Study of Erbitux™ (Cetuximab) in Pediatric Patients With Refractory Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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Phase I Study of Erbitux™ (Cetuximab) in Pediatric Patients With Refractory Solid Tumors

Conditions
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Cancer, Refractory Solid Tumor

Intervention / Treatment
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* Drug: Cetuximab + Irinotecan
* Drug: Cetuximab + Irinotecan


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>1-12 years old | Drug: Cetuximab + Irinotecan<br>* 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.<br>|
| Active Comparator: Group B<br>13-18 years old | Drug: Cetuximab + Irinotecan<br>* Intravenous (IV) cetuximab 75 - 250 mg/m2 depending on dose escalation for MTD, weekly; irinotecan was administered at a dose of 20 mg/m2 or per dose escalation, administered x5 days x2 weeks, separated by 2 days off, every 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Continuous assessment of safety throughout the entire study period and determination of doe-limiting toxicities during and at the end of Cycle 1. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Prior to each 21-day cycle until dose-limiting toxicities | 
| 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. | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | 
| 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. | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | 
| 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. | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | 
| 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. | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | 
| 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. | up to 168 hours after the start of the cetuximab infusion during the first 21-day cycle of the study | 
| 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. | Every other 21-day cycle | 
| 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. | Blood was drawn immediately prior to cetuximab infusions, on a 21-day cycle | 
| 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. | Weekly throughout the study and every 4 weeks thereafter | 
| 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 | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment | 
| 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 | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment | 
| 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 | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment | 
| 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 | pretreatment visit, prior to each treatment cycle, weekly, and at the end of treatment |