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 : Active, not recruiting

First Posted : August 5, 2015

Results First Posted : May 13, 2021

Last Update Posted : December 3, 2021

Sponsor:

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

Layout table for study information

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

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

U.S. FDA Resources

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 :

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.
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 :

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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).
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).
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.
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.
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.
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.
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.
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
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
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.
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.
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

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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

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

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): NCT02516241

Locations

Show 222 study locations

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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 1K1
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 8L6
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
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
Xiamen, China, 361003
Research Site
Xian, China
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, 135-710
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 This link exits the ClinicalTrials.gov site

Redacted Protocol This link exits the ClinicalTrials.gov site

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, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez 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.

Layout table for additonal information

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT02516241
Other Study ID Numbers:	D419BC00001
First Posted:	August 5, 2015 Key Record Dates
Results First Posted:	May 13, 2021
Last Update Posted:	December 3, 2021
Last Verified:	December 2021
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:

Layout table for MeSH terms

Gemcitabine Carboplatin Durvalumab Tremelimumab Antineoplastic Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action	Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antineoplastic Agents, Immunological

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