A Phase 1 Study of Intravesical VAX014 for Instillation in Subjects With Non-Muscle Invasive Bladder Cancer

Phase I Safety and Tolerability of Intravesical VAX014 for Instillation in Subjects With Non-Muscle Invasive Bladder Cancer (NMIBC)

The purpose of this research study is to evaluate the safety, tolerability and activity of VAX014 for Instillation (VAX014) in patients with low-grade Non-Muscle Invasive Bladder Cancer (NMIBC). VAX014 is a targeted oncolytic agent designed to kill tumor cells following instillation into the urinary bladder.

This study will evaluate the safety and tolerability of VAX014 using a 3+3 dose escalation design to determine a maximum tolerated dose (MTD) followed by a dose expansion at the Recommended Phase 2 Dose (RP2D). Both phases of the study will use a Window of Opportunity study design where patients with a single, low-grade Ta lesion will receive VAX014 via a urinary catheter into the bladder, weekly for 6 weeks prior to undergoing Transurethral Resection of Bladder Tumor (TURBT) to assess antitumor activity against the mapped lesion.

Patients enrolled in this study must have low-grade (Ta) Non-Muscle Invasive Bladder Cancer. However, eligible patients may have up to 5 low-grade Ta lesions at screening, and all but a single mapped lesion will be resected prior to receiving VAX014. The mapped lesion is assessed for anti-tumor activity.

VAX014 is a formulation of recombinant bacterial minicells which is designed to selectively target two NMIBC-associated integrin heterodimers to de-stabilize tumor cell membranes, with the result being tumor cell lysis.

Inclusion Criteria:

1. Signed, informed consent
2. Age 18 or more years
3. Pathologically confirmed low-grade Ta urothelial carcinoma (UC) of the urinary bladder
4. NMIBC with one solitary measurable tumor at the start of study, measuring ≥ 5 mm and ≤ 15 mm in greatest diameter (up to 4 additional low-grade Ta lesions, each measuring no more than 15 mm may be removed at screening provided a single lesion remains)
5. Treatment-naïve or failed one previous regimen of intravesical therapy (BCG or chemotherapy)
6. If recurrent disease, then more than 6 months from prior resection, more than 3 months from completion of last intravesical therapy with BCG, and more than 6 weeks from completion of last therapeutic intravesical therapy with chemotherapy
7. If previously treated, recovered from prior treatment-related toxicity to ≤ Grade 1
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 116
9. Absolute neutrophil count (ANC) ≥ 1,500/mm3
10. Platelet count ≥ 100,000/mm3
11. Total bilirubin ≤ 1.5 x upper limit of normal (ULN), or ≤ 3 x ULN in subjects with Gilberts disease
12. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 30 mL/min
13. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x ULN
14. Willingness to participate in collection of pharmacokinetic samples
15. Women of childbearing potential must have a negative serum pregnancy test.
16. All subjects of childbearing potential must be willing to use effective contraception while on treatment and for 3 months after the last dose of VAX014

Exclusion Criteria:

1. Additional papillary disease at screening (in addition to the solitary low-grade Ta lesion detailed in the inclusion criteria) that

   1. Consist of 6 or more lesions
   2. Consists of any lesion with a maximal diameter of greater than 15 mm

2. Confirmed or suspected perforated bladder

3. History of difficult catheterization that in the opinion of the investigator will prevent administration of VAX014

4. Presence or history of any high-grade urothelial cancer (including CIS) or high-grade urine cytology

5. Intravesical chemo-or biological therapy within 6 months of first administration of VAX014

6. UC of the ureters or urethra

7. History of interstitial cystitis

8. History of radiation to the pelvis

9. History of vesicoureteral reflux or an indwelling urinary stent

10. Other known active cancer(s) likely to require treatment or interfere with study objectives over the next two (2) years

11. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy

12. Known HIV, Hepatitis B, or Hepatitis C infection

13. Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months)

14. Major surgery other than diagnostic surgery within 4 weeks of first administration of VAX014

15. Pregnant or currently breast-feeding

16. Psychiatric illness/social situations that would interfere with compliance with study requirements

17. Presence of any sessile appearing tumor suspected of being invasive or high-grade