A Phase III, Multi-center, Randomized Study Evaluating Efficacy of TAR-200 in Combination With Cetrelimab Versus Concurrent Chemoradiotherapy in Participants With Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder Who Are Not Receiving Radical Cystectomy

Study Identifier:
17000139BLC3001
CT.gov Identifier:
NCT04658862
EudraCT Identifier:
2020-002620-36
EU Trial (CTIS) Number:
2023-507188-21-00
Study Contact Information:
(210) 593-5651 or [email protected]
Terminated/Withdrawn

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Study Summary

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

To Evaluate the efficacy and safety of intravesical TAR-200 plus systemic cetrelimab versus CRT in participants with MIBC.

A primary disease assessment will be performed at week 18 to evaluate treatment response in both arms. Subsequent assessments (axial imaging and cystoscopy) will occur at week 24 and every 12 weeks thereafter through study year 2, and then every 24 weeks through study year 5.

Comparison of BI-EFS in subjects receiving TAR-200 in combination with cetrelimab and concurrent chemoradiotherapy

To compare bladder recurrence-free survival (BI-EFS) in subjects treated with TAR-200 plus intravenous (IV) cetrelimab versus concurrent chemoradiation.

The purpose of study is to compare bladder intact-event free survival (BI-EFS) in participants receiving TAR-200 in combination with intravenous (IV) cetrelimab versus concurrent chemoradiotherapy.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Bladder
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    III
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: TAR-200 + Cetrelimab Participants will receive intravesical TAR-200 every 3 weeks (21 days indwelling) for first 18 weeks and thereafter from Week 24 every 12 weeks through study Year 3 in combination with intravenous (IV) Cetrelimab. Biological: Cetrelimab Participants will receive intravenous Cetrelimab. Other Name: JNJ-63723283 Drug: TAR-200 Participants will receive intravesical TAR-200. Other Name: JNJ-17000139 Active Comparator: Chemotherapy (cisplatin or gemcitabine) + Radiation Therapy Participants will receive chemotherapy based on investigator's choice from either cisplatin intravenously once weekly for 4 to 6 treatment weeks or gemcitabine intravenously twice weekly for 4 to 6 treatment weeks as Standard of Care (SOC) along with radiation therapy from either conventional radiotherapy (64 Gray [Gy], bladder only) for up to 6.5 treatment weeks or hypo-fractionated radiotherapy (55 Gy, bladder only) for up to 4 weeks. Drug: Cisplatin Participants will receive cisplatin intravenously. Drug: Gemcitabine Participants will receive gemcitabine intravenously. Radiation: Conventional radiation therapy Participants will receive conventional radiation therapy for bladder (64 gy). Radiation: Hypo-fractioned radiation therapy Participants will receive hypo-fractioned radiation therapy for bladder (55 gy). Intervention Cetrelimab (Treatment Arm 1 - TAR-200 plus Cetrelimab) Participants will receive Cetrelimab every 3 weeks for the first 18 months in combination with TAR-200. Comparator Agent Cisplatin (Treatment Arm 2 - Chemotherapy (cisplatin or gemcitabine) plus radiation therapy) Participants will receive cisplatin intravenously. Participants will receive chemotherapy based on investigators choice from either cisplatin intravenously once weekly for 6 weeks or gemcitabine intravenously twice weekly for 6 weeks as Standard of Care (SOC) along with radiation therapy from either conventional radiotherapy (64 Gray [Gy], bladder only) for up to 6.5 weeks or hypo-fractionated radiotherapy (55 Gy, bladder only) for up to 4 weeks. Comparator Agent Conventional Radiation Therapy (Treatment Arm 2 - Chemotherapy (cisplatin or gemcitabine) plus radiation therapy) Participants will receive conventional radiation therapy for bladder (64 Gray [Gy], bladder only) for up to 6.5 weeks Comparator Agent Gemcitabine (Treatment Arm 2 - Chemotherapy (cisplatin or gemcitabine) plus radiation therapy) Participants will receive gemcitabine intravenously. Participants will receive chemotherapy based on investigators choice from either cisplatin intravenously once weekly for 6 weeks or gemcitabine intravenously twice weekly for 6 weeks as Standard of Care (SOC) along with radiation therapy from either conventional radiotherapy (64 Gray [Gy], bladder only) for up to 6.5 weeks or hypo-fractionated radiotherapy (55 Gy, bladder only) for up to 4 weeks. Comparator Agent Hypo-fractioned radiation therapy (Treatment Arm 2 - Chemotherapy (cisplatin or gemcitabine) plus radiation therapy) Participants will receive hypo-fractionated radiation therapy for bladder (55 Gy) for up to 4 weeks. Intervention TAR-200 (Treatment Arm 1 - TAR-200 plus Cetrelimab) Participants will receive intravesical TAR-200 every 3 weeks (21 days indwelling) for first 18 weeks and thereafter from Week 24 every 12 weeks through study Year 3 in combination with Cetrelimab. test drug Chinese common name: TAR-200 English common name: TAR-200 Dosage form: intravesical drug delivery system Specifications: 0.225g Dosage: Insert an empty catheter into the urethra until the urine returns, inject 2-3 mL of lubricant with a lubricant syringe, and push one end of TAR-200 into the catheter until it is fully expanded , inject a second lube into the end of the catheter, push the TAR-200 through the catheter fully into the bladder through the stylet, and remove the catheter and stylet from the urethra. After 1 cycle, the cystoscope was inserted into the bladder, and the TAR-200 was clamped and removed from the urethra. Medication time course: multiple administrations, 21 days as a dosing cycle, a total of 17 cycles of administration. Chinese common name: Cetrelimab English common name: Cetrelimab Dosage form: injection Specification: 240 mg/bottle Dosage: Take 2 bottles of drug, reconstitute 360 mg of drug with 8 mL of sterile water for injection to 30 mg/mL, and further inject the reconstituted drug solution with 0.9% sodium chloride Dilute and dilute to 100 mL with intravenous infusion: 100 mL/hour (first dose), 200 mL/hour (subsequent doses). Medication time course: multiple administrations, 21 days as a dosing cycle, a total of 27 cycles of administration. control drug Chinese common name: Gemcitabine 100 mg/mL Concentrate for Infusion English common name: Gemcitabine 100 mg/ml Concentrate for Solution for Infusion Trade name: Gemcitabine Dosage form: concentrated injection Specification: 2000 mg/20 ml Dosage: Take the required amount of solution from the vial and dilute it to 27 mg/m2 with 0.9% sodium chloride solution for intravenous drip administration. Medication time course: multiple administrations, 1 week is a dosing cycle, 2 times a week, a total of 6 cycles of administration, completed before the 18th week. Chinese common name: Cisplatin 1 mg/ml Concentrate for Infusion English common name: Cisplatin 1 mg/ml Concentrate for Solution for Infusion Trade name: Cisplatin Dosage Form: Concentrated Injection Specification: 100 mg/100 mL Dosage: Take the solution from the vial and prepare a mixture of 0.9% sodium chloride or 0.9% sodium chloride and 5% dextrose or 0.9% sodium chloride and 5% dextrose A mixture of 0.45% sodium chloride, 2.5% dextrose, and 1.875% mannitol for injection (at least 1 liter) diluted to 35 mg/m2 for intravenous administration. Medication time course: multiple administrations, 1 week as a dosing cycle, once a week, a total of 6 cycles of administration, completed before the 18th week ASCO 2021: Patients will be randomized in a 1:1 ratio and with stratification by 2 factors: Participants in Arm 1 will receive intravesical TAR-200 every 3 weeks for the first 18 weeks on study; and, beginning at week 24, every 12 weeks through study year 3. Cetrelimab will be dosed every 3 weeks until month 18. Participants in Arm 2 will receive standard of care CRT (with either cisplatin or gemcitabine, for up to 6 weeks).
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Terminated/Withdrawn

    Requirements information
    Inclusion criteria
    • Ineligible for or have elected not to undergo radical cystectomy
    • All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade less than (<) 2 prior to randomization
    • Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
    • 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
    • Adequate bone marrow, liver, and renal function: Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding two weeks): Absolute neutrophil count (ANC) greater than or equal to (>=) 1,500/cubic millimeters (mm^3); Platelet count >=80,000/mm^3; Hemoglobin >=9.0 grams per deciliter (g/dL); Liver function: (Total bilirubin less than or equal to (<=) 1.5 * upper limit of normal (ULN) or direct bilirubin <= ULN for participants with total bilirubin levels greater than (>)1.5*ULN (except participants with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dL), and Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to (<=) 2.5* institutional ULN); Renal function: Creatinine clearance >30 mL/min using the Cockcroft-Gault 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
    • As per EUCTR:
    • 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.
    • 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/mm³
    • ii. Platelet count ≥ 80,000/mm³
    • iii. Hemoglobin ≥ 9.0 g/dL
    • b. Liver function:
    • i. Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN (except participants with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dL)
    • ii. ALT and AST ≤ 2.5 × institutional ULN
    • c. Renal function:
    • Creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula. A 24-hour creatinine clearance test will also be accepted where Cockcroft-Gault is not a good predictor.
    • 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 in clinical studies. Investigators will advise participants on options for sperm and ova banking for reproductive conservation.
    • a. A participant must be either:
    • i. Not of childbearing potential
    • ii. Of childbearing potential and practicing true abstinence, or have a vasectomized sole partner, or using at least one highly effective user-independent method of contraception. Must continue throughout the study and for 6 months after the last dose.
    • Participants must not donate eggs or sperm, must not be breastfeeding, and must not plan to conceive during the study or for 6 months after the last dose.
    • b. Participants must wear a condom (with or without spermicide) during any activity that could result in ejaculate transfer during the study and for 6 months after the last dose. If vasectomized, condom use is still required, but the partner need not use contraception.
    • 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
    • Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder. Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study
    • Must not have diffuse CIS 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
    • Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging (chest, abdomen, and pelvis must be performed using Computed tomography [CT] or Magnetic resonance imaging [MRI]) within 42 days prior to randomization
    • 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
    • Evidence of bladder perforation during diagnostic cystoscopy. Participant is eligible if perforation has healed prior to randomization
    • As per ECUTR:
    • 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 multifocal 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 anti-TNF 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 is exclusionary.
    • 15. Received a live virus vaccine within 30 days prior to the initiation of study treatment. Inactivated (non-live or non-replicating) vaccines approved or authorized for emergency use (e.g., 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 corticosteroids at doses >10 mg/day of prednisone or its equivalent, 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 is 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
    • f. Known congestive New York Heart Association Class III-IV heart failure
    • g. Cerebrovascular accident
    • h. Transient ischemic attack
    • i. 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 (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Carolinas
    Myrtle Beach, SC, United States, 29572
    Investigator
    Neal Shore
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Bladder