This pan-tumor trial is designed as a signal-seeking trial to assess efficacy and safety of raludotatug deruxtecan (R-DXd) monotherapy in locally advanced or metastatic solid tumors with various cadherin-6 (CDH6) expression levels, including gynecological cancers (endometrial cancer, cervical cancer, and non-high-grade serous ovarian cancer) and genitourinary cancers (urothelial cancer and clear cell renal cell carcinoma [ccRCC]).

This trial is designed to evaluate the efficacy and safety of R-DXd in locally advanced or metastatic solid tumors with various CDH6 expression levels. Solid tumor types will include gynecological cancers (endometrial cancer, cervical cancer, and non-high-grade serous ovarian cancer) and genitourinary cancers (urothelial cancer and ccRCC).

For all cohorts except ccRCC, the primary endpoint will be objective response rate (ORR) by investigator assessment per RECIST 1.1. For the ccRCC cohort, the primary endpoint will be disease control rate (DCR) by investigator assessment per RECIST 1.1. All cohorts will also have the assessment of safety and tolerability as another primary objective.

Participants must meet all of the following criteria to be eligible for enrollment into the trial:

1. Adults ≥18 years of age on the day of signing the ICF.

2. Participants must have at least 1 lesion, not previously irradiated, amenable to biopsy, and must consent to provide a pre-treatment biopsy from a primary and/or metastatic lesion.

3. Has at least 1 measurable lesion according to RECIST version 1.1 per investigator assessment.

4. Participants must have progressed radiologically on or after their most recent line of systemic therapy.

5. Eastern Cooperative Oncology Group performance status of 0 or 1.

6. Additional inclusion criteria for endometrial cancer cohort

   1. Pathologically or cytologically documented endometrial cancer (carcinoma of any histological subtype or carcinosarcoma), irrespective of MSI or mismatch repair status.
   2. Documented disease progression after having received ≥1 line of therapy (no more than 3), including PBC-containing systemic treatment and an anti-PD-1 therapy containing regimen (combined or sequential) in the advanced/metastatic setting.

7. Additional inclusion criteria for cervical cancer cohort

   1. Pathologically or cytologically documented recurrent or persistent squamous, adenosquamous, or adenocarcinoma of the uterine cervix.
   2. Disease progression after having received ≥1 prior line of therapy that includes systemic therapy in the advanced or metastatic setting.

8. Additional inclusion criterion for non-HGSOC cohort

   a. Pathologically or cytologically documented unresectable or metastatic CCOC, low grade endometrioid, low-grade serous, or mucinous OVC that was previously treated with at least 1 prior line of therapy.

9. Additional inclusion criteria for urothelial cancer cohort

   1. Pathologically or cytologically documented unresectable or metastatic urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra. Histological variants are allowed if urothelial histology is predominant.
   2. Relapsed or progressed after treatment with ≥1 prior line of therapy (maximum of 3) that contains anti-PD-(L)1 therapy in the perioperative or metastatic setting.

10. Additional inclusion criterion for the ccRCC cohort a. Pathologically or cytologically documented unresectable or metastatic ccRCC that was previously treated with no more than 3 prior systemic regimens for locally advanced or metastatic RCC, including both a PD-(L)1 checkpoint inhibitor and a VEGF-TKI in sequence or in combination.

Participants who meet any of the following criteria will be disqualified from entering the trial:

1. Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis
2. Any of the following within the past 6 months prior to enrollment: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.
3. Uncontrolled or significant cardiovascular disease as specified in the protocol.
4. Has a history of (noninfectious) ILD/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Clinically severe pulmonary compromise
6. Chronic steroid treatment (>10 mg/day) with exceptions as noted in the protocol.
7. History of other active malignancy within 3 years prior to enrollment, with the exception of those with a negligible risk of metastasis or death (eg, 5-year OS rate >90%) and treated with expected curative outcome.
8. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Version 5.0, Grade ≤1 or baseline.
9. Prior exposure to other CDH6-targeted agents or an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan, datopotamab deruxtecan).
10. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.
11. Has active or uncontrolled HIV, HBV, or HCV infection.

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.