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

NCT04134000 | Active Not Recruiting Phase 1

• 2 other identifiers: BladderGATE2019-002061-36
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

non-muscle; bladder cancer; näive

Outcome Measures

Primary Outcomes (2)

• Dose limiting toxicity (DLT)

  Incidence and nature of DLT of BCG plus atezolizumab combination in NMIBC, graded according to NCI CTCAE v5.

  Up to 24 months

• Recurrence free survival.

  Time from the date of start of treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression according to RECIST 1.1 as assessed by the Investigator

  Up to 24 months

Secondary Outcomes (3)

• Incidence of Treatment-Emergent Adverse Events

  Up to 24 months

• Patient reported outcome

  Up to 24 months

• Patient reported outcome

  Up to 24 months

Study Arms (1)

Atezolizumab + BCG

EXPERIMENTAL

Ten patient will be enrolled in first cohort, starting on level 0 (DL 0) receiving BCG 1 instillation per week and Atezolizumab 1200 mg IV every three weeks (q3w). The next level of dose in case is necessary is BCG 1/2 instillation per week and Atezolizumab 1200 mg IV every three weeks (q3w)

Drug: Atezolizumab; Drug: BCG

Interventions

Atezolizumab DRUG

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.

Atezolizumab + BCG

BCG DRUG

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.

Atezolizumab + BCG

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients ≥ 18 years old.
• Signed Informed Consent Form
• Histologically confirmed diagnosis of high risk non-muscle-invasive (T1, high grade Ta - G3- and / or carcinoma in situ) transitional cell carcinoma of the bladder
• Never treated with BCG or stopped \>3y ago
• World Health Organization Performance Status (WHO PS) 0-1
• No prior radiation to bladder
• Life expectancy ≥ 5 years
• Adequate hematologic and end-organ function
• The time elapsed between the TURBT and the start of the study treatment will not be less than 4 weeks or more than 12 weeks
• Women who are not postmenopausal or surgically sterile must have a negative serum pregnancy test result within 14 days prior to the first dose of study treatment.
• For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 150 days after the last dose of study drug.
• Tumor tissue biopsy at study entry or availability of an archival specimen obtained within 2 months of study screening
• Willingness to complete all study-related procedures including patient-reported questionnaires

You may not qualify if:

• Muscle-invasive, locally advanced non-resectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, and/or stage IV)
• Previous BCG within a 3 years period
• Life expectancy \<5 years
• WHO PS 2, 3 or 4
• Known additional malignancy that is progressing or requires active treatment
• Active autoimmune disease that has required systemic treatment in the past 2 years
• Evidence of interstitial lung disease or active non-infectious pneumonitis
• Active infection requiring systemic therapy
• Pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial through 150 days after the last dose of study treatment.
• Prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-ligand 2 (L2) agent, or with an agent directed to another co-inhibitory T-cell receptor
• Known human immunodeficiency virus (HIV)
• Known active Hepatitis B or C infection or tuberculosis
• Received a live virus vaccine within 30 days of planned start of study treatment
• Treatment with any approved anti-cancer therapy, including chemotherapy , radiation therapy , or hormonal therapy within 3 weeks prior to the first dose of study treatment
• Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to the first dose of study treatment

Sponsors & Collaborators

• Fundacion Oncosur: lead
• Apices Soluciones S.L.: collaborator

Study Sites (1)

Hospital 12 de Octubre

Madrid, Spain

Location

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

atezolizumab

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Daniel Castellano, MD

  Hospital 12 de Octubre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: open-label, non-randomized, dose de-escalation clinical trial with atezolizumab administered by IV infusion in combination with intravesical BCG.

Study Record Dates

• First Submitted: October 16, 2019
• First Posted: October 21, 2019
• Study Start: February 3, 2020
• Primary Completion: June 1, 2024
• Study Completion: September 1, 2024
• Last Updated: May 21, 2024

Record last verified: 2024-05

Locations

ES (1)