Protocol: ECOG – EA8192

Schema – EA8192

Please Note: Below is partial eligibility, for full eligibility requirements, please contact the Genesys Hurley Cancer Institute, Research Department at (810)762-8181, (810)762-8079 and/or (810)762-8038. Thank you!

Eligibility:

1. Patient must be ≥18 years of age.
2. Patient must have a diagnosis of high grade upper tract urothelial carcinoma proven by biopsy within 12 weeks (84 days) prior to registration/randomization with one of the following:
   1. • Upper urinary tract mass on cross-sectional imaging or
   2. Tumor directly visualized during upper urinary tract endoscopy before referral to medical oncology.      NOTE: Biopsy is SOC and required for enrollment to study. This is vital for best practice.
3. Patients must not have any component of small cell/neuroendocrine carcinoma. Other variant histologic types are permitted provided the predominant (≥ 50%) subtype is urothelial carcinoma.
4. Patients must have no evidence of metastatic disease or clinically enlarged regional lymph nodes (≥1.5 cm short axis) on imaging required within 28 days prior to registration. (Non-regional findings ≥1.5 cm short axis that in the opinion of the investigator are not concerning for involvement based on radiographic characteristics, chronicity, avidity on PET or other imaging or other criteria can be eligible based on investigator discretion).  NOTE: Patients with elevated alkaline phosphatase, calcium or suspicious bone pain/tenderness can also undergo baseline bone scans to evaluate for bone metastasis at the discretion of local provider.
5. Non-urothelial cancer malignancy history: Patient must not have another active (or within two years) second malignancy other than resected non-melanoma skin cancers, resected in situ breast, cervical or other in situ carcinoma, and either clinically insignificant per the investigator (e.g., ≤Gleason 3+4) on active surveillance (or watchful waiting) or previously treated prostate cancer with no rising PSA and no plan to treat..  NOTE: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients in whom concomitant or prior bladder/urethra
   predominant (≥50%) urothelial carcinoma have been surgically resected and demonstrated to be only non-invasive cancer (< cT1N0) are eligible regardless of time elapsed.
6. Urothelial cancer malignancy history: Patient may have a history of resectable urothelial cancer as long as patients meet one of the following:
   • T0, Ta or Tis at any time
   • T1-4a N0 and no evidence of disease (NED) for more than 2 years from the latest therapy [e.g., radical surgery, TURBT, radiation, chemotherapy (neoadjuvant or adjuvant, or with radiation)]. Prior immune checkpoint inhibitor is not allowed. Patient with history of≥pT4b, N+, and/or M1 is not eligible.    NOTE: Patients in whom concomitant or prior bladder/urethra predominant (≥ 50%) urothelial carcinoma have been surgically resected and demonstrated to be only Ta or CIS (< cT1 N0) are eligible regardless of time elapsed.
7. Patient must not have received prior radiation therapy to ≥ 25% of the bone marrow for other diseases.
8. Patient must not have received prior systemic anthracycline therapy.  NOTE: Patients who have received prior intravesical chemotherapy at any time for non-muscle invasive urothelial carcinoma of the bladder are eligible.
9. Patient must not have had a major surgical procedure within 28 days prior to registration/randomization.  NOTE: Cystoscopy/ureteroscopy, stent placement or nephrostomy tube is not considered major surgery.

10. Patient must have life expectancy of ≥ 12 weeks.

11. Patient must have a body weight of > 30 kg.

12. Patient must have ECOG Performance Status 0-2.

Protocol: Alliance – A032001

Schema – A032001

Please Note: Below is partial eligibility, for full eligibility requirement’s, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 and/or (810) 762-8038. Thank you!

Eligibility:

1. Histologically or cytologically-confirmed diagnosis of advanced or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell
   and mixed transitional/non-transitional cell histologies except for small-cell histology), including N3 only disease prior to start of first-line platinum-based chemotherapy.
2. Prior first-line treatment must have consisted of 4-6 cycles of 1st-line therapy (platinum-based chemotherapy; gemcitabine-cisplatin, gemcitabine-carboplatin,
   MVAC or ddMVAC).
3. No more than 1 line of prior chemotherapy for metastatic or locally advanced disease (neoadjuvant or adjuvant chemotherapy will be allowed if given 12 or more
   months prior to registration).
4. Tumor objective response of CR, PR, or SD upon completion of first line platinum based chemotherapy.
5. The last dose of first-line chemotherapy must have been received no less than 3 weeks, and no more than 10 weeks, prior to randomization in the present study.
6. No prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PDL2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other
   antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
7. Age ≥ 18 years.
8. ECOG Performance Status of 0 or 1.

Protocol: Alliance A031701

Schema – A031701

Please Note: Below is a partial list of eligibility, please contact GHCI Research Department for full eligibility requirements.  Thank you!

Eligibility:

1. Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Urothelial carcinoma invading into the prostatic stroma with no histologic muscle
   invasion is allowed, provided the extent of disease is confirmed via imaging and/or EUA. The diagnostic TURBT sample must have been obtained within 60 days
   prior to registration.
2. Clinical stage T2-T4aN0/xM0 disease.
3. Medically appropriate candidate for radical cystectomy as assessed by surgeon.
4. No concomitant multifocal carcinoma in situ; a single focus is allowed.
5. A single muscle-invasive bladder tumor measuring ≤5 cm in size as defined by the surgeons at cystoscopic evaluation. When documented, pathologic size at
   cystoscopy and TURBT will take precedence over radiographic measurements of tumor size.
6. No clinical or radiographic evidence for locally advanced or metastatic disease.
7. No prior anti-PD-1 or anti PD-L1 therapies, or systemic chemotherapy within the past 5 years (prior intravesical induction immunotherapy for non-muscle invasive
   disease is allowed, defined as BCG x6 doses and maintenance therapy); BCG refractory disease, defined as disease recurrence within 3 months of BCG therapy,
   is not allowed. Intravesical chemotherapy is allowed.
8. No prior radiation therapy to the bladder or prostate.
9. Age ≥ 18 years.
10. ECOG Performance Status 0-1.

Protocol: SWOG – S1937

Schema – S1937

Please Note:  Below is a partial list of eligibility, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 or (810) 762-8038 for full eligibility requirements. Thank you!

Eligibility:

1. Participant must have predominant histologically and cytologically proven urothelial carcinoma in a metastatic site.
2. Participant must have evidence of metastatic urothelial carcinoma based on CT or MRI within 28 days prior to registration.
3. Participant must have had progression of disease following prior therapy at the discretion of the treating investigator.
4. Participants must not require immediate CNS-specific treatment, in the opinion of the treating investigator if they have active brain metastases (defined as new or progressive brain metastases) or leptomeningeal disease.
5. Participant must have received previous systemic treatment for metastatic urothelial carcinoma with either a platinum-based chemotherapy regimen, systemic PD1/PDL1 immunotherapy, an antibody drug conjugate such as,
   enfortumab vedotin or sacituzumab govitecan (through standard of care or a clinical trial) . There is no limit to the number of prior regimens patient may have received for urothelial carcinoma.
6. If participant is a candidate for a platinum-based chemotherapy, then participant must have previously received a platinum-based chemotherapy.
7. If participant is a candidate for immunotherapy, then participant must have previously received immunotherapy. If participant is not a candidate for immunotherapy, then participant either: (a) must have had prior anti
   PD1/PDL1 antibody therapy; OR (b) must have not been a candidate for anti PD1/PDL1 antibody therapy in the opinion of the treating physician.
8. Participant is eligible if platinum based chemotherapy and/or anti PDL/PDL1 antibody therapy was provided in perioperative setting before or after radical cystectomy and if there is evidence of progression to metastatic disease within 12 months of the last dose of therapy. For instance, a patient treated with ddMVAC in neoadjuvant setting, then radical cystectomy followed by adjuvant pembrolizumab on AMBASSADOR trial will meet the requirement for prior/concurrent therapy if progression of disease occurs within 12 months of discontinuation of pembrolizumab.
9. Participant must have received any planned surgery prior to registration.
10. Participant must not have progressed within 3 months following last dose of gemcitabine.
11. Must be at least 18 years of age.
12. Zubrod Performance Status 0-2.
13. Participants may have a prior or concurrent malignancy provided the natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen per the opinion of the treating
    investigator.
14. Participants must not be planning to take strong or moderate CYP3A or CYP2C8 inhibitors or inducers if randomized to Arm 1 and SOC regimen chosen is Paclitaxel or Docetaxel. Participants receiving strong or moderate CYP3A or
    CYP2C8 inducers must discontinue use at least 2 weeks prior to randomization.

PROTOCOL: Alliance-A031803

Schema – A031803

Please Note: Below is partial list of eligibility, please contact GHCI Research Department at (810) 762-8181, (810) 762-8079 or (810) 762-8038 for full eligibility requirements. Thank you!

ELIGIBILITY:

1. High grade Ta, T1 or CIS urothelial carcinoma. Accrual of patients with Ta or T1 disease may be closed to ensure adequate patients enrollment to meet the primary endpoint.
2. Persistent disease after completing therapy with at least induction BCG (≥5 doses) and the first round of maintenance or second induction course (≥2 doses).  Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within
   9 months of the last BCG instillation despite having received adequate BCG as defined above.
3. High grade T1 after completing therapy with at least induction BCG (≥5 doses) or after completing therapy with at least induction BCG (≥5 doses) and first round of maintenance or second induction course (≥2 doses).  Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above.
4. Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible.
5. Patients who are disease free at 6 months after starting BCG but have high grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible.  The recurrence must be within 6 months of the last BCG dose.
6. Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy.
7. All visible tumor must be completely resected 60 days prior to registration (residual pure CIS is permitted). All patients must have histologically confirmed urothelial cancer of the bladder within 60 days prior to registration. All patients must have had a cystoscopy without papillary tumor and negative urinary cytology within 21 days of registration. (positive cytology is allowed in patients with pure CIS).
8. All patients with T1 tumors must undergo a re-staging transurethral resection of bladder tumor (TURBT) within 60 days of registration.There must be uninvolved muscularis propria present in the re-staging TURBT.
   The initial TURBT prior to re-staging TURBT may be greater than 60 days prior to registration.
9. Patients must have had imaging with CT or MRI abdomen/pelvis within 90 days of registration demonstrating no evidence of metastasis.
10. Patients cannot have had a history of urothelial carcinoma in the ureters or prostatic urethra 24 months prior to registration.
11. Patients must not have prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
12. Patients must not have received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment.
13. At least 18 years of age.
14. ECOG Performance Status 0-2.
15. Patients must not have received live vaccines within 30 days of study drug administration.