Genitourinary Tumors With Sacituzumab Tirumotecan (RINGQUEST)

RINGQUEST: Exploring Understudied Genitourinary Tumors With Sacituzumab Tirumotecan; a Single-arm, Basket, Phase II Study.

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Papillary Renal Carcinoma; Variant Histology Urothelial Carcinoma
• Intervention / Treatment: Drug: Sacituzumab Tirumotecan (SKB264)

Detailed Description

The study aim to evaluate the efficacy of Sacituzumab Tirumotecan in patients with rare genitourinary tumors: pRCC and VH-UC by means of objective response rate (ORR) according to RECIST 1.1 criteria.

The trial will follow a Simon two-stage design to enroll competitively up to 100 patients, 50 pRCC and 50 VH-UC. The study will enroll the first 15 patients within each cohort 1 and 2, respectively, and monitor for responses. If the interim analysis surpasses the futility threshold (4 or more tumor responses) in any cohort, that cohort will be expanded up to the total expected patients.

All patients will undergo periodic tumor assessments by CT or MRI scan at screening, C4D1, C8D1, C12D1 and every 12 weeks ± 14 days (3 months) thereafter until progression or patient withdrawal. Further CT/MRI scans could be performed upon suspicion of disease progression according to standard clinical practice and physician criteria. Safety safety (AEs, comorbidities) will be assessed at every visit through continuous monitoring of signs and symptoms and periodic laboratory analysis. The study also includes the assessment of patient reported outcomes regarding quality of life (QoL) that will be assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).

Additionally, TROP-2 expression levels and tumor mutations and genetic alterations will be centrally reviewed in tumor biopsies or archival tumor tissue obtained as close as possible to the baseline.

The study includes an exploratory genomic, transcriptomic, and immune-microenvironment characterization analyses that will map responders versus non-responders.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: GUARD Secretary; Phone Number: 0034933931838; Email: info@guardconsortium.org

Study Locations

• Spain
  • Madrid
    • Madrid, Madrid, Spain, 28041
      • Hospital Universitario 12 de Octubre
      • Contact: A responsible person Designated by the Sponsor; Phone Number: 0034934344412; Email: investigacion@mfar.net
      • Principal Investigator: A Principal Investigator designed by the Sponsor, M.D.; Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least 210 days after the last dose of sacituzumab tirumotecan.

Note: The physician investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by WOCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.

Abstains from breastfeeding during the study intervention period and for at least 10 days after study intervention.

Exclusion Criteria:

Medical Conditions

1. Symptomatic brain metastases or leptomeningeal disease. Note: Participants with previously-treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable, and have not required steroid treatment for at least 14 days before the first dose of study intervention.
2. Has an active infection requiring systemic therapy other than those permitted in the inclusion criteria.
3. Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
4. Has a history of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids or has current pneumonitis/interstitial lung disease or has suspected ILD or pneumonitis that cannot be ruled out by standard diagnostic assessments at screening
5. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to >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 <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.

7. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual's ability to cooperate with the requirements of the study, or interfere with the individual's participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the treating physician investigator.

   Prior/Concomitant Therapy

8. Received prior treatment with a TROP-2-targeted antibody drug conjugate (ADC).
9. Received prior treatment with a topoisomerase 1 inhibitor-containing ADC.
10. Received prior systemic anticancer therapy within 2 weeks before the first dose of study intervention.

11. Received prior radiotherapy within 2 weeks before the first dose of study intervention, has radiation-related toxicities, requiring corticosteroids, and/or has had radiation pneumonitis.

    Note: Two weeks or fewer of palliative radiotherapy for non-central nervous system disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.

12. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.

13. Is currently receiving a strong inducer/inhibitor of CYP3A4 that cannot be discontinued for the duration of treatment with study intervention. The required washout period before starting study intervention is 2 weeks.

    Prior/Concurrent Clinical Study Experience

14. Is currently enrolled on another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited.

15. Has received an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.

    Other Exclusions

16. Severe hypersensitivity (Grades ≥3) to study intervention, any of their excipients, and/or to another biologic therapy.
17. Has had major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention. Anticipation of the need for major surgery during the course of treatment with study intervention is also exclusionary.

Note: Participants who underwent major surgery must have adequately recovered from toxicity and/or complications from the surgery before starting study intervention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: papillary renal carcinoma (pRCC); Patients with pRCC will be included in this group. All patients are allocated to same intervention (sacituzumab tirumotecan), regardless of the cohort	Drug: Sacituzumab Tirumotecan (SKB264); Sacituzumab tirumotecan will be administered by IV infusion on Days 1 of each 2-week cycle. There is a maximum duration of exposure for sacituzumab tirumotecan of 78 doses (approximately 3 years). Treatment may be prematurely terminated in case of disease progression, unacceptable toxicity, consent withdrawal, or physician criteria.
Experimental: Cohort 2: variant histology urothelial carcinoma (VH-UC); Patients with VH-UC will be included in this group. All patients are allocated to same intervention (sacituzumab tirumotecan), regardless of the cohort	Drug: Sacituzumab Tirumotecan (SKB264); Sacituzumab tirumotecan will be administered by IV infusion on Days 1 of each 2-week cycle. There is a maximum duration of exposure for sacituzumab tirumotecan of 78 doses (approximately 3 years). Treatment may be prematurely terminated in case of disease progression, unacceptable toxicity, consent withdrawal, or physician criteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Assessed by the investigator through imaging follow-up (CT scan/MRI) using Response evaluation criteria in solid tumors (RECIST) version 1.1. This will be considered as the percentage of patients with confirmed complete response (CR) or partial response (PR) as their overall best response throughout the study period.	Throughout the study period, up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DoR)	Time from the first response (complete response [CR] or partial response [PR]) documentation to the date of the documented progressive disease (PD) as determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first. DoR will be summarized using Kaplan-Meier method.	Throughout the study period, up to 2 years
Progression-free survival (PFS)	Time from first dosing date to the date of confirmed PD according to RECIST 1.1. Patients alive and free of events at the date of the analysis will be censored at their last known tumor assessment. Patients who start a new treatment line without progression will be censored on the date of first dose of the subsequent anticancer treatment. PFS will be summarized using Kaplan-Meier method.	Throughout the study period, up to 2 years
Overall survival (OS)	defined as the time elapsed from the first dose of study treatment until death from any cause. Survival will be assessed by recording patient status at each visit. OS will be summarized using Kaplan-Meier method.	Throughout the study period, up to 2 years
Patient reported health-related quality of life (HRQoL)	assessed through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30), version 3. This is a standard guide with 30 recommendations designed to assess the health of cancer patients. Different scales are measured, including Global Health and Quality of Life, Functional Aspects, and Symptom Scales. The results for each dimension are linearly transformed to generate scores ranging from 0 to 100. Here we will report the total score: The top of the scale (100) represents "The best health you can imagine." The bottom of the scale (0) represents "The worst health you can imagine."	Throughout the study period, up to 2 years
Proportion of adverse events leading to treatment discontinuation	Defined as the percentage of patients who experience AEs leading to temporary or permanent treatment discontinuation	Throughout the study period, up to 2 years

Collaborators and Investigators

• Sponsor: Alianza multidisciplinar para la investigación de los tumores genitourinarios -GUARD
• Collaborators: Merck Sharp & Dohme LLC; MFAR
• Investigators: Study Chair: Guillermo de Velasco, M.D.; Ph.D., Hospital Universitario 12 de Octubre

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: July 16, 2026
• First Submitted That Met QC Criteria: July 16, 2026
• First Posted (Actual): July 21, 2026

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: SC 2025-01; 2026-526048-10-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No