CETRELIMAB for Muscle-invasive bladder cancer (Muscle-Invasive Urothelial Carcinoma of the Bladder)

Inclusion criteria

• {"criterion_text":"- ≥18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.\n- Participants must be willing and able to adhere to the lifestyle restrictions specified in this protocol\n- Histologically proven, cT2-T4a N0, M0 urothelial carcinoma of the bladder. Initial diagnosis must have been within 120 days of randomization date. Participants with variant histologic subtypes (e.g. squamous cell carcinoma) are allowed if urothelial (transitional cell) differentiation is predominant. However, the presence of small cell or neuroendocrine variants will make a participant ineligible.\n- Ineligible for or have elected not to undergo radical cystectomy.\n- All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade ≤ 2 prior to randomization\n- Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2\n- Thyroid function tests are within the normal range per investigator assessment (or stable on hormone supplementation). Investigators may consult an endocrinologist for participant eligibility assessment in the case of equivocal or marginal test results\n- Adequate bone marrow, liver, and renal function: a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding 2 weeks): i. Absolute neutrophil count (ANC) ≥ 1,500/mm^3 ii. Platelet count ≥80,000/mm^3 iii. Hemoglobin ≥9.0 g/dL b. Liver function: i. Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5xULN (except participants with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dL), ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x institutional ULN c. Renal function: Creatinine clearance ≥30 mL/min using the CockcroftGault formula. 24-hour creatinine clearance test will also be accepted for estimating renal function in situations where Cockcroft-Gault formula is not a good predictor of estimating adequate renal function. Note: If cisplatin is chosen as the radio-sensitizing agent, creatinine clearance must be ≥50 mL/min\n- Contraceptive use by participants should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. Investigators will advise participants on the options for banking of sperm and ova, for reproductive conservation. a. A participant must be either of the following: i. Not of childbearing potential ii. Of childbearing potential and practicing true abstinence, or have a sole partner who is vasectomized, or practicing at least 1 highly effective user independent method of contraception. Participant must agree to continue the above throughout the study and for 6 months after the last dose of study treatment. Note: If a participant becomes of childbearing potential after start of the study, the participant must comply with point (ii), as described above. A participant must also agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study treatment, and not be breastfeeding and not planning to become pregnant during the study and for at least 6 months after the last dose of study treatment. Participants should consider preservation of eggs prior to study treatment as anti-cancer treatments may impair fertility. Investigators will advise participants on the options for banking of ova for reproductive Conservation b. Participants must wear a condom (with or without spermicidal foam/gel/film/cream/suppository) when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 6 months after receiving the last dose of study treatment. Partners of participants who can conceive a child, if that partner is of childbearing potential, must also be practicing a highly effective method of contraception. If the participant is vasectomized, they still must wear a condom (with or without spermicidal foam/gel/film/cream/suppository), but their partner is not required to use contraception. A participant must also agree to not donate sperm for the purpose of reproduction during the study and for at least 6 months after the last dose of study treatment, and not plan to conceive a child while enrolled in the study or within 6 months after the last dose of study treatment. Participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility. Investigators will advise participants on the options for banking of sperm for reproductive conservation\n- Must sign an Informed Consent Form (or their legally acceptable representative must sign) indicating that they understand the purpose of, and procedures required for, the study and is willing to participate in the study and agree to store samples when applicable"}

Exclusion criteria

• {"criterion_text":"- Active malignancies other than the disease being treated under study.\n- Received intervening serial intravesical chemotherapy or immunotherapy from the time of pre-screening (diagnostic) or screening (completion) cystoscopy/Transurethral Resection of Bladder Tumor to starting study treatment. Peri-operative intravesical chemotherapy prior to study treatment is allowed per institutional guidelines\n- Prior therapy with an anti-programmed cell death 1, anti-PD-ligand agent, or with an agent directed to another co-inhibitory T-cell receptor.\n- Participants with a history of Grade ≥3 toxic effects when using antiTNF or anti-IL-6 agents.\n- Received prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to starting study treatment or not recovered from adverse events due to a previously administered agent. Participants with a history of prior pelvic radiotherapy are excluded\n- An active autoimmune disease that has required systemic treatment in the past 2 years are excluded.\n- Received a live virus vaccine within 30 days prior to he initiation of study treatment. Inactivated (non-live or non-replicating) vaccines approved or authorized for emergency use (eg, COVID 19) by local health authorities are allowed.\n- Active infection requiring systemic IV therapy within 14 days prior to randomization.\n- A pyeloureteral tube externalized to the skin is exclusionary. Unilateral nephrostomy tube or ureteral stent is permitted if it does not interfere with placement or retention of TAR-200 in the bladder. Participants with unilateral hydronephrosis are permitted; however, participants with bilateral hydronephrosis are excluded.\n- Indwelling urinary catheters are not permitted; however, intermittent catheterization is acceptable.\n- Participants who require immunosuppressive medications including but not limited to systemic corticosteroid at doses >10 mg/day of prednisone or its equivalence, methotrexate, cyclosporine, azathioprine, and TNF-alpha blockers. Use of immunosuppressive medications for the management of immune related adverse events, infusion related reactions, or in participants with contrast allergies is acceptable. Use of inhaled, topical, and intranasal corticosteroids are permitted.\n- Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder.\n- Must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study\n- Human immunodeficiency virus (HIV) infection, unless the participant has been on a stable anti-retroviral therapy regimen for the last 6 months or more and has had no opportunistic infections and a CD4 count of >350 in the last 6 months.\n- Active hepatitis B or C infection\n- Concurrent urinary tract infection that cannot be cleared with antibiotic therapy\n- History of uncontrolled cardiovascular disease including any of the following in the 3 months prior to screening: a. unstable angina, b. myocardial infarction, c. ventricular fibrillation, d. Torsades de Pointes, e. cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure, f. cerebrovascular accident, g. transient ischemic attack; h. pulmonary embolism or other venous thromboembolism\n- Criterion added per Global Amendment 3: The participant is unable to comply with the requirements of this protocol, including any factors that are likely to affect the participant's return for scheduled visits and follow-up.\n- Criterion added per Global Amendment 3: Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.\n- Must not have diffuse carcinoma in situ based on cystoscopy and biopsy. Diffuse, or multi-focal, CIS is defined as the presence of at least 4 distinct CIS lesions in the bladder at the time of the Screening re-TURBT.\n- Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging within 42 days prior to randomization.\n- Presence of any bladder or urethral anatomic feature that, in the opinion of the investigator, may prevent the safe placement, indwelling use, or removal of TAR-200.\n- Evidence of bladder perforation during diagnostic cystoscopy. Participant is eligible if perforation has healed prior to randomization.\n- Bladder post-void residual volume >350 mL at screening after second voided urine.\n- History of clinically significant polyuria with recorded 24-hour urine volumes greater than 4,000-mL.\n- Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior to randomization."}

Primary endpoints

• {"endpoint_text":"- Time from randomization to the first BI-EFS event, including histologically proven presence of muscle-invasive bladder cancer (MIBC), clinical evidence of nodal or metastatic disease (as assessed by RECIST 1.1 criteria), radical cystectomy (RC), or death due to any cause","definition_or_measurement_approach":"Time from randomization to first bladder-intact event-free survival (BI-EFS) event. BI-EFS events include histologically proven MIBC, clinical evidence of nodal or metastatic disease assessed by RECIST 1.1 criteria, radical cystectomy (RC), or death from any cause."}

Secondary endpoints

• {"endpoint_text":"- Time from randomization to first radiologic (as assessed by RECIST 1.1 criteria) or evidence of metastatic disease or death due to any cause","definition_or_measurement_approach":"Time from randomization to first radiologic evidence (assessed by RECIST 1.1) of metastatic disease, or other evidence of metastatic disease, or death from any cause."}
• {"endpoint_text":"- Time from randomization to death","definition_or_measurement_approach":"Overall survival measured as time from randomization to death from any cause."}
• {"endpoint_text":"- The ORR is defined as the proportion of participants who achieve a CR or PR","definition_or_measurement_approach":"Overall response rate (ORR) defined as proportion of participants achieving complete response (CR) or partial response (PR); assessment per study-specified response criteria (translations provided)."}
• {"endpoint_text":"- Frequency and grade of adverse events (AEs) and according to Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (NCI PRO-CTCAE). NCI PROCTCAE assessments will be done for all urinary and all gastrointestinal items in the NCI PRO-CTCAE item library. Laboratory abnormalities:CTCAE grades and NCI PRO-CTCAE grades comparing baseline to the worst post-baseline value.","definition_or_measurement_approach":"Safety assessed by frequency and CTCAE grade of adverse events and by patient-reported outcomes (NCI PRO-CTCAE) for urinary and gastrointestinal items; laboratory abnormalities compared baseline to worst post-baseline values using CTCAE and PRO-CTCAE grading."}

Methods

• Advocacy outreach letters (documents titled 'K2_Advocacy Outreach Letter' present)
• Patient brochures and study brochures (documents titled 'K2_Patient Brochure')
• Patient posters (documents titled 'K2_Patient Poster')
• Caregiver brochures (documents titled 'K2_Caregiver Brochure')
• Community outreach text and program newsletters (documents titled 'K2_Community Outreach Text', 'K2_Program Newsletter')
• Site recruitment materials and study binders (documents titled 'K2_Study Binder')

Portugal

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

11-03-2025

Processing Time Days

321

Number Of Sites

5

Number Of Participants

3

Czechia

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

12-03-2025

Processing Time Days

322

Number Of Sites

2

Number Of Participants

11

Hungary

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

12-03-2025

Processing Time Days

322

Number Of Sites

1

Number Of Participants

5

Belgium

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

17-03-2025

Processing Time Days

327

Number Of Sites

1

Number Of Participants

9

Greece

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

25-09-2025

Processing Time Days

519

Number Of Sites

5

Number Of Participants

18

Austria

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

22-09-2025

Processing Time Days

516

Number Of Sites

2

Number Of Participants

9

Spain

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

24-09-2025

Processing Time Days

518

Number Of Sites

13

Number Of Participants

23

Italy

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

23-09-2025

Processing Time Days

517

Number Of Sites

10

Number Of Participants

42

France

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

23-09-2025

Processing Time Days

517

Number Of Sites

3

Number Of Participants

30

Germany

Earliest CTIS Part Ii Submission Date

25-04-2024

Latest Decision Or Authorization Date

24-09-2025

Processing Time Days

518

Number Of Sites

7

Number Of Participants

21

Primary sponsor

Full Name

Janssen - Cilag International

Organisation Type

Pharmaceutical company

Country Of Registered Address

Belgium

Contract research organisations

Name

PRA Hellas CRO A.E.

Responsibilities

Contract negotiation and study start up (Greece)

Name

Yprime LLC

Responsibilities

Central ePRO vendor

Name

Bioclinica Inc.

Responsibilities

Medical image analysis/review; Central Imaging Review and Adjudication

Name

Laboratory Corporation Of America Holdings

Responsibilities

Central labs and lab logistics; histopathology

Name

Kcas LLC

Responsibilities

Histopathology; PK testing Gemcitabine (blood and urine)

Name

Signant Health Global LLC

Responsibilities

IVRS – treatment randomisation

Third parties

• {"country":"United States","full_name":"Yprime LLC","duties_or_roles":"Central ePRO vendor","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Medical image analysis/review; Primary/surrogate endpoint test; Central Imaging Review and Adjudication","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Laboratory Corporation Of America Holdings","duties_or_roles":"Central labs and lab logistics; histopathology; primary/surrogate endpoint test; routine clinical pathology testing","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Kcas LLC","duties_or_roles":"Histopathology; PK testing Gemcitabine (blood and urine)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"IVRS – treatment randomisation","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"PRA Hellas CRO A.E.","duties_or_roles":"Contract negotiation and study start up (Greece)","organisation_type":"Pharmaceutical company"}