Genitourinary Tumors With Sacituzumab Tirumotecan

RINGQUEST is a Phase 2, open-label, single arm, basket, investigator-initiated clinical trial of sacituzumab tirumotecan in patients with: * Cohort 1: papillary renal carcinoma (pRCC). * Cohort 2: less frequent bladder tumors such as variant histology urothelial carcinoma (VH-UC). The most common VH-UC are nested, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid, giant cell, poorly differentiated, lipid-rich, clear cell, sarcomatoid) bladder cancer and non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (urachal and non-urachal).

Inclusion Criteria: Informed Consent 1. The participant provides written informed consent for the study. 2. Be willing and able to comply with study procedures, laboratory tests, and other requirements of the study. Disease Characteristics 3. Histologically confirmed diagnosis of metastatic or locally advanced unresectable: * Cohort 1: papillary renal carcinoma (pRCC). * Cohort 2: variant histology urothelial carcinoma (VH-UC) including the following subtypes: nested, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid, giant cell, poorly differentiated, lipid-rich, clear cell, sarcomatoid) bladder cancer and non-urothelial bladder cancer of epithelial origin including squamous cell carcinoma and adenocarcinoma (urachal and non-urachal). Note: Variant histology tumors and non-urothelial tumors of ureter, urethra, urachus, or renal pelvis are included. Note: Patients with mixed cell type are eligible if the predominant histology (over 50%) is variant or non-urothelial. All histological classifications will follow the 2022 world health organization (WHO) Classifications. 4. Disease progression after standard treatment or lack of available standard treatment options: * Cohort 1: Prior treatment with PD-1/PD-L1 and or tyrosine kinase inhibitors (TKIs) * Cohort 2: Disease progression after standard treatment. Some VH such as micropapillary, small cell, and sarcomatoid variants are considered highly aggressive and no standard treatments are clearly defined, being considered an orphan disease, so they might be included in the first line in case of lack of available standard treatment options. 5. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Note: Lesions situated in a previously-irradiated area are considered measurable if progression has been shown in such lesions. Demographics 6. Is an individual of any sex/gender and is at least 18 years of age at the time of providing the informed consent. Patient Status 7. Has an eastern cooperative Oncology Group Performance status (ECOG PS) of 0 - 1. 8. Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline (except for alopecia and vitiligo). Note: Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible. 9. Adequate organ function. Specimens must be collected within 10 days before the start of study intervention: absolute neutrophil count (ANC) ≥1500/µL \* Platelets ≥100,000/µL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L \* Measured or calculated creatinine clearance (CrCl) ≥30 mL/min Total bilirubin ≤1.5 × upper limit normal (ULN) OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) Albumin ≥3.0 g/dL \*\* international normalized ratio (INR) or prothrombin time (PT) / activated patial thromboplastin (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants \* without colony-stimulating factors, erythropoietin dependency, and without packed red blood cell (pRBC) transfusion within the preceding 2 weeks. \*\* without albumin supplementation within the last 72 hours. 10. Has provided an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion from any site (primary or metastasis) not previously irradiated. Sites should follow local guidelines regarding fresh tissue collection. Tissue is required for determination of TROP-2 status by the central laboratory. No central pathological review and TROP-2 expression level assessment will be needed to include the patient in the trial. 11. HIV-infected participants must have well-controlled HIV on antirretroviral therapy (ART), defined as: * Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening * Having achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 or the lower limit of quantification using the locally available assay, at the time of screening and for at least 12 weeks before screening * Absence of any AIDS-defining opportunistic infections within the past 12 months * Being on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before randomization and agreeing to continue ART throughout the study Note: The ART regimen must not contain any antiretroviral medications that are strong CYP3A4 inducers/inhibitors/substrates. * HIV testing at screening is not required unless: There is a known history of HIV infection Mandated by local guidelines 12. Participants who are HBsAg positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load before randomization. Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention. \- Hepatitis B testing at screening is not required unless: There is a known history of HBV infection Mandated by local guidelines 13. Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening. Note: Participants must have completed curative antiviral therapy at least 4 weeks before randomization. \- Hepatitis C testing at screening is not required unless: There is a known history of HCV infection Mandated by local guidelines Male Participants 14. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least 120 days after the last dose of sacituzumab tirumotecan: * Refrains from donating sperm. * Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant plus partner use of an additional contraceptive method, as a condom may break or leak. Note: If the participant is azoospermic (vasectomized or secondary to medical cause, documented from the site personnel's review of the participant's medical records, medical examination, or medical history interview), no contraception is required. Female Participants 15. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a women of childbearing potential (WOCBP) OR * Is a WOCBP and: Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Medical history, menstrual history, and recent sexual activity has been reviewed by the physician investigator to decrease the risk for inclusion of a WOCBP with an early undetected pregnancy. The participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction. Uses a contraceptive method that is highly effective (with a failure rate of \480 ms, and/or other serious cardiovascular and cerebrovascular diseases within 6 months before the first dose of study intervention. 6. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) who have undergone potentially curative resection are not excluded. Note: Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate specific antigen \