Solid Tumors
Conditions
Keywords
Epidermal Growth Factor, Pediatric, Solid Tumors, Panitumumab, Dose Limiting Toxicity
Brief summary
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
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.
Interventions
BIOLOGICALPanitumumab
Panitumumab administered by intravenous infusion
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). | — |
| 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 | 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). | 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. |
| 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). | — |
| Number of Participants With Dose-limiting Toxicities (DLTs) | 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. | 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. |
| Number of Participants With Adverse Events (AEs) | From first dose date to end of study date. The median duration of study was 47 days. | 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. |
| Maximum Observed Concentration (Cmax) 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). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Objective Response | 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. | 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. |
| Percentage of Participants With Disease Control | 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. | 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. |
| Number of Participants Who Developed Antibodies to Panitumumab | Before panitumumab administration on Day 1, Day 43, Day 169 and 30 days after last dose for all cohorts. | 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. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 7 centers in the United States. Participants were enrolled from 14 March 2008 to 4 March 2015.
Pre-assignment details
Three dose regimens were to be tested in pediatric patients stratified by age group (1 to 11 versus 12 to 17 years). Participants were enrolled sequentially into each dose group, beginning with the 2.5 mg/kg, 12 to 17 year old cohort, based upon demonstration of sufficient safety.
Participants by arm
| Arm | Count |
|---|---|
| Age 12-17: 2.5 mg/kg QW Participants aged 12 to 17 years received panitumumab 2.5 mg/kg administered by intravenous (IV) infusion weekly (QW) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study. | 6 |
| Age 12-17: 6 mg/kg Q2W Participants aged 12 to 17 years received panitumumab 6 mg/kg administered by IV infusion every 2 weeks (Q2W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study. | 7 |
| Age 12-17: 9 mg/kg Q3W Participants aged 12 to 17 years received panitumumab 9 mg/kg administered by IV infusion every 3 weeks (Q3W) until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study. | 4 |
| Age 1-11: 2.5 mg/kg QW Participants aged 1 to 11 years received panitumumab 2.5 mg/kg administered by IV infusion QW until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study. | 6 |
| Age 1-11: 6 mg/kg Q2W Participants aged 1 to 11 years received panitumumab 6 mg/kg administered by IV infusion Q2W until the participant experienced disease progression, was unable to tolerate study drug, withdrew consent, or other reasons that warranted removal from the study. | 8 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 4 | 0 | 0 | 1 | 1 |
| Overall Study | Disease Progression | 0 | 1 | 0 | 1 | 3 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Protocol-specified Criteria | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Age 12-17: 2.5 mg/kg QW | Age 12-17: 6 mg/kg Q2W | Age 12-17: 9 mg/kg Q3W | Age 1-11: 2.5 mg/kg QW | Age 1-11: 6 mg/kg Q2W | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 13.2 years STANDARD_DEVIATION 0.8 | 15.6 years STANDARD_DEVIATION 1.5 | 15.8 years STANDARD_DEVIATION 1.9 | 7.8 years STANDARD_DEVIATION 3.1 | 8.4 years STANDARD_DEVIATION 2.8 | 11.8 years STANDARD_DEVIATION 4.1 |
| Race/Ethnicity, Customized Asian | 0 participants | 2 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black (or African American) | 1 participants | 1 participants | 0 participants | 1 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White or Caucasian | 5 participants | 4 participants | 3 participants | 4 participants | 7 participants | 23 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 1 Participants | 3 Participants | 4 Participants | 17 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 | 5 / 6 | 7 / 7 | 3 / 4 | 6 / 6 | 7 / 8 |
| serious Total, serious adverse events | 5 / 6 | 3 / 7 | 2 / 4 | 3 / 6 | 5 / 8 |
Outcome results
Primary
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.
Time frame: 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).
Population: PK analysis set; n indicates the number of participants with available data for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 167 day*μg/mL | Standard Deviation 86.1 |
| Age 12-17: 2.5 mg/kg QW | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 306 day*μg/mL | Standard Deviation 178 |
| Age 12-17: 6 mg/kg Q2W | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 1040 day*μg/mL | Standard Deviation 357 |
| Age 12-17: 6 mg/kg Q2W | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 1330 day*μg/mL | Standard Deviation 357 |
| Age 12-17: 9 mg/kg Q3W | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 1580 day*μg/mL | — |
| Age 12-17: 9 mg/kg Q3W | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | NA day*μg/mL | — |
| Age 1-11: 2.5 mg/kg QW | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 255 day*μg/mL | Standard Deviation 70.7 |
| Age 1-11: 2.5 mg/kg QW | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 127 day*μg/mL | Standard Deviation 37.9 |
| Age 1-11: 6 mg/kg Q2W | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 708 day*μg/mL | Standard Deviation 247 |
| Age 1-11: 6 mg/kg Q2W | Area Under the Concentration-time Curve During the Dosing Interval (AUC0-tau) for Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 754 day*μg/mL | — |
Primary
Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab
Time frame: 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).
Population: PK analysis set; n indicates the number of participants with available data for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | First Dose (n=2, 5, 1, 3, 3) | 1.33 days | — |
| Age 12-17: 2.5 mg/kg QW | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | Third Dose (n=2, 2, 0, 1, 1) | 2.94 days | — |
| Age 12-17: 6 mg/kg Q2W | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | First Dose (n=2, 5, 1, 3, 3) | 4.49 days | Standard Deviation 1.09 |
| Age 12-17: 6 mg/kg Q2W | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | Third Dose (n=2, 2, 0, 1, 1) | 4.98 days | — |
| Age 12-17: 9 mg/kg Q3W | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | First Dose (n=2, 5, 1, 3, 3) | 4.27 days | — |
| Age 12-17: 9 mg/kg Q3W | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | Third Dose (n=2, 2, 0, 1, 1) | NA days | — |
| Age 1-11: 2.5 mg/kg QW | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | Third Dose (n=2, 2, 0, 1, 1) | 3.07 days | — |
| Age 1-11: 2.5 mg/kg QW | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | First Dose (n=2, 5, 1, 3, 3) | 2.11 days | Standard Deviation 0.913 |
| Age 1-11: 6 mg/kg Q2W | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | First Dose (n=2, 5, 1, 3, 3) | 4.23 days | Standard Deviation 1.64 |
| Age 1-11: 6 mg/kg Q2W | Half-life (t1/2) for the Terminal Phase (First Dose) or Dosing Interval (Third Dose) of Panitumumab | Third Dose (n=2, 2, 0, 1, 1) | 4.91 days | — |
Primary
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.
Time frame: 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).
Population: Pharmacokinetic (PK) Analysis Set (all participants who received the correct dose of panitumumab and from whom the PK parameters could be assessed); n indicates the number of participants with available data for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Maximum Observed Concentration (Cmax) of Panitumumab | First Dose (n=6, 7, 3, 4, 7) | 52.8 μg/mL | Standard Deviation 11.4 |
| Age 12-17: 2.5 mg/kg QW | Maximum Observed Concentration (Cmax) of Panitumumab | Third Dose (n=3, 5, 1, 3, 2) | 76.6 μg/mL | Standard Deviation 21.1 |
| Age 12-17: 6 mg/kg Q2W | Maximum Observed Concentration (Cmax) of Panitumumab | First Dose (n=6, 7, 3, 4, 7) | 161 μg/mL | Standard Deviation 41.2 |
| Age 12-17: 6 mg/kg Q2W | Maximum Observed Concentration (Cmax) of Panitumumab | Third Dose (n=3, 5, 1, 3, 2) | 187 μg/mL | Standard Deviation 45.2 |
| Age 12-17: 9 mg/kg Q3W | Maximum Observed Concentration (Cmax) of Panitumumab | First Dose (n=6, 7, 3, 4, 7) | 205 μg/mL | Standard Deviation 45.9 |
| Age 12-17: 9 mg/kg Q3W | Maximum Observed Concentration (Cmax) of Panitumumab | Third Dose (n=3, 5, 1, 3, 2) | 327 μg/mL | — |
| Age 1-11: 2.5 mg/kg QW | Maximum Observed Concentration (Cmax) of Panitumumab | Third Dose (n=3, 5, 1, 3, 2) | 60.8 μg/mL | Standard Deviation 15.7 |
| Age 1-11: 2.5 mg/kg QW | Maximum Observed Concentration (Cmax) of Panitumumab | First Dose (n=6, 7, 3, 4, 7) | 42.9 μg/mL | Standard Deviation 8.51 |
| Age 1-11: 6 mg/kg Q2W | Maximum Observed Concentration (Cmax) of Panitumumab | First Dose (n=6, 7, 3, 4, 7) | 120 μg/mL | Standard Deviation 29.4 |
| Age 1-11: 6 mg/kg Q2W | Maximum Observed Concentration (Cmax) of Panitumumab | Third Dose (n=3, 5, 1, 3, 2) | 126 μg/mL | — |
Primary
Minimum Observed Concentration (Cmin) of Panitumumab
Time frame: 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).
Population: PK analysis set; n indicates the number of participants with available data for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Minimum Observed Concentration (Cmin) of Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 6.62 μg/mL | Standard Deviation 6.83 |
| Age 12-17: 2.5 mg/kg QW | Minimum Observed Concentration (Cmin) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 24.2 μg/mL | Standard Deviation 22.9 |
| Age 12-17: 6 mg/kg Q2W | Minimum Observed Concentration (Cmin) of Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 24.7 μg/mL | Standard Deviation 18.6 |
| Age 12-17: 6 mg/kg Q2W | Minimum Observed Concentration (Cmin) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 48.1 μg/mL | Standard Deviation 25.1 |
| Age 12-17: 9 mg/kg Q3W | Minimum Observed Concentration (Cmin) of Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 35.3 μg/mL | — |
| Age 12-17: 9 mg/kg Q3W | Minimum Observed Concentration (Cmin) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | NA μg/mL | — |
| Age 1-11: 2.5 mg/kg QW | Minimum Observed Concentration (Cmin) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 17.3 μg/mL | Standard Deviation 8.83 |
| Age 1-11: 2.5 mg/kg QW | Minimum Observed Concentration (Cmin) of Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 4.87 μg/mL | Standard Deviation 3.64 |
| Age 1-11: 6 mg/kg Q2W | Minimum Observed Concentration (Cmin) of Panitumumab | First Dose (n=4, 7, 2, 4, 5) | 19.7 μg/mL | Standard Deviation 15.5 |
| Age 1-11: 6 mg/kg Q2W | Minimum Observed Concentration (Cmin) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 26.1 μg/mL | — |
Primary
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.
Time frame: From first dose date to end of study date. The median duration of study was 47 days.
Population: Safety Analysis Set (all participants who received at least 1 dose of panitumumab)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event | 5 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 4 | 4 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Any adverse event | 6 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 3 | 4 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Fatal | 4 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse event | 1 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 2 | 5 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Serious adverse events | 5 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Withdrawals due to adverse event | 0 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 1 | 5 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 4 | 0 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 2 | 6 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 3 | 5 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Fatal | 0 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event | 5 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Any adverse event | 7 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse event | 0 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Withdrawals due to adverse event | 0 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Serious adverse events | 3 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 1 | 7 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Any adverse event | 3 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Serious adverse events | 2 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Withdrawals due to adverse event | 0 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Grade 3 | 2 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Grade 1 | 3 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Grade 4 | 0 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Grade 2 | 3 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse event | 0 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Fatal | 0 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event | 3 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 4 | 1 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Any adverse event | 6 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Serious adverse events | 3 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event | 5 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse event | 1 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Withdrawals due to adverse event | 0 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 2 | 4 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 1 | 6 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Grade 3 | 4 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Adverse Events (AEs) | Fatal | 1 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 2 | 7 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 1 | 6 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Withdrawals due to adverse event | 0 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse event | 2 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 4 | 2 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event | 6 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Serious adverse events | 5 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Any adverse event | 8 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Fatal | 1 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Adverse Events (AEs) | Grade 3 | 6 participants |
Primary
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.
Time frame: 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.
Population: DLT Analysis Set (all participants who received at least 1 dose of panitumumab and were evaluated for DLTs and completed at least 28 days (for the 2.5 and 6 mg/kg cohorts) or 21 days (for 9 mg/kg cohort) of therapy unless due to a DLT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants With Dose-limiting Toxicities (DLTs) | 3 participants |
Primary
Serum Clearance (CL) of Panitumumab
Time frame: 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).
Population: PK analysis set; n indicates the number of participants with available data for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Serum Clearance (CL) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 9.92 mL/day/kg | Standard Deviation 4.4 |
| Age 12-17: 2.5 mg/kg QW | Serum Clearance (CL) of Panitumumab | First Dose (n=3, 5, 1, 4, 3) | 19.8 mL/day/kg | Standard Deviation 8.57 |
| Age 12-17: 6 mg/kg Q2W | Serum Clearance (CL) of Panitumumab | First Dose (n=3, 5, 1, 4, 3) | 6.38 mL/day/kg | Standard Deviation 0.466 |
| Age 12-17: 6 mg/kg Q2W | Serum Clearance (CL) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 4.69 mL/day/kg | Standard Deviation 1 |
| Age 12-17: 9 mg/kg Q3W | Serum Clearance (CL) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | NA mL/day/kg | — |
| Age 12-17: 9 mg/kg Q3W | Serum Clearance (CL) of Panitumumab | First Dose (n=3, 5, 1, 4, 3) | 7.15 mL/day/kg | — |
| Age 1-11: 2.5 mg/kg QW | Serum Clearance (CL) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 10.1 mL/day/kg | Standard Deviation 2.44 |
| Age 1-11: 2.5 mg/kg QW | Serum Clearance (CL) of Panitumumab | First Dose (n=3, 5, 1, 4, 3) | 18.7 mL/day/kg | Standard Deviation 6.35 |
| Age 1-11: 6 mg/kg Q2W | Serum Clearance (CL) of Panitumumab | Third Dose (n=3, 5, 0, 3, 2) | 8.05 mL/day/kg | — |
| Age 1-11: 6 mg/kg Q2W | Serum Clearance (CL) of Panitumumab | First Dose (n=3, 5, 1, 4, 3) | 8.06 mL/day/kg | Standard Deviation 1.4 |
Secondary
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.
Time frame: Before panitumumab administration on Day 1, Day 43, Day 169 and 30 days after last dose for all cohorts.
Population: Safety Analysis Set participants with at least one post-baseline immunoassay result
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Number of Participants Who Developed Antibodies to Panitumumab | Binding antibodies | 1 participants |
| Age 12-17: 2.5 mg/kg QW | Number of Participants Who Developed Antibodies to Panitumumab | Neutralizing antibodies | 0 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants Who Developed Antibodies to Panitumumab | Binding antibodies | 0 participants |
| Age 12-17: 6 mg/kg Q2W | Number of Participants Who Developed Antibodies to Panitumumab | Neutralizing antibodies | 0 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants Who Developed Antibodies to Panitumumab | Binding antibodies | 0 participants |
| Age 12-17: 9 mg/kg Q3W | Number of Participants Who Developed Antibodies to Panitumumab | Neutralizing antibodies | 0 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants Who Developed Antibodies to Panitumumab | Neutralizing antibodies | 0 participants |
| Age 1-11: 2.5 mg/kg QW | Number of Participants Who Developed Antibodies to Panitumumab | Binding antibodies | 2 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants Who Developed Antibodies to Panitumumab | Binding antibodies | 0 participants |
| Age 1-11: 6 mg/kg Q2W | Number of Participants Who Developed Antibodies to Panitumumab | Neutralizing antibodies | 0 participants |
Secondary
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.
Time frame: 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.
Population: Safety Analysis Set participants with presence of baseline measurable disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Percentage of Participants With an Objective Response | 0.00 percentage of participants |
| Age 12-17: 6 mg/kg Q2W | Percentage of Participants With an Objective Response | 0.00 percentage of participants |
| Age 12-17: 9 mg/kg Q3W | Percentage of Participants With an Objective Response | 0.00 percentage of participants |
| Age 1-11: 2.5 mg/kg QW | Percentage of Participants With an Objective Response | 0.00 percentage of participants |
| Age 1-11: 6 mg/kg Q2W | Percentage of Participants With an Objective Response | 0.00 percentage of participants |
Secondary
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.
Time frame: 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.
Population: Safety Analysis Set participants with presence of baseline measurable disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age 12-17: 2.5 mg/kg QW | Percentage of Participants With Disease Control | 0.00 percentage of participants |
| Age 12-17: 6 mg/kg Q2W | Percentage of Participants With Disease Control | 33.33 percentage of participants |
| Age 12-17: 9 mg/kg Q3W | Percentage of Participants With Disease Control | 0.00 percentage of participants |
| Age 1-11: 2.5 mg/kg QW | Percentage of Participants With Disease Control | 50.00 percentage of participants |
| Age 1-11: 6 mg/kg Q2W | Percentage of Participants With Disease Control | 66.67 percentage of participants |