The patients in this study will have cancer that has spread from their urinary system to other parts of their body. An AE is considered "serious" if the event: results in death; is life-threatening; results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; requires inpatient hospitalization (except for planned procedures) or leads to prolongation of hospitalization (except if prolongation of planned hospitalization is not caused by an AE); or other medically important events. Cohort E: Ineligible for cisplatin-based chemotherapy, eligible for carboplatin, and no prior treatment for la/mUC. Subject has accessible archival tumor tissue from either the primary tumor or a metastatic site, for which source and availability have been confirmed prior to study treatment. Maintenance therapy does not constitute a new chemotherapy regimen provided there was no progression after the initial platinum-based regimen. Subject with superficial punctate keratitis is allowed if the disorder is being adequately treated. Subject has histologically- or cytologically-confirmed non-squamous NSCLC. Subjects with mixed histology NSCLC are eligible provided there is not any component of neuroendocrine histology. COVID-19 vaccination is permitted. Please remove one or more studies before adding more. Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G). This study will test an experimental drug (enfortumab vedotin) alone and with different combinations of anticancer therapies. For general information, Learn About Clinical Studies. Cohort 2 median follow up time: 13.4 months [range 0.33 to 29.27]). Subject has received prior therapy with an anti-programmed cell death protein-1 (PD-1) or an anti-programmed cell death-ligand 1 (PD-L1) based on subject's tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed or discontinued treatment due to toxicity, or therapy is contraindicated for subject. Formats. ], ORR Per Investigator Assessment [TimeFrame:Up to data cut-off date of 01 Mar 2019 for cohort 1 and 08 Sept 2020 for cohort 2 (Cohort 1 median follow-up time: 10.15 months [range 0.49, 16.46]. This study will examine the safety and anticancer activity of enfortumab vedotin (EV) given intravenously as monotherapy and in combination with other anticancer therapies as first line (1L) and second line (2L) treatment for patients with urothelial cancer. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement. Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum-based standard of care regimen for locally advanced or metastatic disease, and has not received > 2 prior lines of cytotoxic anticancer therapy in the locally advanced or metastatic setting. "Patients with metastatic urothelial cancer typically have a five-year survival rate of just five percent and are in urgent need of new treatment options. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: i. pacemaker) or prior ablation is allowed, Pre-existing sensory grade 2 neuropathy. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Changing chemotherapy agents during platinum-based treatment for the management of toxicities does not constitute a new chemotherapy regimen provided no progression has occurred while on the initial therapy. Listing a study does not mean it has been evaluated by the U.S. Federal Government. A treatment emergent adverse event (TEAE) was defined as a newly occurring or worsening AE after the first dose of study treatment and within 30 days after the last dose of study treatment. The primary goal of the study is to determine the confirmed ORR of enfortumab vedotin. doi: 10.1200/JCO.22.01643. Total bilirubin 1.5 ULN OR direct bilirubin ULN for participants with total bilirubin levels >1.5 ULN, Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) 1.5 ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants, Evidence of NYHA functional class III or IV heart disease, Any of the following within 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack, On-going cardiac dysrhythmias of NCI CTCAE Version 5.0 grade 2. Evidence of urothelial carcinoma from FNA of lymph node OR lymphadenopathy suspicious for nodal disease on cross-sectional imaging, MRI, or u/s. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. The clinical trial is comparing enfortumab vedotin-ejfv to . Both versions of enfortumab vedotin, hybridoma AGS-22M6E (also known as ASG-22ME) and Chinese hamster ovary (CHO) ASG-22CE, show eradication of established tumor xenografts. Purpose: To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4. This study is being done to see how well two drugs (enfortumab vedotin and pembrolizumab) work together to treat patients with urothelial cancer. Enfortumab vedotin will be capped at a maximum dose of 125 mg for each infusion (for patients who weigh > 100 kg). The researchers think the drugs may be more effective if given in combination rather than on their own. Individual Participant Data (IPD) Sharing Statement: Studies a U.S. FDA-regulated Drug Product: Studies a U.S. FDA-regulated Device Product: Patients have already received treatment with platinum-containing chemotherapy. Cohort 2: triple negative breast cancer (TNBC), Cohort 3: squamous non-small cell lung cancer (NSCLC). Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl) GFR or CrCl of 30 mL/min. Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs. Clinical Trials Information. EV consists of monomethyl auristatin E, a microtubule-disrupting agent linked to an antibody targeting Nectin-4. Astellas and Seagen will also present updates from the broader enfortumab vedotin program in four posters at ASCO GU 2022, including: 5 WARNINGS AND PRECAUTIONS 5.1 Skin Reactions - Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. Full Title An Open-label, Multicenter, Multicohort, Phase 2 Study to Evaluate Enfortumab Vedotin in Subjects with Previously Treated Locally Advanced or Metastatic Malignant Solid Tumors (EV-202) Purpose The purpose of this study is to assess the safety and effectiveness of the anticancer drug enfortumab vedotin in people with certain advanced breast and digestive cancers. An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2: Participants with ECOG performance status of 2 must meet the following additional criteria: hemoglobin 10 g/dL, GFR 50 mL/min, may not have NYHA Class III heart failure. Eligible for gemcitabine. This study will also look at the side effects of the drug. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Descriptive statistics will be used to summarize results. Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-ofcare management (e.g. Cohort K: Ineligible for cisplatin-based chemotherapy due to at least 1 of the following: Glomerular filtration rate (GFR) <60 mL/min and 30 mL/min, ECOG performance status of 2, NCI CTCAE Version 4.03 Grade 2 hearing loss, New York Heart Association (NYHA) Class III heart failure. The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per RECIST 1.1) or to death due to any cause, whichever comes first. Enfortumab vedotin-ejfv is the first Nectin-4-directed antibody-drug conjugate to receive FDA approval. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04223856. Patients with history of autoimmune related hypothyroidism on stable dose of thyroid replacement hormone may be eligible for this study, Patients with controlled Type I diabetes mellitus on a stable dose of insulin may be eligible for this study, Has a history of idiopathic pulmonary fibrosis, pneumonitis/interstitial lung disease that requires steroids or has current pneumonitis/interstitial lung disease (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc. PD-1/PD-L1 inhibitors demonstrate durable responses; however, only a minority of pts achieve a response (ORR 24-29%). Talk with your doctor and family members or friends about deciding to join a study. History of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy, Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class IV within 6 months prior to randomization, Receipt of radiotherapy within 2 weeks prior to randomization, Received major surgery (defined as requiring general anesthesia and >24 hour inpatient hospitalization) within 4 weeks prior to randomization, Known severe ( Grade 3) hypersensitivity to any enfortumab vedotin excipient contained in the drug formulation of enfortumab vedotin, History of autoimmune disease that has required systemic treatment in the past 2 years, History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan, Prior allogeneic stem cell or solid organ transplant, Received a live attenuated vaccine within 30 days prior to randomization. requires all requests for clinical trial data be reviewed to determine the qualification of . Pembrolizumab is an immune checkpoint inhibitor (CPI) that is used to treat patients with cancer of the urinary system (urothelial cancer). Active central nervous system (CNS) metastases. Patients with a history of an aids-defining opportunistic infection within the last 12 months or who are on prophylactic antimicrobials related to underlying HIV are not eligible. Drug: Enfortumab vedotin Drug: Pembrolizumab Detailed Description This single arm phase II trial will evaluate the use of enfortumab vedotin and pembrolozumab for high grade upper tract urothelial cancer patients who are unable or unwilling to undergo standard of care nephroureterectomy. The primary goal of the study is to determine the safety, tolerability, and efficacy of enfortumab vedotin alone and in combination with pembrolizumab and/or chemotherapy. Neoadjuvant or adjuvant cytotoxic regimens will count as a prior regimen if relapsed or progressed 6 months after completion. a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. Has a history of poorly controlled human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) related illness. Have adequate organ function as defined in the following table (Table 1). Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible. The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first. Study record managers: refer to the Data Element Definitions if submitting registration or results information. 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