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Study of Durvalumab Given With Chemotherapy, Durvalumab in Combination With Tremelimumab Given With Chemotherapy, or Chemotherapy in Patients With Unresectable Urothelial Cancer (NILE)

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ClinicalTrials.gov Identifier: NCT03682068
Recruitment Status : Recruiting
First Posted : September 24, 2018
Last Update Posted : August 31, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE September 6, 2018
First Posted Date  ICMJE September 24, 2018
Last Update Posted Date August 31, 2020
Actual Study Start Date  ICMJE September 27, 2018
Estimated Primary Completion Date April 28, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
Overall Survival (OS) [ Time Frame: approximately 5 years ]
OS is defined as the time from the date of randomization until death due to any cause
Original Primary Outcome Measures  ICMJE
 (submitted: September 21, 2018)
  • Progression Free Survival (PFS) [ Time Frame: approximately 4 years ]
    PFS (per RECIST 1.1) will be defined as the time from the date of randomization until the date of first objective disease progression or death
  • Overall Survival (OS) [ Time Frame: approximately 4 years ]
    OS is defined as the time from the date of randomization until death due to any cause
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
  • Overall Survival (OS) [ Time Frame: approximately 5 years ]
    Additional analysis beyond the primary endpoint
  • Overall Survival at 24 months (OS24) [ Time Frame: 24 months ]
    The OS24 will be defined as the Kaplan-Meier estimate of OS at 24 months
  • Progression Free Survival (PFS) [ Time Frame: approximately 5 years ]
    PFS (per RECIST 1.1) will be defined as the time from the date of randomization until the date of first objective disease progression or death
  • Alive and Progression Free Survival at 12 months (APF12) [ Time Frame: 12 months ]
    The APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1) at 12 months
  • Objective Response Rate (ORR) [ Time Frame: approximately 5 years ]
    ORR (per RECIST 1.1) is defined as the number (%) of patients with at least 1 visit response of complete response or partial response and will be based on a subset of all randomized patients
  • Duration of Response (DoR) [ Time Frame: approximately 5 years ]
    DoR (per RECIST 1.1) will be defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression
  • Disease Control Rate (DCR) [ Time Frame: approximately 5 years ]
    DCR is defined as the proportion of subjects with the best overall response of complete response, partial response or stable disease per RECIST 1.1
  • Time from randomization to second (PFS2) [ Time Frame: approximately 5 years ]
    PFS2 will be defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the PFS endpoint or death
  • To assess disease-related symptoms, physical functioning, and other Health-related quality of life [ Time Frame: approximately 5 years ]
    Collection of patient reported outcome questionnaires
Original Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2018)
  • Overall Survival at 24 months (OS24) [ Time Frame: 24 months ]
    The OS24 will be defined as the Kaplan-Meier estimate of OS at 24 months
  • Alive and Progression Free Survival at 12 months (APF12) [ Time Frame: 12 months ]
    The APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1) at 12 months
  • Objective Response Rate (ORR) [ Time Frame: approximately 4 years ]
    ORR (per RECIST 1.1) is defined as the number (%) of patients with at least 1 visit response of complete response or partial response and will be based on a subset of all randomized patients
  • Duration of Response (DoR) [ Time Frame: approximately 4 years ]
    DoR (per RECIST 1.1) will be defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression
  • Disease Control Rate (DCR) [ Time Frame: approximately 4 years ]
    DCR is defined as the proportion of subjects with the best overall response of complete response, partial response or stable disease per RECIST 1.1
  • Time from randomization to second (PFS2) [ Time Frame: approximately 4 years ]
    PFS2 will be defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the PFS endpoint or death
  • To assess disease-related symptoms, physical functioning, and other Health-related quality of life [ Time Frame: Approximately 4 years ]
    Collection of patient reported outcome questionnaires
Current Other Pre-specified Outcome Measures
 (submitted: July 7, 2020)
  • To assess safety using a summary of adverse events. [ Time Frame: approximately 5 years ]
    Adverse Events (both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by patient. The number of patients experiencing each Adverse Event will be summarized by treatment arm and CTCAE grade
  • To assess pharmacokinetics of Durvalumab and Tremelimumab [ Time Frame: approximately 5 years ]
    Serum concentrations of Durvalumab and Tremelimumab
  • To assess immunogenicity of Durvalumab and Tremelimumab [ Time Frame: approximately 5 years ]
    Presence of anti-drug antibodies for Durvalumab and Tremelimumab
Original Other Pre-specified Outcome Measures
 (submitted: September 21, 2018)
  • To assess safety using a summary of adverse events. [ Time Frame: approximately 4 years ]
    Adverse Events (both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by patient. The number of patients experiencing each Adverse Event will be summarized by treatment arm and CTCAE grade
  • To assess pharmacokinetics of Durvalumab and Tremelimumab [ Time Frame: approximately 4 years ]
    Serum concentrations of Durvalumab and Tremelimumab
  • To assess immunogenicity of Durvalumab and Tremelimumab [ Time Frame: approximately 4 years ]
    Presence of anti-drug antibodies for Durvalumab and Tremelimumab
 
Descriptive Information
Brief Title  ICMJE Study of Durvalumab Given With Chemotherapy, Durvalumab in Combination With Tremelimumab Given With Chemotherapy, or Chemotherapy in Patients With Unresectable Urothelial Cancer
Official Title  ICMJE A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line Durvalumab in Combination With Standard of Care Chemotherapy and Durvalumab in Combination With Tremelimumab and Standard of Care Chemotherapy Versus Standard of Care Chemotherapy Alone in Patients With Unresectable Locally Advanced or Metastatic Urothelial Cancer.
Brief Summary This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of combining durvalumab ± tremelimumab with standard of care (SoC) chemotherapy (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) followed by durvalumab monotherapy versus SoC alone as first-line chemotherapy in patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Unresectable Locally Advanced Urothelial Cancer
  • Metastatic Urothelial Cancer
Intervention  ICMJE
  • Drug: Durvalumab
    Durvalumab IV (intravenous infusion)
    Other Name: MEDI4736
  • Drug: Tremelimumab
    Tremelimumab IV (intravenous infusion)
  • Drug: Cisplatin + Gemcitabine
    Cisplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.
  • Drug: Carboplatin + Gemcitabine
    Carboplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.
Study Arms  ICMJE
  • Experimental: Durvalumab in Combination with SoC Chemotherapy

    Durvalumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks.

    All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles:

    • cisplatin+ gemcitabine
    • If the patient is cisplatin-ineligible, carboplatin + gemcitabine
    Interventions:
    • Drug: Durvalumab
    • Drug: Cisplatin + Gemcitabine
    • Drug: Carboplatin + Gemcitabine
  • Experimental: Durvalumab in Combination with Tremelimumab+SoC Chemotherapy

    Durvalumab and Tremelimumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks

    Tremelimumab will be provided for 4 cycles.

    All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles:

    • cisplatin+ gemcitabine
    • If the patient is cisplatin-ineligible, carboplatin + gemcitabine
    Interventions:
    • Drug: Durvalumab
    • Drug: Tremelimumab
    • Drug: Cisplatin + Gemcitabine
    • Drug: Carboplatin + Gemcitabine
  • Active Comparator: SoC Chemotherapy

    Patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles:

    • cisplatin+ gemcitabine
    • If the patient is cisplatin-ineligible, carboplatin + gemcitabine
    Interventions:
    • Drug: Cisplatin + Gemcitabine
    • Drug: Carboplatin + Gemcitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 7, 2020)
1434
Original Estimated Enrollment  ICMJE
 (submitted: September 21, 2018)
885
Estimated Study Completion Date  ICMJE March 29, 2024
Estimated Primary Completion Date April 28, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra)
  • Patients who have not been previously treated with first-line chemotherapy. Patients who have received prior definitive chemoradiation, adjuvant or neoadjuvant treatment for locally advanced disease are eligible provided that progression to locally advanced or metastatic disease has occurred >12 months from the last therapy [for chemoradiation and adjuvant treatment] or >12 months from the last surgery [for neoadjuvant treatment].
  • At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion at baseline.
  • World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrolment
  • Adequate organ and marrow function as defined in the protocol
  • Life expectancy ≥12 weeks in the opinion of the investigator
  • Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients.

Key Exclusion Criteria:

  • Prior exposure to immune-mediated therapy (with exclusion of Bacillus Calmette Guerin), including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD L1, or anti-PD-L2 antibodies, except therapeutic anticancer vaccines, which are permitted. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment.
  • No severe concomitant condition that requires immunosuppression medication
  • Untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Patients who may be eligible for or are being considered for radical resection during the course of the study.
  • Any medical contraindications to platinum (cisplatin or carboplatin) based doublet chemotherapy and/or known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Australia,   Brazil,   Bulgaria,   Canada,   China,   Czechia,   Hungary,   India,   Israel,   Italy,   Japan,   Korea, Republic of,   Philippines,   Poland,   Russian Federation,   Spain,   Taiwan,   Thailand,   Turkey,   United States,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03682068
Other Study ID Numbers  ICMJE D933SC00001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
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 rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP