Panitumumab in Children With Solid Tumors

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the safety and pharmacokinetics of up to 3 different dose schedules of panitumumab in pediatric patients with solid tumors.

Detailed Description
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This is an open-label, multi-center, single arm, dose-ranging, clinical study. Panitumumab will be administered by intravenous infusion to 4-6 patients per cohort. Three planned cohorts, stratified by age, will be studied at 100% of the recommended panitumumab dose for each treatment schedule as defined in adults. Enrollment will start with a 2.5 mg/kg once weekly administration to the 12 to < 18 year old patients. Upon demonstration of sufficient safety additional cohorts will open; a 2.5 mg/kg once weekly administration to the 1 to < 12 year old patients and a 6.0 mg/kg once every two weeks to the 12 to < 18 year old patients. The decision to advance to the next cohort will be based on observance of ≤ 33% incidence of a dose limiting toxicity during the evaluation period. Subsequent cohorts of 6.0 mg/kg once every two weeks to the 1 to < 12 year old patients and 9.0 mg/kg once every three weeks to both age groups will open once sufficient safety in each cohort is determined. Participants may stay on study treatment until disease progression.

Official Title
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A Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Panitumumab in Children With Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Biological: Panitumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parents or legal guardian signed-written informed consent 1 to < 18 years of age Histologically or cytologically confirmed solid tumor that has recurred after standard therapy, or for which there is no standard therapy. Subjects with brainstem glioma DO NOT need histologic proof of the diagnosis. Paraffin-embedded tumor tissue from primary tumor or metastasis for determination of epidermal growth factor receptor expression and biomarker testing Central nervous system tumors are allowed Presence of measurable or non-measurable disease. Life expectancy of ≥ 12 weeks. Performance status: Karnofsky ≥ 60% for 12 to <18 years of age; Lansky play scale ≥ 60% for 1 to < 12 years of age. Adequate hematologic function. Adequate renal function. Adequate hepatic function. Magnesium ≥ lower limit of normal (LLN) Adequate pulmonary function All previous therapy-related toxicities must have resolved or return to baseline. Exclusion Criteria: Diagnosis of leukemia, non-Hodgkin's lymphoma, Hodgkin's disease or other hematologic malignancy. Any prior allogeneic transplant. Prior autologous bone marrow or peripheral stem cell transplant less than 3 months prior to enrollment. Substantial radiotherapy to the bone marrow within 6 weeks prior to enrollment. Prior use of any monoclonal antibodies directly targeting the epidermal growth factor receptor (EGFr). Subjects who have received prior tyrosine kinase inhibitors such as gefitinib or erlotinib are eligible. Immunotherapy, radiotherapy, or chemotherapy ≤ 2 weeks prior to enrollment. (≤ 6 weeks for nitrosoureas, mitomycin-C, and liposomal doxorubicin, and ≤ 6 weeks from prior antibody therapy). Requirement to receive concurrent chemotherapy, immunotherapy, radiotherapy (except for pain control) or any other investigational drug while on this study. Prior seizures < 3 months prior to enrollment. Subjects with a history of seizure disorders ≥ 3 months prior to enrollment must be seizure free and on stable anticonvulsant medication(s) for ≥ 3 months prior to enrollment). Presence of a serious uncontrolled medical disorder. Dementia, altered mental status, or any other medical condition or disorder that would prohibit the understanding or rendering of assent (if applicable), or ability to comply with study procedures. Major surgery ≤ 28 days prior to enrollment. Known or suspected history of interstitial lung disease. Active inflammatory bowel disease or other bowel disease causing chronic diarrhea. Known positive test for human immunodeficiency virus infection, hepatitis C virus, acute or chronic hepatitis B infection, or any co-morbid disease that would increase risk of toxicity. Females of childbearing potential not using adequate contraception precautions for the duration of the study treatment and for 2 months after the last administration of investigational product. Pregnant or breast-feeding, or planning to become pregnant during study treatment and within 2 months after the last administration of investigational product. Received investigational therapy or procedure ≤ 30 days prior to enrollment.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panitumumab<br>Participants received panitumumab at planned doses ranging from 2.5 mg/kg weekly (QW) to 9.0 mg/kg every 3 weeks (Q3W) until the patient experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study. | Biological: Panitumumab<br>* Panitumumab administered by intravenous infusion<br>* Other names: Vectibix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) | Any panitumumab related grade 3 or 4 hematologic or non-hematologic toxicity (graded according to the modified Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria) was considered a DLT with the exception of alopecia and fatigue. Hypomagnesemia, nausea, diarrhea, vomiting, and skin or nail toxicities constituted a DLT only of the following occured: • Grade 3 or 4 hypomagnesemia that persisted for at least 5 days despite maximal magnesium replacement; • Grade 3 or 4 diarrhea, nausea, or vomiting that persisted for at least 5 days despite maximum supportive therapy; • Grade 4 skin or nail toxicity. | 28 days from initial administration of panitumumab for the 2.5 and 6 mg/kg cohorts and 21 days from first administration for the 9 mg/kg cohort. | 
| Number of Participants With Adverse Events (AEs) | A serious adverse event is defined as an AE that: • is fatal; • is life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • is a congenital anomaly/birth defect; • other significant medical hazard. The investigator assessed whether adverse events were related to panitumumab. The severity of adverse events was based on CTCAE version 3 (with the exception of skin- or nail-related toxicities which were graded using the CTCAE version 3.0 with modifications), according to the following: Grade 1 = Mild (aware of sign or symptom, but easily tolerated); Grade 2 = Moderate (discomfort enough to cause interference with usual activity); Grade 3 = Severe (incapacitating with inability to work or do usual activity); Grade 4 = Life-threatening or disabling; Grade 5 = Fatal. | From first dose date to end of study date. The median duration of study was 47 days. | 
| Maximum Observed Concentration (Cmax) of Panitumumab | Panitumumab serum concentration was measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the assay was 400 pg/mL. Concentrations below the LLOQ were set to zero. | First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively). | 
| Minimum Observed Concentration (Cmin) of Panitumumab |  | First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively). | 
| Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | The area under the serum concentration-time curve from time zero to the end of the dosing interval (AUCtau), estimated using the linear trapezoidal method. | First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively). | 
| Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab |  | First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively). | 
| Serum Clearance (CL) of Panitumumab |  | First dose (Day 1) and third dose (Day 15/29/43 for the QW, Q2W and Q3W cohorts respectively). Samples were collected over the dosing interval for each treatment cohort (7, 14 or 21 days for QW, Q2W and Q3W cohorts respectively). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Developed Antibodies to Panitumumab | Three validated assays were used to detect the presence of anti-panitumumab antibodies. Two screening immunoassays, an acid-dissociation enzyme-linked immunosorbent assay (ELISA) and a Biacore-based biosensor assay, were used to detect antibodies capable of binding to panitumumab. All samples confirmed to be positive by drug specificity in either screening immunoassay were further tested for neutralizing antibodies in a cell-based epidermal growth factor receptor (EGFR) phosphorylation bioassay. The number of participants who developed antibodies to panitumumab is the number of participants with a non-positive (including missing) antibody result at baseline and a positive antibody result at any post-baseline time point. | Before panitumumab administration on Day 1, Day 43, Day 169 and 30 days after last dose for all cohorts. | 
| Percentage of Participants With an Objective Response | Disease assessments were based on investigator review of scans using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria. A participant was considered a responder if their best response was either a complete or partial response. Participants without a post-baseline assessment were considered non-responders. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. Complete Response (CR): Disappearance of all target and non-target lesions, normalization of tumor markers and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions, no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions, persistence of one or more non-target lesion(s) not qualifying for either CR or progressive disease (PD) or/and maintenance of tumor marker level above normal limits, and no new lesions. | Tumor response was assessed every 8 weeks through week 48 and every 3 months thereafter until disease progression or end of study. The data cut-off for the analysis was 17 June 2015; median duration of study was 47 days. | 
| Percentage of Participants With Disease Control | Disease assessments were based on investigator review of scans using modified RECIST version 1.0 criteria. A participant was considered to have disease control if their best response is either a complete or partial response, or stable disease. Participants without a post-baseline assessment were considered to not have disease control. A complete or partial response was confirmed no less than 4-weeks after the criteria for response were first met. A best overall response of SD requires a visit response of SD or better, no earlier than 49 days after the date of enrollment. Stable disease (SD): Neither sufficient shrinkage of target lesions to qualify for a PR nor sufficient increase to qualify for PD and no progression of existing non-target lesions and no new lesions. | Tumor response was assessed every 8 weeks through week 48 and every 3 months thereafter until disease progression or end of study. The data cut-off for the analysis was 17 June 2015; median duration of study was 47 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epidermal Growth Factor, Pediatric, Solid Tumors, Panitumumab, Dose Limiting Toxicity