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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-muscle-invasive Bladder Cancer
• Intervention / Treatment: Drug: Avelumab; Device: Radiotherapy

• Study Type: Interventional
• Enrollment (Anticipated): 67
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Radiotherapy associated to immunotherapy; 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)	Drug: Avelumab; 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); Device: Radiotherapy; 60-66 Gy in 30-33 Fractions (2 Gy/fractions) given to the whole bladder

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	1 year

Collaborators and Investigators

• Sponsor: Institut Paoli-Calmettes

Study record dates

Study Major Dates

• Study Start (Anticipated): June 15, 2020
• Primary Completion (Anticipated): June 15, 2023
• Study Completion (Anticipated): June 15, 2024

Study Registration Dates

• First Submitted: May 13, 2019
• First Submitted That Met QC Criteria: May 13, 2019
• First Posted (Actual): May 15, 2019

Study Record Updates

• Last Update Posted (Actual): May 16, 2019
• Last Update Submitted That Met QC Criteria: May 14, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: immunotherapy; quality of life; radiotherapy; non-muscle-invasive bladder cancer
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Avelumab
• Other Study ID Numbers: prevert-IPC 2018-046

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No