Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: Potential role as mucosal protectant

Purpose: To evaluate the safety of recombinant human keratinocyte growth factor (KGF) when administered with fluorouracil (FU) in patients with metastatic colorectal cancer. Patients and Methods: Patients (N = 81) received KGF by intravenous (IV) bolus on days 1 to 3, followed by FU 425 mg/m(2)/d IV bolus plus leucovorin 20 mg/m(2)/d IV on days 4 to 8. KGF dose levels were 1, 10, 20, 40, 60, and 80 mug/kg/d. A randomized, placebo-controlled design was employed (2:1 randomization of KGF to placebo). Oral mucositis was assessed by examination on days 1, 4, 8, 15, and 28. In addition, patients provided daily assessments of oral symptoms using a self-administered questionnaire. Results: Skin and oral events occurred in 13 of 18 patients (eight patients, grade 1; four patients, grade 2; and one patient, grade 3) treated with 60 and 80 mug/kg of KGF and three of 1 1 patients treated with 40 mug/kg (grade 1). These symptoms were dose limiting in three cases (ie, in two of 10 patients treated with 80 mug/kg and in one of eight patients treated with 60 mug/kg). The frequency of grade 2 to 4 mucositis was 43% in patients treated with KGF, compared with 67% in patients treated with placebo (P = .06). Patient self-assessments of oral pain and clinical assessments of mucositis showed good correlation (Kendall's tau = 0.75). Conclusion: KGF is generally well tolerated when administered IV at doses up to 40 wg/kg/d for 3 days before a 5-day course of FU plus leucovorin. A clinically meaningful biologic effect was also suggested in that patients treated with the epithelial growth factor KGF had a lower rate of grade 2 to 4 mucositis than did patients treated with placebo. (C) 2003 by American Society of Clinical Oncology.