This phase III trial compares the effect of adding gemcitabine to intravesical Bacillus Calmette Guerin (BCG) versus intravesical BCG alone in patients with non-muscle invasive bladder cancer that has come back after a period of improvement (recurrent). Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid (DNA) and may kill cancer cells. Intravesical BCG is a solution containing the live BCG bacteria that is placed in the bladder via a catheter (intravesical). When the solution comes into direct contact with the bladder wall, it stimulates the body's immune system which kills tumor cells. Giving gemcitabine with intravesical BCG may kill more tumor cells in patients with recurrent non-muscle invasive bladder cancer.

PRIMARY OBJECTIVE:

I. To compare high-grade recurrence-free-survival between treated with gemcitabine with BCG (GemBCG) compared to those treated with BCG alone.

SECONDARY OBJECTIVES:

I. To compare the proportion of patients who remain high grade cancer free on initial post-treatment cystoscopic biopsies/transurethral resection of bladder tumor (TURBT) (week 13/month 3) between those treated with GemBCG compared to those treated with BCG alone.

II. To compare the 6-month (Week 25) complete response rate and the complete response durability between patients treated with GemBCG compared to those treated with BCG alone among patients with pre-treatment CIS.

III. To compare the time to recurrence of any-grade bladder cancer between patients treated with GemBCG compared those treated with BCG alone.

IV. To compare the progression-free-survival between patients treated with GemBCG compared to those treated with BCG alone.

V. To compare the cystectomy-free-survival between patients treated with GemBCG compared to those treated with BCG alone.

VI. To compare the proportion of patients free from BCG-unresponsive NMIBC between those treated with GemBCG compared to those treated with BCG alone.

VII. To determine the safety of and toxicity associated with GemBCG treatment relative to that of BCG treatment alone.

EXPLORATORY OBJECTIVE:

I. To collect tumor tissue/bladder biopsies, blood, and urine samples for biobanking that will enable future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive BCG intravesically over 2 hours once per week (QW) for 6 weeks. 2-6 weeks after completing endoscopic assessment, patients receive BCG over 2 hours QW for 3 weeks at month 3, 6 and 12 in the absence of disease progression or unacceptable toxicity. Patients undergo bladder biopsy, TURBT, cystoscopy, computed tomography (CT) scan/ magnetic resonance imaging (MRI) and blood and urine sample collection throughout the study.

ARM B: Patients receive gemcitabe intravesically over 1 hour twice weekly on weeks 1 and 10 and once weekly on weeks 4 and 7. Patients also receive BCG intravesically over 2 hours QW on weeks 2, 3, 6, 8 and 9. 2-6 weeks after completing endoscopic assessment, patients receive gemcitable intravesically over 1 hour on week 1 and BCG intravesically over 2 hours on week 2-4 at month 3, 6 and 12 in the absence of disease progression or unacceptable toxicity. Patients undergo bladder biopsy, TURBT, cystoscopy, CT scan/MRI and blood and urine sample collection throughout the study.

After completion of study treatment, patients are followed every 3 months for 2 years, then every 6 months for 3 years up to 5 years from randomization.

Inclusion Criteria:

• Documentation of Disease: Histologic confirmation of urothelial carcinoma that is high grade Ta, high grade T1, or Tis (Tis/carcinoma in situ [CIS] only disease) within 120 days prior to randomization

• Any component of neuroendocrine carcinoma (i.e., small cell or large cell) is not allowed. Other histologic subtypes/variant histologies are allowed so long as there is a predominantly urothelial component.

  * Note: Pure squamous cell carcinoma or pure adenocarcinoma without a urothelial component are not allowed

• All visible papillary lesions must be macroscopically resected by TURBT within 90 days of randomization. (Residual CIS is permitted).

  * If the treating urologist did not perform the TURBT, the treating urologist must perform a cystoscopy within 45 days prior to randomization to confirm the absence of visible papillary disease

• All patients with high grade T1 must undergo a restaging TURBT within 90 days of randomization. Patients who undergo a restaging TURBT that shows no residual cancer in the specimen are still eligible for trial based on prior TURBT

• Patients must have BCG-Exposed non muscle invasive bladder carcinoma (NMIBC), defined as recurrent high grade NMIBC within 24 months of last BCG exposure but not meeting the definition of BCG unresponsive disease

  • Note: Up to 26 months from the last BCG instillation is allowed for the treating physician to perform a transurethral resection of bladder tumor (TURBT) so long as there is evidence/suspicion of recurrent disease (by positive cytology, imaging, or cystoscopy) within 24 months of last exposure to BCG.

  • Note: A patient who previously met the definition of BCG unresponsive NMIBC but no longer currently meets unresponsive criteria may still enroll in this trial so long as the treating urologist believes re-treatment with BCG is a reasonable treatment option for that patient.

  • BCG-exposed NMIBC criteria is defined as:

    • Any high grade NMIBC recurrence within 24 months of induction only BCG, or
    • A high grade papillary NMIBC (Ta/T1) recurrence between 6-24 months of last exposure to induction + maintenance BCG, or
    • A high-grade CIS (with or without Ta/T1 papillary disease) recurrence within 12-24 months of last exposure to induction + maintenance BCG.

  • Patient must not have BCG-unresponsive NMIBC, defined as:

    • Persistent or recurrent high-grade papillary NMIBC (Ta/T1) < 6 months of "adequate" BCG, or

    • A high-grade CIS (with or without Ta/T1 papillary disease) recurrence < 12 months of "adequate" BCG, or

    • A high grade T1 recurrence at the first 3-month assessment from induction BCG

    • "Adequate" BCG is defined as ≥5 of 6 doses of induction BCG therapy with either

      • ≥ 2 of 3 doses of maintenance BCG, or
      • ≥ 2 of planned 6 instillations of repeat induction BCG given within a 6 month time period

• More than one prior induction course of BCG and/or prior maintenance BCG is allowed so long as the patient does not currently met the definition of BCG unresponsive disease

• Prior treatment with any intravesical chemotherapy (both perioperative and induction course) for NMIBC is allowed, including gemcitabine either alone or in combination (ie. gemcitabine plus docetaxel) or gemcitabine delivered through a intravesical delivery system (ie. TAR-200)

• Prior treatment with any systemic or intravesical agents for NMIBC is allowed, regardless of whether it is given either alone or in prior combination with BCG (ie. Prior treatment with pembrolizumab, other immune checkpoint inhibitors, nadofaragene firadenovec, nogapendekin alfa inbakicept, cretostimogene grenadenorepvec, etc. are all allowed)

• Patients must not have a history of intolerance to BCG (ie needing to stop BCG induction or maintenance due to toxicity) or intolerance to any other intravesical therapies

• Patients must not have compromised bladder function such that they are unlikely to tolerate further intravesical therapies

• Patient must not have any prior history or current evidence of muscle-invasive (i.e., T2, T3, T4), locally advanced unresectable, or metastatic urothelial carcinoma as assessed on radiographic imaging obtained within 120 days prior to randomization.

  * The radiographic imaging includes a CT Scan or MRI of the abdomen/pelvis with intravenous contrast, with a CT or MRI urogram preferred. If a patient is unable to receive intravenous contrast due to renal function or allergy, then either a CT scan or MRI of the abdomen/pelvis without intravenous contrast is acceptable

• Patients with a history of upper tract urothelial carcinoma are allowed so long as they had localized non-muscle invasive (Ta, T1, Tis) that has been definitively treated with surgery (nephroureterectomy or ureterectomy) with at least one post-treatment disease assessment imaging study that demonstrates no evidence of residual upper tract disease

• Patients with a history of, or current evidence of, non-invasive (Ta/Tis) urothelial carcinoma of the prostatic urethra are eligible so long as a transurethral resection of prostate (TURP) is performed before enrollment and there is prostatic glandular tissue without evidence of lamina propria invasion or prostatic stromal invasion

• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• Age ≥ 18 years

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Not pregnant and not nursing, Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:

  • has achieved menarche at some point
  • has not undergone a hysterectomy or bilateral oophorectomy
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)