Efficacy and Safety Evaluation of EN3348 (Mycobacterial Cell Wall-DNA Complex [MCC]) as Compared With Mitomycin C in the Intravesical Treatment of Subjects With BCG Recurrent/Refractory Non-muscle Invasive Bladder Cancer (EMBARC-RF)

A Phase 3, Randomized, Active-Controlled, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of EN3348 (MCC) as Compared With Mitomycin C in the Intravesical Treatment of Subjects With BCG Recurrent or Refractory Non-Muscle Invasive Bladder Cancer

This is a phase 3 randomized, active-controlled, open-label, multicenter study that will be conducted in approximately 120 investigational sites worldwide. Subjects with either recurrent or refractory NMIBC (Ta high grade, T1 low or high grade, CIS) will be eligible for participation in this study.

Refractory disease is defined as evidence of persistent high grade bladder cancer (Ta HG, T1, and/or CIS) at least 6 months from the start of a full induction course of BCG with or without maintenance/re-treatment at 3 months.

Recurrent disease is defined as reappearance of disease after achieving a tumor-free status by 6 months following a full induction course of BCG with or without maintenance/re-treatment at 3 months. Subjects with recurrent disease must have recurred within 18 months following the last dose of BCG.

Approximately 450 subjects will be randomized. The primary objective of this study is to evaluate the efficacy of intravesical EN3348 as compared with mitomycin C in the treatment of subjects with recurrent or refractory NMIBC. The secondary objective is to evaluate the safety of EN3348 as compared with mitomycin C in the treatment of subjects with BCG recurrent or refractory NMIBC. This study will consist of 4 phases: Screening, Induction, Maintenance and Follow-Up and will be conducted over 3 years.

Study Overview

• Status: Terminated
• Conditions: Carcinoma in Situ; Neoplasm Recurrence, Local; Bladder Neoplasm; Mycobacterium; Transitional Cell, Carcinoma
• Intervention / Treatment: Biological: EN3348; Biological: Mitomycin C

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 2H4
      • Southern Interior Medical Research, Inc.
    • Victoria, British Columbia, Canada, V8V 3N1
      • Pacific Urologic Research
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
    • Newmarket, Ontario, Canada, L3X 1W1
      • Mor Urology Inc.
    • North Bay, Ontario, Canada, P1B 7K8
      • Office of Dr. Bernard Goldfarb
    • Oakville, Ontario, Canada, L6H 3P1
      • The Fe/Male Health Centres
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital - University Health Network
  • Quebec
    • Quebec City, Quebec, Canada, G1R 3S1
      • Centre Hospitalier Universitaire de Quebec- L'Hotel-Dieu de Quebec
• Germany
  • Kirchheim unter Teck, Germany, 73230
    • GUT (Society of Urologic Innovative Therapies), GbR
• Netherlands
  • Nijmegen, Netherlands, 6525
    • Universitair Medisch Centrum St Radboud, Department of Urology
• Poland
  • Gdańsk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Lublin, Poland, 20-954
    • Oddział Urologii, Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie [Department of Urology, Independent Public Teaching Hospital #4 in Lublin]
  • Warszawa, Poland, 20-781
    • Maria Sklodowska-Curie Institute of Oncology
  • Wroclaw, Poland, 51-124
    • Wojewódzki Szpital Specjalistyczny we Wrocławiu
• United Kingdom
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham Urology Centre, NHS Trust
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Alaska Clinical Research Center, LLC
  • Arizona
    • Phoenix, Arizona, United States, 85032
      • BCG Oncology, PC
    • Tucson, Arizona, United States, 85712
      • Arizona Urologic Specialists
  • California
    • Burbank, California, United States, 91505
      • Urology Specialists of Southern California - Burbank
    • Encino, California, United States, 91436
      • Urology Specialist of Southern California - Encino
    • Los Angeles, California, United States, 90017
      • American Institute of Research
    • San Diego, California, United States, 92120
      • San Diego Clinical Trials
    • Tarzana, California, United States, 91356
      • West Coast Clinical Research
    • Torrance, California, United States, 90505
      • Urology Specialists of Southern California - Torrance
  • Colorado
    • Denver, Colorado, United States, 80211
      • The Urology Center of Colorado
    • Denver, Colorado, United States, 80220
      • Genitourinary Surgical Consultants, PC
    • Englewood, Colorado, United States, 80113
      • Urology Associates
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
    • New Britain, Connecticut, United States, 06052
      • Grove Hill Medical Center
  • Florida
    • Coral Springs, Florida, United States, 33071
      • Florida Urological Associates, PA
    • Hialeah, Florida, United States, 33016
      • Urological Research Network
    • Ocala, Florida, United States, 34474
      • Urology Health Team, PLLC
    • Trinity, Florida, United States, 34655
      • Advanced Research Institute, Inc.
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern Medicine
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Deaconess Clinic, Inc.
    • Fort Wayne, Indiana, United States, 46825
      • Northeast Indiana Research, LLC
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Kansas City Urology Care, P.A.
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21237
      • Chesapeake Urology Research Associates
    • Cumberland, Maryland, United States, 21502
      • Corbin Clinical Resources
    • Glen Burnie, Maryland, United States, 21061
      • Chesapeake Urology Research Associates
    • Greenbelt, Maryland, United States, 20770
      • Myron I. Murdock, MD, LLC
    • Towson, Maryland, United States, 21204
      • Chesapeake Urology Research Associates
  • Massachusetts
    • Watertown, Massachusetts, United States, 02472
      • Bay State Urologists
  • Michigan
    • Troy, Michigan, United States, 48084
      • Michigan Institute of Urology
  • New Jersey
    • Mount Laurel, New Jersey, United States, 08054
      • Delaware Valley Urology, LLC Burlington
    • Voorhees, New Jersey, United States, 08043
      • Delaware Valley Urology
  • New York
    • Albany, New York, United States, 12208
      • The Capital Region Medical Research Foundation, Inc.
    • Garden City, New York, United States, 11530
      • AccuMed Research Associates
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Poughkeepsie, New York, United States, 12601
      • Premier Medical Group of the Hudson Valley
    • The Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45212
      • TriState Urologic Services PSC, Inc.
    • Columbus, Ohio, United States, 43220
      • Columbus Urology
    • Middletown, Ohio, United States, 45042
      • Signal Point Clinical Research Center, LLC
    • Toledo, Ohio, United States, 43615
      • Unison Clinical Research
  • Oklahoma
    • Bethany, Oklahoma, United States, 73008
      • Parkhurst Research Organization, LLC
  • Pennsylvania
    • Bala-Cynwyd, Pennsylvania, United States, 19004
      • Urologic Consultants of SE PA
    • Bryn Mawr, Pennsylvania, United States, 19010
      • Urology Health Specialists, LLC
    • Indiana, Pennsylvania, United States, 15701
      • Ilumina Clinical Associates
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15212
      • Triangle Urological Group
    • State College, Pennsylvania, United States, 16801
      • Mount Nittany Physician Group
  • Rhode Island
    • East Providence, Rhode Island, United States, 02915
      • Pharma Resource
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Arlington, Texas, United States, 76017
      • Urology Associates of North Texas
    • Dallas, Texas, United States, 75231
      • Urology Clinics Of North Texas, Pa
    • McAllen, Texas, United States, 78503
      • Urology Associates of South Texas
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Virginia Urology

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:

• Is 18 years of age and older at time of consent signing

• Have either BCG recurrent or refractory NMIBC:

  • Refractory disease is defined as evidence of persistent high grade bladder cancer (Ta HG, T1 and/or CIS) at least 6 months from the start of a full induction course of BCG with or without maintenance/re-treatment at 3 months

  • Recurrent disease is defined as reappearance of disease after achieving a tumor-free status by 6 months following a full induction course of BCG with or without maintenance/re-treatment at 3 months. Subjects with recurrent disease must have recurred within 18 months following the last dose of BCG

    • A full induction course of BCG is defined as at least 5 out of 6 total expected instillations of BCG within a period of 2 months, regardless of dose strength

• Have histologically confirmed NMIBC (according to 2004 WHO classification) within 8 weeks prior to randomization

  • High grade Ta papillary lesion(s)
  • High or low grade T1 papillary lesion(s)(biopsy sample must include evidence of muscularis propria)
  • CIS, with or without Ta or T1 papillary tumor(s) of any grade
• Have had all visible papillary and resectable CIS lesion(s) removed by TURBT within 8 weeks prior to randomization
• Available for the duration of the study including follow-up (approximately 36 months)
• Have an Eastern Cooperative Oncology Group (ECOG) performance status grade of 2 or less

• Have no evidence of urothelial carcinoma involving the upper urinary tract or the urethra (confirmed by extravesical work up, which may include radiological imaging and/or biopsy) within 6 months of randomization:

  • If previous work up occurred more than 6 months from randomization, extravesical work up must be repeated prior to randomization in order to determine eligibility
• Subjects (male and female) of child-bearing potential (including female subjects who are post-menopausal for less than 1 year) must be willing to practice effective contraception (as defined by the Investigator) during the study and be willing and able to continue contraception for 30 days after their last dose of study treatment
• Is able to understand and give written informed consent

Exclusion Criteria:

• Current or previous history of muscle invasive bladder tumors
• Current or previous history of lymph node positive and/or metastatic bladder cancer
• Current evidence of pure squamous cell carcinoma, pure adenocarcinoma or pure undifferentiated carcinoma of the bladder
• Currently receiving systemic cancer therapy (cytotoxic/cytostatic or immunotherapy)
• Currently receiving treatment with a prohibited therapy
• Current or prior history of systemic lupus erythematosus
• Systemic immunotherapy within 6 months of randomization
• Treatment with an investigational agent within 30 days or 5 half lives from randomization, whichever is longer
• Prior treatment with an intravesical chemotherapeutic agent within 3 months of randomization except for single perioperative dose of chemotherapy immediately post-TURBT
• Prior treatment with EN3348 (MCC) or any other mycobacterial cell wall composition or formulation
• Refractory to mitomycin C (failure to achieve tumor-free status following minimum of a 6 week induction course of mitomycin C)
• Contraindication to mitomycin C
• Untreated urinary tract or bladder infection
• ANC <1000/µL and hemoglobin <10 g/dL
• Known cardiovascular disease such as myocardial infarction within the past 3 months, unstable angina pectoris, congestive heart failure (NYHA Class III or IV) or uncontrolled cardiac arrhythmia
• Female subjects who are pregnant or lactating
• Congenital or acquired immune deficiency
• Have current or history of documented or suspected malignancy of any organ system (diagnosed, treated or untreated) within the past 5 years (with the exception of localized transitional cell carcinoma of the ureter treated with ureterectomy or nephroureterectomy, adequately treated basal cell or squamous cell carcinoma of the skin or asymptomatic non-metastatic prostate cancer either previously successfully treated or currently under active surveillance or receiving hormone therapy only)
• Bladder contracture or history of an inability to retain the instillate for a minimum of 1 hour, even with premedication
• Inability to tolerate intravesical administration or intravesical surgical manipulation (cystoscopy or biopsy)
• Clinically significant active infections
• Any medical or psychiatric condition which, in the opinion of the investigator, would preclude the participant from adhering to the protocol or completing the trial per protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EN3348; 8 mg mixed with sterile water for injection for a total volume of 50mL	Biological: EN3348; Induction: 6 weekly instillations. Maintenance: Monthly instillations to Month 12
Active Comparator: Mitomycin C; 40 mg powder will be reconstituted with sterile water for injection to a total volume of 40 mL	Biological: Mitomycin C; Induction: 6 weekly instillations. Maintenance: Monthly instillations to Month 12

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Event-free Survival of Intravesical EN3348 With Mitomycin C.	Primary efficacy endpoint will be event-free survival - the interval from randomization to an event. An event is defined as tumor recurrence, tumor progression to muscle invasive bladder cancer or death, whichever occurs first. Tumor recurrence or progression must be documented by bladder biopsy.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Safety of EN3348 With Mitomycin C [Adverse Events (Other Than Serious Adverse Events) With Frequency Threshold of 5% or Greater].	Safety endpoint displayed includes adverse events (other than serious adverse events) with a frequency threshold of 5% or greater, for each treatment arm. No statistical comparisons have been performed between the 2 treatment arms.	Through study early termination, approximately 23 months from first subject enrolled.

Collaborators and Investigators

• Sponsor: Bioniche Life Sciences Inc.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: September 12, 2010
• First Submitted That Met QC Criteria: September 12, 2010
• First Posted (Estimate): September 14, 2010

Study Record Updates

• Last Update Posted (Actual): August 24, 2017
• Last Update Submitted That Met QC Criteria: August 23, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Neoplasms; Urinary Bladder Neoplasms; Urologic Diseases; Urogenital Neoplasms; Neoplasms by Site; Urologic Neoplasms; Urinary Bladder Diseases; Intravesical drug administration; Mycobacterial cell wall DNA complex
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Disease Attributes; Neoplastic Processes; Neoplasms; Carcinoma in Situ; Carcinoma; Recurrence; Urinary Bladder Neoplasms; Neoplasm Recurrence, Local; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Alkylating Agents; Antibiotics, Antineoplastic; Mitomycins; Mitomycin
• Other Study ID Numbers: EN3348-303