Muscle Invasive Bladder Cancer
Conditions
Keywords
Bladder Cancer, Immunotherapy, PD-L1, Durvalumab (MEDI4736)
Brief summary
A Global Study to Determine the Efficacy and Safety of Durvalumab in Combination with Gemcitabine+Cisplatin for Neoadjuvant Treatment and Durvalumab Alone for Adjuvant Treatment in Patients with Muscle-Invasive Bladder Cancer
Interventions
DRUGDurvalumab
Anti- PD-L1 Antibody
DRUGCisplatin
Chemotherapy Agent
DRUGGemcitabine
Chemotherapy agent
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Inclusion: * Patient resectable muscle-invasive bladder cancer with clinical stage T2-T4aN0/1M0 with transitional and mixed transitional cell histology * Patients must be planning to undergo a radical cystectomy * Patients who have not received prior systemic chemotherapy or immunotherapy for treatment of MIBC * ECOG performance status of 0 or 1 * Must have a life expectancy of at least 12 weeks at randomization Exclusion: * Evidence of lymph node (N2-N3) or metastatic (M1) disease at time of screening. * Prior pelvic radiotherapy treatment within 2 years of randomization to study * Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin \[BCG\]), including but not limited to other anti-CTLA-4, anti-PD-1, anti PD-L1, or anti-PD-L2 antibodies. * Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product (IP). The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection); Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent; Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) * Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. * Uncontrolled intercurrent illness * Active infection including Tuberculosis, Hepatitis B, Hepatitis C, and Human Immunodeficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response (pCR) Rates at Time of Cystectomy | Up to 6 months | pCR rate is defined as the proportion of patients whose pathological staging was T0N0M0 as assessed per central pathology review using specimens obtained via radical cystectomy following the neoadjuvant treatment. The denominator for pCR will be the number of patients in the FAS. |
| Event-free Survival (EFS) Per Central Review Defined as Time From Randomization to Event | Up to 48 months | EFS is defined as the time from randomization to the first recurrence of disease post radical cystectomy, time of first documented progression in patients who were medically precluded for radical cystectomy, or time of expected surgery in patients who refuse to undergo a radical cystectomy or failure to undergo a radical cystectomy in participants with residual disease, or the time of death due to any cause, whichever occurs first |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival at 24 Months (EFS24) Per Central Review Defined as Time From Randomization to Event | Up to 24 months | EFS24 is defined as the Kaplan-Meier estimate of EFS at 24 months after randomization, as assessed per blinded independent central review or by central pathology review if a biopsy is required for a suspected new lesion, and per local investigator or local biopsy review if a biopsy is required for a suspected new lesion |
| Proportion of Patients Who Undergo Cystectomy | Up to 6 months | The proportion of patients who undergo cystectomy is defined as the proportion patients who undergo radical cystectomy after the neoadjuvant treatment. The denominator will be patients in the FAS. |
| Overall Survival | Up to 65 months | OS is defined as the time from the date of randomization until death due to any cause regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy (i.e., date of death or censoring - date of randomization + 1) |
| Metastasis-free Survival Per Investigator Assessment or Local Biopsy Review. | Up to 48 months | MFS is defined as the time from date of randomization until the first recognition of distant metastases or death, whichever occurs first |
| Disease-specific Survival Per Investigator Assessment or Local Biopsy Review. | Up to 48 months | DSS is defined as the time from the date of randomization until death due to bladder cancer |
| Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | Up to 12 months | Whole blood samples for assessing ADA for durvalumab in serum were collected from patients undergoing durvalumab treatment, following the specified assessment schedule. ADA prevalence is the proportion of patients with a positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA includes both treatment-induced and treatment-boosted ADA. Its incidence is the proportion of patients with treatment-emergent ADA positivity. Treatment-boosted ADA refers to a baseline-positive ADA titer that increased ≥4-fold during the study. Persistently positive patients have at least two post-baseline ADA-positive readings, with at least 16 weeks between the first and last, or an ADA-positive result at the final assessment. This includes baseline-positive patients meeting these criteria. Transiently positive is defined by at least one post-baseline ADA-positive reading without being persistently positive, including baseline-positive patients meeting these terms. |
Countries
Australia, Belgium, Brazil, Canada, Chile, Czechia, France, Germany, Israel, Italy, Japan, Netherlands, Philippines, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States, Vietnam
Participant flow
Recruitment details
Patients randomized to treatments Arm 1 or Arm 2, will be treated according to their renal function. Recruitment for borderline renal function patients will be limited to up to 20% of the targeted global population. Recruitment for patients with T2N0 disease will be limited to approximately 40% of the targeted global population; once the 40% cap has been reached, only T2-4N1M0 and T3-4N0M0 patients will be allowed to be enrolled onto the study. Completion status is reported by treatment phase
Participants by arm
| Arm | Count |
|---|---|
| Durvalumab + Gemcitabine + Cisplatin Treatments and dosing regimens: Durvalumab 1500 mg IV q3w (neoadjuvant) 1500 mg IV q4w (adjuvant post-radical cystectomy) Day 1 and Day 8 (gemcitabine 1000 mg/m2 IV) of each 21-day cycle (neoadjuvant) Day 1 and Day 8 (cisplatin 35mg/m2 IV) or Day 1 (cisplatin 70 mg/m2 IV) each 21-day cycle (neoadjuvant) Dosing will be adjusted based on renal function | 533 |
| Gemcitabine + Cisplatin Treatments and dosing regimens: Day 1 and Day 8 (gemcitabine1000 mg/m2 IV) of each 21-day cycle (neoadjuvant) Day 1 and Day 8 (cisplatin 35mg/m2 IV) or Day 1 (cisplatin 70 mg/m2 IV) each 21-day cycle (neoadjuvant) Dosing will be adjusted based on renal function | 530 |
| Total | 1,063 |
Baseline characteristics
| Characteristic | Total | Durvalumab + Gemcitabine + Cisplatin | Gemcitabine + Cisplatin |
|---|---|---|---|
| Age, Continuous | 64.4 Years STANDARD_DEVIATION 8.9 | 64.1 Years STANDARD_DEVIATION 8.9 | 64.6 Years STANDARD_DEVIATION 8.9 |
| Race/Ethnicity, Customized ASIAN | 297 Participants | 152 Participants | 145 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 10 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized HISPANIC OR LATINO | 85 Participants | 44 Participants | 41 Participants |
| Race/Ethnicity, Customized MISSING | 36 Participants | 14 Participants | 22 Participants |
| Race/Ethnicity, Customized NOT HISPANIC OR LATINO | 960 Participants | 483 Participants | 477 Participants |
| Race/Ethnicity, Customized OTHER | 8 Participants | 7 Participants | 1 Participants |
| Race/Ethnicity, Customized WHITE | 712 Participants | 354 Participants | 358 Participants |
| Sex: Female, Male Female | 193 Participants | 96 Participants | 97 Participants |
| Sex: Female, Male Male | 870 Participants | 437 Participants | 433 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 27 / 533 | 29 / 526 |
| other Total, other adverse events | 522 / 530 | 511 / 526 |
| serious Total, serious adverse events | 326 / 530 | 287 / 526 |
Outcome results
Primary
Event-free Survival (EFS) Per Central Review Defined as Time From Randomization to Event
EFS is defined as the time from randomization to the first recurrence of disease post radical cystectomy, time of first documented progression in patients who were medically precluded for radical cystectomy, or time of expected surgery in patients who refuse to undergo a radical cystectomy or failure to undergo a radical cystectomy in participants with residual disease, or the time of death due to any cause, whichever occurs first
Time frame: Up to 48 months
Population: The full analysis set (FAS) includes all randomized patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Event-free Survival (EFS) Per Central Review Defined as Time From Randomization to Event | NA months |
| Gemcitabine + Cisplatin | Event-free Survival (EFS) Per Central Review Defined as Time From Randomization to Event | 46.1 months |
p-value: <0.000195.877% CI: [0.554, 824]Log Rank
Primary
Pathologic Complete Response (pCR) Rates at Time of Cystectomy
pCR rate is defined as the proportion of patients whose pathological staging was T0N0M0 as assessed per central pathology review using specimens obtained via radical cystectomy following the neoadjuvant treatment. The denominator for pCR will be the number of patients in the FAS.
Time frame: Up to 6 months
Population: Full Analysis Set (Intention to Treat): includes all randomized subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Pathologic Complete Response (pCR) Rates at Time of Cystectomy | 199 Participants |
| Gemcitabine + Cisplatin | Pathologic Complete Response (pCR) Rates at Time of Cystectomy | 146 Participants |
p-value: 0.000595% CI: [1.227, 2.084]Regression, Logistic
Secondary
Disease-specific Survival Per Investigator Assessment or Local Biopsy Review.
DSS is defined as the time from the date of randomization until death due to bladder cancer
Time frame: Up to 48 months
Population: The full analysis set (FAS) Intention to treat included all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Disease-specific Survival Per Investigator Assessment or Local Biopsy Review. | NA months |
| Gemcitabine + Cisplatin | Disease-specific Survival Per Investigator Assessment or Local Biopsy Review. | NA months |
p-value: 0.008195% CI: [0.516, 0.907]Log Rank
Secondary
Event-free Survival at 24 Months (EFS24) Per Central Review Defined as Time From Randomization to Event
EFS24 is defined as the Kaplan-Meier estimate of EFS at 24 months after randomization, as assessed per blinded independent central review or by central pathology review if a biopsy is required for a suspected new lesion, and per local investigator or local biopsy review if a biopsy is required for a suspected new lesion
Time frame: Up to 24 months
Population: The full analysis set (FAS) Intention to treat included all randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Event-free Survival at 24 Months (EFS24) Per Central Review Defined as Time From Randomization to Event | 67.8 Percentage of participants |
| Gemcitabine + Cisplatin | Event-free Survival at 24 Months (EFS24) Per Central Review Defined as Time From Randomization to Event | 59.8 Percentage of participants |
p-value: 0.002195% CI: [0.62, 0.9]Chi-squared
Secondary
Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA)
Whole blood samples for assessing ADA for durvalumab in serum were collected from patients undergoing durvalumab treatment, following the specified assessment schedule. ADA prevalence is the proportion of patients with a positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA includes both treatment-induced and treatment-boosted ADA. Its incidence is the proportion of patients with treatment-emergent ADA positivity. Treatment-boosted ADA refers to a baseline-positive ADA titer that increased ≥4-fold during the study. Persistently positive patients have at least two post-baseline ADA-positive readings, with at least 16 weeks between the first and last, or an ADA-positive result at the final assessment. This includes baseline-positive patients meeting these criteria. Transiently positive is defined by at least one post-baseline ADA-positive reading without being persistently positive, including baseline-positive patients meeting these terms.
Time frame: Up to 12 months
Population: The ADA analysis set includes all participants who had non-missing baseline ADA and at least one non-missing post-baseline ADA result.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | ADA positive at any visit (ADA prevalence) | 37 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | Treatment-emergent ADA positive (ADA Incidence) | 8 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | Treatment-boosted ADA | 1 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | Treatment-induced ADA (Positive Post-baseline only) | 7 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | ADA Positive at Baseline only | 29 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | ADA Positive Post-baseline and Positive at Baseline | 1 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | Persistently Positive | 4 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | Transiently Positive | 4 Participants |
| Durvalumab + Gemcitabine + Cisplatin | Immunogenicity of Durvalumab When Used in Combination With Gemcitabine/Cisplatin as Measured by Presence of Antidrug Antibodies (ADA) | nAb Positive at any visit | 6 Participants |
Secondary
Metastasis-free Survival Per Investigator Assessment or Local Biopsy Review.
MFS is defined as the time from date of randomization until the first recognition of distant metastases or death, whichever occurs first
Time frame: Up to 48 months
Population: The full analysis set (FAS) Intention to treat included all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Metastasis-free Survival Per Investigator Assessment or Local Biopsy Review. | NA Months |
| Gemcitabine + Cisplatin | Metastasis-free Survival Per Investigator Assessment or Local Biopsy Review. | NA Months |
p-value: 0.000295% CI: [0.541, 0.826]Log Rank
Secondary
Overall Survival
OS is defined as the time from the date of randomization until death due to any cause regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy (i.e., date of death or censoring - date of randomization + 1)
Time frame: Up to 65 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Overall Survival | NA Months |
| Gemcitabine + Cisplatin | Overall Survival | NA Months |
p-value: 0.010698.457% CI: [0.563, 0.985]Log Rank
Secondary
Proportion of Patients Who Undergo Cystectomy
The proportion of patients who undergo cystectomy is defined as the proportion patients who undergo radical cystectomy after the neoadjuvant treatment. The denominator will be patients in the FAS.
Time frame: Up to 6 months
Population: The full analysis set (FAS) Intention to treat included all randomized patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Durvalumab + Gemcitabine + Cisplatin | Proportion of Patients Who Undergo Cystectomy | 469 Participants |
| Gemcitabine + Cisplatin | Proportion of Patients Who Undergo Cystectomy | 441 Participants |
p-value: 0.026595% CI: [1.047, 2.095]Regression, Logistic