Brief Title: Testing the Addition of an Anti-Cancer Drug, Gemcitabine, to Usual Treatment (BCG Alone) in People Whose Non-Muscle Invasive Bladder Cancer (NMIBC) Came Back After Prior BCG Therapy

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: High Grade Recurrence-free survival (HG-RFS)

Primary Outcome 1 - Timeframe: Up to 5 years

CONDITION

• Recurrent Non-Muscle Invasive Bladder Carcinoma
• Stage 0a Bladder Cancer AJCC v8
• Stage I Bladder Cancer AJCC v8

ELIGIBILITY

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)

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Eugene Pietzak, MD

Role: Study Chair

Affiliation: Alliance for Clinical Trials in Oncology

Overall Contact

Name: Aishwarya Vijendran

Phone: (773) 702-9171

Email: [email protected]

LOCATION