Assessment of Efficacy and Safety of Durvalumab Plus BCG Compared to the Standard Therapy With BCG in Non-muscle Invasive Bladder Cancer

Phase 3Active Not RecruitingNCT03528694

AstraZeneca1,018 enrolled

Overview

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

Patients will be randomized in a 1:1:1 ratio to receive treatment with Durvalumab + BCG combination therapies, or Standard of Care (SoC) therapy.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,018

Conditions

Non-muscle-invasive Bladder Cancer

Interventions

Durvalumab (MEDI4736)BIOLOGICAL

Investigational product

Bacillus Calmette-Guerin (BCG)BIOLOGICAL

Standard of care

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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 exclusion criteria are fulfilled: * Evidence of muscle-invasive, locally advanced, metastatic, and/or extra vesical bladder cancer (ie, T2, T3, T4, and / or stage IV) * Concurrent extravesical (ie, urethra, ureter, or renal pelvis), non-muscle-invasive transitional cell carcinoma of the urothelium * Previous investigational product (IP) assignment in the present study * Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer related conditions (eg, hormone replacement therapy) is acceptable. Chemotherapy for previous instances of NMIBC is acceptable. * Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician * Patients with celiac disease controlled by diet alone * History of another primary malignancy except for * Malignancy treated with curative intent and with no known active disease ≥ 2 years before the first dose of IP and of low potential risk for recurrence during the study period * Adequately treated nonmelanoma skin cancer or lentigo maligna withoutevidence of disease * Adequately treated CIS without evidence of disease * Prostate cancer (tumor/node/metastasis stage) of stage ≤ T2cN0M0 without biochemical recurrence or progression that in the opinion of the Investigator does not require active intervention * Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. 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, computed tomography \[CT\] scan premedication)

Locations (120)

Outcomes

Primary Outcomes

The efficacy of Durvalumab + BCG (induction plus maintenance) combination therapy compared to SoC in terms of Disease free survival (DFS) in patients with NMIBC

Disease-free survival using Investigator disease assessments.

Time frame: Up to 4 years

Secondary Outcomes

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

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.

Time frame: Up to 4 years

To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to BCG (induction and maintenance) alone in terms of OS5

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

Time frame: Up to 7 years

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

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.

Time frame: Up to 7 years

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

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Research Site

Auchenflower, Australia

Research Site

Box Hill, Australia

Research Site

Brisbane, Australia

Research Site

Kogarah, Australia

Research Site

Orange, Australia

Research Site

Parkville, Australia

Research Site

Westmead, Australia

Research Site

Wollongong, Australia

Research Site

Graz, Austria

Research Site

Innsbruck, Austria

...and 110 more locations

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.

Time frame: Up to 4 years

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

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.

Time frame: Up to 4 years

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

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.

Time frame: Up to 7 years

To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of Disease-free survival

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.

Time frame: Up to 7 years

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

Time frame: Up to 24 months

To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of OS5

Time frame: up to 5 years

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

Time frame: Up to 7 years

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

Time frame: Up to 7 years

To assess the efficacy of durvalumab + BCG (induction only) combination therapy compared to BCG (induction and maintenance) alone in terms of time to cystectomy

Time frame: Up to 7 years

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

Time frame: Up to 7 years

To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of Disease-free survival

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.

Time frame: Up to 4 years

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

Time frame: Up to 24 months

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

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)

Time frame: Up to 7 years

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

Time frame: up to 5 years

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

Time frame: up to 5 yeas

To assess the efficacy of durvalumab + BCG (induction and maintenance) combination therapy compared to durvalumab + BCG (induction only) in terms of time to cystectomy

Time frame: up to 5 years

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

Time frame: up to 5 years

Complete response rate (CRR) at 6 months using Investigator disease assessments

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.

Time frame: up to 6 months

EORTC QLQ-C30 and EORTC QLQ-NMIBC24

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

Time frame: up to 5 years

PRO version of the CTCAE with approximately 19 items (PRO-CTCAE) symptoms in countries where language is available

To assess patient-reported treatment tolerability directly using specific PRO-CTCAE symptoms

Time frame: up to 5 years

PK serum concentration of durvalumab

To assess the PK of durvalumab when used in combination with BCG treatment

Time frame: up to 5 years

Presence of ADAs for durvalumab

To investigate the immunogenicity of durvalumab when used in combination with BCG treatment

Time frame: up to 5 years