| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046720 |
| E.1.2 | Term | Urothelial carcinoma bladder stage II |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046721 |
| E.1.2 | Term | Urothelial carcinoma bladder stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10046722 |
| E.1.2 | Term | Urothelial carcinoma bladder stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare bladder intact event-free survival (BI-EFS) in participants receiving TAR-200 in combination with cetrelimab versus concurrent
chemoradiotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare metastasis-free survival (MFS) in participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy
- To compare the Overall Survival (OS) in participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy
- To compare the Overall Response Rate (ORR)
(Complete Response [CR] or Partial Response [PR]) in both treatment arms at Week 18, in participants who are have pathologic stage T1 at baseline
- To assess the safety and tolerability of participants receiving TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 infiltrating urothelial carcinoma of the bladder. Initial diagnosis must have been within 90 days of randomization date. Participants with variant histologic subtypes (e.g. squamous cell carcinoma) are allowed if urothelial (transitional cell) differentiation is predominant (e.g. <20% variant histologic subtype). However, the presence of any neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features 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 within normal range or stable on hormone supplementation per investigator assessment.
7. Adequate bone marrow, liver, and renal function:
a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding two 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 >40 mL/min using the Cockcroft-Gault formula.
8. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. Investigators will advise both male and female participants on the options for banking of sperm and ova, respectively for reproductive conservation.
a. A female 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 women becomes of childbearing potential after start of the study, the woman must comply with point (ii), as described above.
A female 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 drug, 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 drug.
b. A male participant 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. His female partner, if of childbearing potential, must also be practicing a highly effective method of contraception.
If the male participant is vasectomized, he still must wear a condom
(with or without spermicidal foam/gel/film/cream/suppository), but his female partner is not required to use contraception.
A male 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 drug, and not plan to father a child while enrolled in the study or within 6 months after the last dose of study drug.
Male participants should consider preservation of sperm prior to study treatment as anti-cancer treatments may impair fertility. Investigators will advise male participants on the options for banking of sperm for reproductive conservation.
9. A female participant of childbearing potential must have a negative serum test at screening and a negative urine test wtihin 72hrs of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study, that may exceed those listed in the Schedule of Activities.
10. Must sign an Informed Consent Form indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study and agree to store samples when applicable |
|
| E.4 | Principal exclusion criteria |
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.
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, known or suspected autoimmune disease.
15. Received a live virus vaccine within 30 days prior to planned start 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.
18. 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.
19. Indwelling urinary catheters are not permitted; however, intermittent catheterization is acceptable.
20. 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.
21. Must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study.
22. 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.
23. Active hepatitis B or C infection
24. Concurrent urinary tract infection
31. History of uncontrolled cardiovascular disease including any of the following in the preceding 3 months prior to screening: unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure, cerebrovascular accident, or transient ischemic attack; pulmonary embolism or other venous thromboembolism within the preceding 2 months.
35. 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.
36. 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.
For the full list of exclusion criteria please refer to the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Time from randomization to first radiologic (as assessed by RECIST 1.1 criteria) or histologic evidence of metastatic disease or death due to any cause.
- Time from randomization to death.
- Biopsy Response at Week 18
- Frequency and grade of adverse events (AEs) (according to Common Terminology Criteria for Adverse Events [CTCAE] version 5) 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.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Duration of trial
- Biopsy Response at Week 18
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Concurrent with chemoradiotherapy |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| United States |
| European Union |
| Türkiye |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study is considered completed with the last follow-up overall survival assessment for the last participant participating in the study, or 5 years after the last participant is randomized. The final data from the study site will be sent to the sponsor (or designee) after completion of the final participant's survival assessment at that study site, in the time frame specified in the Clinical Trial Agreement |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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