LEGEND Study: EG-70 in NMIBC Patients BCG-Unresponsive and High-Risk NMIBC Incompletely Treated With BCG or BCG-Naïve

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of intravesical administration of EG-70 and 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 for whom BCG therapy is unresponsive and are recommended for radical cystectomy, or high-risk NMIBC patients who are BCG-naïve or have received incomplete BCG treatment.

Detailed Description
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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 patients will be enrolled in Phase 1, and Cohort 1 of Phase 2. Eligible high-risk NMIBC patients who have been incompletely treated or are BCG-naïve will be enrolled starting in Phase 2 in a separate single-arm cohort (Cohort 2). Patients will be treated for up to four 12-week cycles of study drug instillation doses and assessments with follow up assessments.

Official Title
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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

Conditions
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Superficial Bladder Cancer

Intervention / Treatment
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* Drug: EG-70
* Drug: EG-70


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BCG-unresponsive Patients: BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without resected papillary tumors who are ineligible for or have elected not to undergo cystectomy: persistent high-grade disease (Ta, T1, or Tis) after receiving intravesical BCG induction (at least 5 of 6 induction doses) plus maintenance (at least 2 of 3 doses) or recurrence of high-grade papillary disease within 6 months or Tis within 12 months of BCG instillation or T1 high grade disease residual at the first evaluation following induction BCG (at least 5 of 6 doses). BCG-Naïve or BCG-incompletely treated Patients (Phase 2 Only): NMIBC with Cis with or without resected papillary tumors who are ineligible for or have elected not to undergo cystectomy: persistent high-grade disease (Ta, T1, or Tis): after incomplete BCG treatment (at least 1 dose) or who have not yet received any treatment with BCG, but who have previously been treated with at least 1 dose of intravesical chemotherapy following transurethral resection of bladder tumor (TURBT) All Patients: Patients who have previously been treated with an investigational or approved checkpoint inhibitor (e.g., pembrolizumab) 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. A female patient is considered to be of child-producing potential unless she: has had a hysterectomy or bilateral oophorectomy or is age ≥ 60 years and is amenorrhoeic or is age < 60 years and has been amenorrhoeic for ≥ 12 months (including no irregular menses or spotting) in the absence of any medication which induces a menopausal state and has documented ovarian failure by serum oestradiol and follicle-stimulating hormone levels within the institutional laboratory postmenopausal range). All patients of childbearing potential must be willing to consent to using effective double-barrier contraception, i.e., intrauterine device, birth control pills, depo-provera, and condoms while on treatment and for 3 months after their participation in the study ends. In Phase 2, for patients with T1 lesions, Screening biopsy must be considered adequate (contain the muscularis layer). Performance Status: Eastern Cooperative Oncology Group (ECOG) 0, 1, and 2. Hematologic inclusion within 2 weeks of start of treatment: Absolute neutrophil count >1,500/mm3. Hemoglobin >9.0 g/dl. Platelet count >100,000/mm3. Hepatic inclusion within 2 weeks of Day 1: Total bilirubin must be ≤1.5 x the upper limit of normal (ULN). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN for the institution, alkaline phosphatase ≤2.5 x ULN for the institution, unless bone metastasis is present in the absence of liver metastasis. Adequate renal function with creatinine clearance >30 mL/min Prothrombin time and partial thromboplastin time within the normal limits at Screening. Must have satisfactory bladder function with ability to retain study drug for a minimum of 60 minutes. Patient or legally authorized representative (LAR) must be willing and able to comply with all protocol requirements. Patient or LAR must be willing and able to give informed consent and any authorizations required by local law for participation in the study. Exclusion Criteria: Any other malignancy diagnosed within 1 year of study entry (except basal or squamous cell skin cancers or noninvasive cancer of the cervix) is excluded. Concurrent treatment with any chemotherapeutic agent. History of partial cystectomy. Treatment with pembrolizumab within 30 days (Phase 1) or 3 months (Phase 2) prior to Screening. Treatment with last therapeutic agent (including intravesical chemotherapy post-TURBT) within 30 days of Screening (Phase 1 and Phase 2) or treatment with an investigational checkpoint inhibitor within 3 months of Screening (Phase 2 only). Evidence of persistent or ongoing renal failure. 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 1 month prior to Day 1. History of external beam radiation to the pelvis at any time 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-70. History of interstitial cystitis. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy. Known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection. Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>Dose escalation phase | Drug: EG-70<br>* Patients will receive up to four cycles of EG-70 administered as a bladder instillation of a 50 mL volume of study drug via catheter with a targeted retention time of 60 minutes.One cycle lasts approximately 12 weeks and consists of either a 2-dose (Day 1 and Day 8) or 4-dose (Day 1, Day 8, Day 29 and Day 36) regimen.<br>* Other names: Phase 1;|
| Experimental: Phase 2<br>Cohort 1: Recommended Phase 2 dose (RP2D) with eligible BCG-unresponsive NMIBC patients, up to 4 cycles of treatment with EG-70 Cohort 2: RP2D with eligible high-risk NMIBC patients who have been incompletely treated with BCG or are BCG-naïve | Drug: EG-70<br>* Cohort 1 and Cohort 2: Patients will receive up to 4 cycles of EG-70 at the RP2D defined in Phase 1 administered as a bladder instillation of a 50 mL volume of study drug via catheter with a targeted retention time of 60 minutes. One cycle lasts approximately 12 weeks.<br>* Other names: Phase 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Nature, incidence, relatedness, and severity of all AEs and SAEs according to the CTCAE v5.0. | The type, incidence, relatedness and severity of treatment emergent adverse events of EG-70 as assessed by NCI-CTCAE V5.0 will be monitored. | Approximately 2 years | 
| Phase 2: Percentage of patients with cystoscopic CR at 48 weeks, based on exam, urine cytology and appropriate biopsies. | Complete response rate will be measured by determining the number of patients without recurrence of high-grade disease. | Approximately 48 weeks | 
| Phase 2: Nature, incidence, relatedness, and severity of treatment emergent adverse events (as assessed by CTCAE v5.0) | The type, incidence, relatedness and severity of treatment emergent adverse events of EG-70 as assessed by NCI-CTCAE V5.0 will be monitored. | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: The number of patients who experience a DLT through the end of Cycle 1 | To identify the number of patients who experience a DLT through the end of Cycle 1 | Approximately 12 Weeks | 
| Phase 1: CR rate to EG-70 by cystoscopy at approximately 12 weeks. | To evaluate preliminary efficacy of EG-70 by 12 weeks via cystoscopy | Approximately 12 weeks | 
| Phase 2: Progression-free survival (PFS) | To evaluate disease-free survival rate | Approximately 3 years | 
| Phase 2: CR rate at 12, 24, 36, and 96 weeks | To further evaluate CR at the efficacy analysis following each cycle. | Approximately 12, 24, 36, and 96 weeks | 
| Phase 2: Duration of response of the responding patients | Durability will be measured by determining the number of patients without recurrence of high-grade disease. | Approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-muscle invasive bladder cancer (NMIBC), Bacillus calmette- guerin (BCG) failure, BCG unresponsive, NMIBC, Bladder Cancer, LEGEND Study, EG-70, High-risk NMIBC, BCG-naïve, Incomplete BCG treatment