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

Urothelial Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04879329
• Other study ID #: RC48G001
• Secondary ID: KEYNOTE-D78MK-34
• Status: Recruiting
• Phase: Phase 2
• Start date: May 3, 2022
• Est. completion date: March 31, 2026

Study information

• Verified date: June 2024
• Source: Seagen Inc.
• Contact: Seagen Trial Information Support
• Phone: 866-333-7436
• Email: clinicaltrials[@]seagen.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 332
• Est. completion date: March 31, 2026
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Urothelial Carcinoma

Intervention

Drug:
• disitamab vedotin
Given into the vein (IV; intravenous) every 2 weeks.
• pembrolizumab
Given by IV on Day 1 of each 6-week cycle.

Locations

Country	Name	City	State
Argentina	Centro de Oncologia e Investigacion de Buenos Aires (COIBA)	Berazategui	Other
Argentina	Hospital Aleman (HA) Deutsches Hospital	Buenos Aires	Other
Argentina	Hospital Sirio Libanes	Caba	Other
Argentina	Instituto Alexander Fleming	Ciudad Autonoma Buenos Aires	Other
Argentina	Clinica Viedma	Viedma
Australia	Lyell McEwin Hospital	Elizabeth Vale	Other
Australia	Peninsula and South East Oncology	Frankston	Other
Australia	Macquarie University Hospital	New South Whales
Australia	Mater Cancer Care Centre	South Brisbane	Other
Australia	Royal North Shore Hospital	St Leonards	Other
Australia	Princess Alexandra Hospital	Woolloongabba	Other
Belgium	Algemeen Ziekenhuis Maria Middelares	Gent	Other
Belgium	CHU UCL Namur-Site de Saint Elisabeth	Namur	Other
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Centre hospitalier universitaire de Sherbrooke (CHUS)	Sherbrooke	Quebec
Canada	British Columbia Cancer Agency - Vancouver Centre	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Chile	Centro de Estudios Clinicos IC La Serena Research	La Serena	Other
Chile	Instituto Oncologico Fundacion Arturo Lopez Perez (FALP)	Santiago	Other
Chile	Pontificia Universidad Catolica De Chile Santiago	Santiago	Other
Israel	Rambam Health Corp.	Haifa	Other
Israel	Rabin Medical Center	Petach Tikva	Other
Israel	Sheba Medical Center	Ramat Gan	Other
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv	Other
Japan	National Cancer Center Hospital East	Kashiwa-shi	Other
Japan	Osaka International Cancer Institute	Osaka	Other
Japan	Sapporo Medical University Hospital	Sapporo	Other
Japan	Osaka University Hospital	Suita-shi	Other
Japan	Tokushima University Hospital	Tokushima	Other
Japan	The Cancer Institute Hospital of JFCR	Tokyo	Other
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Other
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge	Other
United Kingdom	NHS Greater Glasgow and Clyde (NHSGGC) - The Beatson West of Scotland Cancer Centre	Glasgow	Other
United Kingdom	Barts Health NHS Trust Saint Bartholomews Hospital	London	Other
United Kingdom	Guys and St Thomas Hospital	London
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	University of Colorado Health Memorial Hospital	Colorado Springs	Colorado
United States	Henry Ford Health System	Detroit	Michigan
United States	Karmanos Cancer Institute / Wayne State University	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Florida Cancer Specialists - South Region	Fort Myers	Florida
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Cancer and Hematology Centers of Western Michigan / Spectrum Health Butterworth Campus	Grand Rapids	Michigan
United States	MD Anderson Cancer Center / University of Texas	Houston	Texas
United States	University of Tennessee	Knoxville	Tennessee
United States	North Shore Center for Advanced Medicine Monter Cancer Center / North Shore University Hospital	Lake Success	New York
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	University of California Los Angeles Medical Center	Los Angeles	California
United States	Northwest Georgia Oncology Centers, P.C.	Marietta	Georgia
United States	Medical College of Wisconsin (Milwaukee)	Milwaukee	Wisconsin
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	University of California Irvine Medical Center	Orange	California
United States	Oregon Health and Science University	Portland	Oregon
United States	Kaiser Permanente Southern California	Riverside	California
United States	University of California, San Francisco | HDFCCC - Hematopoietic Malignancies	San Francisco	California
United States	Fred Hutchinson Cancer Center / Seattle Cancer Care Alliance / University of Washington	Seattle	Washington
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Florida Cancer Specialists - Panhandle	Tallahassee	Florida
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	Florida Cancer Specialists - East West Palm Beach, FL (SCRI)	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Seagen Inc.	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  Chile,  Israel,  Japan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Incidence of dose alterations (Cohorts D and E)		Approximately 2 years
Primary	Incidence of laboratory abnormalities (Cohorts D and E)	To be summarized using descriptive statistics.	Approximately 2 years
Primary	Incidence of electrocardiogram (ECG) abnormalities (Cohorts D and E)		Approximately 2 years
Primary	Change from baseline of left ventricular ejection fraction (LVEF) (Cohorts D and E)		Approximately 2 years
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of dose alterations (Cohorts A, B, and C)	To be summarized using descriptive statistics.	Approximately 2 years
Secondary	Incidence of laboratory abnormalities (Cohorts A, B, and C)	To be summarized using descriptive statistics.	Approximately 2 years
Secondary	Incidence of ECG abnormalities (Cohorts A, B, and C)		Approximately 2 years
Secondary	Change from baseline of LVEF (Cohorts A, B, and C)		Approximately 2 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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