Biliary Tract Cancer, Cholangiocarcinoma, Gallbladder Cancer
Conditions
Keywords
Metastatic Biliary Tract Cancer, Cholangiocarcinoma, Gallbladder Cancer, Ampullary cancer, M7824, Bintrafusp alfa, Transforming growth factor-beta, Programmed death-ligand 1
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.
Interventions
DRUGM7824
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.
DRUGPlacebo
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.
DRUGGemcitabine
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).
DRUGCisplatin
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).
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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 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. |
| Double-blind Part: Durable Response of at Least 6 Months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator | Time from first treatment assessed up to 1148 days | 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. |
| 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 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. |
| 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 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. |
| Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Time from first treatment 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. |
Countries
Argentina, Australia, Brazil, Chile, China, France, Germany, Italy, Japan, Poland, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 12 |
| 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. | 149 |
| 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. | 148 |
| Total | 309 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Randomized, not treated | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Total | Double-blinded Part: M7824 + Gemcitabine + Cisplatin | Double-blinded Part: Placebo + Gemcitabine + Cisplatin |
|---|---|---|---|---|
| Age, Continuous | 66 Years STANDARD_DEVIATION 11.9 | 63 Years STANDARD_DEVIATION 10.7 | 63 Years STANDARD_DEVIATION 10.8 | 64 Years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 44 Participants | 22 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 265 Participants | 126 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 189 Participants | 90 Participants | 93 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 8 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) White | 6 Participants | 108 Participants | 51 Participants | 51 Participants |
| Sex: Female, Male Female | 5 Participants | 151 Participants | 68 Participants | 78 Participants |
| Sex: Female, Male Male | 7 Participants | 158 Participants | 80 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 12 | 26 / 149 | 31 / 146 |
| other Total, other adverse events | 12 / 12 | 142 / 149 | 134 / 146 |
| serious Total, serious adverse events | 5 / 12 | 36 / 149 | 58 / 146 |
Outcome results
Primary
Double-blind Part: Overall Survival
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)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Double-blind Part: Overall Survival | 11.5 Months |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | Double-blind Part: Overall Survival | 11.5 Months |
Primary
Safety Run-in Part: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
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)
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Double-blind Part: Durable Response of at Least 6 Months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator
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.
Time frame: 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.
Secondary
Double-blind Part: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)
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 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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 |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | 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) | 7.0 Months |
Secondary
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
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 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).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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 |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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 |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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 |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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 |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | 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 | 16 Participants |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | 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 | 140 Participants |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | 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 | 133 Participants |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | 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 | 58 Participants |
Secondary
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)
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)
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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 |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | 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) | 31.5 Percentage of participants |
Secondary
Double-blind Part: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC)
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 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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 |
| Double-blinded Part: M7824 + Gemcitabine + Cisplatin | 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) | 5.5 Months |
Secondary
Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities
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 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Hemoglobin low | 6 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Leukocytes low | 4 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Neutrophils low | 6 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Platelets low | 3 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Bilirubin high | 1 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Creatinine high | 1 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Lipase high | 1 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Potassium low | 1 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Lymphocytes low | 2 Participants |
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities | Corrected Calcium high | 1 Participants |
Secondary
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
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 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Safety Run-In Part: M7824 + Gemcitabine + Cisplatin | 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: M7824 + Gemcitabine + Cisplatin | 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: M7824 + Gemcitabine + Cisplatin | 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 |