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

Sponsor
EMD Serono Research & Development Institute, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT04066491
Collaborator
Merck KGaA, Darmstadt, Germany (Industry)
309
94
3
39.4
3.3
0.1

Study Details

Study Description

Brief Summary

Study consisted of an open-label, safety run-in part and a randomized, double-blind, placebo-controlled Phase 2/3 part. In the Phase 2/3 part, the study was evaluated whether bintrafusp alfa in combination with the current standard of care (SoC) (gemcitabine plus cisplatin) improves overall survival (OS) in chemotherapy and immunotherapy-naïve participants with locally advanced or metastatic Biliary Tract Cancer (BTC) compared to placebo, gemcitabine and cisplatin.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
309 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Sep 20, 2019
Actual Primary Completion Date :
May 20, 2021
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Safety Run-In Part: M7824 + Gemcitabine + Cisplatin

Drug: M7824
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-sepcified 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.

Drug: Gemcitabine
Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W).

Drug: Cisplatin
Cisplatin was received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W).

Experimental: Double-blinded Part: M7824 + Gemcitabine + Cisplatin

Drug: Gemcitabine
Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W).

Drug: Cisplatin
Cisplatin was received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W).

Placebo Comparator: Double-blinded Part: Placebo + Gemcitabine + Cisplatin

Drug: Placebo
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.

Drug: Gemcitabine
Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W).

Drug: Cisplatin
Cisplatin was received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W).

Outcome Measures

Primary Outcome Measures

  1. Safety Run-in Part: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) [Day 1 up to Day 21 of Cycle 1 (each Cycle is of 21 days)]

    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.

  2. Double-blind Part: Overall Survival [Time from study day 1 up to data cutoff (assessed up to 609 days)]

    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.

Secondary Outcome Measures

  1. 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 [Time from first treatment to up to data cutoff (assessed up to 609 days)]

    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.

  2. Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities [Time from first treatment to up to data cutoff (assessed up to 609 days)]

    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.

  3. 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) [Time from randomization of study drug until the first documentation of PD or death, assessed approximately up to 609 days]

    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.

  4. 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) [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.

  5. 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) [From first documented objective response to PD or death due to any cause, assessed approximately 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.

  6. Durable Response of at Least 6 Months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 [Time from first treatment assessed up to 1199 days]

  7. 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 [Time from first treatment to up to data cutoff (assessed up to 609 days)]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Are participants with histologically or cytologically confirmed locally advanced or metastatic BTC

  • Participants must have available tumor tissue (primary or metastatic) (archival or fresh biopsies) before the first administration of study treatment

  • At least 1 measurable lesion according to RECIST 1.1

  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing

  • Life expectancy of >= 12 weeks, as judged by the Investigator

  • Adequate hematological function, hepatic function, renal function, coagulation function as defined in the protocol

  • Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals

  • Other protocol defined inclusion criteria could apply

Exclusion Criteria:
  • Previous and/or intercurrent cancers

  • Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression

  • Participants with symptomatic central nervous system (CNS) metastases

  • Significant acute or chronic infection including known history of positive test for human immunodeficiency virus (HIV), active tuberculosis, uncontrolled biliary infection and active bacterial or fungal infection requiring systemic therapy (with the exception of hepatitis B and hepatitis C) requiring systemic therapy at study entry and at Week 1 Day 1 prior to dosing.

  • Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent

  • History of or concurrent interstitial lung disease

  • History of hypersensitivity reactions to bintrafusp alfa, anaphylaxis, or recent (within 5 months) uncontrolled asthma, cardiovascular/cerebrovascular disease

  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization

  • Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints)

  • Other protocol defined exclusion criteria could apply

Contacts and Locations

Locations

Site City State Country Postal Code
1 Ironwood Cancer & Research Centers - Chandler II Chandler Arizona United States 85224
2 Banner MD Anderson Cancer Center Gilbert Arizona United States 85234
3 Mayo Clinic Arizona Phoenix Arizona United States 85054
4 Beverly Hills Cancer Center Beverly Hills California United States 90211
5 Mayo Clinic in Florida - Department of Neurology Jacksonville Florida United States 32224
6 Mount Sinai Medical Center Miami Beach Florida United States 33140
7 University of Kansas Medical Center Research Institute, Inc. - University of Kansas Cancer Center/Bloch Pavilion Westwood Kansas United States 66216
8 Sidney Kimmel Comprehensive Cancer Center at John Hopkins Baltimore Maryland United States 21287
9 Mayo Clinic - Rochester Rochester Minnesota United States 55905
10 Methodist Transplant Physicians Dallas Texas United States 75203
11 MD Anderson Cancer Center - Unit 429 Houston Texas United States 77030
12 Renovatio Clinical - CENTRAL SITE The Woodlands Texas United States 77380
13 Hospital de Gastroenterologia Dr. Carlos Bonorino Udaondo Ciudad Autonoma Buenos Aires Argentina
14 Instituto de Investigaciones Metabolicas (IDIM) Ciudad Autonoma Buenos Aires Argentina
15 Instituto Medico Especializado Alexander Fleming Ciudad Autonoma Buenos Aires Argentina
16 Centro Oncologico Riojano Integral (CORI) La Rioja Argentina
17 CEDIT Salta Argentina
18 Centro Medico San Roque S.R.L. San Miguel de Tucuman Argentina
19 Fundacion ARS Medica San Salvador de Jujuy Argentina
20 Blacktown Hospital - PARENT Blacktown Australia
21 Monash Health Clayton Australia
22 Epworth Freemasons Melbourne Australia
23 Icon Cancer Care South Brisbane South Brisbane Australia
24 INCA - Instituto Nacional de Câncer Rio de Janeiro Brazil
25 CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia Santo André Brazil
26 Fundação Faculdade Regional de Medicina de São José do Rio Preto Sao Jose Rio Preto Brazil
27 A. C. Camargo Cancer Center São Paulo Brazil
28 ICESP - Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira São Paulo Brazil
29 IC la serena Research La Serena Chile
30 Centro de Investigación Clínica Bradford Hill Santiago Chile
31 Hospital Clínico Universidad de Chile Santiago Chile
32 Prosalud Santiago Chile
33 Instituto Clinico Oncologico del Sur (ICOS) Temuco Chile
34 Beijing Cancer Hospital Beijing China
35 Beijing Friendship Hospital, Capital Medical University Beijing China
36 West China Hospital, Sichuan University Chengdu China
37 Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine Hangzhou China
38 The Affiliated Hospital of Qingdao University Qingdao China
39 Fudan University Shanghai Cancer Hospital Shanghai China
40 The Second Affiliated Hospital of Soochow University Suzhou China
41 Tianjin Medical University Cancer Institute & Hospital Tianjin China
42 Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
43 ICO - Site Paul Papin - service d'oncologie medicale Angers Cedex 2 France
44 Centre Georges François Leclerc - Oncologie Médicale Dijon cedex France
45 CHU Lille - Hôpital Claude Huriez Lille cedex France
46 ICO - Site René Gauducheau Saint Herblain France
47 CHU de Toulouse - Hôpital Ranguei Toulouse Cedex 9 France
48 Vivantes Klinikum Neukoelln - Haematologie und Onkologie Berlin Germany
49 Universitaetsklinikum Bonn AoeR - Medizinische Klinik I Gastroenterologie Bonn Germany
50 Universitaetsklinikum Carl Gustav Carus TU Dresden - Medizinische Klinik I Dresden Germany
51 Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt Germany
52 Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz - Medizinische Klinik I - HCC Ambulanz Mainz Germany
53 Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma) - UOC Oncologia Verona Italy
54 Chiba Cancer Center Chiba-shi Japan
55 National Cancer Center Hospital - Dept of Hepatobiliary and Pancreatic Oncology Chuo-ku Japan
56 NHO Kyushu Cancer Center - Dept of Gastroenterology/Hepatology/Pancreatology Fukuoka-shi Japan
57 National Cancer Center Hospital East Kashiwa-shi Japan
58 Cancer Institute Hospital of JFCR - Dept of Hepato,Biliary and Pancreatic Medicine Koto-ku Japan
59 Kyorin University Hospital Mitaka-shi Japan
60 Aichi Cancer Center Hospital Nagoya-shi Japan
61 Osaka City University Hospital Osaka-shi Japan
62 Kindai University Hospital Osakasayama-shi Japan
63 Kanagawa Cancer Center Yokohama-shi Japan
64 Chungnam National University Hospital - Department of Internal Medicine (Rheumatology) Daejeon Korea, Republic of
65 Seoul National University Bundang Hospital Seongnam-si Korea, Republic of
66 Asan Medical Center Seoul Korea, Republic of
67 Korea University Anam Hospital Seoul Korea, Republic of
68 Korea University Guro Hospital Seoul Korea, Republic of
69 Samsung Medical Center Seoul Korea, Republic of
70 Seoul National University Hospital Seoul Korea, Republic of
71 Severance Hospital, Yonsei University Health System Seoul Korea, Republic of
72 The Catholic University of Korea, Seoul St. Mary's Hospital Seoul Korea, Republic of
73 Centrum Onkologii-Instytut im.M.Sklodowskiej Curie Gliwice Poland
74 Pratia Krakow Poland
75 Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy Warszawa Poland
76 ETG Zamosc Zamosc Poland
77 Hospital Clinic i Provincial de Barcelona - Servicio de Oncologia Barcelona Spain
78 Hospital Universitari Vall d'Hebron - Dept of Oncology Barcelona Spain
79 Hospital San Pedro de Alcantara - Servicio de Oncologia Caceres Spain
80 Hospital Universitario Reina Sofia - Dept of Oncology Cordoba Spain
81 ICO l´Hospitalet - Hospital Duran i Reynals L'Hospitalet de Llobregat Spain
82 Hospital General Universitario Gregorio Marañon - Servicio de Oncologia Medica Madrid Spain
83 Hospital Universitario Clinico San Carlos - Servicio de Oncologia Madrid Spain
84 Hospital Universitario HM Madrid Sanchinarro - Servicio de Oncologia Madrid Spain
85 Hospital Clinico Universitario de Valencia - Servicio de Hematologia y Oncologia Medica Valencia Spain
86 Hospital Universitari i Politecnic La Fe - Servicio de Oncologia Medica Valencia Spain
87 Kaohsiung Chang Gung Memorial Hospital Kaohsiung Taiwan
88 China Medical University Hospital Taichung Taiwan
89 Taichung Veterans General Hospital Taichung Taiwan
90 National Cheng Kung University Hospital Tainan Taiwan
91 National Taiwan University Hospital Taipei Taiwan
92 Taipei Veterans General Hospital Taipei Taiwan
93 Chang Gung Memorial Hospital, Linkou Taoyuan Taiwan
94 The Christie - Dept of Oncology Manchester United Kingdom

Sponsors and Collaborators

  • EMD Serono Research & Development Institute, Inc.
  • Merck KGaA, Darmstadt, Germany

Investigators

  • Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier:
NCT04066491
Other Study ID Numbers:
  • MS200647_0055
  • 2019-001992-35
First Posted:
Aug 26, 2019
Last Update Posted:
Jun 13, 2022
Last Verified:
May 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by EMD Serono Research & Development Institute, Inc.
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail First participant signed informed consent: 20-Sep-2019, Primary Analysis cutoff date: 20-May-2021.
Arm/Group Title Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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. 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.
Period Title: Overall Study
STARTED 12 149 148
Treated 12 149 146
COMPLETED 8 38 39
NOT COMPLETED 4 111 109

Baseline Characteristics

Arm/Group Title Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin Total
Arm/Group Description 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. 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. 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 of all reporting groups
Overall Participants 12 149 148 309
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
66
(11.9)
64
(10.6)
63
(10.8)
63
(10.7)
Sex: Female, Male (Count of Participants)
Female
5
41.7%
78
52.3%
68
45.9%
151
48.9%
Male
7
58.3%
71
47.7%
80
54.1%
158
51.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
1
8.3%
21
14.1%
22
14.9%
44
14.2%
Not Hispanic or Latino
11
91.7%
128
85.9%
126
85.1%
265
85.8%
Unknown or Not Reported
0
0%
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
1
0.7%
0
0%
1
0.3%
Asian
6
50%
93
62.4%
90
60.8%
189
61.2%
Native Hawaiian or Other Pacific Islander
0
0%
1
0.7%
0
0%
1
0.3%
Black or African American
0
0%
0
0%
1
0.7%
1
0.3%
White
6
50%
51
34.2%
51
34.5%
108
35%
More than one race
0
0%
0
0%
1
0.7%
1
0.3%
Unknown or Not Reported
0
0%
3
2%
5
3.4%
8
2.6%

Outcome Measures

1. Primary Outcome
Title Safety Run-in Part: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
Description 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.
Time Frame Day 1 up to Day 21 of Cycle 1 (each Cycle is of 21 days)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Safety Run-In Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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.
Measure Participants 12
Count of Participants [Participants]
0
0%
2. Primary Outcome
Title Double-blind Part: Overall Survival
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.
Time Frame Time from study day 1 up to data cutoff (assessed up to 609 days)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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.
Measure Participants 18 23
Median (Full Range) [Months]
11.5
11.5
3. Secondary Outcome
Title 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
Description 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.
Time Frame Time from first treatment to up to data cutoff (assessed up to 609 days)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Safety Run-In Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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.
Measure Participants 12
Participants with TEAEs
12
100%
Participants with Serious TEAEs
5
41.7%
Participants with Treatment-related TEAEs
11
91.7%
4. Secondary Outcome
Title Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities
Description 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.
Time Frame Time from first treatment to up to data cutoff (assessed up to 609 days)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Safety Run-In Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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.
Measure Participants 12
Hemoglobin low
6
50%
Leukocytes low
4
33.3%
Neutrophils low
6
50%
Platelets low
3
25%
Alanine Aminotransferase high
2
16.7%
Bilirubin high
1
8.3%
Creatinine high
1
8.3%
Lipase high
1
8.3%
Potassium low
1
8.3%
Lymphocytes low
2
16.7%
Corrected Calcium high
1
8.3%
5. Secondary Outcome
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)
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.
Time Frame Time from randomization of study drug until the first documentation of PD or death, assessed approximately up to 609 days

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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.
Measure Participants 44 49
Median (95% Confidence Interval) [Months]
5.6
5.5
6. Secondary Outcome
Title 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)
Description 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.
Time Frame Time from randomization of study drug up to data cut off (assessed up to 609 days)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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.
Measure Participants 77 73
Number (95% Confidence Interval) [Percentage of participants]
19.5
162.5%
31.5
21.1%
7. Secondary Outcome
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)
Description 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.
Time Frame From first documented objective response to PD or death due to any cause, assessed approximately up to 609 days

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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.
Measure Participants 7 9
Median (Full Range) [Months]
12.5
7.0
8. Secondary Outcome
Title Durable Response of at Least 6 Months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
Description
Time Frame Time from first treatment assessed up to 1199 days

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title
Arm/Group Description
9. Secondary Outcome
Title 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
Description 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.
Time Frame Time from first treatment to up to data cutoff (assessed up to 609 days)

Outcome Measure Data

Analysis Population Description
Safety analysis set included all participants who were administered at least one dose of any study treatment (M7824, placebo, gemcitabine or cisplatin).
Arm/Group Title Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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.
Measure Participants 149 146
Participants with TEAEs
145
1208.3%
140
94%
Participants with Serious TEAEs
36
300%
58
38.9%
Participants with Treatment-related TEAEs
136
1133.3%
133
89.3%
Participants with AESIs
8
66.7%
16
10.7%

Adverse Events

Time Frame Time from first treatment to up to data cutoff (assessed up to 609 days)
Adverse Event Reporting Description Safety Run-In Part: 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 and double-blinded part safety analysis set included all randomized participants who were administered at least one dose of study treatment (M7824, Placebo, Gemcitabine or Cisplatin).
Arm/Group Title Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Arm/Group Description 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. 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. 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.
All Cause Mortality
Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 7/12 (58.3%) 26/149 (17.4%) 31/146 (21.2%)
Serious Adverse Events
Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 5/12 (41.7%) 36/149 (24.2%) 58/146 (39.7%)
Blood and lymphatic system disorders
Anaemia 0/12 (0%) 2/149 (1.3%) 7/146 (4.8%)
Febrile neutropenia 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Neutropenia 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Pancytopenia 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Thrombocytopenia 1/12 (8.3%) 2/149 (1.3%) 0/146 (0%)
Cardiac disorders
Cardiac arrest 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Endocrine disorders
Adrenal insufficiency 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Hypophysitis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Hypopituitarism 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Hypothyroidism 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Eye disorders
Ulcerative keratitis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Gastrointestinal disorders
Abdominal pain 0/12 (0%) 1/149 (0.7%) 1/146 (0.7%)
Abdominal pain upper 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Ascites 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Colitis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Duodenal ulcer haemorrhage 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Gastric haemorrhage 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Gastric stenosis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Gastric ulcer 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Gastrointestinal haemorrhage 1/12 (8.3%) 1/149 (0.7%) 2/146 (1.4%)
Gastrointestinal vascular malformation haemorrhagic 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Haematochezia 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Intestinal obstruction 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Lower gastrointestinal haemorrhage 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Nausea 0/12 (0%) 0/149 (0%) 3/146 (2.1%)
Obstruction gastric 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Pancreatitis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Rectal haemorrhage 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Upper gastrointestinal haemorrhage 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Vomiting 0/12 (0%) 0/149 (0%) 3/146 (2.1%)
General disorders
Asthenia 1/12 (8.3%) 0/149 (0%) 1/146 (0.7%)
Chills 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Death 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Disease progression 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Fatigue 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Hernia 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Malaise 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Oedema peripheral 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Pyrexia 1/12 (8.3%) 2/149 (1.3%) 4/146 (2.7%)
Hepatobiliary disorders
Bile duct stenosis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Bile duct stone 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Biliary obstruction 1/12 (8.3%) 3/149 (2%) 1/146 (0.7%)
Cholangitis 0/12 (0%) 5/149 (3.4%) 6/146 (4.1%)
Cholecystitis 1/12 (8.3%) 1/149 (0.7%) 1/146 (0.7%)
Cholestasis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Hepatic failure 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Immune-mediated hepatitis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Jaundice cholestatic 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Immune system disorders
Anaphylactic shock 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Infections and infestations
Abdominal infection 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Bacteraemia 0/12 (0%) 0/149 (0%) 2/146 (1.4%)
Biliary sepsis 0/12 (0%) 0/149 (0%) 2/146 (1.4%)
Biliary tract infection 0/12 (0%) 3/149 (2%) 2/146 (1.4%)
COVID-19 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Diarrhoea infectious 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Herpes simplex encephalitis 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Klebsiella infection 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Liver abscess 0/12 (0%) 2/149 (1.3%) 1/146 (0.7%)
Pneumonia 0/12 (0%) 1/149 (0.7%) 1/146 (0.7%)
Pseudomonas infection 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Sepsis 0/12 (0%) 0/149 (0%) 2/146 (1.4%)
Soft tissue infection 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Urinary tract infection 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Vascular device infection 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Injury, poisoning and procedural complications
Incisional hernia 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Infusion related reaction 0/12 (0%) 0/149 (0%) 3/146 (2.1%)
Traumatic intracranial haemorrhage 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Investigations
Alanine aminotransferase increased 0/12 (0%) 0/149 (0%) 2/146 (1.4%)
Blood albumin decreased 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Blood bilirubin increased 0/12 (0%) 3/149 (2%) 2/146 (1.4%)
Blood sodium decreased 0/12 (0%) 1/149 (0.7%) 1/146 (0.7%)
Lipase increased 0/12 (0%) 1/149 (0.7%) 1/146 (0.7%)
Lymphocyte count decreased 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Neutrophil count decreased 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Platelet count decreased 0/12 (0%) 2/149 (1.3%) 1/146 (0.7%)
Transaminases increased 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Metabolism and nutrition disorders
Decreased appetite 0/12 (0%) 0/149 (0%) 2/146 (1.4%)
Dehydration 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Hypomagnesaemia 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Hyponatraemia 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Musculoskeletal and connective tissue disorders
Bone pain 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Metastases to bone 0/12 (0%) 2/149 (1.3%) 0/146 (0%)
Squamous cell carcinoma 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Squamous cell carcinoma of skin 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Tumour associated fever 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Nervous system disorders
Cerebral infarction 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Cerebral ischaemia 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Encephalopathy 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Facial paralysis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Haemorrhage intracranial 0/12 (0%) 0/149 (0%) 2/146 (1.4%)
Ischaemic cerebral infarction 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Product Issues
Device occlusion 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Renal and urinary disorders
Acute kidney injury 1/12 (8.3%) 0/149 (0%) 2/146 (1.4%)
Dysuria 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Haematuria 0/12 (0%) 1/149 (0.7%) 1/146 (0.7%)
Renal failure 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Tubulointerstitial nephritis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Respiratory, thoracic and mediastinal disorders
Epistaxis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Pleural effusion 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Respiratory distress 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Respiratory failure 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Skin and subcutaneous tissue disorders
Dermatitis 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Erythema multiforme 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Urticaria 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Vascular disorders
Embolism 0/12 (0%) 0/149 (0%) 2/146 (1.4%)
Hypertension 0/12 (0%) 0/149 (0%) 1/146 (0.7%)
Pelvic venous thrombosis 0/12 (0%) 1/149 (0.7%) 0/146 (0%)
Other (Not Including Serious) Adverse Events
Safety Run-In Part: M7824 + Gemcitabine + Cisplatin Double-blinded Part: Placebo + Gemcitabine + Cisplatin Double-blinded Part: M7824 + Gemcitabine + Cisplatin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 12/12 (100%) 142/149 (95.3%) 134/146 (91.8%)
Blood and lymphatic system disorders
Anaemia 6/12 (50%) 79/149 (53%) 78/146 (53.4%)
Leukopenia 1/12 (8.3%) 7/149 (4.7%) 4/146 (2.7%)
Lymphopenia 1/12 (8.3%) 1/149 (0.7%) 1/146 (0.7%)
Neutropenia 1/12 (8.3%) 40/149 (26.8%) 25/146 (17.1%)
Thrombocytopenia 1/12 (8.3%) 12/149 (8.1%) 14/146 (9.6%)
Cardiac disorders
Bradycardia 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Tachycardia 1/12 (8.3%) 1/149 (0.7%) 0/146 (0%)
Ear and labyrinth disorders
Ear congestion 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Ear discomfort 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Tinnitus 1/12 (8.3%) 0/149 (0%) 3/146 (2.1%)
Eye disorders
Eye pain 1/12 (8.3%) 1/149 (0.7%) 0/146 (0%)
Retinal haemorrhage 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Vision blurred 1/12 (8.3%) 1/149 (0.7%) 0/146 (0%)
Gastrointestinal disorders
Abdominal distension 1/12 (8.3%) 3/149 (2%) 5/146 (3.4%)
Abdominal pain 2/12 (16.7%) 11/149 (7.4%) 13/146 (8.9%)
Abdominal pain lower 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Abdominal pain upper 2/12 (16.7%) 6/149 (4%) 5/146 (3.4%)
Aphthous ulcer 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Ascites 0/12 (0%) 9/149 (6%) 1/146 (0.7%)
Constipation 4/12 (33.3%) 51/149 (34.2%) 40/146 (27.4%)
Diarrhoea 3/12 (25%) 15/149 (10.1%) 20/146 (13.7%)
Dyspepsia 1/12 (8.3%) 10/149 (6.7%) 6/146 (4.1%)
Gingival bleeding 1/12 (8.3%) 0/149 (0%) 13/146 (8.9%)
Nausea 6/12 (50%) 72/149 (48.3%) 64/146 (43.8%)
Rectal haemorrhage 1/12 (8.3%) 1/149 (0.7%) 1/146 (0.7%)
Stomatitis 0/12 (0%) 6/149 (4%) 16/146 (11%)
Vomiting 1/12 (8.3%) 32/149 (21.5%) 31/146 (21.2%)
General disorders
Asthenia 2/12 (16.7%) 18/149 (12.1%) 23/146 (15.8%)
Fatigue 4/12 (33.3%) 35/149 (23.5%) 29/146 (19.9%)
Generalised oedema 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Malaise 0/12 (0%) 11/149 (7.4%) 5/146 (3.4%)
Mucosal inflammation 1/12 (8.3%) 4/149 (2.7%) 1/146 (0.7%)
Oedema peripheral 1/12 (8.3%) 10/149 (6.7%) 9/146 (6.2%)
Pyrexia 3/12 (25%) 19/149 (12.8%) 33/146 (22.6%)
Hepatobiliary disorders
Cholangitis 1/12 (8.3%) 3/149 (2%) 2/146 (1.4%)
Hyperbilirubinaemia 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Infections and infestations
Clostridium difficile infection 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Cystitis 1/12 (8.3%) 1/149 (0.7%) 4/146 (2.7%)
Herpes zoster 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Nasopharyngitis 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Oral candidiasis 1/12 (8.3%) 1/149 (0.7%) 0/146 (0%)
Pneumonia 1/12 (8.3%) 1/149 (0.7%) 0/146 (0%)
Systemic candida 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Urinary tract infection 0/12 (0%) 4/149 (2.7%) 9/146 (6.2%)
Injury, poisoning and procedural complications
Infusion related reaction 1/12 (8.3%) 3/149 (2%) 6/146 (4.1%)
Investigations
Alanine aminotransferase increased 2/12 (16.7%) 20/149 (13.4%) 13/146 (8.9%)
Amylase increased 2/12 (16.7%) 8/149 (5.4%) 4/146 (2.7%)
Aspartate aminotransferase increased 2/12 (16.7%) 22/149 (14.8%) 13/146 (8.9%)
Blood albumin decreased 1/12 (8.3%) 4/149 (2.7%) 1/146 (0.7%)
Blood alkaline phosphatase increased 1/12 (8.3%) 8/149 (5.4%) 7/146 (4.8%)
Blood bilirubin increased 0/12 (0%) 14/149 (9.4%) 9/146 (6.2%)
Blood creatinine increased 1/12 (8.3%) 7/149 (4.7%) 6/146 (4.1%)
Blood magnesium decreased 1/12 (8.3%) 3/149 (2%) 2/146 (1.4%)
Creatinine renal clearance decreased 1/12 (8.3%) 9/149 (6%) 4/146 (2.7%)
Gamma-glutamyltransferase increased 1/12 (8.3%) 10/149 (6.7%) 4/146 (2.7%)
Haemoglobin decreased 1/12 (8.3%) 0/149 (0%) 3/146 (2.1%)
Iron binding capacity total decreased 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Lipase increased 2/12 (16.7%) 9/149 (6%) 5/146 (3.4%)
Neutrophil count decreased 5/12 (41.7%) 59/149 (39.6%) 28/146 (19.2%)
Platelet count decreased 3/12 (25%) 38/149 (25.5%) 34/146 (23.3%)
White blood cell count decreased 3/12 (25%) 36/149 (24.2%) 19/146 (13%)
Metabolism and nutrition disorders
Decreased appetite 3/12 (25%) 36/149 (24.2%) 30/146 (20.5%)
Diabetes mellitus 1/12 (8.3%) 1/149 (0.7%) 0/146 (0%)
Hypercalcaemia 1/12 (8.3%) 4/149 (2.7%) 3/146 (2.1%)
Hypocalcaemia 1/12 (8.3%) 4/149 (2.7%) 1/146 (0.7%)
Hypokalaemia 1/12 (8.3%) 10/149 (6.7%) 7/146 (4.8%)
Hypomagnesaemia 0/12 (0%) 13/149 (8.7%) 8/146 (5.5%)
Hyponatraemia 0/12 (0%) 8/149 (5.4%) 10/146 (6.8%)
Hypophosphataemia 1/12 (8.3%) 3/149 (2%) 1/146 (0.7%)
Musculoskeletal and connective tissue disorders
Back pain 1/12 (8.3%) 6/149 (4%) 8/146 (5.5%)
Myalgia 0/12 (0%) 10/149 (6.7%) 0/146 (0%)
Nervous system disorders
Dizziness 0/12 (0%) 13/149 (8.7%) 8/146 (5.5%)
Dysgeusia 2/12 (16.7%) 3/149 (2%) 6/146 (4.1%)
Headache 0/12 (0%) 13/149 (8.7%) 12/146 (8.2%)
Peripheral sensory neuropathy 1/12 (8.3%) 1/149 (0.7%) 5/146 (3.4%)
Taste disorder 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Psychiatric disorders
Adjustment disorder 1/12 (8.3%) 1/149 (0.7%) 0/146 (0%)
Anxiety 1/12 (8.3%) 6/149 (4%) 3/146 (2.1%)
Insomnia 1/12 (8.3%) 2/149 (1.3%) 12/146 (8.2%)
Renal and urinary disorders
Pollakiuria 1/12 (8.3%) 2/149 (1.3%) 0/146 (0%)
Respiratory, thoracic and mediastinal disorders
Cough 3/12 (25%) 9/149 (6%) 3/146 (2.1%)
Dyspnoea exertional 1/12 (8.3%) 0/149 (0%) 3/146 (2.1%)
Epistaxis 2/12 (16.7%) 3/149 (2%) 19/146 (13%)
Pulmonary embolism 1/12 (8.3%) 1/149 (0.7%) 2/146 (1.4%)
Skin and subcutaneous tissue disorders
Alopecia 0/12 (0%) 16/149 (10.7%) 5/146 (3.4%)
Blister 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Dermatitis 1/12 (8.3%) 0/149 (0%) 3/146 (2.1%)
Erythema multiforme 1/12 (8.3%) 1/149 (0.7%) 2/146 (1.4%)
Palmar-plantar erythrodysaesthesia syndrome 1/12 (8.3%) 0/149 (0%) 1/146 (0.7%)
Pigmentation disorder 1/12 (8.3%) 0/149 (0%) 0/146 (0%)
Pruritus 4/12 (33.3%) 14/149 (9.4%) 35/146 (24%)
Rash 6/12 (50%) 21/149 (14.1%) 36/146 (24.7%)
Rash maculo-papular 0/12 (0%) 4/149 (2.7%) 10/146 (6.8%)
Rash papular 1/12 (8.3%) 0/149 (0%) 1/146 (0.7%)
Skin lesion 1/12 (8.3%) 0/149 (0%) 1/146 (0.7%)
Urticaria 1/12 (8.3%) 6/149 (4%) 3/146 (2.1%)
Vascular disorders
Hypertension 1/12 (8.3%) 11/149 (7.4%) 6/146 (4.1%)

Limitations/Caveats

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

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Communication Center
Organization Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Phone +49-6151-72-5200
Email service@emdgroup.com
Responsible Party:
EMD Serono Research & Development Institute, Inc.
ClinicalTrials.gov Identifier:
NCT04066491
Other Study ID Numbers:
  • MS200647_0055
  • 2019-001992-35
First Posted:
Aug 26, 2019
Last Update Posted:
Jun 13, 2022
Last Verified:
May 1, 2022