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

Sponsor

Seagen Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05911295

Collaborator

RemeGen Co., Ltd. (Industry), Merck Sharp & Dohme LLC (Industry)

700

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Carcinoma	Drug: disitamab vedotin Drug: pembrolizumab Drug: gemcitabine Drug: cisplatin Drug: carboplatin	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

700 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Anticipated Study Start Date :

Aug 31, 2023

Anticipated Primary Completion Date :

Jun 30, 2026

Anticipated Study Completion Date :

Apr 30, 2029

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Disitamab vedotin arm

disitamab vedotin + pembrolizumab

Drug: disitamab vedotin

Given into the vein (IV; intravenous) every 2 weeks

Other Names:

RC48, RC48-ADC

Drug: pembrolizumab

400mg given by IV every 6 weeks

Other Names:

Keytruda

Active Comparator: Standard of care arm

gemcitabine + cisplatin OR carboplatin

Drug: gemcitabine

1000 mg/m^2 given by IV on days 1 and 8 of every 3-week cycle

Other Names:

Gemzar

Drug: cisplatin

70 mg^2 given by IV on day 1 of every 3-week cycle

Drug: carboplatin

Area under the plasma concentration-time curve (AUC) 4.5 or 5 given by IV on day 1 of every 3-week cycle

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Objective response rate (ORR) per RECIST v1.1 by BICR [Approximately 3 years]
The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1.
ORR per RECIST v1.1 by investigator assessment [Approximately 3 years]
The proportion of participants with confirmed CR or PR according to RECIST v1.1.
Duration of Response (DOR) per RECIST v1.1 by BICR [Approximately 3 years]
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.
DOR per RECIST v1.1 by investigator assessment [Approximately 3 years]
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.
Control Rate (DCR) per RECIST v1.1 by BICR [Approximately 3 years]
The proportion of participants with confirmed CR, PR, or stable disease according to RECIST v1.1.
DCR per RECIST v1.1 by investigator assessment [Approximately 3 years]
The proportion of participants with confirmed CR, PR, or stable disease according to RECIST v1.1.
PFS per RECIST v1.1 by investigator assessment [Approximately 3 years]
The time from randomization to first documentation of disease progression per RECIST v1.1, or to death due to any cause.
Number of participants with adverse events (AEs) [Through 30 days after the last study treatment; approximately 2 years]
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.
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 [Approximately 2 years]
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.
Time to Deterioration in EORTC QLQ-C30 GHS/QoL Score [Approximately 2 years]
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.
Time to pain progression [Approximately 2 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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