Trial Outcomes & Findings for Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) in Participants With 1L BTC (NCT NCT04066491)

Last Updated: 2023-11-14

Results Overview

A DLT is a toxicity related to the study intervention that meets the following criteria as evaluated in the open-label, safety run-in: Grade 3 or 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; Grade 3 or 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 Grade 5 toxicity.

Recruitment status

TERMINATED

Study phase

PHASE2/PHASE3

Target enrollment

309 participants

Primary outcome timeframe

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

Results posted on

2023-11-14

Participant Flow

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

Participant milestones

Participant milestones
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Participants 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.	Double-blinded Part: Placebo + Gemcitabine + Cisplatin Participants received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until crtiterion pre-sepcified 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin Participants 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 crtiterion pre-sepcified 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.
Overall Study STARTED	12	149	148
Overall Study Treated	12	149	146
Overall Study COMPLETED	12	149	146
Overall Study NOT COMPLETED	0	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Participants 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.	Double-blinded Part: Placebo + Gemcitabine + Cisplatin Participants received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until crtiterion pre-sepcified 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin Participants 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 crtiterion pre-sepcified 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.
Overall Study Randomized, not treated	0	0	2

Baseline Characteristics

Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) in Participants With 1L BTC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=12 Participants Participants 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.	Double-blinded Part: Placebo + Gemcitabine + Cisplatin n=149 Participants Participants received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until crtiterion pre-sepcified 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin n=148 Participants Participants 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 crtiterion pre-sepcified 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.	Total n=309 Participants Total of all reporting groups
Age, Continuous	66 Years STANDARD_DEVIATION 11.9 • n=93 Participants	64 Years STANDARD_DEVIATION 10.6 • n=4 Participants	63 Years STANDARD_DEVIATION 10.8 • n=27 Participants	63 Years STANDARD_DEVIATION 10.7 • n=483 Participants
Sex: Female, Male Female	5 Participants n=93 Participants	78 Participants n=4 Participants	68 Participants n=27 Participants	151 Participants n=483 Participants
Sex: Female, Male Male	7 Participants n=93 Participants	71 Participants n=4 Participants	80 Participants n=27 Participants	158 Participants n=483 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants	21 Participants n=4 Participants	22 Participants n=27 Participants	44 Participants n=483 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants n=93 Participants	128 Participants n=4 Participants	126 Participants n=27 Participants	265 Participants n=483 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants
Race (NIH/OMB) Asian	6 Participants n=93 Participants	93 Participants n=4 Participants	90 Participants n=27 Participants	189 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	1 Participants n=483 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	1 Participants n=483 Participants
Race (NIH/OMB) White	6 Participants n=93 Participants	51 Participants n=4 Participants	51 Participants n=27 Participants	108 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	1 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	3 Participants n=4 Participants	5 Participants n=27 Participants	8 Participants n=483 Participants

PRIMARY outcome

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

Population: The DLT analysis set included all participants who experienced at least one DLT (either by Investigator or by Safety Monitoring Committee (SMC) or who completed the safety run-in, that is the 21-day DLT evaluation period, receiving at least one infusion of M7824 and of both gemcitabine and cisplatin and not being withdrawn during the DLT evaluation period for reasons other than toxicity.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=12 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin Participants 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 crtiterion pre-sepcified 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.
Safety Run-in Part: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)	0 Participants	—

PRIMARY outcome

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

Population: Intent-to-Treat analysis set included all randomized participants. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=18 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin n=23 Participants Participants 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 crtiterion pre-sepcified 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.
Double-blind Part: Overall Survival	11.5 Months Interval 0.9 to 15.2	11.5 Months Interval 0.2 to 13.9

SECONDARY outcome

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

Population: The safety run-in (SRI) analysis set includes all participants from the safety run-in part who were administered any dose of any study intervention.

Adverse Event (AE) was defined any untoward medical occurrence in a participant 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.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=12 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin Participants 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 crtiterion pre-sepcified 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.
Safety Run-in Part: Number of Participants 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 Participants with TEAEs	12 Participants	—
Safety Run-in Part: Number of Participants 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 Participants with Serious TEAEs	5 Participants	—
Safety Run-in Part: Number of Participants 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 Participants with Treatment-related TEAEs	11 Participants	—

SECONDARY outcome

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

Population: The safety run-in (SRI) analysis set includes all participants from the safety run-in part who were administered any dose of any study intervention.

Laboratory investigation included hematology and biochemistry. The number of participants 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.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=12 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin Participants 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 crtiterion pre-sepcified 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.
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Hemoglobin low	6 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Leukocytes low	4 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Neutrophils low	6 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Platelets low	3 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Alanine Aminotransferase high	2 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Bilirubin high	1 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Creatinine high	1 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Lipase high	1 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Potassium low	1 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Lymphocytes low	2 Participants	—
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities Corrected Calcium high	1 Participants	—

SECONDARY outcome

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

Population: The intent-to-treat (ITT) analysis set includes all randomized participants. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=44 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin n=49 Participants Participants 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 crtiterion pre-sepcified 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.
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)	5.6 Months Interval 4.2 to 6.9	5.5 Months Interval 2.8 to 6.7

SECONDARY outcome

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

Percentage of participants 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.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=77 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin n=73 Participants Participants 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 crtiterion pre-sepcified 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.
Double-blind Part: Percentage of Participants 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)	19.5 Percentage of participants Interval 11.3 to 30.1	31.5 Percentage of participants Interval 21.1 to 43.4

SECONDARY outcome

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

DOR was defined for participants 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.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=7 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin n=9 Participants Participants 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 crtiterion pre-sepcified 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.
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)	12.5 Months Interval 2.7 to 12.5	7.0 Months Interval 1.4 to 8.3

SECONDARY outcome

Timeframe: Time from first treatment assessed up to 1148 days

Population: Based on a review of data conducted by the Independent Data Monitoring Committee (IDMC), Sponsor decided to discontinue this study as the study was unlikely to achieve the primary objective of overall survival. Subsequently, the data for this outcome measure was not collected and analyzed.

Durable Response was defined as the number of participants 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

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

Population: Safety analysis set included all participants who were administered at least one dose of any study treatment (M7824, placebo, gemcitabine or cisplatin).

AE was defined any untoward medical occurrence in a participant 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. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and should be closely followed. For this study, AESIs include the following: Infusion-related reactions including immediate hypersensitivity; Immune-related AEs; Transforming growth factor beta (TGFβ) inhibition mediated skin reactions; Anemia; Bleeding AEs.

Outcome measures

Outcome measures
Measure	Safety Run-In Part: M7824 + Gemcitabine + Cisplatin n=149 Participants Participants 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 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.	Double-blinded Part: M7824 + Gemcitabine + Cisplatin n=146 Participants Participants 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 crtiterion pre-sepcified 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.
Double-blind Part: Number of Participants 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 Participants with TEAEs	145 Participants	140 Participants
Double-blind Part: Number of Participants 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 Participants with Serious TEAEs	36 Participants	58 Participants
Double-blind Part: Number of Participants 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 Participants with Treatment-related TEAEs	136 Participants	133 Participants
Double-blind Part: Number of Participants 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 Participants with AESIs	8 Participants	16 Participants

Adverse Events

Safety Run-In Part: M7824 + Gemcitabine + Cisplatin

Serious events: 5 serious events

Other events: 12 other events

Deaths: 7 deaths

Double-blinded Part: Placebo + Gemcitabine + Cisplatin

Serious events: 36 serious events

Other events: 142 other events

Deaths: 26 deaths

Double-blinded Part: M7824 + Gemcitabine + Cisplatin

Serious events: 58 serious events

Other events: 134 other events

Deaths: 31 deaths

Serious adverse events

Other adverse events

Additional Information

Communication Center

Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place