Cancer, Refractory Solid Tumor
Conditions
Brief summary
The purpose of this clinical research study is to establish the maximum tolerated dose and recommended Phase II dose of Erbitux™ in combination with Irinotecan in pediatric and adolescent patients with refractory solid tumors.
Interventions
DRUGCetuximab + Irinotecan
Intravenous (IV) cetuximab 75 - 250 mg/m2 depending on dose escalation for MTD, weekly; irinotecan was administered at a dose of 16 or 20 mg/m2 or per dose escalation, administered x5 days x2 weeks, separated by 2 days off, every 21 days.
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of a solid tumor which has progressed on, or following standard therapy, or for which no standard effective therapy is known. * Children age 1-18 years.
Exclusion criteria
* Presence of active infection. * Requirement to receive concurrent chemotherapy immunotherapy, radiotherapy, or any other investigational drug while on study. * Inadequate bone marrow, hepatic, or renal function.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | Continuous assessment of safety throughout the entire study period and determination of doe-limiting toxicities during and at the end of Cycle 1. | MTD of cetuximab intravenous (IV) weekly + irinotecan IV x5 days x2 weeks (in a 3-week cycle) and RPIID of cetuximab IV weekly, as measured by dose-limiting toxicities (see outcome measure 2) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | The single dose pharmacokinetics (PK) of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; Cmax was evaluated based on concentration-time profile. |
| Area Under the Curve, Extrapolated to Infinity (AUC[INF]) | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; AUC(INF) was evaluated based on concentration-time profile. |
| Terminal Half-Life (T-Half) | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; T-half was evaluated based on concentration-time profile. |
| Clearance Corrected for Body Surface Area (CL/BSA) | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; CL/BSA was evaluated based on concentration-time profile. |
| Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA) | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; VSS/BSA was evaluated based on concentration-time profile. |
| Tumor Response | Every other 21-day cycle | Non-central nervous system (CNS) tumors evaluated using Response Evaluation Criteria In Solid Tumors (RECIST), criteria to define when cancer patients improve (respond), stay the same (stable), or worsen (progression). CNS tumors evaluated based on measurements by investigator, dependence on corticosteroids, and neurologic exam. |
| Number of Participants With a Dose-Limiting Toxicity | Prior to each 21-day cycle until dose-limiting toxicities | Dose-limiting toxicities (DLTs)=serious drug side effects preventing further dose escalation. If 1 of the first 3 subjects developed a DLT during cycle 1 up to 3 additional subjects were enrolled at that dose level. The maximum dose level at which DLTs occurred in fewer than 2 out of 3 to 6 subjects was defined as the Maximum Tolerated Dose (MTD). |
| Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Weekly throughout the study and every 4 weeks thereafter | Toxicity assessments performed at least weekly from the 1st dose of study drug until at least 30 days after the final dose of study drug and thereafter every 4 weeks until all study-related toxicities resolved, returned to baseline, or were deemed irreversible, whichever was longer. Grade 3=severe AE; grade 4=disabling or life threatening. |
| Grade 3-4 Laboratory Abnormalities - Leukopenia | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment | Blood samples were collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe AE; Grade 4=Life-threatening or disabling AE |
| Grade 3-4 Laboratory Abnormalities - Neutropenia | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment | Blood samples were collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe and undesirable AE; Grade 4=Life-threatening or disabling AE |
| Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment | Blood samples collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe AE; Grade 4=Life-threatening or disabling AE |
| Grade 3/4 Laboratory Abnormalities - Hypomagnesemia | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment | Blood samples were collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe AE; Grade 4=Life-threatening or disabling AE |
| Human Anti-cetuximab Antibody (HACA) Response | Blood was drawn immediately prior to cetuximab infusions, on a 21-day cycle | In order to be considered positive for anti-cetuximab a sample had to: 1) be evaluable (i.e., have a pre and at least one post-treatment timepoint), 2) have an anti-cetuximab value \> 7 ng/mL and 3) have a post-treatment sample at least twice the pre-treatment level. |
Countries
United States
Participant flow
Pre-assignment details
48 subjects were enrolled; 1 additional subject withdrew informed consent before any measurements or treatment. 46 subjects (27 in the 1- to 12-yrs-old group and 19 subjects in the 13- to 18-yrs-old group) were treated; 2 subjects in the 13-18 yrs group were not treated, and are NOT included in Participant Flow or Baseline Characteristics tables.
Participants by arm
| Arm | Count |
|---|---|
| 1- to 12-years-old | 27 |
| 13- to 18-years-old | 19 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Deterioration without progression | 2 | 0 |
| Overall Study | Disease progression/relapse | 20 | 15 |
| Overall Study | Study Closure | 1 | 0 |
| Overall Study | Study Drug Toxicity | 1 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | 1- to 12-years-old | 13- to 18-years-old | Total |
|---|---|---|---|
| Age, Continuous | 8.0 years | 16.0 years | 10 years |
| Disease diagnosis CNS Primary Tumor | 17 Participants | 9 Participants | 26 Participants |
| Disease diagnosis Non-CNS Primary Tumor | 10 Participants | 10 Participants | 20 Participants |
| Performance Status <50 | 0 Participants | 0 Participants | 0 Participants |
| Performance Status ≥50-70 | 8 Participants | 3 Participants | 11 Participants |
| Performance Status >70-100 | 19 Participants | 16 Participants | 35 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 14 Participants | 35 Participants |
| Sex: Female, Male Female | 15 Participants | 9 Participants | 24 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 22 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 | 14 / 14 | 8 / 10 | 3 / 3 | 12 / 12 | 7 / 7 |
| serious Total, serious adverse events | 7 / 14 | 7 / 10 | 0 / 3 | 6 / 12 | 4 / 7 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan
MTD of cetuximab intravenous (IV) weekly + irinotecan IV x5 days x2 weeks (in a 3-week cycle) and RPIID of cetuximab IV weekly, as measured by dose-limiting toxicities (see outcome measure 2)
Time frame: Continuous assessment of safety throughout the entire study period and determination of doe-limiting toxicities during and at the end of Cycle 1.
Population: As-treated population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: 75/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | MTD cetuximab (in combination w/ irinotecan) | 250 mg/m2 |
| Group A: 75/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | MTD irinotecan (in combination w/ cetuximab) | 16 mg/m2 |
| Group A: 75/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | RPIID cetuximab (in combination with irinotecan) | 250 mg/m2 |
| Group A: 75/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | RPIID irinotecan (in combination with cetuximab) | 16 mg/m2 |
| Group A: 150/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | RPIID irinotecan (in combination with cetuximab) | 20 mg/m2 |
| Group A: 150/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | MTD cetuximab (in combination w/ irinotecan) | 250 mg/m2 |
| Group A: 150/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | RPIID cetuximab (in combination with irinotecan) | 250 mg/m2 |
| Group A: 150/20 | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RPIID) of Cetuximab in Combination With Irinotecan | MTD irinotecan (in combination w/ cetuximab) | 20 mg/m2 |
Secondary
Area Under the Curve, Extrapolated to Infinity (AUC[INF])
The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; AUC(INF) was evaluated based on concentration-time profile.
Time frame: up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group A: 75/20 | Area Under the Curve, Extrapolated to Infinity (AUC[INF]) | 1598.3 µg•h/mL | Standard Deviation 863.32 |
| Group A: 150/20 | Area Under the Curve, Extrapolated to Infinity (AUC[INF]) | 8871.2 µg•h/mL | Standard Deviation 1861.1 |
| Group A 150/16 | Area Under the Curve, Extrapolated to Infinity (AUC[INF]) | 17706.0 µg•h/mL | Standard Deviation 6384.5 |
| Group A: 250/16 | Area Under the Curve, Extrapolated to Infinity (AUC[INF]) | 1925.2 µg•h/mL | Standard Deviation 460.6 |
| Group B: 75/20 | Area Under the Curve, Extrapolated to Infinity (AUC[INF]) | 7027.3 µg•h/mL | Standard Deviation 239.5 |
| Group B: 150/20 | Area Under the Curve, Extrapolated to Infinity (AUC[INF]) | 13410.4 µg•h/mL | Standard Deviation 5484.5 |
Secondary
Clearance Corrected for Body Surface Area (CL/BSA)
The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; CL/BSA was evaluated based on concentration-time profile.
Time frame: up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: 75/20 | Clearance Corrected for Body Surface Area (CL/BSA) | 0.057 L/h/m2 | Standard Deviation 0.041 |
| Group A: 150/20 | Clearance Corrected for Body Surface Area (CL/BSA) | 0.017 L/h/m2 | Standard Deviation 0.004 |
| Group A 150/16 | Clearance Corrected for Body Surface Area (CL/BSA) | 0.015 L/h/m2 | Standard Deviation 0.005 |
| Group A: 250/16 | Clearance Corrected for Body Surface Area (CL/BSA) | 0.040 L/h/m2 | Standard Deviation 0.01 |
| Group B: 75/20 | Clearance Corrected for Body Surface Area (CL/BSA) | 0.021 L/h/m2 | Standard Deviation 0.001 |
| Group B: 150/20 | Clearance Corrected for Body Surface Area (CL/BSA) | 0.020 L/h/m2 | Standard Deviation 0.009 |
Secondary
Grade 3/4 Laboratory Abnormalities - Hypomagnesemia
Blood samples were collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe AE; Grade 4=Life-threatening or disabling AE
Time frame: pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A: 250/16 | Grade 3/4 Laboratory Abnormalities - Hypomagnesemia | 1 Participants |
Secondary
Grade 3-4 Laboratory Abnormalities - Leukopenia
Blood samples were collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe AE; Grade 4=Life-threatening or disabling AE
Time frame: pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A: 75/20 | Grade 3-4 Laboratory Abnormalities - Leukopenia | 3 Participants |
| Group A: 150/20 | Grade 3-4 Laboratory Abnormalities - Leukopenia | 0 Participants |
| Group A 150/16 | Grade 3-4 Laboratory Abnormalities - Leukopenia | 3 Participants |
| Group A: 250/16 | Grade 3-4 Laboratory Abnormalities - Leukopenia | 4 Participants |
| Group B: 75/20 | Grade 3-4 Laboratory Abnormalities - Leukopenia | 2 Participants |
| Group B: 150/20 | Grade 3-4 Laboratory Abnormalities - Leukopenia | 2 Participants |
| Group B: 250/20 | Grade 3-4 Laboratory Abnormalities - Leukopenia | 4 Participants |
Secondary
Grade 3-4 Laboratory Abnormalities - Neutropenia
Blood samples were collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe and undesirable AE; Grade 4=Life-threatening or disabling AE
Time frame: pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A: 75/20 | Grade 3-4 Laboratory Abnormalities - Neutropenia | 3 Participants |
| Group A: 150/20 | Grade 3-4 Laboratory Abnormalities - Neutropenia | 0 Participants |
| Group A 150/16 | Grade 3-4 Laboratory Abnormalities - Neutropenia | 3 Participants |
| Group A: 250/16 | Grade 3-4 Laboratory Abnormalities - Neutropenia | 3 Participants |
| Group B: 75/20 | Grade 3-4 Laboratory Abnormalities - Neutropenia | 3 Participants |
| Group B: 150/20 | Grade 3-4 Laboratory Abnormalities - Neutropenia | 1 Participants |
| Group B: 250/20 | Grade 3-4 Laboratory Abnormalities - Neutropenia | 4 Participants |
Secondary
Grade 3-4 Laboratory Abnormalities - Thrombocytopenia
Blood samples collected at selected times (pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment) for clinical laboratory evaluations. Grade 3= Severe AE; Grade 4=Life-threatening or disabling AE
Time frame: pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A: 75/20 | Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | 1 Participants |
| Group A: 150/20 | Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | 0 Participants |
| Group A 150/16 | Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | 3 Participants |
| Group A: 250/16 | Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | 2 Participants |
| Group B: 75/20 | Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | 0 Participants |
| Group B: 150/20 | Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | 0 Participants |
| Group B: 250/20 | Grade 3-4 Laboratory Abnormalities - Thrombocytopenia | 4 Participants |
Secondary
Human Anti-cetuximab Antibody (HACA) Response
In order to be considered positive for anti-cetuximab a sample had to: 1) be evaluable (i.e., have a pre and at least one post-treatment timepoint), 2) have an anti-cetuximab value \> 7 ng/mL and 3) have a post-treatment sample at least twice the pre-treatment level.
Time frame: Blood was drawn immediately prior to cetuximab infusions, on a 21-day cycle
Population: Cohort comprises all enrolled participants who were tested for HACA. Evaluable participants had normal baseline HACA (≤ 7 ng/dL) and ≥1 postbaseline HACA levels; unevaluable participants either did not have enough sample for analysis or did not have a pre- and postinfusion sample for immunogenicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: 75/20 | Human Anti-cetuximab Antibody (HACA) Response | Evaluable Participants | 27 Participants |
| Group A: 75/20 | Human Anti-cetuximab Antibody (HACA) Response | Unevaluable Participants | 15 Participants |
| Group A: 75/20 | Human Anti-cetuximab Antibody (HACA) Response | Participants with positive HACA level | 1 Participants |
Secondary
Maximum Plasma Concentration (Cmax)
The single dose pharmacokinetics (PK) of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; Cmax was evaluated based on concentration-time profile.
Time frame: up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group A: 75/20 | Maximum Plasma Concentration (Cmax) | 50.5 µg/mL | Standard Deviation 16.7 |
| Group A: 150/20 | Maximum Plasma Concentration (Cmax) | 112.9 µg/mL | Standard Deviation 24.7 |
| Group A 150/16 | Maximum Plasma Concentration (Cmax) | 163.7 µg/mL | Standard Deviation 31.1 |
| Group A: 250/16 | Maximum Plasma Concentration (Cmax) | 53.4 µg/mL | Standard Deviation 21.7 |
| Group B: 75/20 | Maximum Plasma Concentration (Cmax) | 83.1 µg/mL | Standard Deviation 13.2 |
| Group B: 150/20 | Maximum Plasma Concentration (Cmax) | 148.5 µg/mL | Standard Deviation 28.1 |
Secondary
Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs)
Toxicity assessments performed at least weekly from the 1st dose of study drug until at least 30 days after the final dose of study drug and thereafter every 4 weeks until all study-related toxicities resolved, returned to baseline, or were deemed irreversible, whichever was longer. Grade 3=severe AE; grade 4=disabling or life threatening.
Time frame: Weekly throughout the study and every 4 weeks thereafter
Population: All treated patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Grade 3-4 AEs | 4 Participants |
| Group A: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | SAEs | 2 Participants |
| Group A: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| Group A: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths (total) | 0 Participants |
| Group A: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths within 30 days of last dose | 0 Participants |
| Group A: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths (total) | 5 Participants |
| Group A: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Grade 3-4 AEs | 4 Participants |
| Group A: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | AEs leading to discontinuation of study treatment | 1 Participants |
| Group A: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths within 30 days of last dose | 2 Participants |
| Group A: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | SAEs | 4 Participants |
| Group A 150/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | SAEs | 0 Participants |
| Group A 150/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths (total) | 2 Participants |
| Group A 150/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| Group A 150/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths within 30 days of last dose | 0 Participants |
| Group A 150/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Grade 3-4 AEs | 2 Participants |
| Group A: 250/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| Group A: 250/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths (total) | 5 Participants |
| Group A: 250/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths within 30 days of last dose | 3 Participants |
| Group A: 250/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | SAEs | 6 Participants |
| Group A: 250/16 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Grade 3-4 AEs | 5 Participants |
| Group B: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | SAEs | 5 Participants |
| Group B: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | AEs leading to discontinuation of study treatment | 2 Participants |
| Group B: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths within 30 days of last dose | 0 Participants |
| Group B: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Grade 3-4 AEs | 7 Participants |
| Group B: 75/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths (total) | 3 Participants |
| Group B: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths (total) | 1 Participants |
| Group B: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths within 30 days of last dose | 0 Participants |
| Group B: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | SAEs | 3 Participants |
| Group B: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | AEs leading to discontinuation of study treatment | 1 Participants |
| Group B: 150/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Grade 3-4 AEs | 4 Participants |
| Group B: 250/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths within 30 days of last dose | 1 Participants |
| Group B: 250/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | SAEs | 4 Participants |
| Group B: 250/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Deaths (total) | 1 Participants |
| Group B: 250/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | Grade 3-4 AEs | 4 Participants |
| Group B: 250/20 | Number of Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) | AEs leading to discontinuation of study treatment | 0 Participants |
Secondary
Number of Participants With a Dose-Limiting Toxicity
Dose-limiting toxicities (DLTs)=serious drug side effects preventing further dose escalation. If 1 of the first 3 subjects developed a DLT during cycle 1 up to 3 additional subjects were enrolled at that dose level. The maximum dose level at which DLTs occurred in fewer than 2 out of 3 to 6 subjects was defined as the Maximum Tolerated Dose (MTD).
Time frame: Prior to each 21-day cycle until dose-limiting toxicities
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: 75/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with a dose-limiting toxicity | 1 Participants |
| Group A: 75/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with no dose-limiting toxicity | 5 Participants |
| Group A: 150/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with a dose-limiting toxicity | 2 Participants |
| Group A: 150/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with no dose-limiting toxicity | 4 Participants |
| Group A 150/16 | Number of Participants With a Dose-Limiting Toxicity | Subjects with no dose-limiting toxicity | 3 Participants |
| Group A 150/16 | Number of Participants With a Dose-Limiting Toxicity | Subjects with a dose-limiting toxicity | 0 Participants |
| Group A: 250/16 | Number of Participants With a Dose-Limiting Toxicity | Subjects with no dose-limiting toxicity | 12 Participants |
| Group A: 250/16 | Number of Participants With a Dose-Limiting Toxicity | Subjects with a dose-limiting toxicity | 0 Participants |
| Group B: 75/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with a dose-limiting toxicity | 1 Participants |
| Group B: 75/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with no dose-limiting toxicity | 7 Participants |
| Group B: 150/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with a dose-limiting toxicity | 0 Participants |
| Group B: 150/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with no dose-limiting toxicity | 4 Participants |
| Group B: 250/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with no dose-limiting toxicity | 6 Participants |
| Group B: 250/20 | Number of Participants With a Dose-Limiting Toxicity | Subjects with a dose-limiting toxicity | 1 Participants |
Secondary
Terminal Half-Life (T-Half)
The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; T-half was evaluated based on concentration-time profile.
Time frame: up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: 75/20 | Terminal Half-Life (T-Half) | 31.0 hours | Standard Deviation 13.9 |
| Group A: 150/20 | Terminal Half-Life (T-Half) | 75.2 hours | Standard Deviation 18.7 |
| Group A 150/16 | Terminal Half-Life (T-Half) | 110.3 hours | Standard Deviation 43.1 |
| Group A: 250/16 | Terminal Half-Life (T-Half) | 37.9 hours | Standard Deviation 6.3 |
| Group B: 75/20 | Terminal Half-Life (T-Half) | 61.1 hours | Standard Deviation 10.5 |
| Group B: 150/20 | Terminal Half-Life (T-Half) | 81.9 hours | Standard Deviation 20.4 |
Secondary
Tumor Response
Non-central nervous system (CNS) tumors evaluated using Response Evaluation Criteria In Solid Tumors (RECIST), criteria to define when cancer patients improve (respond), stay the same (stable), or worsen (progression). CNS tumors evaluated based on measurements by investigator, dependence on corticosteroids, and neurologic exam.
Time frame: Every other 21-day cycle
Population: All treated subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: 75/20 | Tumor Response | Partial Response | 2 Participants |
| Group A: 75/20 | Tumor Response | Progressive Disease | 10 Participants |
| Group A: 75/20 | Tumor Response | Not Assessable/Unable to Determine | 4 Participants |
| Group A: 75/20 | Tumor Response | Stable Disease | 10 Participants |
| Group A: 150/20 | Tumor Response | Progressive Disease | 11 Participants |
| Group A: 150/20 | Tumor Response | Partial Response | 0 Participants |
| Group A: 150/20 | Tumor Response | Stable Disease | 8 Participants |
| Group A: 150/20 | Tumor Response | Not Assessable/Unable to Determine | 1 Participants |
Secondary
Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA)
The single dose PK of cetuximab was administered with an intravenous dose of irinotecan 16 to 20 mg/m2; VSS/BSA was evaluated based on concentration-time profile.
Time frame: up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: 75/20 | Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA) | 2.081 L/m2 | Standard Deviation 0.666 |
| Group A: 150/20 | Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA) | 1.860 L/m2 | Standard Deviation 0.564 |
| Group A 150/16 | Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA) | 2.157 L/m2 | Standard Deviation 0.362 |
| Group A: 250/16 | Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA) | 2.138 L/m2 | Standard Deviation 0.453 |
| Group B: 75/20 | Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA) | 1.887 L/m2 | Standard Deviation 0.262 |
| Group B: 150/20 | Volume of Distribution at Steady State Corrected for Body Surface Area (VSS/BSA) | 2.179 L/m2 | Standard Deviation 0.25 |