| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Muscle-Invasive Urothelial Carcinoma of the Bladder
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 100000004864 |
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| 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 | 100000004864 |
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| 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 | 100000004864 |
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| 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 | 100000004864 |
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| 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 determine the anti-tumor effects of TAR 200 in combination with Cetrelimab and Cetrelimab alone
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of up to 4 dosing cycles of TAR-200 in combination with cetrelimab and cetrelimab alone prior to RC
• To determine the recurrence-free survival (RFS) in participants receiving TAR-200 in combination with cetrelimab and cetrelimab alone |
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| 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)
2. Histologically proven, cT2-T4a N0, M0 infiltrating urothelial carcinoma (AJCC 2017) of the bladder. Initial diagnosis must have been within 90 days of randomization date. Participants with variant histologic subtypes (eg squamous differentiation) are allowed if urothelial differentiation is predominant (eg, <20% variant histologic subtype).
3. Participants with an individual intravesical tumor size of ≤3 cm following TURBT are eligible. Participants with persistent multifocal tumors at screening must undergo a second debulking, re-staging TURBT to reduce the tumor burden. Participants will be ineligible if any individual tumor is >3 cm.
4. Deemed eligible for and willing to undergo RC by the attending urologist.
5 Eastern Cooperative Oncology Group (ECOG) performance status Grade 0 or 1
6.Thyroid function tests within normal range or stable on hormone supplementation per Investigator assessment.
7. Adequate bone marrow, liver, and renal function (kindly refer to study protocol for further details)
8. Participants must refuse cisplatin-based combination
chemotherapy (and understand the risk and benefits of doing so)
or be deemed ineligible for cisplatin-based chemotherapy by
meeting at least one of the following criteria:
• GFR <60 mL/min/1.73 m2 (assessed using the CKD-EPI equation)
• Common Terminology Criteria for Adverse Events (CTCAE) version
5.0 Grade ≥2 audiometric hearing loss
• CTCAE version 5.0 Grade ≥2 peripheral neuropathy
9. Prior systemic chemotherapy for indications other than urothelial
cell carcinoma of the bladder is permitted, but interval between
this treatment and study enrollment must exceed 24 months. All
toxicities attributed to prior anti-cancer therapy other than
alopecia and fatigue must have resolved to Grade 1 (NCI-CTCAE
version 5.0) or baseline before administration of study drug.
Participants with toxicities attributed to prior anticancer therapy
which are not expected to resolve and result in long lasting
sequelae, such as peripheral neuropathy after platinum-based
therapy or audiometric hearing loss, are ineligible.
10.All adverse events associated with any prior surgery must have
resolved to CTCAE version 5.0 Grade <2 prior to randomization.
11.Contraceptive use by men or women should be consistent with
local regulations regarding the use of contraceptive methods for
participants participating in clinical studies
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 woman becomes of childbearing potential after start of the study, the woman must comply with point (ii), as described above.
A female participant must also:
• agrees to not donate eggs (ova, oocytes, or freeze for future use) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study drug.
• 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 a minimum of 6 months after the last dose of study drug
• not plan to father a child while enrolled in this study or within 6 months after the last dose of study drug
12.A female participant of childbearing potential must have a negative serum or urine test at screening and within 72 hours 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
13.Must sign an informed consent form (ICF) (or their legally acceptable representative must sign)
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| E.4 | Principal exclusion criteria |
1.Active malignancies other than the disease being treated under study.
2.Must not have received prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 2 years prior to starting study treatment
3.Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder.
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.Uncontrolled adrenal insufficiency.
7.A history of clinically significant polyuria with recorded 24-hour urine volumes greater than 4,000 mL.
8.History of uncontrolled cardiovascular disease
9.Must not have active tuberculosis.
10.Has had an allogeneic tissue/solid organ transplant.
11.Pyeloureteral tube externalized to the skin is exclusionary.
12.Indwelling catheters are not permitted;
13.Participants with an active, known or suspected autoimmune disease.
14.Participants must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study
15.Known human immunodeficiency virus infection.
16.Evidence of active hepatitis B or C infection
17.Concurrent urinary tract infection, defined as a symptomatic infection with a positive urine culture with a bacterial count of ≥105 colony forming units /mL in urine voided from women, or >104 CFU/mL in urine voided from men, or in straight-catheter urine from women.
18.Active, uncontrolled urogenital bacterial, viral or fungal infections, including UTI. Skin/nail fungal infections are not exclusionary.
19.Evidence of interstitial lung disease or active non-infectious pneumonitis.
20.Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
21.Participants who have had a history of acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
22.Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
23.Not recovered from adverse events due to a previously administered agent.
24.Prior systemic chemotherapy for urothelial cell carcinoma of the bladder at any time.
25.Pelvic radiotherapy administered less than 6 months prior to screening.
26.Received a live virus vaccine within 30 days of planned start of study treatment
27.Active autoimmune disease that has required systemic treatment in the past 2 years.
28.Active infection requiring systemic intravenous therapy within 14 days prior to randomization.
29.Received intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/TURBT to starting study treatment.
30.Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
31.Participants with a history of Grade ≥3 toxic effects when using anti-TNF or anti-IL-6 agents are excluded.
32.Participants still recovering from toxicity of prior anticancer therapy which was received more than 24 months prior to enrollment (except toxicities which are not clinically significant such as alopecia, skin discoloration).
33.Participants who require immunosuppressive medications
34.Participants with a history of allergy to protein-based therapies and participants with a history of any significant drug allergy are excluded.
35.Known hypersensitivity to any study component including:
a.Gemcitabine (or other drug excipients) or chemically-related drugs,
b.TAR-200 device constituent materials,
c.TAR-200 Urinary Placement Catheter materials,
d.Cetrelimab excipients or chemically-related drugs
Refer to the TAR-200 IB and cetrelimab IB for complete information on excipients.
36.Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior to enrollment.
37.Participants with evidence of bladder perforation during diagnostic cystoscopy. Participant is eligible if perforation has resolved prior to dosing.
38.Bladder post-void residual (PVR) volume >350mL at screening after second voided urine.
39.Participants who have not recovered from the effects of major surgery or significant traumatic injury at least 14 days before randomization
(Kindly refer Protocol section 5.2 "Exclusion Criteria" for detailed information)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| pCR rate at radical cystectomy (RC) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At time of RC planned within 6 weeks after the Week 9 visit |
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| E.5.2 | Secondary end point(s) |
• Frequency and grade of adverse events (AEs)
• Laboratory abnormalities
• Recurrence-free survival (RFS) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Frequency and grade of adverse events (AEs)
From the signing of the ICF until 100 days after last dose of study
drug; thereafter (study follow-up phase) all study drug-related
serious adverse events should be reported
•Laboratory abnormalities :
At different timepoints specified in the protocol
•Recurrence-free survival (RFS)
At Week 6, RC visit, and every 12 weeks post RC until Week 108.
Additionally (follow-up phase), when clinically indicated.
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| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 49 |
| 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 |
| Israel |
| Korea, Republic of |
| United States |
| United Kingdom |
| European Union |
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| 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
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The end of study is considered as approximately 2 years after the last randomized participant receives RC. The final data from the study site will be sent to the Sponsor (or designee) after completion of the final participant assessment at that study site, in the time frame specified in the Clinical Trial Agreement.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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