Non-muscle-invasive Bladder Cancer
Conditions
Keywords
Durvalumab, BCG, MEDI4736, NMIBC, PD-L1, DFS, OS
Brief summary
This is a randomized, open-label, multi-center, global, phase III study to determine the efficacy and safety of Durvalumab + BCG combination therapy in the treatment of patients with non-muscle-invasive bladder cancer
Detailed description
Patients will be randomized in a 1:1:1 ratio to receive treatment with Durvalumab + BCG combination therapies, or Standard of Care (SoC) therapy.
Interventions
BIOLOGICALDurvalumab (MEDI4736)
Investigational product
BIOLOGICALBacillus Calmette-Guerin (BCG)
Standard of care
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
For inclusion in the study, patients should fulfill the following criteria: * Aged at least 18 years * BCG-naïve (patients who have not received prior intravesical BCG or who previously received but stopped BCG more than 3 years before study entry are eligible) * Local histological confirmation (based on pathology report) of high-risk transitional cell carcinoma of the urothelium of the urinary bladder confined to the mucosa or submucosa. A high risk tumor is defined as one of the following * T1 tumor * High grade/ G3 tumor * CIS * Multiple and recurrent and large (with diameter of largest tumor ≥3 cm) tumors (all conditions must be met in this point) * Complete resection of all Ta/T1 papillary disease prior to randomization, with the TURBT removing high-risk NMIBC performed not more than 4 months before randomization in the study. Patients with residual CIS after TURBT are eligible * No prior radiotherapy for bladder cancer * No prior exposure to immune-mediated therapy of cancer including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 antibodies. Patients who have been treated with anticancer vaccines will be excluded
Exclusion criteria
Patients should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The efficacy of Durvalumab + BCG (induction plus maintenance) combination therapy compared to SoC in terms of Disease free survival (DFS) in patients with NMIBC | Up to 4 years | Disease-free survival using Investigator disease assessments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to BCG (induction and maintenance) alone in terms of DFS 24 months | Up to 4 years | Proportion of patients alive and disease free at 24 months using Investigator disease assessments. DFS24 is defined as the proportion of patients alive and disease-free at 24 months after randomization, per Investigator disease assessment. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to BCG (induction and maintenance) alone in terms of OS5 | Up to 7 years | Overall survival at 5 years. 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). Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to BCG (induction and maintenance) alone in terms of any disease-free survival | Up to 7 years | Any disease-free survival using Investigator disease assessments. Any disease-free survival (aDFS) is defined similarly as DFS, except that aDFS includes recurrence of low/medium risk NMIBC. This will be based on Investigator disease assessments. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to BCG (induction and maintenance) alone in terms of Time to MIBC and/or Metastatic Disease | Up to 4 years | Time to MIBC and/or metastatic disease using Investigator disease assessments. Time to MIBC and/or metastatic disease is defined as the time from the date of randomization until the date of first documented MIBC and/or metastatic disease as assessed by Investigator. Time to MIBC and/or metastatic disease does not include deaths. If patients died without MIBC and/or metastatic disease, they will be censored at the time of death. All other censoring rules per DFS analysis will be applied including censoring patients with an event after 2 missed visits and patients with no evaluable disease assessments or no baseline data. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to BCG (induction and maintenance) alone with respect to time to cystectomy | Up to 4 years | Time to cystectomy using Investigator disease assessments. Time to cystectomy is defined as the time from the date of randomization until the date of cystectomy as reported by Investigator. Patients who died prior to cystectomy will be censored at the time of death. Patients who have not had a cystectomy at the time of analysis will be censored at the last recorded date on which the patient was known to be alive. No other censoring rules per the DFS analysis will be applied. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to BCG (induction and maintenance) alone in terms of time to development of upper tract urothelial carcinoma | Up to 7 years | Time to development of upper tract urothelial carcinoma using Investigator disease assessments. Time to development of upper tract urothelial carcinoma (TTUTUC) is defined as the time from the date of randomization until the date of development of upper tract urothelial carcinoma as assessed by Investigator using CT urography or ureteroscopy (less common). TTUTUC does not include deaths. Patients who died without upper tract urothelial carcinoma will be censored at the time of death. Other censoring rules per DFS analysis will be applied, including censoring patients with no baseline data but excluding censoring patients with an event after 2 missed visits as evaluation of the upper urinary tract is not part of regular disease assessment and is performed as clinically indicated. |
| To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of Disease-free survival | Up to 7 years | Any disease-free survival (aDFS) is defined similarly as DFS, except that aDFS includes recurrence of low/medium risk NMIBC. This will be based on Investigator disease assessments. |
| To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of patients alive and disease free at 24 months | Up to 24 months | Proportion of patients alive and disease free at 24 months using Investigator disease assessments. DFS24 is defined as the proportion of patients alive and disease-free at 24 months after randomization, per Investigator disease assessment |
| To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of OS5 | up to 5 years | Overall survival at 5 years. 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). |
| To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of any disease-free survival | Up to 7 years | Any disease-free survival using Investigator disease assessments. Any disease-free survival (aDFS) is defined similarly as DFS, except that aDFS includes recurrence of low/medium risk NMIBC. This will be based on Investigator disease assessments. |
| To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of Time to MIBC and/or metastatic disease | Up to 7 years | Time to MIBC and/or metastatic disease using Investigator disease assessments. Time to MIBC and/or metastatic disease is defined as the time from the date of randomization until the date of first documented MIBC and/or metastatic disease as assessed by Investigator. Time to MIBC and/or metastatic disease does not include deaths. If patients died without MIBC and/or metastatic disease, they will be censored at the time of death. All other censoring rules per DFS analysis will be applied including censoring patients with an event after 2 missed visits and patients with no evaluable disease assessments or no baseline data. |
| To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of time to cystectomy | Up to 7 years | Time to cystectomy using Investigator disease assessments. Time to cystectomy is defined as the time from the date of randomization until the date of cystectomy as reported by Investigator. Patients who died prior to cystectomy will be censored at the time of death. Patients who have not had a cystectomy at the time of analysis will be censored at the last recorded date on which the patient was known to be alive. No other censoring rules per the DFS analysis will be applied. |
| To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone time to development of upper tract urothelial carcinoma | Up to 7 years | Time to development of upper tract urothelial carcinoma using Investigator disease assessments. Time to development of upper tract urothelial carcinoma (TTUTUC) is defined as the time from the date of randomization until the date of development of upper tract urothelial carcinoma as assessed by Investigator using CT urography or ureteroscopy (less common). TTUTUC does not include deaths. Patients who died without upper tract urothelial carcinoma will be censored at the time of death. Other censoring rules per DFS analysis will be applied, including censoring patients with no baseline data but excluding censoring patients with an event after 2 missed visits as evaluation of the upper urinary tract is not part of regular disease assessment and is performed as clinically indicated. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of Disease-free survival | Up to 4 years | Disease-free survival using Investigator disease assessments.Any disease-free survival (aDFS) is defined similarly as DFS, except that aDFS includes recurrence of low/medium risk NMIBC. This will be based on Investigator disease assessments. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of Proportion of patients alive and disease free at 24 months | Up to 24 months | Proportion of patients alive and disease free at 24 months using Investigator disease assessments. DFS24 is defined as the proportion of patients alive and disease-free at 24 months after randomization, per Investigator disease assessment. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of Overall survival at 5 years | Up to 7 years | 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). The proportion of patients alive at 5 years (OS5) |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of any disease-free survival | up to 5 years | Any disease-free survival using Investigator disease assessments. Any disease-free survival (aDFS) is defined similarly as DFS, except that aDFS includes recurrence of low/medium risk NMIBC. This will be based on Investigator disease assessments. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of time to MIBC and/or metastatic disease | up to 5 yeas | Time to MIBC and/or metastatic disease using Investigator disease assessments. Time to MIBC and/or metastatic disease is defined as the time from the date of randomization until the date of first documented MIBC and/or metastatic disease as assessed by Investigator. Time to MIBC and/or metastatic disease does not include deaths. If patients died without MIBC and/or metastatic disease, they will be censored at the time of death. All other censoring rules per DFS analysis will be applied including censoring patients with an event after 2 missed visits and patients with no evaluable disease assessments or no baseline data. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of time to cystectomy | up to 5 years | Time to cystectomy using Investigator disease assessments. Time to cystectomy is defined as the time from the date of randomization until the date of cystectomy as reported by Investigator. Patients who died prior to cystectomy will be censored at the time of death. Patients who have not had a cystectomy at the time of analysis will be censored at the last recorded date on which the patient was known to be alive. No other censoring rules per the DFS analysis will be applied. |
| To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of Time to development of upper tract urothelial carcinoma | up to 5 years | Time to development of upper tract urothelial carcinoma using Investigator disease assessments. Time to development of upper tract urothelial carcinoma (TTUTUC) is defined as the time from the date of randomization until the date of development of upper tract urothelial carcinoma as assessed by Investigator using CT urography or ureteroscopy (less common). TTUTUC does not include deaths. Patients who died without upper tract urothelial carcinoma will be censored at the time of death. Other censoring rules per DFS analysis will be applied, including censoring patients with no baseline data but excluding censoring patients with an event after 2 missed visits as evaluation of the upper urinary tract is not part of regular disease assessment and is performed as clinically indicated. |
| Complete response rate (CRR) at 6 months using Investigator disease assessments | up to 6 months | To assess the efficacy of durvalumab + BCG combination therapy compared to BCG (induction and maintenance) for patients with CIS prior to study entry or at baseline cystoscopy. |
| EORTC QLQ-C30 and EORTC QLQ-NMIBC24 | up to 5 years | To assess disease-related symptoms and HRQoL in patients with NMIBC treated with durvalumab + BCG (induction and maintenance) combination therapy and durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone and compared to each other using the EORTC QLQ-C30 questionnaire and the EORTC QLQ-NMIBC24 questionnaire |
| PRO version of the CTCAE with approximately 19 items (PRO-CTCAE) symptoms in countries where language is available | up to 5 years | To assess patient-reported treatment tolerability directly using specific PRO-CTCAE symptoms |
| PK serum concentration of durvalumab | up to 5 years | To assess the PK of durvalumab when used in combination with BCG treatment |
| Presence of ADAs for durvalumab | up to 5 years | To investigate the immunogenicity of durvalumab when used in combination with BCG treatment |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Japan, Netherlands, Poland, Russia, Spain, United Kingdom
Outcome results
None listed