Intravesical Gemcitabine and Docetaxel for BCG naïve Non-muscle Invasive Bladder Cancer

A single-arm, two-stage, open-label, phase 2 study investigating the safety and efficacy of intravesical gemcitabine/docetaxel for bacillus Calmette-Guerin (BCG)-naïve patients with non-muscle invasive bladder cancer (NMIBC).

All participants will receive an induction course of gemcitabine/docetaxel instillations (administered once a week for six consecutive weeks) followed by monthly maintenance instillations if initial efficacy is seen. In addition to providing initial efficacy data, this study will provide safety and long-term efficacy data on the combination regimen studied. A tolerable safety profile and demonstrated efficacy would support a potential, randomized phase 3 trial comparing the experimental combination therapy and standard of care intravesical BCG therapy.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically confirmed intermediate or high-risk non-muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis stage) on TURBT obtained within 90 days of registration defined according to modified EORTC risk criteria summarized as follows:

   1. Low-risk tumors: Initial or recurrent tumor \> 12 months after resection with all of the following:

      * Solitary tumor
      * Low-grade
      * \< 3 cm
      * No carcinoma in situ (CIS)
   2. Intermediate-risk tumors: All tumors not defined in the two adjacent categories (between the category of low- and high-risk)
   3. High-risk tumors: Any of the following:

      * T1 tumor
      * High-grade
      * CIS
      * Multiple and recurrent and large (\> 3 cm) Ta low-grade tumors (all conditions must be met for this point of Ta low-grade tumors)
   4. Note #1: Low-risk tumors as defined above are not eligible
   5. Note #2: Mixed histologies are permitted, provided a component of urothelial carcinoma is present
   6. Note #3: All patients with high-grade T1 (HGT1) should undergo a restaging TURBT
2. Eastern Cooperative Oncology Group (ECOG) (WHO) performance status 0, 1, or 2
3. Age ≥ 18 years old at time of consent
4. Evidence of post-menopausal status or negative urinary or serum pregnancy test or female pre-menopausal patients is required. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

   1. Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
   2. Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
5. Subjects who give a written informed consent obtained according to local guidelines.

Exclusion Criteria:

1. Subjects with muscle-invasive (i.e. T2, T3, T4), locally advanced unresectable, or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 90 days prior to study registration. The required radiographic imaging includes:

   1. Abdomen/Pelvis - CT scan
   2. Chest - chest x-ray or CT scan
2. Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) urothelial carcinoma of any stage.

   a. Note: Subjects with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.
3. Subjects with another active second malignancy with an estimated overall survival from the second malignancy of \< 12 months. Subjects with another second active malignancy that are deemed to have an estimated overall survival of \>12 months are eligible.
4. Subjects who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.
5. Subjects who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities.
6. Pregnant or breast-feeding women.
7. Subjects unwilling or unable to comply with the protocol.
8. Patients with prior systemic gemcitabine or docetaxel use for a non-bladder malignancy may enroll and receive treatment.