Urothelial Carcinoma
Conditions
Keywords
Urothelial Cancer, Bladder Cancer, HER2 Mutations, HER2 Overexpression, HER2 Amplification, RC48, Seattle Genetics
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.
Interventions
DRUGdisitamab vedotin
Given into the vein (IV; intravenous) every 2 weeks.
DRUGpembrolizumab
Given by IV on Day 1 of each 6-week cycle.
Sponsors
Seagen, a wholly owned subsidiary of Pfizer
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Duration of treatment; approximately 2 years | The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 |
| Incidence of adverse events (AEs) (Cohorts D and E) | Approximately 2 years | 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. |
| Incidence of dose alterations (Cohorts D and E) | Approximately 2 years | — |
| Incidence of laboratory abnormalities (Cohorts D and E) | Approximately 2 years | To be summarized using descriptive statistics. |
| 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) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| PK parameter - Maximum concentration (Cmax) (Cohorts D and E) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| PK parameter - Time to maximum concentration (Tmax) (Cohorts D and E) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| PK parameter - Trough concentration (Ctrough) (Cohorts D and E) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| cORR per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G) | Duration of treatment; approximately 2 years | The proportion of participants with confirmed CR or PR according to RECIST v1.1 |
| Confirmed Duration of Response (DOR) per RECIST v1.1 by BICR (Cohorts A, B, C, and G) | From start of treatment to completion of response assessment; approximately 2 years | 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. |
| Confirmed DOR per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G) | From start of treatment to completion of response assessment; approximately 2 years | 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. |
| Progression-free survival (PFS) per RECIST v1.1 by BICR (Cohorts A, B, C, and G) | From start of treatment to completion of response assessment; approximately 2 years | 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. |
| PFS per RECIST v1.1 by investigator assessment (Cohorts A, B, C, and G) | From start of treatment to completion of response assessment; approximately 2 years | 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. |
| Disease control rate (DCR) per RECIST v1.1 by BICR (Cohorts A, B, C, and G) | From start of treatment to completion of response assessment; approximately 2 years | 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. |
| DCR per RECIST v1.1 by investigator (Cohorts A, B, C, and G) | From start of treatment to completion of response assessment; approximately 2 years | 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. |
| Overall survival (OS) (Cohorts A, B, C, and G) | Duration of study; approximately 3 years | The time from start of study treatment or randomization (if applicable) to the date of death due to any cause. |
| Incidence of adverse events (AEs) (Cohorts A, B, C, and G) | Approximately 2 years | 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. |
| Incidence of dose alterations (Cohorts A, B, C, and G) | Approximately 2 years | To be summarized using descriptive statistics. |
| Incidence of laboratory abnormalities (Cohorts A, B, C, and G) | Approximately 2 years | To be summarized using descriptive statistics. |
| Incidence of ECG abnormalities (Cohorts A, B, C, and G) | Approximately 2 years | — |
| Change from baseline of LVEF (Cohorts A, B, C, and G) | Approximately 2 years | — |
| PK parameter - AUC (Cohorts A, B, C, and G) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| PK parameter - Cmax (Cohorts A, B, C, and G) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| PK parameter - Tmax (Cohorts A, B, C, and G) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| PK parameter - Ctrough (Cohorts A, B, C, and G) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| PK parameter of pembrolizumab - Cmax (Cohort E) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| Incidence of anti-drug antibodies (ADAs) against disitamab vedotin (All Cohorts) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| Incidence of anti-drug antibodies (ADAs) against pembrolizumab (Cohorts C and E) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
| Incidence of neutralizing antibodies (NABs) against disitamab vedotin (All Cohorts) | Through 30-37 days following the last dose of DV; up to approximately 2 years | To be summarized using descriptive statistics. |
Countries
Argentina, Australia, Belgium, Canada, Chile, Israel, Italy, Japan, Spain, Turkey (Türkiye), United Kingdom, United States
Contacts
CONTACTPfizer CT.gov Call Center
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Outcome results
None listed