A Study of TAR-200 in Combination With Cetrelimab Versus Concurrent Chemoradiotherapy in Participants With Muscle-invasive Bladder Cancer (MIBC) of the Bladder

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Janssen - Cilag International

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Apr 2021 → ongoing

Decision date (initial)

2024-06-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Janssen Research & Development LLC

External identifiers

EU CT number

2023-507188-21-00

EudraCT number

2020-002620-36

ClinicalTrials.gov

NCT04658862

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Pharmacokinetic, Pharmacogenetic, Therapy, Safety

To compare bladder intact event-free survival (BI-EFS) in participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy.

Secondary objectives 4

1. To compare metastasis-free survival (MFS) in participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy
2. To compare the Overall Survival (OS) in participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy
3. To compare the Overall Response Rate (ORR)(Complete Response [CR] or Partial Response [PR]) in both treatment arms at Week 18
4. To assess the safety and tolerability of participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy

Conditions and MedDRA coding

Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. ≥18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
2. 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.
3. Ineligible for or have elected not to undergo radical cystectomy.
4. 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
5. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
6. 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
7. 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
8. 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
9. 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
10. Participants must be willing and able to adhere to the lifestyle restrictions specified in this protocol

Exclusion criteria 26

1. Active malignancies other than the disease being treated under study.
2. Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder.
3. 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.
4. Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging within 42 days prior to randomization.
5. 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.
6. Evidence of bladder perforation during diagnostic cystoscopy. Participant is eligible if perforation has healed prior to randomization.
7. Bladder post-void residual volume >350 mL at screening after second voided urine.
8. History of clinically significant polyuria with recorded 24-hour urine volumes greater than 4,000-mL.
9. 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.
10. 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
11. 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.
12. Participants with a history of Grade ≥3 toxic effects when using antiTNF or anti-IL-6 agents.
13. 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
14. An active autoimmune disease that has required systemic treatment in the past 2 years are excluded.
15. 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.
16. Active infection requiring systemic IV therapy within 14 days prior to randomization.
17. 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.
18. Indwelling urinary catheters are not permitted; however, intermittent catheterization is acceptable.
19. 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.
20. Must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study
21. 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.
22. Active hepatitis B or C infection
23. Concurrent urinary tract infection that cannot be cleared with antibiotic therapy
24. 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
25. 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.
26. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 4

1. Time from randomization to first radiologic (as assessed by RECIST 1.1 criteria) or evidence of metastatic disease or death due to any cause
2. Time from randomization to death
3. The ORR is defined as the proportion of participants who achieve a CR or PR
4. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Janssen - Cilag International

Sponsor organisation

Janssen - Cilag International

Address

Turnhoutseweg 30

City

Beerse

Postcode

2340

Country

Belgium

Scientific contact point

Organisation

Janssen - Cilag International

Contact name

CTIS point of Contact

Public contact point

Organisation

Janssen - Cilag International

Contact name

CTIS point of Contact

Third parties 6

Locations

10 EU/EEA countries · 49 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 164 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications