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This trial is to assess the safety and tolerability of Sym004, administered weekly or biweekly as monotherapy in Japanese subjects with advanced solid tumors.This study consisted of two parts, a dose-escalation part ("Part-A") and a dose-expansion part ("Part-B"). In Part-A, Sym004 will be administered weekly or biweekly as monotherapy in Japanese subjects with advanced solid tumors. In Part-B, Sym004 will be administered weekly as monotherapy to Japanese subjects with advanced esophageal squamous cell carcinoma (ESCC) as dose-expansion. A subject will receive Sym004 administration weekly at a dose that will determined to be the MTD or a dose that will lower than the MTD and determined to be appropriate with recommendation by Safety monitoring committee (SMC). The dose going to used in Part-B will be determined after safety confirmation of weekly regimens in Part-A of this trial.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sym004 | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sym004 | Drug | Part-A (dose-escalation): Sym004 will be administered intravenously either weekly at 6 to 12 milligram per kilogram (mg/kg) or biweekly at 18 mg/kg from Week 1 until unacceptable toxicity, disease progression, or consent withdrawal. Part-B (dose-expansion): After the maximum tolerated dose (MTD) is determined in Part-A, up to 30 additional subjects will continue to receive treatment in Part-B. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A | DLT: any of the following National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Grade 4 hematologic or Grade 3/4 non-hematologic toxicities that occurred during DLT observation period of Part A, and were considered by Investigator to be at least possibly related to study treatment, and confirmed by Safety Monitoring Committee. Hematological toxicities: Grade 4 neutropenia, febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding episodes. Nonhematological toxicities: Grade 3 or higher non-hematological toxicity with exception of Grade 3 fatigue/skin toxicity; Grade 3 nausea/vomiting without appropriate prophylactic therapy; Grade 3 diarrhoea recovered within 2 days with adequate treatment or did not accompany fever/dehydration; Grade 3 or 4 laboratory liver parameter abnormalities with duration of less than 3 days. | Week 1 up to Week 4 (Part A) |
| Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was 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. AEs were considered treatment emergent if they started on or after the day of first administration of the Sym004 or if they started prior to administration but worsened after receiving the first dose of treatment. | Baseline up to 4 weeks after the last Sym004 administration, up to a maximum of 41.1 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Responsible | Merck Serono Co., Ltd. Japan, an business of Merck KGaA, Darmstadt, Germany | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Please contact the Merck KGaA Communication Center located in | Darmstadt | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30099818 | Derived | Kojima T, Yamazaki K, Kato K, Muro K, Hara H, Chin K, Goddemeier T, Kuffel S, Watanabe M, Doi T. Phase I dose-escalation trial of Sym004, an anti-EGFR antibody mixture, in Japanese patients with advanced solid tumors. Cancer Sci. 2018 Oct;109(10):3253-3262. doi: 10.1111/cas.13767. Epub 2018 Sep 25. |
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A total of 60 subjects were screened for eligibility, out of which and 51 subjects were randomized into the study.
First/Last subject (informed consent): 30 October 2013/10 Jun 2015. Study completion date: 30 October 2015. Clinical data cut-off: 30 October 2015. The study was conducted by 6 Investigators in 6 sites in Japan.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part A: Sym004 6 mg/kg | Sym004 was administered at a dose of 6 milligram per kilogram (mg/kg) by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| FG001 | Part A: Sym004 9/6 mg/kg | Sym004 was administered at a dose of 9 mg/kg by intravenous infusion at Week 1 followed by a maintenance dose of 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| FG002 | Part A: Sym004 12 mg/kg | Sym004 was administered at a dose of 12 mg/kg by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| FG003 | Part A: Sym004 18 mg/kg | Sym004 was administered at a dose of 18 mg/kg by intravenous infusion biweekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| FG004 | Part B: Sym004 12 mg/kg | Sym004 was administered at a dose of 12 mg/kg by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety analysis set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004.
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| ID | Title | Description |
|---|---|---|
| BG000 | Part A: Sym004 6 mg/kg | Sym004 was administered at a dose of 6 milligram per kilogram (mg/kg) by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A | DLT: any of the following National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Grade 4 hematologic or Grade 3/4 non-hematologic toxicities that occurred during DLT observation period of Part A, and were considered by Investigator to be at least possibly related to study treatment, and confirmed by Safety Monitoring Committee. Hematological toxicities: Grade 4 neutropenia, febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding episodes. Nonhematological toxicities: Grade 3 or higher non-hematological toxicity with exception of Grade 3 fatigue/skin toxicity; Grade 3 nausea/vomiting without appropriate prophylactic therapy; Grade 3 diarrhoea recovered within 2 days with adequate treatment or did not accompany fever/dehydration; Grade 3 or 4 laboratory liver parameter abnormalities with duration of less than 3 days. | DLT Analysis Set consisted of all subjects who received at least 3 of 4 weekly administrations (for weekly dosing cohort) or who received 2 biweekly administrations (for biweekly dosing cohort) and experienced a DLT during DLT observation period. | Posted | Number | subjects | Week 1 up to Week 4 (Part A) |
Baseline up to 4 weeks after the last Sym004 administration, up to a maximum of 41.1 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part A: Sym004 6 mg/kg | Sym004 was administered at a dose of 6 milligram per kilogram (mg/kg) by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac arrest | Cardiac disorders | MedDRA 18.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| C569270 | futuximab |
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| Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) only. | Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4 |
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Dose normalized AUC for AUC0-168 was calculated as AUC(0-168)/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1 |
| Dose Nornamized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Dose normalized AUC for AUC0-168 was calculated as AUC(0-168)/Dose. Results were to be assessed for weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) only. | Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4 |
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1 |
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5 |
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. Dose normalized AUC for AUC0-336 was calculated as AUC(0-336)/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1 |
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. Dose normalized AUC for AUC0-336 was calculated as AUC(0-336)/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5 |
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1 |
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | Pre-infusion, end of infusion, 4, 8, 12 and 24 hours post-infusion at Week 5 |
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Dose normalized AUC for AUC0-inf was calculated as AUC(0-inf)/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1 |
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. Dose normalized AUC for AUC0-inf was calculated as AUC(0-inf)/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. Dose normalized AUC for AUC0-inf was calculated as AUC(0-inf)/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
| Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | Terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Terminal t1/2 are presented for both monoclonal antibodies. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
| Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Terminal t1/2 are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
| Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose | Terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Terminal t1/2 are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
| Clearance (CL) of Sym004 at Week 1: Single Dose | Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). CL are presented for both monoclonal antibodies. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
| Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). CLss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
| Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). CLss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
| Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug needed to be uniformly distributed to produce the desired serum concentration of a drug. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Vz are presented for both monoclonal antibodies. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
| Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug needed to be uniformly distributed to produce the desired serum concentration of a drug. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Vss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
| Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug needed to be uniformly distributed to produce the desired serum concentration of a drug. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Vss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
| Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Cmax are presented for both monoclonal antibodies. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
| Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Cmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
| Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Cmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
| Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Dose Normalized Cmax are presented for both monoclonal antibodies. Dose normalized Cmax was calculated as Cmax/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
| Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized Cmax are presented for both monoclonal antibodies. Dose normalized Cmax was calculated as Cmax/Dose. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
| Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized Cmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. Dose normalized Cmax was calculated as Cmax/Dose. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
| Trough Concentrations (Ctrough) of Sym004 | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Ctrough are presented for both monoclonal antibodies. | Pre-infusion at Week 2, 3, 5, 6, 7, 8, End of Trial (up to 41.1 weeks) and Follow up (up to 45.1 Weeks) |
| Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Tmax are presented for both monoclonal antibodies. | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
| Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Tmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
| Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Tmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
| Percentage of Subjects With Best Overall Response | Percentage of subjects with best overall response (defined as confirmed CR or PR) according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) was reported. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimiter (mm). PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmed CR or PR was defined as the response that was confirmed at an interval of at least 4 weeks. | Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks) |
| Duration of Overall Response | The duration of overall response was measured from the time measurement criteria were first met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmed CR or PR was defined as the response that was confirmed at an interval of at least 4 weeks. | Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 Weeks |
| Percentage of Subjects With Disease Control | Percentage of subjects with disease control (defined as confirmed CR, confirmed PR, or confirmed SD) ) according to RECIST Version 1.1 was reported. CR: disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Confirmed CR or PR: response confirmed at an interval of at least 4 weeks. Confirmed SD: response confirmed at an interval of at least 6 weeks. | Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks) |
| Duration of Disease Control | Duration of disease control measured from the time measurement criteria were first met for CR, PR, or SD (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented. CR: disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 weeks |
| Time to Progression | Time to progression was defined as the time from date of subject enrollment until the date that disease progression was objectively documented. TTP estimated using the Kaplan-Meier estimates. TTP was planned to be reported for Part B alone and Part A/B combined reporting arms. | Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks |
| Progression-free Survival Time | The Progression-free survival time was measured from the date of subject enrollment until the date that disease progression was objectively documented or death. Progression-free survival time estimated with using the Kaplan-Meier method. Progression-free survival time was planned to be reported for Part B alone and Part A/B combined reporting arms. | Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks |
| Anti-drug Antibody Titers | Week 1 (pre-dose) up to Follow-up assessment (up to maximum 45.1 Weeks) |
| Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | IHC is a staining process performed on fresh/frozen cancer tissue. IHC is used to show whether or not the cancer cells have Human Epidermal Growth Receptor (HER2) and/or hormone receptors on their surface. A value designated the IHC score was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+: 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). Minimum score of 0 to a maximum score of 300; the maximum score indicates the strongest expression. | Week 1 (pre-dose), Week 4 and Week 5 |
| Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1 (pre-dose) and Week 4. |
| Part A: Sym004 9/6 mg/kg |
Sym004 was administered at a dose of 9 mg/kg by intravenous infusion at Week 1 followed by a maintenance dose of 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| BG002 | Part A: Sym004 12 mg/kg | Sym004 was administered at a dose of 12 mg/kg by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| BG003 | Part A: Sym004 18 mg/kg | Sym004 was administered at a dose of 18 mg/kg by intravenous infusion biweekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| BG004 | Part B: Sym004 12 mg/kg | Sym004 was administered at a dose of 12 mg/kg by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| BG005 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| ID | Title | Description |
|---|---|---|
| OG000 | Part A: Sym004 6 mg/kg | Sym004 was administered at a dose of 6 milligram per kilogram (mg/kg) by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| OG001 | Part A: Sym004 9/6 mg/kg | Sym004 was administered at a dose of 9 mg/kg by intravenous infusion at Week 1 followed by a maintenance dose of 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| OG002 | Part A: Sym004 12 mg/kg | Sym004 was administered at a dose of 12 mg/kg by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
| OG003 | Part A: Sym004 18 mg/kg | Sym004 was administered at a dose of 18 mg/kg by intravenous infusion biweekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. |
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| Primary | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was 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. AEs were considered treatment emergent if they started on or after the day of first administration of the Sym004 or if they started prior to administration but worsened after receiving the first dose of treatment. | Safety analysis set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004. | Posted | Number | subjects | Baseline up to 4 weeks after the last Sym004 administration, up to a maximum of 41.1 weeks |
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| Secondary | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. | The Pharmacokinetics (PK) Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1 |
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| Secondary | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) only. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL | Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4 |
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| Secondary | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Dose normalized AUC for AUC0-168 was calculated as AUC(0-168)/Dose. | The Pharmacokinetics (PK) Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1 |
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| Secondary | Dose Nornamized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Dose normalized AUC for AUC0-168 was calculated as AUC(0-168)/Dose. Results were to be assessed for weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) only. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4 |
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| Secondary | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL | Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1 |
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| Secondary | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here, "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL | Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5 |
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| Secondary | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. Dose normalized AUC for AUC0-336 was calculated as AUC(0-336)/Dose. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1 |
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| Secondary | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. Dose normalized AUC for AUC0-336 was calculated as AUC(0-336)/Dose. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here, "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5 |
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| Secondary | Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL | Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1 |
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| Secondary | Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here AUC are presented for both monoclonal antibodies. Results were to be assessed for biweekly dosing cohort (Part A: Sym004 18 mg/kg) only. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here, "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL | Pre-infusion, end of infusion, 4, 8, 12 and 24 hours post-infusion at Week 5 |
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| Secondary | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Dose normalized AUC for AUC0-inf was calculated as AUC(0-inf)/Dose. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1 |
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| Secondary | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. Dose normalized AUC for AUC0-inf was calculated as AUC(0-inf)/Dose. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
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| Secondary | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized AUC are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. Dose normalized AUC for AUC0-inf was calculated as AUC(0-inf)/Dose. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg*h/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
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| Secondary | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | Terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Terminal t1/2 are presented for both monoclonal antibodies. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
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| Secondary | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Terminal t1/2 are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
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| Secondary | Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose | Terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Terminal t1/2 are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
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| Secondary | Clearance (CL) of Sym004 at Week 1: Single Dose | Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). CL are presented for both monoclonal antibodies. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter/hour | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
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| Secondary | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). CLss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter/hour | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
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| Secondary | Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Clearance at steady state was reported. Clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). CLss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter/hour | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
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| Secondary | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug needed to be uniformly distributed to produce the desired serum concentration of a drug. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Vz are presented for both monoclonal antibodies. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
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| Secondary | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug needed to be uniformly distributed to produce the desired serum concentration of a drug. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Vss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified monoclonal antibody. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
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| Secondary | Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Volume of distribution was defined as the theoretical volume in which the total amount of drug needed to be uniformly distributed to produce the desired serum concentration of a drug. Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Vss are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liter | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
|
|
|
| Secondary | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Cmax are presented for both monoclonal antibodies. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | microgram per milliliter (μg/mL) | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
|
|
|
| Secondary | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Cmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg/mL | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
|
|
|
| Secondary | Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Cmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg/mL | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
|
|
|
| Secondary | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Dose Normalized Cmax are presented for both monoclonal antibodies. Dose normalized Cmax was calculated as Cmax/Dose. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
|
|
|
| Secondary | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized Cmax are presented for both monoclonal antibodies. Dose normalized Cmax was calculated as Cmax/Dose. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
|
|
|
| Secondary | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Here dose normalized Cmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. Dose normalized Cmax was calculated as Cmax/Dose. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg/mL/mg | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
|
|
|
| Secondary | Trough Concentrations (Ctrough) of Sym004 | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Ctrough are presented for both monoclonal antibodies. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" =subjects who were evaluable for this outcome and "n" =subjects who were evaluable for specified time frame. | Posted | Mean | Standard Deviation | μg/mL | Pre-infusion at Week 2, 3, 5, 6, 7, 8, End of Trial (up to 41.1 weeks) and Follow up (up to 45.1 Weeks) |
|
|
|
| Secondary | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Tmax are presented for both monoclonal antibodies. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Median | Full Range | hours | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 |
|
|
|
| Secondary | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Tmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were only applicable for Week 4 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was not applicable for Week 4 assessment. | The PK Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. Here "Number of Participants Analyzed" signifies those subjects who were evaluable for this outcome measure. | Posted | Median | Full Range | hours | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 |
|
|
|
| Secondary | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Sym004 is a mixture of two mouse-human chimeric immunoglobulin G1 anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (called monoclonal antibodies [mAb] 992 and mAb 1024). Tmax are presented for both monoclonal antibodies. Weekly dosing cohorts (Part A: Sym004 6 mg/kg, Part A: Sym004 9/6 mg/kg, Part A: Sym004 12 mg/kg, Part B: Sym004 12 mg/kg) were not applicable for Week 5 assessment. Biweekly dosing cohort (Part A: Sym004 18 mg/kg) was only applicable for Week 5 assessment. | The PK Analysis Set consisted of all subjects who received at least 1 administration of Sym004 and who provided sufficient data for a concentration time profile for Sym004. | Posted | Median | Full Range | hours | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 |
|
|
|
| Secondary | Percentage of Subjects With Best Overall Response | Percentage of subjects with best overall response (defined as confirmed CR or PR) according to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) was reported. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimiter (mm). PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmed CR or PR was defined as the response that was confirmed at an interval of at least 4 weeks. | Efficacy Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who had baseline tumor assessment and at least 1 tumor assessment according to RECISTv1.1 after first dose of trial medication. | Posted | Number | percentage of subjects | Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks) |
|
|
|
| Secondary | Duration of Overall Response | The duration of overall response was measured from the time measurement criteria were first met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented. CR was defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Confirmed CR or PR was defined as the response that was confirmed at an interval of at least 4 weeks. | Efficacy Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who had baseline tumor assessment and at least 1 tumor assessment according to RECISTv1.1 after first dose of trial medication. Here, "Number of Participants Analyzed" signifies those subjects who achieved confirmed CR or PR. | Posted | Median | Full Range | Weeks | Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 Weeks |
|
|
|
| Secondary | Percentage of Subjects With Disease Control | Percentage of subjects with disease control (defined as confirmed CR, confirmed PR, or confirmed SD) ) according to RECIST Version 1.1 was reported. CR: disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Confirmed CR or PR: response confirmed at an interval of at least 4 weeks. Confirmed SD: response confirmed at an interval of at least 6 weeks. | Efficacy Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who had baseline tumor assessment and at least 1 tumor assessment according to RECISTv1.1 after first dose of trial medication. | Posted | Number | 95% Confidence Interval | percentage of subjects | Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks) |
|
|
|
| Secondary | Duration of Disease Control | Duration of disease control measured from the time measurement criteria were first met for CR, PR, or SD (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented. CR: disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Efficacy Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who had baseline tumor assessment and at least 1 tumor assessment according to RECISTv1.1 after first dose of trial medication. Here, "Number of Participants Analyzed" signifies those subjects who achieved disease control. | Posted | Median | Full Range | Weeks | Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 weeks |
|
|
|
| Secondary | Time to Progression | Time to progression was defined as the time from date of subject enrollment until the date that disease progression was objectively documented. TTP estimated using the Kaplan-Meier estimates. TTP was planned to be reported for Part B alone and Part A/B combined reporting arms. | Efficacy Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who had baseline tumor assessment and at least 1 tumor assessment according to RECISTv1.1 after first dose of trial medication. | Posted | Median | 95% Confidence Interval | months | Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks |
|
|
|
| Secondary | Progression-free Survival Time | The Progression-free survival time was measured from the date of subject enrollment until the date that disease progression was objectively documented or death. Progression-free survival time estimated with using the Kaplan-Meier method. Progression-free survival time was planned to be reported for Part B alone and Part A/B combined reporting arms. | Efficacy Analysis Set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004 and who had baseline tumor assessment and at least 1 tumor assessment according to RECISTv1.1 after first dose of trial medication. | Posted | Median | 95% Confidence Interval | months | Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks |
|
|
|
| Secondary | Anti-drug Antibody Titers | Anti-drug Antibody (ADA) titer could not be estimated because there were no subjects who were confirmed to have ADA positive test results during the confirmatory analysis. | Posted | Week 1 (pre-dose) up to Follow-up assessment (up to maximum 45.1 Weeks) |
|
|
| Secondary | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | IHC is a staining process performed on fresh/frozen cancer tissue. IHC is used to show whether or not the cancer cells have Human Epidermal Growth Receptor (HER2) and/or hormone receptors on their surface. A value designated the IHC score was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+: 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). Minimum score of 0 to a maximum score of 300; the maximum score indicates the strongest expression. | The Biomarker analysis set consisted of all subjects who received at least 1 administration of Sym004 and who had at least 1 biomarker evaluation. | Posted | Number | percentage of subjects | Week 1 (pre-dose), Week 4 and Week 5 |
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|
|
| Secondary | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | The Biomarker analysis set consisted of all subjects who received at least 1 administration of Sym004 and who had at least 1 biomarker evaluation. | Posted | Number | percentage of subjects | Week 1 (pre-dose) and Week 4. |
|
|
|
| 0 |
| 3 |
| 3 |
| 3 |
| EG001 | Part A: Sym004 9/6 mg/kg | Sym004 was administered at a dose of 9 mg/kg by intravenous infusion at Week 1 followed by a maintenance dose of 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. | 0 | 6 | 6 | 6 |
| EG002 | Part A: Sym004 12 mg/kg | Sym004 was administered at a dose of 12 mg/kg by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. | 2 | 6 | 6 | 6 |
| EG003 | Part A: Sym004 18 mg/kg | Sym004 was administered at a dose of 18 mg/kg by intravenous infusion biweekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. | 0 | 6 | 6 | 6 |
| EG004 | Part B: Sym004 12 mg/kg | Sym004 was administered at a dose of 12 mg/kg by intravenous infusion weekly until unacceptable toxicity, disease progression, or consent withdrawal, or until the subject met any of the criteria for treatment or trial discontinuation. | 9 | 30 | 30 | 30 |
| Dysphagia | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Lung infection | Infections and infestations | MedDRA 18.1 | Non-systematic Assessment |
|
| Compression fracture | Injury, poisoning and procedural complications | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Metastases to central nervous system | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 18.1 | Non-systematic Assessment |
|
| Bronchial obstruction | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Dyspnoea at rest | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Interstitial lung disease | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Pulmonary fistula | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Toxic skin eruption | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Venous thrombosis limb | Vascular disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Eosinophilia | Blood and lymphatic system disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Conjunctival hyperaemia | Eye disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Eye discharge | Eye disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Cheilitis | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Gingival bleeding | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Face oedema | General disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Malaise | General disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Conjunctivitis | Infections and infestations | MedDRA 18.1 | Non-systematic Assessment |
|
| Herpes zoster | Infections and infestations | MedDRA 18.1 | Non-systematic Assessment |
|
| Lung infection | Infections and infestations | MedDRA 18.1 | Non-systematic Assessment |
|
| Paronychia | Infections and infestations | MedDRA 18.1 | Non-systematic Assessment |
|
| Peritonitis | Infections and infestations | MedDRA 18.1 | Non-systematic Assessment |
|
| Infusion related reaction | Injury, poisoning and procedural complications | MedDRA 18.1 | Non-systematic Assessment |
|
| Overdose | Injury, poisoning and procedural complications | MedDRA 18.1 | Non-systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood magnesium decreased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Blood urine present | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Electrocardiogram QT prolonged | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Weight increased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| White blood cell count decreased | Investigations | MedDRA 18.1 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hypernatraemia | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Tumour pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 18.1 | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Peripheral motor neuropathy | Nervous system disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Peripheral sensory neuropathy | Nervous system disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hirsutism | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Pain of skin | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Pruritus generalised | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Skin atrophy | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Skin exfoliation | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Skin fissures | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Skin hyperpigmentation | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA 18.1 | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 18.1 | Non-systematic Assessment |
|
Not provided
Not provided
| Serious TEAEs |
|
| TEAE leading to Discontinuation |
|
| TEAEs Leading to Death |
|
| mAb1024 |
|
| mAb1024 (n=2, 4, 6, 5) |
|
| mAb1024 |
|
| mAb1024 (n= 2, 4, 6, 5) |
|
| mAb1024 (3, 6, 6, 6, 6) |
|
| mAb1024 (n= 2, 4, 6, 4) |
|
| mAb1024 (n= 3,6,6,6,6) |
|
| mAb1024 (n= 2, 4, 6, 4) |
|
| mAb1024 (n= 3,6,6,6,6) |
|
| mAb1024 (n= 2, 4, 6, 4) |
|
| mAb1024 (n= 3,6,6,6,6) |
|
| mAb1024 (n= 2, 4, 6, 4) |
|
| mAb1024 |
|
| mAb1024 |
|
| mAb1024 |
|
| mAb1024 |
|
| mAb992 Week 3 pre-dose (n= 3, 6, 5, 6, 26) |
|
| mAb992 Week 5 pre-dose (n= 2, 5, 6, 0, 23) |
|
| mAb992 Week 6 pre-dose (n= 3, 5, 5, 4, 21) |
|
| mAb992 Week 7 pre-dose (n= 2, 4, 4, 4, 21) |
|
| mAb992 Week 8 pre-dose (n= 2, 4, 3, 2, 12) |
|
| mAb992 End of Trial(up to 41.1weeks)(n=3,6,6,6,27) |
|
| mAb992 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) |
|
| mAb1024 Week 2 pre-dose (n= 3, 6, 6, 6, 29) |
|
| mAb1024 Week 3 pre-dose (n= 3, 6, 5, 6, 26) |
|
| mAb1024 Week 5 pre-dose (n= 2, 5, 6, 0, 23) |
|
| mAb1024 Week 6 pre-dose (n= 3, 5, 5, 4, 21) |
|
| mAb1024 Week 7 pre-dose (n= 2, 4, 4, 4, 21) |
|
| mAb1024 Week 8 pre-dose (n= 2, 4, 3, 2, 12) |
|
| mAb1024End of Trial(up to 41.1weeks)(n=3,6,6,6,27) |
|
| mAb1024 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) |
|
| mAb1024 |
|
| mAb1024 |
|
| PR |
|
| Week 1: greater than (>) 0-less than(<) 100 Score |
|
| Week 1: 100 - <200 Score |
|
| Week 1: 200 - 300 Score |
|
| Week 1: Missing |
|
| Week 4: 0 Score |
|
| Week 4: >0 - <100 Score |
|
| Week 4: 100 - <200 Score |
|
| Week 4: 200 - 300 Score |
|
| Week 4: Missing |
|
| Week 5: 0 Score |
|
| Week 5: >0 - <100 Score |
|
| Week 5: 100 - <200 Score |
|
| Week 5: 200 - 300 Score |
|
| Week 5: Missing |
|
| Week 1: EGFR-FISH Negative |
|
| Week 1: missing |
|
| Week 4: EGFR-FISH Positive |
|
| Week 4: EGFR-FISH Negative |
|
| Week 4: missing |
|