An open-label, randomized, controlled Phase III study of disitamab vedotin in combination with pembrolizumabversus chemotherapy in subjects with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (IHC 1+ and greater)
Previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (IHC 1+ and greater)
This study will enrol participants with urothelial cancer (UC). UC can include cancer of the bladder, kidney, or the tubes that carry pee through the body (ureter, urethra). This study will try to find out if the drugs disitamab vedotin with pembrolizumab work better than platinum-containing chemotherapy to treat patients with UC. This study will also test what side effects happen when participants take these drugs together. A side effect is anything a drug does to the body besides treating the disease. Participants in this study will have cancer that has spread through the body (metastatic) or spread near where it started (locally advanced). The method of randomisation is by stratified randomisation. Participants will be randomized in a 1:1 ratio to experimental or control arm based on the following stratification factors: cisplatin eligibility (eligible or ineligible), presence of liver metastases (yes or no), HER2 status (positive (high) or low), and intent of avelumab maintenance use (yes or no). Participants in the disitamab vedotin arm will get the study drug disitamab vedotin once every 2 weeks and pembrolizumab once every 6 weeks. Participants in the standard-of-care arm will get gemcitabine once a week for 2 weeks with either cisplatin or carboplatin once every 3 weeks. All study medication will be given by intravenous administration at the following doses: Arm A: Disitamab Vedotin 1.5 mg/kg Pembrolizumab 400 mg Arm B: Gemcitabine 1000 mg/m2 Carboplatin AUC 4.5 or 5 Cisplatin 70 mg/m2
Due to the character limit, please find the full list of inclusion criteria in the protocol 1. Age ≥18 years at the time of informed consent (IC). 2. Following baseline lab data, lab values collected within 7 days prior to randomization are acceptable: 2.1. Hb ≥9 g/dL without transfusion 2.2. ANC ≥1.5 × 109/L 2.3. Platelet count ≥100 × 109/L 2.4. ALT and AST ≤2.5 × upper limit of normal (ULN) without liver metastases or ≤5 × ULN with liver metastases 2.5. Serum total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for subjects with total bilirubin >1.5 × ULN; serum total bilirubin ≤3 × ULN for subjects with Gilbert's syndrome 2.6. CrCl ≥30 mL/min, as calculated using the Cockcroft-Gault formula 2.7. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN. Subjects receiving anticoagulant therapy are eligible and are required to have INR/PT and aPTT within therapeutic range. Note: In subjects transfused before the study, the transfusion (such as red blood cell, whole blood, or plasma transfusion) must be ≥14 days prior to start of therapy to establish adequate lab parameters independent from transfusion support 3. Subjects of childbearing potential under the following conditions: 3.1. Must have a negative serum pregnancy test result within 72 hrs prior to the first dose 3.2. Must agree not to try to become pregnant during the study and for at least 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab 3.3. Must agree not to breastfeed or donate ova, from the time of IC and continuing through 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab 3.4. If sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of contraception, starting at time of and continuing through ≥2 months after the final dose of disitamab vedotin and 4 months after the final
Due to the character limit, please find the full list of exclusion criteria in the protocol. 1. Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab. 2. Subject has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study intervention, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study intervention. Subjects must have recovered from all radiation-related toxicities and must not require corticosteroids. 3. Subjects who previously received treatment with an MMAE agent or anti-HER2 therapy 4. Ongoing sensory or motor neuropathy Grade 2 or higher. 5. Subjects with acute, chronic, or symptomatic infections 6. Has a diagnosis of immunodeficiency condition/disorder (ie, immunoglobulin A [IgA] deficiency, etc.) or is receiving chronic systemic steroid therapy (dose >10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 7. Subjects with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, noninfectious pneumonitis, interstitial lung disease, or idiopathic pneumonitis are excluded. Subjects with current pneumonitis or interstitial lung disease are also excluded. 8. Subjects with a history of another invasive malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. 8.1. Subjects with adequately resected early-stage non-melanoma skin cancer or carcinoma in situ are allowed. 8.2. Subjects with a history of prostate cancer (T2NXMX or lower with Gleason score ≤7) treated with definitive intent (surgically or with radiation therapy), provided that the subject is considered prostate cancer free and the following cr