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Clinical Trial Results:
A Phase II/III, Multicenter, Randomized, Placebo-controlled Study of Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) as First-line Treatment of Biliary Tract Cancer

Summary
EudraCT number	2019-001992-35
Trial protocol	DE FR PL ES IT
Global end of trial date	10 Nov 2022

Results information
Results version number	v2(current)
This version publication date	05 Nov 2023
First version publication date	20 Oct 2022
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

MS200647_0055

ISRCTN number

-

US NCT number

NCT04066491

WHO universal trial number (UTN)

-

Sponsor organisation name

Merck Healthcare KGaA, Darmstadt, Germany

Sponsor organisation address

Frankfurter Strasse 250, Darmstadt, Germany, 64293

Public contact

Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com

Scientific contact

Communication Centre, Merck Healthcare KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

10 Nov 2022

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

10 Nov 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The aim of the study was to evaluate whether bintrafusp alfa in combination with the current standard of care (SoC) (gemcitabine plus cisplatin) improves overall survival (OS) in chemotherapy and immunotherapy-naïve subjects with locally advanced or metastatic Biliary Tract Cancer (BTC) compared to placebo, gemcitabine and cisplatin.

Protection of trial subjects

Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

20 Sep 2019

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 15

Country: Number of subjects enrolled

Japan: 53

Country: Number of subjects enrolled

Korea, Republic of: 91

Country: Number of subjects enrolled

Taiwan: 28

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Germany: 7

Country: Number of subjects enrolled

Poland: 12

Country: Number of subjects enrolled

Spain: 20

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

Argentina: 16

Country: Number of subjects enrolled

Brazil: 1

Country: Number of subjects enrolled

Chile: 24

Country: Number of subjects enrolled

United States: 21

Worldwide total number of subjects

309

EEA total number of subjects

49

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

152

From 65 to 84 years

157

85 years and over

0

Subject disposition

Top of page

Recruitment details

-

Screening details

This study was conducted in 2 parts: Safety run-in part and double-blind part. Subjects who enrolled in safety run-in part of study were not eligible to participate in double-blind part.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Safety Run-In Part: M7824 + Gemcitabine + Cisplatin

Arm description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of Complete Response), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 milligram per meter square (mg/m^2) and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks.

Arm type

Experimental

Investigational medicinal product name

M7824

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received intravenous infusion of M7824 at a dose of 2400 mg Q3W 2 years (in case of Complete Response), otherwise until criterion pre-specified in protocol for discontinuation is met.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Cisplatin intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles Q3W.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Gemcitabine intravenously at a dose of 1000 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles Q3W.

Double-blinded Part: Placebo + Gemcitabine + Cisplatin

Arm description

Subjects received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received intravenous infusion of M7824 matched placebo, Q3W until 2 years (in case of complete response), otherwise until criterion pre-specified in protocol for discontinuation is met.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Cisplatin intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles Q3W.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Gemcitabine intravenously at a dose of 1000 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles Q3W.

Double-blinded Part: M7824 + Gemcitabine + Cisplatin

Arm description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Arm type

Experimental

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Cisplatin intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles Q3W.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received Gemcitabine intravenously at a dose of 1000 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles Q3W.

Investigational medicinal product name

M7824

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received intravenous infusion of M7824 at a dose of 2400 mg Q3W 2 years (in case of Complete Response), otherwise until criterion pre-specified in protocol for discontinuation is met.

Number of subjects in period 1	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Started	12	149	148
Treated	12	149	146
Completed	12	149	146
Not completed	0	0	2
Randomized, not treated	-	-	2

Baseline characteristics

Top of page

Reporting group title

Safety Run-In Part: M7824 + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of Complete Response), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 milligram per meter square (mg/m^2) and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks.

Reporting group title

Double-blinded Part: Placebo + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Reporting group title

Double-blinded Part: M7824 + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Reporting group values	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin	Total
Number of subjects	12	149	148	309
Age categorical
Units:
Age Continuous
Units: Years
arithmetic mean (standard deviation)	66 ± 11.9	64 ± 10.6	63 ± 10.8	-
Sex: Female, Male
Units: Subjects
Female	5	78	68	151
Male	7	71	80	158
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	21	22	44
Not Hispanic or Latino	11	128	126	265
Unknown or Not Reported	0	0	0	0
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	0	1
Asian	6	93	90	189
Native Hawaiian or Other Pacific Islander	0	1	0	1
Black or African American	0	0	1	1
White	6	51	51	108
More than one race	0	0	1	1
Unknown or Not Reported	0	3	5	8

End points

Top of page

Reporting group title

Safety Run-In Part: M7824 + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of Complete Response), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 milligram per meter square (mg/m^2) and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks.

Reporting group title

Double-blinded Part: Placebo + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Reporting group title

Double-blinded Part: M7824 + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Primary: Safety Run-in Part: Number of Subjects Who Experienced Dose Limiting Toxicities (DLTs)

Top of page

End point title

Safety Run-in Part: Number of Subjects Who Experienced Dose Limiting Toxicities (DLTs) ^[1] ^[2]

End point description

DLT: toxicity related to study intervention that meets, following criteria as evaluated in open-label, safety run-in: Grade (Gr) 3/4 Immune-related adverse event (irAE) that needs permanent discontinuation of M7824 treatment; a malignant skin lesion induced by M7824 that is local and can be resected with a negative resection margin is not a DLT; Gr 3/4 nonhematologic toxicity other than irAE, A life threatening hematological toxicity (unless clearly attributable to chemotherapy alone), which is hardly medically manageable, including a bleeding event resulting in urgent intervention and admission to an intensive care unit and Gr5 toxicity. DLT analysis set: all subjects who experienced at least 1 DLT (either by Investigator/by Safety Monitoring Committee (SMC)/who completed safety run-in, receiving at least 1 infusion of M7824 and of both gemcitabine and cisplatin and not being withdrawn during the DLT evaluation period for reasons other than toxicity.

End point type

Primary

End point timeframe

Day 1 up to Day 21 of Cycle 1 (each Cycle is of 21 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only safety run-in part. Therefore, other arms has not been selected.

End point values	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	12
Units: Subjects	0

No statistical analyses for this end point

Primary: Double-blind Part: Overall Survival

Top of page

End point title

Double-blind Part: Overall Survival ^[3] ^[4]

End point description

Overall Survival was defined as the time from study day 1 to the date of death due to any cause. The overall survival was analyzed by using the Kaplan-Meier method. Intent-to-Treat analysis set included all randomized subjects. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Time from study day 1 up to data cutoff (assessed up to 609 days)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only double-blind part. Therefore, other arms has not been selected.

End point values	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	18	23
Units: Months
median (full range (min-max))	11.5 (0.9 to 15.2)	11.5 (0.2 to 13.9)

No statistical analyses for this end point

Secondary: Safety Run-in Part: Number of Subjects With Grade Greater than or Equal (>=) 3 Laboratory Abnormalities

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End point title

Safety Run-in Part: Number of Subjects With Grade Greater than or Equal (>=) 3 Laboratory Abnormalities ^[5]

End point description

Laboratory investigation included hematology and biochemistry. The number of subjects with Grade >=3 laboratory abnormalities were reported. Severity of grade 3 or higher TEAEs were graded using NCI-CTCAE v5.0 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. The safety run-in (SRI) analysis set included all subjects from the safety run-in part who were administered any dose of any study intervention.

End point type

Secondary

End point timeframe

Time from first treatment up to data cutoff (assessed up to 609 days)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only safety run-in part. Therefore, other arms has not been selected.

End point values	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	12
Units: Subjects
Hemoglobin low	6
Leukocytes low	4
Neutrophils low	6
Platelets low	3
Alanine Aminotransferase high	2
Bilirubin high	1
Creatinine high	1
Lipase high	1
Potassium low	1
Lymphocytes low	2
Corrected Calcium high	1

No statistical analyses for this end point

Secondary: Safety Run-in Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs) and Treatment Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0

Top of page

End point title

Safety Run-in Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs) and Treatment Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 ^[6]

End point description

Adverse Event (AE) was defined any untoward medical occurrence in a subject administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Safety run-in (SRI) analysis set included all subjects from the safety run-in part who were administered any dose of any study intervention.

End point type

Secondary

End point timeframe

Time from first treatment up to data cutoff (assessed up to 609 days)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only safety run-in part. Therefore, other arms has not been selected.

End point values	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	12
Units: Subjects
Subjects with TEAEs	12
Subjects with Serious TEAEs	5
Subjects with Treatment-related TEAEs	11

No statistical analyses for this end point

Secondary: Double-blind Part: Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)

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End point title

Double-blind Part: Percentage of Subjects With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) ^[7]

End point description

Percentage of subjects with confirmed objective response that is at least one overall assessment of complete response (CR) or partial response (PR) reported here. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by IRC. Intent-to-Treat analysis set included all randomized subjects. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Time from randomization of study drug up to data cut off (assessed up to 609 days)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only double-blind part. Therefore, other arms has not been selected.

End point values	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	77	73
Units: Percentage of subjects
number (confidence interval 95%)	19.5 (11.3 to 30.1)	31.5 (21.1 to 43.4)

No statistical analyses for this end point

Secondary: Double-blind Part: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC)

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End point title

Double-blind Part: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC) ^[8]

End point description

Progression free survival was defined as the time from randomization of study intervention until the first documentation of disease progression (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Intent-to-Treat analysis set included all randomized subjects. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Time from randomization of study drug until the first documentation of PD or death, assessed up to 609 days

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only double-blind part. Therefore, other arms has not been selected.

End point values	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	44	49
Units: Months
median (confidence interval 95%)	5.6 (4.2 to 6.9)	5.5 (2.8 to 6.7)

No statistical analyses for this end point

Secondary: Double-blind Part: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)

Top of page

End point title

Double-blind Part: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC) ^[9]

End point description

DOR was defined for subjects with objective response, as the time from first documentation of objective response (confirmed Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by IRC. Results were calculated based on Kaplan-Meier estimates. Intent-to-Treat analysis set included all randomized subjects. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first documented objective response to PD or death due to any cause, assessed up to 609 days

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only double-blind part. Therefore, other arms has not been selected.

End point values	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	7	9
Units: Months
median (full range (min-max))	12.5 (2.7 to 12.5)	7.0 (1.4 to 8.3)

No statistical analyses for this end point

Secondary: Double-blind Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Treatment Related TEAEs and Adverse Events of Special Interest (AESIs) According to NCI-CTCAE version 5.0

Top of page

End point title

Double-blind Part: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Treatment Related TEAEs and Adverse Events of Special Interest (AESIs) According to NCI-CTCAE version 5.0 ^[10]

End point description

AE: any untoward medical occurrence in a subject administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE: AE that resulted in any of following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE: events with onset date/worsening during the on-treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious/non-serious AEs that are of clinical interest and should be closely followed. AESIs include following: Infusion-related reactions including immediate hypersensitivity; Immune-related AEs; Transforming growth factor beta (TGFβ) inhibition mediated skin reactions; Anemia; Bleeding AEs. Safety analysis set: all subjects who were administered at least 1 dose of any study treatment (M7824, placebo, gemcitabine or cisplatin).

End point type

Secondary

End point timeframe

Time from first treatment up to data cutoff (assessed up to 609 days)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only double-blind part. Therefore, other arms has not been selected.

End point values	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	149	146
Units: Subjects
Subjects with TEAEs	145	140
Subjects with Serious TEAEs	36	58
Subjects with Treatment-related TEAEs	136	133
Subjects with AESIs	8	16

No statistical analyses for this end point

Secondary: Double-blind Part: Durable Response of at least 6 months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator

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End point title

Double-blind Part: Durable Response of at least 6 months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator ^[11]

End point description

Durable Response was defined as the number of subjects with confirmed objective response (CR or PR) according to RECIST 1.1, determined by Investigator with duration of at least 6 months. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. Based on a review of data conducted by the Independent Data Monitoring Committee (IDMC), Sponsor has decided to discontinue this study as the study is unlikely to achieve the primary objective of overall survival. Subsequently, the data for this endpoint was not collected and analyzed.

End point type

Secondary

End point timeframe

Time from first treatment assessed up to 1148 days

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: It was planned to report data for only double-blind part. Therefore, other arms has not been selected.

End point values	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Number of subjects analysed	0 ^[12]	0 ^[13]
Units: subjects

Notes
[12] - Data for this endpoint was not collected and analyzed.
[13] - Data for this endpoint was not collected and analyzed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Time from first treatment up to data cutoff (assessed up to 609 days)

Adverse event reporting additional description

Safety Run-In Part: The safety run-in (SRI) analysis set includes all subjects from the safety run-in part who were administered any dose of any study intervention and double-blinded part safety analysis set included all randomized subjects who were administered at least one dose of study treatment (M7824, Placebo, Gemcitabine or Cisplatin).

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Double-blinded Part: Placebo + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Reporting group title

Safety Run-In Part: M7824 + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of Complete Response), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 milligram per meter square (mg/m^2) and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks.

Reporting group title

Double-blinded Part: M7824 + Gemcitabine + Cisplatin

Reporting group description

Subjects received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of CR), otherwise until criterion pre-specified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 mg/m^2 and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks. In case of any missed dose for chemotherapy, gemcitabine and cisplatin combination administered on Day 15 of that cycle or at the end of the scheduled 8 cycles (up to 16 administrations of gemcitabine and cisplatin combination). The administration of the missed dose on Day 15 or at the end of 8 cycles is Investigator’s clinical decision.

Serious adverse events	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Total subjects affected by serious adverse events
subjects affected / exposed	36 / 149 (24.16%)	5 / 12 (41.67%)	58 / 146 (39.73%)
number of deaths (all causes)	26	7	31
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	2 / 149 (1.34%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Embolism
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 149 (1.34%)	1 / 12 (8.33%)	4 / 146 (2.74%)
occurrences causally related to treatment / all	1 / 2	0 / 1	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hernia
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Chills
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Product issues
Device occlusion
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Lymphocyte count decreased
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood sodium decreased
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	3 / 149 (2.01%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood albumin decreased
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	2 / 149 (1.34%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Incisional hernia
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	3 / 146 (2.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nervous system disorders
Cerebral infarction
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Ischaemic cerebral infarction
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 149 (1.34%)	0 / 12 (0.00%)	7 / 146 (4.79%)
occurrences causally related to treatment / all	1 / 2	0 / 0	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 149 (1.34%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Ulcerative keratitis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric stenosis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Gastrointestinal vascular malformation haemorrhagic
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Rectal haemorrhage
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	3 / 146 (2.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	3 / 146 (2.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	5 / 149 (3.36%)	0 / 12 (0.00%)	6 / 146 (4.11%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cholecystitis
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Jaundice cholestatic
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary obstruction
subjects affected / exposed	3 / 149 (2.01%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dermatitis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypopituitarism
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adrenal insufficiency
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	3 / 149 (2.01%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes simplex encephalitis
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	2 / 149 (1.34%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Soft tissue infection
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 149 (0.67%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 149 (0.00%)	0 / 12 (0.00%)	2 / 146 (1.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Double-blinded Part: Placebo + Gemcitabine + Cisplatin	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin	Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Total subjects affected by non serious adverse events
subjects affected / exposed	142 / 149 (95.30%)	12 / 12 (100.00%)	134 / 146 (91.78%)
Vascular disorders
Hypertension
subjects affected / exposed	11 / 149 (7.38%)	1 / 12 (8.33%)	6 / 146 (4.11%)
occurrences all number	11	1	6
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	10 / 149 (6.71%)	1 / 12 (8.33%)	9 / 146 (6.16%)
occurrences all number	10	1	9
Mucosal inflammation
subjects affected / exposed	4 / 149 (2.68%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	4	1	1
Malaise
subjects affected / exposed	11 / 149 (7.38%)	0 / 12 (0.00%)	5 / 146 (3.42%)
occurrences all number	11	0	5
Generalised oedema
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Fatigue
subjects affected / exposed	35 / 149 (23.49%)	4 / 12 (33.33%)	29 / 146 (19.86%)
occurrences all number	35	4	29
Asthenia
subjects affected / exposed	18 / 149 (12.08%)	2 / 12 (16.67%)	23 / 146 (15.75%)
occurrences all number	18	2	23
Pyrexia
subjects affected / exposed	19 / 149 (12.75%)	3 / 12 (25.00%)	33 / 146 (22.60%)
occurrences all number	19	3	33
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	2 / 146 (1.37%)
occurrences all number	1	1	2
Epistaxis
subjects affected / exposed	3 / 149 (2.01%)	2 / 12 (16.67%)	19 / 146 (13.01%)
occurrences all number	3	2	19
Dyspnoea exertional
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	3 / 146 (2.05%)
occurrences all number	0	1	3
Cough
subjects affected / exposed	9 / 149 (6.04%)	3 / 12 (25.00%)	3 / 146 (2.05%)
occurrences all number	9	3	3
Psychiatric disorders
Adjustment disorder
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	1	1	0
Anxiety
subjects affected / exposed	6 / 149 (4.03%)	1 / 12 (8.33%)	3 / 146 (2.05%)
occurrences all number	6	1	3
Insomnia
subjects affected / exposed	2 / 149 (1.34%)	1 / 12 (8.33%)	12 / 146 (8.22%)
occurrences all number	2	1	12
Investigations
Alanine aminotransferase increased
subjects affected / exposed	20 / 149 (13.42%)	2 / 12 (16.67%)	13 / 146 (8.90%)
occurrences all number	20	2	13
Amylase increased
subjects affected / exposed	8 / 149 (5.37%)	2 / 12 (16.67%)	4 / 146 (2.74%)
occurrences all number	8	2	4
Aspartate aminotransferase increased
subjects affected / exposed	22 / 149 (14.77%)	2 / 12 (16.67%)	13 / 146 (8.90%)
occurrences all number	22	2	13
Blood albumin decreased
subjects affected / exposed	4 / 149 (2.68%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	4	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	8 / 149 (5.37%)	1 / 12 (8.33%)	7 / 146 (4.79%)
occurrences all number	8	1	7
Blood bilirubin increased
subjects affected / exposed	14 / 149 (9.40%)	0 / 12 (0.00%)	9 / 146 (6.16%)
occurrences all number	14	0	9
Blood creatinine increased
subjects affected / exposed	7 / 149 (4.70%)	1 / 12 (8.33%)	6 / 146 (4.11%)
occurrences all number	7	1	6
Blood magnesium decreased
subjects affected / exposed	3 / 149 (2.01%)	1 / 12 (8.33%)	2 / 146 (1.37%)
occurrences all number	3	1	2
Creatinine renal clearance decreased
subjects affected / exposed	9 / 149 (6.04%)	1 / 12 (8.33%)	4 / 146 (2.74%)
occurrences all number	9	1	4
Gamma-glutamyltransferase increased
subjects affected / exposed	10 / 149 (6.71%)	1 / 12 (8.33%)	4 / 146 (2.74%)
occurrences all number	10	1	4
Haemoglobin decreased
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	3 / 146 (2.05%)
occurrences all number	0	1	3
Iron binding capacity total decreased
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Lipase increased
subjects affected / exposed	9 / 149 (6.04%)	2 / 12 (16.67%)	5 / 146 (3.42%)
occurrences all number	9	2	5
Neutrophil count decreased
subjects affected / exposed	59 / 149 (39.60%)	5 / 12 (41.67%)	28 / 146 (19.18%)
occurrences all number	59	5	28
White blood cell count decreased
subjects affected / exposed	36 / 149 (24.16%)	3 / 12 (25.00%)	19 / 146 (13.01%)
occurrences all number	36	3	19
Platelet count decreased
subjects affected / exposed	38 / 149 (25.50%)	3 / 12 (25.00%)	34 / 146 (23.29%)
occurrences all number	38	3	34
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	3 / 149 (2.01%)	1 / 12 (8.33%)	6 / 146 (4.11%)
occurrences all number	3	1	6
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Tachycardia
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	1	1	0
Nervous system disorders
Dizziness
subjects affected / exposed	13 / 149 (8.72%)	0 / 12 (0.00%)	8 / 146 (5.48%)
occurrences all number	13	0	8
Taste disorder
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	5 / 146 (3.42%)
occurrences all number	1	1	5
Headache
subjects affected / exposed	13 / 149 (8.72%)	0 / 12 (0.00%)	12 / 146 (8.22%)
occurrences all number	13	0	12
Dysgeusia
subjects affected / exposed	3 / 149 (2.01%)	2 / 12 (16.67%)	6 / 146 (4.11%)
occurrences all number	3	2	6
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	79 / 149 (53.02%)	6 / 12 (50.00%)	78 / 146 (53.42%)
occurrences all number	79	6	78
Lymphopenia
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	1	1	1
Leukopenia
subjects affected / exposed	7 / 149 (4.70%)	1 / 12 (8.33%)	4 / 146 (2.74%)
occurrences all number	7	1	4
Neutropenia
subjects affected / exposed	40 / 149 (26.85%)	1 / 12 (8.33%)	25 / 146 (17.12%)
occurrences all number	40	1	25
Thrombocytopenia
subjects affected / exposed	12 / 149 (8.05%)	1 / 12 (8.33%)	14 / 146 (9.59%)
occurrences all number	12	1	14
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	3 / 146 (2.05%)
occurrences all number	0	1	3
Ear discomfort
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Ear congestion
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Eye disorders
Eye pain
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	1	1	0
Vision blurred
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	1	1	0
Retinal haemorrhage
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	11 / 149 (7.38%)	2 / 12 (16.67%)	13 / 146 (8.90%)
occurrences all number	11	2	13
Abdominal distension
subjects affected / exposed	3 / 149 (2.01%)	1 / 12 (8.33%)	5 / 146 (3.42%)
occurrences all number	3	1	5
Abdominal pain lower
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Abdominal pain upper
subjects affected / exposed	6 / 149 (4.03%)	2 / 12 (16.67%)	5 / 146 (3.42%)
occurrences all number	6	2	5
Diarrhoea
subjects affected / exposed	15 / 149 (10.07%)	3 / 12 (25.00%)	20 / 146 (13.70%)
occurrences all number	15	3	20
Constipation
subjects affected / exposed	51 / 149 (34.23%)	4 / 12 (33.33%)	40 / 146 (27.40%)
occurrences all number	51	4	40
Ascites
subjects affected / exposed	9 / 149 (6.04%)	0 / 12 (0.00%)	1 / 146 (0.68%)
occurrences all number	9	0	1
Aphthous ulcer
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Dyspepsia
subjects affected / exposed	10 / 149 (6.71%)	1 / 12 (8.33%)	6 / 146 (4.11%)
occurrences all number	10	1	6
Gingival bleeding
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	13 / 146 (8.90%)
occurrences all number	0	1	13
Vomiting
subjects affected / exposed	32 / 149 (21.48%)	1 / 12 (8.33%)	31 / 146 (21.23%)
occurrences all number	32	1	31
Stomatitis
subjects affected / exposed	6 / 149 (4.03%)	0 / 12 (0.00%)	16 / 146 (10.96%)
occurrences all number	6	0	16
Rectal haemorrhage
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	1	1	1
Nausea
subjects affected / exposed	72 / 149 (48.32%)	6 / 12 (50.00%)	64 / 146 (43.84%)
occurrences all number	72	6	64
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Cholangitis
subjects affected / exposed	3 / 149 (2.01%)	1 / 12 (8.33%)	2 / 146 (1.37%)
occurrences all number	3	1	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	16 / 149 (10.74%)	0 / 12 (0.00%)	5 / 146 (3.42%)
occurrences all number	16	0	5
Blister
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Dermatitis
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	3 / 146 (2.05%)
occurrences all number	0	1	3
Erythema multiforme
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	2 / 146 (1.37%)
occurrences all number	1	1	2
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	0	1	1
Urticaria
subjects affected / exposed	6 / 149 (4.03%)	1 / 12 (8.33%)	3 / 146 (2.05%)
occurrences all number	6	1	3
Rash papular
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	0	1	1
Rash maculo-papular
subjects affected / exposed	4 / 149 (2.68%)	0 / 12 (0.00%)	10 / 146 (6.85%)
occurrences all number	4	0	10
Rash
subjects affected / exposed	21 / 149 (14.09%)	6 / 12 (50.00%)	36 / 146 (24.66%)
occurrences all number	21	6	36
Pruritus
subjects affected / exposed	14 / 149 (9.40%)	4 / 12 (33.33%)	35 / 146 (23.97%)
occurrences all number	14	4	35
Pigmentation disorder
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Skin lesion
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	0	1	1
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	2 / 149 (1.34%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	2	1	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	6 / 149 (4.03%)	1 / 12 (8.33%)	8 / 146 (5.48%)
occurrences all number	6	1	8
Myalgia
subjects affected / exposed	10 / 149 (6.71%)	0 / 12 (0.00%)	0 / 146 (0.00%)
occurrences all number	10	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	4 / 149 (2.68%)	0 / 12 (0.00%)	9 / 146 (6.16%)
occurrences all number	4	0	9
Systemic candida
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Pneumonia
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	1	1	0
Oral candidiasis
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	1	1	0
Herpes zoster
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Cystitis
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	4 / 146 (2.74%)
occurrences all number	1	1	4
Clostridium difficile infection
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 149 (0.00%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	0	1	0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	4 / 149 (2.68%)	1 / 12 (8.33%)	3 / 146 (2.05%)
occurrences all number	4	1	3
Diabetes mellitus
subjects affected / exposed	1 / 149 (0.67%)	1 / 12 (8.33%)	0 / 146 (0.00%)
occurrences all number	1	1	0
Decreased appetite
subjects affected / exposed	36 / 149 (24.16%)	3 / 12 (25.00%)	30 / 146 (20.55%)
occurrences all number	36	3	30
Hypocalcaemia
subjects affected / exposed	4 / 149 (2.68%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	4	1	1
Hypomagnesaemia
subjects affected / exposed	13 / 149 (8.72%)	0 / 12 (0.00%)	8 / 146 (5.48%)
occurrences all number	13	0	8
Hyponatraemia
subjects affected / exposed	8 / 149 (5.37%)	0 / 12 (0.00%)	10 / 146 (6.85%)
occurrences all number	8	0	10
Hypophosphataemia
subjects affected / exposed	3 / 149 (2.01%)	1 / 12 (8.33%)	1 / 146 (0.68%)
occurrences all number	3	1	1
Hypokalaemia
subjects affected / exposed	10 / 149 (6.71%)	1 / 12 (8.33%)	7 / 146 (4.79%)
occurrences all number	10	1	7

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Were there any global substantial amendments to the protocol? Yes

11 Oct 2019

• To describe a single primary endpoint (overall survival) in the randomized, double-blind part of the study rather than dual primary endpoints. • To remove the requirement for initial progressive disease as determined by the Investigator to be verified by an Independent Review Committee (IRC). • The analysis of progression-free survival (PFS) and other tumor-based efficacy endpoints was based on Investigator assessment; analysis based on IRC assessment was only performed if the study is not expanded to Phase III. • To acknowledge that, for the purposes of marketing authorization in Japan, if the study was not expanded into Phase III, it will not be acceptable as a confirmatory study. • To provide additional information on the power to detect differences in efficacy among the different biliary tract cancer anatomical subgroups. • To exclude subjects with history of bleeding diathesis and provide further guidance on dose modifications for bleeding events according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) severity grade and site of bleeding. • To include additional patient-reported outcome measures to enable subjects experience of the study intervention to be further characterized. • To allow chemotherapy to be given on Day 15 of a given cycle if administration on Day 1 or Day 8 was not possible.

27 Jul 2020

• Updated maximal number of subjects for Phase II. • Updated text to clarify that initial 150 subjects recruited in Phase II were analyzed for an expansion decision into Phase III. • Updated a minimum follow-up period at least 19 weeks for the first 150 subjects randomized were included. • Updated assumptions of sample size calculation (i.e., number of subjects and time periods). • Added the information about the Independent Data Monitoring Committee (IDMC) and Independent Review Committee (IRC) responsibility for Phase II and Phase III study. • Added clarification that Independent Review Committee (IRC) used in Phase II only. • Updated exclusion criteria 2, 5 and 16. • Clarified administration of chemotherapy and dose modification for neutropenia and thrombocytopenia in the case of gemcitabine and/or cisplatin-related adverse drug reactions. • Clarified the magnetic resonance imaging (MRI) areas. • Removed the information for central imaging read and interpretation for all scans. • Added Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). • Clarified that radiological images collected from the remaining 350 subjects must be submitted.

20 Apr 2021

• An additional criterion has been added to the definition of the efficacy analysis set was used for the analysis for decision on the expansion to Phase III sample size. • Futility criterion was introduced for expansion decision and Overall Survival (OS) analysis. • A description was added to provide clarity on the type of study population to be analyzed for efficacy and safety analysis for expansion into Phase III. This clarification would also help IDMC’s assessment of efficacy and safety data and to provide their recommendation for expansion into the Phase III. • A note has been added to guide in checking enrollment of the study population. • Further information was added to explain the rationale for selecting antibiotics-naïve subjects for expansion decision. • Edits are done to highlight dose modification of the study intervention in a specific condition. • Inclusion criterion number 2 has been updated. • Exclusion criterion number 5 and 13 has been updated. • Details were added on study treatment administration. Edits were done in this section to indicate dose modification of M7824/placebo to 1200 mg was allowed in the study.

14 Jul 2021

• Text was revised to include a summary of the additional criterion for expansion into Phase III. • Exclusion criterion 10 was split into 2 separate bullets without change in content. • Text related to local requirements for dosing of gemcitabine and cisplatin was revised. Links to Sections 6.6.3 and 6.6.4 referring to dose modification instructions for gemcitabine and cisplatin were added.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Data collection and analysis of Pharmacokinetics and Immunogenicity were omitted and not conducted due to business reason.

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