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

Brief Title

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.

Completion Date

2025-12-31

Completion Date Type

Estimated

Conditions

Urothelial Cancer

Eligibility 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.

Inclusion 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.

Gender

All

Gender Based

false

Keywords

Urothelial Cancer

Phase III

Healthy Volunteers

No

Last Update Post Date

Tue, 08/26/2025 - 12:00

Last Update Post Date Type

Estimated

Last Update Submit Date

Mon, 08/25/2025 - 12:00

Maximum Age

130 Years

Minimum Age

18 Years

NCT Id

NCT02516241

Org Class

Industry

Org Full Name

AstraZeneca

Org Study Id

D419BC00001

Overall Status

Active, not recruiting

Phases

Phase 3

Primary Completion Date

Mon, 01/27/2020 - 12:00

Primary Completion Date Type

Actual

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

Primary Outcomes

Outcome Description

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.

Outcome Measure

To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set

Outcome 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).

Outcome Description

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.

Outcome Measure

To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set

Outcome 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).

Secondary Ids

Secondary Id

2015-001633-24

Secondary Outcomes

Outcome Description

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.

Outcome 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).

Outcome Measure

OS, Full Analysis Set - Durvalumab Monotherapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy

Outcome Description

Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.

Outcome Time Frame

From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).

Outcome Measure

Alive at 24 Months (OS24), Full Analysis Set

Outcome Description

Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.

Outcome Time Frame

From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).

Outcome Measure

Alive at 24 Months (OS24), PD-L1-High Analysis Set

Outcome Description

Alive at 24 months (OS24) is defined as the Kaplan-Meier estimate of OS at 24 months.

Outcome Time Frame

From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).

Outcome Measure

Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set

Outcome Description

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.

Outcome 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).

Outcome Measure

PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy

Outcome Description

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.

Outcome 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).

Outcome Measure

Alive and Progression-free at 12 Months (APF12), Full Analysis Set

Outcome Description

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.

Outcome 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).

Outcome Measure

Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set

Outcome Description

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.

Outcome 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).

Outcome Measure

Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set

Outcome Description

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.

Outcome 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).

Outcome Measure

PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy

Outcome Description

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.

Outcome 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).

Outcome Measure

Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy

Outcome Description

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.

Outcome 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).

Outcome Measure

Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population

Outcome Description

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.

Outcome 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).

Outcome Measure

Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

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

Outcome Description

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.

Outcome 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)

Outcome Measure

Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC

Outcome Description

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.

Outcome 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).

Outcome Measure

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

Outcome Description

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).

Outcome 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).

Outcome Measure

Duration of Response (DoR), Full Analysis Set

Outcome Description

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).

Outcome 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).

Outcome Measure

Duration of Response (DoR), PD-L1-High Analysis Set

Outcome Description

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).

Outcome 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).

Outcome Measure

Duration of Response (DoR), PD-L1-Low/Negative Analysis Set

Outcome Description

Blood samples were collected to determine the serum concentration of durvalumab.

Outcome 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.

Outcome Measure

Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set

Outcome Description

Blood samples were collected to determine the serum concentration of tremelimumab.

Outcome 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.

Outcome Measure

Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set

Outcome Description

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.

Outcome Time Frame

At week 0, 4, 12 and 24, and at follow-up Month 3.

Outcome Measure

Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients

Outcome Description

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.

Outcome Time Frame

At week 0, 4, 12 and at follow-up Month 3.

Outcome Measure

Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients

Outcome Description

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.

Outcome 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).

Outcome Measure

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

Outcome Description

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 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).

Outcome Measure

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

Outcome Description

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 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).

Outcome Measure

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

Outcome Description

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.

Outcome 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).

Outcome Measure

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

Outcome Description

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.

Outcome 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).

Outcome Measure

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

Outcome Description

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.

Outcome 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).

Outcome Measure

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