Patients must be BCG-unresponsive; a patient is BCG-unresponsive if they meet one or more of the following criteria:\r\n* Patient has persistent or recurrent high-grade Ta/CIS urothelial carcinoma after completing therapy with at least induction BCG (>= 5 doses) and first round maintenance or second induction BCG (>= 2 doses)\r\n* Patient has high grade T1 urothelial carcinoma after induction BCG (>= 5 doses) only or after induction BCG (>= 5 doses) and first round maintenance or second induction BCG (>= 2 doses)\r\n* Patient is disease-free at 6 months after starting BCG (i.e., complete response) but then experiences a high-grade recurrence within 6 months after the last BCG dose
Patients must not have received prior intravesical BCG or intradermal BCG
Prior therapy with intravesical Bacillus Calmette-Guerin (BCG) within 6 weeks of treatment.
Histologically confirmed presence of BCG-unresponsive CIS (with or without Ta or T1 disease) or histologically confirmed presence of BCG-unresponsive high-grade Ta or T1 disease.
BCG-unresponsive disease as defined as: (a) Persistent or recurrent CIS (+/- recurrent Ta/T1 disease) within 12 months of receiving adequate BCG (at least five of six doses doses of an initial induction course plus either at least two of three doses of maintenance therapy or at least two of six doses of a second induction course); or (b) Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG (at least five of six doses of an initial induction course plus either at least two of three doses of maintenance therapy or at least two of six doses of a second induction course); or (c) T1 high-grade disease at the first evaluation following an induction BCG course alone (at least five of six doses of an initial induction course).
Recurrence of BCG unresponsive Ta/T1 disease > 6 months after last BCG instillation or BCG unresponsive CIS > 12 months after last BCG instillation.
For subjects with NMIBC, failure or intolerance of prior BCG therapy; failure is defined as evidence of TCC on cystoscopic examination and biopsy or cystoscopic examination and urine cytology at least 6 weeks from completion of last BCG or intravesical treatment
Patients must have a diagnosis of transitional cell carcinoma (TCC) of the urinary bladder confirmed at the study institution. The patient must have demonstrated nonmuscle-invasive bladder cancer refractory or recurrent to standard intravesical therapy. Refractory disease is defined as failure to achieve tumor-free status by 6 months of initiation of adequate BCG therapy. Recurrent disease is defined as reappearance of disease after achieving a tumor-free status by 6 months of initiation of adequate BCG therapy. Adequate BCG therapy includes at least 6 weeks induction plus 3 additional doses of either induction or maintenance. Patients with a history of other intravesical agents (except nab-rapamycin or gemcitabine) in addition to standard BCG will also be allowed to enroll. All grossly visible disease must be fully resected and pathologic stage will be confirmed at the institution where the patient is enrolled. This will include stage Ta, T1, Tis and exclude all patients with muscle invasion (T2).
Documented BCG-refractory disease defined as failure to achieve a tumor free state after at least 2 prior induction courses of intravesical BCG therapy; NOTE: For patients with residual non-invasive tumors (i.e. Ta, T1, Tis) after an initial 6-week induction course of intravesical BCG therapy, a second induction course of intravesical BCG therapy is required; patients with persistent non-invasive tumors (i.e. Ta, T1, Tis) despite an initial 6-week and second induction intravesical BCG therapy course are considered BCG-refractory and, therefore, eligible for study; patients with non-invasive tumor recurrences (i.e. Ta, T1, Tis) after only an initial 6-week induction course of intravesical BCG therapy are considered BCG-resistant and not eligible for study until persistent non-invasive tumor (i.e. Ta, T1, Tis) is demonstrated after a second induction course of intravesical BCG therapy has been administered; there is no maximum limit on the number of prior BCG therapy courses; in addition, there is no maximum limit on the number of prior non-BCG intravesical therapy courses (i.e. gemcitabine, valrubicin, interferon, mitomycin C, etc.)
Scheduled for induction BCG intravesical therapy
Patient received BCG treatment for UC during the 6 months prior to Visit 1.
Has had prior systemic anti-cancer therapy for the treatment of bladder cancer. Prior intravesical therapies, whether Bacillus Calmette-Guerin (BCG) (including but not limited to: persistent high-grade disease or recurrence within 6 months of receiving at least two courses of intravesical BCG [at least five of six induction doses and at least two of three maintenance doses]; or T1 high-grade disease at the first evaluation following induction BCG alone [at least five of six induction doses]), chemotherapy or otherwise, will remain eligible.
Active tuberculosis or bacille Calmette-Guerin (BCG) infection
Administration of intravesical BCG within 4 weeks before cycle 1, day 1
Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the Food and Drug Administration (FDA): Subjects must have received at least two courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course); please note exception above for persistent T1 disease; there is no upper limit on the amount of prior BCG a subject may have received
Patients must have received last BCG dose within a year of enrollment
The investigator must document that he/she believes the subject would not benefit from additional BCG treatment at the time of study entry
Patient must have BCG unresponsive non-muscle-invasive bladder cancer defined as: Persistent or recurrence of carcinoma in situ (CIS) within 12 months, or recurrence of CIS with Ta/T1 papillary disease within 12 months, or recurrence of high grade Ta or T1 papillary disease alone within 6 months of receiving at least two courses of intravesical BCG (at least five of six induction doses and at least two doses of either a maintenance course of BCG or a 2nd re-induction of BCG; or T1 high-grade disease at the first evaluation following induction of BCG alone (at least five of six induction doses)
Subjects must have received intravesical treatment with at least two doses of BCG within six months of nivolumab treatment initiation
Must have pathologically confirmed urothelial carcinoma in situ (CIS) of the bladder and meet one of the following criteria\r\n* Persistence of high-grade CIS at 6 months following an adequate course of BCG; OR\r\n* Stage/grade progression at 3 months after induction BCG; OR\r\n* Recurrence of high-grade CIS after achieving a disease-free state (i.e., complete response [CR]) following induction of an adequate course of BCG that occurs < 9 months after the last exposure to BCG; OR\r\n* Persistent CIS noted on the bladder biopsies within 3 months of completing at least 2 induction BCG (minimum of five weekly instillations)\r\nAn adequate course of BCG should be defined as at least one course of induction (minimum of five weekly instillations) and one maintenance (two of three instillations) in a 6 months period, with an exception for any patient with grade/stage progression after induction BCG (minimum of five weekly instillations)
Patients must have a histologically documented recurrence of non-muscle-invasive bladder carcinoma (T1HG, T1HG after repeat transurethral resection [reTUR]) or BCG refractory; if patient has received BCG they can be Ta, Tis, or T1)\r\n* Note: Gross disease is not allowed, however positive urine cytology and carcinoma in situ is permitted
Patients must be BCG-unresponsive; a patient is BCG-unresponsive if they meet one of more of the following criteria:\r\n* Patient has persistent or recurrent high-grade Ta/carcinoma in situ (CIS)/ urothelial carcinoma after completing therapy with at least induction BCG (>= 5 doses) and first round maintenance or second induction BCG (>= 2 doses); patient has high grade T1 urothelial carcinoma after induction BCG (>= 5 doses) only or after induction BCG (>= 5 doses) and first round maintenance or second induction BCG (>= 2 doses)\r\n* Patient is disease-free at completion of BCG (i.e., complete response) but then experiences a high-grade recurrence before or at the 6 month follow-up cystoscopy\r\n* Recurrence after treatment with at least 3 doses of a BCG refractory agent (for example, though not limited to, gemcitabine, docetaxel, valrubicin or an interferon adenovirus)
In their treating physician’s opinion is a good candidate for BCG therapy
Individuals who are not a good candidate for BCG in their treating physician’s opinion
BCG-unresponsive high risk non-muscle-invasive bladder cancer after treatment with adequate BCG therapy
Patients with bladder CIS, or completely resected high grade Ta/T1 lesions that are BCG unresponsive; unresponsive is BCG refractory and/or BCG relapsing\r\n* BCG refractory: persistent high-grade disease at 6 months despite receiving at least 5-6 induction instillations and at least one maintenance (two of three instillations) in a 6 month period\r\n* BCG relapsing: recurrence of high-grade disease after achieving a disease-free state at 6 months after receiving at least 5-6 induction instillations and at least one maintenance (two of three instillations) in a 6 month period
Prior chemotherapy or immunotherapy for metastatic urothelial cancer; prior neoadjuvant or adjuvant chemotherapy with first progression > 12 months is allowed; prior intravesical treatments such as Bacillus Calmette-Guerin (BCG) are allowed, however no BCG is allowed within 4 weeks prior to initiation of study treatment
Patients have failed at least one previous induction course of intravesical 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; for the purposes of the study, “BCG-refractory” and “BCG-resistant” subjects will be considered to have “BCG-persistent” disease
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 for Adverse Events (CTCAE) version (v) 5.0
Are \BCG Unresponsive\ which refers to patients with high-grade NMIBC who are unlikely to benefit from and who will not receiving further intravesical BCG. The term \BCG unresponsive\ includes patients who did not respond to BCG treatment and have a persistent high-grade recurrence within 12 months after BCG was initiated, and those who despite an initial complete response (CR) to BCG, relapse with high-grade CIS within 12 months of their last intravesical treatment with BCG or relapse with high-grade Ta/T1 NMIBC within 6 months of their last intravesical treatment with BCG. The following criteria define the patients who may be included in the study:
Have received at least 2 previous courses of BCG within a 12 month period - defined as at least 5 of 6 induction BCG instillations and at least 2 out of 3 instillations of maintenance BCG, or at least two of six instillations of a second induction course, where maintenance BCG is not given
Exception: those who have T1 high-grade disease at first evaluation after induction BCG alone (at least 5 of 6 doses) may qualify in the absence of disease progression
At the time of tumor recurrence, patients with CIS alone or high-grade Ta/T1 with CIS should be within 12 months of last exposure to BCG and patients with Ta/T1 without CIS should be within 6 months of last exposure to BCG
No maximum limit to the amount of BCG administered
previous intravesical BCG therapy, which can be given at least 5 weeks before the diagnostic biopsy required for entry into the study
Subjects must have received adequate BCG treatment defined as at least 2 courses of BCG, i.e., at least one induction and one maintenance course or at least 2 induction courses. The initial induction course must be at least 5 treatments within a 7-week period. The second course (induction or maintenance) must be at least 2 treatments within a 6-week period. The \5+2\ doses of BCG must be given within approximately 1 year (i.e., the start of one course to start of the second course within 12 months ±1 month) and for the same disease episode for which the subject is enrolling. Treatment must be considered \full-dose\ BCG (see Section 10). If additional doses or courses of BCG above the minimum \5+2\ are given, these do not have to be within the same approximate 12 month timeframe. Subjects who were unable to receive at least 5 doses of BCG in a first course and at least 2 doses of BCG in a second course due to intolerance are not eligible. Subjects who began their initial course of BCG with \full-dose\ BCG and required dose-reductions due to adverse events but are still able to tolerate at least \5+2\ doses of BCG are considered to meet the requirement for \adequate BCG.\ Subjects who received less than \full dose\ BCG (e.g., 1/3rd dosing) as a standard regimen and not due to dose reductions because of AEs are not eligible. The BCG may have been given in combination with interferon. When BCG is given simultaneously in combination with interferon, 1/3rd dosing of BCG is acceptable.
The subject's disease is refractory or has relapsed following adequate BCG treatment. Refractory disease is defined as disease which persists at the first evaluation following adequate BCG. Relapsed disease is defined as having a complete response to adequate BCG but recurs at a subsequent evaluation. Subjects will enroll into one of three cohorts based on their type of disease and the time to refractory/relapsed disease following their last dose of BCG as follows:
Cohort 1: Subjects with CIS with or without associated papillary disease whose disease is determined to be refractory or relapsed within 6 months of the last dose of adequate BCG treatment.
Cohort 2: Subjects with CIS with or without associated papillary disease whose disease is determined to be refractory or relapsed more than 6 months but within 11 months of the last dose of adequate BCG treatment.
Patients must have received at least two or more prior courses of intravesical therapy per recommended schedules. BCG must have been one of the prior therapies administered.
Patients can have either failed BCG induction therapy within a six-month period or have been successfully treated with BCG, but subsequently found to have recurrence. The first standard course of intravesical BCG therapy must include at least six weekly treatments (allowable range of instillations per course is 4-9). The second course of BCG therapy must include at least two weekly treatments.
disease recurrence within 18 months of BCG maintenance OR
disease recurrence within 24 months of BCG induction
Patients must have a high grade urothelial carcinoma stage Ta or T1 that has recurred within 540 days after completion of the initial treatment (transurethral resection bladder tumor [TURBT] and intravesical bacillus Calmette-Guerin [BCG] immunotherapy) or on initial presentation with a T1 high grade tumor, the participating urologist judged BCG therapy is contraindicated or unsuitable because the patient is found to be intolerant of BCG therapy or because this patient may be immuno-compromised in ways other than that mentioned in severe, active co-morbidity or because the patient refuses BCG therapy
Active tuberculosis or bacillus Calmette-Guerin (BCG) infection
Administration of intravesical bacillus Calmette-Guerin (BCG) within 4 weeks before cycle 1, day 1
Any approved anti-cancer therapy within 3 weeks prior to enrollment o Administration of intravesical bacillus Calmette-Guerin (BCG) > 4 weeks before cycle 1, day 1 is allowed
The patient must have BCG refractory or recurrent non-muscle invasive bladder cancer\r\n* Refractory disease is defined as evidence of persistent high risk bladder cancer (high grade Ta, T1 and/or CIS) at the first cystoscopic exam after the initial 6 week induction course of BCG or at the 6 month cystoscopic exam\r\n* Recurrent disease is defined as reappearance disease after achieving a tumor- free status by 6 months following a full induction course of BCG with or without maintenance BCG; participants must have recurred with high grade and/or invasive disease within 18 months following the last dose of BCG\r\n** Low-grade superficial (Ta) disease will not be considered recurrent\r\n** Patients must exhibit disease recurrence receiving some form of standard intravesical therapy that must include a minimum of one induction course of BCG and may also include prior exposure to mitomycin, interferon, single agent gemcitabine or taxane therapy or maintenance
Not have received bacillus Calmette-Guérin (BCG) or have completed previous BCG treatment > 12 months prior to the baseline staging procedure.
Prior vaccination with BCG for tuberculosis disease
Patients who are known purified protein derivative (PPD) positive will be screened for active tuberculosis prior to starting treatment with BCG
Known allergy to BCG or MMC
Prior systemic infection with BCG
High-risk NMIBC defined by the following: BCG-unresponsive NMIBC: Persistence of high-grade CIS at 6 months following an adequate course of BCG; or Stage/grade progression at 3 months after induction BCG; or Recurrence of high-grade CIS after achieving a disease-free state (i.e., CR) following induction of an adequate course of BCG that occurs less than (<) 6 months after the last exposure to BCG BCG-relapsing NMIBC: Recurrence of high-grade CIS after achieving a disease-free state following induction of an adequate course of BCG that occurs greater than or equal to (>/=) 6 months after the last exposure to BCG Very high-risk (VHR) BCG-naïve NMIBC: VHR NMIBC, defined as having at least 1 of the following: Multiple and/or large (greater than [>] 3 centimeters [cm]) T1, (HG/G3) tumors; T1, (HG/G3) tumor with concurrent CIS; T1, G3 with CIS in prostatic urethra; Micropapillary variant of non-muscle invasive urothelial carcinoma
For BCG-unresponsive and BCG-relapsing NMIBC, participants must have received an adequate course of BCG
History of prior significant toxicity or intolerance to BCG requiring discontinuation of treatment
History of prior systemic BCG infection
Immunotherapy =< 28 days prior to pre-registration (e.g. intravesical Bacillus Calmette-Guerin [BCG])
Determined by treating urologist to be a good candidate for BCG induction therapy
Have a history of tuberculosis and/or received BCG percutaneous vaccination
Subjects must have failed at least two prior courses of BCG with or without recombinant interferon alpha administration or be BCG intolerant. This includes either two six week induction courses of BCG or a 6 week induction course followed by a 3 week mini-induction course of maintenance BCG.
At least 3 months must have passed since last BCG therapy or intravesical treatment for bladder carcinoma.
Failure of prior intravesical treatment(s), one of which must include a course of BCG; failure is defined as evidence of TCC on cystoscopic examination and biopsy or cystoscopic examination and urine cytology at least 6 weeks from completion of last treatment
Treatment with intravesical BCG or chemotherapy for a patient’s current < T2 tumor during the 12 months prior to the current diagnosis