Renal Retention in High Grade Upper Tract Urothelial Cancer

Inclusion Criteria:

1. Male/female participants who are at least 18 years of age on the day of signinginformed consent with histologically confirmed diagnosis of histologicallydocumented, high grade upper tract urothelial cancer, (UTUC can be diagnosed bydirect visualization and biopsy, or by 3 dimensional imaging and positive urinecytology) will be enrolled in this study.

2. Patients must refuse definitive radical nephroureterectomy (RNU), or be medicallyineligible for surgery. To be medically ineligible, patients must, in the opinion ofthe clinical team, be at high risk of complications intra or perioperative whichwould adversely impact morbidity and mortality, including risk of CKD and ESRD.

3. Subjects must not have received prior systemic therapy for locally advanced ormetastatic urothelial carcinoma (in other locations such as the bladder orcontralateral ureter or renal pelvis) with the following exceptions:

4. Subjects who received neoadjuvant chemotherapy with recurrence >12 months fromcompletion of therapy are permitted

5. Subjects that received adjuvant chemotherapy following cystectomy withrecurrence >12 months from completion of therapy are permitted

6. Subjects may have radiographic evidence of N1 disease (Metastasis ≤2 cm in greatestdimension, in a single lymph node)

7. Subjects must be age 18 years or older.

8. Archival tumor tissue will be used for eligibility.

9. Subjects must have an ECOG Performance Status score of 0 or 2

10. Subjects must have adequate hematologic and organ function as defined by thebaseline laboratory values in Table 3. Transfusion of red blood cells to meeteligibility criteria is allowed. Table 3 - Baseline Laboratory Values Hematological: ANC: ≥1500/μL Platelets: ≥100,000/μL Hemoglobin: ≥9.0 g/dL or ≥5.6 mmol/L Hepatic: Total Bilirubin: ≤1.5× ULN AST (SGOT) and ALT (SGPT): No adjustment in the startingdose is required when administering PADCEV to patients with mild hepatic impairment (total bilirubin 1 to 1.5 × ULN and AST any, or total bilirubin ≤ULN and AST >ULN).

11. A female subject of childbearing potential is anyone born female who has experiencedmenarche and who has not undergone surgical sterilization (e.g., hysterectomy,bilateral salpingectomy, bilateral oophorectomy) or has not completed menopause.Menopause is defined clinically as 12 months of amenorrhea in a person over age 45in the absence of other biological, physiological, or pharmacological causes. Femalesubjects of childbearing potential must meet the following conditions:

• Agree not to try to become pregnant during the study and for at least 6 monthsafter the final dose of study drug.

• Must have a negative urine or serum pregnancy test (minimum sensitivity of 25mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 1 day prior to administration of study drug. Female subjects with falsepositive results and documented verification of negative pregnancy status areeligible for participation.

• If heterosexually active, must consistently use highly effective methods ofbirth control, with a failure rate of less than 1% (as described in Appendix L)starting at screening, throughout the study period, and for at least 6 monthsafter the final dose of study drug.

• Female subjects must agree not to breastfeed or donate ova starting atscreening and throughout the study period, and for at least 6 months after thefinal dose of study drug.

10. A male subject who can father children is anyone born male who has testes and whohas not undergone surgical sterilization (e.g., vasectomy followed by a clinicaltest proving that the procedure was effective). Male subjects who can fatherchildren, must meet the following conditions:

• Must not donate sperm starting at screening and throughout the study period,and for at least 6 months after the final dose of study drug. Male subjectswill be informed about the negative risk to reproductive function and fertilityfrom the study treatment. Prior to treatment male subjects should be advised toseek information on fertility preservation and sperm cryoconservation.

• Must consistently use highly effective methods of birth control, with a failurerate of less than 1% (as described in Appendix L) starting at screening andcontinue throughout study period and for at least 6 months after the final doseof study drug.

• Male subjects with a pregnant or breastfeeding partner(s) must consistently useone of 2 contraception options for preventing secondary exposure to seminalfluid (as described in Appendix L) for the duration of the pregnancy or timepartner is breastfeeding throughout the study period and for at least 6 monthsafter the final dose of study drug.

11. Subjects must provide written informed consent.

Exclusion Criteria:

1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs.

2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for anymalignancy, including earlier stage UC, defined as a PD-1 inhibitor orPD-L1inhibitor (including, but not limited to, atezolizumab, pembrolizumab,nivolumab, durvalumab, or avelumab).

3. Subjects who have previously received any prior treatment with an agent directed toanother stimulatory or co inhibitory T-cell receptor (including but not limited toCD137 agonists, CTLA-4 inhibitors, or OX-40 agonists).

4. Subjects who have received anti-cancer treatment with chemotherapy, biologics, orinvestigational agents not otherwise prohibited by exclusion criterion 1-3 that isnot completed 4 weeks prior to first dose of study treatment (ongoing hormonal/antihormonal treatment, e.g., for breast cancer, is allowed, provided that the subjectis eligible per exclusion criteria 14).

5. Subjects with uncontrolled diabetes. Uncontrolled diabetes is defined as hemoglobinA1c (HbA1c) ≥8% or HbA1c 7% to <8% with associated diabetes symptoms (polyuria orpolydipsia) that are not otherwise explained.

6. Subjects with an estimated life expectancy <12 weeks

7. Subjects with ongoing sensory or motor neuropathy Grade 2 or higher.

8. Subjects with ongoing clinically significant toxicity associated with priortreatment (including radiotherapy or surgery) that has not resolved to ≤ Grade 1 orreturned to baseline.

9. Currently receiving systemic antimicrobial treatment for active infection (viral,bacterial, or fungal) at the time of treatment initiation. Routine antimicrobialprophylaxis is permitted.

10. Subjects who have known active hepatitis B (defined as HBsAg reactive) or knownactive hepatitis C virus (defined as HCV RNA [qualitative] detected) infection,testing for hepatitis B and hepatitis C is required if mandated by country healthauthority. Subjects who have been curatively treated for hepatitis C infection arepermitted if they have documented sustained virologic response of 12 weeks.

11. Has a known history of human immunodeficiency virus (HIV) infection. Testing is notrequired unless mandated by the local health authority.

12. Subjects with conditions requiring high doses of steroids (>10 mg/day of prednisoneor equivalent) or other immunosuppressive medications are excluded. Inhaled ortopical steroids are permitted in the absence of active autoimmune disease.Physiologic replacement doses of corticosteroids are permitted for subjects withadrenal insufficiency.

13. Subjects with another active second malignancy other than non-melanoma skin cancersand biochemical relapsed prostate cancer. Subjects that have completed all necessarytherapy and are considered to be at less than 30% risk of relapse are not consideredto have an active second malignancy and are eligible for enrollment.

14. Patients may have a history of resected urothelial cancer of the bladder orcontralateral upper tract, (including neoadjuvant chemotherapy) in the followingcategories. These disease states are not exclusions and patients with this historywill have this recorded and be considered for study on a case by case basis:

• pT0, Tis, or T1N0 and have no evidence of disease (NED) for more than 2 yearsfrom surgery or chemotherapy;

• pT2-3aN0 and NED for more than 3 years from surgery or chemotherapy; or

• >pT3b, or N+ and NED for more than 5 years from surgery or chemotherapy.

• Patients with concomitant HG UTUC bilaterally will be considered for protocolon a case by case basis.

15. Subjects with a documented history of a cerebral vascular event (stroke or transientischemic attack), unstable angina, myocardial infarction, or cardiac symptomsconsistent with NYHA Class IV within 6 months prior to treatment initiation (Appendix D).

16. Subjects who have received radiotherapy within 2 weeks prior to treatmentinitiation. Subject must have recovered adequately from the toxicity from theintervention prior to starting study treatment. Participants must have recoveredfrom all radiation-related toxicities, not require corticosteroids, and not have hadradiation pneumonitis.

17. Subjects who have received major surgery within 4 weeks prior to treatmentinitiation. Subject must have recovered adequately from complications from theintervention prior to starting study treatment.

18. Subjects with known severe (≥ Grade 3) hypersensitivity to any enfortumab vedotinexcipient contained in the drug formulation of enfortumab vedotin (includinghistidine, trehalose dihydrate, and polysorbate 20). Subjects with known severe (≥Grade 3) hypersensitivity to any pembrolizumab excipient contained in the drugformulations of pembrolizumab. Subjects with known severe (≥ Grade 3)hypersensitivity to the platinum agent selected by the investigator for studytreatment. Subjects with known severe (≥ Grade 3) hypersensitivity to thegemcitabine.

19. Subjects with active keratitis or corneal ulcerations. Subjects with superficialpunctate keratitis are allowed if the disorder is being adequately treated in theopinion of the investigator.

20. History of autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs).

21. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency) is not considered aform of systemic treatment and is allowed.

22. Brief (<7 days) use of systemic corticosteroids is allowed when use isconsidered standard of care.

23. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, orresolved childhood asthma/atopy will not be excluded.

24. Subjects requiring intermittent use of bronchodilators, inhaled steroids, orlocal steroid injections will not be excluded.

25. Subjects with hypothyroidism that is stable with hormone replacement orSjögren's syndrome will not be excluded.

26. Subjects with a history of idiopathic pulmonary fibrosis, organizing pneumonia,drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitison screening chest CT scan. Has a history of (non-infectious)pneumonitis/interstitial lung disease that required steroids or has currentpneumonitis/interstitial lung disease.

27. Subjects who have received a prior allogeneic stem cell or solid organ transplant. Subjects who have received a live vaccine or live-attenuated vaccine within 30 daysprior to treatment initiation. Administration of killed vaccines is allowed. Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particularcountry is allowed in the study as long as they are mRNA vaccines, adenoviralvaccines, or inactivated vaccines. These vaccines will be treated just as any otherconcomitant therapy. Investigational vaccines (i.e., those not licensed or approvedfor Emergency Use) are not allowed.

28. Seasonal influenza vaccines for injection are generally killed virus vaccines andare allowed; however, intranasal influenza vaccines (e.g., FluMist®) are liveattenuated vaccines and are not allowed.

29. Subjects with active tuberculosis

30. Subjects with another underlying medical condition that, in the opinion of theinvestigator, would impair the ability of the subject to receive or tolerate theplanned treatment and follow-up; any known psychiatric or substance abuse disordersthat would interfere with cooperating with the requirements of the study.