1–35 cycles). DLTs occurred at the 12 mg bid dose level and consisted of grade 3 hypertension (HT), grade 3 fatigue, and failure to administer ≥75% of E7080 in the 1st cycle due to recurrent grade 2 proteinuria (PU). The MTD was determined to be 10 mg bid, and an expanded cohort of 26 pts with melanoma was treated at this dose level. The most frequent treatment-emergent adverse events (TEAE) were HT and PU (Table). Other ≥ grade 2 TEAEs were fatigue (30.7%), anorexia (19.2%), decreased weight (19.2%), diarrhea (11.5%) and dysphonia (7.7%). 43 pts were evaluable for response: 9 pts (21%) achieved a PR with 56% pts having clinical benefit (CB = PR + SD ≥6 months). PRs were observed in melanoma (n=3), endometrial (n=1), renal (n=1), thyroid (n=3), and islet cell (n=1) cancers. 9 pts with melanoma were ongoing in the expansion cohort at data cutoff, and 7 out of 17 evaluable melanoma pts achieved SD ≥6 months. Conclusions: The MTD of E7080 is 10 mg bid administered continuously in pts with advanced solid tumors. E7080 has manageable toxicities related mainly to VEGF inhibition. Antitumor activity was observed in melanoma, thyroid, endometrial, and renal cancer. These cancer types will be prospectively studied in clinical trials with E7080. Incidence of PU and HT: 10 mg bid cohort (n=26) Incidence of PU and HT: 10 mg bid cohort (n=26) CTC AE grade PU, n (%) HT, n (%) Total 15 (57.7) 13 (50.0) 1 7 (26.9) 0 (0.0) 2 5 (19.2) 9 (34.6) 3 2 (7.7) 4 (15.4) 4 1 (3.8) 0 (0.0) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai Eisai Eisai