A double-blind, 4-block randomized, placebo-controlled, adaptive phase 2/3 trial to confirm efficacy and safety of BLS-ILB-E710c in patients with cervical intraepithelial neoplasia 2/3 with extension study

초록

Objectives Current treatments for high-grade cervical intraepithelial neoplasia are ablative, so non-invasive treatments are needed as alternatives. For the development of alternative treatment, we designed an adaptive phase II/III trial to confirm the safety and efficacy of BLS-ILB-E710c, which is an orally administered agent expressing human papillomavirus (HPV) 16 E7 antigen on the surface of Lactobacillus casei in patients with cervical intraepithelial neoplasia 2 or 3 (CIN 2/3). Methods Safety and efficacy of BLS-ILB-E710c were assessed in CIN 2/3 associated with HPV16 in a double-blind, 4-block randomized, placebo-controlled, seamless two-part, adaptive phase II/III study. The adaptive phase II/III trial consisted of two parts: the optimal dose of BLS-ILB-E710c was determined based on the histopathological regression in phase II, and the efficacy of BLS-ILB-E710c was assessed in Phase III. Patients with CIN 2/3 aged between 20 and 49 years were enrolled at 13 academic gynecology practices in Korea and were randomized (2:1) to receive 1,000 mg BLS-ILB-E710c or placebo orally at 0, 1, 3, and 7 weeks. The primary endpoint was a regression to CIN1 or normal at 16 weeks after the first dose. The secondary endpoint included pathologic regression at 32 weeks as well as change in Reid's colposcopic index, expression of P16INK4a/Ki-67, CD8+, and persistence of HPV16 at 16 and 32 weeks. The safety was assessed by the occurrence of treatment-emergent adverse events (TEAE). The trial is registered at ClinicalTrials.gov (number NCT03274206). Results Between August 30, 2017, and April 24, 2020, 116 patients received either BLS-ILB-E710c (n = 76) or placebo (n = 40). In the analysis of pathologic regression rates at 16 weeks, 28 (38.36%) of 73 BLS-ILB-E710c recipients and 14 (36.84%) of placebo recipients showed regression (percentage point difference 1.51% [95% CI: −17.45-20.48], which was not significantly different. In subgroup analysis for the pathologic regression group at 16 weeks, the difference of CD8+ in cervical lesions was higher in BLS-ILB-E710c recipients (1.33 ± 0.92%) than placebo recipients (0.71 ± 0.39%) (P < 0.05). The occurrence of TEAE and adverse drug reactions was not different in both groups, while severe adverse events did not occur in both groups. Conclusions In the analysis of efficacy and safety of BLS-ILB-E710c for CIN 2/3 patients, the histopathologic remission rates at week 16, the primary efficacy endpoint, did not demonstrate superiority in the BLS-ILB-E710c group compared to the placebo group. In subgroup analysis, the rates of elimination of HPV16, the change of CD8+, and the rates of CIN3 regression at 32 weeks compared to 16 weeks were different. These results will have the expected efficacy when the evaluation period is extended, and the subject is specified.