Solid Tumors
Conditions
Keywords
MSB0011359C
Brief summary
The main purpose of this study was to assess the safety and tolerability of MSB0011359C. Study consists of dose-escalation part and an expansion part in participants with metastatic or locally advanced solid tumors, for which no standard effective therapy exists or a standard therapy had failed.
Interventions
DRUGMSB0011359C
Subjects with metastatic or locally advanced solid tumors received intravenous infusion of MSB0011359C over 1 hour once every two weeks for up to 12 months until confirmed progressive disease (PD), unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product (IMP) occurs.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able and willing to give written informed consent and had signed the appropriate written informed consent form (ICF), prior to performance of any trial activities * Eligible male and female participants aged greater than or equal to (\>=)20 years * Histologically or cytologically proven metastatic or locally advanced solid tumors, for which no effective standard therapy exists or standard therapy had failed * Eastern Cooperative Oncology Group performance status (ECOG) performance status of 0 to 1 at trial entry * Life expectancy \>=12 weeks as judged by the Investigator. * Adequate hematological function defined by white blood cell (WBC) count \>=3\*10\^9/Liter with absolute neutrophil count (ANC) \>=1.5\*10\^9/Liter, lymphocyte count \>=0.5\* 10\^9/Liter, platelet count \>=75\*10\^9/Liter, and Hemoglobin (Hgb) \>= 9 grams per deciliter (g/dL) (in absence of blood transfusion) * Adequate hepatic function defined by a total bilirubin level \<=1.5 × Upper limit of normal (ULN), an AST level \<= 2.5 × ULN, and an ALT level \<= 2.5 × ULN * Adequate renal function defined by an estimated creatinine clearance \>50 milliliter per minute (mL/min) according to the Cockcroft-Gault formula or by measure of creatinine clearance from 24 hour urine collection Other protocol-defined
Exclusion criteria
could apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) | Baseline up to Week 3 | A DLT was defined as any grade greater than or equal to (\>=) 3 adverse event suspected to be related to investigational medicinal product (IMP) by the Investigator and / or Sponsor occurring in the DLT evaluation period confirmed by the Safety Monitoring Committee (SMC) to be relevant for the IMP treatment. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. |
| Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Escalation Phase: Area Under The Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M7824 | Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43 | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. |
| Dose-Escalation Phase: Number of Participants With Positive Serum Titers of Anti-Drug Antibodies of M7824 | Predose, Day 15, 43, 85 and every 6-weekly until progression or end of the treatment whichever occur first, assessed up to 3 years | The detection of antibodies to M7824 was performed using a validated electrochemiluminescence (ECL) immunoassay with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of M7824 were reported. |
| Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Date of randomization up to 2 years | BOR was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. BOR was defined as sum of complete response and partial response (CR+PR). For target lesions (TLs), CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the sum of largest diameter (SLD) of the TLs, taking as a reference the baseline SLD. |
| Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Date of randomization up to 2 years | BOR was assessed by investigator according to RECIST Version 1.1. BOR was defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the SLD of the TLs, taking as a reference the baseline SLD. |
| Dose-Escalation Phase: Maximum Serum Concentration (Cmax) of M7824 | Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43 | Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve. |
| Expansion Part: Duration of Response (DOR) | Up to 2 years | Duration of response according to RECIST 1.1 as adjudicated by the IRC was defined as the time from first confirmed response until the first documented disease progression that was subsequently confirmed. It was analyzed using Kaplan-Meier method. |
| Expansion Part: Disease Control Rate | Up to 2 years | The disease control rate was defined as the percentage of participants with BOR. The BOR per IRC adjudication was determined according to RECIST 1.1. BOR is defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD. |
| Expansion Part: Progression Free Survival (PFS) Time | Date of randomization until death or progressive disease assessed up to 2 years | PFS was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PFS was assessed as RECIST v1.1 as adjudicated by IRC. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Expansion Part: Overall Survival (OS) Time | Date of randomization until death assessed up to 2 years | OS was defined as the time from randomization to death due to any cause. |
| Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Up to 2 years | The BOR per Independent Endpoint Review Committee (IRC) adjudication was determined according to RECIST 1.1. BOR is defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the SLD of the TLs, taking as a reference the baseline SLD. |
| Dose-Escalation Phase: Terminal Half Life (t1/2) of M7824 | Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43 | t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. |
| Dose-Escalation Phase: Area Under the Serum Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of M7824 | Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43 | Area under the serum concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation. |
Countries
Japan, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) Participants with metastatic or locally advanced solid tumors received intravenous (IV) infusion of M7824 at a dose of 3.0 milligrams per kilogram (mg/kg) over 1 hour once every two weeks for up to 12 months until confirmed progressive disease (PD), unacceptable toxicity, or any criterion for withdrawal from the study or investigational medicinal product (IMP) whichever occurs first. | 4 |
| Dose Escalation Cohort: M7824 (10 mg/kg) Participants with metastatic or locally advanced solid tumors received intravenous infusion of M7824 at a dose of 10 mg/kg over 1 hour once every two weeks for up to 12 months until confirmed PD, unacceptable toxicity, or any criterion for withdrawal from study or IMP whichever occurs first. | 3 |
| Expansion Cohort: Biliary Tract Cancer Participants received intravenous infusion of M7824 at a flat dose of 1200 over 1 hour once every two weeks until PD has been confirmed by a subsequent scan, unacceptable toxicity, or occurrence of any criterion for withdrawal from the study or the IMP occurs. | 30 |
| Dose Escalation Cohort: M7824 (20 mg/kg) Participants with metastatic or locally advanced solid tumors received intravenous infusion of M7824 at a dose of 20 mg/kg over 1 hour once every two weeks for up to 12 months until confirmed PD, unacceptable toxicity, or any criterion for withdrawal from the study or IMP whichever occurs first. | 7 |
| Expansion Cohort: Gastric Cancer (GC) Participants received intravenous infusion of M7824 at a flat dose of 1200 over 1 hour once every two weeks until PD has been confirmed by a subsequent scan, unacceptable toxicity, or occurrence of any criterion for withdrawal from the study or the IMP occurs. | 31 |
| Expansion Cohort: Esophageal Squamous Cell Cancer Participants received intravenous infusion of M7824 at a flat dose of 1200 over 1 hour once every two weeks until PD has been confirmed by a subsequent scan, unacceptable toxicity, or occurrence of any criterion for withdrawal from the study or the IMP occurs. | 30 |
| Expansion Cohort: Hepatocellular Carcinoma (3 mg/kg) Participants received intravenous infusion of M7824 at a dose of 3 mg/kg over 1 hour once every two weeks until PD has been confirmed by a subsequent scan, unacceptable toxicity, or occurrence of any criterion for withdrawal from the study or the IMP occurs. | 3 |
| Expansion Cohort: Hepatocellular Carcinoma (10 mg/kg) Participants received intravenous infusion of M7824 at a dose of 10 mg/kg over 1 hour once every two weeks until PD has been confirmed by a subsequent scan, unacceptable toxicity, or occurrence of any criterion for withdrawal from the study or the IMP occurs. | 6 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 3 | 3 | 3 | 23 | 22 | 23 | 3 | 5 |
| Overall Study | Other | 1 | 0 | 1 | 6 | 4 | 3 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 3 | 1 | 5 | 3 | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Escalation Cohort: M7824 (3 mg/kg) | Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Cohort: Biliary Tract Cancer | Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Cohort: Gastric Cancer (GC) | Expansion Cohort: Esophageal Squamous Cell Cancer | Expansion Cohort: Hepatocellular Carcinoma (3 mg/kg) | Expansion Cohort: Hepatocellular Carcinoma (10 mg/kg) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 51 Years STANDARD_DEVIATION 8.7 | 57 Years STANDARD_DEVIATION 18.5 | 63 Years STANDARD_DEVIATION 9.3 | 54 Years STANDARD_DEVIATION 10.9 | 62 Years STANDARD_DEVIATION 11.5 | 60 Years STANDARD_DEVIATION 9.9 | 58 Years STANDARD_DEVIATION 16.5 | 56 Years STANDARD_DEVIATION 13.2 | 61 Years STANDARD_DEVIATION 11.1 |
| Race/Ethnicity, Customized Ethnicity-Japanese | 4 Participants | 3 Participants | 12 Participants | 7 Participants | 12 Participants | 17 Participants | 3 Participants | 6 Participants | 64 Participants |
| Race/Ethnicity, Customized Ethnicity-Korean | 0 Participants | 0 Participants | 15 Participants | 0 Participants | 14 Participants | 3 Participants | 0 Participants | 0 Participants | 32 Participants |
| Race/Ethnicity, Customized Ethnicity-Taiwanese | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 5 Participants | 10 Participants | 0 Participants | 0 Participants | 18 Participants |
| Race/Ethnicity, Customized Race-Asian | 4 Participants | 3 Participants | 30 Participants | 7 Participants | 31 Participants | 30 Participants | 3 Participants | 6 Participants | 114 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 11 Participants | 5 Participants | 5 Participants | 4 Participants | 1 Participants | 1 Participants | 32 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 19 Participants | 2 Participants | 26 Participants | 26 Participants | 2 Participants | 5 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 23 / 30 | 22 / 31 | 24 / 30 | 3 / 4 | 3 / 3 | 3 / 7 | 3 / 3 | 5 / 6 |
| other Total, other adverse events | 28 / 30 | 30 / 31 | 30 / 30 | 4 / 4 | 3 / 3 | 6 / 7 | 1 / 3 | 6 / 6 |
| serious Total, serious adverse events | 18 / 30 | 18 / 31 | 14 / 30 | 4 / 4 | 0 / 3 | 5 / 7 | 2 / 3 | 3 / 6 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicity (DLT)
A DLT was defined as any grade greater than or equal to (\>=) 3 adverse event suspected to be related to investigational medicinal product (IMP) by the Investigator and / or Sponsor occurring in the DLT evaluation period confirmed by the Safety Monitoring Committee (SMC) to be relevant for the IMP treatment.
Time frame: Baseline up to Week 3
Population: DLT analysis set included all participants with data used for implementing the dose-escalation schedule. These participants received all study treatment administrations in the DLT evaluation period or stopped treatment because of DLTs in the DLT evaluation period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Number of Participants With Dose Limiting Toxicity (DLT) | 0 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Number of Participants With Dose Limiting Toxicity (DLT) | 0 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Number of Participants With Dose Limiting Toxicity (DLT) | 1 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs.
Time frame: First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years
Population: Safety Analysis Set (SAF) included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 4 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 3 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 6 Participants |
| Expansion Cohort: Biliary Tract Cancer | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 28 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 30 Participants |
| Expansion Cohort: Esophageal Squamous Cell Cancer | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 30 Participants |
| Expansion Cohort: Hepatocellular Carcinoma (3 mg/kg) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 2 Participants |
| Expansion Cohort: Hepatocellular Carcinoma (10 mg/kg) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) Version 4.03 | 6 Participants |
Primary
Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.
Time frame: First study drug administration up to 30 days after the last drug administration assessed up to approximately 5 years
Population: Safety analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 1 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 2 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 3 Participants |
| Expansion Cohort: Biliary Tract Cancer | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 19 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 16 Participants |
| Expansion Cohort: Esophageal Squamous Cell Cancer | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 19 Participants |
| Expansion Cohort: Hepatocellular Carcinoma (3 mg/kg) | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 0 Participants |
| Expansion Cohort: Hepatocellular Carcinoma (10 mg/kg) | Number of Participants With Treatment-Related Adverse Events (TRAEs) According to NCI-CTCAE Version 4.03 | 0 Participants |
Secondary
Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator
BOR was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. BOR was defined as sum of complete response and partial response (CR+PR). For target lesions (TLs), CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the sum of largest diameter (SLD) of the TLs, taking as a reference the baseline SLD.
Time frame: Date of randomization up to 2 years
Population: Full analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Progressive disease | 1 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Stable disease | 2 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Complete response | 0 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Partial response | 1 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Not evaluable | 0 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Stable disease | 1 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Complete response | 0 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Partial response | 0 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Progressive disease | 2 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Not evaluable | 0 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Not evaluable | 2 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Progressive disease | 4 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Complete response | 0 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Stable disease | 0 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Part: Number of Participants With Best Overall Response (BOR) As Assessed By Investigator | Partial response | 1 Participants |
Secondary
Dose-Escalation Phase: Area Under The Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M7824
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
Time frame: Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43
Population: Pharmacokinetic analysis set included all participants who completed at least 1 infusion of M7824, and who provided at least 1 post dose sample with a measurable concentration of M7824. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Phase: Area Under The Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M7824 | 9600 hr*mcg/mL | Geometric Coefficient of Variation 15.2 |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Phase: Area Under The Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M7824 | 34600 hr*mcg/mL | Geometric Coefficient of Variation 29.7 |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Phase: Area Under The Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of M7824 | 61700 hr*mcg/mL | Geometric Coefficient of Variation 26.6 |
Secondary
Dose-Escalation Phase: Area Under the Serum Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of M7824
Area under the serum concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated by linear trapezoidal summation.
Time frame: Pre-dose, 0, 4 hour post dose on Day 1, 2, 8, 15, 29, 43
Population: Pharmacokinetic analysis set included all participants who completed at least 1 infusion of M7824, and who provided at least 1 post dose sample with a measurable concentration of M7824. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Phase: Area Under the Serum Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of M7824 | 7940 hour*microgram per milliliter(hr*mcg/mL) | Geometric Coefficient of Variation 16.7 |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Phase: Area Under the Serum Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of M7824 | 29200 hour*microgram per milliliter(hr*mcg/mL) | Geometric Coefficient of Variation 25.3 |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Phase: Area Under the Serum Concentration Time Curve From Zero to Last Sampling Time (AUC0-t) of M7824 | 51300 hour*microgram per milliliter(hr*mcg/mL) | Geometric Coefficient of Variation 24.7 |
Secondary
Dose-Escalation Phase: Maximum Serum Concentration (Cmax) of M7824
Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Population: Pharmacokinetic analysis set included all participants who completed at least 1 infusion of M7824, and who provided at least 1 post dose sample with a measurable concentration of M7824. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Phase: Maximum Serum Concentration (Cmax) of M7824 | 54.6 Micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 17.9 |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Phase: Maximum Serum Concentration (Cmax) of M7824 | 211 Micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 21.7 |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Phase: Maximum Serum Concentration (Cmax) of M7824 | 331 Micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 19.2 |
Secondary
Dose-Escalation Phase: Number of Participants With Positive Serum Titers of Anti-Drug Antibodies of M7824
The detection of antibodies to M7824 was performed using a validated electrochemiluminescence (ECL) immunoassay with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of M7824 were reported.
Time frame: Predose, Day 15, 43, 85 and every 6-weekly until progression or end of the treatment whichever occur first, assessed up to 3 years
Population: Immunogenicity Analysis Set included participants who received at least 1 dose of study drug and who had at least 1 valid result of ADA at any time point.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Phase: Number of Participants With Positive Serum Titers of Anti-Drug Antibodies of M7824 | 1 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Phase: Number of Participants With Positive Serum Titers of Anti-Drug Antibodies of M7824 | 0 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Phase: Number of Participants With Positive Serum Titers of Anti-Drug Antibodies of M7824 | 3 Participants |
Secondary
Dose-Escalation Phase: Terminal Half Life (t1/2) of M7824
t1/2 was the time measured for the concentration to decrease by one half, determined as 0.693/Lambda z, here Lambda z was the terminal elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.
Time frame: Pre-dose, 0, 4 hour post dose on Day 1, 2,8,15,29,43
Population: Pharmacokinetic analysis set included all participants who completed at least 1 infusion of M7824, and who provided at least 1 post dose sample with a measurable concentration of M7824. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Dose-Escalation Phase: Terminal Half Life (t1/2) of M7824 | 132 hours | Geometric Coefficient of Variation 12.8 |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Dose-Escalation Phase: Terminal Half Life (t1/2) of M7824 | 138 hours | Geometric Coefficient of Variation 17.4 |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Dose-Escalation Phase: Terminal Half Life (t1/2) of M7824 | 150 hours | Geometric Coefficient of Variation 24.4 |
Secondary
Expansion Part: Best Overall Response (BOR) As Assessed By Investigator
BOR was assessed by investigator according to RECIST Version 1.1. BOR was defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the SLD of the TLs, taking as a reference the baseline SLD.
Time frame: Date of randomization up to 2 years
Population: Full analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Complete response | 1 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Progressive disease | 17 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Stable disease | 4 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Not evaluable | 2 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Partial response | 6 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Progressive disease | 16 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Complete response | 2 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Partial response | 5 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Stable disease | 5 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Not evaluable | 3 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Partial response | 6 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Progressive disease | 17 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Complete response | 0 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Not evaluable | 2 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Best Overall Response (BOR) As Assessed By Investigator | Stable disease | 5 Participants |
Secondary
Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC)
The BOR per Independent Endpoint Review Committee (IRC) adjudication was determined according to RECIST 1.1. BOR is defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in the SLD of the TLs, taking as a reference the baseline SLD.
Time frame: Up to 2 years
Population: Full analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Complete response (CR) | 2 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Partial Response (PR) | 4 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Stable disease (SD) | 6 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Non-CR/Non-PD | 0 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Progressive disease (PD) | 16 Participants |
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Not evaluable (NE) | 2 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Progressive disease (PD) | 21 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Not evaluable (NE) | 2 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Complete response (CR) | 3 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Stable disease (SD) | 2 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Non-CR/Non-PD | 0 Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Partial Response (PR) | 3 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Non-CR/Non-PD | 3 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Progressive disease (PD) | 18 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Complete response (CR) | 0 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Stable disease (SD) | 3 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Partial Response (PR) | 3 Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Not evaluable (NE) | 3 Participants |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Non-CR/Non-PD | 0 Participants |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Partial Response (PR) | 0 Participants |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Stable disease (SD) | 1 Participants |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Not evaluable (NE) | 1 Participants |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Progressive disease (PD) | 1 Participants |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Complete response (CR) | 0 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Progressive disease (PD) | 6 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Stable disease (SD) | 0 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Partial Response (PR) | 0 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Not evaluable (NE) | 0 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Non-CR/Non-PD | 0 Participants |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: BOR According to RECIST 1.1 As Adjudicated By The Independent Review Committee (IRC) | Complete response (CR) | 0 Participants |
Secondary
Expansion Part: Disease Control Rate
The disease control rate was defined as the percentage of participants with BOR. The BOR per IRC adjudication was determined according to RECIST 1.1. BOR is defined as sum of CR and PR. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD.
Time frame: Up to 2 years
Population: Full analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Disease Control Rate | 40.0 Percentage of Participants |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Disease Control Rate | 22.6 Percentage of Participants |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Disease Control Rate | 20 Percentage of Participants |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: Disease Control Rate | 1 Percentage of Participants |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: Disease Control Rate | 0 Percentage of Participants |
Secondary
Expansion Part: Duration of Response (DOR)
Duration of response according to RECIST 1.1 as adjudicated by the IRC was defined as the time from first confirmed response until the first documented disease progression that was subsequently confirmed. It was analyzed using Kaplan-Meier method.
Time frame: Up to 2 years
Population: Full analysis set included all participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Duration of Response (DOR) | NA Months |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Duration of Response (DOR) | 20.8 Months |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Duration of Response (DOR) | 7.0 Months |
Secondary
Expansion Part: Overall Survival (OS) Time
OS was defined as the time from randomization to death due to any cause.
Time frame: Date of randomization until death assessed up to 2 years
Population: Full analysis set included all participants who received at least 1 dose of study treatment. Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Overall Survival (OS) Time | 12.7 Months |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Overall Survival (OS) Time | 10.1 Months |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Overall Survival (OS) Time | 11.9 Months |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: Overall Survival (OS) Time | 4.4 Months |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: Overall Survival (OS) Time | 4.0 Months |
Secondary
Expansion Part: Progression Free Survival (PFS) Time
PFS was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PFS was assessed as RECIST v1.1 as adjudicated by IRC. PD is defined as at least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Date of randomization until death or progressive disease assessed up to 2 years
Population: Full analysis set included all participants who received at least 1 dose of study treatment. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Cohort: M7824 (3 mg/kg) | Expansion Part: Progression Free Survival (PFS) Time | 2.5 Months |
| Dose Escalation Cohort: M7824 (10 mg/kg) | Expansion Part: Progression Free Survival (PFS) Time | 1.3 Months |
| Dose Escalation Cohort: M7824 (20 mg/kg) | Expansion Part: Progression Free Survival (PFS) Time | 1.4 Months |
| Expansion Cohort: Biliary Tract Cancer | Expansion Part: Progression Free Survival (PFS) Time | 2.1 Months |
| Expansion Cohort: Gastric Cancer (GC) | Expansion Part: Progression Free Survival (PFS) Time | 1.2 Months |