Solid Tumors
Conditions
Keywords
Solid tumors, Sym004, Phase 1
Brief summary
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.
Interventions
DRUGSym004
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.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Japanese male or female subjects aged greater than or equal to 20 years at the time of informed consent signature * Histologically or cytologically confirmed cancer * Refractory or recurrent advanced late stage solid tumors without available therapeutic options which are likely to provide patient benefit (failure and/or intolerance to standard anti-cancer therapy) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Life expectancy of at least 3 months * Written informed consent given before any trial-related activities are carried out * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Subjects with symptomatic brain metastases * Subjects who received total resection or irradiation of the target lesion * Received any of the following medications within 4 weeks before the first administration of Sym004 at Week 1: cytotoxic or cytostatic anti-cancer therapy, antibody therapy, tyrosine kinase inhibitors, and any investigational agent * Received vaccine therapy as anticancer treatment within 12 weeks before the first administration of Sym004 at Week 1 * Diarrhea of greater than Grade 1 according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 (v4.03) * Skin manifestation of greater than Grade 1 according to NCI-CTCAE (v4.03) * Magnesium of less than 0.9 milligram per deciliter (mg/dL) * Abnormal organ or bone marrow function as defined in the protocol * Received immunosuppressive agents (including systemic corticosteroids used at doses above 20 milligram per day (mg/day) of prednisolone or equivalent) within 4 weeks before the first administration of Sym004 at Week 1 * Active severe infection, any other concurrent disease or medical conditions that are deemed to interfere with the conduct of the trial as judged by the Investigator * Known human immunodeficiency virus (HIV) positive, active Hepatitis B or C, or uncontrolled allergic conditions or allergy to Sym004 or its components * Clinically significant cardiac disease or concurrent, uncontrolled medical condition * Known previous Grade 3 to 4 infusion-related reactions, according to NCI-CTCAE (v4.03), with chimeric monoclonal antibodies * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A | Week 1 up to Week 4 (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. |
| Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Baseline up to 4 weeks after the last Sym004 administration, up to a maximum of 41.1 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1 | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4 | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1 | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5 | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1 | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5 | 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. |
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1 | 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. |
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12 and 24 hours post-infusion at Week 5 | 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. |
| Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1 | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 | 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. |
| Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 | 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. |
| Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 | 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. |
| Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 | 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. |
| Clearance (CL) of Sym004 at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 | 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. |
| Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 | 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. |
| Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 | 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. |
| Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 | 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. |
| Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 | 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. |
| Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 | 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. |
| Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 | 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. |
| Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 | 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. |
| Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 | 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. |
| Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 | 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. |
| Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 | 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. |
| Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 | 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. |
| Trough Concentrations (Ctrough) of Sym004 | 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) | 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. |
| Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1 | 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. |
| Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4 | 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. |
| Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5 | 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. |
| Percentage of Subjects With Best Overall Response | 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) | 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. |
| Duration of Overall Response | Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 Weeks | 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. |
| Percentage of Subjects With Disease Control | 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) | 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. |
| Duration of Disease Control | Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 weeks | 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. |
| Time to Progression | Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks | 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. |
| Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1 | 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. |
| 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) | Week 1 (pre-dose), Week 4 and Week 5 | 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. |
| Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1 (pre-dose) and Week 4. | — |
| Progression-free Survival Time | Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks | 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. |
| 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 | Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4 | 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. |
Countries
Germany
Participant flow
Recruitment details
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.
Pre-assignment details
A total of 60 subjects were screened for eligibility, out of which and 51 subjects were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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. | 6 |
| 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. | 6 |
| 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. | 6 |
| 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. | 30 |
| Total | 51 |
Baseline characteristics
| Characteristic | Part A: Sym004 6 mg/kg | Part A: Sym004 9/6 mg/kg | Part A: Sym004 12 mg/kg | Part A: Sym004 18 mg/kg | Part B: Sym004 12 mg/kg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 3.51 | 62.5 years STANDARD_DEVIATION 5.09 | 66.5 years STANDARD_DEVIATION 5.96 | 59.0 years STANDARD_DEVIATION 9.32 | 61.2 years STANDARD_DEVIATION 7.2 | 61.6 years STANDARD_DEVIATION 7.03 |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 3 Participants | 6 Participants | 24 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 6 / 6 | 6 / 6 | 30 / 30 |
| serious Total, serious adverse events | 0 / 3 | 0 / 6 | 2 / 6 | 0 / 6 | 9 / 30 |
Outcome results
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.
Time frame: Week 1 up to Week 4 (Part A)
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Sym004 6 mg/kg | Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A | 0 subjects |
| Part A: Sym004 9/6 mg/kg | Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A | 0 subjects |
| Part A: Sym004 12 mg/kg | Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A | 0 subjects |
| Part A: Sym004 18 mg/kg | Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A | 0 subjects |
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.
Time frame: Baseline up to 4 weeks after the last Sym004 administration, up to a maximum of 41.1 weeks
Population: Safety analysis set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Sym004 6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part A: Sym004 6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 3 subjects |
| Part A: Sym004 6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 0 subjects |
| Part A: Sym004 6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAE leading to Discontinuation | 0 subjects |
| Part A: Sym004 9/6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAE leading to Discontinuation | 0 subjects |
| Part A: Sym004 9/6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 0 subjects |
| Part A: Sym004 9/6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 6 subjects |
| Part A: Sym004 9/6 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part A: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 2 subjects |
| Part A: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part A: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAE leading to Discontinuation | 0 subjects |
| Part A: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 6 subjects |
| Part A: Sym004 18 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 0 subjects |
| Part A: Sym004 18 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 6 subjects |
| Part A: Sym004 18 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAE leading to Discontinuation | 0 subjects |
| Part A: Sym004 18 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Death | 0 subjects |
| Part B: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | Serious TEAEs | 9 subjects |
| Part B: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs | 30 subjects |
| Part B: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAEs Leading to Death | 3 subjects |
| Part B: Sym004 12 mg/kg | Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death | TEAE leading to Discontinuation | 4 subjects |
Secondary
Anti-drug Antibody Titers
Time frame: Week 1 (pre-dose) up to Follow-up assessment (up to maximum 45.1 Weeks)
Population: 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.
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 3685.5 μg*h/mL | Geometric Coefficient of Variation 38.1 |
| Part A: Sym004 6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 4109.0 μg*h/mL | Geometric Coefficient of Variation 25.6 |
| Part A: Sym004 9/6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 6572.1 μg*h/mL | Geometric Coefficient of Variation 30.5 |
| Part A: Sym004 9/6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 5893.1 μg*h/mL | Geometric Coefficient of Variation 33.3 |
| Part A: Sym004 12 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 8957.3 μg*h/mL | Geometric Coefficient of Variation 29.3 |
| Part A: Sym004 12 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 10213 μg*h/mL | Geometric Coefficient of Variation 24.1 |
| Part A: Sym004 18 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 12783 μg*h/mL | Geometric Coefficient of Variation 26 |
| Part A: Sym004 18 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 15917 μg*h/mL | Geometric Coefficient of Variation 30.6 |
| Part B: Sym004 12 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 10336 μg*h/mL | Geometric Coefficient of Variation 27.4 |
| Part B: Sym004 12 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 7073.5 μg*h/mL | Geometric Coefficient of Variation 15.1 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb1024 (n=2, 4, 6, 5) | NA μg*h/mL | — |
| Part A: Sym004 6 mg/kg | 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 | mAb992 (n=2, 5, 6, 5) | NA μg*h/mL | — |
| Part A: Sym004 9/6 mg/kg | 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 | mAb1024 (n=2, 4, 6, 5) | 9738.5 μg*h/mL | Geometric Coefficient of Variation 36.8 |
| Part A: Sym004 9/6 mg/kg | 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 | mAb992 (n=2, 5, 6, 5) | 7111.1 μg*h/mL | Geometric Coefficient of Variation 41.7 |
| Part A: Sym004 12 mg/kg | 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 | mAb992 (n=2, 5, 6, 5) | 15298 μg*h/mL | Geometric Coefficient of Variation 41.4 |
| Part A: Sym004 12 mg/kg | 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 | mAb1024 (n=2, 4, 6, 5) | 21422 μg*h/mL | Geometric Coefficient of Variation 45.5 |
| Part A: Sym004 18 mg/kg | 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 | mAb992 (n=2, 5, 6, 5) | 13053 μg*h/mL | Geometric Coefficient of Variation 18.7 |
| Part A: Sym004 18 mg/kg | 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 | mAb1024 (n=2, 4, 6, 5) | 22016 μg*h/mL | Geometric Coefficient of Variation 32.2 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb992 | 17318 μg*h/mL | Geometric Coefficient of Variation 27 |
| Part A: Sym004 6 mg/kg | 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 | mAb1024 | 22458 μg*h/mL | Geometric Coefficient of Variation 29.7 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb992 | 24755 μg*h/mL | Geometric Coefficient of Variation 31.8 |
| Part A: Sym004 6 mg/kg | 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 | mAb1024 | 32336 μg*h/mL | Geometric Coefficient of Variation 30.8 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose | mAb992 | 19896 μg*h/mL | Geometric Coefficient of Variation 28.9 |
| Part A: Sym004 6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose | mAb1024 | 27554 μg*h/mL | Geometric Coefficient of Variation 30.7 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12 and 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose | mAb992 | 30127 μg*h/mL | Geometric Coefficient of Variation 36.6 |
| Part A: Sym004 6 mg/kg | Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose | mAb1024 | 43308 μg*h/mL | Geometric Coefficient of Variation 37.8 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb992 | 0.023552 Liter/hour | Geometric Coefficient of Variation 29.9 |
| Part A: Sym004 6 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb1024 | 0.018 Liter/hour | Geometric Coefficient of Variation 25.6 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 2, 5, 6, 5) | NA Liter/hour | — |
| Part A: Sym004 6 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | NA Liter/hour | — |
| Part A: Sym004 9/6 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 0.017 Liter/hour | Geometric Coefficient of Variation 30.6 |
| Part A: Sym004 9/6 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 2, 5, 6, 5) | 0.022778 Liter/hour | Geometric Coefficient of Variation 27.3 |
| Part A: Sym004 12 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 2, 5, 6, 5) | 0.023015 Liter/hour | Geometric Coefficient of Variation 29.3 |
| Part A: Sym004 12 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 0.016 Liter/hour | Geometric Coefficient of Variation 32.9 |
| Part A: Sym004 18 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 2, 5, 6, 5) | 0.023589 Liter/hour | Geometric Coefficient of Variation 15 |
| Part A: Sym004 18 mg/kg | Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 0.014 Liter/hour | Geometric Coefficient of Variation 28.2 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 0.031385 Liter/hour | Geometric Coefficient of Variation 21.9 |
| Part A: Sym004 6 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 0.036626 Liter/hour | Geometric Coefficient of Variation 26.7 |
| Part A: Sym004 9/6 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 0.032967 Liter/hour | Geometric Coefficient of Variation 37.7 |
| Part A: Sym004 9/6 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 0.027622 Liter/hour | Geometric Coefficient of Variation 37.4 |
| Part A: Sym004 12 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 0.029012 Liter/hour | Geometric Coefficient of Variation 22.5 |
| Part A: Sym004 12 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 0.023033 Liter/hour | Geometric Coefficient of Variation 23.1 |
| Part A: Sym004 18 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 0.029615 Liter/hour | Geometric Coefficient of Variation 30.3 |
| Part A: Sym004 18 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 0.021383 Liter/hour | Geometric Coefficient of Variation 30.9 |
| Part B: Sym004 12 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 0.021058 Liter/hour | Geometric Coefficient of Variation 17.6 |
| Part B: Sym004 12 mg/kg | Clearance (CL) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 0.032202 Liter/hour | Geometric Coefficient of Variation 24.6 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 22.50 μg*h/mL/mg | Geometric Coefficient of Variation 29.5 |
| Part A: Sym004 6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 25.09 μg*h/mL/mg | Geometric Coefficient of Variation 20.1 |
| Part A: Sym004 9/6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 25.91 μg*h/mL/mg | Geometric Coefficient of Variation 27.7 |
| Part A: Sym004 9/6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 23.24 μg*h/mL/mg | Geometric Coefficient of Variation 30.7 |
| Part A: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 25.79 μg*h/mL/mg | Geometric Coefficient of Variation 18 |
| Part A: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 29.41 μg*h/mL/mg | Geometric Coefficient of Variation 11.1 |
| Part A: Sym004 18 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 21.69 μg*h/mL/mg | Geometric Coefficient of Variation 24.8 |
| Part A: Sym004 18 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 27.01 μg*h/mL/mg | Geometric Coefficient of Variation 26 |
| Part B: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb1024 | 33.17 μg*h/mL/mg | Geometric Coefficient of Variation 27.8 |
| Part B: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose | mAb992 | 22.70 μg*h/mL/mg | Geometric Coefficient of Variation 17.5 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb992 | 29.39 μg*h/mL/mg | Geometric Coefficient of Variation 27.1 |
| Part A: Sym004 6 mg/kg | 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 | mAb1024 | 38.11 μg*h/mL/mg | Geometric Coefficient of Variation 26.9 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb992 | 42.45 μg*h/mL/mg | Geometric Coefficient of Variation 29.9 |
| Part A: Sym004 6 mg/kg | 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 | mAb1024 | 55.46 μg*h/mL/mg | Geometric Coefficient of Variation 25.7 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb1024 (3, 6, 6, 6, 6) | 31.86 μg*h/mL/mg | Geometric Coefficient of Variation 21.9 |
| Part A: Sym004 6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb992 (3, 6, 6, 6, 7) | 27.30 μg*h/mL/mg | Geometric Coefficient of Variation 26.7 |
| Part A: Sym004 9/6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb992 (3, 6, 6, 6, 7) | 30.33 μg*h/mL/mg | Geometric Coefficient of Variation 37.7 |
| Part A: Sym004 9/6 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb1024 (3, 6, 6, 6, 6) | 36.20 μg*h/mL/mg | Geometric Coefficient of Variation 37.4 |
| Part A: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb992 (3, 6, 6, 6, 7) | 34.471 μg*h/mL/mg | Geometric Coefficient of Variation 22.5 |
| Part A: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb1024 (3, 6, 6, 6, 6) | 43.41 μg*h/mL/mg | Geometric Coefficient of Variation 23.1 |
| Part A: Sym004 18 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb992 (3, 6, 6, 6, 7) | 33.77 μg*h/mL/mg | Geometric Coefficient of Variation 30.3 |
| Part A: Sym004 18 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb1024 (3, 6, 6, 6, 6) | 46.77 μg*h/mL/mg | Geometric Coefficient of Variation 30.9 |
| Part B: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb1024 (3, 6, 6, 6, 6) | 47.48 μg*h/mL/mg | Geometric Coefficient of Variation 17.5 |
| Part B: Sym004 12 mg/kg | Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose | mAb992 (3, 6, 6, 6, 7) | 31.05 μg*h/mL/mg | Geometric Coefficient of Variation 24.6 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb992 | 51.67 μg*h/mL/mg | Geometric Coefficient of Variation 36.2 |
| Part A: Sym004 6 mg/kg | 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 | mAb1024 | 74.28 μg*h/mL/mg | Geometric Coefficient of Variation 36.3 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb992 (n= 1, 5, 6, 5) | NA μg*h/mL/mg | — |
| Part A: Sym004 6 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 4) | NA μg*h/mL/mg | — |
| Part A: Sym004 9/6 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 4) | 94.91 μg*h/mL/mg | Geometric Coefficient of Variation 44.7 |
| Part A: Sym004 9/6 mg/kg | 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 | mAb992 (n= 1, 5, 6, 5) | 59.65 μg*h/mL/mg | Geometric Coefficient of Variation 37.3 |
| Part A: Sym004 12 mg/kg | 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 | mAb992 (n= 1, 5, 6, 5) | 77.86 μg*h/mL/mg | Geometric Coefficient of Variation 65.2 |
| Part A: Sym004 12 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 4) | 118.1 μg*h/mL/mg | Geometric Coefficient of Variation 57.5 |
| Part A: Sym004 18 mg/kg | 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 | mAb992 (n= 1, 5, 6, 5) | 72.22 μg*h/mL/mg | Geometric Coefficient of Variation 17.1 |
| Part A: Sym004 18 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 4) | 136.9 μg*h/mL/mg | Geometric Coefficient of Variation 46.8 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 0.334 μg/mL/mg | Geometric Coefficient of Variation 8.4 |
| Part A: Sym004 6 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 0.306 μg/mL/mg | Geometric Coefficient of Variation 19.8 |
| Part A: Sym004 9/6 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 0.353 μg/mL/mg | Geometric Coefficient of Variation 26 |
| Part A: Sym004 9/6 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 0.336 μg/mL/mg | Geometric Coefficient of Variation 23.5 |
| Part A: Sym004 12 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 0.334 μg/mL/mg | Geometric Coefficient of Variation 13.4 |
| Part A: Sym004 12 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 0.346 μg/mL/mg | Geometric Coefficient of Variation 22 |
| Part A: Sym004 18 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 0.268 μg/mL/mg | Geometric Coefficient of Variation 19.1 |
| Part A: Sym004 18 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 0.317 μg/mL/mg | Geometric Coefficient of Variation 15.6 |
| Part B: Sym004 12 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 0.471 μg/mL/mg | Geometric Coefficient of Variation 58.7 |
| Part B: Sym004 12 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 0.284 μg/mL/mg | Geometric Coefficient of Variation 13 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb992 | 0.318 μg/mL/mg | Geometric Coefficient of Variation 25 |
| Part A: Sym004 6 mg/kg | Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb1024 | 0.380 μg/mL/mg | Geometric Coefficient of Variation 20.2 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 5) | NA μg*h/mL/mg | — |
| Part A: Sym004 6 mg/kg | 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 | mAb992 (n= 2, 5, 6, 5) | NA μg*h/mL/mg | — |
| Part A: Sym004 9/6 mg/kg | 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 | mAb992 (n= 2, 5, 6, 5) | 43.90 μg*h/mL/mg | Geometric Coefficient of Variation 27.3 |
| Part A: Sym004 9/6 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 5) | 59.12 μg*h/mL/mg | Geometric Coefficient of Variation 30.6 |
| Part A: Sym004 12 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 5) | 60.85 μg*h/mL/mg | Geometric Coefficient of Variation 32.9 |
| Part A: Sym004 12 mg/kg | 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 | mAb992 (n= 2, 5, 6, 5) | 43.45 μg*h/mL/mg | Geometric Coefficient of Variation 29.3 |
| Part A: Sym004 18 mg/kg | 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 | mAb1024 (n= 2, 4, 6, 5) | 72.36 μg*h/mL/mg | Geometric Coefficient of Variation 28.2 |
| Part A: Sym004 18 mg/kg | 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 | mAb992 (n= 2, 5, 6, 5) | 42.38 μg*h/mL/mg | Geometric Coefficient of Variation 15 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 0.570 μg/mL/mg | Geometric Coefficient of Variation 7.1 |
| Part A: Sym004 6 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 0.486 μg/mL/mg | Geometric Coefficient of Variation 4.4 |
| Part A: Sym004 9/6 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 0.524 μg/mL/mg | Geometric Coefficient of Variation 31.4 |
| Part A: Sym004 9/6 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 0.553 μg/mL/mg | Geometric Coefficient of Variation 32.3 |
| Part A: Sym004 12 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 0.516 μg/mL/mg | Geometric Coefficient of Variation 18.4 |
| Part A: Sym004 12 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 0.629 μg/mL/mg | Geometric Coefficient of Variation 12.9 |
| Part A: Sym004 18 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 0.752 μg/mL/mg | Geometric Coefficient of Variation 24.3 |
| Part A: Sym004 18 mg/kg | Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 0.466 μg/mL/mg | Geometric Coefficient of Variation 12.8 |
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.
Time frame: Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 weeks
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Sym004 6 mg/kg | Duration of Disease Control | 6.10 Weeks |
| Part A: Sym004 9/6 mg/kg | Duration of Disease Control | 5.35 Weeks |
| Part A: Sym004 12 mg/kg | Duration of Disease Control | 24.60 Weeks |
| Part A: Sym004 18 mg/kg | Duration of Disease Control | 6.10 Weeks |
| Part B: Sym004 12 mg/kg | Duration of Disease Control | 5.90 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.
Time frame: Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 Weeks
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Sym004 12 mg/kg | Duration of Overall Response | 25.85 Weeks |
| Part B: Sym004 12 mg/kg | Duration of Overall Response | 10.40 Weeks |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 50.131 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 29.2 |
| Part A: Sym004 6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 54.660 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 15.6 |
| Part A: Sym004 9/6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 85.088 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 25.3 |
| Part A: Sym004 9/6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 89.443 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 26.2 |
| Part A: Sym004 12 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 120.37 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 33.6 |
| Part A: Sym004 12 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 116.18 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 31.2 |
| Part A: Sym004 18 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 187.03 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 23.9 |
| Part A: Sym004 18 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 157.71 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 18.6 |
| Part B: Sym004 12 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb992 | 88.589 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 15 |
| Part B: Sym004 12 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose | mAb1024 | 146.92 microgram per milliliter (μg/mL) | Geometric Coefficient of Variation 56.3 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb992 | 187.40 μg/mL | Geometric Coefficient of Variation 24.3 |
| Part A: Sym004 6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb1024 | 224.0 μg/mL | Geometric Coefficient of Variation 24.7 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 76.094 μg/mL | Geometric Coefficient of Variation 16.4 |
| Part A: Sym004 6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 89.26 μg/mL | Geometric Coefficient of Variation 10.2 |
| Part A: Sym004 9/6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 91.70 μg/mL | Geometric Coefficient of Variation 33.4 |
| Part A: Sym004 9/6 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 86.763 μg/mL | Geometric Coefficient of Variation 34 |
| Part A: Sym004 12 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 181.62 μg/mL | Geometric Coefficient of Variation 31.6 |
| Part A: Sym004 12 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 221.3 μg/mL | Geometric Coefficient of Variation 21.1 |
| Part A: Sym004 18 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 231.9 μg/mL | Geometric Coefficient of Variation 32.8 |
| Part A: Sym004 18 mg/kg | Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 143.79 μg/mL | Geometric Coefficient of Variation 23.4 |
Secondary
Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method.
Time frame: Week 1 (pre-dose) and Week 4.
Population: The Biomarker analysis set consisted of all subjects who received at least 1 administration of Sym004 and who had at least 1 biomarker evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Sym004 6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: missing | 100.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: missing | 100.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: missing | 100.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: missing | 100.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: missing | 100.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: missing | 100.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: missing | 100.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: missing | 100.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Negative | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Negative | 23.1 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: missing | 46.2 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Negative | 53.8 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: missing | 76.9 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 4: EGFR-FISH Positive | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method. | Week 1: EGFR-FISH Positive | 0.0 percentage of subjects |
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.
Time frame: Week 1 (pre-dose), Week 4 and Week 5
Population: The Biomarker analysis set consisted of all subjects who received at least 1 administration of Sym004 and who had at least 1 biomarker evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: Missing | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: Missing | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 100 - <200 Score | 33.3 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 200 - 300 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: Missing | 100.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 100 - <200 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: greater than (>) 0-less than(<) 100 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 100 - <200 Score | 33.3 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 200 - 300 Score | 66.7 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 200 - 300 Score | 66.7 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: Missing | 100.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 200 - 300 Score | 83.3 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 200 - 300 Score | 16.7 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: Missing | 16.7 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: Missing | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 100 - <200 Score | 83.3 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 200 - 300 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 100 - <200 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 100 - <200 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: greater than (>) 0-less than(<) 100 Score | 0.0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 100 - <200 Score | 16.7 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 100 - <200 Score | 33.3 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: Missing | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: Missing | 100.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 200 - 300 Score | 66.7 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: greater than (>) 0-less than(<) 100 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 200 - 300 Score | 83.3 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 200 - 300 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: Missing | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 100 - <200 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 100 - <200 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 200 - 300 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: Missing | 100.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 200 - 300 Score | 66.7 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: Missing | 16.7 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: greater than (>) 0-less than(<) 100 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 200 - 300 Score | 100.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: Missing | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 100 - <200 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 0 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: >0 - <100 Score | 0.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 100 - <200 Score | 16.7 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 0 Score | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: Missing | 15.4 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 200 - 300 Score | 23.1 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 0 Score | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 100 - <200 Score | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 200 - 300 Score | 76.9 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: greater than (>) 0-less than(<) 100 Score | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 100 - <200 Score | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: >0 - <100 Score | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 1: 0 Score | 7.7 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: Missing | 100.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 5: 200 - 300 Score | 0.0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: 100 - <200 Score | 46.2 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: Missing | 15.4 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC) | Week 4: >0 - <100 Score | 15.4 percentage of subjects |
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Sym004 6 mg/kg | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part A: Sym004 6 mg/kg | Percentage of Subjects With Best Overall Response | PR | 0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Subjects With Best Overall Response | PR | 0 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Subjects With Best Overall Response | PR | 33.3 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Subjects With Best Overall Response | PR | 0 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Subjects With Best Overall Response | PR | 16.7 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Subjects With Best Overall Response | CR | 0 percentage of subjects |
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Sym004 6 mg/kg | Percentage of Subjects With Disease Control | 66.7 percentage of subjects |
| Part A: Sym004 9/6 mg/kg | Percentage of Subjects With Disease Control | 66.7 percentage of subjects |
| Part A: Sym004 12 mg/kg | Percentage of Subjects With Disease Control | 50.0 percentage of subjects |
| Part A: Sym004 18 mg/kg | Percentage of Subjects With Disease Control | 16.7 percentage of subjects |
| Part B: Sym004 12 mg/kg | Percentage of Subjects With Disease Control | 56.7 percentage of subjects |
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.
Time frame: Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Sym004 6 mg/kg | Progression-free Survival Time | 2.12 months |
| Part A: Sym004 9/6 mg/kg | Progression-free Survival Time | 2.30 months |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 66.478 hours | Geometric Coefficient of Variation 10 |
| Part A: Sym004 6 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 74.075 hours | Geometric Coefficient of Variation 8.8 |
| Part A: Sym004 9/6 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 79.041 hours | Geometric Coefficient of Variation 18.8 |
| Part A: Sym004 9/6 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 91.303 hours | Geometric Coefficient of Variation 21.7 |
| Part A: Sym004 12 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 82.865 hours | Geometric Coefficient of Variation 21.1 |
| Part A: Sym004 12 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 100.05 hours | Geometric Coefficient of Variation 24.3 |
| Part A: Sym004 18 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 134.48 hours | Geometric Coefficient of Variation 27.8 |
| Part A: Sym004 18 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 111.69 hours | Geometric Coefficient of Variation 18.9 |
| Part B: Sym004 12 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 87.257 hours | Geometric Coefficient of Variation 21.1 |
| Part B: Sym004 12 mg/kg | Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 100.57 hours | Geometric Coefficient of Variation 34.8 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose | mAb992 | 130.39 hours | Geometric Coefficient of Variation 26.4 |
| Part A: Sym004 6 mg/kg | Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose | mAb1024 | 163.6 hours | Geometric Coefficient of Variation 36.3 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | NA hours | — |
| Part A: Sym004 6 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | NA hours | — |
| Part A: Sym004 9/6 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | 85.228 hours | Geometric Coefficient of Variation 24.4 |
| Part A: Sym004 9/6 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 117.8 hours | Geometric Coefficient of Variation 27.5 |
| Part A: Sym004 12 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 155.9 hours | Geometric Coefficient of Variation 37.4 |
| Part A: Sym004 12 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | 135.98 hours | Geometric Coefficient of Variation 52.5 |
| Part A: Sym004 18 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 163.8 hours | Geometric Coefficient of Variation 27.5 |
| Part A: Sym004 18 mg/kg | Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | 132.14 hours | Geometric Coefficient of Variation 13.9 |
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.
Time frame: Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Sym004 6 mg/kg | Time to Progression | 2.37 months |
| Part A: Sym004 9/6 mg/kg | Time to Progression | 2.33 months |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Sym004 6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb992 | 2.07 hours |
| Part A: Sym004 6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb1024 | 2.05 hours |
| Part A: Sym004 9/6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb1024 | 7.20 hours |
| Part A: Sym004 9/6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb992 | 5.12 hours |
| Part A: Sym004 12 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb1024 | 6.66 hours |
| Part A: Sym004 12 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb992 | 5.73 hours |
| Part A: Sym004 18 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb992 | 7.21 hours |
| Part A: Sym004 18 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb1024 | 7.15 hours |
| Part B: Sym004 12 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb1024 | 7.13 hours |
| Part B: Sym004 12 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose | mAb992 | 6.30 hours |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Sym004 6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb992 | 7.03 hours |
| Part A: Sym004 6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb1024 | 5.28 hours |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Sym004 6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 10.1 hours |
| Part A: Sym004 6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 2.07 hours |
| Part A: Sym004 9/6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 5.94 hours |
| Part A: Sym004 9/6 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 6.13 hours |
| Part A: Sym004 12 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 9.13 hours |
| Part A: Sym004 12 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 5.18 hours |
| Part A: Sym004 18 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 | 7.10 hours |
| Part A: Sym004 18 mg/kg | Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 | 5.13 hours |
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.
Time frame: 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)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 8.38333 μg/mL | Standard Deviation 2.562935 |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 19.8700 μg/mL | Standard Deviation 9.570564 |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 25.5833 μg/mL | Standard Deviation 21.14422 |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 23.8000 μg/mL | Standard Deviation 9.525382 |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 31.8700 μg/mL | Standard Deviation 23.97075 |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | NA μg/mL | — |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 10.6767 μg/mL | Standard Deviation 2.688128 |
| Part A: Sym004 6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 16.3617 μg/mL | Standard Deviation 7.384964 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 36.1125 μg/mL | Standard Deviation 24.42487 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 22.7517 μg/mL | Standard Deviation 14.69928 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | 31.8900 μg/mL | Standard Deviation 17.43852 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 35.2440 μg/mL | Standard Deviation 18.90163 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | 22.9260 μg/mL | Standard Deviation 11.37231 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 20.2433 μg/mL | Standard Deviation 8.704451 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 16.7033 μg/mL | Standard Deviation 8.283479 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | NA μg/mL | — |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 26.3340 μg/mL | Standard Deviation 13.43829 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | 34.6050 μg/mL | Standard Deviation 19.4955 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 25.7500 μg/mL | Standard Deviation 16.36742 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | 24.8650 μg/mL | Standard Deviation 13.70631 |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | NA μg/mL | — |
| Part A: Sym004 9/6 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | 25.4667 μg/mL | Standard Deviation 58.32014 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 38.7017 μg/mL | Standard Deviation 12.01645 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 70.9875 μg/mL | Standard Deviation 61.0528 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 29.4483 μg/mL | Standard Deviation 9.716758 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | 98.6550 μg/mL | Standard Deviation 46.85021 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | 122.283 μg/mL | Standard Deviation 79.73053 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 128.858 μg/mL | Standard Deviation 41.31495 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 107.843 μg/mL | Standard Deviation 76.48666 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | 66.0267 μg/mL | Standard Deviation 37.84088 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 69.9460 μg/mL | Standard Deviation 21.36079 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 57.7280 μg/mL | Standard Deviation 29.34743 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | 166.207 μg/mL | Standard Deviation 52.8701 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 92.4920 μg/mL | Standard Deviation 47.20264 |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part A: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | 13.8400 μg/mL | Standard Deviation 32.25929 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 45.1117 μg/mL | Standard Deviation 17.24716 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | 1.24833 μg/mL | Standard Deviation 2.197339 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 54.9275 μg/mL | Standard Deviation 13.15679 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 15.3600 μg/mL | Standard Deviation 6.817337 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | NA μg/mL | — |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 64.3750 μg/mL | Standard Deviation 20.56197 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 36.1700 μg/mL | Standard Deviation 7.608184 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | NA μg/mL | — |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 58.6967 μg/mL | Standard Deviation 17.29509 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 24.7000 μg/mL | Standard Deviation 11.16315 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | NA μg/mL | — |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 90.9275 μg/mL | Standard Deviation 26.82442 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | NA μg/mL | — |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | 3.73333 μg/mL | Standard Deviation 6.795639 |
| Part A: Sym004 18 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 27.8641 μg/mL | Standard Deviation 12.33288 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | 60.4542 μg/mL | Standard Deviation 25.37663 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 66.1524 μg/mL | Standard Deviation 65.22446 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 53.2224 μg/mL | Standard Deviation 30.76489 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | 71.0739 μg/mL | Standard Deviation 67.33365 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | 5.63333 μg/mL | Standard Deviation 11.64986 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 8 pre-dose (n= 2, 4, 3, 2, 12) | 93.0283 μg/mL | Standard Deviation 47.35483 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 32.6969 μg/mL | Standard Deviation 12.62782 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Week 2 pre-dose (n= 3, 6, 6, 6, 29) | 20.1517 μg/mL | Standard Deviation 8.411459 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024End of Trial(up to 41.1weeks)(n=3,6,6,6,27) | 11.2478 μg/mL | Standard Deviation 19.88056 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 7 pre-dose (n= 2, 4, 4, 4, 21) | 94.4729 μg/mL | Standard Deviation 52.582 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 5 pre-dose (n= 2, 5, 6, 0, 23) | 82.6235 μg/mL | Standard Deviation 49.01981 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb992 Follow up (up to 45.1 Weeks)(n=1,2,3,4,19) | NA μg/mL | — |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 6 pre-dose (n= 3, 5, 5, 4, 21) | 80.0024 μg/mL | Standard Deviation 35.72029 |
| Part B: Sym004 12 mg/kg | Trough Concentrations (Ctrough) of Sym004 | mAb1024 Week 3 pre-dose (n= 3, 6, 5, 6, 26) | 44.6531 μg/mL | Standard Deviation 17.9182 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb992 | 4.3988 Liter | Geometric Coefficient of Variation 24.4 |
| Part A: Sym004 6 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose | mAb1024 | 4.20 Liter | Geometric Coefficient of Variation 27.7 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | NA Liter | — |
| Part A: Sym004 6 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | NA Liter | — |
| Part A: Sym004 9/6 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 2.85 Liter | Geometric Coefficient of Variation 20.6 |
| Part A: Sym004 9/6 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | 2.7931 Liter | Geometric Coefficient of Variation 15.4 |
| Part A: Sym004 12 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 3.71 Liter | Geometric Coefficient of Variation 21.3 |
| Part A: Sym004 12 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | 4.4777 Liter | Geometric Coefficient of Variation 26.2 |
| Part A: Sym004 18 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb1024 (n= 2, 4, 6, 4) | 3.40 Liter | Geometric Coefficient of Variation 24.9 |
| Part A: Sym004 18 mg/kg | Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose | mAb992 (n= 1, 5, 6, 5) | 4.4383 Liter | Geometric Coefficient of Variation 17.9 |
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.
Time frame: Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Sym004 6 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 3.3543 Liter | Geometric Coefficient of Variation 16.7 |
| Part A: Sym004 6 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 3.5130 Liter | Geometric Coefficient of Variation 36.1 |
| Part A: Sym004 9/6 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 3.7593 Liter | Geometric Coefficient of Variation 21.9 |
| Part A: Sym004 9/6 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 3.6384 Liter | Geometric Coefficient of Variation 17.6 |
| Part A: Sym004 12 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 3.4688 Liter | Geometric Coefficient of Variation 17.8 |
| Part A: Sym004 12 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 3.3245 Liter | Geometric Coefficient of Variation 3.4 |
| Part A: Sym004 18 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 4.7726 Liter | Geometric Coefficient of Variation 23.3 |
| Part A: Sym004 18 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 4.1483 Liter | Geometric Coefficient of Variation 29.1 |
| Part B: Sym004 12 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb1024 (n= 3,6,6,6,6) | 3.0558 Liter | Geometric Coefficient of Variation 47 |
| Part B: Sym004 12 mg/kg | Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose | mAb992 (n= 3,6,6,6,7) | 4.0536 Liter | Geometric Coefficient of Variation 10.8 |