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Bladder PREserVation by RadioTherapy and Immunotherapy in BCG Unresponsive Non-muscle Invasive Bladder Cancer (PREVERT)

Primary Purpose

Non-muscle-invasive Bladder Cancer

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Avelumab

Radiotherapy

About this trial

This is an interventional treatment trial for Non-muscle-invasive Bladder Cancer focused on measuring non-muscle-invasive bladder cancer, radiotherapy, immunotherapy, quality of life

Eligibility Criteria

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

Inclusion Criteria:

Age ≥18 years.
ECOG performance status ≤2.
Patients having provided written informed consent prior to any study-related procedures.
Life expectancy ≥ 12 months.
High risk NMIBC (high grade, T1, or CIS) histologically confirmed by a systematic 2nd look complete re-TURBT.
BCG unresponsive NMIBC defined as persistent high-grade disease at 6 months despite adequate BCG treatment (BCG refractory) or recurrence of high-grade disease within 6 months of the last BCG exposure (BCG relapsing disease).
Inclusion within 9 months after last BCG exposure.
Patient unfit for radical cystectomy because of age, comorbidities, or patient's refusal.
No sign of pelvic involvement or distant metastasis on CT scan.
Haematological and biological parameters allowing pelvic radiotherapy and anti-PDL1 administration:
- White blood cell count ≥4000/mm3
- Platelet count ≥100000 cells/mm3
- Haemoglobin level ≥9 g/dL or corrected after transfusion
- Glomerular filtration rate ≥25 mL/min.
- Adequate hepatic function: AST (SGOT) and ALT (SGPT) ≤2.5 x ULN, or ≤3.5 x ULN in the case of concurrent disease with known etiology and for which a corrective treatment is possible.
Patients of childbearing potential: use of a medically acceptable method of contraception during the study and for 120 days after the last study treatment.
Patients affiliated to the social security scheme.
Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.

Exclusion Criteria:

Stage ≥pT2 tumors.
Low grade recurrence / Ta recurrence after BCG therapy.
Recurrence > 1 year after last BCG instillation.
Prior pelvic irradiation.
Histology other than urothelial or squamous cell carcinomas (e.g., adenocarcinomas, micropapillary, sarcomas, or small cell histological types).
History of neoplastic disease, during the 3 years before registration, except completely resected cutaneous basal-cell carcinomas, carcinoma in-situ or localized prostate cancer without biochemical recurrence following definitive treatment.
Prior treatment with CD137 agonists or immune checkpoint inhibitors, including anticytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4), anti-programmed death-1 receptor (anti-PD-1), and anti-programmed death-ligand 1 (anti-PD-L1) therapeutic antibodies.
Contraindications for pelvic radiotherapy (e.g., inflammatory bowel disease).

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Radiotherapy associated to immunotherapy

Arm Description

Radiotherapy: 60-66 Gy in 30-33 Fractions (2 Gy/fractions) given to the whole bladder Concomitant administration of Avelumab 10mg/kg Infuse IV over 30-minutes: 1 cycle 5 days before External Beam RadioTherapy, then every 21 days x 8 cycles (6 months)

Outcomes

Primary Outcome Measures

High-risk recurrence-free survival at 1 year

Delay between date of inclusion and reappearance of high-risk disease (high grade, T1, or CIS) at cystoscopy

Secondary Outcome Measures

Full Information

NCT ID

NCT03950362

First Posted

May 13, 2019

Last Updated

May 14, 2019

Sponsor

Institut Paoli-Calmettes

1. Study Identification

Unique Protocol Identification Number

NCT03950362

Brief Title

Bladder PREserVation by RadioTherapy and Immunotherapy in BCG Unresponsive Non-muscle Invasive Bladder Cancer

Acronym

PREVERT

Official Title

Bladder PREserVation by RadioTherapy and Immunotherapy in BCG Unresponsive Non-muscle Invasive Bladder Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

May 2019

Overall Recruitment Status

Not yet recruiting

Study Start Date

June 15, 2020 (Anticipated)

Primary Completion Date

June 15, 2023 (Anticipated)

Study Completion Date

June 15, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institut Paoli-Calmettes

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

About two-thirds of newly diagnosed cases of bladder cancer are non-muscle-invasive bladder cancer (NMIBC). It is advocated that patients with high-risk NMIBC receive an adjuvant course of intravesical Bacille Calmette-Guerin (BCG) as first-line treatment. However, a substantial proportion of patients will 'fail' BCG. Radical cystectomy remains the treatment of choice for NMIBC who have failed intravesical therapy, but there are situations when surgery is not feasible due to competing co-morbidities or a patient's desire for bladder preservation. For these patients, the potential options available are limited. In MIBC, radiotherapy (RT) in association with chemotherapy, has been shown to produce 10-year overall survival rates comparable to those of radical cystectomy in selected cases. At the opposite, results from trials assessing radiotherapy with or without chemotherapy in patients with NMIBC are less documented and discordant. Immunotherapy with immune-checkpoint blockade therapies is increasing as an option and has shown very promising results for several cancers, including bladder carcinoma. An established body of published work has shown that radiation enhances many of the steps needed for the generation of antigen-specific immune responses, including inflammatory tumor-cell death, dendritic cell activation, and antigen cross-presentation. Several groups have reported improved local control when checkpoint blockade immunotherapy is added to radiation in different tumor types. On the one hand, radiotherapy might stimulate the induction of local endogenous immune responses by anti-PD-1 treatment. On the other hand, active immune stimulation by anti-PD-1 treatment within the tumor microenvironment might maximize radiation-induced antitumor immunity. Combination immunoradiotherapy using PD-1/PD-L1 signaling blockade could therefore offer an interesting strategy in bladder tumors, especially as an optional bladder preservation treatment for BCG unresponsive NMIBC. The originality of the therapeutic strategy is the use of radiation (local treatment) combined with checkpoint blockade immunotherapy (systemic treatment). Radiotherapy might increase response rates by creating a more permissive tumor microenvironment through increasing PD-L1 expression on tumor cells and stimulating the accumulation and activation of CD8+ T cells. Avelumab seems to have a specific cytotoxic activity suggesting its interest in local control of the disease, especially in association with radiotherapy.

6. Conditions and Keywords

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

Non-muscle-invasive Bladder Cancer

Keywords

non-muscle-invasive bladder cancer, radiotherapy, immunotherapy, quality of life

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

67 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Radiotherapy associated to immunotherapy

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Avelumab

Intervention Description

Administration of Avelumab 10mg/kg Infuse IV over 30-minutes: 1 cycle 5 days before External Beam RadioTherapy, then every 21 days x 8 cycles (6 months)

Intervention Type

Device

Intervention Name(s)

Radiotherapy

Intervention Description

60-66 Gy in 30-33 Fractions (2 Gy/fractions) given to the whole bladder

Primary Outcome Measure Information:

Title

High-risk recurrence-free survival at 1 year

Description

Delay between date of inclusion and reappearance of high-risk disease (high grade, T1, or CIS) at cystoscopy

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age ≥18 years. ECOG performance status ≤2. Patients having provided written informed consent prior to any study-related procedures. Life expectancy ≥ 12 months. High risk NMIBC (high grade, T1, or CIS) histologically confirmed by a systematic 2nd look complete re-TURBT. BCG unresponsive NMIBC defined as persistent high-grade disease at 6 months despite adequate BCG treatment (BCG refractory) or recurrence of high-grade disease within 6 months of the last BCG exposure (BCG relapsing disease). Inclusion within 9 months after last BCG exposure. Patient unfit for radical cystectomy because of age, comorbidities, or patient's refusal. No sign of pelvic involvement or distant metastasis on CT scan. Haematological and biological parameters allowing pelvic radiotherapy and anti-PDL1 administration: White blood cell count ≥4000/mm3 Platelet count ≥100000 cells/mm3 Haemoglobin level ≥9 g/dL or corrected after transfusion Glomerular filtration rate ≥25 mL/min. Adequate hepatic function: AST (SGOT) and ALT (SGPT) ≤2.5 x ULN, or ≤3.5 x ULN in the case of concurrent disease with known etiology and for which a corrective treatment is possible. Patients of childbearing potential: use of a medically acceptable method of contraception during the study and for 120 days after the last study treatment. Patients affiliated to the social security scheme. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol. Exclusion Criteria: Stage ≥pT2 tumors. Low grade recurrence / Ta recurrence after BCG therapy. Recurrence > 1 year after last BCG instillation. Prior pelvic irradiation. Histology other than urothelial or squamous cell carcinomas (e.g., adenocarcinomas, micropapillary, sarcomas, or small cell histological types). History of neoplastic disease, during the 3 years before registration, except completely resected cutaneous basal-cell carcinomas, carcinoma in-situ or localized prostate cancer without biochemical recurrence following definitive treatment. Prior treatment with CD137 agonists or immune checkpoint inhibitors, including anticytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4), anti-programmed death-1 receptor (anti-PD-1), and anti-programmed death-ligand 1 (anti-PD-L1) therapeutic antibodies. Contraindications for pelvic radiotherapy (e.g., inflammatory bowel disease).

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Dominique Genre, MD

Phone

+33491223778

drci.up@ipc.unicancer.fr

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Bladder PREserVation by RadioTherapy and Immunotherapy in BCG Unresponsive Non-muscle Invasive Bladder Cancer

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