Atezolizumab and BCG in High Risk BCG naïve Non-muscle Invasive Bladder Cancer (NMIBC) Patients (BladderGATE)

Summary

Patients with high-risk non-muscle invasive bladder cancer (NMIBC) are usually managed by transurethral resection of their bladder tumor (TURBT) alone plus additional intravesical therapy to deliver high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT. Although the exact mechanism of bacillus Calmette-Guerin (BCG) antitumor action is unknown, its intravesical instillation triggers a variety of local immune responses, which appear to correlate with antitumor activity. BCG induction plus maintenance is the current, guideline-recommended standard of care for high-risk NMIBC. Both recent evidence and guidelines suggest that full-dose BCG maintenance after the first BCG dose of induction course as used in the SWOG 8507 and European Organization for Research and Treatment of Cancer (EORTC) 30911 and 30962 trials, is the most appropriate maintenance schedule. High-risk NMIBC patients following adequate treatment have a recurrence rate at 1 and 2 years of 25 and 30% respectively after treatment with the current standard (BCG), which is clearly unsatisfactory. Programmed death ligand 1 (PD-L1) is a surface glycoprotein that functions as an inhibitor of T-cells and plays a crucial role in suppression of cellular immune response. It is implicated in tumor immune escape by inducing apoptosis of activated antigen-specific CD8 T-cells, impairing cytokine production and diminishing the toxicity of activated T-cells. PD-L1 expression by immunohistochemistry using the Ventana SP142 assay on tumor-infiltrating immune cell (IC) status defined by the percentage of PD-L1 positive ICs: IC0 (\<1%); IC1 (≥1% but\<5%); and IC2/3 (≥5%PD-L1) has been demonstrated to be higher (IC2/3) in resection and TURBT specimens versus biopsies from primary lesions or metastatic sites. In patients with metastatic bladder cancer, treatment with the PD-L1 inhibitor atezolizumab (1200 mg, every 3 weeks) resulted in objective response rates of 26% in the IC2/3 group, 18% in the IC1/2/3 group and 15% in all patients. The median overall survival was 11.4 months in the IC2/3 group, 8.8 months in the IC1/2/3, and 7.9 months in all patients. Grade 3-4 related treatment-related adverse events occurred in 16% and grade 3-4 immune-mediated adverse events occurred in 5% of treated patients. In murine models with invasive bladder cancer, anti-PD-1 plus CpG has shown to increase survival in mice, with anti-PD-1 plus CpG being superior to either agent alone. Taken together, these results confirmed the clinical activity of atezolizumab in metastatic bladder cancer, which could be beneficial in patients with NMIBC in combination with standard approaches such as BCG.

Conditions

• Invasive Bladder Cancer

Interventions

DRUG

Atezolizumab

1200 mg IV q3w until recurrence of disease, disease progression (e.g., muscle-invasive or metastatic UBC), symptomatic deterioration (i.e., uncontrollable pain secondary to disease or unmanageable ascites, etc.) attributed to disease progression as determined by the investigator, Intolerable toxicity related to atezolizumab, including development of an immune-mediated adverse event determined by the investigator to be unacceptable given the individual patient's potential response to therapy and severity of the event, any medical condition that may jeopardize the patient's safety if he or she continues on study treatment, use of another non-protocol anti-cancer therapy or pregnancy.

DRUG

BCG

1 or 1/2 instillation per week until recurrence of disease, disease progression (e.g., muscle-invasive or metastatic UBC), symptomatic deterioration (i.e., uncontrollable pain secondary to disease or unmanageable ascites, etc.) attributed to disease progression as determined by the investigator, Intolerable toxicity related to atezolizumab, including development of an immune-mediated adverse event determined by the investigator to be unacceptable given the individual patient's potential response to therapy and severity of the event, any medical condition that may jeopardize the patient's safety if he or she continues on study treatment, use of another non-protocol anti-cancer therapy or pregnancy.

Sponsors & Collaborators

• Apices Soluciones S.L.

  collaborator INDUSTRY

• Fundacion Oncosur

  lead NETWORK

Principal Investigators

• Daniel Castellano, MD · Hospital 12 de Octubre

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-02-03

Primary Completion

2024-06-30

Completion

2024-09-30

Countries

• Spain

Study Locations