A Phase 1/2 Study of EG-70 as an Intravesical Administration to Patients With BCG Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) and High-Risk NMIBC Patients Who Are BCG Naïve or Received Incomplete BCG Treatment
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- enGene, Inc.
- 入组人数
- 350
- 试验地点
- 191
- 主要终点
- Phase 1: Nature, incidence, relatedness, and severity of all AEs and SAEs according to the CTCAE v5.0.
研究概览
简要总结
This study will evaluate the safety and efficacy of intravesical administration of detalimogene (EG-70) in the bladder and its effect on bladder tumors in patients with NMIBC.
This study study consists of two phases; a Phase 1 dose-escalation to establish safety and recommended the phase 2 dose, followed by a Phase 2 study to establish how effective the treatment is. The Study will include patients with: NMIBC with CIS for whom BCG therapy is unresponsive, and other high risk patients with NMIBC.
A Substudy will include a surfactant bladder rinse prior to the instillation of detalimogene in patients with NMIBC with CIS for whom BCG therapy is unresponsive.
详细描述
EG-70 is a novel non-viral gene therapy. EG-70 is designed to elicit a local immune response following delivery of the study gene therapy to the bladder urothelium. This approach of local administration through bladder instillation has the potential to induce a potent immune response exclusively at the site of the tumor, resulting in greater therapeutic benefit while reducing undesirable systemic toxicity.
Eligible BCG-unresponsive NMIBC with CIS patients will be enrolled in Phase 1, and Cohort 1 of Phase 2. Eligible high-risk NMIBC patients will be enrolled in Phase 2 into separate cohorts include: BCG-naïve patients or BCG-exposed (incompletely treated) patients with Carcinoma in situ (CIS), and BCG-unresponsive HG Ta/T1 papillary disease without CIS.
Patients will be treated for up to four 12-week cycles of study drug instillation doses and assessments with follow up assessments. Patients with complete response following four treatment cycles will enter up to 8 maintenance treatment cycles.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •BCG-unresponsive Patients:
- •BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without coexisting papillary Ta/T1 tumors who are ineligible for or have elected not to undergo cystectomy, and have experienced CIS disease within 12 months of treatment where: adequate BCG regimen consists of at least 2 courses of BCG where the first course (induction) must have included at least 5 or 6 doses and the second course may have included a re-induction (at least 2 treatments) or maintenance (at least 2 doses), and Cis must be documented or indicated by pathology
- •Phase 2 Only:
- •BCG-Naïve or BCG-incompletely treated Patients with CIS or BCG-unresponsive, HG Ta/T1 papillary disease without CIS:
- •NMIBC with current Cis of the bladder, with or without coexisting papillary Ta/T1 NMIBC tumor(s), who are ineligible for or have elected not to undergo cystectomy, where: either: cohort 2a) no treatment with BCG but may have previously been treated with at least 1 dose of intravesical chemotherapy following transurethral resection of bladder tumor (TURBT) and Cis must be documented or cohort 2b) indicated by pathology incomplete BCG treatment (at least 1 dose and less than the 5+2 doses required for adequate dosing per Cohort 1) or cohort 3) patients who are BCG-unresponsive following adequate treatment, with HG Ta/T1 papillary disease without CIS.
- •All Patients with High Grade NMIBC:
- •Patients who have previously been treated with a checkpoint inhibitor and failed treatment are eligible for inclusion 30 days post-treatment (Phase 1) or 3 months post-treatment (Phase 2).
- •Male or non-pregnant, non-lactating female, 18 years or older.
- •Women of childbearing potential must have a negative pregnancy test at Screening.
- •Female patients of childbearing potential must be willing to consent to using highly effective birth control methods; Male patients are required to utilize a condom for the duration of the study treatment through 3 months post-dose.
- •In Phase 2, for patients with T1 lesions may be eligible after repeat TURBT if pathology shows non-invasive (Ta or less) or no disease.
- •Performance Status: Eastern Cooperative Oncology Group 0, 1, and
- •Hematologic inclusion: a. Absolute neutrophil count >1,500/mm
- •b. Hemoglobin >9.0 g/dL. c. Platelet count >100,000/mm
- •Hepatic inclusion: a. Total bilirubin must be ≤1.5 x the upper limit of normal (ULN). b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase ≤2.5 x ULN.
- •Adequate renal function with creatinine clearance >30 mL/min
- •Prothrombin time and partial thromboplastin time ≤1.25 x ULN or within the therapeutic range if on anticoagulation therapy.
- •Must have satisfactory bladder function with ability to retain study drug for 60 minutes.
排除标准
- •Active malignancies (i.e., progressing or requiring treatment change in the last 24 months). Exceptions allowed under Sponsor review.
- •Concurrent treatment with any chemotherapeutic agent.
- •History of partial cystectomy.
- •Treatment with last therapeutic agent (including intravesical chemotherapy post-TURBT) within 30 days of Screening (prior to the screening biopsy).
- •Patients who have received systemic immunosuppressive medication including high-dose corticosteroids.
- •History of severe asthma or other respiratory diseases.
- •History of unresolved vesicoureteral reflux or an indwelling urinary stent.
- •History of unresolved hydronephrosis due to ureteral obstruction.
- •Participation in any other research protocol involving administration of an investigational agent within 30 Days prior to screening or any prior treatment of NMIBC with any investigational gene or immunotherapy agent.
- •History of external beam radiation to the pelvis or prostate brachytherapy within the last 12 months.
- •History of interstitial lung disease and/or pneumonitis in patients who have previously received a PD-1 or PD-L1 inhibitor therapy.
- •Evidence of metastatic disease.
- •History of difficult catheterization that in the opinion of the Investigator will prevent administration of EG-
- •Active interstitial cystitis on cystoscopy or biopsy.
- •Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
- •Known human immunodeficiency virus, Hepatitis B, or Hepatitis C infection.
- •Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months).
- •Hypersensitivity to any of the excipients of the study drug.
- •Exclusionary for Bladder Rinse cohorts: known allergy to polidocanol
研究组 & 干预措施
Phase 2
Cohort 1: Recommended Phase 2 dose (RP2D) with eligible BCG-unresponsive NMIBC patients with CIS, up to 4 cycles of treatment with EG-70. Patients in Complete Response continue to Maintenance Treatment.
Cohorts 2A, 2B and 3: RP2D with eligible high-risk NMIBC patients with CIS who are BCG-naïve, BCG-exposed (incompletely treated with BCG) or BCG-unresponsive HG Ta/T1 papillary disease without CIS
干预措施: EG-70 (phase 2) Master Protocol (Drug)
Phase 1
Dose escalation phase
干预措施: EG-70 (phase 1) (Drug)
Phase 1 Substudy Surfactant Bladder Rinse
BCG-unresponsive NMIBC patients with CIS, up to 4 cycles of treatment with EG-70. Patients in Complete Response continue to Maintenance Treatment.
Bladder Rinse Cohort: a 5-minute bladder rinse prior to administration of RP2D of detalimogene voraplasmid (EG-70) with a shortened administration time of 30 minutes.
干预措施: Surfactant Bladder Pre-Rinse and EG-70 (Substudy) (Drug)
结局指标
主要结局
Phase 1: Nature, incidence, relatedness, and severity of all AEs and SAEs according to the CTCAE v5.0.
时间窗: Approximately 2 years
The type, incidence, relatedness and severity of treatment emergent adverse events of EG-70 as assessed by NCI-CTCAE V5.0 will be monitored.
Phase 2: Nature, incidence, relatedness, and severity of treatment emergent adverse events (as assessed by CTCAE v5.0)
时间窗: Approximately 3 years
The type, incidence, relatedness and severity of treatment emergent adverse events of EG-70 as assessed by NCI-CTCAE V5.0 will be monitored.
Phase 2: Percentage of patients with cystoscopic CR at 48 weeks, based on exam, urine cytology and appropriate biopsies.
时间窗: Approximately 48 weeks
Complete response rate will be measured by determining the number of patients without recurrence of high-grade disease.
Phase 2: Percentage of patients with cystoscopic CR at any time, based on exam, urine cytology and appropriate biopsies.
时间窗: Approximately 24 weeks
Complete response rate will be measured by determining the number of patients without recurrence of disease.
次要结局
- Phase 2: Progression-free survival (PFS)(Approximately 3 years)
- Phase 1: CR rate to EG-70 by cystoscopy at approximately 12 weeks.(Approximately 12 weeks)
- Phase 2: CR rate at 12, 24, 36, and 96 weeks(Approximately 12, 24, 36, and 96 weeks)
- Phase 2: Duration of response of the responding patients(Approximately 3 years)
- Phase 2: Quality of Life Assessment(24 weeks)
- Phase 1: The number of patients who experience a DLT through the end of Cycle 1(Approximately 12 Weeks)