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Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer

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ClinicalTrials.gov Identifier: NCT02516241
Recruitment Status : Recruiting
First Posted : August 5, 2015
Last Update Posted : September 6, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE July 13, 2015
First Posted Date  ICMJE August 5, 2015
Last Update Posted Date September 6, 2019
Actual Study Start Date  ICMJE November 2, 2015
Estimated Primary Completion Date September 23, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 5, 2017)
  • To assess the efficacy of MEDI4736 + tremelimumab combination therapy versus SoC in terms of OS in patients with unresectable Stage IV UC [ Time Frame: Up to 4 years ]
  • To assess the efficacy of MEDI4736 monotherapy versus SoC in terms of OS in patients with unresectable Stage IV PD-L1- High UC [ Time Frame: up to 4 years ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
To assess PFS of MEDI4736 in combination with tremelimumab to standard of care (SoC) chemotherapy
Change History Complete list of historical versions of study NCT02516241 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 5, 2017)
  • To assess the efficacy of MEDI4736 monotherapy compared to SoC in terms of PFS in patients with PD-L1-High UC [ Time Frame: 4 years ]
  • To assess the efficacy of MEDI4736 + tremelimumab combination therapy versus SoC in terms of PFS in patients with UC [ Time Frame: 4 years ]
  • To further assess the efficacy of MEDI4736 + tremelimumab combination therapy compared to SoC in terms of ORR [ Time Frame: 4 years ]
  • To further assess the efficacy of MEDI4736 monotherapy compared to SoC in terms of ORR [ Time Frame: 4 years ]
  • To assess disease-related symptoms and HRQoL in UC patients treated with MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy compared with SoC and each other using the FACT-BL questionnaire [ Time Frame: 4 years ]
  • To assess the serum concentration of MEDI4736/tremelimumab of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy [ Time Frame: up to 6 months ]
  • To investigate the immunogenicity of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy [ Time Frame: 4 years ]
  • To assess the objective response rate (ORR) of MEDI4736 monotherapy in patients who are not cisplatin-eligible [ Time Frame: 4 years ]
  • To assess the duration of response (DoR) of MEDI4736 monotherapy in patients who are not cisplatin-eligible [ Time Frame: 4 years ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
  • PFS in programmed death-ligand 1 (PD-L1)-negative patients [ Time Frame: Up to 3 years ]
    To assess PFS of MEDI4736 + tremelimumab to SoC chemotherapy, and to monotherapy in patients with PD-L1-negative
  • Overall survival (OS) [ Time Frame: Up to 4 years ]
    To assess OS of MEDI4736 + tremelimumab to SoC chemotherapy
  • Objective response rate (ORR) [ Time Frame: Up to 3 years ]
    To further assess ORR of MEDI4736 + tremelimumab to SoC chemotherapy
  • Functional Assessment of Cancer Therapy - Bladder Cancer (FACT-BL) [ Time Frame: Up to 3 years ]
    To assess disease-related symptoms
  • Anti-drug Antibodies (ADAs) [ Time Frame: Up to 1 year ]
    To investigate the immunogenicity of monotherapy and MEDI4736 + tremelimumab
  • Incidence of adverse events [ Time Frame: Up to 15 months ]
    To assess the safety and tolerability
  • PFS [ Time Frame: Up to 3 years ]
    To assess PFS of MEDI4736 monotherapy to SoC chemotherapy
  • Pharmacokinetics of tremelimumab: Peak concentration (Cmax) [ Time Frame: Up to 1 year ]
    Peak concentration in MEDI4736 + tremelimumab combination therapy
  • Pharmacokinetics of MEDI4736: Trough concentration (Ctrough) [ Time Frame: Up to 1 year ]
    Trough concentration in MEDI4736 monotherapy and in combination with tremelimumab
  • Pharmacokinetics of tremelimumab: Trough concentration (Ctrough) [ Time Frame: Up to 1 year ]
    Trough concentration in MEDI4736 + tremelimumab combination therapy
  • Pharmacokinetics of MEDI4736: Peak concentration (Cmax) [ Time Frame: Up to 1 year ]
    Peak concentration in MEDI4736 monotherapy and in combination with tremelimumab
Current Other Pre-specified Outcome Measures
 (submitted: December 5, 2017)
To use summary of adverse events to assess the safety of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy compared to SoC [ Time Frame: 4 years ]
AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by patient. The number of patients experiencing each AE will be summarized by treatment arm and CTCAE grade.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer
Official Title  ICMJE A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination With Tremelimumab Versus Standard of Care Chemotherapy in Patients With Unresectable Stage IV Urothelial Cancer
Brief Summary A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Stage IV Urothelial Cancer
Detailed Description This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy and MEDI4736 (Durvalumab) in combination with tremelimumab versus SoC (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) first-line chemotherapy in treatment-naïve patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) and to allow sufficient flexibility for Investigators and patients to select the agents that reflect their normal clinical practice and national guidelines. The patients enrolled in the study will be randomized 1:1:1 to receive treatment with combination therapy, monotherapy, or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility). Patients will be treated with MEDI4736 (Durvalumab) or MEDI4736 (Durvalumab) with tremelimumab, or treated with SoC until progressive disease (PD) is confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients will be followed for up to 2 years.
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 Urothelial Cancer
Intervention  ICMJE
  • Drug: MEDI4736 (Durvalumab)
    IV infusion
  • Drug: Tremelimumab
    IV infusion
  • Drug: Cisplatin
    IV infusion
  • Drug: Carboplatin
    IV infusion
  • Drug: Gemcitabine
    IV infusion
Study Arms  ICMJE
  • Experimental: Combination Therapy
    MEDI4736 (Durvalumab) + Tremelimumab
    Interventions:
    • Drug: MEDI4736 (Durvalumab)
    • Drug: Tremelimumab
  • Experimental: Monotherapy
    MEDI4736 (Durvalumab)
    Intervention: Drug: MEDI4736 (Durvalumab)
  • Active Comparator: Standard of Care
    Standard of Care Chemotherapy Treatment
    Interventions:
    • Drug: Cisplatin
    • Drug: Carboplatin
    • Drug: 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: December 5, 2017)
1200
Original Estimated Enrollment  ICMJE
 (submitted: August 4, 2015)
525
Estimated Study Completion Date  ICMJE September 23, 2019
Estimated Primary Completion Date September 23, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma of the urothelium who have not been previously treated with first-line chemotherapy.
  • Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria: • Creatinine clearance (calculated or measured) <60 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or by measured 24-hour urine collection for determination • Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing loss • CTCAE Grade ≥2 peripheral neuropathy • New York Heart Association ≥Class III heart failure.
  • Tumor PD-L1 status, with Immunohistochemical (IHC) assay confirmed by a reference laboratory, must be known prior to randomization.

Exclusion Criteria:

  • Prior exposure to immune-mediated therapy, including but not limited to, other anti cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment.
  • History of allogenic organ transplantation that requires use of immunosuppressive agents.
  • Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion: • Patients with vitiligo or alopecia • Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement • Any chronic skin condition that does not require systemic therapy • Patients without active disease in the last 3 years may be included but only after consultation with AstraZeneca • Patients with celiac disease controlled by diet alone may be included but only after consultation with AstraZeneca.
  • Brain metastases or spinal cord compression unless the patient's condition is stable and off steroids for at least 14 days prior to the start of study treatment. Patients with suspected or known brain metastases at screening should have an MRI (preferred)/CT, preferably with IV contrast to access baseline disease status.
  • Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product (IP). 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, CT scan premedication).
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.
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
Contact: AstraZeneca Cancer Study Locator Service 1-877-400-4656 AstraZeneca@emergingmed.com
Listed Location Countries  ICMJE Canada,   Mexico,   Australia,   Austria,   Belgium,   Brazil,   China,   Denmark,   France,   Germany,   Greece,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Poland,   Portugal,   Russian Federation,   Spain,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02516241
Other Study ID Numbers  ICMJE D419BC00001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date September 2019

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