Disitamab Vedotin With Pembrolizumab vs Chemotherapy in Previously Untreated Urothelial Cancer Expressing HER2

Study Overview
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Brief Summary
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This study will enroll participants with urothelial cancer (UC). UC can include cancer of the bladder, kidney, or the tubes that carry pee through the body (ureter, urethra). This study will try to find out if the drugs disitamab vedotin with pembrolizumab works better than platinum-containing chemotherapy to treat patients with UC. This study will also test what side effects happen when participants take these drugs together. A side effect is anything a drug does to the body besides treating the disease. Participants in this study will have cancer that has spread through the body (metastatic) or spread near where it started (locally advanced). In this study, there are 2 different groups. Participants will be assigned to a group randomly. Participants in the disitamab vedotin arm will get the study drug disitamab vedotin once every two weeks and pembrolizumab once every 6 weeks. Participants in the standard of care arm will get gemcitabine once a week for 2 weeks with either cisplatin or carboplatin once every 3 weeks.

Official Title
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An Open-label, Randomized, Controlled Phase 3 Study of Disitamab Vedotin in Combination With Pembrolizumab Versus Chemotherapy in Subjects With Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma That Expresses HER2 (IHC 1+ and Greater)

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Drug: disitamab vedotin
* Drug: pembrolizumab
* Drug: gemcitabine
* Drug: cisplatin
* Drug: carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathological confirmation of locally advanced unresectable or metastatic urothelial carcinoma (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra. Measurable disease by investigator assessment per RECIST v1.1. Participant must not have received prior systemic therapy for LA/mUC. Exception will be made for neoadjuvant or adjuvant therapy, if disease recurrence/progression occurred more than 12 months after the last dose of therapy. Eligible to receive cisplatin- or carboplatin-containing chemotherapy. Able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks from a muscle-invasive or metastatic UC lesion or biopsy of metastatic UC prior to treatment initiation. If archival tissue is not available a newly obtained baseline biopsy of an accessible tumor lesion is required within 28 days of cycle 1 day 1. HER2 expression of 1+ or greater on immunohistochemistry (IHC). Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2 within 7 days prior to randomization. Exclusion Criteria: Known hypersensitivity to disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab or any of their components. History of severe/life threatening immune-related adverse event (irAE) with PD-(L)1 inhibitors are excluded. Central nervous system (CNS) and/or leptomeningeal metastasis. Participants with treated CNS metastases are permitted if all of the following are met. CNS metastases have been clinically stable for at least 4 weeks and baseline scans show no evidence of new or worsening CNS metastasis. Participant is on a stable dose of ≤ 10 mg/day of prednisone or equivalent for at least 2 weeks. History of or active autoimmune disease that has required systemic treatment in the past 2 years. 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). Prior solid organ or bone marrow transplantation. Pleural effusion or ascites with symptoms or requiring symptomatic treatment. Estimated life expectancy <12 week Prior treatment with an MMAE agent or anti-HER2 therapy

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Disitamab vedotin arm<br>disitamab vedotin + pembrolizumab | Drug: disitamab vedotin<br>* Given into the vein (IV; intravenous) every 2 weeks<br>* Other names: RC48, RC48-ADC;Drug: pembrolizumab<br>* 400mg given by IV every 6 weeks<br>* Other names: Keytruda;|
| Active Comparator: Standard of care arm<br>gemcitabine + cisplatin OR carboplatin | Drug: gemcitabine<br>* 1000 mg/m^2 given by IV on days 1 and 8 of every 3-week cycle<br>* Other names: Gemzar;Drug: cisplatin<br>* 70 mg^2 given by IV on day 1 of every 3-week cycle<br>Drug: carboplatin<br>* Area under the plasma concentration-time curve (AUC) 4.5 or 5 given by IV on day 1 of every 3-week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR) | The time from randomization to first documentation of disease progression per RECIST v1.1 by BICR, or to death due to any cause. | Approximately 3 years | 
| Overall survival (OS) | The time from date of randomization to date of death due to any cause. | Approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) per RECIST v1.1 by BICR | The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1. | Approximately 3 years | 
| ORR per RECIST v1.1 by investigator assessment | The proportion of participants with confirmed CR or PR according to RECIST v1.1. | Approximately 3 years | 
| Duration of Response (DOR) per RECIST v1.1 by BICR | The time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause. | Approximately 3 years | 
| DOR per RECIST v1.1 by investigator assessment | The time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause. | Approximately 3 years | 
| Control Rate (DCR) per RECIST v1.1 by BICR | The proportion of participants with confirmed CR, PR, or stable disease according to RECIST v1.1. | Approximately 3 years | 
| DCR per RECIST v1.1 by investigator assessment | The proportion of participants with confirmed CR, PR, or stable disease according to RECIST v1.1. | Approximately 3 years | 
| PFS per RECIST v1.1 by investigator assessment | The time from randomization to first documentation of disease progression per RECIST v1.1, or to death due to any cause. | Approximately 3 years | 
| Number of participants with adverse events (AEs) | Any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Through 30 days after the last study treatment; approximately 2 years | 
| Number of participants with laboratory abnormalities |  | Through 30 days after the last study treatment; approximately 2 years | 
| Treatment discontinuation rate due to AEs |  | Approximately 2 years | 
| Number of electrocardiogram (ECG) abnormalities |  | Through 30 days after the last study treatment; approximately 2 years | 
| Change from baseline of left ventricular ejection fraction (LVEF) |  | Through 2 years after last study treatment; approximately 4 years | 
| Change from baseline to Week 16 in European Organization for Research and Treatment of Cancer core Quality of Life questionnaire (EORTC QLQ-C30) Global Health Status (GHS)/QoL Score | The EORTC QLQ-C30 is used to evaluate health-related quality of life, functioning, disease symptoms, and treatment-related side effects. Scores range from 0-100. For GHS/QoL and functional scales, higher scores represent higher QoL or functioning. For symptom scales, higher scores represent more symptoms/worse status. | Approximately 2 years | 
| Time to Deterioration in EORTC QLQ-C30 GHS/QoL Score | The time from the date of randomization to the date of first deterioration (change from baseline ≥10) in GHS/QoL score with no subsequent recovery. The EORTC QLQ-C30 is used to evaluate health-related quality of life, functioning, disease symptoms, and treatment-related side effects. Scores range from 0-100. For GHS/QoL and functional scales, higher scores represent higher QoL or functioning. For symptom scales, higher scores represent more symptoms/worse status. | Approximately 2 years | 
| Time to pain progression | The time from the date of randomization to whichever of the following occurs earlier: an increase in Numeric Rating Scale (NRS) for pain intensity of 2 points or more from baseline at 2 consecutive visits, an increase in number of opioid or analgesic use from baseline, or initiation of opioid or analgesic use. NRS for pain intensity asks participants to best describe their pain at its worst in the last 24 hours from 0 to 10. On the NRS, 0 means no pain and 10 means pain as bad as you can imagine. | Approximately 2 years | 

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