Clinical trial NCT04879329: A Study of Disitamab Vedotin Alone or With Pembrolizumab in Urothelial Cancer That Expresses HER2
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Urothelial Carcinoma
Keywords: Urothelial Cancer
Bladder Cancer
HER2 Mutations
HER2 Overexpression
HER2 Amplification
RC48
Seattle Genetics
Lead sponsor: Seagen Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-05-10
Enrollment: 372
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Cohorts A, B, C, D, and G will enroll simultaneously. Cohort E will begin enrollment after Cohort D participants have completed the DLT evaluation period.
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Cohort G

* 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 therapy containing enfortumab vedotin as monotherapy or in combination with pembrolizumab

  * The last administration of enfortumab vedotin must be 90 days from the start of study treatment. Intervening therapies are allowed between the final dose of enfortumab vedotin and the start of disitamab vedotin.
* 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

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

Cohort G

* 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 G)
* Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
* Prior 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

There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.

Primary outcomes:
measure: 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, C, and G)
timeFrame: Duration of treatment; approximately 2 years
measure: Incidence of adverse events (AEs) (Cohorts D and E)
timeFrame: Approximately 2 years
measure: Incidence of dose alterations (Cohorts D and E)
timeFrame: Approximately 2 years
measure: Incidence of laboratory abnormalities (Cohorts D and E)
timeFrame: Approximately 2 years
measure: Incidence of electrocardiogram (ECG) abnormalities (Cohorts D and E)
timeFrame: Approximately 2 years
measure: Change from baseline of left ventricular ejection fraction (LVEF) (Cohorts D and E)
timeFrame: Approximately 2 years
measure: Pharmacokinetic (PK) parameter - Area under the curve (AUC) (Cohorts D and E)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: PK parameter - Maximum concentration (Cmax) (Cohorts D and E)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: PK parameter - Time to maximum concentration (Tmax) (Cohorts D and E)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: PK parameter - Trough concentration (Ctrough) (Cohorts D and E)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
Secondary outcomes:
measure: cORR per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G)
timeFrame: Duration of treatment; approximately 2 years
measure: Confirmed Duration of Response (DOR) per RECIST v1.1 by BICR (Cohorts A, B, C, and G)
timeFrame: From start of treatment to completion of response assessment; approximately 2 years
measure: Confirmed DOR per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G)
timeFrame: From start of treatment to completion of response assessment; approximately 2 years
measure: Progression-free survival (PFS) per RECIST v1.1 by BICR (Cohorts A, B, C, and G)
timeFrame: From start of treatment to completion of response assessment; approximately 2 years
measure: PFS per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G)
timeFrame: From start of treatment to completion of response assessment; approximately 2 years
measure: Disease control rate (DCR) per RECIST v1.1 by BICR (Cohorts A, B, C, and G)
timeFrame: From start of treatment to completion of response assessment; approximately 2 years
measure: DCR per RECIST v1.1 by investigator (Cohorts A, B, C, and G)
timeFrame: From start of treatment to completion of response assessment; approximately 2 years
measure: Overall survival (OS) (Cohorts A, B, C, and G)
timeFrame: Duration of study; approximately 3 years
measure: Incidence of adverse events (AEs) (Cohorts A, B, C, and G)
timeFrame: Approximately 2 years
measure: Incidence of dose alterations (Cohorts A, B, C, and G)
timeFrame: Approximately 2 years
measure: Incidence of laboratory abnormalities (Cohorts A, B, C, and G)
timeFrame: Approximately 2 years
measure: Incidence of ECG abnormalities (Cohorts A, B, C, and G)
timeFrame: Approximately 2 years
measure: Change from baseline of LVEF (Cohorts A, B, C, and G)
timeFrame: Approximately 2 years
measure: PK parameter - AUC (Cohorts A, B, C, and G)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: PK parameter - Cmax (Cohorts A, B, C, and G)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: PK parameter - Tmax (Cohorts A, B, C, and G)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: PK parameter - Ctrough (Cohorts A, B, C, and G)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: PK parameter of pembrolizumab - Cmax (Cohort E)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: Incidence of anti-drug antibodies (ADAs) against disitamab vedotin (All Cohorts)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: Incidence of anti-drug antibodies (ADAs) against pembrolizumab (Cohorts C and E)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
measure: Incidence of neutralizing antibodies (NABs) against disitamab vedotin (All Cohorts)
timeFrame: Through 30-37 days following the last dose of DV; up to approximately 2 years
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center
state: California
city: Orange
country: United States
facility: University of California Irvine Medical Center
state: California
city: Riverside
country: United States
facility: Kaiser Permanente Southern California
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco | HDFCCC - Hematopoietic Malignancies
state: California
city: Colorado Springs
country: United States
facility: University of Colorado Health Memorial Hospital
state: Colorado
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South Region
state: Florida
city: Tallahassee
country: United States
facility: Florida Cancer Specialists - Panhandle
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists - East West Palm Beach, FL (SCRI)
state: Florida
city: Marietta
country: United States
facility: Northwest Georgia Oncology Centers, P.C.
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute / Wayne State University
state: Michigan
city: Grand Rapids
country: United States
facility: Cancer and Hematology Centers of Western Michigan / Spectrum Health Butterworth Campus
state: Michigan
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Lake Success
country: United States
facility: North Shore Center for Advanced Medicine Monter Cancer Center / North Shore University Hospital
state: New York
city: New York
country: United States
facility: New York University (NYU) Cancer Institute
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University at Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Knoxville
country: United States
facility: University of Tennessee
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center / University of Texas
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center / Seattle Cancer Care Alliance / University of Washington
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin (Milwaukee)
state: Wisconsin
city: Berazategui
country: Argentina
facility: Centro de Oncologia e Investigacion de Buenos Aires (COIBA)
state: Other
city: Buenos Aires
country: Argentina
facility: Hospital Aleman (HA) Deutsches Hospital
state: Other
city: Caba
country: Argentina
facility: Hospital Sirio Libanes
state: Other
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Instituto Alexander Fleming
state: Other
city: Cordoba
country: Argentina
facility: Instituto Oncologico de Cordoba
state: Other
city: Caba
country: Argentina
facility: Fundacion Cenit
city: Viedma
country: Argentina
facility: Clinica Viedma
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: Other
city: Frankston
country: Australia
facility: Peninsula and South East Oncology
state: Other
city: South Brisbane
country: Australia
facility: Mater Cancer Care Centre
state: Other
city: St Leonards
country: Australia
facility: GenesisCare North Shore (Oncology)
state: Other
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Other
city: New South Whales
country: Australia
facility: Macquarie University Hospital
city: Gent
country: Belgium
facility: Algemeen Ziekenhuis Maria Middelares
state: Other
city: Namur
country: Belgium
facility: CHU UCL Namur-Site de Saint Elisabeth
state: Other
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency - Vancouver Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke (CHUS)
state: Quebec
city: La Serena
country: Chile
facility: Centro de Estudios Clinicos IC La Serena Research
state: Other
city: Santiago
country: Chile
facility: Pontificia Universidad Catolica De Chile Santiago
state: Other
city: Santiago
country: Chile
facility: Instituto Oncologico Fundacion Arturo Lopez Perez (FALP)
state: Other
city: Haifa
country: Israel
facility: Rambam Health Corp.
state: Other
city: Petach Tikva
country: Israel
facility: Rabin Medical Center
state: Other
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
state: Other
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
state: Other
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
state: Other
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Other
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
state: Other
city: Sapporo
country: Japan
facility: Sapporo Medical University Hospital
state: Other
city: Suita-shi
country: Japan
facility: Osaka University Hospital
state: Other
city: Tokushima
country: Japan
facility: Tokushima University Hospital
state: Other
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Other
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
state: Other
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
state: Other
city: Madrid
country: Spain
facility: MD Anderson Cancer Center - Madrid
state: Other
city: Sabadell
country: Spain
facility: Hospital Universitari Parc Tauli
state: Other
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Other
city: Seville
country: Spain
facility: Hospital Universitario Virgen del Rocio
state: Other
city: Bebington
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
state: Other
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Other
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde (NHSGGC) - The Beatson West of Scotland Cancer Centre
state: Other
city: London
country: United Kingdom
facility: Barts Health NHS Trust Saint Bartholomews Hospital
state: Other
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: Other
city: London
country: United Kingdom
facility: Guys and St Thomas Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: