Open-Label, Single-Arm, Phase 1b Clinical Trial of NAI Plus Pembrolizumab With Short Course of Enfortumab Vedotin in Treatment-Naïve Participants With Metastatic Urothelial Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Assess the safety and tolerability of the treatment regimen (NAI, EV, and pembrolizumab).
研究概览
简要总结
This phase Ib trial will investigate the effect of N-803 in combination with pembrolizumab and enfortumab vedotin in treating participants with urothelial cancer that has spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic).
详细描述
This is an open label, phase 1b single arm trial with a safety lead-in cohort to determine the preliminary efficacy and safety of EV plus pembrolizumab and NAI in participants with unresectable locally advanced or mUC who are treatment-naïve in the metastatic setting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Age ≥ 18 years old.
- •Histologically or cytologically confirmed locally advanced/ mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as >50% urothelial component is present (mixed histology other than small cell/ neuroendocrine are allowed).
- •No prior systemic treatment for locally advanced/mUC.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤
- •Measurable disease according to RECIST v1.
- •Prior perioperative systemic therapy including neoadjuvant or adjuvant chemotherapy, immune checkpoint inhibitors, and EV is allowed if treatment was completed >12 months before trial enrollment.
- •Participants enrolling in the trial must agree with discontinuing EV upon demonstrating confirmed CR/PR/SD at the second or third scan timepoint on treatment (after 5.5 to 8 months of intended EV treatment).
- •Adequate organ and marrow function as defined below:
- •Leukocytes ≥ institutional lower limit of normal (LLN)
- •Absolute neutrophil count (ANC) ≥ 1,500/μL
- •Platelets ≥ 100,000/μL
- •Total bilirubin < 1.5 × institutional upper limit of normal (ULN) (if previously abnormal due to non-malignant causes such as Gilbert's disease bilirubin ≤ 2 × ULN will be permitted.)
- •Aspartate aminotransferase (AST) (SGOT)/ alanine aminotransferase (ALT) (SGPT) ≤ 2.5 × institutional upper limit of normal (ULN)
- •Creatinine clearance ≥ 30 mL/min/1.73 m2 calculated using the Cockcroft-Gault equation
- •Must have archival tumor tissue available or have disease amenable to a fresh biopsy for diagnosis confirmation and correlative studies.
- •Human immunodeficiency virus (HIV)-infected individuals with undetectable viral load within 6 months are eligible for this trial. Trial participants who are on antiretroviral therapy (ART) should be on established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrollment.
- •For participants with history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable, and the participant should be on suppressive antiviral therapy, if indicated. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured, with HCV viral load below the level of quantification. A participant who is HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution is eligible for this trial. For individuals with HCV infection who are currently on treatment, they are eligible if HCV viral load is below the level of quantification.
- •Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
- •Participants who are on beta blockers can enroll in the trial, but discontinuation of beta-blockers should be strongly considered at the time of initiating NAI. Beta blocker use can continue per physician discretion if necessary.
- •Agreement to practice effective contraception for female participants of childbearing potential and nonsterile males. Female participants of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Female participants of childbearing potential must have a negative pregnancy test and adhere to using a highly effective method of contraception (refer to Section 4.1.3) prior to screening and agree to continue its use during the study or be surgically sterilized (eg, hysterectomy) while on study and for 7 months post last dose of study drug. Male participants must agree to use barrier methods of birth control while on study and to advise their female partners to use a highly effective method of contraception for 7 months post last dose of study drug.
- •Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Symptomatic or untreated central nervous system (CNS) metastases. Note: Participants with previously treated brain or CNS metastases are eligible if the participant have recovered from any acute effects of surgery or radiotherapy and do not require steroids (prednisone equivalent ≥ 10 mg daily), and any whole brain radiation therapy or any stereotactic radiosurgery was completed at least 2 weeks prior to initiation of therapy.
- •History of active autoimmune disease and on active management with immunosuppressive agents within the past 2 years.
- •History of interstitial lung disease.
- •Congestive heart failure (New York Heart Association class III or IV)
- •Participants on systemic intravenous (IV) or oral corticosteroid therapy (prednisone equivalent ≥ 10 mg daily) or other immunosuppressive agents such as azathioprine or cyclosporin A. For these participants, these excluded treatments must be discontinued at least 1 week prior to enrollment for recent short course use (≤ 14 days) or discontinued at least 4 weeks prior to enrollment for long term use (> 14 days).
- •Note: The use of corticosteroids as premedication for contrast-enhanced studies is allowed prior to enrollment and on study. Participants requiring hormone replacement with corticosteroids if the steroids are administered only for the purpose of hormonal replacement or participants treated at doses ≤ 10 mg of prednisone or equivalent per day are allowed.
- •History of uncontrolled diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥ 8%.
- •Grade ≥ 2 peripheral neuropathy at baseline.
- •Radiotherapy or major surgery within 2 weeks prior to treatment start.
- •History of another significant life-limiting malignancy within 2 years prior to the first dose of study drug. Participants with nonmelanoma skin cancer, curatively treated localized prostate cancer, or carcinoma in situ of any type (if complete resection was done) are allowed.
- •History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to EV and/or pembrolizumab and/or NAI.
- •Received hematopoietic stem cell transplantation or solid organ transplantation.
- •Known active keratitis or corneal ulcerations.
- •Received or will receive a live vaccine within 30 days prior to the first administration of study intervention.
- •Note: Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved COVID-19 vaccines are permitted.
- •Pregnant and nursing women.
- •Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
- •Severe uncontrolled intercurrent illness that would limit compliance with study requirements in the judgement of the Investigator.
研究组 & 干预措施
Treatment
Participants will start combined treatment with EV/Pembrolizumab (P) and NAI. Treatment will consist of up to 12 cycles of EV and up to 35 cycles of NAI and pembrolizumab (2 years).
干预措施: Nogapendekin Alfa Inbakicept (NAI) (Drug)
Treatment
Participants will start combined treatment with EV/Pembrolizumab (P) and NAI. Treatment will consist of up to 12 cycles of EV and up to 35 cycles of NAI and pembrolizumab (2 years).
干预措施: enfortumab vedotin (EV) (Drug)
Treatment
Participants will start combined treatment with EV/Pembrolizumab (P) and NAI. Treatment will consist of up to 12 cycles of EV and up to 35 cycles of NAI and pembrolizumab (2 years).
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Assess the safety and tolerability of the treatment regimen (NAI, EV, and pembrolizumab).
时间窗: From the date of first dose of study product to 30 days after the last dose of study product.
The proportion of participants with treatment-emergent adverse events (TEAEs), as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.
12-month progression-free survival (PFS) of participants with locally advanced or metastatic urothelial carcinoma (mUC) receiving EV plus pembrolizumab and NAI
时间窗: From the date of first dose of study drugs to the date of disease progression or death (any cause)
Percentage of participants alive and progression free at 12 months, defined as the time from the date of first dose of study drugs (C1D1) to the date of disease progression or death (any cause), whichever occurs first, by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Proportion of participants with reported Treatment-Emergent Adverse Events
时间窗: Up to 2 years
Treatment emergent adverse events will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version (v) 5.0.
Number of participants with reported Dose-limiting toxicities (DLTs)
时间窗: Up to 28 days
Safety will be evaluated by assessing for DLTs in the first 6 participants treated with the study drug combination. If \>33% or \>2 of the first six participants experiences a DLT, the dose will be reviewed, and study will be considered for modification.
Percentage of participants alive and progression free at 12 months (PFS12)
时间窗: 12 months
The percentage of participants alive and progression free at 12 months is defined from the date of first dose of study drugs (C1D1) to the date of disease progression or death (any cause), whichever occurs first, by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. If disease progression or death from any cause is not observed prior to initiating subsequent anti-cancer therapy or completing study participation, the PFS will be censored as the last available disease assessment. Kaplan Meier analyses will be used to estimate 12 month PFS with 90% confidence interval.
次要结局
- To evaluate the preliminary efficacy of the treatment regimen (EV, pembrolizumab, and NAI)(12 months)
- To evaluate PFS, ORR, DOR, and CBR using immune RECIST (iRECIST).(From date of first dose of study drugs to the end of the follow up period, up to five years.)
- Complete Response (CR) Rate(Up to 2 years)
- Clinical Benefit Rate (CBR)(Up to 24 weeks)
- Objective Response Rate (ORR)(Up to 2 years)
- Median Overall Survival (OS)(Up to 5 years)
- Median Duration of Response (DOR)(Up to 5 years)
- Median Progression-Free Survival (PFS)(Up to 5 years)
研究者
Vadim S Koshkin
Principal Investigator
University of California, San Francisco