Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02516241
Recruitment Status : Active, not recruiting
First Posted : August 5, 2015
Results First Posted : May 13, 2021
Last Update Posted : August 17, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE July 13, 2015
First Posted Date  ICMJE August 5, 2015
Results First Submitted Date  ICMJE January 25, 2021
Results First Posted Date  ICMJE May 13, 2021
Last Update Posted Date August 17, 2021
Actual Study Start Date  ICMJE November 2, 2015
Actual Primary Completion Date January 27, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 21, 2021)
  • 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.
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
Current Secondary Outcome Measures  ICMJE
 (submitted: April 21, 2021)
  • 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.
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 Not Provided
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 * 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.

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 26, 2020)
1126
Original Estimated Enrollment  ICMJE
 (submitted: August 4, 2015)
525
Estimated Study Completion Date  ICMJE March 3, 2022
Actual Primary Completion Date January 27, 2020   (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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan,   Australia,   Austria,   Belgium,   Brazil,   Canada,   China,   Denmark,   France,   Germany,   Greece,   Israel,   Italy,   Korea, Republic of,   Mexico,   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
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date August 2021

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