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

Phase 2

Active, not recruiting

Conditions: Bladder Cancer
Urothelial Carcinoma Bladder

Interventions: Drug: Gemcitabine
Drug: Docetaxel

Registration Number: NCT04386746

Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary: 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).

Detailed Description: 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 27

Inclusion Criteria

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
Eastern Cooperative Oncology Group (ECOG) (WHO) performance status 0, 1, or 2
Age ≥ 18 years old at time of consent
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).
Subjects who give a written informed consent obtained according to local guidelines.

Exclusion Criteria

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
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.
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.
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.
Subjects who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities.
Pregnant or breast-feeding women.
Subjects unwilling or unable to comply with the protocol.
Patients with prior systemic gemcitabine or docetaxel use for a non-bladder malignancy may enroll and receive treatment.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intravesical Gemcitabine/Docetaxel	Gemcitabine	Gemcitabine/Docetaxel induction is given intravesically in sequential order once a week for six consecutive weeks. One gram of gemcitabine in 50 ml of sterile water is slowly instilled into the bladder via a Foley catheter and the catheter is clamped for 60 minutes. The bladder is then drained and 40 mg of docetaxel in 50 ml of NSS is then slowly instilled via the Foley catheter into the bladder. The catheter is again clamped for 60 minutes before draining. If initial efficacy seen, patients will have monthly maintenance instillations of Gemcitabine/Docetaxel.
Intravesical Gemcitabine/Docetaxel	Docetaxel	Gemcitabine/Docetaxel induction is given intravesically in sequential order once a week for six consecutive weeks. One gram of gemcitabine in 50 ml of sterile water is slowly instilled into the bladder via a Foley catheter and the catheter is clamped for 60 minutes. The bladder is then drained and 40 mg of docetaxel in 50 ml of NSS is then slowly instilled via the Foley catheter into the bladder. The catheter is again clamped for 60 minutes before draining. If initial efficacy seen, patients will have monthly maintenance instillations of Gemcitabine/Docetaxel.

Primary Outcome Measures

Name	Time	Method
3-Month Complete Response Rate	3 months	Number of patients with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage as assessed by cystoscopy with biopsy and urine cytology.

Secondary Outcome Measures

Name	Time	Method
12-Month Relapse-Free Survival Rate	12 months	Proportion of patients alive and with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage.
24-Month Relapse-Free Survival Rate	24 months	Proportion of patients alive and with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage.
Safety Profile as Assessed by Proportion of Adverse Events by Type	Up to 24 months	Proportion of adverse events by type, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Safety Profile as Assessed by Proportion of Adverse Events by Grade	Up to 24 months	Proportion of adverse events by grade, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Number of Gene Alterations as Measured by RNA-seq	12 months	Number of gene alterations as measured by RNA-seq. Compare results to 12-month Relapse-Free Survival rate using statistical methods.
Type of Gene Alterations as Measured by RNA-seq	12 months	Type of gene alterations as measured by RNA-seq. Compare results to 12-month Relapse-Free Survival rate using statistical methods.
Number of DNA Mutations as Measured by Whole Transcriptome	12 months	Number of DNA mutations as measured by whole transcriptome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Number of DNA Mutations as Measured by Whole Exome	12 months	Number of DNA mutations as measured by whole exome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Number of DNA Mutations as Measured by Panel DNA Sequencing	12 months	Number of DNA mutations as measured by panel DNA sequencing. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Type of DNA Mutations as Measured by Whole Transcriptome	12 months	Type of DNA mutations as measured by whole transcriptome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Type of DNA Mutations as Measured by Whole Exome	12 months	Type of DNA mutations as measured by whole exome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Type of DNA Mutations as Measured by Panel DNA Sequencing	12 months	Type of DNA mutations as measured by panel DNA sequencing. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Numbers of T-cell Subpopulations	12-months	Numbers of t-cell subpopulations utilizing IHC staining and flow cytometry. Compare results to 12-month Relapse-Free Survival rate using statistical analysis.
Ratio of T-cell Subpopulations	12-months	Ratio of t-cell subpopulations utilizing IHC staining and flow cytometry. Compare results to 12-month Relapse-Free Survival rate using statistical analysis.