Randomized Phase I Trial of Recombinant Human Keratinocyte Growth Factor Plus Chemotherapy: Potential Role as Mucosal Protectant

• DOI: 10.1200/jco.2003.10.079
• Publication Date: 2003-04-15T23:15:17Z
• Authors: Neal J. Meropol; Robert A. Somer; John Gutheil; Robert J. Pelley; Manuel R. Modiano; Eric K. Rowinsky; Mace L. Rothenberg; Spencer W. Redding; Cuneyt M. Serdar; Bin Yao; Robert Heard; Lee S. Rosen
• Keywords: Adult; Aged, 80 and over; Male; Fibroblast Growth Factor 7; Mucous Membrane; Leucovorin; Lipase; Middle Aged; Recombinant Proteins; 3. Good health; Fibroblast Growth Factors; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Amylases; Antineoplastic Combined Chemotherapy Protocols; Humans; Female; Fluorouracil; Infusions, Intravenous; Aged

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/m2/d IV bolus plus leucovorin 20 mg/m2/d IV on days 4 to 8. KGF dose levels were 1, 10, 20, 40, 60, and 80 μg/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 μg/kg of KGF and three of 11 patients treated with 40 μg/kg (grade 1). These symptoms were dose limiting in three cases (ie, in two of 10 patients treated with 80 μg/kg and in one of eight patients treated with 60 μg/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 μg/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.