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Phase I Study of Transforming Growth Factor-ß3 Mouthwashes for Prevention of Chemotherapy-induced Mucositis

Department of Internal Medicine, Divisions of Medical Oncology [A. N. M. W., W. T. A. v. d. G., L. S. H., H. T-B., N. H. M., E. G. E. d. V.] and Endocrinology [W. J. S.], Department of Oral and Maxillofacial Surgery [F. K. L. S.], and Department of Pathology [W. T.], University Hospital Groningen, 9700 RB Groningen; and Novartis Pharma, 6800 LZ Arnhem [A. H. J. A. M. v. B.], the Netherlands

The purpose of this study was to establish the safety and tolerability of recombinant transforming growth factor-ß3 (TGF-ß3; CGP 46614) mouthwashes intended for prevention of chemotherapy-induced mucositis. Local effects were especially analyzed by objective and subjective measurements of mucositis. Secondary aims were analysis of potential systemic exposure and development of anti-TGF-ß3-antibodies. Eleven breast cancer patients received chemotherapy with 1.5 g/m² cyclophosphamide i.v., 80 mg/m² epirubicin i.v., and 1.0 g/m² 5-fluorouracil i.v. (n = 8) or 1.6 g/m² carboplatin i.v., 480 mg/m² thiotepa i.v., and 6 g/m² cyclophosphamide i.v. divided over 4 days (n = 3). TGF-ß3 mouthwashes (10 ml; provided by Novartis, Basel, Switzerland) were administered for 4 days, four times a day, starting 1 day before chemotherapy. The dose was escalated in following patients from 25 µg/ml (n = 3) to 50 µg/ml (n = 3) and 100 µg/ml (n = 5). Clinically, the mucosa was scored objectively and according to WHO criteria. The percentage of viable oral epithelial cells was determined by trypan blue dye exclusion. Morphology of cells was assessed in buccal smears. Plasma samples were collected for determination of TGF-ß3 levels and anti-TGF-ß3-antibodies. Adverse events were recorded by the patient in a diary. Mouthwashes with TGF-ß3 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/m² cyclophosphamide i.v., 80 mg/m² epirubicin i.v., and 1.0 g/m² 5-fluorouracil i.v. was stable, whereas in patients treated with 1.6 g/m² carboplatin i.v., 480 mg/m² thiotepa i.v., and 6 g/m² cyclophosphamide i.v. divided over 4 days, an increase was observed. The morphology of buccal cells showed a transient shift from mature to immature cells in the first week. Neither systemic absorption of TGF-ß3 nor development of TGF-ß3-antibodies was observed. TGF-ß3 mouthwashes were well tolerated and deserve further study in preventing chemotherapy-induced mucositis.

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