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

Phase 3

Terminated

Conditions: Transitional Cell, Carcinoma
Mycobacterium
Neoplasm Recurrence, Local
Carcinoma in Situ
Bladder Neoplasm

Interventions: Biological: EN3348
Biological: Mitomycin C

Registration Number: NCT01200992

Lead Sponsor: Bioniche Life Sciences Inc.

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 84

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EN3348	EN3348	8 mg mixed with sterile water for injection for a total volume of 50mL
Mitomycin C	Mitomycin C	40 mg powder will be reconstituted with sterile water for injection to a total volume of 40 mL

Primary Outcome Measures

Name	Time	Method
Comparison of Event-free Survival of Intravesical EN3348 With Mitomycin C.	1 year	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.

Secondary Outcome Measures

Name	Time	Method
Comparison of Safety of EN3348 With Mitomycin C [Adverse Events (Other Than Serious Adverse Events) With Frequency Threshold of 5% or Greater].	Through study early termination, approximately 23 months from first subject enrolled.	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.

Trial Locations

Locations (70): Princess Margaret Hospital - University Health Network
🇨🇦
Toronto, Ontario, Canada
Kansas City Urology Care, P.A.
🇺🇸
Overland Park, Kansas, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Alaska Clinical Research Center, LLC
🇺🇸
Anchorage, Alaska, United States
West Coast Clinical Research
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Tarzana, California, United States
American Institute of Research
🇺🇸
Los Angeles, California, United States
Urology Specialists of Southern California - Burbank
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Burbank, California, United States
Urology Specialist of Southern California - Encino
🇺🇸
Encino, California, United States
San Diego Clinical Trials
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San Diego, California, United States
Urology Specialists of Southern California - Torrance
🇺🇸
Torrance, California, United States
Urology Associates
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Englewood, Colorado, United States
Florida Urological Associates, PA
🇺🇸
Coral Springs, Florida, United States
Northwestern Medicine
🇺🇸
Chicago, Illinois, United States
Urological Research Network
🇺🇸
Hialeah, Florida, United States
Urology Health Team, PLLC
🇺🇸
Ocala, Florida, United States
University of Chicago
🇺🇸
Chicago, Illinois, United States
Deaconess Clinic, Inc.
🇺🇸
Evansville, Indiana, United States
Northeast Indiana Research, LLC
🇺🇸
Fort Wayne, Indiana, United States
University of Maryland
🇺🇸
Baltimore, Maryland, United States
Corbin Clinical Resources
🇺🇸
Cumberland, Maryland, United States
Chesapeake Urology Research Associates
🇺🇸
Towson, Maryland, United States
Myron I. Murdock, MD, LLC
🇺🇸
Greenbelt, Maryland, United States
Bay State Urologists
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Watertown, Massachusetts, United States
Michigan Institute of Urology
🇺🇸
Troy, Michigan, United States
The Capital Region Medical Research Foundation, Inc.
🇺🇸
Albany, New York, United States
Columbia University Medical Center
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New York, New York, United States
Delaware Valley Urology
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Voorhees, New Jersey, United States
Accumed Research Associates
🇺🇸
Garden City, New York, United States
Premier Medical Group of the Hudson Valley
🇺🇸
Poughkeepsie, New York, United States
TriState Urologic Services PSC, Inc.
🇺🇸
Cincinnati, Ohio, United States
Unison Clinical Research
🇺🇸
Toledo, Ohio, United States
Signal Point Clinical Research Center, LLC
🇺🇸
Middletown, Ohio, United States
Columbus Urology
🇺🇸
Columbus, Ohio, United States
Parkhurst Research Organization, LLC
🇺🇸
Bethany, Oklahoma, United States
Urologic Consultants of SE PA
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Bala-Cynwyd, Pennsylvania, United States
Ilumina Clinical Associates
🇺🇸
Indiana, Pennsylvania, United States
Triangle Urological Group
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Pittsburgh, Pennsylvania, United States
Pharma Resource
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East Providence, Rhode Island, United States
Mount Nittany Physician Group
🇺🇸
State College, Pennsylvania, United States
Carolina Urologic Research Center
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Myrtle Beach, South Carolina, United States
Urology Clinics of North Texas, PA
🇺🇸
Dallas, Texas, United States
Pacific Urologic Research
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Victoria, British Columbia, Canada
Urology Associates of North Texas
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Arlington, Texas, United States
Urology Associates of South Texas
🇺🇸
McAllen, Texas, United States
London Health Sciences Centre
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London, Ontario, Canada
Mor Urology Inc.
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Newmarket, Ontario, Canada
Office of Dr. Bernard Goldfarb
🇨🇦
North Bay, Ontario, Canada
The Fe/Male Health Centres
🇨🇦
Oakville, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦
Toronto, Ontario, Canada
GUT (Society of Urologic Innovative Therapies), GbR
🇩🇪
Kirchheim unter Teck, Germany
Nottingham Urology Centre, NHS Trust
🇬🇧
Nottingham, United Kingdom
Uniwersyteckie Centrum Kliniczne
🇵🇱
Gdańsk, Poland
Delaware Valley Urology, LLC Burlington
🇺🇸
Mount Laurel, New Jersey, United States
Centre Hospitalier Universitaire de Quebec- L'Hotel-Dieu de Quebec
🇨🇦
Quebec City, Quebec, Canada
Universitair Medisch Centrum St Radboud, Department of Urology
🇳🇱
Nijmegen, Netherlands
University of Connecticut Health Center
🇺🇸
Farmington, Connecticut, United States
Arizona Urologic Specialists
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Tucson, Arizona, United States
Grove Hill Medical Center
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New Britain, Connecticut, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
Wojewódzki Szpital Specjalistyczny we Wrocławiu
🇵🇱
Wroclaw, Poland
Maria Sklodowska-Curie Institute of Oncology
🇵🇱
Warszawa, Poland
Southern Interior Medical Research, Inc.
🇨🇦
Kelowna, British Columbia, Canada
Oddział Urologii, Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie [Department of Urology, Independent Public Teaching Hospital #4 in Lublin]
🇵🇱
Lublin, Poland
Urology Health Specialists, LLC
🇺🇸
Bryn Mawr, Pennsylvania, United States
BCG Oncology, PC
🇺🇸
Phoenix, Arizona, United States
The Urology Center of Colorado
🇺🇸
Denver, Colorado, United States
Genitourinary Surgical Consultants, PC
🇺🇸
Denver, Colorado, United States
Advanced Research Institute, Inc.
🇺🇸
Trinity, Florida, United States
Virginia Urology
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Richmond, Virginia, United States
Montefiore Medical Center
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The Bronx, New York, United States