RUTIVAC-1 study: A randomized, double-blind, placebo-controlled phase I trial to evaluate the immunomodulatory effect of RUTI in individuals with high-risk non-muscle-invasive bladder cancer treated with intravesical BCG

BackgroundDespite standard-of-care therapy with transurethral resection of bladder tumor and intravesical BCG instillation, a large percentage of patients (pts) with non-muscle invasive bladder cancer (NMIBC) have disease recurrence/progression. Thus, novel combination therapies are needed to improve BCG efficacy. RUTI® consists in cell wall nanofragments of Mycobacterium tuberculosis strain RUTI in a liposomal suspension. RUTIVAC-1 (NCT03191578) is a randomized, double-blind, placebo-controlled Phase I trial designed to evaluate the use of RUTI® as a heterologous prime-boost strategy in NMIBC pts.MethodsHigh-grade, BCG-naïve NMIBC pts were randomized 1:1 to receive two subcutaneous doses of either placebo or RUTI® (25 μg) before BCG. Primary endpoint: immunological changes after RUTI® vaccination (assessed by flow cytometry). Secondary endpoints: efficacy (rates of recurrence and progression) and safety at 3 years.ResultsForty pts were randomized to placebo or RUTI® (n=20 each). Baseline characteristics were similar in both groups (median age 70 years, 90% male, high-grade T1 65% and Ta 32.5%; 4% CIS). RUTI® induced a vaccine-specific T cell response with a sustained increase over time of specific effector CD4 and CD8 T-cells coexpressing several activation markers. Placebo group showed skewed CD4+CD25+ T cell upregulation whereas RUTI® group displayed a more balance, polyfunctional response (increased CD25+, CD137+, OX40+ and CD69+ CD4 T cells). Over a 3-year follow-up period, 15%, (3 pts/group) experienced recurrence and 5% (2 pts, both in the placebo group) progressed (median time to progression 16.6 months). The median time to recurrence appeared shorter in placebo (3.9 months) vs RUTI® (13.1 months). RUTI® was safe and well tolerated (2 grade 1 injection site reactions in the RUTI® group).ConclusionsRUTI® vaccination before intravesical BCG treatment in high-risk NMIBC pts is safe, very well tolerated, and significantly impacts immune response. This modulation might be associated with the extended disease-free survival seen in the RUTI® vaccinated pts.Clinical trial identificationNCT03191578; EudraCT 2016-004311-12.Legal entity responsible for the studyArchivel Farma.FundingArchivel Farma.DisclosureM. Amat: Financial Interests, Institutional, Full or part-time Employment: Archivel Farma. All other authors have declared no conflicts of interest.