Disitamab vedotin with pembrolizumab vs chemotherapy in previously untreated urothelial cancer expressing HER2
- Conditions
- Previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (IHC 1+ and greater)Cancer
- Registration Number
- ISRCTN11908197
- Lead Sponsor
- Seagen Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 700
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 dose of pembrolizumab
4. The subject must provide documented IC
5. Subject must be willing and able to comply with the trial procedures and the follow-up schedule
6. Subjects must have LA/mUC with histopathological confirmation (Stage IIIB-IV per American Joint Committee on Cancer, Cancer Staging Atlas 8th ed.), including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as urothelial (transitional cell histology) carcinoma is the predominant cell type
7. Subjects must have measurable disease by investigator assessment according to RECIST v1.1. Note: Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy
8. Subjects must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions:
8.1. Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred >12 months after the last dose of therapy
9. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, per the investigator’s evaluation. Subjects meeting any of the following criteria should be considered cisplatin-ineligible, and will receive carboplatin:
9.1. CrCl <60 mL/min but =30 mL/min within 7 days of randomization (measured by the Cockcroft-Gault formula). Note:
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 criteria are met: Subjects who have undergone an adequate surgical resection must have undetectable prostate-specific antigen (PSA) for =1 yr and at screening. Subjects who have had radiation must have a PSA doubling time >1 yr (based on at least 3 values determined >1 month apart) and a total PSA value that does not meet Phoenix criteria for biochemical recurrence (ie, <2.0 ng/mL above nadir). Subjects with untreated low-risk prostate cancer (Gleason score =6) on active surveillance with PSA doubling time >1 month (based on at least 3 values determined <1 month apart) are also eligible.
8.3. Malignancies that can be cured after treatment (including but not limited to adequately treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or radical treatment of ductal carcinoma in situ to the breast).
9. Uncontrolled cardiac disease
10. Subjects who have received radiotherapy within 2 weeks prior to randomization
11. Subjects who have received major surgery within 4 weeks prior to randomization.
12. History of severe/life-threatening irAE with PD-(L)1 inhibitors are excluded. Please consult with medical monitor.
12.1. Grade =3 pneumonitis IMAEs, cardiomyopathy, etc
12.2. Grade 4 diarrhea/colitis IMAEs, hepatitis IMAEs, rash IMAEs c. Grade 3/4 adrenal insufficiency, hypophysitis, uveitis, hypothyroidism
13. Subjects requiring chronic oxygen therapy or have Grade =3 pulmonary disease unrelated to underlying malignancy
14. CNS and/or leptomeningeal
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 1. Progression-free survival (PFS) measured per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 by blinded independent central review (BICR). Tumour assessments will occur every 8 weeks (±7 days), starting from randomization. Starting after Week 72, tumour assessments will be undertaken every 12 weeks (±14 days). Responses (CR or partial response [PR]) are to be confirmed with repeat scans at least 4 weeks after the first documentation of response.<br>2. Overall survival (OS), after progression and discontinuation of study treatment, is measured every 12 weeks (±1 week) in person, by phone, or by consulting public records.
- Secondary Outcome Measures
Name Time Method