C66 Malignant neoplasm of ureter Malignant neoplasm of ureter
Conditions
Interventions
Disitamab Vedotin : 1.5 mg/kg Infusion time approximately 60 minutes. Q2W . Days 1, 15, and 29 of 42-day cycles. Pembrolizumab: 400 mg Infusion over 30 minutes (±10 minutes). Q42 days . Day 1 of42-day
Sponsors
Seagen Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 2. 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. 3. Subjects must have measurable disease by investigator assessment according to RECIST v1.1. 1. Age 18 years and older at the time of consent or considered an adult by local regulations. 4. Subjects must not have received prior systemic therapy for locally advanced or metastatic UC 5. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, per the investigator’s evaluation. 6. Subjects must be willing and able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks from a muscle-invasive or metastatic UC lesion or a biopsy sample of metastatic UC. 7. HER2 expression of 1+ or greater on IHC determined by central laboratory. 8. An ECOG performance status score of 0, 1, or 2 within 7 days prior to randomization. a. Subjects with ECOG 2 must meet additional criteria: Hb =10 g/dL, CrCl =50 mL/min, and heart failure severity less than New York Heart Association 9. Adequate baseline cardiac parameters: a. LVEF =50% b. Fridericia’s corrected QT interval (QTcF) 1.5 × ULN; serum total bilirubin =3 × ULN for subjects with Gilbert's syndrome , f. CrCl =30 mL/min, g. 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 laboratory parameters independent from transfusion support. 11. Subjects of childbearing potential (as defined in Section 10.4) under the following conditions: a. Must have a negative serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [ß-hCG]) result within 72 hours prior to the first dose of study intervention. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation. b. 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. c. Must agree not to breastfeed or donate ova, from the time of informed consent and continuing through 2 months after the final dose of disitamab vedotin and 4 months after the final dose of pembrolizumab. d. If sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least one of which must be highly effective (as defined in Section 10.4) starting at time of info
Exclusion criteria
Exclusion criteria: 4. History of or active autoimmune disease that has required systemic treatment in the past 2 years 2. History of severe/life threatening irAE with PD-(L)1 inhibitors are excluded. 3. CNS and/or leptomeningeal metastasis. 1. Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab. 5. Subjects 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. 6. Subjects with prior solid organ or bone marrow transplantation. 7. Pleural effusion or ascites with symptoms or requiring symptomatic treatment. 8. Subjects with an estimated life expectancy 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. 15. Subjects with 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. 16. 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. a. Subjects with adequately resected early-stage non-melanoma skin cancer or carcinoma in situ are allowed. b. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Progression-free survival is a preferred endpoint that directly reflects treatment effectiveness and is not confounded by subsequent therapy (FDA 2018). As this is an open-label study, PFS will be assessed by a central imaging vendor blinded to treatment assignment (BICR) according to RECIST v1.1 to minimize bias. Overall survival Overall survival is considered the gold standard endpoint and is a well-established endpoint for oncology drug approval in metastatic UC. Both first-line cisplatin-containing chemotherapy and second-line pembrolizumab have demonstrated an OS benefit in metastatic UC (Loehrer 1992; von der Maase 2000; Bellmunt 2017). However, the OS endpoint may be impacted by subsequent therapies or noncancer related causes of death (eg, accidents, comorbidities, and natural deaths in the elderly). With these considerations, this study has been designed to test both PFS and OS as dual primary endpoints, providing the opportunity to robustly evaluate the clinical benefit of the combination of disitamab vedotin plus pembrolizumab over the standard of care. NAME OF THE RESULT: Progression-free survival PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: During the study (6 years);Progression-free survival is a preferred endpoint that directly reflects treatment effectiveness and is not confounded by subsequent therapy (FDA 2018). As this is an open-label study, PFS will be assessed by a central imaging vendor blinded to treatment assignment (BICR) according to RECIST v1.1 to minimize bias. Overall survival Overall survival is considered the gold standard endpoint and is a well-established endpoint for oncology drug approval in metastatic UC. Both first-line cisplatin-containing chemotherapy and second-line pembrolizumab have demonstrated an OS benefit in metastatic UC (Loehrer 1992; von der Maase 2000; Bellmunt 2017). However, the OS endpoint may be impacted by subsequent therapies or noncancer related caus | — |
Secondary
| Measure | Time frame |
|---|---|
| DOR is defined as the time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause, whichever comes first. DOR will only be calculated for the subjects achieving a confirmed CR or PR. DOR per investigator and per BICR will be analyzed. DOR will be summarized descriptively by Kaplan-Meier methods. PFS, per investigator assessment, is defined as the time from randomization to first documentation of disease progression per RECIST v1.1, or to death due to any cause, whichever comes first. The same censoring rules outlined for PFS per BICR will be applied to PFS per investigator. NAME OF THE RESULT: duration of response (DOR) PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: During the study (6 years);Progression-free survival is a preferred endpoint that directly reflects treatment effectiveness and is not confounded by subsequent therapy (FDA 2018). As this is an open-label study, PFS will be assessed by a central imaging vendor blinded to treatment assignment (BICR) according to RECIST v1.1 to minimize bias. Overall survival Overall survival is considered the gold standard endpoint and is a well-established endpoint for oncology drug approval in metastatic UC. Both first-line cisplatin-containing chemotherapy and second-line pembrolizumab have demonstrated an OS benefit in metastatic UC (Loehrer 1992; von der Maase 2000; Bellmunt 2017). However, the OS endpoint may be impacted by subsequent therapies or noncancer related causes of death (eg, accidents, comorbidities, and natural deaths in the elderly). With these considerations, this study has been designed to test both PFS and OS as dual primary endpoints, providing the opportunity to robustly evaluate the clinical benefit of the combination of disitamab vedotin plus pembrolizumab over the standard of care. NAME OF THE RESULT: Progression-free survival PE | — |
Countries
Argentina, Australia, Austria, Brazil, Chile, Germany, Greece, Israel, Japan, Korea South, Norway, Peru, Portugal, Singapore, Switzerland, Taiwan, Turkey, United States
Contacts
Public ContactELIZABETH BEATRIZ ROSPIGLIOSI
RPS PERU S.A.C.
Outcome results
None listed