A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II TRIAL TO EVALUATE THE IMMUNOMODULATORY EFFECT OF RUTI® IN INDIVIDUALS WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) TREATED WITH INTRAVESICAL BACILLUS CALMETTE-GUÉRIN (BCG)

INTERVENTION: Product Name: RUTI Pharmaceutical Form: Suspension for injection INN or Proposed INN: RUTI Current Sponsor code: RUTI Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 66.7‐ Pharmaceutical form of the placebo: Injection Route of administration of the placebo: Subcutaneous use CONDITION: High‐Risk Non‐Muscle‐Invasive Bladder Cancer ; MedDRA version: 19.0 Level: PT Classification code 10005003 Term: Bladder cancer System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] SECONDARY OUTCOME: Secondary end point(s): • Recurrence date.; • Disease worsening.; • Death date.; • Safety of RUTI® .: ; o Proportion of patients who develop a Grade 3 or 4 local reactions. ; o Proportion of patients who develop a Grade 3 or 4 systemic reactions.; o A descriptive summary of any local and systemic events, including severity, durability and relationship to study product. Timepoint(s) of evaluation of this end point: From baseline to end‐of‐study. INCLUSION CRITERIA: 1. Written ICF for participation in the study. 2. Age =18 years. 3. General health status according to WHO = 2. 4. Have primary histologically confirmed T1 and/or high grade tumors and/or CIS. 5. All visible papillary tumors must be completely resected. 6. Early postoperative (within 24 hours of TURBT) single dose chemotherapy is allowed. 7. BCG therapy indication. 8. Never treated with BCG immunotherapy 9. Willing to comply with study visits and procedures as per protocol 10. Use of reliable contraception (see section 8.6) from the screening visit to 30 days after the last RUTI® or placebo injection. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40 PRIMARY OUTCOME: Main Objective: To evaluate the systemic and mucosal immunological response of RUTI® administration prior to intravesical BCG therapy in individuals with high‐risk NMIBC. ; Immunological changes will be evaluated after completion of intravesical BCG therapy. Primary end point(s): • Changes in the systemic Th1 immune response will be evaluated as:; o IFN‐? production assessed by ELISPOT after ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with PPD.; o IFN‐? and IL‐2 production assessed by intracellular staining after ex vivo stimulation of PBMCs with PPD.; o IFN‐? secretion after long‐term stimulation of whole blood assessed by ELISA after stimulation with PPD.; ; • Changes in the local Th1/Th2 immune response.; o Th‐1 (T‐bet+) and Th2 (GATA‐3+) cells present in the peritumoral tissue in samples from TURBT and after the induction course (VISIT1). ; o Urine levels of IL‐2, IL‐8, IL‐6, IL‐1RA, IL‐10, IL‐12 (p70), and TRAIL by LUMINEX. Secondary Objective: • To determine the efficacy of RUTI® administration prior to intravesical BCG therapy in individuals with high‐risk NMIBC at 12, 24 and 36 months after randomization in terms of:; ‐ Recurrence rate; ‐ Disease worsening; ‐ Overall survival; • To analyze the correlation of rates of recurrence with systemic and local immunological changes.; • To evaluate the safety and tolerability of RUTI® in individuals with high‐risk NMIBC. Timepoint(s) of evaluation of this end point: • Changes in the systemic Th1 immune response will assessed in RUTI1, RUTI2, BCG1, BCG6 and BCG12 samples. Depending on the results further assessment will be performed in BCG9 and BCG15 samples. ; ; • Changes in the local Th1/Th2 immune response:; o Th‐1 (T‐bet+) and Th2 (GATA‐3+) cells present in the peritumoral tissue in samples from TURBT and after the induction course (VISIT1). ; o Urine parameters will be assessed in samples from RUTI1, RUTI2, BCG1, BCG6, VISIT1 and BCG12. Depending on the results, further assessment will be performed in BCG9 and BCG15 samples.