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

• ClinicalTrials.gov Identifier: NCT02516241
• Recruitment Status: Active, not recruiting
• First Posted: August 5, 2015
• Results First Posted: May 13, 2021
• Last Update Posted: May 25, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

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

Condition or disease	Intervention/treatment	Phase
Urothelial Cancer	Drug: MEDI4736 (Durvalumab); Drug: Tremelimumab; Drug: Cisplatin; Drug: Carboplatin; Drug: Gemcitabine	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1126 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 MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination With Tremelimumab Versus Standard of Care Chemotherapy in Patients With Unresectable Stage IV Urothelial Cancer
• Actual Study Start Date: November 2, 2015
• Actual Primary Completion Date: January 27, 2020
• Estimated Study Completion Date: March 29, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Combination Therapy; MEDI4736 (Durvalumab) + Tremelimumab	Drug: MEDI4736 (Durvalumab); IV infusion; Drug: Tremelimumab; IV infusion
Experimental: Monotherapy; MEDI4736 (Durvalumab)	Drug: MEDI4736 (Durvalumab); IV infusion
Active Comparator: Standard of Care; Standard of Care Chemotherapy Treatment	Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Gemcitabine; IV infusion

Outcome Measures

Primary Outcome Measures :

1. To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set [ Time Frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
2. To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set [ Time Frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.

Secondary Outcome Measures :

1. OS, Full Analysis Set - Durvalumab Monotherapy vs SoC [ Time Frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
2. OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC [ Time Frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
3. OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [ Time Frame: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
   The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
4. Alive at 24 Months (OS24), Full Analysis Set [ Time Frame: From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020). ]
   Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
5. Alive at 24 Months (OS24), PD-L1-High Analysis Set [ Time Frame: From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020). ]
   Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
6. Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set [ Time Frame: From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020). ]
   Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.
7. PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

   Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression.

   Median PFS was calculated using the Kaplan-Meier technique.

8. PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

   Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression.

   Median PFS was calculated using the Kaplan-Meier technique.

9. PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

   Progression free survival (PFS) (per RECIST 1.1, as assessed by investigator) was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anticancer therapy prior to progression.

   Median PFS was calculated using the Kaplan-Meier technique.

10. Alive and Progression-free at 12 Months (APF12), Full Analysis Set [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). ]
    Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
11. Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). ]
    Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
12. Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). ]
    Alive and progression-free at 12 months (APF12) was defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by investigator) at 12 months.
13. PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1).

    Median PFS2 was calculated using the Kaplan-Meier technique.

14. PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1).

    Median PFS2 was calculated using the Kaplan-Meier technique.

15. PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    Time from randomization to second progression or death (PFS2) was defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death (ie, date of PFS2 event or censoring - date of randomization +1).

    Median PFS2 was calculated using the Kaplan-Meier technique.

16. Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
    Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
17. Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
    Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
18. Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
    Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.
19. Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years). ]

    Objective response rate ORR (per RECIST 1.1 as assessed by investigator) is defined as the number (%) of patients with at least 1 visit response of CR or PR.

    unconfirmed responses are excluded.

20. Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020). ]
    Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
21. Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020). ]
    Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
22. Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020). ]
    Disease control rate (DCR) at 6 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 24 weeks (-7 days, i.e., 161 days), following the start of study treatment.
23. Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020) ]
    Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
24. Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). ]
    Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
25. Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020). ]
    Disease control rate (DCR) at 12 months is defined as the percentage of patients who have a best objective response (BoR) of CR or PR, or who have demonstrated SD for a minimum interval of 48 weeks (-7 days, i.e., 329 days), following the start of study treatment.
26. Duration of Response (DoR), Full Analysis Set [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
    Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was 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 (i.e. date of PFS event or censoring - date of first response + 1).
27. Duration of Response (DoR), PD-L1-High Analysis Set [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
    Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was 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 (i.e. date of PFS event or censoring - date of first response + 1).
28. Duration of Response (DoR), PD-L1-Low/Negative Analysis Set [ Time Frame: Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]
    Duration of response (DoR) (per RECIST 1.1 as assessed by investigator) was 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 (i.e. date of PFS event or censoring - date of first response + 1).
29. Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set [ Time Frame: Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3. ]
    Blood samples were collected to determine the serum concentration of durvalumab.
30. Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set [ Time Frame: Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3. ]
    Blood samples were collected to determine the serum concentration of tremelimumab.
31. Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients [ Time Frame: At week 0, 4, 12 and 24, and at follow-up Month 3. ]
    Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Durvalumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
32. Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients [ Time Frame: At week 0, 4, 12 and at follow-up Month 3. ]
    Serum Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for Tremelimumab using validated assays. Tiered analysis will be performed to include screening, confirmatory, and titer assay components, and positive-negative cut points previously statistically determined from drug-naïve validation samples will be used. Persistently positive is defined as having at least 2 post-baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least one post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. The category may include patients meeting these criteria who are ADA positive at baseline.
33. Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score.

    All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104).

    NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4.

    Higher score represent worse outcome.

34. Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score.

    All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104).

    NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4.

    Higher score represent worse

35. Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    the change from baseline in the following total/index scores will be evaluated as secondary endpoints: FACT-BL TOI (refer to as TOI), FACT-BL Total score, and NFBlSI-18 score.

    All the 5 subscales (PWB (0-28), FWB (0-28), EWB (0-24), SWB (0-28), and BlCS(0-48)) are summed as the FACT-BL total score (range 0-156), while the sum of PWB, FWB and BICS constitutes the FACT-BL TOI (range 0-104).

    NFBlSI-18 (range 0-72) is based on the scores of 16 items (GP4, C2, BL1, GP3, GE6, GE1, C6, BL5, GF5, GP2, GP1, GP6, C3, GP5, GF3, GF7) and 2 extra items "I feel weak all overall" and "I feel light-headed (dizzy)". The range of each item is 0-4.

    Higher score represent worse

36. Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively.

    Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL.

    Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.

37. Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively.

    Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL.

    Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.

38. Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC [ Time Frame: At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years). ]

    Fatigue will be based on the question of "I have a lack of energy" and pain will be based on the question of "I have pain", according to GP1 and GP4 in PWB, respectively.

    Improvement in fatigue is defined at least 1 point improvement from baseline using GP1 of FACT-BL.

    Deterioration in pain is defined as at least 1 point deterioration from baseline using GP4 of FACT-BL.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

Research Site

Los Angeles, California, United States, 90095

Research Site

Stanford, California, United States, 94305

United States, Colorado

Research Site

Aurora, Colorado, United States, 80045

United States, Connecticut

Research Site

New Haven, Connecticut, United States, 06520

United States, Florida

Research Site

Tampa, Florida, United States, 33612

United States, Georgia

Research Site

Atlanta, Georgia, United States, 30322

United States, Kentucky

Research Site

Louisville, Kentucky, United States, 40202

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02215

United States, Michigan

Research Site

Ann Arbor, Michigan, United States, 48109

Research Site

Detroit, Michigan, United States, 48201

United States, Nebraska

Research Site

Omaha, Nebraska, United States, 68130

United States, New York

Research Site

New York, New York, United States, 10021

Research Site

New York, New York, United States, 10029

United States, Tennessee

Research Site

Memphis, Tennessee, United States, 38120

Research Site

Nashville, Tennessee, United States, 37203

United States, Washington

Research Site

Seattle, Washington, United States, 98101

Australia

Research Site

Box Hill, Australia, 3128

Research Site

Elizabeth Vale, Australia, 5112

Research Site

Macquarie University, Australia, 2109

Research Site

St Leonards, Australia, 2065

Research Site

Waratah, Australia, 2298

Austria

Research Site

Linz, Austria, 4010

Research Site

Wien, Austria, 1090

Research Site

Wien, Austria, 1140

Belgium

Research Site

Brussels, Belgium, 1000

Research Site

Bruxelles, Belgium, 1200

Research Site

Leuven, Belgium, 3000

Research Site

Liège, Belgium, 4000

Brazil

Research Site

Barretos, Brazil, 14784-400

Research Site

Belo Horizonte, Brazil, 30380-472

Research Site

Ijui, Brazil, 98700-000

Research Site

Itajai, Brazil, 88310-110

Research Site

Porto Alegre, Brazil, 90035-003

Research Site

Porto Alegre, Brazil, 90610-000

Research Site

Porto Alegre, Brazil, 91350-200

Research Site

Rio de Janeiro, Brazil, 20231-050

Research Site

Rio de Janeiro, Brazil, 22793-080

Research Site

Sao Paulo, Brazil, 01209-000

Research Site

Sao Paulo, Brazil, 01321-001

Research Site

Sao Paulo, Brazil, 01509-900

Research Site

São José do Rio Preto, Brazil, 15090-000

Canada, Alberta

Research Site

Calgary, Alberta, Canada, T2N 4N2

Research Site

Edmonton, Alberta, Canada, T6G 1Z2

Canada, British Columbia

Research Site

Kelowna, British Columbia, Canada, V1Y 5L3

Research Site

Vancouver, British Columbia, Canada, V5Z 4E6

Canada, Nova Scotia

Research Site

Halifax, Nova Scotia, Canada, B3H 1V7

Canada, Ontario

Research Site

Hamilton, Ontario, Canada, L8V 5C2

Research Site

Newmarket, Ontario, Canada, L3Y 2P9

Research Site

Oshawa, Ontario, Canada, L1G 2B9

Research Site

Ottawa, Ontario, Canada, K1H 1C4

Research Site

Toronto, Ontario, Canada, M4N 3M5

Research Site

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Research Site

Sherbrooke, Quebec, Canada, J1H 5N4

Canada

Research Site

Quebec, Canada, G1R 3S1

China

Research Site

Beijing, China, 100034

Research Site

Beijing, China, 100039

Research Site

Beijing, China, 100191

Research Site

Changchun, China, 130012

Research Site

Changsha, China, 410013

Research Site

Chongqing, China, 400038

Research Site

Hangzhou, China, 310009

Research Site

Hangzhou, China, 310014

Research Site

Nanjing, China, 210008

Research Site

Shanghai, China, 200000

Research Site

Shanghai, China, 200032

Research Site

Shanghai, China, 200072

Research Site

Shanghai, China, 200080

Research Site

Shanghai, China, 200127

Research Site

Shenyang, China, 110001

Research Site

Tianjin, China, 300211

Research Site

Xi'an, China, 710061

Research Site

Xiamen, China, 361003

Denmark

Research Site

Herlev, Denmark, 2730

Research Site

København Ø, Denmark, 2100

Research Site

Odense C, Denmark, 5000

Research Site

Århus C, Denmark, 8000

France

Research Site

Bordeaux, France, 33000

Research Site

Bordeaux, France, 33076

Research Site

Caen Cedex, France, 14076

Research Site

Lyon Cedex 08, France, 69008

Research Site

Marseille cedex 09, France, 13273

Research Site

Paris Cedex 10, France, 75475

Research Site

Poitiers Cedex, France, 86021

Research Site

Suresnes Cedex, France, 92151

Research Site

Toulouse, France, 31059

Research Site

Villejuif, France, 94805

Germany

Research Site

Düsseldorf, Germany, 40225

Research Site

Erlangen, Germany, 91054

Research Site

Hannover, Germany, 30625

Research Site

Heidelberg, Germany, 69120

Research Site

Jena, Germany, 07747

Research Site

München, Germany, 81675

Research Site

Münster, Germany, 48149

Greece

Research Site

Athens, Greece, 11528

Research Site

Heraklion, Greece, 711 11

Research Site

Holargos, Athens, Greece, 155 62

Research Site

Kaliftaki, N.Kifissia, Athens, Greece, 14564

Research Site

Maroussi, Athens, Greece, 15125

Research Site

Patras, Greece, 26500

Research Site

Thessaloniki, Greece, 56 429

Israel

Research Site

Haifa, Israel, 31096

Research Site

Jerusalem, Israel, 91120

Research Site

Petach-Tikva, Israel, 4941492

Research Site

Ramat Gan, Israel, 5265601

Research Site

Zerifin, Israel, 70300

Italy

Research Site

Arezzo, Italy, 52100

Research Site

Meldola, Italy, 47014

Research Site

Milano, Italy, 20132

Research Site

Milano, Italy, 20133

Research Site

Napoli, Italy, 80131

Research Site

Orbassano, Italy, 10043

Research Site

Pavia, Italy, 27100

Research Site

Roma, Italy, 00152

Research Site

San Giovanni Rotondo, Italy, 71013

Japan

Research Site

Akita-shi, Japan, 010-8543

Research Site

Bunkyo-ku, Japan, 113-8603

Research Site

Fukuoka-shi, Japan, 811-1347

Research Site

Hakata-shi, Japan, 812-0033

Research Site

Hirosaki-shi, Japan, 036-8563

Research Site

Hiroshima-shi, Japan, 730-8518

Research Site

Izumo-shi, Japan, 693-8501

Research Site

Kagoshima-shi, Japan, 890-8520

Research Site

Kanazawa-shi, Japan, 920-8641

Research Site

Kita-gun, Japan, 761-0793

Research Site

Kobe-shi, Japan, 650-0047

Research Site

Koshigaya-shi, Japan, 343-8555

Research Site

Koto-ku, Japan, 135-8550

Research Site

Kumamoto-shi, Japan, 860-0008

Research Site

Kyoto-shi, Japan, 606-8507

Research Site

Matsuyama-shi, Japan, 791-0280

Research Site

Morioka-shi, Japan, 028-3695

Research Site

Nagasaki-shi, Japan, 852-8501

Research Site

Nagoya-shi, Japan, 460-0001

Research Site

Nagoya-shi, Japan, 466-8560

Research Site

Osaka-shi, Japan, 541-8567

Research Site

Osaka-shi, Japan, 545-8586

Research Site

Osakasayama-shi, Japan, 589-8511

Research Site

Saga-shi, Japan, 840-8571

Research Site

Sagamihara-shi, Japan, 252-0315

Research Site

Sakura-shi, Japan, 285-8741

Research Site

Sapporo-shi, Japan, 060-8648

Research Site

Suita-shi, Japan, 565-0871

Research Site

Takatsuki-shi, Japan, 569-8686

Research Site

Yokohama-shi, Japan, 232-0024

Research Site

Yokohama-shi, Japan, 236-0004

Korea, Republic of

Research Site

Incheon, Korea, Republic of, 21565

Research Site

Seongnam-si, Korea, Republic of, 13620

Research Site

Seoul, Korea, Republic of, 02841

Research Site

Seoul, Korea, Republic of, 03080

Research Site

Seoul, Korea, Republic of, 03722

Research Site

Seoul, Korea, Republic of, 05505

Research Site

Seoul, Korea, Republic of, 6351

Mexico

Research Site

Guadalajara, Mexico, 44280

Research Site

León, Mexico, 37000

Research Site

Mexico, D.F, Mexico, 01120

Research Site

Mexico, Mexico, 06760

Research Site

Monterrey, Mexico, 64460

Research Site

México, Mexico, 04739

Netherlands

Research Site

Amsterdam, Netherlands, 1066 CX

Research Site

Amsterdam, Netherlands, 1081 HV

Research Site

Breda, Netherlands, 4819 EV

Research Site

Enschede, Netherlands, 7512 KZ

Research Site

Groningen, Netherlands, 9713 GZ

Research Site

Leiden, Netherlands, 2333 ZA

Research Site

Maastricht, Netherlands, 6229 HX

Research Site

Nijmegen, Netherlands, 6525 GA

Poland

Research Site

Gdańsk, Poland, 80-214

Research Site

Gdańsk, Poland, 80-462

Research Site

Gdynia, Poland, 81-519

Research Site

Gliwice, Poland, 44-101

Research Site

Olsztyn, Poland, 10-228

Research Site

Otwock, Poland, 05-400

Research Site

Szczecin, Poland, 70-111

Research Site

Warszawa, Poland, 02-781

Portugal

Research Site

Lisboa, Portugal, 1649-035

Research Site

Loures, Portugal, 2674-514

Research Site

Porto, Portugal, 4099-001

Russian Federation

Research Site

Moscow, Russian Federation, 105229

Research Site

Moscow, Russian Federation, 115478

Research Site

Murmansk, Russian Federation, 183047

Research Site

Nizhnyi Novgorod, Russian Federation, 603001

Research Site

Obninsk, Russian Federation, 249036

Research Site

Omsk, Russian Federation, 644013

Research Site

Saint Petersburg, Russian Federation, 191015

Research Site

Saint-Petersburg, Russian Federation, 197758

Research Site

St. Petersburg, Russian Federation, 194354

Research Site

St. Petersburg, Russian Federation, 199178

Research Site

St.Petersburg, Russian Federation, 191014

Research Site

Ufa, Russian Federation, 450054

Research Site

Yaroslavl, Russian Federation, 150054

Spain

Research Site

Badajoz, Spain, 06008

Research Site

Badalona, Spain, 08916

Research Site

Barcelona, Spain, 08003

Research Site

Barcelona, Spain, 08243

Research Site

Elche(Alicante), Spain, 03202

Research Site

Madrid, Spain, 08035

Research Site

Madrid, Spain, 28007

Research Site

Madrid, Spain, 28040

Research Site

Madrid, Spain, 28041

Research Site

Madrid, Spain, 28050

Research Site

Pozuelo de Alarcon, Spain, 28223

Research Site

Santiago de Compostela, Spain, 15706

Research Site

Sevilla, Spain, 41013

Taiwan

Research Site

Kaohsiung, Taiwan

Research Site

Taichung, Taiwan, 00407

Research Site

Tainan, Taiwan, 704

Research Site

Taipei, Taiwan, 10002

Research Site

Taipei, Taiwan, 112

Research Site

Taoyuan City, Taiwan, 333

Turkey

Research Site

Ankara, Turkey, 06230

Research Site

Edirne, Turkey, 22030

Research Site

Izmir, Turkey, 35100

United Kingdom

Research Site

Cambridge, United Kingdom, CB2 0QQ

Research Site

Cardiff., United Kingdom, CF14 2TL

Research Site

Glasgow, United Kingdom, G12 0YN

Research Site

Leeds, United Kingdom, LS9 7TF

Research Site

London, United Kingdom, E1 1BB

Research Site

London, United Kingdom, SE1 9RT

Research Site

Manchester, United Kingdom, M20 4BX

Research Site

Sheffield, United Kingdom, S10 2SJ

Research Site

Southampton, United Kingdom, SO16 6YD

Research Site

Wirral, United Kingdom, CH63 4JY

Sponsors and Collaborators

AstraZeneca

  Study Documents (Full-Text)

Documents provided by AstraZeneca:

Study Protocol  [PDF] December 3, 2019

Statistical Analysis Plan  [PDF] December 4, 2019

More Information

Additional Information:

Redacted SAP 

Redacted Protocol 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bogemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suarez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. doi: 10.1016/S1470-2045(20)30541-6. Epub 2020 Sep 21. Erratum In: Lancet Oncol. 2021 Jan;22(1):e5.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02516241
• Other Study ID Numbers: D419BC00001
• First Posted: August 5, 2015
• Results First Posted: May 13, 2021
• Last Update Posted: May 25, 2023
• Last Verified: May 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

Keywords provided by AstraZeneca:

Urothelial Cancer; Phase III

Additional relevant MeSH terms:

Carboplatin; Gemcitabine; Durvalumab; Tremelimumab; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological