An Open-label, Randomized, Controlled Phase 3 Study of Enfortumab Vedotin in Combination With Pembrolizumab Versus Chemotherapy Alone in Previously Untreated Locally Advanced or Metastatic Urothelial Cancer
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 886
- 试验地点
- 481
- 主要终点
- Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Blinded Independent Central Review (BICR)
研究概览
简要总结
This study is being done to see how well two drugs (enfortumab vedotin and pembrolizumab) work together to treat patients with urothelial cancer. The study will compare these drugs to other drugs that are usually used to treat this cancer (standard of care). The patients in this study will have cancer that has spread from their urinary system to other parts of their body.
详细描述
Japan PMDA has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan.
This study is being conducted to evaluate the combination of enfortumab vedotin + pembrolizumab versus standard of care gemcitabine + platinum-containing chemotherapy, in subjects with previously untreated locally advanced or metastatic urothelial cancer.
Enfortumab vedotin may be administered for an unlimited number of cycles until a protocol defined reason for study discontinuation occurs. Pembrolizumab may be administered for a maximum of 35 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first. Cisplatin or carboplatin plus gemcitabine may be administered for a maximum of 6 cycles or a protocol-defined reason for study discontinuation occurs, whichever is first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically documented, unresectable locally advanced or metastatic urothelial carcinoma
- •Measurable disease by investigator assessment according to RECIST v1.1
- •Participants 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
- •Participants must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
- •Participants that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted
- •Participants that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted
- •Must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator's judgment
- •Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization
- •Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2
- •Adequate hematologic and organ function
排除标准
- •Previously received enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADCs)
- •Received prior treatment with a programmed cell death ligand-1 (PD-(L)-1) inhibitor for any malignancy, including earlier stage urothelial cancer (UC), defined as a PD-1 inhibitor or PD-L1 inhibitor
- •Received prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor
- •Received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment
- •Uncontrolled diabetes
- •Estimated life expectancy of less than 12 weeks
- •Active central nervous system (CNS) metastases
- •Ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline
- •Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
- •Known active hepatitis B, active hepatitis C, or human immunodeficiency virus (HIV) infection.
- •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
- •Active keratitis or corneal ulcerations
- •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
研究组 & 干预措施
Arm B
Gemcitabine + cisplatin or carboplatin
干预措施: Gemcitabine (Drug)
Arm A
Enfortumab vedotin + pembrolizumab
干预措施: Pembrolizumab (Drug)
Arm B
Gemcitabine + cisplatin or carboplatin
干预措施: Carboplatin (Drug)
Arm A
Enfortumab vedotin + pembrolizumab
干预措施: Enfortumab vedotin (Drug)
Arm B
Gemcitabine + cisplatin or carboplatin
干预措施: Cisplatin (Drug)
结局指标
主要结局
Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Blinded Independent Central Review (BICR)
时间窗: From the date of randomization to first documentation of PD or death due to any cause, whichever occurred first (maximum exposure to treatment was up to 39.2 months)
PFS was defined as the time from date of randomization to first documentation of disease progression (PD), or to death due to any cause, whichever occurred first. PD: at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). PD could also be unequivocal progression of non-target lesions or the presence of unequivocal new lesions. Kaplan-Meier method was used for analysis.
Overall Survival (OS)
时间窗: From randomization to date of death due to any cause or censoring date, whichever occurred first (maximum exposure to treatment was up to 39.2 months)
OS was defined as the time from the date of randomization to the date of death from any cause. In the absence of death, OS was censored at the date the participant was last known to be alive. Kaplan-Meier method was used for analysis.
次要结局
- Percentage of Participants With Objective Response Rate (ORR) Per RECIST v1.1 by BICR(From first dose till CR/PR or PD or death, whichever occurred first (maximum up to approximately 7.4 years))
- Time to Pain Progression (TTPP)(From the date of randomization to date of pain progression (maximum up to approximately 7.4 years))
- Change From Baseline in Worst Pain Using BPI-SF at Week 26(Baseline, Week 26)
- PFS Per RECIST v1.1 by Investigator Assessment(From the date of randomization to first documentation of PD or death due to any cause, whichever occurred first (maximum up to approximately 7.4 years))
- ORR Per RECIST v1.1 by Investigator Assessment(From first dose till CR/PR or PD or death, whichever occurred first (maximum up to approximately 7.4 years))
- Duration of Response (DOR) Per RECIST v1.1 by BICR(From the date of first documented response of CR or PR to the first documented disease progression or to death from any cause, whichever occurred first (maximum up to approximately 7.4 years))
- DOR Per RECIST v1.1 by Investigator Assessment(From the date of first documented response of CR or PR to the first documented disease progression or to death from any cause, whichever occurred first (maximum up to approximately 7.4 years))
- Disease Control Rate (DCR) Per RECIST v1.1 by BICR(From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to approximately 7.4 years))
- DCR Per RECIST v1.1 by Investigator Assessment(From the date of randomization to the date of PD or death from any cause or censoring date, whichever occurred first (maximum up to approximately 7.4 years))
- Mean Scores in Patient Reported Outcome (PRO) Assessment Measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L)(End of study (approximately up to 7.4 years))
- Change From Baseline in PRO Assessment Measured by the EQ-5D-5L(Baseline, End of study (approximately up to 7.4 years))
- Change From Baseline in PRO Assessment Measured by EORTC QLQ-C30(Baseline, End of study (approximately up to 7.4 years))
- Mean Scores in PRO Assessment Measured by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)(End of study (approximately up to 7.4 years))
- Number of Participants With Treatment Emergent Adverse Events Adverse Events (AEs)(From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years))
- Number of Participants With Serious TEAE(From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years))
- Number of Participants With Grade 3-5 TEAE(From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years))
- Number of Participants Related to Treatment AEs(From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years))
- Number of Participants With Laboratory Abnormalities(From start of treatment up to 37 days after last dose of study drug (approximately up to 7.4 years))
- Number of Participants With Treatment Discontinuation Rate Due to AEs(During study (approximately up to 7.4 years))