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

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

• Signed, informed consent
• Age 18 or more years
• Pathologically confirmed low-grade Ta urothelial carcinoma (UC) of the urinary bladder
• 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)
• Treatment-naïve or failed one previous regimen of intravesical therapy (BCG or chemotherapy)
• 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
• If previously treated, recovered from prior treatment-related toxicity to ≤ Grade 1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 116
• Absolute neutrophil count (ANC) ≥ 1,500/mm3
• Platelet count ≥ 100,000/mm3
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN), or ≤ 3 x ULN in subjects with Gilberts disease
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 30 mL/min
• Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x ULN
• Willingness to participate in collection of pharmacokinetic samples
• Women of childbearing potential must have a negative serum pregnancy test.
• 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

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

• Consist of 6 or more lesions
• Consists of any lesion with a maximal diameter of greater than 15 mm
• Confirmed or suspected perforated bladder
• History of difficult catheterization that in the opinion of the investigator will prevent administration of VAX014
• Presence or history of any high-grade urothelial cancer (including CIS) or high-grade urine cytology
• Intravesical chemo-or biological therapy within 6 months of first administration of VAX014
• UC of the ureters or urethra
• History of interstitial cystitis
• History of radiation to the pelvis
• History of vesicoureteral reflux or an indwelling urinary stent
• Other known active cancer(s) likely to require treatment or interfere with study objectives over the next two (2) years
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
• Known HIV, Hepatitis B, or Hepatitis C infection
• Significant cardiovascular risk (e.g., coronary stenting within 8 weeks, myocardial infarction within 6 months)
• Major surgery other than diagnostic surgery within 4 weeks of first administration of VAX014
• Pregnant or currently breast-feeding
• Psychiatric illness/social situations that would interfere with compliance with study requirements
• Presence of any sessile appearing tumor suspected of being invasive or high-grade