| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Muscle-Invasive Urothelial Carcinoma (NMIBC) 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 | 100000004864 |
|
| 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 |
|
| 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 |
|
| 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 |
|
| 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 evaluate the overall Complete Response (CR) rate in participants treated with TAR-200 in combination with cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2), or cetrelimab alone (Cohort 3) with Carcinoma in Situ (CIS), with or without concomitant high-grade Ta or T1 papillary disease. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the duration of response (DoR) in participants treated with TAR-200 in combination with IV cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2), or IV cetrelimab alone (Cohort 3) with CIS (with or without concomitant Ta or T1 papillary disease) who achieve a CR.
- To determine the overall survival (OS) in all participants.
- To evaluate the pharmacokinetics (PK) of gemcitabine and major metabolite 2’,2’-difluorodeoxyuridine (dFdU) in urine and plasma in TAR-200 in
combination with cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2).
- To evaluate the PK and immunogenicity of cetrelimab inserum when cetrelimab is administered with and without TAR-200
- To evaluate health-related quality of life (HRQoL) in all participants.
- To assess the safety and tolerability of participants receiving TAR-200 in combination with IV cetrelimab (Cohort 1), or TAR-200 alone (Cohort 2), or cetrelimab alone (Cohort 3). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥18 years male or female (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
2. Histologically confirmed diagnosis of persistent or recurrent CIS (or
Tis), with or without papillary disease (T1, high-grade Ta) within 12
months of completion of the last dose of BCG therapy, in patients who
have received adequate BCG.
3. All visible papillary disease must be fully resected (absent) prior to
randomization (residual CIS acceptable) and documented in the eCRF at
Screening cystoscopy.
4. Participants must be willing to undergo all study procedures (e.g., multiple cystoscopies from Screening through the end of study and TURBT/bladder biopsy for assessment of recurrence/progression).
5. Participants must be ineligible for or have elected not to undergo radical cystectomy.
6. BCG-unresponsive high-risk NMIBC after treatment with adequate BCG therapy defined as a minimum of 5 of 6 full doses of an induction course (adequate induction) plus 2 of 3 doses of a maintenance course, or at least 2 of 6 doses of a second induction course.
7. All AEs associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade <2 prior to screening.
8. 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.
9. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2.
10. Thyroid function tests within normal range or stable on hormone supplementation per investigator assessment. Investigators may
consult an endocrinologist for participant eligibility assessment in the
case of equivocal or marginal test results.
11. Adequate bone marrow, liver, and renal function
12. 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)
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, 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. Female
participants should consider preservation of eggs prior to study
treatment as anti-cancer treatments may impair fertility. Investigators
will advise female participants on the options of banking of ova for
reproductive conservation.
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. Male participants
should consider preservation of sperm prior to study treatment as anticancer
treatments may impair fertility.
Investigators will advise male participants on the options for banking of
sperm for reproductive conservation.
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 this study or within 6 months
after the last dose of study drug.
13. A female participant of childbearing potential must have a negative
serum test at screening and a negative urine test within 72hours 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.
14. Participants must be willing and able to adhere to the lifestyle
restrictions specified in this protocol |
|
| E.4 | Principal exclusion criteria |
1. Histologically confirmed, muscle-invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, and/or Stage IV).
2. Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder. Ta/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. Active malignancies other than the disease being treated under study:
a. skin cancer (non-melanoma or melanoma) that is considered completely cured.
b. non-invasive cervical cancer that is considered completely cured.
c. adequately treated lobular carcinoma in situ 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)
4. Presence of any bladder or urethral anatomic feature (eg. urethral stricture) that may prevent the safe insertion, indwelling use, or removal
of TAR-200, or passage of a urethral catheter for intravesical chemotherapy, or administration of intravesical BCG. Participants with tumors involving the prostatic urethra in men will be excluded
5. Evidence of bladder perforation during diagnostic cystoscopy.
6. Bladder post-void residual volume > 350mL at Screening after second voided urine.
7. No history of acute ischemic heart disease within 30 days of cohort assignment, or history of uncontrolled cardiovascular disease.
8. A history of clinically significant polyuria with recorded 24-hour urine volumes greater than 4000 mL.
9. Participants with an active, known or suspected autoimmune disease.
10. 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.
11. Active infection requiring systemic IV therapy.
12. Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior to screening.
13. Indwelling catheters are not permitted; however, intermittent catheterization is acceptable.
14. Received serial intervening intravesical chemotherapy or immunotherapy from the time of pre-screening or screening cystoscopy/TURBT to starting study treatment. Peri-operative intravesical chemotherapy prior to study is allowed per institutional guidelines.
15. Prior therapy with an anti-programmed -cell death 1, anti-PD-ligand 2 agent, or with an agent directed to another co-inhibitory T-cell receptor.
16. Participants with a history of Grade ≥3 toxic effects when using anti-
TNF or anti-IL-6 agents are excluded.
17. Not recovered from toxicity of prior anticancer therapy (except
toxicities which are not clinically significant such as alopecia, skin discoloration). 18. Participants who require immunosuppressive medications.
19. Participants must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study.
20. 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.
21. Active hepatitis B or C infection (for example, participants with history of hepatitis C infection but undectable hepatitis C virus PCR test and participants with history of hepatitis B infection with positive HBsAg antibody and undetectable PCR are allowed).
22. Concurrent urinary tract infection, defined as a symptomatic infection with a positive urine culture with a bacterial count of ≥10^5 colony forming units (CFU)/mL in urine voided from women, or >10^4 CFU/mL in urine voided from men, or in straight-catheter urine from women.
23. Participants with a history of allergy to protein-based therapies and
participants with a history of any significant drug allergy are excluded.
24. Known hypersensitivity to any component of the drug formulation for
cetrelimab.
25. Known hypersensitivity to gemcitabine (or other drug excipients) or
chemically-related drugs.
26. Known hypersensitivity to the TAR-200 device constituent or the
(TAR-200) UPC materials.
27. Evidence of radiographic features associated with pulmonary fibrosis/advanced interstitial lung disease or active non-infectious pneumonitis
28. Participants must not have active tuberculosis.
29. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
30. Major surgery within 4 weeks before screening (TURBT is not considered major surgery).
31. Any condition for which participation would not be in the best interest of the participants or that could prevent, limit, or confound the protocol-specified assessments. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall CR rate will be measured by determining the proportion of participants without presence of high-grade disease using results from cystoscopy
and centrally read urine cytology at any time point. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| date of disease progression/death |
|
| E.5.2 | Secondary end point(s) |
- DOR is defined as the date of first CR achieved to the date of first evidence of recurrence or progression or death, using cystoscopy, centrally read bladder biopsy and urine cytology, and imaging, if available. Twelve month DOR will be determined.
- OS, defined as the time from randomization to death; if a participant has not died at the time of analysis, the participant will be censored at the date last known alive.
- Gemcitabine and dFdU concentrations in urine and plasma.
- Serum concentration and incidence of anti-cetrelimab antibodies.
- Change from baseline and time to symptom deterioration in EORTC
QLQ-C30 and EORTC QLQ-NMIBC24.
- Frequency and grade of adverse events (AEs) (according to Common
Terminology Criteria for Adverse Events [CTCAE] version 5).
- Laboratory abnormalities: CTCAE grades comparing baseline to the
worst post-baseline value; other safety data, such as vital signs, will be
considered as appropriate.
- assessment of product quality compliants. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 12 months after achievement of a CR
- date of disease progression/death
- Week 24 and 48
|
|
| 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 | 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 113 |
| 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 |
| Australia |
| Canada |
| Japan |
| Korea, Republic of |
| United States |
| European Union |
| Russian Federation |
| Turkey |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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