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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: disitamab vedotin
* Drug: pembrolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cohorts A, B, C, and D will enroll simultaneously. Cohort E will begin enrollment after Cohort D participants have completed the DLT evaluation period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A - DV monotherapy for HER2-positive tumor types<br>Disitamab vedotin monotherapy | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks.<br>* Other names: RC48-ADC;|
| Experimental: Cohort B - DV monotherapy for HER2-low tumor types<br>Disitamab vedotin monotherapy | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks.<br>* Other names: RC48-ADC;|
| Experimental: Cohort C - Non-randomized combination therapy<br>Disitamab vedotin + pembrolizumab | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks.<br>* Other names: RC48-ADC;Drug: pembrolizumab<br>* Given by IV on Day 1 of each 6-week cycle.<br>* Other names: Keytruda;|
| Experimental: Cohort C - Randomized combination therapy<br>Disitamab vedotin + pembrolizumab | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks.<br>* Other names: RC48-ADC;Drug: pembrolizumab<br>* Given by IV on Day 1 of each 6-week cycle.<br>* Other names: Keytruda;|
| Experimental: Cohort C - Randomized monotherapy<br>Disitamab vedotin monotherapy | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks.<br>* Other names: RC48-ADC;|
| Experimental: Cohort D - DV monotherapy (Japan only)<br>Disitamab vedotin monotherapy | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks.<br>* Other names: RC48-ADC;|
| Experimental: Cohort E - DV combination therapy (Japan only)<br>Disitamab vedotin + pembrolizumab | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks.<br>* Other names: RC48-ADC;Drug: pembrolizumab<br>* Given by IV on Day 1 of each 6-week cycle.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Duration of treatment; approximately 2 years | 
| Incidence of adverse events (AEs) (Cohorts D and E) | 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. | Approximately 2 years | 
| Incidence of dose alterations (Cohorts D and E) |  | Approximately 2 years | 
| Incidence of laboratory abnormalities (Cohorts D and E) | To be summarized using descriptive statistics. | Approximately 2 years | 
| Incidence of electrocardiogram (ECG) abnormalities (Cohorts D and E) |  | Approximately 2 years | 
| Change from baseline of left ventricular ejection fraction (LVEF) (Cohorts D and E) |  | Approximately 2 years | 
| Pharmacokinetic (PK) parameter - Area under the curve (AUC) (Cohorts D and E) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| PK parameter - Maximum concentration (Cmax) (Cohorts D and E) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| PK parameter - Time to maximum concentration (Tmax) (Cohorts D and E) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| PK parameter - Trough concentration (Ctrough) (Cohorts D and E) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cORR per RECIST v1.1 by investigator assessment (Cohorts A, B, and C) | The proportion of participants with confirmed CR or PR according to RECIST v1.1 | Duration of treatment; approximately 2 years | 
| Confirmed Duration of Response (DOR) per RECIST v1.1 by BICR (Cohorts A, B, and C) | 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. | From start of treatment to completion of response assessment; approximately 2 years | 
| Confirmed DOR per RECIST v1.1 by investigator assessment (Cohorts A, B, and C) | 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. | From start of treatment to completion of response assessment; approximately 2 years | 
| Progression-free survival (PFS) per RECIST v1.1 by BICR (Cohorts A, B, and C) | 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. | From start of treatment to completion of response assessment; approximately 2 years | 
| PFS per RECIST v1.1 by investigator assessment (Cohorts A, B, and C) | 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. | From start of treatment to completion of response assessment; approximately 2 years | 
| Disease control rate (DCR) per RECIST v1.1 by BICR (Cohorts A, B, and C) | 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. | From start of treatment to completion of response assessment; approximately 2 years | 
| DCR per RECIST v1.1 by investigator (Cohorts A, B, and C) | 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. | From start of treatment to completion of response assessment; approximately 2 years | 
| Overall survival (OS) (Cohorts A, B, and C) | The time from start of study treatment or randomization (if applicable) to the date of death due to any cause. | Duration of study; approximately 3 years | 
| Incidence of adverse events (AEs) (Cohorts A, B, and C) | 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. | Approximately 2 years | 
| Incidence of dose alterations (Cohorts A, B, and C) | To be summarized using descriptive statistics. | Approximately 2 years | 
| Incidence of laboratory abnormalities (Cohorts A, B, and C) | To be summarized using descriptive statistics. | Approximately 2 years | 
| Incidence of ECG abnormalities (Cohorts A, B, and C) |  | Approximately 2 years | 
| Change from baseline of LVEF (Cohorts A, B, and C) |  | Approximately 2 years | 
| PK parameter - AUC (Cohorts A, B, and C) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| PK parameter - Cmax (Cohorts A, B, and C) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| PK parameter - Tmax (Cohorts A, B, and C) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| PK parameter - Ctrough (Cohorts A, B, and C) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| PK parameter of pembrolizumab - Cmax (Cohort E) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| Incidence of anti-drug antibodies (ADAs) against disitamab vedotin (All Cohorts) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| Incidence of anti-drug antibodies (ADAs) against pembrolizumab (Cohorts C and E) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 
| Incidence of neutralizing antibodies (NABs) against disitamab vedotin (All Cohorts) | To be summarized using descriptive statistics. | Through 30-37 days following the last dose of DV; up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RC48, Urothelial Cancer, Bladder Cancer, HER2 Mutations, HER2 Overexpression, HER2 Amplification, Seattle Genetics