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

A Phase III Randomized, Open-Label, Multi-Center, Global Study of Durvalumab and Bacillus Calmette-Guerin (BCG) Administered as Combination Therapy Versus BCG Alone in High-Risk, BCG Naïve Non-Muscle Invasive Bladder Cancer Patients

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

Study Overview

• Status: Active, not recruiting
• Conditions: Non-muscle-invasive Bladder Cancer
• Intervention / Treatment: Biological: Durvalumab (MEDI4736); Biological: Bacillus Calmette-Guerin (BCG)

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.

• Study Type: Interventional
• Enrollment (Actual): 1018
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Auchenflower, Australia, 4066
    • Research Site
  • Box Hill, Australia, 3128
    • Research Site
  • Brisbane, Australia, 4122
    • Research Site
  • Kogarah, Australia, 2217
    • Research Site
  • Orange, Australia, 2800
    • Research Site
  • Parkville, Australia, 3000
    • Research Site
  • Westmead, Australia, 2145
    • Research Site
  • Wollongong, Australia, 2500
    • Research Site
• Austria
  • Graz, Austria, 8036
    • Research Site
  • Innsbruck, Austria, 6020
    • Research Site
  • Linz, Austria, 4020
    • Research Site
  • Salzburg, Austria, 5020
    • Research Site
  • Wien, Austria, 1090
    • Research Site
• Belgium
  • Brussels, Belgium, 1070
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Roeselare, Belgium, 8800
    • Research Site
• Canada
  • Quebec, Canada, G1J 1Z4
    • Research Site
  • Ontario
    • Kingston, Ontario, Canada, K7L 3J7
      • Research Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • Research Site
    • Montreal, Quebec, Canada, H2X 3E4
      • Research Site
• France
  • Amiens, France, 80480
    • Research Site
  • Angers Cedex 01, France, 49033
    • Research Site
  • Bordeaux Cedex, France, 33076
    • Research Site
  • LYON cedex 03, France, 69437
    • Research Site
  • Marseille, France, 13003
    • Research Site
  • Montpellier CEDEX 5, France, 34295
    • Research Site
  • Strasbourg Cedex, France, 67091
    • Research Site
  • Suresnes Cedex, France, 92151
    • Research Site
• Germany
  • Berlin, Germany, 10117
    • Research Site
  • Duisburg, Germany, 47169
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Heidelberg, Germany, 69120
    • Research Site
  • Köln, Germany, 50968
    • Research Site
  • Marburg, Germany, 35043
    • Research Site
  • Mettmann, Germany, 40822
    • Research Site
  • Mühlheim An Der Ruhr, Germany, 45468
    • Research Site
  • München, Germany, 81377
    • Research Site
  • Münster, Germany, 48149
    • Research Site
  • Nürtingen, Germany, 72622
    • Research Site
  • Wesel, Germany, 46483
    • Research Site
  • Würselen, Germany, 52146
    • Research Site
  • Zirndorf, Germany, 90513
    • Research Site
• Japan
  • Bunkyo-ku, Japan, 113-8603
    • Research Site
  • Fukuoka, Japan, 812-8582
    • Research Site
  • Hirosaki-shi, Japan, 036-8563
    • Research Site
  • Kanazawa-shi, Japan, 920-8641
    • Research Site
  • Kita-gun, Japan, 761-0793
    • Research Site
  • Koshigaya-shi, Japan, 343-8555
    • Research Site
  • Koto-ku, Japan, 135-8550
    • Research Site
  • Matsuyama-shi, Japan, 791-0280
    • Research Site
  • Miyazaki-city, Japan, 889-1692
    • Research Site
  • Nagasaki-shi, Japan, 852-8501
    • Research Site
  • Nagoya-shi, Japan, 467-0001
    • Research Site
  • Okayama-shi, Japan, 700-8558
    • Research Site
  • Osaka-shi, Japan, 541-8567
    • Research Site
  • Osaka-shi, Japan, 545-8586
    • Research Site
  • Osakasayama-shi, Japan, 589-8511
    • Research Site
  • Sapporo-shi, Japan, 060-8543
    • Research Site
  • Shinjuku-ku, Japan, 160-8582
    • Research Site
  • Toyama-shi, Japan, 930-0194
    • Research Site
  • Tsukuba-shi, Japan, 305-8576
    • Research Site
  • Yokohama-shi, Japan, 232-0024
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Research Site
  • Breda, Netherlands, 4818 CK
    • Research Site
  • Utrecht, Netherlands, 3543 AZ
    • Research Site
• Poland
  • Białystok, Poland, 15-950
    • Research Site
  • Gdańsk, Poland, 80-214
    • Research Site
  • Grudziądz, Poland, 86-300
    • Research Site
  • Koszalin, Poland, 75-581
    • Research Site
  • Piotrków Trybunalski, Poland, 97-300
    • Research Site
  • Poznań, Poland, 61-731
    • Research Site
  • Warszawa, Poland, 02-781
    • Research Site
  • Warszawa, Poland, 02-005
    • Research Site
  • Wroclaw, Poland, 53-413
    • Research Site
  • Wrocław, Poland, 50-556
    • Research Site
• Russian Federation
  • Ivanovo, Russian Federation, 153040
    • Research Site
  • Krasnoyarsk, Russian Federation, 660133
    • Research Site
  • Moscow, Russian Federation, 125367
    • Research Site
  • Moscow, Russian Federation, 115280
    • Research Site
  • Moscow, Russian Federation, 105077
    • Research Site
  • Nizhniy Novgorod, Russian Federation, 603074
    • Research Site
  • Obninsk, Russian Federation, 249036
    • Research Site
  • Omsk, Russian Federation, 644013
    • Research Site
  • Saint Petersburg, Russian Federation, 195271
    • Research Site
  • Saint-Petersburg, Russian Federation, 194354
    • Research Site
  • St Petersburg, Russian Federation, 194044
    • Research Site
  • St. Petersburg, Russian Federation, 197758
    • Research Site
  • St. Petersburg, Russian Federation, 194017
    • Research Site
  • St.Petersburg, Russian Federation, 191014
    • Research Site
  • Vologda, Russian Federation, 160012
    • Research Site
  • Yaroslavl, Russian Federation, 150054
    • Research Site
• Spain
  • Badajoz, Spain, 06008
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 08025
    • Research Site
  • Barcelona, Spain, 8003
    • Research Site
  • Barcelona, Spain, 08208
    • Research Site
  • Elche(Alicante), Spain, 03202
    • Research Site
  • Madrid, Spain, 28046
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Madrid, Spain, 08035
    • Research Site
  • Malaga, Spain, 29010
    • Research Site
  • Oviedo, Spain, 33011
    • Research Site
  • Pamplona, Spain, 31008
    • Research Site
  • Pozuelo de Alarcon, Spain, 28223
    • Research Site
  • Sevilla, Spain, 41009
    • Research Site
  • Sevilla, Spain, 41014
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
  • Valencia, Spain, 46014
    • Research Site
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Research Site
  • Glasgow, United Kingdom, G12 0YN
    • Research Site
  • Guildford, United Kingdom, CU2 7XX
    • Research Site
  • London, United Kingdom, NW1 2PG
    • Research Site
  • London, United Kingdom, SE1 9RT
    • Research Site
  • London, United Kingdom, E1 1BB
    • Research Site
  • Sheffield, United Kingdom, S10 2JF
    • Research Site
  • Southampton, United Kingdom, S016 6YD
    • Research Site
  • Taunton, United Kingdom, TA1 5DA
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Durvalumab plus BCG (induction + maintenance); Durvalumab (MEDI4736) plus Bacillus Calmette-Guerrin (BCG) combination therapy	Biological: Durvalumab (MEDI4736); Investigational product; Biological: Bacillus Calmette-Guerin (BCG); Standard of care
Experimental: Durvalumab plus BCG (induction only); Durvalumab (MEDI4736) plus Bacillus Calmette-Guerrin (BCG) combination therapy	Biological: Durvalumab (MEDI4736); Investigational product; Biological: Bacillus Calmette-Guerin (BCG); Standard of care
Active Comparator: BCG treatment (Standard of care therapy); Bacillus Calmette-Guerrin (BCG) standard of care treatment	Biological: Bacillus Calmette-Guerin (BCG); Standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The efficacy of Durvalumab + BCG (induction plus maintenance) therapy compare to SoC in terms of DFS after 24 months of last subject's last dose of IP		Up to 4 years
Disease-related symptoms and HRQoL in patients with NMIBC treated with Durvalumab + BCG combination therapies compared to SoC and compared to each other using the EORTC QLQ-C30 questionnaire	EORTC QLQ-C30 measures cancer patients' functioning (HRQoL) and symptoms for all cancer types and consists of functional, symptom and a global measure of health status scales	Up to 4 years
Patient-reported treatment tolerability using specific PRO CTCAE symptoms		Up to 4 years
The serum concentration of Durvalumab plus BCG combination therapies		Up to 4 years
The immunogenicity of Durvalumab when used in combination with BCG treatment assessed by descriptive summary of presence of ADAs	Serum will be tested for the presence of anti-drug antibodies.	Up to 4 years
The efficacy of Durvalumab + BCG (induction plus maintenance) therapy compare to SoC in terms of OS		Up to 7 years
The efficacy of Durvalumab + BCG (induction plus maintenance) combination therapy compared to SoC in terms of time to muscle invasive bladder cancer and/or metastatic disease		Up to 7 years
The efficacy of Durvalumab + BCG (induction only) combination therapy compared to SoC in terms of DFS after 24 months of last subject's last dose of IP		Up to 4 years
The efficacy of Durvalumab + BCG combination therapies compared to each other in terms of DFS after 24 months of last subject's last dose of IP		Up to 4 years
The efficacy of Durvalumab + BCG (induction only) combination therapy compared to SoC in terms of OS		Up to 7 years
The efficacy of Durvalumab + BCG combination therapies compared to each other in terms of OS		Up to 7 years
The efficacy of Durvalumab + BCG (induction only) combination therapy compared to SoC in terms of time to muscle invasive bladder cancer and/or metastatic disease		Up to 7 years
The efficacy of Durvalumab + BCG combination therapies compared to each other in terms of time to muscle invasive bladder cancer and/or metastatic disease		Up to 7 years
Disease-related symptoms and HRQoL in patients with NMIBC treated with Durvalumab + BCG combination therapies compared to SoC and compared to each other using the the EORTC QLQ NMIBC24 questionnaire	EORTC QLQ-NMIBC24 assesses disease-specific symptoms of patients with intermediate to high-risk NMIBC.	Up to 4 years
The efficacy of durvalumab + BCG combination therapy compared to SoC in terms of CRR for patients with CIS prior to study entry or at baseline cystoscopy	CRR at 6 months in patients with CIS prior to the study entry or at baseline cystoscopy	Up to 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of treatment-related adverse events as assessed by CTCAE v4.0 in patients receiving Durvalumab + BCG combination therapies compared to SoC	The safety and tolerability profile of Durvalumab + BCG combination therapies compared to SoC using vital signs, laboratory data, electrocardiograms (ECGs), and adverse event data.	Up to 4 years

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2018
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: February 28, 2018
• First Submitted That Met QC Criteria: May 10, 2018
• First Posted (Actual): May 18, 2018

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: PD-L1; NMIBC; BCG; OS; Durvalumab; MEDI4736; DFS
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Adjuvants, Immunologic; Durvalumab; BCG Vaccine
• Other Study ID Numbers: D419JC00001; 2017-002979-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes