Brief Title: Disitamab Vedotin in Subjects With HER2 Expressing Urothelial Carcinoma

PRIMARY OUTCOMES

Primary Outcome 1 - Measure:

Primary Outcome 1 - Timeframe: N/A

CONDITION

• Urothelial Carcinoma

ELIGIBILITY

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)

- * Prior HER2-directed therapy

- * 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.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Medical Monitor

Role: Study Director

Affiliation: Seagen Inc.

Overall Contact

Name: Seagen Trial Information Support

Phone: 866-333-7436

Email: clinicaltrials@seagen.com

LOCATION