| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BCG-naïve High-Risk Non-Muscle Invasive Bladder Cancer |
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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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare event-free survival (EFS) in participants with BCG-naïve HR--NMIBC (high-grade papillary Ta, any T1, or Carcinoma in Situ [CIS]), receiving TAR-200 in combination with systemic intravenous (IV) cetrelimab versus intravesical BCG. |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
- To compare the overall complete response (CR) rate and the duration of CR in participants with BCG-naïve CIS receiving TAR-200 in combination with systemic IV cetrelimab versus intravesical BCG.
- To compare recurrence-free survival (RFS) in participants with BCG-naïve HR-NMIBC high-grade papillary Ta or T1, receiving TAR-200 in combination with systemic IV cetrelimab versus intravesical BCG.
- To compare time to progression (TTP) in participants with BCG-naïve HR-NMIBC high-grade papillary Ta or T1 or CIS receiving TAR-200 in combination with systemic IV cetrelimab versus intravesical BCG.
- To compare overall survival (OS) in participants with BCG-naïve HR--NMIBC, high-grade papillary Ta or any T1, or CIS receiving TAR-200 in combination with systemic IV
cetrelimab versus intravesical BCG.
For the full list of secondary objectives, please refer the protocol.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
1. Age ≥18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
Disease Characteristic
2. Histologically confirmed initial diagnosis (within 90 days of the initial signed informed consent) of HR-NMIBC (high-grade Ta,any T1 or CIS), [AJCC 2017], in participants who are BCG-naïve. Mixed histology tumors are allowed if urothelial differentiation (transitional cell histology) is predominant. However, the presence of neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features will make a participant ineligible.
3. BCG-naïve (participants who have not received prior intravesical BCG or who previously received but stopped BCG more than 3 years before date of randomization are eligible) (Kamat 2016).
4. Participants must be willing to undergo all study procedures (eg, multiple cystoscopies from Screening through the end of study and TURBT/bladder biopsy for assessment of
recurrence/progression).
5. All visible papillary disease must be fully resected (absent) prior to date of randomization and documented at baseline cystoscopy.
6. All AEs associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade <2 prior to date of randomization.
Type of Participant
7. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2.
8. Thyroid function tests within normal range or stable per Investigator assessment. Investigators may consult an endocrinologist for participant eligibility assessment in the case of equivocal or marginal tests results.
9. 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) ≥1,000/mm3
ii. Platelet count ≥75,000/mm3
iii. Hemoglobin ≥8.0 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:
i. Creatinine clearance >40 mL/min using the Cockcroft-Gault formula.
Sex and Contraceptive/Barrier Requirements
For inclusion criteria 10-11 Please see the protocol.
Informed Consent
12. Participants must sign the informed consent form (ICF) 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.
13. Participants must be willing and able to adhere to the lifestyle restrictions specified in this protocol.
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| E.4 | Principal exclusion criteria |
Disease Characteristics
1. Histologically confirmed, muscle invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (ie, ≥T2).
2. Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder (ie, urethra, ureter, or renal pelvis). Ta/any T1/CIS of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephroureterectomy more than 24 months prior to randomization.
3. N+ and/or M+ per Blinded Independent central Review (BICR) of computed tomography (CT)/magnetic resonance (MR) Urography and Chest CT.
Medical Conditions
4. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Potential allowed exceptions include the following (others may be allowed with Sponsor approval).
a. skin cancer (non-melanoma or melanoma) that is considered completely cured.
b. non-invasive cervical cancer treated that is considered completely cured.
c. adequately treated lobular carcinoma in situ (LCIS) and ductal CIS
d. history of localized breast cancer and receiving antihormonal agents
e. history of localized prostate cancer (N0M0) and receiving androgen deprivation therapy
f. Localized prostate cancer (N0M0):
i. with a Gleason score of 6, treated within the last 24 months or untreated and under surveillance,
ii. with a Gleason score of 3+4 that has been treated more than 6 months prior to full study Screening and considered to have a very low risk of recurrence,
iii. or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.
5. Presence of any bladder or urethral anatomic feature (eg, urethral stricture) that, in the opinion of the Investigator, may prevent the safe insertion, indwelling use, removal of TAR-200, or administration of intravesical BCG. Participants with tumors involving the prostatic urethra in men will be excluded.
6. A history of clinically significant polyuria with recorded 24-hour urine volumes greater than 4000 mL.
7. Received a live virus vaccine within 30 days of planned start of study treatment. Inactivated (non-live) vaccines approved or authorized for emergency use (eg,COVID-19) by local health authorities are allowed.
8. Participants should not have a history of acute ischemic heart disease within 42 days of randomization, or 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, or
h. pulmonary embolism or other venous thromboembolism in the 3 months prior to Screening.
9. Indwelling catheters are not permitted; however, intermittent catheterization is acceptable.
10. Participants must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study (including, but not limited to active viral, alcoholic, or other autoimmune hepatitis, cirrhosis, or inherited liver disease).
11. Active hepatitis B or C infection (for example, participants with history of hepatitis C infection but undetectable hepatitis C virus polymerase chain reaction (PCR) test and participants with history of hepatitis B infection with positive HBsAg antibody and
undetectable PCR are allowed).
12. 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.
13. Participants with congenital immunodeficiencies
14. Evidence of radiographic features associated with pulmonary fibrosis/advanced interstitial lung disease (pulmonary consult may be required by the Investigator) as determined by blinded independent central review (BICR) of chest CT, medical history of pneumonitis/interstitial lung disease, or active non-infectious pneumonitis/interstitial lung disease.
15. Evidence of active tuberculin infection (eg, positive Mantoux test).
16. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
17. Major surgery and/or not fully recovered within 4 weeks before first dose (TURBT is not considered major surgery).
18. Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participants (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
For exclusion criteria 19-34 please see the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
event-free survival (EFS)
EFS will be measured as the time from randomization to either the time of the first high-grade recurrence, progression, or death due to any cause, whichever occurs first For participants with CIS, persistent disease at 6 months (Week 24) is also considered an EFS event. Progression is defined as:
1) an increase of stage from Ta to T1 or from CIS to T1
OR
2) progression to muscle invasive bladder cancer (MIBC) (T≥2) or to lymph node (N+) or to distant disease (M+), whichever occurs first. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| event-free survival (EFS) will be measured as the time from randomization to either the time of the first high-grade recurrence, progression, or death due to any cause, whichever occurs first. |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints :
- Overall complete response (CR) rate will be measured by determining the proportion of participants with CIS who have no presence of high-grade disease at 6 months. Duration of CR is defined from the time of first CR achieved to first evidence of recurrence, progression or death due to any cause (whichever occurs first) for participants who achieve a CR.
- Recurrence-free survival (RFS) will be measured as the time from randomization to the time of the first recurrence of high-grade disease, or death due to any cause, whichever occurs first.
- Time to progression (TTP) will be measured as the time from randomization to the date of first documented evidence of disease progression or death due to disease progression, whichever occurs first.
- Overall Survival (OS), defined as the time from randomization to death, due to any cause.
For the full list of secondary objectives, please refer the protocol.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall complete response (CR) rate
- at 6 months
Recurrence-free survival (RFS)
-Throughout the Study
Time to progression (TTP)
-throughout the Study
Overall survival (OS)
- Defined as the time from the date of randomization to death, from any cause.
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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) | 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 | 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) | Yes |
| 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 | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| Mexico |
| Taiwan |
| United States |
| France |
| Poland |
| Netherlands |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Portugal |
| Russian Federation |
| United Kingdom |
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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
|
| The end of study is considered as 5 years after the last participant is randomized in the study. This will ensure a minimum of 2 years of disease assessments following the final dose of study drug or study drug comparator. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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