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

JRCT ID: jRCT2031230309

Registered date:28/08/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Urothelial carcinoma
• Date of first enrollment: 04/12/2023
• Target sample size: 12
• Countries of recruitment: Argentina,Japan,Australia,Japan,Canada,Japan,Chile,Japan,Israel,Japan,United Kingdom,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

Cohorts A, B, and D (Japan)
Disitamab vedotin 1.5 mg/kg administered intravenously (IV) every 2 weeks (Day 1 of each 2-week cycle)

Cohort C
- Single-arm part and combination arm of the randomized part
Disitamab vedotin 1.5 mg/kg IV every 2 weeks (Days 1, 15, and 29 of each 6-week cycle) + pembrolizumab 400 mg IV on Day 1 of each 6-week cycle

- Monotherapy arm of the randomized part
Disitamab vedotin 1.5 mg/kg IV every 2 weeks (Days 1, 15, and 29 of each 6-week cycle)

Cohort E (Japan)
Disitamab vedotin 1.5 mg/kg IV every 2 weeks (Days 1, 15, and 29 of each 6-week cycle) + pembrolizumab 400 mg IV on Day 1 of each 6-week cycle

Outcome(s)

Primary Outcome

Cohorts A, B, and C
- 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 D and E
- Incidence of adverse events (AEs)
- Incidence of dose alterations
- Incidence of laboratory abnormalities
- Incidence of electrocardiogram (ECG) abnormalities
- Change from baseline of left ventricular ejection fraction (LVEF)
- Pharmacokinetic (PK) parameter - Area under the curve (AUC)
- PK parameter - Maximum concentration (Cmax)
- PK parameter - Time to maximum concentration (Tmax)
- PK parameter - Trough concentration (Ctrough)

Secondary Outcome

Cohorts A, B, and C
- cORR per RECIST v1.1 by investigator assessment
- Confirmed Duration of Response (DOR) per RECIST v1.1 by BICR
- Confirmed DOR per RECIST v1.1 by investigator assessment
- Progression-free survival (PFS) per RECIST v1.1 by BICR
- PFS per RECIST v1.1 by investigator assessment
- Disease control rate (DCR) per RECIST v1.1 by BICR
- DCR per RECIST v1.1 by investigator
- Overall survival
- Incidence of AEs
- Incidence of dose alterations
- Incidence of laboratory abnormalities
- Incidence of ECG abnormalities
- Change from baseline of LVEF
- PK parameter - AUC
- PK parameter - Cmax
- PK parameter - Tmax
- PK parameter - Ctrough

Cohort E
- PK parameter of pembrolizumab - Cmax

Cohorts C and E
- Incidence of anti-drug antibodies (ADAs) against pembrolizumab

All Cohorts
- Incidence of ADAs against disitamab vedotin
- Incidence of neutralizing antibodies against disitamab vedotin

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Cohorts A and B
- Histopathologically-confirmed, locally-advanced, unresectable or metastatic urothelial cancer (LA/mUC), including urothelial cancer (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 Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1)
- Human epidermal growth factor receptor 2 (HER2)-expression status determined by the central laboratory to be immunohistochemistry (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 (Japan)
- 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 (Japan)
- 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

Exclude 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 monomethyl auristatin E (MMAE)-based antibody-drug conjugates (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 (Japan)
- 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)
- Any prior history of >= Grade 3 non-hematological adverse effects (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 (Japan)
- 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

Related Information

• Primary Sponsor: Sokolowski Kevin
• Secondary ID(s): NCT04879329