Bladder Neoplasms
Conditions
Brief summary
A randomized, double-blind, placebo-controlled Phase 3 multicenter study to assess the efficacy and safety of intravesical instillation of gemcitabine versus placebo immediately after transurethral resection of the bladder tumor.
Interventions
DRUGGemcitabine
2000 mg, intravesicular instillation x 1 immediately post transurethral resection of the bladder tumor (TUR-BT)
DRUGPlacebo
intravesicular instillation x 1 immediately post transurethral resection of the bladder tumor (TUR-BT)
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Clinical evidence of superficial transitional cell carcinoma of the bladder * Males or females at least 18 years of age * Karnofsky Performance Status greater than or equal to 70% * Patient compliance and geographic proximity that allow adequate follow-up * Female patients with reproductive potential must use a reliable contraceptive method if appropriate (for example, intrauterine device \[IUD\], birth control pills, or barrier device) during the study. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of study enrollment. * Signed informed consent.
Exclusion criteria
* Clinical evidence of muscle-invasive or locally advanced bladder cancer * Clinical evidence of upper urinary tract tumor * Distant metastases * Other malignancies within the last 2 years, except non-melanotic skin tumors, carcinoma in situ of the cervix or organ-confined prostate cancer after curative therapy * Severe concomitant psychiatric disease * Febrile, active infection * Other serious concomitant disorders that would compromise the safety of the patient or his/her ability to complete the study according to the protocol, at the discretion of the investigator (for example, unstable angina pectoris, uncontrolled diabetes mellitus)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-Free Survival (RFS) | Surgery to recurrence or death (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months) | Defined as the time from study enrollment to the date of the first procedure confirming histopathological recurrence or disease progression or death from any cause. Recurrence-free survival (RFS) was censored at the date of the last follow-up visit for participants who were still alive and who had no recurrence/progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recurrence | Surgery to recurrence (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months) | Time from enrollment to first confirmation of histopathological recurrence or disease progression. Time to recurrence was censored on date of death for patients who died, and on date of last visit for patients who were alive, without recurrence. |
| Recurrence-Free Survival (RFS) in Subgroups | Surgery to recurrence or death (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months) | Defined as the time from study enrollment to the date of the first procedure confirming histopathological recurrence or disease progression or death from any cause. Recurrence-free survival was censored at the date of the last follow-up visit for participants who were still alive and who had no recurrence/progression. |
| Tumor Recurrence Type | Surgery to recurrence (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months) | Tumor recurrence type (superficial, stage pTA or pT1; or muscle-invasive, stage≥pT2) was classified according to American Joint Committee on Cancer Staging Criteria for Bladder Cancer (AJCC Cancer Staging Manual, 6th edition). |
Countries
Germany
Participant flow
Pre-assignment details
355 participants were enrolled and randomized (included here in disposition); however, due to study design, only 328 (N=166 Gemcitabine and N=162 Placebo) actually received study drug (Full Analysis Set).
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine Gemcitabine: 2000 mg, intravesicular instillation x 1 immediately post transurethral resection of the bladder tumor (TUR-BT) | 166 |
| Placebo Placebo: intravesicular instillation x 1 immediately post transurethral resection of the bladder tumor (TUR-BT) | 162 |
| Total | 328 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death, Other Cause | 3 | 6 |
| Overall Study | Death, Study Disease | 1 | 1 |
| Overall Study | Discontinued Prior to Instillation | 13 | 14 |
| Overall Study | Lost to Follow-up | 23 | 21 |
| Overall Study | Not Eligible | 41 | 38 |
| Overall Study | Other | 2 | 0 |
| Overall Study | Pathological Specimen Lost | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Treatment Change | 2 | 0 |
| Overall Study | Tumor Recurrence | 49 | 48 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Gemcitabine | Placebo | Total |
|---|---|---|---|
| Age Continuous | 63.2 years STANDARD_DEVIATION 11.9 | 66.3 years STANDARD_DEVIATION 11 | 64.7 years STANDARD_DEVIATION 11.5 |
| Karnofsky Performance Status 100 - Normal no complaints; no evidence of disease | 118 participants | 104 participants | 222.0 participants |
| Karnofsky Performance Status 70 - Unable to carry on normal activity | 1 participants | 1 participants | 2.0 participants |
| Karnofsky Performance Status 80 - Activity with effort; some signs of disease | 13 participants | 7 participants | 20.0 participants |
| Karnofsky Performance Status 90 - Normal activity; minor signs of disease | 33 participants | 49 participants | 82.0 participants |
| Karnofsky Performance Status Unspecified | 1 participants | 1 participants | 2.0 participants |
| Newly Diagnosed versus Recurrent Disease Newly Diagnosed | 123 participants | 122 participants | 245.0 participants |
| Newly Diagnosed versus Recurrent Disease Recurrent Disease | 43 participants | 40 participants | 83.0 participants |
| Race/Ethnicity White | 166 participants | 162 participants | 328 participants |
| Region of Enrollment Germany | 131 participants | 126 participants | 257.0 participants |
| Region of Enrollment Turkey | 35 participants | 36 participants | 71.0 participants |
| Results of Initial Transurethral Resection of a Bladder Tumor (TUR-BT): Number of Visible Lesions 1 Lesion | 87 participants | 96 participants | 183.0 participants |
| Results of Initial Transurethral Resection of a Bladder Tumor (TUR-BT): Number of Visible Lesions 2 Lesions | 42 participants | 27 participants | 69.0 participants |
| Results of Initial Transurethral Resection of a Bladder Tumor (TUR-BT): Number of Visible Lesions 3 Lesions | 18 participants | 14 participants | 32.0 participants |
| Results of Initial Transurethral Resection of a Bladder Tumor (TUR-BT): Number of Visible Lesions 4 Lesions | 7 participants | 10 participants | 17.0 participants |
| Results of Initial Transurethral Resection of a Bladder Tumor (TUR-BT): Number of Visible Lesions >=5 Lesions | 8 participants | 10 participants | 18.0 participants |
| Results of Initial Transurethral Resection of a Bladder Tumor (TUR-BT): Number of Visible Lesions No Lesions (No Specific Sites Documented) | 4 participants | 5 participants | 9.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage Cis: Carcinoma in situ (Flat Tumor) | 5 participants | 6 participants | 11.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage No Malignancy | 21 participants | 22 participants | 43.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage pT0: No Evidence of Primary Tumor | 0 participants | 0 participants | 0.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage pT1: Tumor Invades Subepithelial Connective Tissue | 31 participants | 36 participants | 67.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage >=pT2: Tumor Invades Wider Area | 12 participants | 10 participants | 22.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage pTa: Noninvasive Papillary Carcinoma | 93 participants | 88 participants | 181.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage pTx: Primary Tumor Cannot be Assessed | 3 participants | 0 participants | 3.0 participants |
| Results of Transurethral Resection of Bladder Tumor (TUR-BT): Final Pathological Disease Stage Unspecified | 1 participants | 0 participants | 1.0 participants |
| Results of Transurethral Resection on a Bladder Tumor (TUR-BT): Final Disease Grade G1 - Well Differentiated | 59 participants | 66 participants | 125.0 participants |
| Results of Transurethral Resection on a Bladder Tumor (TUR-BT): Final Disease Grade G2 - Moderately Differentiated | 50 participants | 48 participants | 98.0 participants |
| Results of Transurethral Resection on a Bladder Tumor (TUR-BT): Final Disease Grade G3 - Poorly Differentiated | 25 participants | 24 participants | 49.0 participants |
| Results of Transurethral Resection on a Bladder Tumor (TUR-BT): Final Disease Grade G4 - Undifferentiated | 3 participants | 1 participants | 4.0 participants |
| Results of Transurethral Resection on a Bladder Tumor (TUR-BT): Final Disease Grade GX - Unknown | 8 participants | 1 participants | 9.0 participants |
| Results of Transurethral Resection on a Bladder Tumor (TUR-BT): Final Disease Grade Unspecified | 21 participants | 22 participants | 43.0 participants |
| Sex: Female, Male Female | 39 Participants | 26 Participants | 65.0 Participants |
| Sex: Female, Male Male | 127 Participants | 136 Participants | 263.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 166 | 36 / 162 |
| serious Total, serious adverse events | 17 / 166 | 10 / 162 |
Outcome results
Primary
Recurrence-Free Survival (RFS)
Defined as the time from study enrollment to the date of the first procedure confirming histopathological recurrence or disease progression or death from any cause. Recurrence-free survival (RFS) was censored at the date of the last follow-up visit for participants who were still alive and who had no recurrence/progression.
Time frame: Surgery to recurrence or death (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months)
Population: This is the Full Analysis Set population and contains all randomized participants who received the single instillation of Gemcitabine or Placebo.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine | Recurrence-Free Survival (RFS) | 37.2 Months |
| Placebo | Recurrence-Free Survival (RFS) | 40.2 Months |
Comparison: Sample-size calculation based on estimated 1-year recurrence-free survival (RFS) rates of 63% (gemcitabine) and 50% (placebo). 191 critical events were required to detect a difference in RFS (80% power, log-rank test, alpha=0.050). Sample size of 328 patients with clinical evidence of superficial bladder cancer needed to observe these 191 events within a 24-month follow-up period, assuming 246 of these patients would receive instillation and have histopathological diagnosis of pTa/pT1(G1-3/Gx).p-value: 0.77795% CI: [0.643, 1.392]Log Rank
Secondary
Recurrence-Free Survival (RFS) in Subgroups
Defined as the time from study enrollment to the date of the first procedure confirming histopathological recurrence or disease progression or death from any cause. Recurrence-free survival was censored at the date of the last follow-up visit for participants who were still alive and who had no recurrence/progression.
Time frame: Surgery to recurrence or death (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months)
Population: Because median time for RFS was not reached in all subgroups, patients (%) with RFS are reported as post-hoc outcome #6. There was no statistically significant difference between treatment arms in any subgroup. Population consists of randomized patients with histopathologically confirmed papillary superficial transitional cell carcinoma of bladder.
Secondary
Time to Recurrence
Time from enrollment to first confirmation of histopathological recurrence or disease progression. Time to recurrence was censored on date of death for patients who died, and on date of last visit for patients who were alive, without recurrence.
Time frame: Surgery to recurrence (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months)
Population: Because median time to recurrence was not reached in placebo arm, percentages of participants without recurrence are reported as post-hoc outcome measure (see #5. Post-hoc Outcome Measure). Efficacy Eligible population consists of randomized patients with histopathologically confirmed papillary superficial transitional cell carcinoma of bladder.
Secondary
Tumor Recurrence Type
Tumor recurrence type (superficial, stage pTA or pT1; or muscle-invasive, stage≥pT2) was classified according to American Joint Committee on Cancer Staging Criteria for Bladder Cancer (AJCC Cancer Staging Manual, 6th edition).
Time frame: Surgery to recurrence (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months)
Population: Efficacy Eligible population consists of the Full Analysis Set participants with histopathologically confirmed papillary superficial transitional cell carcinoma of the bladder.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine | Tumor Recurrence Type | No Tumor Recurrence | 76 participants |
| Gemcitabine | Tumor Recurrence Type | Superficial Tumor - Stage pTa or pT1 | 44 participants |
| Gemcitabine | Tumor Recurrence Type | Muscle-Invasive Tumor - Any Stage ≥pT2 | 3 participants |
| Gemcitabine | Tumor Recurrence Type | pTx - Tumor Cannot be Assessed | 1 participants |
| Placebo | Tumor Recurrence Type | pTx - Tumor Cannot be Assessed | 0 participants |
| Placebo | Tumor Recurrence Type | No Tumor Recurrence | 78 participants |
| Placebo | Tumor Recurrence Type | Muscle-Invasive Tumor - Any Stage ≥pT2 | 1 participants |
| Placebo | Tumor Recurrence Type | Superficial Tumor - Stage pTa or pT1 | 45 participants |
Post Hoc
Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months
RFS rate was estimated using Kaplan-Meier method. RFS was analyzed in different subgroups based on risk, disease status, and concomitant Bacillus Calmette-Guerin (BCG) instillations. Risk: Grading (G1,G2,G3) was performed according to American Joint Committee on Cancer Staging Criteria for Bladder Cancer. Newly diagnosed disease: Initial diagnosis at study entry. Recurrent disease: history of at least one superficial bladder tumor that was surgically treated and relapsed prior to study entry. With BCG: received at least one instillation of BCG during study. Without BCG: didn't receive BCG.
Time frame: Surgery to recurrence or death (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months)
Population: Efficacy Eligible population consists of the Full Analysis Set (randomized) participants with histopathologically confirmed papillary superficial transitional cell carcinoma of the bladder.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Low Risk (G1/G2) - 24 Months (N=106, N=109) | 63.9 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Recurrent Disease - 12 Months (N=30, N=26) | 72.2 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Low Risk (G1/G2) - 12 Months (N=106, N=109) | 78.5 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Recurrent Disease - 24 Months (N=30, N=26) | 59.5 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Newly Diagnosed Disease - 12 Months (N=94, N=98) | 79.3 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | With BCG - 12 Months (N=13, N=21) | 61.5 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | High Risk (G3) - 12 Months (N=13, N=14) | 66.7 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | With BCG - 24 Months (N=13, N=21) | 49.2 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Without BCG - 12 Months (N=111, N=103) | 79.9 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Newly Diagnosed Disease - 24 Months (N=94, N=98) | 65.4 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Without BCG - 24 Months (N=111, N=103) | 65.8 percentage of participants |
| Gemcitabine | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | High Risk (G3) - 24 Months (N=13, N=14) | 57.1 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Without BCG - 24 Months (N=111, N=103) | 60.1 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | With BCG - 24 Months (N=13, N=21) | 63.5 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Low Risk (G1/G2) - 12 Months (N=106, N=109) | 78.4 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Low Risk (G1/G2) - 24 Months (N=106, N=109) | 64.3 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | High Risk (G3) - 12 Months (N=13, N=14) | 42.4 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | High Risk (G3) - 24 Months (N=13, N=14) | 31.8 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Newly Diagnosed Disease - 12 Months (N=94, N=98) | 79.8 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Newly Diagnosed Disease - 24 Months (N=94, N=98) | 63.6 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Recurrent Disease - 12 Months (N=30, N=26) | 58.9 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Recurrent Disease - 24 Months (N=30, N=26) | 50.5 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | With BCG - 12 Months (N=13, N=21) | 79.4 percentage of participants |
| Placebo | Percentage of Participants in Subgroups With Recurrence-Free Survival (RFS) at 12 and 24 Months | Without BCG - 12 Months (N=111, N=103) | 74.5 percentage of participants |
Post Hoc
Percentage of Participants Without Tumor Recurrence
Because median time to recurrence was not reached, percentage of participants without event was estimated using Kaplan-Meier method. Time to recurrence was censored on date of death for patients who died, and on date of last visit for patients who were alive, without recurrence.
Time frame: Surgery to recurrence (Follow-up assessments were performed at 3 and 6 months after the first TUR-BT, and every 6 months thereafter, until recurrence/progression of disease, or until the end of study, up to 24 months)
Population: Efficacy Eligible population contains the Full Analysis Set participants with histopathologically confirmed papillary superficial transitional cell carcinoma of the bladder.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine | Percentage of Participants Without Tumor Recurrence | Recurrence-Free at 12 Months | 78.4 percentage of participants |
| Gemcitabine | Percentage of Participants Without Tumor Recurrence | Recurrence-Free at 24 Months | 66.3 percentage of participants |
| Placebo | Percentage of Participants Without Tumor Recurrence | Recurrence-Free at 12 Months | 76.9 percentage of participants |
| Placebo | Percentage of Participants Without Tumor Recurrence | Recurrence-Free at 24 Months | 63.7 percentage of participants |