A Randomised, Double-Blind, Placebo Controlled, Multicentre Trial of ATL-104, a Swallowable Mouthwash, in Patients with Oral Mucositis Following Peripheral Blood Stem Cell Transplantion (PBSCT).

Abstract

Mucositis is a serious complication of PBSCT. ATL-104 is a recombinant protein, the L-form of phytohaemagglutinin, a potent mitogenic for epithelial cells of the GI tract, resistant to acid and protease degradation. A prospective, pilot study was conducted to assess the effect of ATL-104 on mucositis in patients receiving high dose melphalan (66%) or BEAM (34%) before an autologous PBSCT. Each dose consisted of 15mL of solution containing 50, 100, or 150mg ATL-104 or placebo. For 3 days prior to chemotherapy and for 3 days following transplantation patients swilled the solution in the mouth for 15–30 seconds and then swallowed. Assessments were made for 28 days following dosing or until discharge, for pain, ulceration and the other factors which contribute to the WHO (World Health Organisation) or WCCNR (Western Consortium Cancer Research Nurses) mucositis scales. The first part of the study used a dose ascending design, commencing with 50 mg ATL-104, with patients randomised 3:1, active:placebo. A safety review was performed after 8 patients at each dose. After completion of the 150 mg cohort, a randomised parallel arm design with all doses and placebo was used (1:1:1:1). In total, 63 patients (46 M, 17 F) were treated; 15/16 patients in each group; 54 received all six doses and were fully assessed. ATL-104 at all doses produced a consistent reduction in duration of all grades of oral mucositis, compared to placebo (no statistical significance testing planned). For WHO grades 3–4, the reduction was 4.4, 4.2 and 3.4 days for ATL-104 50mg, 100mg and 150mg respectively, a fall of between 51%–64%, compared with placebo. There were also reductions in the duration of mucositis on the WCCNR scale. There was a reduction in the duration of ulceration scored 1–4, of 2.7, 0.8 and 2.4 days for ATL-104 50mg, 100mg and 150mg respectively, a fall of between 15–43% compared to placebo. No clear effect of ATL-104 on the incidence of mucositis or patients perception of pain was apparent. ATL-104 was well tolerated at all doses. Conclusion: ATL-104 warrants further investigation in larger, randomised, clinical trials.PlaceboATL-104 50 mgATL104 100mgATL-104 150 mgIncidence WHO Grades 3–4 Mucositis (%)50463167Duration WHO Grades 3–4 Mucositis (days/SD)6.7 (1.5)2.3 (1.5)2.5 (1.7)3.3 (1.7)Incidence WHO Grades 2–4 Mucositis (%)71627767Duration WHO Grades 2–4 Mucositis (days/SD)6.9 (4.0)4.0 (2.3)4.9 (3.6)4.8 (4.5)Incidence WCCNR Grades 2–3 Mucositis (%)93928593Duration WCCNR Grades 2–3 Mucosits (days/SD)11.6 (5.3)8.2 (4.7)8.1 (4.0)7.8 (2.5)Incidence of Mouth Ulcers Scored 1–4 (%)71626268Duration Mouth Ulcers Scored 1–4 (days/SD)6.3 (4.2)3.6 (2.5)5.5 (3.8)3.9 (2.1)Incidence Pain/Soreness 1–10 (%)77537783Duration Pain/Soreness 1–10 (days/SD)7.4 (4.4)7.0 (3.9)5.3 (3.4)6.4 (3.4)