Preoperative Bintrafusp Alfa in Operable Urothelial Carcinoma of the Bladder

NCT04878250 | Unknown Phase 2 DMC

• 1 other identifier: PEBBLE
• Study Type: interventional
• Target: 49
• Locations: 0 countries
• Sites: N/A

Brief Summary

PEBBLE is an open-label, international, multicentre, window of opportunity phase II trial that aims to evaluate the effects of short-term preoperative therapy with bintrafusp alfa in patients with histologically confirmed urothelial carcinoma requiring radical surgery with bilateral pelvic lymph node dissection. Eligible patients will receive 4 doses of bintrafusp alfa (1200mg flat dose) at 14 day intervals before undergoing radical surgery. Patients will attend study visits at 6, 12 and 24 weeks following their surgery. After the 24-week post-surgical visit, patients will enter a follow up phase during which they will be contacted annually for 2 years after their surgery to collect survival and disease status data. The efficacy of bintrafusp alfa will be assessed on CT/MRI scan images and tumour tissue samples collected at baseline and after treatment with bintrafusp alfa.

Conditions

Transitional Cell Carcinoma; Bladder Cancer

Outcome Measures

Primary Outcomes (1)

• Pathological complete response rate (pCRR)

  No microscopic evidence (pT0/Tis/Cis) of residual disease in the bladder based on histological evaluation of the resected bladder specimen collected during radical surgery

  Post - treatment with 4 cycles of bintrafusp alfa (1 cycle = 14 days)

Secondary Outcomes (4)

• Dynamic changes in TGFb, T-effector signatures and CD8 count measured in tumour samples.

  Pre - and post - treatment with 4 cycles of bintrafusp alfa (1 cycle = 14 days)

• Incidence, nature and severity of adverse events (AE) graded according to NCI-CTCAE v5.0

  From time of consent until the safety visit, an average of 22 weeks.

• Disease free survival (DFS) defined as time between the date of enrolment to first evidence of relapse based on local investigator assessments or death, whichever occurs first.

  Up to 2 years

• Overall survival (OS) defined as the time between the date of enrolment and death due to any cause.

  Up to 2 years

Study Arms (1)

Bintrafusp alfa

EXPERIMENTAL

Drug: Bintrafusp alfa

Interventions

Bintrafusp alfa DRUG

4 doses of bintrafusp alfa (1200mg flat dose) administered intravenously at 14 day intervals before undergoing radical cystectomy.

Bintrafusp alfa

Eligibility Criteria

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

You may qualify if:

• Willing and able to provide written informed consent
• Ability to comply with the protocol
• Age ≥ 18 years
• Histopathologically confirmed urothelial carcinoma (T2-T4aN0-1M0) of the bladder where radical cystectomy with bilateral pelvic lymph node dissection is indicated. Patients with "variant histology" such as micropapillary, plasmocytoid, nested, sarcomatoid, microcystic, squamous and adeno variants of urothelial carcinoma are required to have more than 50% of tumor tissue with transitional cell pattern.
• Residual disease after TURBT or endoscopy (surgical opinion, cystoscopy or radiological presence).
• Fit and planned for surgery (according to local guidelines).
• N0-1 and M0 disease CT or MRI (within 4 weeks of enrolment). Patients with N2 disease on cross sectional imaging are excluded from the study.
• Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing.
• Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Negative serum pregnancy test within 14 days of Day 1 Cycle 1 for female patients of childbearing potential.
• Highly effective method of contraception throughout the study until 2 months after the last dose of bintrafusp alfa for female patients of childbearing potential and 4 months after the last dose of bintrafusp alfa for male patients.
• Adequate haematologic and end-organ function within 4 weeks prior to the first study treatment.

You may not qualify if:

• Pregnant and lactating female patients.
• Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
• Previous intravenous chemotherapy or immune therapy for bladder cancer.
• Patients with prior allogeneic stem cell or solid organ transplantation.
• Prior treatment with CD137 agonists, anti-CTLA-4, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
• Has received any prior radiotherapy to the bladder.
• Patients must not have had oral or intravenous (IV) steroids for 14 days prior to Cycle 1 Day 1. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed at physiologic doses ≤ 10 mg/day of prednisone or equivalent.
• Received therapeutic IV antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible).
• Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study. Seasonal flu vaccines that do not contain a live virus are permitted.
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin \[IL\]-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.
• Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment.
• Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).
• Malignancies other than urothelial carcinoma of the bladder within 3 years prior to enrolment with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA \< 10 ng/mL undergoing active surveillance and treatment naive).
• Severe infections within 4 weeks prior to enrolment including but not limited to hospitalisation for complications of infection, bacteraemia, or severe pneumonia.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to enrolment, unstable arrhythmias, or unstable angina.

Sponsors & Collaborators

• Queen Mary University of London: lead

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms

Interventions

bintrafusp alfa protein, human

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Thomas Powles

  Queen Mary University of London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

PEBBLE Trial Coordinator

CONTACT

+44 (0) 2078828764; bci-pebble@qmul.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2021
• First Posted: May 7, 2021
• Study Start: June 1, 2021
• Primary Completion: July 1, 2023
• Study Completion: January 1, 2025
• Last Updated: May 7, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share