The primary objective of this study is to identify if reduced number of BCG instillations are not inferior to standard number and dose intravesical BCG treatment in patients with high grade NMIBC. The primary endpoint for inferiority analysis is…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint is the time to first recurrence.
Secondary outcome
Secondary endpoints:
- number and grade of recurrent tumors
- rate of progression to a higher stage (T2 or higher)
- incidence and severity of side effects.
Background summary
Intravesical instillation of BCG is a widely accepted strategy to prevent
recurrence of non muscle invasive bladder cancer. The most accepted treatment
schedule is induction of BCG: weeks 1 through 6 plus maintenance (weeks 1,2,3)
at months 3,6 and 12, but it is unknown how many administrations are really
necessary. Scientific evidence prones to the hypothesis that after an initial
sensitization to BCG antigens has occurred the number of instillations can be
reduced for a proper anamnestic immune response resulting in similar clinical
efficacy and potentially less side-effects and costs.
Study objective
The primary objective of this study is to identify if reduced number of BCG
instillations are not inferior to standard number and dose intravesical BCG
treatment in patients with high grade NMIBC. The primary endpoint for
inferiority analysis is time to first recurrence.
The secondary objectives are to identify if number and grade of recurrent
tumors, rate of progression to a higher stage (T2 or higher) of the disease and
safety, specifically the presence of treatment related toxicity > grade 2
differ between the two study arms.
Study design
This is a multicentre prospective, randomized, parallel group, not blinded,
trial to compare the efficacy and safety of two different adjuvant treatment
schedules:
1) Induction cycle BCG-full dose; weeks 1 through 6 plus maintenance cycles at
months 3, 6 and 12 (wks 1,2,3); total 15 full dose BCG instillations
2) Induction cycle BCG-full dose (reduced frequency); weeks 1,2, and 6 plus
maintenance cycles at months 3, 6 and 12 (wks 1,3); total 9 full dose BCG
instillations.
BCG intravesical instillation therapy is registered as adjuvant treatment for
the prevention of recurrence of NMIBC and can be considered as standard
treatment for the type of patients requested in this trial. For each individual
centre, one of the three locally available BCG strains in Europe will be used:
BCG Tice, BCG Medac or BCG Connaught.
• In case of patients having Ta high grade tumor in the initial resection; a)
patients can be included in the study provided muscle is present and reported
in the specimen and the Ta high grade tumor has been totally removed, or b)
patients undergo a re-TUR at the discretion of the investigator.
• Patients having T1 high grade tumor in the initial resection, should undergo
a re-TUR. Patients with histological detection of T1 tumor in the re-TUR should
undergo a second re-TUR. These patients are eligible for the study provided
muscle is present and reported in the specimen and the patients are,
macro¬scopically and histologically confirmed, free of T1 tumors in the
(re-)re-TUR specimen.
A re-TUR (or re-reTUR) should be performed within 4-8 weeks after initial
resection (or re-TUR).
Treatment with the randomised treatment schedule will start 2 weeks after and
no later than 6 weeks after the last resection (re-TUR).
The first maintenance therapy should be given 3 months (12 weeks) after the
last instillation of the induction BCG cycle (week 6) and hereafter at months 6
(24 weeks) and 12 (48 weeks) after the last instillation of the induction BCG
cycle (Appendix 13: Checklists). Standard Dose Instillations will take place
with 1 vial of BCG. The weekly BCG instillations during induction and
maintenance cycles have to be conducted within 7 ± 2 days.Follow up cystoscopy
and cytology will be done every 3 months the first 2 years and bi-annually
until the fifth year.
Intervention
After randomisation, study objects will have one of the two following different
adjuvant treatment schedules:
1) Induction cycle BCG-full dose; weeks 1 through 6 plus maintenance cycles at
months 3, 6 and 12 (wks 1,2,3); total 15 full dose BCG instillations
2) Induction cycle BCG-full dose (reduced frequency); weeks 1,2, and 6 plus
maintenance cycles at months 3, 6 and 12 (wks 1,3); total 9 full dose BCG
instillations.
Study burden and risks
The burden and risks associated with participation in the study is considered
minimal and acceptable. The number of visits and treatments is equal to or less
compared what patients with these criteria is offered when they are treated on
a standard way which is BCG intravesical instillation therapy. Extra in this
study are the symptoms and quality of life questionnaires that need to be
completed. A potential risk for patients in the reduced frequency arm is that
the treatment is less effective with respect to the prevention of recurrence
compared to the standard frequency arm. A potential benefit is that side
effects, both in quantity and quality, are expected to be less in the reduced
frequency arm compared to the standard frequency arm. The risks related to the
expected treatment outcome, quality and quantity of side effects of the study
medication can be considered as acceptable. Surgical procedures, laboratory and
radiological evaluations are not considered extra and are performed according
to standard practice or at the investigators discretion for monitoring eventual
recurrence or progression of disease. Possible benefit for the patient is that
the patient is followed according to the latest standards and guidelines of
treatment of NMIBC.
For the optional sub-studies, there is slightly more burden (collection of
urine and donation of blood). The risk are are neglible. (See also F6)
Mr. E.N. Van Kleffensstraat 5
Arnhem 6842 CV
NL
Mr. E.N. Van Kleffensstraat 5
Arnhem 6842 CV
NL
Listed location countries
Age
Inclusion criteria
1. Presence of high grade* (Ta-T1) urothelial papillary carcinoma of the bladder with or without CIS
1.1. Tumors can be primary or recurrent
1.2. Tumors can be single or multiple
2a. In case of a Ta high grade tumor in the initial resection, a re-TUR can be performed at the discretion of the investigator. Initial resection or re-TUR must include the deep resection or cold cup biopsy (deep enough to obtain muscle tisssue) of the (initial) tumor site(s)
2b. In case of a T1 high grade in the initial resection a re-TUR should be performed at weeks 4-8 after initial resection, which must include the deep resection or cold cup biopsy (deep enough to obtain muscle tisssue) of the (initial) tumor site(s)
3. Re-re-TUR should be performed at weeks 4-8 after re-TUR in case of histological detection of T1 low/high grade in the re-TUR, which must include the deep resection or cold cup biopsy (deep enough to obtain muscle tisssue) of the initial tumor site(s)
4. Histopathologically confirmed absence of T1 low/high grade tumor in the re-TUR specimen and/or re-re-TUR specimen
5. All visible papillary tumors must be completely resected
6. If the patient is male, he must use a condom during sexual intercourse during the first week after BCG treatment. If the patient is female, and of childbearing potential, she must practice adequate contraception for 30 days prior to administration of study treatment, have a negative pregnancy test and continue such precautions during all study treatment period and for 3 months after of the last BCG treatment.
7. Signed and dated informed consent form.
8. Patient is clinically fit enough to receive BCG bladder instillations.
Exclusion criteria
1. Any previous intravesical BCG therapy
2. Presence of primary CIS only
3. Presence of histopathologically proven muscle invasive urothelial carcinoma of the bladder at first or re-TUR surgical specimens
4. Presence of any tumors in upper urinary tract or in the prostatic urethra at any time
5. Presence of any other histological type of resected tumor other than urothelial carcinoma on the first or second resection
6. Presence of another malignancy within 5 years except for basal cell carcinoma of the skin or localised prostate cancer in active surveillance
7. Presence of pregnancy or lactation
8. Presence of active tuberculosis, any form of immunodeficiency (eg HIV + serology, transplant recipients) and/or any other contraindication of BCG therapy
9. Patients who have received any systemic cytostatic agents or multi-installation intravesical chemotherapy in the last 3 months prior to randomisation. Early postoperative (within 6 hours of resection) single dose chemotherapy is allowed after the first resection. However, it should not be given after (re-)re-TUR if the patient is considered eligible for this study
10. Patients with uncontrollable UTI
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-019181-91-NL |
| CCMO | NL49845.091.14 |