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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 : April 21, 2023
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Description
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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).

Condition or disease Intervention/treatment Phase
Unresectable Locally Advanced Urothelial Cancer Metastatic Urothelial Cancer Drug: Durvalumab Drug: Tremelimumab Drug: Cisplatin + Gemcitabine Drug: Carboplatin + Gemcitabine Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1292 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Actual Study Start Date : September 27, 2018
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : October 30, 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arms and Interventions
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Arm Intervention/treatment
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
 Drug: Durvalumab
Durvalumab IV (intravenous infusion)
Other Name: MEDI4736

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.
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
 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.
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
 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.


Outcome Measures
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Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: approximately 5 years ]
    Additional analysis beyond the primary endpoint

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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


Other Outcome Measures:
  1. 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

  2. To assess pharmacokinetics of Durvalumab and Tremelimumab [ Time Frame: approximately 5 years ]
    Serum concentrations of Durvalumab and Tremelimumab

  3. To assess immunogenicity of Durvalumab and Tremelimumab [ Time Frame: approximately 5 years ]
    Presence of anti-drug antibodies for Durvalumab and Tremelimumab


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03682068


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
More Information
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03682068    
Other Study ID Numbers: D933SC00001
First Posted: September 24, 2018    Key Record Dates
Last Update Posted: April 21, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
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
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
renal pelvis
ureters
urinary bladder
urethra
bladder cancer
Additional relevant MeSH terms:
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Carboplatin
Gemcitabine
Durvalumab
Tremelimumab
Antineoplastic Agents
 Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological