A Study of Disitamab Vedotin Alone or With Pembrolizumab in Urothelial Cancer That Expresses HER2

A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC) Alone or in Combination With Pembrolizumab in Subjects With Locally-Advanced Unresectable or Metastatic Urothelial Carcinoma That Expresses HER2

This study is being done to see if a drug called disitamab vedotin, alone or with pembrolizumab, works to treat HER2 expressing urothelial cancer. It will also test how safe the drug is for participants. Participants will have cancer that has spread in the body near where it started (locally advanced) and cannot be removed (unresectable) or has spread through the body (metastatic). It will also study what side effects happen when participants get the drug. A side effect is anything a drug does to your body besides treating the disease.

Urothelial Cancer, Bladder Cancer, HER2 Mutations, HER2 Overexpression, HER2 Amplification, RC48, Seattle Genetics

Cohorts A, B, C, and D will enroll simultaneously. Cohort E will begin enrollment after Cohort D participants have completed the DLT evaluation period.

Confirmed Objective Response Rate (cORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1) by blinded independent central review (BICR) (Cohorts A, B, and C)

The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1

Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

The time from first documentation of objective tumor response (confirmed CR or PR) to the first documentation of tumor progression per RECIST v1.1 or death due to any cause.

The time from first documentation of objective tumor response (confirmed CR or PR) to the first documentation of tumor progression per RECIST v1.1 or death due to any cause.

The time from the start of study treatment or randomization (if applicable) to the first documentation of disease progression per RECIST v1.1 or death due to any cause.

The time from the start of study treatment or randomization (if applicable) to the first documentation of disease progression per RECIST v1.1 or death due to any cause.

The proportion of participants who have achieved objective response (confirmed CR or PR as per RECIST v1.1 criteria) or stable disease (SD) lasting at least 5 weeks.

The proportion of participants who have achieved objective response (confirmed CR or PR as per RECIST v 1.1 criteria) or SD lasting at least 5 weeks.

The time from start of study treatment or randomization (if applicable) to the date of death due to any cause.

Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

Inclusion Criteria: Cohorts A and B Histopathologically-confirmed, locally-advanced, unresectable or metastatic urothelial cancer (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra Participants must have received only 1 or 2 lines of prior systemic treatment for LA/mUC, including 1 line of platinum-containing chemotherapy At least one measurable lesion by investigator assessment based on RECIST version 1.1. HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 Cohort C Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra No prior systemic therapy for LA/mUC Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy At least one measurable lesion by investigator assessment based on RECIST v1.1. Participant is eligible to receive cisplatin- or carboplatin- containing chemotherapy per investigator evaluation HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, on the provided tumor tissue sample ECOG performance status of 0, 1, or 2 Cohort D Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra Based on a participant's eligibility to receive treatment with standard of care therapies in Japan, participants must have received all of the following lines of therapy for LA/mUC: a. One prior line of platinum-containing chemotherapy. b. Prior therapy with PD-(L)1 inhibitors as (neo)adjuvant therapy, first-line maintenance therapy or as second line treatment. c. Prior enfortumab vedotin therapy. At least one measurable lesion by investigator assessment based on RECIST v1.1. ECOG performance status of 0 or 1 Cohort E Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra No prior systemic therapy for LA/mUC Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy. At least one measurable lesion by investigator assessment based on RECIST v1.1. Participant is eligible to receive cisplatin- or carboplatin- containing chemotherapy per investigator evaluation HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, in the provided tumor sample ECOG performance status of 0 or 1 Exclusion Criteria: Cohorts A and B Known hypersensitivity to disitamab vedotin or any of their components Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohorts A and B) Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia) Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy Major surgery that has not fully recovered within 4 weeks prior to dose administration Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline Cohort C Known hypersensitivity to disitamab vedotin, pembrolizumab, or any of their components Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study defined as Cycle 1 Day 1 for the single-arm part of Cohort C and as randomization date for the randomized part of Cohort C) Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia) Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy Major surgery that has not fully recovered within 4 weeks prior to dose administration Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug Participants who have previously received any prior treatment with an agent directed to another stimulatory or co-inhibitory T cell receptor (including but not limited to CD137 agonists, CAR-T cell therapy, CTLA-4 inhibitors, or OX-40 agonists) are excluded. Cohort D Known hypersensitivity to disitamab vedotin or any of their components Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohort D) Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia) Any prior history of ≥ Grade 3 non-hematological AEs related to prior therapy Major surgery that has not fully recovered within 4 weeks prior to dose administration Peripheral sensory or motor neuropathy ≥ Grade 1 at baseline Cohort E Known hypersensitivity to disitamab vedotin, pembrolizumab, or any of their components Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohort E) Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia) Any prior history of ≥ Grade 3 non-hematological AEs related to prior therapy Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy Major surgery that has not fully recovered within 4 weeks prior to dose administration Peripheral sensory or motor neuropathy ≥ Grade 1 at baseline Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.