Phase I study of transforming growth factor-beta 3 mouthwashes for prevention of chemotherapy-induced mucositis

The purpose of this study was to establish the safety and tolerability of r ecombinant transforming growth factor-beta 3 (TGF-beta 3; CGP 46614) mouthw ashes intended for prevention of chemotherapy-induced mucositis. Local effe cts were especially analyzed by objective and subjective measurements of mu cositis. Secondary aims were analysis of potential systemic exposure and de velopment of anti-TGF-beta 3-antibodies. Eleven breast cancer patients rece ived chemotherapy with 1.5 g/m(2) cyclophosphamide i.v., 80 mg/m(2) epirubi cin i.v., and 1.0 g/m(2) 5-fluorouracil i.v. (n = 8) or 1.6 g/m(2) carbopla tin i.v., 480 mg/m(2) thiotepa i.v., and 6 g/m(2) cyclophosphamide i.v. div ided over 4 days (n = 3). TGF-beta 3 mouthwashes (10 mi; provided by Novart is, Basel, Switzerland) were administered for 4 days, four times a day, sta rting 1 day before chemotherapy. The dose was escalated in following patien ts from 25 mu g/ml (n = 3) to 50 mu g/ml (n = 3) and 100 mu g/ml (n = 5). C linically, the mucosa was scored objectively and according to WHO criteria. The percentage of viable oral epithelial cells was determined by trypan bl ue dye exclusion. Morphology of cells was assessed in buccal smears. Plasma samples were collected for determination of TGF-beta 3 levels and anti-TGP -beta 3-antibodies. Adverse events were recorded by the patient in a diary. Mouthwashes with TGF-beta 3 were well tolerated. Three patients scored for mucositis > grade 0 (WHO grading criteria). The percentage of viable oral epithelial cells in patients treated with 1.5 g/m(2) cyclophosphamide i.v., 80 mg/m(2) epirubicin i.v., and 1.0 g/m(2) 5-fluorouracil i.v. was stable, whereas in patients treated with 1.6 g/m(2) carboplatin i.v., 480 mg/m(2) thiotepa i.v., and 6 g/m(2) cyclophosphamide i.v. divided over 4 days, an i ncrease was observed. The morphology of buccal cells showed a transient shi ft from mature to immature cells in the first week. Neither systemic absorp tion of TGF-beta 3 nor development of TGF-beta 3-antibodies was observed. T GF-beta 3 mouthwashes were well tolerated and deserve further study in prev enting chemotherapy-induced mucositis.