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

Primary Purpose

Invasive Bladder Cancer

Status

Active

Phase

Phase 1

Locations

Spain

Study Type

Interventional

Intervention

Atezolizumab

BCG

About this trial

This is an interventional treatment trial for Invasive Bladder Cancer focused on measuring non-muscle, bladder cancer, näive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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
Allergy or hypersensitivity to components of the atezolizumab or BCG formulation
Prior allogeneic stem cell or solid organ transplantation
History of idiopathic pulmonary fibrosis, organizing pneumonia , drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
Serum albumin < 2.5 g/dL
Severe infections within 4 weeks prior to the first dose of study treatment
Signs or symptoms of infection within 2 weeks prior to the first dose of study treatment
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to the first dose of study treatment
Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina
Major surgical procedure other than for diagnosis within 4 weeks prior to the first dose of study treatment, or anticipation of need for a major surgical procedure during the course of the study
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
History of prior systemic BCG infection

Sites / Locations

Hospital 12 de Octubre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Atezolizumab + BCG

Arm Description

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)

Outcomes

Primary Outcome Measures

Dose limiting toxicity (DLT)

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

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

Secondary Outcome Measures

Incidence of Treatment-Emergent Adverse Events

Incidence of Adverse Events (AEs) per patient

Patient reported outcome

The change from baseline in patient-reported symptoms, function, and Health-related quality of life (HRQoL), as measured by the EORTC Quality of Life Questionnaire (QLQ)-C30.

Patient reported outcome

The change from baseline in patient-reported symptoms, function, and HRQoL, as measured by the EORTC Quality of Life Questionnaire (QLQ)-NMIBC24

Full Information

NCT ID

NCT04134000

First Posted

October 16, 2019

Last Updated

February 6, 2023

Sponsor

Fundacion Oncosur

Collaborators

Apices Soluciones S.L.

1. Study Identification

Unique Protocol Identification Number

NCT04134000

Brief Title

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

Acronym

BladderGATE

Official Title

Phase Ib Trial of Atezolizumab and BCG in High Risk BCG naïve Non-muscle Invasive Bladder Cancer (NMIBC) Patients: BladderGATE Study

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

February 3, 2020 (Actual)

Primary Completion Date

February 2024 (Anticipated)

Study Completion Date

February 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Fundacion Oncosur

Collaborators

Apices Soluciones S.L.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Invasive Bladder Cancer

Keywords

non-muscle, bladder cancer, näive

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Model Description

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

Masking

None (Open Label)

Allocation

N/A

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Atezolizumab + BCG

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Atezolizumab

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

BCG

Intervention Description

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.

Primary Outcome Measure Information:

Title

Dose limiting toxicity (DLT)

Description

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

Time Frame

Up to 24 months

Title

Recurrence free survival.

Description

Time Frame

Up to 24 months

Secondary Outcome Measure Information:

Title

Incidence of Treatment-Emergent Adverse Events

Description

Incidence of Adverse Events (AEs) per patient

Time Frame

Up to 24 months

Title

Patient reported outcome

Description

The change from baseline in patient-reported symptoms, function, and Health-related quality of life (HRQoL), as measured by the EORTC Quality of Life Questionnaire (QLQ)-C30.

Time Frame

Up to 24 months

Title

Patient reported outcome

Description

The change from baseline in patient-reported symptoms, function, and HRQoL, as measured by the EORTC Quality of Life Questionnaire (QLQ)-NMIBC24

Time Frame

Up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: 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 Allergy or hypersensitivity to components of the atezolizumab or BCG formulation Prior allogeneic stem cell or solid organ transplantation History of idiopathic pulmonary fibrosis, organizing pneumonia , drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. Serum albumin < 2.5 g/dL Severe infections within 4 weeks prior to the first dose of study treatment Signs or symptoms of infection within 2 weeks prior to the first dose of study treatment Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to the first dose of study treatment Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina Major surgical procedure other than for diagnosis within 4 weeks prior to the first dose of study treatment, or anticipation of need for a major surgical procedure during the course of the study Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications History of prior systemic BCG infection

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel Castellano, MD

Organizational Affiliation

Hospital 12 de Octubre

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hospital 12 de Octubre

City

Madrid

Country

Spain

12. IPD Sharing Statement

Learn more about this trial

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

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