Bladder Cancer, Urothelial Carcinoma Bladder
Conditions
Keywords
NMIBC
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.
Interventions
DRUGGemcitabine
1g gemcitabine in 50ml sterile water; instilled once weekly for 6 weeks and then once monthly for ≤ 21 months.
DRUGDocetaxel
37.5mg docetaxel in 50ml normal saline solution (NSS); instilled once weekly for 6 weeks and then once monthly for ≤ 21 months.
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 3 months | Number of gene alterations as measured by RNA-seq. Compare results to 3-month Complete Response rate using statistical methods. |
| Type of Gene Alterations as Measured by RNA-seq | 3 months | Type of gene alterations as measured by RNA-seq. Compare results to 3-month Complete Response rate using statistical methods. |
| Number of DNA Mutations as Measured by Whole Transcriptome | 3 months | Number of DNA mutations as measured by whole transcriptome. Compare results to 3-month Complete Response rate. |
| 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. |
| Number of DNA Mutations as Measured by Panel DNA Sequencing | 3 months | Number of DNA mutations as measured by panel DNA sequencing. Compare results to 3-month Complete Response rate. |
| Type of DNA Mutations as Measured by Whole Transcriptome | 3 months | Type of DNA mutations as measured by whole transcriptome. Compare results to 3-month Complete Response rate. |
| Type of DNA Mutations as Measured by Whole Exome | 3 months | Type of DNA mutations as measured by whole exome. Compare results to 3-month Complete Response rate. |
| Type of DNA Mutations as Measured by Panel DNA Sequencing | 3 months | Type of DNA mutations as measured by panel DNA sequencing. Compare results to 3-month Complete Response rate. |
| Numbers of T-cell Subpopulations | 3 months | Numbers of t-cell subpopulations utilizing immunohistochemical (IHC) staining and flow cytometry. Compare results to 3-month Complete Response rate using statistical analysis. |
| Ratio of T-cell Subpopulations | 3 months | Ratio of t-cell subpopulations utilizing IHC staining and flow cytometry. Compare results to 3-month Complete Response rate using statistical analysis. |
| Number of DNA Mutations as Measured by Whole Exome | 3 months | Number of DNA mutations as measured by whole exome. Compare results to 3-month Complete Response rate. |
Countries
United States
Participant flow
Pre-assignment details
27 subjects signed consent to be screened for eligibility. * 1 subject signed consent, but did not meet the eligibility criteria to start the study (screen failure) * 26 subjects received study treatment (1 subject withdrew consent after first dose of study therapy)
Participants by arm
| Arm | Count |
|---|---|
| Intravesical Gemcitabine/Docetaxel Gemcitabine: 1g gemcitabine in 50ml sterile water; instilled once weekly for 6 weeks and then once monthly for ≤ 21 months.
Docetaxel: 37.5mg docetaxel in 50ml normal saline solution (NSS); instilled once weekly for 6 weeks and then once monthly for ≤ 21 months. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Intravesical Gemcitabine/Docetaxel |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Pre-trial pathologic stage CIS alone | 3 Participants |
| Pre-trial pathologic stage HGT1 with CIS | 7 Participants |
| Pre-trial pathologic stage HGT1 without CIS | 7 Participants |
| Pre-trial pathologic stage HgTa | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 26 |
| other Total, other adverse events | 23 / 26 |
| serious Total, serious adverse events | 2 / 26 |
Outcome results
Primary
3-Month Complete Response Rate
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.
Time frame: 3 months
Population: 1 patient withdrew consent and data was not collected.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravesical Gemcitabine/Docetaxel | 3-Month Complete Response Rate | 25 Participants |
Secondary
12-Month Relapse-Free Survival Rate
Proportion of patients alive and with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage.
Time frame: 12 months
Secondary
24-Month Relapse-Free Survival Rate
Proportion of patients alive and with no evidence of recurrent high grade urothelial carcinoma of the bladder of any stage.
Time frame: 24 months
Secondary
Number of DNA Mutations as Measured by Panel DNA Sequencing
Number of DNA mutations as measured by panel DNA sequencing. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Time frame: 12 months
Secondary
Number of DNA Mutations as Measured by Panel DNA Sequencing
Number of DNA mutations as measured by panel DNA sequencing. Compare results to 3-month Complete Response rate.
Time frame: 3 months
Secondary
Number of DNA Mutations as Measured by Whole Exome
Number of DNA mutations as measured by whole exome. Compare results to 3-month Complete Response rate.
Time frame: 3 months
Secondary
Number of DNA Mutations as Measured by Whole Exome
Number of DNA mutations as measured by whole exome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Time frame: 12 months
Secondary
Number of DNA Mutations as Measured by Whole Transcriptome
Number of DNA mutations as measured by whole transcriptome. Compare results to 3-month Complete Response rate.
Time frame: 3 months
Secondary
Number of DNA Mutations as Measured by Whole Transcriptome
Number of DNA mutations as measured by whole transcriptome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Time frame: 12 months
Secondary
Number of Gene Alterations as Measured by RNA-seq
Number of gene alterations as measured by RNA-seq. Compare results to 3-month Complete Response rate using statistical methods.
Time frame: 3 months
Secondary
Number of Gene Alterations as Measured by RNA-seq
Number of gene alterations as measured by RNA-seq. Compare results to 12-month Relapse-Free Survival rate using statistical methods.
Time frame: 12 months
Secondary
Numbers of T-cell Subpopulations
Numbers of t-cell subpopulations utilizing IHC staining and flow cytometry. Compare results to 12-month Relapse-Free Survival rate using statistical analysis.
Time frame: 12-months
Secondary
Numbers of T-cell Subpopulations
Numbers of t-cell subpopulations utilizing immunohistochemical (IHC) staining and flow cytometry. Compare results to 3-month Complete Response rate using statistical analysis.
Time frame: 3 months
Secondary
Ratio of T-cell Subpopulations
Ratio of t-cell subpopulations utilizing IHC staining and flow cytometry. Compare results to 3-month Complete Response rate using statistical analysis.
Time frame: 3 months
Secondary
Ratio of T-cell Subpopulations
Ratio of t-cell subpopulations utilizing IHC staining and flow cytometry. Compare results to 12-month Relapse-Free Survival rate using statistical analysis.
Time frame: 12-months
Secondary
Safety Profile as Assessed by Proportion of Adverse Events by Grade
Proportion of adverse events by grade, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Time frame: Up to 24 months
Secondary
Safety Profile as Assessed by Proportion of Adverse Events by Type
Proportion of adverse events by type, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
Time frame: Up to 24 months
Secondary
Type of DNA Mutations as Measured by Panel DNA Sequencing
Type of DNA mutations as measured by panel DNA sequencing. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Time frame: 12 months
Secondary
Type of DNA Mutations as Measured by Panel DNA Sequencing
Type of DNA mutations as measured by panel DNA sequencing. Compare results to 3-month Complete Response rate.
Time frame: 3 months
Secondary
Type of DNA Mutations as Measured by Whole Exome
Type of DNA mutations as measured by whole exome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Time frame: 12 months
Secondary
Type of DNA Mutations as Measured by Whole Exome
Type of DNA mutations as measured by whole exome. Compare results to 3-month Complete Response rate.
Time frame: 3 months
Secondary
Type of DNA Mutations as Measured by Whole Transcriptome
Type of DNA mutations as measured by whole transcriptome. Compare results to 12-month Relapse Free Survival rate using statistical analysis.
Time frame: 12 months
Secondary
Type of DNA Mutations as Measured by Whole Transcriptome
Type of DNA mutations as measured by whole transcriptome. Compare results to 3-month Complete Response rate.
Time frame: 3 months
Secondary
Type of Gene Alterations as Measured by RNA-seq
Type of gene alterations as measured by RNA-seq. Compare results to 12-month Relapse-Free Survival rate using statistical methods.
Time frame: 12 months
Secondary
Type of Gene Alterations as Measured by RNA-seq
Type of gene alterations as measured by RNA-seq. Compare results to 3-month Complete Response rate using statistical methods.
Time frame: 3 months