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

This study will evaluate the safety and efficacy of intravesical administration of 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 patients with NMIBC with Cis who are BCG-naïve or inadequately treated.

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 will be enrolled starting in Phase 2 in separate single are 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 the four 12-week cycles will enter up to 4 maintenance treatment cycles, and those remaining in complete response will enter another 4 maintenance treatment cycles or follow up assessments.

Eligibility Criteria:
Inclusion Criteria:

BCG-unresponsive Patients:

1. 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:
2. 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:
3. 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).
4. Male or non-pregnant, non-lactating female, 18 years or older.
5. Women of childbearing potential must have a negative pregnancy test at Screening.
6. 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.
7. 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.
8. Performance Status: Eastern Cooperative Oncology Group 0, 1, and 2.
9. Hematologic inclusion: a. Absolute neutrophil count \>1,500/mm3. b. Hemoglobin \>9.0 g/dL. c. Platelet count \>100,000/mm3.
10. 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.
11. Adequate renal function with creatinine clearance \>30 mL/min
12. Prothrombin time and partial thromboplastin time ≤1.25 x ULN or within the therapeutic range if on anticoagulation therapy.
13. Must have satisfactory bladder function with ability to retain study drug for 60 minutes.

Exclusion Criteria:

1. Active malignancies (i.e., progressing or requiring treatment change in the last 24 months). Exceptions allowed under Sponsor review.
2. Concurrent treatment with any chemotherapeutic agent.
3. History of partial cystectomy.
4. Treatment with last therapeutic agent (including intravesical chemotherapy post-TURBT) within 30 days of Screening (prior to the screening biopsy).
5. Patients who have received systemic immunosuppressive medication including high-dose corticosteroids.
6. History of severe asthma or other respiratory diseases.
7. History of unresolved vesicoureteral reflux or an indwelling urinary stent.
8. History of unresolved hydronephrosis due to ureteral obstruction.
9. 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.
10. History of external beam radiation to the pelvis or prostate brachytherapy within the last 12 months.
11. History of interstitial lung disease and/or pneumonitis in patients who have previously received a PD-1 or PD-L1 inhibitor therapy.
12. Evidence of metastatic disease.
13. History of difficult catheterization that in the opinion of the Investigator will prevent administration of EG-70.
14. Active interstitial cystitis on cystoscopy or biopsy.
15. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
16. Known human immunodeficiency virus, Hepatitis B, or Hepatitis C infection.
17. Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months).
18. Hypersensitivity to any of the excipients of the study drug.