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Study of Bacillus Calmette-Guerin (BCG) Combined With PANVAC Versus BCG Alone in Adults With High Grade Non-Muscle Invasive Bladder Cancer Who Failed At Least 1 Course of BCG

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ClinicalTrials.gov Identifier: NCT02015104
Recruitment Status : Completed
First Posted : December 19, 2013
Results First Posted : January 22, 2020
Last Update Posted : January 22, 2020
Sponsor:
Collaborator:
Rutgers Cancer Institute of New Jersey
Information provided by (Responsible Party):
Vladimir Valera Romero, M.D. Ph.D, National Cancer Institute (NCI)

Brief Summary:

Background:

- Many cancers produce two particular proteins. The immune system can target these to attack the cancer. The PANVAC vaccine puts genes for these proteins inside a virus vaccine so the body sees the proteins as foreign invaders and attacks them. Researchers will test PANVAC on people with high grade non-muscle invasive bladder cancer. They will give it to people who have not responded to the usual treatment, bacillus Calmette-Guerin (BCG) over several weeks. They want to see if PANVAC plus BCG is better than BCG alone.

Objective:

- To compare the effects of PANVAC plus BCG therapy, to BCG therapy alone.

Eligibility:

- Adults 18 and older with high grade non-muscle invasive bladder cancer who failed at least 1 course of BCG.

Design:

  • Participants will be screened with blood and urine tests and abdominal scans.
  • Participants will be randomly assigned to get BCG only or BCG plus PANVAC.
  • They will have up to 10 visits over 15 weeks. Most of these are part of usual cancer care.
  • They will have blood and urine tests.
  • All participants will get BCG in 6 weekly injections.
  • One group will also get PANVAC in 5 injections over 15 weeks.
  • Between weeks 17 and 20, participants will undergo tests of the tumor area as part of their usual care. They will have cystoscopy, exam under anesthesia, and bladder biopsy. Results will be used to evaluate the different treatments.
  • Participants will have quarterly follow-up visits for up to 2 years.

Condition or disease Intervention/treatment Phase
Bladder Cancer Biological: BCG intravesical live (TICE Bacillus Calmette-Guerin (BCG)) Biological: PANVAC Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Prospective, Phase II Study to Determine the Efficacy of Bacillus Calmette-Guerin (BCG) Given in Combination With PANVAC[TM] Versus BCG Given Alone in Adults With High Grade Non-Muscle Invasive Bladder Cancer (NMIBC) Who Failed at Least 1 Induction Course of BCG
Actual Study Start Date : December 18, 2013
Actual Primary Completion Date : September 18, 2018
Actual Study Completion Date : May 2, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: Bacillus Calmette-Guerin (BCG) + PANVAC
Intravesical TICE BCG (50mg) once weekly starting in week 3 for a total of 6 weeks. PANVAC-V 2 x 10^8 pfu subcutaneous (SQ) at week 0 only; PANVAC-F 1 x 10^9 pfu SQ at weeks 3, 7, 11, and 15
Biological: BCG intravesical live (TICE Bacillus Calmette-Guerin (BCG))
TICE BCG for intravesical use, is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis

Biological: PANVAC
A recombinant virus vector vaccine containing genes for human carcinoembryonic antigen (CEA), mucin-1 (MUC-1) and three co-stimulatory molecules (designated Triad of costimulatory molecules (TRICOM): B7.1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte function-associated antigen-3 (LFA-3).

Experimental: Bacillus Calmette-Guerin (BCG) Alone
Intravesical TICE BCG (50mg) once weekly starting in week 3 for a total of 6 weeks
Biological: BCG intravesical live (TICE Bacillus Calmette-Guerin (BCG))
TICE BCG for intravesical use, is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis




Primary Outcome Measures :
  1. Percentage of Participants Without Recurrence (Recurrence-free Survival (RFS)) With Bacillus Calmette-Guerin (BCG) + PANVAC Compared With BCG Alone at 6 and 12 Months [ Time Frame: Assessed from start of therapy to 6 and 12 months following therapy ]
    RFS is defined as the time from the start of intravesical Bacillus Calmette-Guerin (TICE BCG) therapy (week 3) until disease recurrence or death due to any cause in each arm. Recurrence is suspected and/or determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a transurethral resection of bladder tumor (TURBT). Positive cytology in the absence of pathologic confirmation is not considered to be a recurrence.


Secondary Outcome Measures :
  1. Percentage of Participants Without Progression (Progression-Free Survival (PFS)) at 6 and 12 Months [ Time Frame: Assessed from start of therapy to 6 and 12 months following therapy ]
    PFS is the duration of time from start of TICE BCG therapy (week 3) to time of progression or death due to any cause in each study arm, whichever occurs first. Progression is defined as upstaging from a lower stage to a higher stage (e.g., Ta to T1 or T1 to T2-4; or any N+ or M+ in these high grade tumors.).TNM Classification in non-muscle invasive bladder cancer: Ta = Non-invasive papillary carcinoma; T1 = Tumor invades the subepithelial connective tissue; T2-4 = size of primary tumor; N+ or M+ = lymph node involvement and metastasis.

  2. Time to Recurrence [ Time Frame: Week 3 until recurrence or 12 months (whichever occurred first) ]
    TTR is the duration of time measured from the start of TICE BCG therapy (week 3) until recurrence is noted. Recurrence is suspected and/or determined by urine cytology and/or cystoscopic exam and then confirmed pathologically after a TURBT. Positive cytology in the absence of pathologic confirmation is not considered to be a recurrence.

  3. Number of Participants With Serious and Non-Serious Adverse Events [ Time Frame: Adverse events were assessed from the date treatment consent was signed to the date off study. Approximately 50 months and 12 days for BCG + PANVAC Arm/Group, and 43 months and 12 days for BCG Alone Arm/Group. ]
    Serious and non-serious adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  4. Overall Survival (OS) [ Time Frame: up to 50 months ]
    OS is defined as the time from treatment start date until date of death or date last known alive.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

3.1.1.1 Patients must have histologically confirmed localized high grade (G3) transitional cell carcinoma (urothelial carcinoma) of the bladder that is stage Ta, T1, and/or carcinoma in-situ (CIS) confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) 45 days prior to study entry. This can be obtained at an outside hospital prior to entry into the study or at the NCI. However, all outside pathology specimens will require that the formalin-fixed paraffin embedded tissues be re-read by the Laboratory of Pathology, NCI. For patients enrolled at collaborating trial sites, diagnosis must be confirmed by the Department of Pathology at the institution where the patient is enrolled on the trial.

Pathology can also be reviewed by the Laboratory of Pathology at the NCI if the participating trial site prefers another pathologic evaluation.

3.1.1.2 Patients have failed at least one previous induction course of intravesical Bacillus Calmette-Guerin (BCG), defined as histologically confirmed persistent or relapsing tumor present on post-BCG endoscopic evaluation. All BCG failures will be considered for inclusion into the study, including BCG-refractory, -resistant, and relapsing, as defined in the Rationale and Background. For the purposes of the study, BCG-refractory and BCG-resistant subjects will be considered to have BCG-persistent disease.

3.1.1.3 Patients who are not currently candidates for radical cystectomy (e.g. patient refuses surgery, comorbidities preclude major surgery, etc.).

3.1.1.4 Age >18 years.

--Because no dosing or adverse event data are currently available on the use of BCG in combination with PANVAC in patients <18 years of age, children are excluded from this study.

3.1.1.5 Eastern Cooperative Oncology Group (ECOG) performance status <2.

3.1.1.6 Patients must have normal organ and marrow function as defined below:

  • absolute neutrophil count greater than or equal to1,500/mcL
  • platelets greater than or equal to 50,000/mcL
  • total bilirubin less than or equal to 1.5 X institutional upper limit of normal
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT) less than or equal to 3 X institutional upper limit of normal
  • estimated glomerular filtration rate (GFR) (calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation) greater than or equal to 30 mL/min/1.73 sq.m.

3.1.1.7 Computerized Tomography (CT) urogram or Magnetic Resonance Imaging (MRI) urogram. If urogram protocol not available or contrast allergy/poor renal function preclude such imaging, then noncontrast CT or MRI of the abdomen/pelvis within 45 days of study entry will suffice.

3.1.1.8 Chest x-ray negative for metastatic disease.

3.1.1.9 Ability of patient to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

3.1.2.1 Previous pelvic radiation for bladder or prostate cancer if performed <12 months prior to enrollment into the study.

3.1.2.2 Patients who are receiving any other concurrent investigational agents (patients are eligible to enroll 4 weeks after completion of prior agent).

3.1.2.3 Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. There will be at least a 3 week delay from the time of a previous bladder biopsy/transurethral resection of bladder tumor (TURBT) to allow for adequate bladder healing prior to enrollment.

3.1.2.4 Patients with a history of encephalitis, multiple sclerosis, or seizures within the last year (from seizure disorder or brain metastasis) should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

3.1.2.5 History of allergy or untoward reaction to prior vaccination with vaccinia virus

3.1.2.6 Patients should have no evidence of being immunocompromised as listed below:

  • Human immunodeficiency virus positivity due to the potential for decreased tolerance and risk for severe side effects
  • Active autoimmune diseases requiring treatment or a history of autoimmune disease that might be stimulated by vaccine treatment. This requirement is due to the potential risks of exacerbating autoimmunity. Patients with endocrine disease that is controlled by replacement therapy including thyroid disease and adrenal disease and vitiligo may be enrolled.
  • History of splenectomy

3.1.2.7 Uncontrolled intercurrent illness which would interfere with the ability of the patient to carry out the treatment program, including, but not limited to, active second malignancy other than a cancer that has been successfully treated resulting in a high likelihood of long-term survival (e.g. completely resected basal cell or squamous cell carcinoma of the skin, stage 1 renal cell carcinoma treated with partial nephrectomy, treated low risk prostate cancer, etc.), inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), active diverticulitis, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

3.1.2.8 Pregnant women are excluded from this study because the vaccines used in the study may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the vaccine, breastfeeding should be discontinued if the mother is treated with vaccines. These potential risks may also apply to other agents used in this study. Patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately

3.1.2.9 Concurrent use of systemic steroids, except for physiologic doses of systemic steroids for replacement or local (topical, nasal, or inhaled) steroid use. Limited doses of systemic steroids to prevent intravenous (IV) contrast, allergic reaction, or anaphylaxis (in patients who have known contrast allergies) are allowed. Although topical steroids are allowed, steroid eye-drops are contraindicated

3.1.2.10 Altered immune function, including immunodeficiency or history of immunodeficiency; eczema; history of eczema, or other eczematoid skin disorders; or those with acute, chronic or exfoliative skin conditions (e.g. atopic dermatitis, burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds). There is an increased risk to patients or contacts with eczema, atopic dermatis, and other immune deficiencies who are at risk for eczema vaccination.

3.1.2.11 Medical conditions which, in the opinion of the investigators, would jeopardize the patient or the integrity of the data obtained

3.1.2.12 Serious hypersensitivity reaction to egg products

3.1.2.13 Chronic hepatitis infection, including B and C, because of potential immune impairment

3.1.2.14 Clinically significant cardiomyopathy or cardiac complications, including recent myocardial infarction or cerebrovascular accident within one year, and/or unstable or uncontrolled angina

3.1.2.15 Previous intolerance to BCG intravesical therapy suggested by development of systemic BCG infection in the past and/or grade 4 or greater adverse effect by Common Terminology Criteria in Adverse Events (CTCAE) v4.0.

3.1.2.16 Patients unable to avoid close contact or household contact with the following high-risk individuals for three weeks after the Day 1 vaccination: (a) children less than or equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent extensive eczema or other eczematoid skin disorders, or (d) immunocompromised individuals, such as those with human immunodeficiency virus (HIV).

3.1.3 Inclusion of Women and Minorities:

Both men and women of all races and ethnic groups are eligible for this trial.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02015104


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
United States, New Jersey
Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08901
Sponsors and Collaborators
National Cancer Institute (NCI)
Rutgers Cancer Institute of New Jersey
Investigators
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Principal Investigator: Vladimir Valera Romero, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Vladimir Valera Romero, M.D. Ph.D, National Cancer Institute (NCI):
Informed Consent Form  [PDF] May 8, 2018

Additional Information:
Publications:
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Responsible Party: Vladimir Valera Romero, M.D. Ph.D, Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02015104    
Other Study ID Numbers: 140036
14-C-0036
First Posted: December 19, 2013    Key Record Dates
Results First Posted: January 22, 2020
Last Update Posted: January 22, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Vladimir Valera Romero, M.D. Ph.D, National Cancer Institute (NCI):
Urothelial Carcinoma
Vaccines
Immunotherapy
TICE BCG
Intravesical Treatment
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
BCG Vaccine
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs