History of Changes for Study: NCT03875235

Study Identification


Unique Protocol ID:	D933AC00001
Brief Title:	Durvalumab or Placebo in Combination With Gemcitabine/Cisplatin in Patients With 1st Line Advanced Biliary Tract Cancer (TOPAZ-1) (TOPAZ-1)
Official Title:	A Phase III Randomized, Double-Blind Placebo Controlled, Multi-Regional, International Study of Durvalumab in Combination With Gemcitabine Plus Cisplatin Versus Placebo in Combination With Gemcitabine Plus Cisplatin for Patients With First-Line Advanced Biliary Tract Cancers
Secondary IDs:

Study Status


Record Verification:	August 2022
Overall Status:	Active, not recruiting
Study Start:	April 16, 2019
Primary Completion:	August 11, 2021 [Actual]
Study Completion:	March 31, 2025 [Anticipated]

First Submitted:	March 13, 2019
First Submitted that Met QC Criteria:	March 13, 2019
First Posted:	March 14, 2019 [Actual]

Last Update Submitted that Met QC Criteria:
Last Update Posted:	September 6, 2022 [Actual]

Study Description


Brief Summary:	Durvalumab or Placebo in Combination With Gemcitabine/Cisplatin in Patients With 1st Line Advanced Biliary Tract Cancer (TOPAZ-1)
Detailed Description:	A Phase III Randomized, Double-Blind Placebo Controlled, Multi-Regional, International Study of Durvalumab in Combination with Gemcitabine Plus Cisplatin Versus Placebo in Combination with Gemcitabine Plus Cisplatin for Patients With First-Line Advanced Biliary Tract Cancers.

Conditions


Conditions:	Biliary Tract Neoplasms
Keywords:	First-Line Advanced Biliary Tract Cancers (BTC) Durvalumab Gemcitabine/Cisplatin Placebo

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 3
Interventional Study Model:	Parallel Assignment
	Durvalumab in Combination with Gemcitabine plus Cisplatin Placebo in Combination with Gemcitabine plus Cisplatin
Number of Arms:	2
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:	Randomized
Enrollment:	810 [Actual]

Arms and Interventions

Arms	Assigned Interventions
Experimental: Treatment Arm Durvalumab + Gemcitabine + Cisplatin	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Placebo Comparator: Placebo Arm Placebo + Gemcitabine + Cisplatin	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.

Outcome Measures

[See Results Section.]


Primary Outcome Measures:
1.	Overall Survival (OS) [ Time Frame: From baseline until death due to any cause. Assessed up to maximum of approximately 27 months. ] Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis in the global cohort was pre-specified after approximately 397 OS events occurred in both arms (58% maturity).
2.	Overall Survival (OS) Rate at 18 Months [ Time Frame: From baseline until death due to any cause. Calculated at 18 months using the Kaplan-Meier technique. ] Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis in the global cohort was pre-specified after approximately 397 OS events occurred in both arms (58% maturity).
3.	Overall Survival (OS) Rate at 24 Months [ Time Frame: From baseline until death due to any cause. Calculated at 24 months using the Kaplan-Meier technique. ] Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis in the global cohort was pre-specified after approximately 397 OS events occurred in both arms (58% maturity).
Secondary Outcome Measures:
1.	Progression-free Survival (PFS) [ Time Frame: Tumor assessments every 6 weeks after randomization for the first 24 weeks and then every 8 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Assessed up to maximum of approximately 27 months. ] PFS based on investigator assessments according to RECIST version 1.1 was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
2.	Progression-free Survival (PFS) Rate at 9 Months [ Time Frame: Tumor assessments every 6 weeks after randomization for the first 24 weeks and then every 8 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Calculated at 9 months using the Kaplan-Meier technique. ] PFS based on investigator assessments according to RECIST version 1.1 was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
3.	Progression-free Survival (PFS) Rate at 12 Months [ Time Frame: Tumor assessments every 6 weeks after randomization for the first 24 weeks and then every 8 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Calculated at 12 months using the Kaplan-Meier technique ] PFS based on investigator assessments according to RECIST version 1.1 was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
4.	Objective Response Rate (ORR) [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months. ] Disease assessments based on investigator assessments were determined by using RECIST version 1.1 guidelines. The ORR was defined as the percentage of patients with confirmed complete response (CR) or confirmed partial response (PR). The CR was defined as disappearance of all target and non-target lesions and no new lesions. The PR was defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed CR or PR was defined as 2 CRs or 2 PRs with no evidence of progression in-between. Patients who discontinued randomized treatment without progression, received a subsequent anti-cancer therapy and then responded were not included as responders for ORR.
5.	Duration of Response (DoR) [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months. ] The DoR was defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments by using RECIST version 1.1 or death in absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1) . A confirmed CR was defined in above outcome measures. The PD was defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. Median DoR was calculated using Kaplan-Meier method.
6.	Duration of Response (DoR): Percentage Remaining in Response at 9 Months [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Calculated at 9 months using the Kaplan-Meier technique ] The DoR was defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments by using RECIST version 1.1 or death in absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1) . A confirmed CR was defined in above outcome measures. The PD was defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. Median DoR was calculated using Kaplan-Meier method.
7.	Duration of Response (DoR): Percentage Remaining in Response at 12 Months [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Calculated at 12 months using the Kaplan-Meier technique ] The DoR was defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments by using RECIST version 1.1 or death in absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1) . A confirmed CR was defined in above outcome measures. The PD was defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. Median DoR was calculated using Kaplan-Meier method.
8.	Disease Control Rate (DCR) - Overall [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months. ] Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR), partial response (PR) or stable disease (SD).
9.	Disease Control Rate (DCR) - 24 Weeks [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization. ] Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 24 or who have stable disease (SD) at least 24 weeks following start of treatment.
10.	Disease Control Rate (DCR) - 32 Weeks [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. ] Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 32 or who have stable disease (SD) at least 32 weeks following start of treatment.
11.	Disease Control Rate (DCR) - 48 Weeks [ Time Frame: Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. ] Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 48 or who have stable disease (SD) at least 48 weeks following start of treatment.

Eligibility


Minimum Age:	18 Years
Maximum Age:	130 Years
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	Inclusion Histologically confirmed, unresectable advanced or metastatic biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma. Patients with previously untreated disease if unresectable or metastatic at initial diagnosis will be eligible. Patient with recurrent disease >6 months after curative surgery or >6 months after the completion of adjuvant therapy (chemotherapy and/or radiation) will be eligible. WHO/ECOG PS of 0 or 1 Exclusion History of another primary malignancy Brain metastases or spinal cord compression Uncontrolled intercurrent illness Major surgical procedure within 28 days prior to the first dose of IP. Prior locoregional therapy such as radioembolization

Contacts/Locations


Study Officials:	Gordon Cohen Study Director AstraZeneca
Locations:	United States, California
	Research Site Los Angeles, California, United States, 90027
	Research Site Orange, California, United States, 92868
	United States, District of Columbia
	Research Site Washington, District of Columbia, United States, 20007
	United States, Florida
	Research Site Fort Myers, Florida, United States, 33905
	Research Site Saint Petersburg, Florida, United States, 33705
	United States, Kansas
	Research Site Westwood, Kansas, United States, 66205
	United States, Kentucky
	Research Site Louisville, Kentucky, United States, 40202
	United States, Massachusetts
	Research Site Burlington, Massachusetts, United States, 01805
	United States, Missouri
	Research Site Saint Louis, Missouri, United States, 63110
	United States, North Carolina
	Research Site Chapel Hill, North Carolina, United States, 27514
	United States, Oregon
	Research Site Portland, Oregon, United States, 97213
	United States, Pennsylvania
	Research Site Philadelphia, Pennsylvania, United States, 19111
	United States, Tennessee
	Research Site Chattanooga, Tennessee, United States, 37404
	Research Site Nashville, Tennessee, United States, 37203
	United States, Washington
	Research Site Seattle, Washington, United States, 98109
	Argentina
	Research Site Buenos Aires, Argentina, 1280
	Research Site Buenos Aires, Argentina, C1118AAT
	Research Site Buenos Aires, Argentina, C1426ANZ
	Research Site Caba, Argentina, C1012AAR
	Research Site Caba, Argentina, C1019ABS
	Research Site Rosario, Argentina, 2000
	Research Site San Salvador de Jujuy, Argentina, 4600
	Bulgaria
	Research Site Burgas, Bulgaria, 8000
	Research Site Sofia, Bulgaria, 1330
	Research Site Sofia, Bulgaria, 1407
	Research Site Sofia, Bulgaria, 1606
	Research Site Varna, Bulgaria, 9010
	Chile
	Research Site Puerto Montt, Chile, 5480000
	Research Site Santiago, Chile, 7630370
	Research Site Temuco, Chile, 4810218
	Research Site Viña del Mar, Chile, 2540488
	China
	Research Site Baoding, China, 071000
	Research Site Beijing, China, 100021
	Research Site Beijing, China, 100142
	Research Site Bengbu, China, 233060
	Research Site Chongqing, China, 400038
	Research Site Foshan, China, 528000
	Research Site Guangzhou, China, 510062
	Research Site Hangzhou, China, 310003
	Research Site Hangzhou, China, 310009
	Research Site Harbin, China, 150081
	Research Site Hefei, China, 230001
	Research Site Hefei, China, 230601
	Research Site Jinan, China, 250014
	Research Site Nanchang, China, 330006
	Research Site Nanjing, China, 210002
	Research Site Shandong, China
	Research Site Shanghai, China, 200032
	Research Site Shenyang, China, 100003
	Research Site Suzhou, China, 215004
	Research Site Xian, China, 710061
	Research Site Zhengzhou, China, 450008
	Research Site Zhuhai, China, 519000
	France
	Research Site Clichy, France, 92210
	Research Site Dijon Cedex, France, 21079
	Research Site Montpellier CEDEX 5, France, 34295
	Research Site Nice, France, 6189
	Research Site PARIS Cedex 12, France, 75571
	Research Site Pessac, France, 33604
	Research Site Poitiers, France, 86021
	Hong Kong
	Research Site Hong Kong, Hong Kong, 150001
	Research Site Hong Kong, Hong Kong
	Research Site HongKong, Hong Kong, 00000
	Research Site Kowloon, Hong Kong
	India
	Research Site Gurgaon, India, 122001
	Research Site Kolkata, India, 700160
	Research Site Mumbai, India, 400012
	Research Site New Delhi, India, 110085
	Italy
	Research Site Faenza, Italy, 48018
	Research Site Firenze, Italy, 50134
	Research Site Milano, Italy, 20132
	Research Site Napoli, Italy, 80131
	Research Site Roma, Italy, 00168
	Research Site Verona, Italy, 37134
	Japan
	Research Site Chuo-ku, Japan, 104-0045
	Research Site Kashiwa, Japan, 227-8577
	Research Site Kitaadachi-gun, Japan, 362-0806
	Research Site Mitaka-shi, Japan, 181-8611
	Research Site Osaka-shi, Japan, 541-8567
	Research Site Suita-shi, Japan, 565-0871
	Research Site Wakayama-shi, Japan, 641-8510
	Research Site Yokohama-shi, Japan, 241-8515
	Korea, Republic of
	Research Site Seongnam-si, Korea, Republic of, 13620
	Research Site Seoul, Korea, Republic of, 03080
	Research Site Seoul, Korea, Republic of, 03722
	Research Site Seoul, Korea, Republic of, 06351
	Research Site Seoul, Korea, Republic of, 06591
	Research Site Seoul, Korea, Republic of, 152-703
	Poland
	Research Site Gdańsk, Poland, 80-214
	Research Site Kościerzyna, Poland, 83-400
	Research Site Olsztyn, Poland, 10-228
	Research Site Poznan, Poland, 60-780
	Research Site Warszawa, Poland, 02-106
	Research Site Wrocław, Poland, 50-556
	Research Site Łódź, Poland, 93-513
	Russian Federation
	Research Site Barnaul, Russian Federation, 656049
	Research Site Kostroma, Russian Federation, 156005
	Research Site Moscow, Russian Federation, 115478
	Research Site Moscow, Russian Federation, 121467
	Research Site Moscow, Russian Federation, 125284
	Research Site Omsk, Russian Federation, 644033
	Research Site Saint-Petersburg, Russian Federation, 197022
	Research Site Saint-Petersburg, Russian Federation, 197758
	Taiwan
	Research Site Chiayi, Taiwan, 613
	Research Site Kaohsiung, Taiwan, 824
	Research Site Kaohsiung, Taiwan, 83301
	Research Site Taichung, Taiwan, 40705
	Research Site Tainan, Taiwan, 704
	Research Site Taipei, Taiwan, 11217
	Research Site Taipei City, Taiwan, 10050
	Research Site Taoyuan, Taiwan, 333
	Thailand
	Research Site Bangkok, Thailand, 10330
	Research Site Bangkok, Thailand, 10400
	Research Site Hat Yai, Thailand, 90110
	Research Site Khon Kaen, Thailand, 40002
	Research Site Muang, Thailand, 50200
	Research Site Sisaket, Thailand, 33000
	Turkey
	Research Site Ankara, Turkey, 06100
	Research Site Istanbul, Turkey, 34030
	Research Site Izmir, Turkey, 35100
	Research Site Mersin, Turkey, 33110
	United Kingdom
	Research Site Bristol, United Kingdom, BS2 8ED
	Research Site Cambridge, United Kingdom, CB2 0QQ
	Research Site London, United Kingdom, NW3 2QG
	Research Site London, United Kingdom, W12 0NN
	Research Site Manchester, United Kingdom, M20 4BX
	Research Site Oxford, United Kingdom, OX3 7LE
	Research Site Romford, United Kingdom, RM7 0AG
	Research Site Sheffield, United Kingdom, S10 2SJ

IPDSharing


Plan to Share IPD:	Yes 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 Information: 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

References


Citations:
Links:	URL: https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D933AC00001&attachmentIdentifier=f0f0274f-a72a-4d83-8200-e6a74d44d8fe&fileName=D933AC00001_-___Statistical_Analysis_Plan-redact.pdf&versionIdentifier= Description: Related Info
	URL: https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D933AC00001&attachmentIdentifier=88a80119-302b-4810-bce2-623ab0a77f31&fileName=d933ac00001-oncology-late-phase-master-csp-v8-redact.pdf&versionIdentifier= Description: Related Info
	URL: https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D933AC00001&attachmentIdentifier=7f0ef0d5-6fe8-4acc-8de5-143b4c68c4d9&fileName=d933ac00001-study-synopsis-redact.pdf&versionIdentifier= Description: Related Info
Available IPD/Information:

Document Section


	Study Protocol Document Date: January 17, 2022 Uploaded: 08/10/2022 10:02 File Name: Prot_000.pdf
	Statistical Analysis Plan Document Date: October 12, 2021 Uploaded: 08/10/2022 10:01 File Name: SAP_001.pdf

Quality Control Review Comment provided by the National Library of Medicine:

The Document Type or Document Date appear inconsistent with information in an uploaded study document.
Required information appears to be missing.

Study Results

Participant Flow

Recruitment Details

The study is active, not recruiting and conducted in 17 countries.The study includes global cohort (685 patients) and China cohort (130 patients).

Pre-assignment Details

Eligible patients previously untreated for unresectable locally advanced or metastatic Biliary Tract Cancer (BTC) were randomized in a 1:1 ratio with either Durvalumab in combination with Gemcitabine/Cisplatin or Placebo in combination with Gemcitabine/Cisplatin. Randomization was stratified by disease status (initially unresectable versus recurrent) and primary tumor site (IHCC versus EHCC versus GBC).

Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Quality Control Review Comment provided by the National Library of Medicine: Information within the Participant Flow module appears inconsistent.

Period Title: Overall Study
Started	341	344
Treated	338	342
Completed	0	0
Not Completed	341	344
Reason Not Completed
Ongoing study treatment	63	20
Off treatment	77	91
Withdrawal by Subject	3	10
Death	198	223

Baseline Characteristics


Arm/Group Title		Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin	Total
Arm/Group Description		Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Total of all reporting groups
Overall Number of Baseline Participants		341	344	685
Baseline Analysis Population Description
Age, Continuous Mean (Standard Deviation) Unit of measure: Years	Number Analyzed	341 Participants	344 Participants	685 Participants
		62.2(10.49)	62.6(10.66)	62.4(10.57)
Age, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	341 Participants	344 Participants	685 Participants
Age group (years)	< 65 years	181 53.08%	184 53.49%	365 53.28%
	>=65 - < 75 years	122 35.78%	114 33.14%	236 34.45%
	>= 75 years	38 11.14%	46 13.37%	84 12.26%
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	341 Participants	344 Participants	685 Participants
	Female	172 50.44%	168 48.84%	340 49.64%
	Male	169 49.56%	176 51.16%	345 50.36%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants	Number Analyzed	341 Participants	344 Participants	685 Participants
Race	American Indian of Alaska Native	0 0%	1 0.29%	1 0.15%
	Asian	185 54.25%	201 58.43%	386 56.35%
	Black or African American	8 2.35%	6 1.74%	14 2.04%
	White	131 38.42%	124 36.05%	255 37.23%
	Other	17 4.99%	12 3.49%	29 4.23%

Outcome Measures

1. Primary Outcome:

Title

Overall Survival (OS)

Description

Overall Survival (OS) was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The second interim analysis in the global cohort was pre-specified after approximately 397 OS events occurred in both arms (58% maturity).

Time Frame

From baseline until death due to any cause. Assessed up to maximum of approximately 27 months.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Median (95% Confidence Interval) Unit of Measure: Months	12.8(11.1 to 14.0)	11.5(10.1 to 12.5)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Durvalumab + Gemcitabine + Cisplatin, Placebo + Gemcitabine + Cisplatin
	Comments	The 2-sided significance level for OS at the second interim analysis was 3%.
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.021
	Comments	The analysis was performed using a stratified log-rank test adjusting for disease status (initially unresectable versus recurrent) and primary tumor location (IHCC versus EHCC versus GBC), and tested at 0.03 significance level.
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-sided) 97% 0.64 to 0.99
	Estimation Comments	The HR and CI were estimated from a stratified Cox proportional hazard model adjusting for disease status and primary tumor location. A HR < 1 favors Durvalumab, associated with a longer overall survival than Placebo.


Other Statistical Analysis		95% CI 0.66 to 0.97

Quality Control Review Comment provided by the National Library of Medicine:

A free-text field appears to include results data or conclusions drawn from the data. All results data must be reported in a tabular format.

2. Primary Outcome:

Title

Overall Survival (OS) Rate at 18 Months

Description

Time Frame

From baseline until death due to any cause. Calculated at 18 months using the Kaplan-Meier technique.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Number (95% Confidence Interval) Unit of Measure: Percentage of Participants	35.1(29.1 to 41.2)	25.6(19.9 to 31.7)

3. Primary Outcome:

Title

Overall Survival (OS) Rate at 24 Months

Description

Time Frame

From baseline until death due to any cause. Calculated at 24 months using the Kaplan-Meier technique.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Number (95% Confidence Interval) Unit of Measure: Percentage of Participants	24.9(17.9 to 32.5)	10.4(4.7 to 18.8)

4. Secondary Outcome:

Title

Progression-free Survival (PFS)

Description

PFS based on investigator assessments according to RECIST version 1.1 was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.

Time Frame

Tumor assessments every 6 weeks after randomization for the first 24 weeks and then every 8 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Assessed up to maximum of approximately 27 months.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Median (95% Confidence Interval) Unit of Measure: Months	7.2(6.7 to 7.4)	5.7(5.6 to 6.7)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Durvalumab + Gemcitabine + Cisplatin, Placebo + Gemcitabine + Cisplatin
	Comments	The 2-sided significance level for PFS at the second interim analysis was 4.81%.
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.001
	Comments	The p-value is based on a stratified log-rank test adjusting for disease status (initially unresectable versus recurrent) and primary tumor location (IHCC versus EHCC versus GBC), and tested at 0.0481 significance level.
	Method	Log Rank
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-sided) 95.19% 0.63 to 0.89
	Estimation Comments	The HR and CI were estimated from a stratified Cox proportional hazard model adjusting for disease status and primary tumor location. A HR < 1 favors Durvalumab, associated with a longer overall progression free survival than Placebo.


Other Statistical Analysis		95% CI 0.63 to 0.89

Quality Control Review Comment provided by the National Library of Medicine:

A free-text field appears to include results data or conclusions drawn from the data. All results data must be reported in a tabular format.

5. Secondary Outcome:

Title

Progression-free Survival (PFS) Rate at 9 Months

Description

Time Frame

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Number (95% Confidence Interval) Unit of Measure: Percentage of Participants	34.8(29.6 to 40.0)	24.6(20.0 to 29.5)

6. Secondary Outcome:

Title

Progression-free Survival (PFS) Rate at 12 Months

Description

Time Frame

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Number (95% Confidence Interval) Unit of Measure: Percentage of Participants	16.0(12.0 to 20.6)	6.6(4.1 to 9.9)

7. Secondary Outcome:

Title

Objective Response Rate (ORR)

Description

Disease assessments based on investigator assessments were determined by using RECIST version 1.1 guidelines. The ORR was defined as the percentage of patients with confirmed complete response (CR) or confirmed partial response (PR). The CR was defined as disappearance of all target and non-target lesions and no new lesions. The PR was defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed CR or PR was defined as 2 CRs or 2 PRs with no evidence of progression in-between. Patients who discontinued randomized treatment without progression, received a subsequent anti-cancer therapy and then responded were not included as responders for ORR.

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months.

Outcome Measure Data

Analysis Population Description

Full analysis set - subjects with measurable disease at baseline


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	343
Measure Type: Number Unit of Measure: Percentage of Participants	26.7	18.7

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	Durvalumab + Gemcitabine + Cisplatin, Placebo + Gemcitabine + Cisplatin
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.011
	Comments	[Not specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.60
	Confidence Interval	(2-sided) 95% 1.11 to 2.31
	Estimation Comments	OR and CI were estimated from a stratified CMH test adjusting for disease status & primary tumor location. An odds ratio > 1 favors Durvalumab+Gemcitabine+Cisplatin, associated with a longer overall response rate than Placebo+Gemcitabine+Cisplatin.

Quality Control Review Comment provided by the National Library of Medicine:

A free-text field appears to include results data or conclusions drawn from the data. All results data must be reported in a tabular format.

8. Secondary Outcome:

Title

Duration of Response (DoR)

Description

The DoR was defined as the time from the date of first documented OR (confirmed CR or confirmed PR) until date of documented progression (PD) based on investigator assessments by using RECIST version 1.1 or death in absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1) . A confirmed CR was defined in above outcome measures. The PD was defined at least 20% increase in sum of diameters of target lesions (compared with nadir at 2 consecutive visits with an absolute increase of 5 mm), unequivocal progression of existing non-target lesions or new lesion. For participants who were alive and no documented PD at the time of data cutoff for analysis, DoR was censored at the last evaluable disease assessment date. Median DoR was calculated using Kaplan-Meier method.

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months.

Outcome Measure Data

Analysis Population Description

Full analysis set - subjects with objective response and measurable disease at baseline


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	91	64
Median (95% Confidence Interval) Unit of Measure: Months	6.4(5.9 to 8.1)	6.2(4.4 to 7.3)

9. Secondary Outcome:

Title

Duration of Response (DoR): Percentage Remaining in Response at 9 Months

Description

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Calculated at 9 months using the Kaplan-Meier technique

Outcome Measure Data

Analysis Population Description

Full analysis set - subjects with objective response and measurable disease at baseline


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	91	64
Measure Type: Number Unit of Measure: Percentage of Participants	32.6	25.3

10. Secondary Outcome:

Title

Duration of Response (DoR): Percentage Remaining in Response at 12 Months

Description

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Calculated at 12 months using the Kaplan-Meier technique

Outcome Measure Data

Analysis Population Description

Full analysis set - subjects with objective response and measurable disease at baseline


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	91	64
Measure Type: Number Unit of Measure: Percentage of Participants	26.1	15.0

11. Secondary Outcome:

Title

Disease Control Rate (DCR) - Overall

Description

Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR), partial response (PR) or stable disease (SD).

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter. Assessed up to maximum of approximately 27 months.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Measure Type: Number Unit of Measure: Percentage of Participants	85.3	82.6

12. Secondary Outcome:

Title

Disease Control Rate (DCR) - 24 Weeks

Description

Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 24 or who have stable disease (SD) at least 24 weeks following start of treatment.

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Measure Type: Number Unit of Measure: Percentage of Participants	57.5	48.3

13. Secondary Outcome:

Title

Disease Control Rate (DCR) - 32 Weeks

Description

Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 32 or who have stable disease (SD) at least 32 weeks following start of treatment.

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Measure Type: Number Unit of Measure: Percentage of Participants	41.9	36.3

14. Secondary Outcome:

Title

Disease Control Rate (DCR) - 48 Weeks

Description

Disease control rate based on investigator assessments according to RECIST version 1.1 was defined as the rate of best objective response of complete response (CR) or partial response (PR) by week 48 or who have stable disease (SD) at least 48 weeks following start of treatment.

Time Frame

Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter.

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin	Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.	Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
Overall Number of Participants Analyzed	341	344
Measure Type: Number Unit of Measure: Percentage of Participants	35.2	27.0

Adverse Events


Time Frame	From first dose of study medication up to 90 days after the last dose of study medication or until the initiation of the first subsequent therapy (whichever comes first)
Adverse Event Reporting Description	There were 341 patients randomized to Durvalumab + Gemcitabine + Cisplatin and 344 patients randomized to Placebo + Gemcitabine + Cisplatin (Full Analysis Set). Five of these patients did not receive treatment (resulting in 338 in Durvalumab arm and 342 in Placebo arm for Safety Analysis Set). Hence, the Total numbers at risk for all-cause mortality is 341 (Durvalumab) and 344 (Placebo), while the Total number at Risk by any Serious/Other Adverse Event is 338 (Durvalumab) and 342 (Placebo).
Quality Control Review Comment provided by the National Library of Medicine: There does not appear to be sufficient information to understand the Time Frame.

Arm/Group Title	Durvalumab + Gemcitabine + Cisplatin		Placebo + Gemcitabine + Cisplatin
Arm/Group Description	Drug: Durvalumab IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.		Drug: Placebo IV infusion every 3 weeks with gemcitabine plus cisplatin up to 8 cycles followed by monotherapy every 4 weeks until disease progression or other discontinuation criteria.
All-Cause Mortality
	Durvalumab + Gemcitabine + Cisplatin		Placebo + Gemcitabine + Cisplatin
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	198 / 341 (58.06%)		226 / 344 (65.7%)
Serious Adverse Events
	Durvalumab + Gemcitabine + Cisplatin		Placebo + Gemcitabine + Cisplatin
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	160 / 338 (47.34%)		149 / 342 (43.57%)
Blood and lymphatic system disorders
Anaemia ^{† A}	12 / 338 (3.55%)	16	4 / 342 (1.17%)	4
Bicytopenia ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Febrile neutropenia ^{† A}	4 / 338 (1.18%)	4	5 / 342 (1.46%)	5
Myelosuppression ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Neutropenia ^{† A}	2 / 338 (0.59%)	3	3 / 342 (0.88%)	3
Pancytopenia ^{† A}	2 / 338 (0.59%)	2	1 / 342 (0.29%)	1
Thrombocytopenia ^{† A}	3 / 338 (0.89%)	3	4 / 342 (1.17%)	4
Cardiac disorders
Acute coronary syndrome ^{† A}	2 / 338 (0.59%)	2	0 / 342 (0%)	0
Angina pectoris ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Atrial fibrillation ^{† A}	2 / 338 (0.59%)	2	0 / 342 (0%)	0
Sinus tachycardia ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Ear and labyrinth disorders
Vertigo ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Endocrine disorders
Adrenal insufficiency ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Eye disorders
Cataract ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Optic ischaemic neuropathy ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Gastrointestinal disorders
Abdominal distension ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Abdominal pain ^{† A}	1 / 338 (0.3%)	1	8 / 342 (2.34%)	8
Anal fistula ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Ascites ^{† A}	4 / 338 (1.18%)	5	6 / 342 (1.75%)	6
Diarrhoea ^{† A}	4 / 338 (1.18%)	4	5 / 342 (1.46%)	6
Duodenal obstruction ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	3
Duodenal stenosis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Duodenal ulcer ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Fistula of small intestine ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Gastric perforation ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Gastritis ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	2
Haematochezia ^{† A}	1 / 338 (0.3%)	2	0 / 342 (0%)	0
Ileus ^{† A}	3 / 338 (0.89%)	3	3 / 342 (0.88%)	3
Immune-mediated enterocolitis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Inguinal hernia ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Intestinal obstruction ^{† A}	2 / 338 (0.59%)	3	0 / 342 (0%)	0
Large intestine perforation ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Lower gastrointestinal haemorrhage ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Melaena ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Nausea ^{† A}	1 / 338 (0.3%)	1	3 / 342 (0.88%)	3
Obstruction gastric ^{† A}	2 / 338 (0.59%)	2	0 / 342 (0%)	0
Pancreatitis ^{† A}	2 / 338 (0.59%)	2	0 / 342 (0%)	0
Pancreatitis acute ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Rectal haemorrhage ^{† A}	1 / 338 (0.3%)	2	0 / 342 (0%)	0
Small intestinal obstruction ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	2
Upper gastrointestinal haemorrhage ^{† A}	5 / 338 (1.48%)	5	2 / 342 (0.58%)	2
Vomiting ^{† A}	5 / 338 (1.48%)	6	5 / 342 (1.46%)	5
General disorders
Asthenia ^{† A}	1 / 338 (0.3%)	1	2 / 342 (0.58%)	2
Death ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	2
Device related thrombosis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Fatigue ^{† A}	6 / 338 (1.78%)	6	4 / 342 (1.17%)	4
Malaise ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Peripheral swelling ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Pyrexia ^{† A}	13 / 338 (3.85%)	16	8 / 342 (2.34%)	8
Sudden death ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Hepatobiliary disorders
Autoimmune hepatitis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Biliary obstruction ^{† A}	6 / 338 (1.78%)	8	7 / 342 (2.05%)	8
Biloma rupture ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Cholangitis ^{† A}	25 / 338 (7.4%)	42	17 / 342 (4.97%)	20
Cholangitis acute ^{† A}	4 / 338 (1.18%)	5	4 / 342 (1.17%)	7
Cholecystitis ^{† A}	1 / 338 (0.3%)	3	4 / 342 (1.17%)	4
Cholecystitis acute ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Cholestasis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Gallbladder obstruction ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Gallbladder rupture ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Hepatic cytolysis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Hepatic failure ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Hepatic function abnormal ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Hepatic haemorrhage ^{† A}	1 / 338 (0.3%)	2	0 / 342 (0%)	0
Hepatitis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Hyperbilirubinaemia ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Jaundice ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Jaundice cholestatic ^{† A}	4 / 338 (1.18%)	4	5 / 342 (1.46%)	5
Portal vein thrombosis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Immune system disorders
Anaphylactic shock ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Infections and infestations
Abdominal infection ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Abdominal wall abscess ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Abscess intestinal ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Acinetobacter sepsis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Appendicitis ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	2
Arthritis bacterial ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Bacteraemia ^{† A}	1 / 338 (0.3%)	1	5 / 342 (1.46%)	5
Biliary abscess ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Biliary sepsis ^{† A}	4 / 338 (1.18%)	4	2 / 342 (0.58%)	2
Biliary tract infection ^{† A}	5 / 338 (1.48%)	7	7 / 342 (2.05%)	8
Bronchitis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Catheter site infection ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Cellulitis ^{† A}	2 / 338 (0.59%)	2	0 / 342 (0%)	0
Cholangitis infective ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Clostridium difficile infection ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Covid-19 ^{† A}	4 / 338 (1.18%)	4	2 / 342 (0.58%)	2
Covid-19 pneumonia ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Device related infection ^{† A}	2 / 338 (0.59%)	3	3 / 342 (0.88%)	3
Device related sepsis ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Escherichia sepsis ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Gallbladder empyema ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Gastroenteritis escherichia coli ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Infection ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Infectious pleural effusion ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Klebsiella infection ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	2
Liver abscess ^{† A}	1 / 338 (0.3%)	1	2 / 342 (0.58%)	2
Lower respiratory tract infection ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Nasopharyngitis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Neutropenic sepsis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Peritonitis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Pneumocystis jirovecii pneumonia ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Pneumonia ^{† A}	6 / 338 (1.78%)	7	7 / 342 (2.05%)	8
Pyelonephritis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Sepsis ^{† A}	11 / 338 (3.25%)	11	9 / 342 (2.63%)	12
Septic shock ^{† A}	1 / 338 (0.3%)	1	4 / 342 (1.17%)	6
Urinary tract infection ^{† A}	6 / 338 (1.78%)	6	1 / 342 (0.29%)	1
Injury, poisoning and procedural complications
Ankle fracture ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Chemical peritonitis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Fall ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Femoral neck fracture ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Femur fracture ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Incisional hernia ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Infusion related reaction ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Lower limb fracture ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Overdose ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Post procedural complication ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Procedural pain ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Spinal fracture ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Transfusion reaction ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Investigations
Alanine aminotransferase increased ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Blood bilirubin increased ^{† A}	1 / 338 (0.3%)	1	4 / 342 (1.17%)	4
Blood creatinine increased ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Liver function test increased ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Neutrophil count decreased ^{† A}	3 / 338 (0.89%)	4	2 / 342 (0.58%)	2
Platelet count decreased ^{† A}	4 / 338 (1.18%)	4	3 / 342 (0.88%)	3
Metabolism and nutrition disorders
Decreased appetite ^{† A}	3 / 338 (0.89%)	3	2 / 342 (0.58%)	2
Diabetic ketoacidosis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Gout ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Hypercalcaemia ^{† A}	2 / 338 (0.59%)	3	1 / 342 (0.29%)	1
Hyperglycaemia ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Hyperkalaemia ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Hypoglycaemia ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Hypokalaemia ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Hypomagnesaemia ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Hyponatraemia ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Musculoskeletal and connective tissue disorders
Arthritis ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	2
Back pain ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Immune-mediated arthritis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Polymyositis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Colorectal cancer ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Tumour associated fever ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Tumour pain ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Nervous system disorders
Altered state of consciousness ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Cerebral haemorrhage ^{† A}	2 / 338 (0.59%)	2	0 / 342 (0%)	0
Cerebral infarction ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Cerebrovascular accident ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Dizziness ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Encephalopathy ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Hepatic encephalopathy ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Ischaemic stroke ^{† A}	4 / 338 (1.18%)	4	1 / 342 (0.29%)	1
Product Issues
Device malfunction ^{† A}	2 / 338 (0.59%)	2	2 / 342 (0.58%)	3
Device occlusion ^{† A}	0 / 338 (0%)	0	4 / 342 (1.17%)	4
Stent malfunction ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Psychiatric disorders
Adjustment disorder ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	2
Confusional state ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Personality change ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Suicide attempt ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Renal and urinary disorders
Acute kidney injury ^{† A}	8 / 338 (2.37%)	11	4 / 342 (1.17%)	4
Azotaemia ^{† A}	1 / 338 (0.3%)	2	0 / 342 (0%)	0
Haematuria ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Nephropathy toxic ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Renal failure ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Asphyxia ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Dyspnoea ^{† A}	0 / 338 (0%)	0	2 / 342 (0.58%)	2
Hiccups ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Interstitial lung disease ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Obstructive airways disorder ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Pleural effusion ^{† A}	1 / 338 (0.3%)	1	1 / 342 (0.29%)	1
Pneumonia aspiration ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Pneumonitis ^{† A}	2 / 338 (0.59%)	2	2 / 342 (0.58%)	2
Pneumothorax ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	2
Pulmonary embolism ^{† A}	6 / 338 (1.78%)	6	4 / 342 (1.17%)	4
Pulmonary oedema ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Respiratory failure ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Vascular disorders
Angiopathy ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Arterial thrombosis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Deep vein thrombosis ^{† A}	1 / 338 (0.3%)	1	2 / 342 (0.58%)	2
Hypertension ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Hypotension ^{† A}	1 / 338 (0.3%)	1	2 / 342 (0.58%)	2
Jugular vein thrombosis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Peripheral artery thrombosis ^{† A}	1 / 338 (0.3%)	1	0 / 342 (0%)	0
Thrombosis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
Venous thrombosis ^{† A}	0 / 338 (0%)	0	1 / 342 (0.29%)	1
†Indicates events were collected by systematic assessment. ATerm from vocabulary, MedDRA 24.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Durvalumab + Gemcitabine + Cisplatin		Placebo + Gemcitabine + Cisplatin
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	326 / 338 (96.45%)		330 / 342 (96.49%)
Blood and lymphatic system disorders
Anaemia ^{† A}	159 / 338 (47.04%)	246	149 / 342 (43.57%)	246
Leukopenia ^{† A}	20 / 338 (5.92%)	43	17 / 342 (4.97%)	34
Neutropenia ^{† A}	106 / 338 (31.36%)	212	101 / 342 (29.53%)	204
Thrombocytopenia ^{† A}	42 / 338 (12.43%)	67	42 / 342 (12.28%)	76
Endocrine disorders
Hypothyroidism ^{† A}	22 / 338 (6.51%)	22	11 / 342 (3.22%)	11
Gastrointestinal disorders
Abdominal pain ^{† A}	46 / 338 (13.61%)	59	54 / 342 (15.79%)	62
Abdominal pain upper ^{† A}	35 / 338 (10.36%)	41	30 / 342 (8.77%)	35
Constipation ^{† A}	108 / 338 (31.95%)	133	99 / 342 (28.95%)	117
Diarrhoea ^{† A}	54 / 338 (15.98%)	69	47 / 342 (13.74%)	74
Dyspepsia ^{† A}	21 / 338 (6.21%)	24	25 / 342 (7.31%)	26
Nausea ^{† A}	136 / 338 (40.24%)	211	117 / 342 (34.21%)	201
Stomatitis ^{† A}	23 / 338 (6.8%)	29	22 / 342 (6.43%)	25
Vomiting ^{† A}	59 / 338 (17.46%)	81	57 / 342 (16.67%)	84
General disorders
Asthenia ^{† A}	47 / 338 (13.91%)	76	48 / 342 (14.04%)	70
Fatigue ^{† A}	87 / 338 (25.74%)	151	86 / 342 (25.15%)	123
Oedema peripheral ^{† A}	27 / 338 (7.99%)	31	17 / 342 (4.97%)	23
Pyrexia ^{† A}	60 / 338 (17.75%)	98	49 / 342 (14.33%)	84
Infections and infestations
Urinary tract infection ^{† A}	18 / 338 (5.33%)	25	19 / 342 (5.56%)	20
Investigations
Alanine aminotransferase increased ^{† A}	29 / 338 (8.58%)	37	34 / 342 (9.94%)	44
Aspartate aminotransferase increased ^{† A}	23 / 338 (6.8%)	30	31 / 342 (9.06%)	39
Blood bilirubin increased ^{† A}	9 / 338 (2.66%)	10	20 / 342 (5.85%)	22
Blood creatinine increased ^{† A}	10 / 338 (2.96%)	12	33 / 342 (9.65%)	43
Gamma-glutamyltransferase increased ^{† A}	12 / 338 (3.55%)	15	18 / 342 (5.26%)	27
Neutrophil count decreased ^{† A}	89 / 338 (26.33%)	225	105 / 342 (30.7%)	262
Platelet count decreased ^{† A}	68 / 338 (20.12%)	126	77 / 342 (22.51%)	175
Weight decreased ^{† A}	20 / 338 (5.92%)	20	20 / 342 (5.85%)	24
White blood cell count decreased ^{† A}	37 / 338 (10.95%)	78	46 / 342 (13.45%)	104
Metabolism and nutrition disorders
Decreased appetite ^{† A}	85 / 338 (25.15%)	102	79 / 342 (23.1%)	91
Hypokalaemia ^{† A}	28 / 338 (8.28%)	38	16 / 342 (4.68%)	24
Hypomagnesaemia ^{† A}	32 / 338 (9.47%)	48	29 / 342 (8.48%)	34
Hyponatraemia ^{† A}	22 / 338 (6.51%)	25	21 / 342 (6.14%)	23
Musculoskeletal and connective tissue disorders
Arthralgia ^{† A}	20 / 338 (5.92%)	22	14 / 342 (4.09%)	15
Back pain ^{† A}	28 / 338 (8.28%)	32	22 / 342 (6.43%)	24
Myalgia ^{† A}	15 / 338 (4.44%)	20	19 / 342 (5.56%)	22
Nervous system disorders
Dizziness ^{† A}	21 / 338 (6.21%)	24	16 / 342 (4.68%)	20
Dysgeusia ^{† A}	20 / 338 (5.92%)	24	16 / 342 (4.68%)	22
Headache ^{† A}	23 / 338 (6.8%)	26	14 / 342 (4.09%)	18
Psychiatric disorders
Insomnia ^{† A}	32 / 338 (9.47%)	34	36 / 342 (10.53%)	36
Respiratory, thoracic and mediastinal disorders
Cough ^{† A}	22 / 338 (6.51%)	23	18 / 342 (5.26%)	18
Dyspnoea ^{† A}	22 / 338 (6.51%)	26	17 / 342 (4.97%)	20
Skin and subcutaneous tissue disorders
Alopecia ^{† A}	28 / 338 (8.28%)	30	15 / 342 (4.39%)	15
Pruritus ^{† A}	38 / 338 (11.24%)	46	28 / 342 (8.19%)	30
Rash ^{† A}	38 / 338 (11.24%)	56	27 / 342 (7.89%)	34
Rash maculo-papular ^{† A}	18 / 338 (5.33%)	21	8 / 342 (2.34%)	9
Vascular disorders
Hypertension ^{† A}	19 / 338 (5.62%)	31	20 / 342 (5.85%)	23
†Indicates events were collected by systematic assessment. ATerm from vocabulary, MedDRA 24.0

More Information


Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study. There is NOT an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact:
Name/Official Title:	Global Clinical Lead
Organization:	AstraZeneca Clinical Study Information Center
Phone:	1-877-240-9479
Email:	information.center@astrazeneca.com