Gemcitabine hydrochloride for Non‑muscle-invasive bladder cancer (NMIBC)

Inclusion criteria

• {"criterion_text":"- 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\n- Adequate bone marrow, liver, and renal function (creatinine clearance >30 mL/min)\n- Contraceptive use by participants 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 (including participants temporarily withholding 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.\n- 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\n- Participants must be willing and able to adhere to the lifestyle restrictions specified in this protocol\n- Histologically confirmed diagnosis of persistent or recurrent HRNMIBC, CIS (OR Tis) [AJCC, 2017], with or without papillary disease (T1, high-grade Ta) or papillary disease only (high-grade Ta or any T1 and absence of CIS), within 12 months of completion of the last dose of BCG therapy, in patients who have received adequate BCG\n- All visible papillary disease must be fully resected (absent) prior to randomization (residual CIS is acceptable for participants eligible for Cohorts 1, 2, and 3 only) and documented in the eCRF at Screening cystoscopy. For patients with papillary disease only (Cohort 4), local urine cytology at screening must be negative or atypical (for HGUC)\n- 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)\n- Participants must be ineligible for or have elected not to undergo radical cystectomy\n- 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\n- All AEs associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade <2 prior to screening\n- 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\n- Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2"}

Exclusion criteria

• {"criterion_text":"- Presence or history of histologically confirmed, muscle-invasive, locally advanced, nonresectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, and/or Stage IV)\n- Active infection requiring systemic IV therapy within 14 days prior to randomization\n- 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\n- Indwelling catheters are not permitted; however, intermittent catheterization is acceptable\n- 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\n- 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\n- Not recovered from toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration)\n- No clinically significant liver disease that precludes participant treatment regimens prescribed on the study\n- Human immunodeficiency virus (HIV) infection, unless the participant has been on a stable anti-retroviral therapy regimen for the last 6 months or more prior to randomization and has had no opportunistic infections and a CD4 count of >350 in the last 6 months\n- Active hepatitis B or C infection (for example, participants with history of hepatitis C infection but undetectable hepatitis C virus PCR test and participants with history of hepatitis B infection with positive HBsAg antibody and undetectable PCR are allowed)\n- 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\n- No 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\n- Known hypersensitivity to gemcitabine (or other drug excipients) or chemically-related drugs\n- Known hypersensitivity to the TAR-200 device constituent or the (TAR-200) UPC materials\n- Evidence of radiographic features associated with pulmonary fibrosis/advanced interstitial lung disease or active non-infectious pneumonitis\n- Participants must not have active tuberculosis\n- Major surgery within 4 weeks before screening (TURBT is not considered major surgery)\n- 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\n- Active malignancies (ie progressing or requiring treatment change in the last 24 months prior to randomization) 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)\n- 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\n- Evidence of bladder perforation during diagnostic cystoscopy\n- Bladder post-void residual volume > 350mL at Screening after second voided urine\n- No history of acute ischemic heart disease within 30 days of cohort assignment, or history of uncontrolled cardiovascular disease\n- History of clinically significant polyuria with recorded 24-hour urine volumes greater than 4000 mL\n- 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 (eg, COVID-19) by local health authorities are allowed"}

Primary endpoints

• {"endpoint_text":"- 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 timepoint","definition_or_measurement_approach":"Measured by determining the proportion of participants without presence of high-grade disease using results from cystoscopy and centrally read urine cytology at any timepoint"}
• {"endpoint_text":"- Cohort 4 only: DFS will be measured as the time from the date of first dose of study treatment to either the time of the first recurrence of highrisk disease, progression, or death due to any cause, whichever occurs first.","definition_or_measurement_approach":"DFS defined as time from date of first dose to first recurrence of high-risk disease, progression, or death due to any cause; whichever occurs first"}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"DOR defined as date of first CR to date of first evidence of recurrence, progression or death using cystoscopy, centrally read bladder biopsy and urine cytology, and imaging if available; 12-month DOR determined"}
• {"endpoint_text":"- To determine the overall survival (OS) in all participants","definition_or_measurement_approach":"OS defined as time from date of first dose to death; participants not deceased at analysis censored at last known alive date"}
• {"endpoint_text":"- Gemcitabine and dFdU concentrations in urine and plasma","definition_or_measurement_approach":"PK measurement of gemcitabine and major metabolite (dFdU) concentrations in urine and plasma"}
• {"endpoint_text":"- Serum concentration and incidence of anti-cetrelimab antibodies","definition_or_measurement_approach":"Measurement of cetrelimab serum concentrations and assessment of incidence of anti-cetrelimab antibodies (immunogenicity)"}
• {"endpoint_text":"- Change from baseline and time to symptom deterioration in EORTC QLQ-C30 and EORTC QLQ-NMIBC24","definition_or_measurement_approach":"Patient-reported outcomes using EORTC QLQ-C30 and QLQ-NMIBC24 instruments; change from baseline and time to symptom deterioration assessed"}
• {"endpoint_text":"- Frequency and grade of adverse events (AEs) (according to Common Terminology Criteria for Adverse Events [CTCAE] version 5)","definition_or_measurement_approach":"Safety assessed by frequency and CTCAE v5 grade of adverse events"}
• {"endpoint_text":"- Laboratory abnormalities: CTCAE grades comparing baseline to the worst post-baseline value; other safety data, such as vital signs, will be considered as appropriate","definition_or_measurement_approach":"Laboratory abnormalities graded per CTCAE comparing baseline to worst post-baseline value; other safety data (vitals) considered as appropriate"}

France

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

24-03-2026

Processing Time Days

691

Number Of Sites

19

Number Of Participants

39

Belgium

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

23-03-2026

Processing Time Days

690

Number Of Sites

6

Number Of Participants

20

Spain

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

25-03-2026

Processing Time Days

692

Number Of Sites

8

Number Of Participants

14

Netherlands

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

24-03-2026

Processing Time Days

691

Number Of Sites

2

Number Of Participants

8

Greece

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

30-03-2026

Processing Time Days

697

Number Of Sites

3

Number Of Participants

3

Germany

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

25-03-2026

Processing Time Days

692

Number Of Sites

5

Number Of Participants

14

Portugal

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

30-03-2026

Processing Time Days

697

Number Of Sites

4

Number Of Participants

7

Italy

Earliest CTIS Part Ii Submission Date

02-05-2024

Latest Decision Or Authorization Date

27-03-2026

Processing Time Days

694

Number Of Sites

4

Number Of Participants

25

Primary sponsor

Full Name

Janssen - Cilag International

Organisation Type

Pharmaceutical company

Country Of Registered Address

Belgium

Contract research organisations

Name

Icon (Lr) Limited

Responsibilities

sponsor duties codes: 1, 12, 2, 5, 6

Name

PRA Hellas CRO A.E.

Responsibilities

Contract negotiation and study start up (Greece); sponsor duties codes: 1, 15

Third parties

• {"country":"Ireland","full_name":"Icon (Lr) Limited","duties_or_roles":"codes: 1, 12, 2, 5, 6","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Kcas LLC","duties_or_roles":"codes: 15 (PK testing Gemacitabine (blood and urine) histopathologhy), 4, 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"code: 15 (central labs and lab logistics histopathology primary/surrogate endpoint test)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Memorial Sloan Kettering Cancer Center","duties_or_roles":"codes: 15 (histopathology), 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"codes: 15 (IVRS30 – treatment randomisation), 3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Yprime LLC","duties_or_roles":"codes: 15 (Central ePRO vendor), 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Greece","full_name":"PRA Hellas CRO A.E.","duties_or_roles":"codes: 1, 15 (Contract negotiation and study start up (Greece))","organisation_type":"Pharmaceutical company"}