Lack of efficacy

This study, BC-819-18-204, is a Phase 2, open-label, monotherapy, single-arm, multicenter clinical trial of BC-819 (inodiftagene vixteplasmid) in patients with NMIBC adequately treated with Bacillus Calmette-Guerin (BCG) whose disease is BCG unresponsive according to the US Food and Drug Administration (FDA) guidance.

BC-819 (inodiftagene vixteplasmid) is a recombinant DNA plasmid that directs the expression of a potent toxin specifically in malignant cells but not in normal tissue. It has been designed to exploit the established biology of the H19 gene, which is upregulated and expressed at high levels only in malignant cells, to produce bacterial diphtheria toxin only in bladder cancer tissue. BC-819 is administered directly into the bladder to enable maximal topical exposure to target bladder cancer cells.

Inclusion Criteria:

1. Male or female patients ≥18 years of age at the time of consent

2. Patient must have been adequately treated with BCG defined as at least one of the following (FDA 2018):

   1. At least five of six doses of an initial induction course plus at least two of three doses of maintenance therapy
   2. At least five of six doses of an initial induction course plus at least two of six doses of a second induction course
   3. A single course of induction BCG can qualify if the patient has T1 high-grade disease at first evaluation (see 3c)

3. Patient must be BCG-unresponsive defined as at least one of the following (FDA 2018):

   1. Persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy. An assessment within 15 months can also qualify when no assessment was done 12 months after completion of adequate BCG therapy.
   2. Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy. An assessment within 9 months can also qualify when no assessment was done 6 months after completion of adequate BCG therapy.
   3. T1 high-grade disease at the first evaluation following a single course of induction BCG qualifies (Lerner et al. 2015, Steinberg et al. 2016)

4. Patient must have, at study entry, NMIBC indicated by 1 or more of the following:

   1. Ta or T1 high-grade disease
   2. CIS disease

5. Patient must have no known evidence of concomitant upper tract urothelial carcinoma or urothelial carcinoma within the prostatic urethra within 6 months of enrollment

6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2

7. Patient must have adequate hematologic function, as demonstrated by the following:

   1. Hemoglobin level ≥10 g/dL
   2. Absolute neutrophil count ≥1.5 x 109/L
   3. Platelet count ≥100 x 109/L

8. Patient must have adequate liver and renal function as demonstrated by the following:

   1. Aspartate aminotransferase and alanine aminotransferase each ≤3.0 x upper limit of normal
   2. Total bilirubin ≤1.5 x upper limit of normal, unless prior documentation of Gilbert's syndrome in which case, 3.0 mg/dL is allowed
   3. Serum creatinine ≤1.5 x upper limit of normal or measured or calculated creatinine clearance ≥30 mL/min

9. Female patients of childbearing potential must use maximally effective birth control during the period of therapy and for 1 month after the last study drug infusion

10. Male patients who are sexually active must be willing to use a double barrier contraceptive method upon study enrollment, during the course of the study, and for 1 month after the last study drug infusion

Exclusion Criteria:

1. Patient has current or previous evidence of muscle invasive (muscularis propria) or metastatic bladder cancer disease
2. Patient has received prior investigational therapy for NMIBC
3. Patient has received any therapy for NMIBC within 10 weeks before the start of study treatment other than surgical resection, 1 dose of chemotherapy, and previous BCG
4. Patient is intolerant to previous BCG treatment in the absence of meeting other criteria for BCG unresponsiveness and adequate BCG therapy
5. Patient has received external beam radiation therapy for bladder cancer at any time or for any other condition
6. Patient has an active infection, including urinary tract infection (viral, bacterial, or fungal) and cystitis
7. Patient has urinary tract signs or symptoms that preclude retention of drug in the bladder; this does not include anticholinergic drugs
8. Patient is known to have tested positive for human immunodeficiency virus (HIV). No HIV testing is required if patient is not known have tested positive
9. Patient is female and is pregnant or breastfeeding
10. Patient has a known presence or history of malignancy of other organ system within the 5 years before study start, with the exception of non-melanoma skin cancer; very low or low-risk prostate cancer; or patients who have been disease free for at least 2 years following stage 1 or 2 cancer