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

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

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.

Study Overview

• Status: Terminated
• Conditions: Non-muscle Invasive Bladder Cancer (NMIBC)
• Intervention / Treatment: Drug: inodiftagene vixteplasmid

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alaska
    • Anchorage, Alaska, United States, 99503
      • Alaska Urological Institute
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Tucson, Arizona, United States, 85715
      • Urological Associates of Southern Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Arkansas Urology
  • California
    • Los Angeles, California, United States, 90017
      • American Institute of Research
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
  • Colorado
    • Denver, Colorado, United States, 80211
      • The Urology Center Of Colorado
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Jacksonville, Florida, United States, 33209
      • University of Florida Health Jacksonville, Shands Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • North Idaho Urology
    • Meridian, Idaho, United States, 83642
      • Idaho Urologic Institute, PA
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Hospital and Health Systems (Outpatient Care Center)
  • Kansas
    • Westwood, Kansas, United States, 66205
      • The University of Kansas Cancer Center
    • Wichita, Kansas, United States, 67226
      • Wichita Urology Group
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinical Foundation
    • New Orleans, Louisiana, United States, 70114
      • Tulane University School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Medical Institution
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • Spectrum Health Medical Group
    • Troy, Michigan, United States, 48084
      • Michigan Institute of Urology, PC
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University
  • New Jersey
    • Belleville, New Jersey, United States, 08043
      • New Jersey Urology, LLC
    • Voorhees, New Jersey, United States, 08103
      • MD Anderson Cancer Center at Cooper
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical College - NY Presbyterian Hospital
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • UNC Chapel Hill Hospital, Urology Clinic
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Greensboro, North Carolina, United States, 27403
      • Alliance Urology Specialists, PA
    • Huntersville, North Carolina, United States, 28078
      • Carolina Urology Partners, PLLC
  • Ohio
    • Toledo, Ohio, United States, 43614
      • University of Toledo, Dept. of Urology and Kidney Transplant
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Bala-Cynwyd, Pennsylvania, United States, 19004
      • MidLantic Urology
    • Philadelphia, Pennsylvania, United States, 19104
      • The Hospital of the University of Pennsylvania
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University South Carolina
    • Greenville, South Carolina, United States, 29605
      • Regional Urology
  • Tennessee
    • Nashville, Tennessee, United States, 37209
      • Urology Associates, P.C.
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Medical Center
    • Houston, Texas, United States, 77030
      • The Methodist Hospital d/b/a Houston Methodist Hospital
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Virginia Urology
    • Virginia Beach, Virginia, United States, 23462
      • Urology of Virginia
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Single Arm BC-819; inodiftagene vixteplasmid	Drug: inodiftagene vixteplasmid; 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; Other Names: BC-819

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Anchiano Therapeutics Israel Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 20, 2019
• Primary Completion (ACTUAL): November 18, 2019
• Study Completion (ACTUAL): December 18, 2019

Study Registration Dates

• First Submitted: October 18, 2018
• First Submitted That Met QC Criteria: October 23, 2018
• First Posted (ACTUAL): October 25, 2018

Study Record Updates

• Last Update Posted (ACTUAL): August 19, 2020
• Last Update Submitted That Met QC Criteria: August 10, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: BCG-unresponsive
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: BC-819-18-204

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No