Bladder Cancer
Conditions
Keywords
Noninvasive Bladder Cancer
Brief summary
The purpose of this study was to evaluate the 2-Year Recurrence Rate of bladder cancer in randomized patients with tumor histology Ta, G1-G2 who received TransUrethral Resection of Bladder Tumor (TURBT) plus apaziquone versus those who received TURBT plus placebo.
Detailed description
This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study. Within 14 days of Screening, eligible patients underwent a TURBT during Visit 1 (Day 0) following which they were immediately randomized in a 1:1 ratio to receive either placebo or 4 mg apaziquone, instilled in a volume of 40 mL into the bladder within 6 hours from the end of the TURBT procedure. After a 60-minute retention period, study drug was drained from the bladder. A postoperative follow-up examination and review of the local pathology report were performed at Visit 2, which occurred 21 days (±10 days) after the TURBT (Week 3). * If the histology of the patient's tumor was confirmed as Ta, G1-G2 (ie, low grade according to World Health Organization \[WHO\]/International Society of Urologic Pathology \[ISUP\] classification), no further treatment was given and the patient was observed cystoscopically every 3 months through Year 2 for tumor recurrence (Visit 3 through Visit 10). * If the histology of the patient's tumor was other than Ta, G1 or G2 (low grade \[WHO/ISUP classification\]), further treatment was given in accordance with current treatment guidelines, and the patient was followed up cystoscopically every 3 months through Year 2 for tumor recurrence (Visit 3 through Visit 10). All patients were to be followed for 2 years.
Interventions
DRUGApaziquone
A single intravesical dose of Apaziquone 4mg in 40ml instilled into the bladder post-TURBT
DRUGPlacebo
A single intravesical dose of placebo instilled into the bladder post-TURBT
PROCEDURETURBT
TransUrethral Resection of the Bladder Tumor
Sponsors
Spectrum Pharmaceuticals, Inc
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
(All questions must be answered YES) * Has the patient given written informed consent? * Is the patient at least 18 years old? * Does the patient have transitional cell carcinoma of the bladder with clinically apparent stage Ta, grade G1-G2? * If the patient is a female of childbearing potential, is she using an acceptable/effective method of contraception? * If the patient is a female of childbearing potential, has she had a negative serum pregnancy test within the past 14 days? * Is the patient willing and able to abide by the protocol?
Exclusion criteria
(All questions must be answered NO) * Does the patient have more than 4 bladder tumors? * Does any single bladder tumor exceed 3.5 cm in diameter? * Does the patient have a single, primary (no previous diagnosis of TCC) bladder tumor \<0.5 cm? * Has the patient ever received Apaziquone? * Does the patient have, or has the patient ever had, any bladder tumor known to be other than stage Ta or grade G1 or G2 (low grade \[WHO/ISUP classification\])? * Does the patient have, or has the patient ever had any bladder tumor with histology other than transitional cell carcinoma? * Does the patient have, or has the patient ever had, carcinoma in situ (CIS)? * Does the patient have an active urinary tract infection? * Does the patient have a bleeding disorder or a screening platelet count \< 100 x 10\^9/L? * Does the patient have any unstable medical condition that would make it unsafe for him/her to undergo TURBT under general or spinal anesthesia? * Does the patient have a screening hemoglobin \< 10 mg/dL, a screening absolute neutrophil count \< 1.5 x 10\^9/L or a screening creatinine \> 2 mg/dL? * Does the patient have a known immunodeficiency disorder? * Has the patient received any investigational treatment within the past 30 days? * Is the patient breast feeding? * Does the patient have a history of interstitial cystitis? * Does the patient have a history of allergy to red color food dye? * Has the patient had transitional cell carcinoma of the bladder within the past 4 months?
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Rate at 2 Years | 2 years | The percentage of participants with histologically confirmed recurrence of the bladder tumor at any time after randomization and on or before year 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Rate at 2 Years | 2 years | The percentage of participants that progress to either a higher stage or grade from the histologically confirmed stage and grade at time of randomization. |
| Time to Progression | 2 years | The number of months from randomization to progression to either a higher stage or grade of the patient's bladder tumor. |
| Number of Recurrences Per Patient | 2 years | The number of histologically confirmed recurrences during the course of the study. |
| Time to Recurrence | 2 years | The number of months from randomization to histologically confirmed recurrence of the patient's bladder tumor. |
| Disease Free Survival | 2 years | The number of months from randomization to histologically confirmed recurrence of the patient's bladder tumor or death from any cause |
| Overall Survival | 2 years | The number of months from randomization to death from any cause. |
| Disease Free Interval | 2 years | The number of months from randomization to histologically confirmed progression of the patient's bladder tumor or death from any cause |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Apaziquone Apaziquone: TURBT + a single intravesical dose of Apaziquone 4mg in 40ml instilled into the bladder post-TURBT | 406 |
| Placebo Placebo: TURBT + a single intravesical dose of placebo instilled into the bladder post-TURBT | 396 |
| Total | 802 |
Baseline characteristics
| Characteristic | Apaziquone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 67.5 years STANDARD_DEVIATION 10.92 | 68.2 years STANDARD_DEVIATION 10.72 | 67.8 years STANDARD_DEVIATION 10.82 |
| Age, Customized Age <65 | 159 Participants | 146 Participants | 305 Participants |
| Age, Customized Age 65-75 | 140 Participants | 139 Participants | 279 Participants |
| Age, Customized Age >75 | 107 Participants | 111 Participants | 218 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 17 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 393 Participants | 379 Participants | 772 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 9 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 392 Participants | 383 Participants | 775 Participants |
| Region of Enrollment Poland | 25 participants | 21 participants | 46 participants |
| Region of Enrollment United States | 381 participants | 375 participants | 756 participants |
| Sex: Female, Male Female | 108 Participants | 102 Participants | 210 Participants |
| Sex: Female, Male Male | 298 Participants | 294 Participants | 592 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 406 | 13 / 396 |
| other Total, other adverse events | 312 / 406 | 285 / 396 |
| serious Total, serious adverse events | 93 / 406 | 98 / 396 |
Outcome results
Primary
Recurrence Rate at 2 Years
The percentage of participants with histologically confirmed recurrence of the bladder tumor at any time after randomization and on or before year 2.
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Apaziquone | Recurrence Rate at 2 Years | Recurrence | 112 Participants |
| Apaziquone | Recurrence Rate at 2 Years | Non-Recurrence | 183 Participants |
| Placebo | Recurrence Rate at 2 Years | Recurrence | 121 Participants |
| Placebo | Recurrence Rate at 2 Years | Non-Recurrence | 150 Participants |
p-value: 0.106895% CI: [0.54, 1.06]Cochran-Mantel-Haenszel
Secondary
Disease Free Interval
The number of months from randomization to histologically confirmed progression of the patient's bladder tumor or death from any cause
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apaziquone | Disease Free Interval | 22.9 months | Standard Error 0.26 |
| Placebo | Disease Free Interval | 22.0 months | Standard Error 0.34 |
Secondary
Disease Free Survival
The number of months from randomization to histologically confirmed recurrence of the patient's bladder tumor or death from any cause
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apaziquone | Disease Free Survival | 18.0 months | Standard Error 0.48 |
| Placebo | Disease Free Survival | 16.4 months | Standard Error 0.55 |
Secondary
Number of Recurrences Per Patient
The number of histologically confirmed recurrences during the course of the study.
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apaziquone | Number of Recurrences Per Patient | 0.6 times | Standard Deviation 1.03 |
| Placebo | Number of Recurrences Per Patient | 0.9 times | Standard Deviation 1.21 |
Secondary
Overall Survival
The number of months from randomization to death from any cause.
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apaziquone | Overall Survival | 20.3 months | Standard Error 0.13 |
| Placebo | Overall Survival | 23.7 months | Standard Error 0.14 |
Secondary
Progression Rate at 2 Years
The percentage of participants that progress to either a higher stage or grade from the histologically confirmed stage and grade at time of randomization.
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Apaziquone | Progression Rate at 2 Years | Progression | 30 Participants |
| Apaziquone | Progression Rate at 2 Years | Non-Progression | 265 Participants |
| Placebo | Progression Rate at 2 Years | Progression | 39 Participants |
| Placebo | Progression Rate at 2 Years | Non-Progression | 232 Participants |
Secondary
Time to Progression
The number of months from randomization to progression to either a higher stage or grade of the patient's bladder tumor.
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apaziquone | Time to Progression | 22.9 months | Standard Error 0.26 |
| Placebo | Time to Progression | 22.0 months | Standard Error 0.34 |
Secondary
Time to Recurrence
The number of months from randomization to histologically confirmed recurrence of the patient's bladder tumor.
Time frame: 2 years
Population: Target Ta, G1-G2 Population: patients who had 4 or fewer tumors that were ≤ 3.5 cm each at the time of randomization and who had subsequent histological confirmation from the central pathology lab that the tumors resected at the time of randomization were Ta, Grade 1 or 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apaziquone | Time to Recurrence | 18.3 months | Standard Error 0.47 |
| Placebo | Time to Recurrence | 16.7 months | Standard Error 0.55 |
p-value: 0.041295% CI: [0.59, 0.99]Log Rank