Bladder Cancer

Condition: Urinary Bladder Neoplasms

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04241185

Sponsor: Merck Sharp & Dohme LLC

Phase: Phase 3

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Has a histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology
• Has clinically nonmetastatic bladder cancer (N0M0)
• Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the protocol-specified radiosensitizing chemotherapy regimens
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Demonstrates adequate organ function
• Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of CRT treatment:
• Refrain from donating sperm
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP)
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days the time needed to eliminate each study intervention after the last dose of study intervention; and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: MK-3475
• 120 days and CRT
• 180 days

Exclusion Criteria:

• Has the presence of diffuse carcinoma in situ (CIS) (multiple foci of CIS) throughout the bladder
• Has the presence of urothelial carcinoma (UC) at any site outside of the urinary bladder in the previous 2 years except for Ta stage/T1 stage/CIS of the upper tract if the participant has undergone a complete nephroureterectomy
• Has a known additional malignancy that is progressing or has required active therapy within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ that has undergone potentially curative therapy
• Has the presence of bilateral hydronephrosis
• Has limited bladder function with frequency of small amounts of urine (< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter
• Has received prior pelvic/local radiation therapy or any antineoplastic treatment for muscle-invasive bladder cancer (MIBC). Treatment for non-muscle invasive bladder cancer (NMIBC) with intravesical instillation therapy that was completed ≥28 days prior to randomization is allowed. Prior systemic treatment of NMIBC is not permitted.
• Received prior therapy with an anti-PD-1 (programmed cell death protein 1), anti-PD-L1 (programmed death-ligand 1), or anti-PD-L2 (programmed cell death 1 ligand 2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], OX 40, or CD137 [cluster of differentiation 137])
• Has received a live vaccine within 30 days before the first dose of study medication
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study medication
• Has known severe hypersensitivity (≥Grade 3) to the selected chemotherapy regimen, and/or any of their excipients and excipients of pembrolizumab
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study medication
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
• Has a history of non-infectious pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of hepatitis B or known active hepatitis C virus infection
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
• Has had an allogenic tissue/solid organ transplant

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Condition: Bladder Cancer

Study Type: Observational [Patient Registry]

Clinical Trials Identifier NCT 8-digits: NCT03413982

Sponsor: University of Kansas Medical Center

Phase:

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Patients who present to clinic with presumed bladder cancer or have a diagnosis of bladder cancer are eligible to participate
• Patients can participate in any additional research studies during the patients' participation within this protocol.

Exclusion Criteria:

• Patients who do not have presumed bladder cancer will not be eligible

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Condition: Sarcopenia, Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03362801

Sponsor: University Hospital, Caen

Eligibility:

• Age: minimum 65 Years maximum N/A
• Gender: All

Inclusion Criteria:

• confirmed urothelial bladder carcinoma ( RTUV)
• indication of radical cystectomy
• Able, informed and with informed consent for the study
• affiliated to the social security system
• talking French

Exclusion Criteria:

• Life expectancy <6 months
• other active malignant tumors or other severe concomitant chronic pathologies affecting the general condition of the patient and / or likely to limit compliance with the requirements of the study.
• treatments incompatible with the study: previous corticosteroid treatment prolonged for more than one month (induces iatrogenic sarcopenia).

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Condition: Patients With High-risk MIBC

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03333356

Sponsor: UNICANCER

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

1. To be eligible, the patients must fulfil all of the following inclusion criteria:
2. Patients with histologically-confirmed muscle-invasive bladder cancer, either with pure urothelial carcinomas, or dominant urothelial carcinomas (>50%) combined with other histological variants including: micropapillary, epidermoid, or adenocarcinomas, are eligible. Patients with small cell variants, pure adenocarcinomas, or pure epidermoid carcinomas are not eligible.
3. Patients with radical cystectomy and pelvic lymph nodes dissection with no microscopic residual disease (R0 and R1). Note that only R1 patients without urinary diversion as orthotropic neo-bladder replacement are eligible for the study, to limit cystectomy bed radiation induced toxicities.
4. Patients with tumours of TNM staging: pN0-2, M0 by imagery, and pT3a, pT3b, pT4a, and pT4b, as well as, pTX-pN1-2, pTX-NX-R1 are eligible.
5. Patients having received neo-adjuvant or adjuvant chemotherapy treatment are eligible. Randomization is allowed only if AE due to chemotherapy are ≤grade 2 at randomization.
6. Patients ≥18 years old.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤
8. Absolute neutrophil count (ANC) ≥1500 cells/mm³.
9. Platelets ≥100000 cells/mm³.
10. Haemoglobin ≥8 g/dL (Note: following a blood transfusion or another intervention if required).
11. Adequate hepatic function: aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤2.5 x upper limit of normal (ULN); or ≤3.5 x ULN in the case of concurrent disease with known etiology and for which a corrective treatment is possible.
12. Adequate renal function: clearance >30 mL/min (MDRD).
13. Patients having provided written informed consent prior to any study-related procedures.
14. Patients affiliated to the social security scheme.
15. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.

Exclusion Criteria:

• Patient must not be enrolled if he/she fulfils any of the following non-inclusion criteria: 1. Patients with R1 resection and with orthotropic neo-bladder reconstruction as urinary diversion are not eligible. 2. Patients with clinical or radiological evidence of metastases or N3 staged bladder cancer are not eligible. 3. Prior invasive solid tumours or haematological malignancies unless disease free for a minimum of 3 years prior to randomisation except:
• skin basal cell carcinoma,
• in situ epithelioma of the cervix,
• or prostate cancer: incidentally discovered during cystoprostatectomy and pelvic lymph node dissection and with a good prognosis (T stage
• Unstable angina or congestive heart failure that required hospitalization in the 6 months before randomisation.
• Transmural myocardial infarction in the 6 months prior to randomisation.
• Acute bacterial or fungal infection requiring intravenous antibiotics at randomisation.
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of randomisation.
• Severe hepatic disease: Child-Pugh Class B or C hepatic disease.
• Known acquired immune deficiency syndrome (AIDS); the study treatment could impact blood count. 9. Patients with any other disease or illness which requires hospitalization or is incompatible with the study treatment are not eligible. 10. Patients unable to comply with study obligations for geographic, social, or physical reasons, or who are unable to understand the purpose and procedures of the study. 11. Patients enrolled in another therapeutic study within 30 days prior of randomisation. 12. Person deprived of their liberty or under protective custody or guardianship.

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Condition: Bladder Cancer, Radiation Therapy Complication, Quality of Life

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT04282876

Sponsor: Aarhus University Hospital

Phase:

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: Male

Inclusion Criteria:

• T2-T4 bladder cancer
• radiation therapy
• able to fill out questionnaires
• signed informed consent

Exclusion Criteria:

• KAD prior to TUR-B
• dementia or other cognitive impairment
• metastatic disease

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Condition: Bladder Cancer, Muscle Invasive Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03747419

Sponsor: Dana-Farber Cancer Institute

Phase: Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• to participate in the study. Inclusion Criteria:
• Histologically confirmed transitional cell (urothelial) carcinoma of the bladder that is invasive into the muscularis propria (≥T2 disease) within 6 months of enrollment date. The presence of variant histologies (squamous, adenocarcinoma, micropapillary, etc.) is allowed. Note: A prior diagnosis of non-muscle-invasive bladder cancer (≤T1) managed with transurethral resection with or without intravesicular therapy (now with muscle invasion) is allowed.
• Inability to receive cisplatin-based chemotherapy, as defined by creatinine clearance <60 ml/min, ECOG PS ≤2, grade 2 or higher hearing loss, NYHA class 3 or higher, neuropathy (grade 2 or higher), or patient refusal to receive cisplatin-based chemotherapy. Additional Inclusion Criteria:
• Male or female subjects aged ≥18 years
• ECOG performance status ≤2 or Karnofsky score ≥60% (see Appendix A)
• Life expectancy of greater than 1 year
• Demonstrate normal organ and marrow function
• Estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula.
• Women of child-bearing age must have a negative serum pregnancy test at screening.
• Women of child-bearing potential and men must agree to use a highly effective method of contraception (hormonal or barrier method of birth control, or abstinence) beginning prior to study entry, for the duration of study participation, and for at least 30 days after last avelumab treatment administration if the risk of conception exists
• Ability to start study treatment (first cycle of Avelumab) within 1-8 weeks of the most recent pre-study TURBT.
• Ability to understand and willingness to sign a written informed consent document Exclusion Criteria:
• Prior intravenous therapy for treatment of bladder cancer
• Prior pelvic radiation
• Any component of small cell histology in the bladder biopsy
• Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment
• Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroid, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed.
• History of another malignancy within 5 years prior to randomization except for: non-muscle-invasive bladder cancer (i.e., ≤T1), completely resected basal cell or squamous cell skin cancer, completed resected carcinoma-in-situ of any site, or localized prostate cancer managed definitively with a non-radiation based approach. Additional

Exclusion Criteria:

• Prior intravenous therapy for treatment of bladder cancer
• Prior pelvic radiation
• Any component of small cell histology in the bladder biopsy
• Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment
• Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroid, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed.
• History of another malignancy within 5 years prior to randomization except for: non-muscle-invasive bladder cancer (i.e., ≤T1), completely resected basal cell or squamous cell skin cancer, completed resected carcinoma-in-situ of any site, or localized prostate cancer managed definitively with a non-radiation based approach. Additional Exclusion Criteria:
• Evidence of lymph node involvement or metastatic disease on CT of the chest, abdomen, and pelvis. To be considered positive, a lymph node must measure >15 mm in short axis.
• Clinically significant (i.e. active) cardiovascular disease: symptomatic congestive heart failure (≥ New York Heart Association Classification Class II), unstable angina pectoris, serious cardiac arrhythmia requiring medication, or CVA/stroke/MI (< 6 months prior to enrollment)
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
• Breast feeding women who are unwilling to stop breastfeeding during treatment and for at least one month after the duration of treatment
• Patients with known history of testing positive for HIV or known acquired immunodeficiency syndrome
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
• Active infection requiring intravenous antibiotic therapy
• Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines
• Major surgery within the last 30 days (with the exception of TURBT).
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
• Prior organ transplantation including allogenic stem-cell transplantation
• Patient is unwilling to stop (or wishes to start) taking herbal and natural remedies that may have immune-modulating effects during the study period
• Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Pregnant women are excluded from this study.

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Condition: Bladder Cancer

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT04235764

Sponsor: National Cancer Institute (NCI)

Phase:

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Patients requiring surgical removal of the bladder at the NIH Clinical Center. NOTE: Reasons for need for surgical removal of bladder include cancer or benign condition for which a surgeon determined surgical removal of the bladder is recommended. Patient's with invasive bladder cancer requiring cystectomy are eligible for enrollment. Bladder cancer remains the most common reason for cystectomy. Patients with clinical advanced disease and having other treatments/or participating in other trials remain eligible for enrollment in this study.
• Men and women
• Age greater than or less than 18 years
• Deemed clinically appropriate for the planned surgical procedure.
• Ability of subject to understand and the willingness to sign a written informed consent document.
• Subjects will be asked to co-enroll in 15-C-0087, "Care of the Urothelial Cancer Patient and Prospective Collection of Biospecimens from Healthy Volunteers and Urothelial Cancer Patients." NOTE: Most participants are expected to already be enrolled in 15-C-0087 prior to entry in this study.

Exclusion Criteria:

• Cystectomy during pregnancy would subject the fetus to significant risk of miscarriage or premature labor. For this reason, pregnant women are ineligible for this study.

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Condition: Bladder Cancer

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT03789682

Sponsor: Fudan University

Phase:

Eligibility:

• Age: minimum 18 Years maximum 85 Years
• Gender: All

Inclusion Criteria:

• patients with non-metastatic muscle invasive bladder cancer
• pathology confirmed urothelial carcinoma
• underwent cystectomy and pelvic lymph node dissection

Exclusion Criteria:

• not enough tissue for immunohistochemistry
• patients with a second neoplasm

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Condition: Bladder Cancer, NMIBC, Non-Muscle Invasive Bladder Cancer, Urothelial Carcinoma Recurrent

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03914794

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Phase: Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Prior histologically confirmed low- or intermediate-risk non-muscle invasive urothelial carcinoma of the bladder (NMIBC) defined according to the following characteristics:
• Low Risk
• Initial tumor with all of the following:
• Solitary tumor
• Ta tumor
• Low-grade
• <3 cm
• No CIS
• Intermediate Risk --- All tumors not defined in the two adjacent categories (between the category of low- and high-risk)
• High Risk
• T1 tumor
• High-grade
• CIS
• Multiple and recurrent and large (>3 cm) Ta low-grade tumors (all conditions must be met for this point on Ta low-grade tumors)
• Documented tumor recurrence as noted in standard of care follow up cystoscopy.
• ECOG (WHO) performance status 0-2
• Age ≥ 18 years old
• Patients must have the following laboratory values:
• White blood cell count (WBC) > 3.0 K/mm3
• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
• Platelets ≥ 100 K/mm3
• Hemoglobin (Hgb) ≥ 9 g/dL
• Serum total bilirubin: ≤ 1.5 x ULN
• ALT and AST ≤ 3.0 x ULN
• Serum calcium < ULN
• Serum phosphate < ULN
• Serum creatinine ≤ 1.5 x ULN or serum creatinine > 1.5
• 3 x ULN if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the modified Cockcroft-Gault equation
• Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

• Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive urothelial carcinoma.
• Patients with high grade urothelial carcinoma on their most recent urine cytology.
• Patients with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. (Patients that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment.)
• Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
• Patients who have received prior selective fibroblast growth factor receptor targeting agents (i.e. pemigatinib, dovitinib, BGJ398, AZD4547, JNJ-42756493, etc.).
• Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities
• Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury

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Condition: Non-Muscle Invasive Bladder Cancer ("NMIBC") Unresponsive/Intolerant to BCG

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03945162

Sponsor: Theralase® Technologies Inc.

Phase: Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• 1. Be willing and able to provide a written Informed Consent Form ("ICF") for the Study. 2. Be > 18 years of age on day of signing ICF. 3. Have histologically confirmed NMIBC CIS via biopsy with/without resected papillary disease (Ta, T1) (high grade) using the 2004 World Health Organization ("WHO") / International Society of Urologic Pathology classification system. The most recent cystoscopy / TURBT must have been performed within 12 weeks of the Study Treatment date to confirm: histology, grade and stage. 4. Intolerant to BCG or considered BCG-Unresponsive, which is at least one of the following:
• At least five of six doses of an initial induction course, plus at least two of three doses of maintenance therapy, or
• At least five of six doses of an initial induction course, plus at least two of six doses of a second induction course. 5. Are not candidates for cystectomy on medical grounds or refuse radical cystectomy. 6. Have an Eastern Cooperative Oncology Group ("ECOG") performance score of 0 to 2. 7. Have satisfactory bladder function. Ability to retain Study Drug for a minimum of 60 minutes. 8. Are available for the duration of the Study including follow-up (approximately 15 months). 9. Female patients of childbearing potential must have a negative Human Chorionic Gonadotropin ("HCG") pregnancy test taken during the screening visit and confirmed prior to the Study Treatment. 10. Female patients of childbearing potential must be willing to use 2 methods of birth control (i.e.: oral contraceptive, pills, diaphragm or condoms) or be surgically sterile, or abstain from heterosexual activity for two weeks after the Study Treatment. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.

Exclusion Criteria:

1. Past or current muscle invasive (i.e.: T2, T3, T4) or metastatic urothelial carcinoma.
2. Has concurrent extravesical (i.e.: urethra, ureter, renal pelvis, prostate or prostatic ducts) non-muscle invasive transitional cell carcinoma of the urothelium. (confirmed by staging to exclude extravesical disease, which may include radiological imaging and/or biopsy) within 3 months of enrollment: If previous work up occurred more than 3 months prior to enrollment, staging for extravesical disease must be repeated prior to enrolment in order to determine eligibility.
3. Active gross hematuria.
4. Have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer or localized prostate cancer under active surveillance with Gleason 6 disease. A history of prostate cancer that was treated with definitive intent (surgically or through radiation therapy) is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower Prostate-Specific Antigen ("PSA") undetectable for 2 years while off androgen deprivation therapy or no more than 2 consecutive rising PSAs.
5. Have a history or current evidence of any condition, therapy, surgery or laboratory abnormality that, in the opinion of the PI, might confound the results of the Study, interfere with the patient's participation in the Study, or is not in the best interest of the patient to participate.
6. Currently receiving treatment with a prohibited concomitant therapy (refer to 12.2.1, Prohibited Medications).
7. Participated in a study with an investigational agent or device within 1 month from the first dose of current Study treatment.
8. Prior treatment with an intravesical chemotherapeutic agent within 1 month of the first dose of current Study Drug, with the exception of a single perioperative dose of chemotherapy immediately post-TURBT (not considered treatment).
9. Have an active infection requiring systemic therapy, including active or intractable Urinary Tract Infection ("UTI"), not resolved prior to the procedure.
10. Has any contraindication to general or spinal anesthesia.
11. Is pregnant or breastfeeding within the projected duration of Study II, starting with the screening visit through to two weeks following the second Ruvidar® (TLD-1433) instillation.

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Condition: Bladder Cancer, Patient Engagement, Patient Empowerment, Ileal Conduit

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04055311

Sponsor: Northwell Health

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• (a) male or female patients diagnosed with BC
• (b) undergoing bladder removal surgery and one of the following urinary diversions: 1) ileal conduit, 2) neobladder or 3) Indiana pouch.
• (c) did not need or completed neo-adjuvant chemotherapy,
• (d) able to communicate with ease in English

Exclusion Criteria:

• (a) the caregiving relationship is temporary (e.g., an out-of-town relative provides temporary support) as stated by both patient and caregiver.

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Condition: Urothelial Carcinoma, Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03869190

Sponsor: Hoffmann-La Roche

Phase: Phase 1/Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• for mUC Cohort:
• Histologically documented, locally advanced or metastatic UC (also termed TCC or urothelial cell carcinoma of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra)
• Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status by means of central testing
• Disease progression during or following treatment with no more than one platinum-containing regimen for inoperable, locally advanced or metastatic UC or disease recurrence
• ECOG Performance Status of 0 or 1
• Measurable disease (at least one target lesion) according to RECIST v1.1
• Adequate hematologic and end-organ function
• Negative HIV test at screening
• Negative total hepatitis B core antibody (HBcAb) test and hepatitis C virus (HCV) antibody at screening
• Tumor accessible for biopsy
• For women of childbearing potential: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating eggs
• For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm Inclusion Criteria for MIBC Cohorts:
• ECOG PS of 0 or 1
• Fit and planned-for cystectomy
• Histologically documented MIBC (pT2-4, N0, M0), also termed TCC or urothelial cell carcinoma of the urinary bladder
• N0 or M0 disease by CT or MRI
• Adequate hematologic and end-organ function
• Availability of TURBT specimen
• Negative HIV, HBcAb, and HCV test at screening
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating eggs as outlined for each specific treatment arm
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm Exclusion Criteria for mUC Cohort:
• Prior treatment with a T-cell co-stimulating therapy or a CPI including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• Prior treatment with any of the protocol-specified study treatments including treatment with poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, nectin-4 targeting agents, signal regulatory protein alpha-targeting agents, or TIGIT-targeting agents, Trop-2 targeting agents, FAP-directed therapies, 4-1BB (CD137)-directed therapies, or topoisomerase 1 inhibitors
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
• Eligibility only for the control arm
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressant medication during study treatment
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled tumor-related pain
• Uncontrolled or symptomatic hypercalcemia
• Symptomatic, untreated, or actively progressing CNS metastases
• History of leptomeningeal disease
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis
• History of malignancy other than UC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Active tuberculosis
• Severe infection within 4 weeks prior to initiation of study treatment
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Significant cardiovascular disease
• Uncontrolled hypertension
• Grade 3 or greater hemorrhage or bleeding event within 28 days prior to initiation of study treatment
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study
• Additional drug-specific exclusion criteria might apply Exclusion for MIBC Cohorts:
• Prior treatment with systemic immunostimulatory agents prior to the initiation of study treatment
• Eligibility only for the control arm
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment, with the following exceptions: Patients who received acute, low-dose, systemic immunosuppressant medications, or a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after Medical Monitor approval has been obtained. Patients who received mineralocorticoids, corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• Severe infection within 4 weeks prior to initiation of study treatment
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study
• Also includes all the mUC exclusion criteria Additional Exclusion Criteria for Atezo+Tira and Atezo (Atezolizumab) +Tira+Cis (Cisplatin)+Gem (Gemcitabine) in the MIBC Cohorts:
• Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening. Additional

Exclusion Criteria:

• for mUC Cohort:
• Prior treatment with a T-cell co-stimulating therapy or a CPI including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• Prior treatment with any of the protocol-specified study treatments including treatment with poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, nectin-4 targeting agents, signal regulatory protein alpha-targeting agents, or TIGIT-targeting agents, Trop-2 targeting agents, FAP-directed therapies, 4-1BB (CD137)-directed therapies, or topoisomerase 1 inhibitors
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
• Eligibility only for the control arm
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressant medication during study treatment
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled tumor-related pain
• Uncontrolled or symptomatic hypercalcemia
• Symptomatic, untreated, or actively progressing CNS metastases
• History of leptomeningeal disease
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis
• History of malignancy other than UC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Active tuberculosis
• Severe infection within 4 weeks prior to initiation of study treatment
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Significant cardiovascular disease
• Uncontrolled hypertension
• Grade 3 or greater hemorrhage or bleeding event within 28 days prior to initiation of study treatment
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study
• Additional drug-specific exclusion criteria might apply Exclusion for MIBC Cohorts:
• Prior treatment with systemic immunostimulatory agents prior to the initiation of study treatment
• Eligibility only for the control arm
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment, with the following exceptions: Patients who received acute, low-dose, systemic immunosuppressant medications, or a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after Medical Monitor approval has been obtained. Patients who received mineralocorticoids, corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• Severe infection within 4 weeks prior to initiation of study treatment
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study
• Also includes all the mUC exclusion criteria Additional Exclusion Criteria for Atezo+Tira and Atezo (Atezolizumab) +Tira+Cis (Cisplatin)+Gem (Gemcitabine) in the MIBC Cohorts:
• Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening. Additional Exclusion Criteria for the Cisplatin-Eligible MIBC Cohort:
• Patients who decline neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate.
• Impaired renal function.

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Condition: Bladder Cancer, Bladder Neoplasm, Bladder Tumor

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04081246

Sponsor: Chinese University of Hong Kong

Eligibility:

• Age: minimum 18 Years maximum 80 Years
• Gender: All

Inclusion Criteria:

• Age 18 to 80 years old with informed consent
• Bladder tumours with maximal dimension of ≥ 3cm

Exclusion Criteria:

• Bladder tumour detected during intravesical Bacillus Calmette-Guerin therapy (These patients warrant more aggressive treatment, i.e. radical cystectomy)
• Estimated glomerular filtration rate of <60mL/min.
• Presence of clinically significant cardiovascular disease (History of acute myocardial infarction, presence of uncontrolled angina within 3 months before screening, New York Heart Association Class III or IV congestive heart failure, presence of ventricular arrhythmias, or presence of second-degree or third-degree heart block)
• Presence of GOLD Stage III or IV chronic obstructive pulmonary disease
• History of bleeding disorder or use of anti-coagulant
• Presence of other active malignancy
• ECOG performance status ≥ 2 (Ambulatory and capable of all self care but unable to carry our any work activities. Confined to bed or chair less than 50% of waking hours)
• Pregnancy
• Presence of metallic foreign body or implant which is not MRI compatible
• Known history of claustrophobia

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Condition: Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03664869

Sponsor: Turku University Hospital

Phase: Phase 3

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Histologically proven non-muscle-invasive tumour types confined to the urinary bladder
• Carcinoma in situ with or without a papillary tumour(s)
• Ta tumour(s) of high-grade
• Any T1 tumour(s)
• Written informed consent is required from every eligible patient
• Second resection performed in case of T1 tumour
• Adequate physical and mental condition to participate in the study (as judged by treating physician

Exclusion Criteria:

• Ta low grade tumour(s)
• Muscle invasive (pT≥2) tumors
• Urothelial cancer involving the prostatic urethra or upper urinary tract
• Non-urothelial bladder cancer.
• Prior BCG failure (If the patient has previously been successfully treated with BCG, and duration from the last instillation is >12 months, participation may be considered, if bladder preserving is chosen)
• Prior or concurrent immunotherapy
• Any medication or condition considered as contraindication to BCG or MMC (as judged by the treating physician)
• Urethral stricture, stone disease, chronic urinary tract infection or any other urological condition that may comprise study participation (as judged by the treating physician)
• Known allergy to MMC or BCG
• Age < 18 years
• Pregnancy or lactating patient
• Other untreated or unstable malignancy in risk of recurrence/progression (as judged by the treating physician)
• Cardiac pacemaker
• Expected survival time less than one year
• Expected poor compliance

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Condition: Bladder Cancer

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT03973307

Sponsor: East and North Hertfordshire NHS Trust

Phase:

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Patients aged ≥ 18 years of age
• Patients under investigation for bladder cancer due to undergo investigative standard of care biopsy

Exclusion Criteria:

• Patients aged < 18 years of age
• Patients who are currently undergoing radiation therapy.
• Proposed subject has no bladder (due to surgical removal).
• No cystoscopy and/or pathology information for proposed subject (following cystoscopy for final inclusion in study results)
• Patients unable or unwilling to provide consent
• Patients currently on investigational drug trials
• Patients with Catheter in Situ

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Condition: Superficial Bladder Cancer, Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03379909

Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Phase: Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Age > 18 years.
• Patients with primary or recurrent suspectedTa or T1, G1 or G2 (low grade) urothelial carcinoma of the bladder with no suspicion of carcinoma in situ.
• Patients must have at least 1 lesion but no more than 5.
• There must be one index lesion measuring between 0.5 and 1.0 cm in its greatest dimension.
• Bimanual examination immediately following cystoscopyshould be carried out and no mass should be felt.
• Adequate renal function (eGFR >50 ml/min/1.73m2 according to CKD-EPI). (47)
• Adequate liver function (bilirubin <1.5 times upper limit of normal, ALAT or ASAT <2.5 the upper limit of normal).
• Eligible patients must be fully informed of the investigational nature of the study and written signed informed consent must be obtained prior to any study specific investigations.
• Mentally, physically, and geographically able to undergo treatment and follow up.

Exclusion Criteria:

• Patients with positive cytology (suspected for high-grade urothelial carcinoma, TPS 4 or TPS 5) or suspected grade 3 tumours.
• Patients with diabetes mellitus receiving metformin or having received metformin in the past 6 months.
• Patients who have received intravesical treatment (chemotherapy or immunotherapy) within the last 3 months.
• Patients that are currently receiving other anti-cancer therapy.
• Patients with existing urinary tract infection or recurrent severe bacterial cystitis.
• Patients that need to be treated with a transurethral catheter.
• Patients with urogenital tumours with histology other than urothelial carcinoma (i.e. squamous cell or adenocarcinoma) or with urothelial carcinoma involving the upper tract or the prostatic urethra.
• Patients with a history of other primary malignancy (other than squamous or basal cell skin cancers or cone biopsied CIS of the uterine cervix or prostate carcinoma treated curatively with normal PSA values at inclusion) in the last five years.
• Patients with active, uncontrolled impairment of the renal, hepatobiliary, cardiovascular, gastrointestinal, urogenital, neurologic or hematopoietic systems that, in the opinion of the investigator, would predispose to the development of complications from the administration of metformin.
• Patients who are using loop diuretics, cimetidine, ranitidine, cetirizine, trimethoprim, vandetanib, kinidine and/or HIV medication, for which no reasonable alternative is available.
• Women who are pregnant or lactating. Individuals of reproductive potential may not participate unless agreeing to use an effective contraceptive method for themselves and/or their sexual partner.
• Patients with ECOG-WHO performance status of 3 or 4.
• Patients with a known history of alcohol abuse.
• Patients with a known hypersensitivity to metformin.
• Patients who in the investigator's opinion, cannot comply with provisions of the protocol or do not understand the nature of the study.

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Condition: Urinary Bladder Cancer, Invasive Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03844256

Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Phase: Phase 1/Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Be willing and able to provide written informed consent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Wish to preserve their bladder function or be ineligible for cystectomy.
• Must have undergone transurethral biopsy of the bladder tumor, within 35 days of planned treatment commencement. The patient should have a histologically-confirmed diagnosis of muscle-invasive T2-T4a, N0-1M0 urothelial cell carcinoma of the bladder.
• Must have undergone maximal transurethral resection of the bladder tumour, to an extent that is judged as safe by the urologist performing the resection, within 35 days of planned treatment commencement.
• Subjects with tumors of mixed urothelial/non-urothelial cell histology are allowed, but urothelial cell carcinoma must be the predominant histology (>50%). Subjects with predominant or exclusively non-urothelial cell histology are not allowed.
• Have planned for chemoradiotherapy as definitive treatment.
• Have a performance status of 0 or 1 on the ECOG Performance Scale
• Have a bladder function that is accessible for cystoscopical follow up.
• Demonstrate adequate organ function. All screening labs should be performed within 28 days of registering the patient on the trial.
• Female participants of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registering the patient. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female participants of childbearing potential should be willing to one highly effective method of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 5 month after the last dose of study medication Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
• Male participants should agree to use condoms starting with the first dose of study therapy through 7 month after the last dose of study therapy.
• Willing to consent to the use of their collected tumor specimen, blood and urine as detailed in the protocol for future scientific research including but not limited to DNA, RNA and protein based biomarker detection.

Exclusion Criteria:

• Has DPD deficiency.
• Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) urothelial cell carcinoma of the urothelium. Patients who have involvement of the prostatic urethra with urothelial cell cancer may be included if the location can be safely incorporated in the radiation field.
• Extensive or multifocal bladder carcinoma in situ (CIS) precluding curative chemoradiotherapy.
• Evidence of distant metastatic disease on a CT or FDG PET/CT chest/abdomen/pelvis performed within 28 days prior to study entry. Up to 3 metastatic lymphnodes in the pelvis (below the common iliac arteries) are allowed, if these can be incorporated in the radiotherapy field.
• Prior pelvic lymph-adenectomy
• Prior pelvic radiotherapy
• Has had prior intravenous chemotherapy, targeted small molecule therapy, or radiation therapy for treatment of bladder cancer. Prior intravesical use of BCG and MMC is permissible.
• Unsuitable for concurrent MMC / capecitabine based ChRT based on pre-existing medical conditions.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy over 10mg daily prednisone (or equivalent) or any other form of immunosuppressive therapy within 14 days prior to registering the patient. Patients with adrenal insufficiency receiving replacement dose steroids are allowed on the trial.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to nivolumab and/or ipilimumab or any of its excipients.
• Prior or concurrent known additional malignancy of any site unless disease free for 5 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, Stage T1a well differentiated prostatic carcinoma in men (Gleason = 3+3, PSA <5)
• Has any history of active autoimmune disease, Stevens-Johnson syndrome or Guillain-Barre. Exceptions to this are: 1. Patients with autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 2. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has an Human Immunodeficiency Virus (HIV) infection with a PCR detectable viral load.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

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Condition: Non-Muscle Invasive Bladder Cancer (NMIBC)

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT04179162

Sponsor: Memorial Sloan Kettering Cancer Center

Phase: Phase 1/Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Recurrent for persistent high-grade NMIBC Ta/T1/Tis (Ta/T1 with CIS is preferred, but not required) within 24 months of the last treatment with BCG (with or without IFN) o Up to 26 months from the last BCG treatment is allowed for the treating physician to perform a transurethral resection of bladder tumor (TURBT) so long as there is evidence of recurrent disease (by positive cytology, imaging, or office cystoscopy) within 24 months of last BCG transurethral resection of bladder tumor (TURBT)
• Pathologic confirmation of stage, grade, and urothelial histology by the Department of Pathology at MSK
• All visible papillary lesions macroscopically resected within 60 days of treatment initiation
• Absence of urothelial carcinoma involving the upper urinary tract (documented by radiological imaging or ureteroscopy) within 12 months from the start of treatment
• Receipt of restaging transurethral resection (TUR) for any tumor with invasion into the lamina propria (HGT1) as part of standard care
• Age ≥18 years
• Karnofsky performance status ≥60%
• Informed consent

Exclusion Criteria:

• Positive pregnancy test
• Known contraindications to BCG
• History of systemic hypersensitivity reaction or history of febrile systemic BCG reaction
• Febrile illness or persistent gross hematuria
• Active tuberculosis
• Immunosuppression due to congenital or acquired immune deficiency, concurrent immune suppressive disease, systemic cancer therapy, or chronic immunosuppressive therapy other than topical or inhaled corticosteroids
• History of or currently being treated for muscle-invasive (i.e., stage T2 or higher) or metastatic urothelial cell carcinoma
• Evidence of concurrent extravesical (i.e., urethra, ureter, or renal pelvis) urothelial cell carcinoma
• BCG-unresponsive NMIBC as defined by the FDA:
• HGT1 within 3 months after an induction BCG course (received ≥5 of 6 doses)
• Persistent or recurrent high-grade NMIBC (Tis, Ta, T1) within 6 months of ≥5 of 6 doses of induction BCG therapy and ≥2 of 3 doses of maintenance BCG therapy

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Condition: Bladder Adenocarcinoma, Bladder Clear Cell Adenocarcinoma, Bladder Mixed Adenocarcinoma, Bladder Neuroendocrine Carcinoma, Bladder Small Cell Neuroendocrine Carcinoma, Bladder Squamous Cell Carcinoma, Chromophobe Renal Cell Carcinoma, Collecting Duct Carcinoma, Invasive Bladder Giant Cell Urothelial Carcinoma, Invasive Bladder Lymphoepithelioma-Like Carcinoma, Invasive Bladder Nested Urothelial Carcinoma, Invasive Bladder Plasmacytoid Urothelial Carcinoma, Invasive Bladder Sarcomatoid Urothelial Carcinoma, Invasive Bladder Urothelial Carcinoma, Kidney Medullary Carcinoma, Large Cell Neuroendocrine Carcinoma, Malignant Testicular Leydig Cell Tumor, Malignant Testicular Sertoli Cell Tumor, Metastatic Bladder Carcinoma, Metastatic Bladder Clear Cell (Glycogen-Rich) Urothelial Carcinoma, Metastatic Bladder Giant Cell Urothelial Carcinoma, Metastatic Bladder Large Cell Neuroendocrine Carcinoma, Metastatic Bladder Lipid-Rich Urothelial Carcinoma, Metastatic Bladder Micropapillary Urothelial Carcinoma, Metastatic Bladder Plasmacytoid Urothelial Carcinoma, Metastatic Bladder Sarcomatoid Urothelial Carcinoma, Metastatic Bladder Small Cell Neuroendocrine Carcinoma, Metastatic Bladder Squamous Cell Carcinoma, Metastatic Chromophobe Renal Cell Carcinoma, Metastatic Kidney Medullary Carcinoma, Metastatic Malignant Genitourinary System Neoplasm, Metastatic Papillary Renal Cell Carcinoma, Metastatic Penile Carcinoma, Metastatic Prostate Small Cell Neuroendocrine Carcinoma, Metastatic Sarcomatoid Renal Cell Carcinoma, Metastatic Urethral Carcinoma, Papillary Renal Cell Carcinoma, Sarcomatoid Renal Cell Carcinoma, Stage IV Bladder Cancer AJCC v8, Stage IV Penile Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, Stage IV Urethral Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8, Urachal Adenocarcinoma, Urethral Clear Cell Adenocarcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03866382

Sponsor: National Cancer Institute (NCI)

Phase: Phase 2

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• Metastatic disease defined as new or progressive lesions on cross-sectional imaging or bone scan. Patients must have at least:
• One measurable site of disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• One bone lesion on bone scan (tec99 or sodium fluoride [NaF] PET/CT, CT or MRI) for the bone-only cohort.
• Histologically confirmed diagnosis of one of the following metastatic cohorts:
• Small cell/ neuroendocrine carcinoma of the bladder (Cohort A)- All urothelial carcinomas with any amount of neuroendocrine differentiation (including small cell differentiation) will be included. If the tumor is purely neuroendocrine, metastasis from another site of origin should be clinically excluded
• Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra clear cell adenocarcinoma (Cohort B)
• must be pure (per World Health Organization [WHO] definition), (i.e. urothelial carcinoma with glandular differentiation is not considered a pure adenocarcinoma
• Squamous cell carcinoma of the bladder (Cohort C)
• must be pure (i.e. urothelial carcinoma with squamous differentiation is not considered a pure squamous cell carcinoma)
• Plasmacytoid urothelial carcinoma (Cohort D)
• Tumor should show predominantly > or equal ~ 50% plasmacytoid histology (including all types of discohesive growth, such as tumors with signet-ring and/or rhabdoid features as well)
• Any penile cancer (Cohort E)
• Sarcomatoid renal cell carcinoma (Cohort F)
• Tumor should be predominantly sarcomatoid ~ 50% (including rhabdoid differentiation) is also unclassified renal cell carcinomas (RCCs): all (assuming they are high grade with metastasis) malignant angiomyolipomas are allowed
• Other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to (Cohort G) : Micropapillary (Tumor should show predominantly > or equal 50% micropapillary architecture), giant cell, lipid-rich, clear cell and nested variants (Tumor should predominantly > or equal 50% show these features), large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer (Only treatment-naïve primary small cell of prostate with any amount of small cell component allowed. Post-treatment small cell prostatic carcinomas are not allowed), Malignant testicular Sertoli or Leydig cell tumors, and papillary and chromophobe RCC
• Note: Translocation positive renal cell carcinoma patients are eligible. However, AREN1721 should be considered before this trial
• Sarcomatoid urothelial carcinoma (Cohort H)
• Tumor should show predominantly ~ 50% sarcomatoid differentiation
• Renal medullary carcinoma (Cohort I)
• Per World Health Organization (WHO) definition, ideally confirmed with immunostains
• Bone-only metastatic GU tumors (non-prostate) (Cohort J)
• All genitourinary histologies, except prostate are eligible
• Renal Collecting Duct Carcinoma (Cohort K)
• Per WHO definition (medullary involvement, predominant tubular morphology, desmoplastic stromal reaction, high grade cytology, infiltrative growth pattern, and absence of other renal cell carcinoma subtype or urothelial carcinoma)
• Urethra carcinoma (Cohort L)
• May be of any histology but if urothelial carcinoma then must be isolated to the urethra and not have metachronous or synchronous urothelial carcinoma of the bladder
• H&E slides from diagnostic tumor tissue for retrospective central pathology review
• Patients may have received up to 2 systemic anti-cancer treatments or be treatment naive. Patients with small cell carcinoma should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients in the bone-only cohort may be urothelial carcinoma histology but must receive standard cisplatin-based chemotherapy (if cisplatin-eligible)
• Age >= 18 years
• Patients must be able to swallow oral formulation of the tablets
• Karnofsky performance status >= 80%
• Absolute neutrophil count (ANC) >= 1,000/mcL
• Platelet count >= 75,000/mcL
• Total bilirubin =< 1.5 x upper limit of normal (ULN). For subjects with known Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total bilirubin =< 3.0 mg/dL
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x institutional upper limit of normal (ULN) (or =< 5 x ULN for patients with liver metastases or Gilbert's disease)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology [CKD-EPI] equation or Cockcroft-Gault formula) for patients with creatinine levels above institutional normal
• Hemoglobin >= 9 g/dL (transfusion of packed red blood cells [PRBCs] allowed)
• Serum albumin >= 3.2 g/dL
• Lipase and amylase =< 2.0 x ULN and no radiologic (on baseline anatomical imaging) or clinical evidence of pancreatitis
• Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib will not be allowed. Also, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed
• No prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4 inhibitors. With the exception of bone-only (cohort J) or urethral tumors (cohort L) with "urothelial carcinoma" histology
• Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of highly active antiretroviral therapy (HAART), no clinically significant drug-drug interactions are anticipated with the current HAART regimen, CD4 counts are greater than 350 and viral load is undetectable
• Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication only and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc. are eligible but should be considered for rheumatologic evaluation for the presence of target organ involvement and potential need for systemic treatment
• Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones or medications (e.g. thyroiditis managed with propylthiouracil [PTU] or methimazole) including physiologic oral corticosteroids are eligible
• Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, and gastrointestinal (GI) obstruction, within 12 months are not eligible
• Women of childbearing potential must have a negative pregnancy test =< 7 days prior to registration
• Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea >= 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
• Pregnant women may not participate in this study because with cabozantinib, nivolumab, and ipilimumab have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib, nivolumab, and ipilimumab, breastfeeding should be discontinued if the mother is treated with these agents
• The patient has received no cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2 weeks before the first dose of study treatment
• The patient has received no radiation therapy:
• To the lungs and mediastinum or abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy
• To brain metastasis within 3 weeks for whole-brain radiotherapy (WBXRT), and 2 weeks for stereotactic body radiation therapy (SBRT) before the first dose of study treatment
• To the abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy
• To any other site(s) within 2 weeks before the first dose of study treatment
• The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment
• The patient has received no prior treatment with a small molecule kinase inhibitor within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment
• The patient has received no prior treatment with hormonal therapy within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. Subjects receiving gonadotropin-releasing hormone (GnRH) agonists and antagonists are allowed to participate
• The patient has not received any other type of investigational agent within 14 days before the first dose of study treatment
• The patient must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia, neuropathy and other non-clinically significant adverse events (AEs) defined as lab elevation with no associated symptoms or sequelae
• The patient may not have active brain metastases or epidural disease. Patients with brain metastases previously treated with whole brain radiation or radiosurgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility
• No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor Xa inhibitors, low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted
• No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort) or strong CYP3A4 inhibitors
• Because the lists of these agents are constantly changing, it is important to regularly consult medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• The patient has not experienced any of the following:
• Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
• Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood per day within 1 months before the first dose of study treatment
• Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• The patient has no tumor invading any major blood vessels
• The patient has no evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib. Patients with rectal tumor masses are not eligible
• The patient has no uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders including:
• Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening.
• Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
• Any history of congenital long QT syndrome
• Any of the following within 6 months before registration of study treatment:
• Unstable angina pectoris
• Clinically-significant cardiac arrhythmias (patients with atrial fibrillation are eligible)
• Stroke (including transient ischemic attack [TIA], or other ischemic event)
• Myocardial infarction
• Cardiomyopathy
• No significant gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
• Any of the following that have not resolved within 28 days before the first dose of study treatment:
• Active peptic ulcer disease
• Acute diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or malabsorption syndrome
• None of the following within 2 years before the first dose of study treatment:
• Abdominal fistula or genitourinary fistula
• Gastrointestinal perforation
• Bowel obstruction or gastric outlet obstruction
• Intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 2 years before the first dose of study treatment
• Disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement are not eligible
• No other clinically significant disorders such as:
• Severe active infection requiring IV systemic treatment within 14 days before the first dose of study treatment
• Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
• History of organ or allogeneic stem cell transplant
• Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment (for asymptomatic patients with an elevated thyroid-stimulating hormone [TSH], thyroid replacement may be initiated if clinically indicated without delaying the start of study treatment)
• No history of major surgery as follows:
• Major surgery within 3 months of the first dose of cabozantinib; however, if there were no wound healing complications, patients with rapidly growing aggressive cancers, may start as soon as 6 weeks if wound has completely healed post-surgery
• Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications excluding core biopsies and mediport placement
• Complete wound healing from prior surgery must be confirmed before the first dose of cabozantinib irrespective of the time from surgery
• No history of severe hypersensitivity reaction to any monoclonal antibody
• No evidence of active malignancy, requiring systemic treatment within 2 years of registration
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in study
• No positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. If HBV sAG is positive, subsequent ribonucleic acid (RNA) polymerase chain reaction (PCR) must be negative
• No patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include, but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease

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Condition: Bladder Cancer, Urinary Tract Cancer, Urothelial Cancer, Healthy Volunteers

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT02379429

Sponsor: National Cancer Institute (NCI)

Phase:

Eligibility:

• Age: minimum 18 Years maximum N/A
• Gender: All

Inclusion Criteria:

• FOR UROTHELIAL CANCER PARTICIPANTS:
• Adults (>= 18 years of age) with biopsy-proven or suspected urothelial cancer who require and are willing to undergo diagnostic or therapeutic intervention as part of their diagnosis, standard of care treatment, or follow-up/surveillance for their neoplasm.
• ECOG performance status of 0-3.
• Must be willing and able to provide informed consent. EXCLUSION CRITERIA:
• Subjects who are pregnant.
• Subjects co-morbidities preclude diagnostic or therapeutic intervention. Co-morbidities include: --Ongoing treatment for another non-skin malignancy.
• History of hepatitis B/C or HIV. Patients who are HIV positive are excluded from this study because treatment with immunomodulatory agents for immunosuppressed patients would affect sample analysis and skew the data. ELIGIBILITY CRITERIA FOR HEALTHY VOLUNTEERS INCLUSION CRITERIA: -Adults (greater than or equal to 18 years of age) and able to give informed consent.

Exclusion Criteria:

• Subjects who are pregnant.
• Subjects co-morbidities preclude diagnostic or therapeutic intervention. Co-morbidities include: --Ongoing treatment for another non-skin malignancy.
• History of hepatitis B/C or HIV. Patients who are HIV positive are excluded from this study because treatment with immunomodulatory agents for immunosuppressed patients would affect sample analysis and skew the data.

Eligibility Criteria:

• FOR HEALTHY VOLUNTEERS INCLUSION CRITERIA: -Adults (greater than or equal to 18 years of age) and able to give informed consent. EXCLUSION CRITERIA:
• Subjects who are pregnant.
• Diagnosis of cancer requiring treatment other than minor resection of basal cell or squamous cell skin cancers.
• Heart, lung, kidney disease, or other medical conditions as per Principal Investigator discretion.
• History of acute or chronic hepatitis B/C or HIV infection. Patients who are HIV positive are excluded from this study because treatment with immunomodulatory agents for immunosuppressed patients would affect sample analysis and skew the data.
• Healthy volunteers who are family members with germline mutations.

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