A Phase 1/2 Study of EG-70 as an Intravesical Administration to Patients with BCG-Unresponsive NMIBC and High-Risk NMIBC who are BCG Naïve/Received Incomplete BCG Treatment

This study will evaluate the safety and tolerability of EG-70, a gene therapy, which is given inside the bladder, and its effectiveness on eliminating bladder tumors in patients with Non Muscle Invasive Bladder Cancer (NMIBC) who have failed BCG therapy and have been recommended to have their bladder removed.  Giving the study drug inside the bladder is to expose cells in the lining of the bladder, including your cancerous cells, to genes that may cause an immune response inside the bladder and kill the tumor cells. 

The LEGEND study will have 2 phases. Both phases will test how safe and effective the study drug is, but Phase 1 is also designed to determine what dose and dosing schedule will be used in Phase 2. Phase 2 will further test how safe and effective the determined dose and dosing schedule are.

 Patient enrollment criteria is as follows:

 INCLUSION CRITERIA

 BCG-Unresponsive Patients (Phase 1 and Phase 2-Cohort 1):

1. BCG-unresponsive NMIBC with Cis of the bladder, with or without coexisting papillary Ta/T1 tumor(s) who are ineligible for or have elected not to undergo cystectomy, and have experienced 1) persistent disease within 12 months of treatment or 2) a recurrence within 6 months of completion of adequate BCG therapy, 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 of 6 treatments) or maintenance (at least 2 of 3 doses),
• Patients with BCG-unresponsive NMIBC may have received subsequent approved treatment for NMIBC that discontinued no more than 4 months of Screening, and
• Cis must be documented or indicated by pathology at Screening or within 4 months of Screening (provided no therapy for Cis disease was given after the most recent biopsy).

BCG-Naïve or BCG-Incompletely Treated Patients (Phase 2-Cohort 2 Only):

2. 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: a) incomplete BCG (at least 1 dose) treatment or b) no treatment with BCG due to unavailability, but who 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 indicated by pathology within 4 months of or at Screening (without Cis treatment).

All Patients (Note if criterion specifies Phase 1 or 2 and Cohort):

3. Patients who have previously been treated with an investigational or approved checkpoint

inhibitor (e.g., pembrolizumab) are eligible for inclusion 30 days post-treatment (Phase 1) or 3 months post-treatment (Phase 2).

4. Male or on-pregnant, non-lactating female, 18 years or older.

5. Women of child-bearing potential must have a negative pregnancy test at Screening. A

female patient is considered to be of child-bearing 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 postmenopausal range).

6. Female patients of child-bearing 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; 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, Screening biopsy must be considered adequate (contain the muscularis layer).

8. Performance Status: Eastern Cooperative Oncology Group 0, 1, and 2.

9. Hematologic inclusion at Screening:

• Absolute neutrophil count >1,500/mm3.
• Hemoglobin >9.0 g/dL.
• Platelet count >100,000/mm3.

10. Hepatic inclusion at Screening:

• Total bilirubin must be ≤1.5 x the upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN, 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 at Screening or within the therapeutic range if on anticoagulation therapy.

13. Must have satisfactory bladder function with ability to retain study drug for a minimum of 60 minutes.

14. Patient or legally authorized representative (LAR) must be willing and able to comply with all protocol requirements.

15. 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

 Patients may not enter the study if any of the following apply:

 1. Any malignancy other than NMIBC diagnosed within 1 year of study entry (except basal or squamous cell skin cancers or noninvasive cancer of the cervix), or any malignancy that has required therapy for active disease within the last 12 months.

2. Concurrent treatment with any chemotherapeutic agent.

3. History of partial cystectomy.

4. Treatment with pembrolizumab within 30 days (Phase 1) or 3 months (Phase 2) prior to Screening.

5. Treatment with last therapeutic agent (including intravesical chemotherapy post-TURBT) within 30 days of Screening (Phase 1 and Phase 2).

6. Evidence of persistent or ongoing renal failure.

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 (not approved) 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 at any time 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. Consideration by the Investigator that the patient is an unsuitable candidate for the study; due to a personal issue (e.g., inability to comply with protocol or relationship to study staff or Sponsor), mental health considerations, or other reason, that may impede successful study participation.