Codex: Study of Inodiftagene Vixteplasmid (BC-819) in Unresponsive NMIBC

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2 Study of BC-819 in Patients With Non-Muscle Invasive Bladder Cancer Whose Disease is Unresponsive to Bacillus Calmette-Guerin

Conditions
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Non-muscle Invasive Bladder Cancer (NMIBC)

Intervention / Treatment
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* Drug: inodiftagene vixteplasmid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥18 years of age at the time of consent Patient must have been adequately treated with BCG defined as at least one of the following (FDA 2018): At least five of six doses of an initial induction course plus at least two of three doses of maintenance therapy At least five of six doses of an initial induction course plus at least two of six doses of a second induction course A single course of induction BCG can qualify if the patient has T1 high-grade disease at first evaluation (see 3c) Patient must be BCG-unresponsive defined as at least one of the following (FDA 2018): 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. 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. T1 high-grade disease at the first evaluation following a single course of induction BCG qualifies (Lerner et al. 2015, Steinberg et al. 2016) Patient must have, at study entry, NMIBC indicated by 1 or more of the following: Ta or T1 high-grade disease CIS disease Patient must have no known evidence of concomitant upper tract urothelial carcinoma or urothelial carcinoma within the prostatic urethra within 6 months of enrollment Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Patient must have adequate hematologic function, as demonstrated by the following: Hemoglobin level ≥10 g/dL Absolute neutrophil count ≥1.5 x 109/L Platelet count ≥100 x 109/L Patient must have adequate liver and renal function as demonstrated by the following: Aspartate aminotransferase and alanine aminotransferase each ≤3.0 x upper limit of normal 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 Serum creatinine ≤1.5 x upper limit of normal or measured or calculated creatinine clearance ≥30 mL/min 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 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: Patient has current or previous evidence of muscle invasive (muscularis propria) or metastatic bladder cancer disease Patient has received prior investigational therapy for NMIBC 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 Patient is intolerant to previous BCG treatment in the absence of meeting other criteria for BCG unresponsiveness and adequate BCG therapy Patient has received external beam radiation therapy for bladder cancer at any time or for any other condition Patient has an active infection, including urinary tract infection (viral, bacterial, or fungal) and cystitis Patient has urinary tract signs or symptoms that preclude retention of drug in the bladder; this does not include anticholinergic drugs 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 Patient is female and is pregnant or breastfeeding 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm BC-819<br>inodiftagene vixteplasmid | Drug: inodiftagene vixteplasmid<br>* BC-819 at 20 mg/50 mL, instilled intravesically into the bladder, with a retention time of at least 30 minutes (up to 2 hours). Induction Phase (weekly treatments): 10 weekly treatments; Maintenance Phase: treatment every 3 weeks for up to 84 additional weeks<br>* Other names: BC-819;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Patients With Baseline CIS That Achieve a Complete Response After Treatment With BC-819 (Measured at 12 Weeks) | Complete response is defined as at least one of the following: Negative cystoscopy and negative (including atypical) urine cytology Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or prostatic urethra and random bladder biopsies are negative The complete response in patients with CIS for this endpoint was documented on or after the Week 12 response assessment and on or prior to the Week 48 assessment. Duration of complete response in patients with CIS was calculated from the documented onset of the complete response to the assessment where the patient no longer met the definition of complete response. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Absence of High-grade Recurrent or Persistent Disease at 48 Weeks (Overall Population and Subgroup of Patients With CIS) | Time to recurrence (Kaplan-Meier plot) recurrence is defined as the reappearance or persistence of high-grade disease, or new high-grade disease. Recurrence must be biopsy proven. Persistence, appearance, or presence of lower grade disease was not considered to be a recurrence event | 48 weeks | 
| Percentage of Patients With Absence of High-grade Recurrent or Persistent Disease at 12, 24, 36, 72, and 96 Weeks (Overall Population and Subgroup of Patients With CIS) | Time to recurrence (Kaplan-Meier plot) recurrence is defined as the reappearance or persistence of high-grade disease, or new high-grade disease. Recurrence must be biopsy proven. Persistence, appearance, or presence of lower grade disease was not considered to be a recurrence event. | 12, 24, 36, 72, and 96 weeks | 
| Percentage of Patients Who Are Progression-free at 48, 72, and 96 Weeks | The incidence of PFS at 48, 72, and 96 weeks as well as time to progression estimated using Kaplan-Meir methods. Progression is defined as the development of T2 or greater disease. Sensitivity analyses was performed and included any of the following as progressions: An increase in stage from Ta or CIS to T1, or Development of T2 or greater, or Lymph node disease, or Distant metastasis | 48, 72, and 96 weeks | 
| Overall Survival of Patients Enrolled in the Study at 48, 72, and 96 Weeks | Overall survival of patients enrolled in the study at 48, 72, and 96 weeks and survival time was estimated using Kaplan-Meier methods | 48, 72, and 96 weeks | 
| Quality of Life in Patients Treated With BC-819 | Measured by the The European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30), a general questionnaire for assessing quality of life in cancer patients, and the Non-Muscle Invasive Bladder Cancer Questionnaire (QLQ-NMIBC24 ) for patients with NBIMC disease. EORTC QLQ-C30 include five functional scales , three symptom scales, a global health status/quality of life scale, and six single items. QLQ-NMIBC24 include five multi-item symptom scales, one multi-item functional scale, and five single-item measures.These scales range in score 0-100 scale and an for functional scales, a higher a higher score corresponds to greater function or quality of life. For symptom scales, a higher score corresponds to greater symptom burden. | 48, 72, and 96 weeks | 
| Assessment of Safety | The safety was evaluated by assessment of AEs according to CTCAE version 5.0, regardless of relationship to study medication. | 9 months | 
| Time to Recurrence (Kaplan-Meier Plot) | Time to recurrence (Kaplan-Meier plot) recurrence is defined as the reappearance or persistence of high-grade disease, or new high-grade disease. Recurrence must be biopsy proven. Persistence, appearance, or presence of lower grade disease was not considered to be a recurrence event | 12, 24, 36, 72, and 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BCG-unresponsive