SGNDV-001 is an open-label, randomized, multicenter, 2-arm, controlled phase 3 study in previously untreated subjects with locally advanced or metastatic urothelial cancer (LA/mUC) that expresses HER2 (immunohistochemistry [IHC] 1+ and greater). The study compares the efficacy of disitamab vedotin in combination with pembrolizumab (experimental arm, Arm A) versus platinum-containing chemotherapy (control arm, Arm B).
Subjects must have previously untreated LA/mUC, ECOG performance status score of 0 to 2, and be eligible for platinum-containing therapy. Subjects must have tumors that express HER2, defined as IHC 1+, 2+, or 3+. HER2 expression will be evaluated at a central laboratory and be performed on the most recent archival or fresh tumor tissue sample from a muscle-invasive or metastatic UC lesion. Subjects must have measurable disease according to RECIST v1.1.
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Arms and Interventions
Arm A
Population and HER2 Status :
Untreated LA/mUC; HER2 expressing (HER2 IHC ≥1+)
Open-Label Study Treatment (Randomized 1:1)
Disitamab vedotin (DV)+ pembrolizumab (combination therapy) until progression
Arm B
Population and HER2 Status :
Untreated LA/mUC; HER2 expressing (HER2 IHC ≥1+)
Open-Label Study Treatment (Randomized 1:1)
Cisplatin/Carboplatin + Gemcitabine x 4-6 cycles, maintenance avelumab as clinically appropriate and available
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.
Notes: Adequate baseline cardiac and laboratory parameters
Exclusion Criteria
This is not a complete list of inclusion and exclusion criteria. Please connect with a Principal Investigator for further information.
- 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
Primary outcomes
- Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR)
- Overall survival (OS)
Secondary outcomes
- Objective response rate (ORR) per RECIST v1.1 by BICR
- ORR per RECIST v1.1 by investigator assessment
- Duration of Response (DOR) per RECIST v1.1 by BICR
- DOR per RECIST v1.1 by investigator assessment
- Disease control Rate (DCR) per RECIST v1.1 by BICR
- DCR per RECIST v1.1 by investigator assessment
- PFS per RECIST v1.1 by investigator assessment
- Number of participants with adverse events (AEs)
- Number of participants with laboratory abnormalities
- Treatment discontinuation rate due to AEs
- Number of electrocardiogram (ECG) abnormalities
- Change from baseline of left ventricular ejection fraction (LVEF)
- 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
- Time to Deterioration in EORTC QLQ-C30 GHS/QoL Score
- Time to pain progression
Protocol Amendment 02, DV-001 HCP Page, 14Aug24