Brain Cancer
Conditions
Keywords
high-grade astrocytomas, newly diagnosed diffuse pontine tumors, External beam radiation therapy, cetuximab, irinotecan, POETIC
Brief summary
Standard treatment for patients with diffuse pontine tumors is radiation therapy, but less than 10% of patients are cured. Adding standard chemotherapy has not improved the cure rate. Standard treatment for high-grade astrocytomas is surgery and radiation. The surgeon removes as much of the tumor as she or he can. Radiation after that tries to kill any cancer cells that are left. Some patients also get chemotherapy. These are anti-cancer drugs. They can be given during or after radiation. Current standard treatments do not cure many patients. In this study the doctors are adding a new medication called cetuximab to the treatment and will also use a chemotherapy medication (irinotecan) that has been promising for patients treated for recurrent disease.
Interventions
OTHERcetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan
External beam radiation therapy (5940 cGy in 180 cGy fractions) with weekly cetuximab (250 mg/m2/dose).4-8 weeks rest, 10 cycles of irinotecan (16 mg/m2/day x 5 consecutive days x 2 weeks) with weekly cetuximab (250 mg/m2/dose) at about 21 day intervals. Research biological evaluations will be performed in consenting patients as an optional portion of the study. Cetuximab is to be given every 7 days (+/- 2 days). Cetuximab does not need to be given on Day 1 of each week.
Sponsors
Children's Healthcare of Atlanta
Dana-Farber Cancer Institute
M.D. Anderson Cancer Center
Phoenix Children's Hospital
Alberta Children's Hospital
University of Colorado, Denver
Seattle Children's Hospital
Johns Hopkins University
Children's Mercy Hospital Kansas City
University of Florida
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have either (1) histologic proof of a high-grade astrocytoma reviewed by a POETIC institutional pathologist or (2) a radiological diagnosis via MRI scan of a typical diffuse pontine tumor made by a POETIC institutional neuroradiologist. Patients with a radiological diagnosis via MRI scan of a typical diffuse pontine tumor will be enrolled on the diffuse pontine tumor arm of the study regardless of histology in cases that are biopsied. Note: For collaborating non-POETIC institutions, the reviews may be done by an institutional pathologist/neuroradiologist. * Patients must begin study prescribed therapy within 42 days of neurosurgical resection or biopsy of the tumor (high-grade astrocytoma patients) or radiological diagnosis (diffuse pontine tumor patients). * Age ≥ 3-years and \< 22-years-old. * Brain MRI (and any other studies done according to clinical indications) must not show any definitive evidence of leptomeningeal or extra-neural metastases. * ANC ≥ 1000/μL and platelet count ≥ 100,000/μL * Patients must have adequate organ function as defined by: * Hepatic: total bilirubin \< 1.5 mg/dl, AST ≤ 2.5 x the upper limit of normal. * Renal: serum creatinine ≤ 1.5 x the upper limit of normal for age, or calculated creatinine clearance or nuclear GFR ≥ 70 ml/min/1.73 m2. * The patient, or for minors, a parent or legal guardian, must give informed written consent indicating they are aware of the investigational nature of this study.
Exclusion criteria
* Evidence of leptomeningeal or extra-neural metastatic disease. * Prior radiation therapy or chemotherapy * Pregnancy, mothers unwilling to refrain from breast-feeding, and sexually mature patients unwilling to practice an effective form of birth control. * Other significant concomitant medical illnesses that would compromise the patient's ability to receive all prescribed study therapy. * Prior therapy which specifically and directly targets the EGFR pathway. * Prior severe infusion reaction to a monoclonal antibody. * Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction. * Patients with known Gilbert's Syndrome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With High-grade Astrocytoma and Diffuse Pontine Tumors Achieving One Year Progression Free Survival. | 1 year | — |
| Number of Participants Experiencing Toxicity | 2 years | To determine the safety of cetuximab administered weekly in conjunction with involved field external beam radiation therapy for diffuse pontine tumors and high-grade astrocytomas, toxicities will be assessed via the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | 2 years | — |
| Number of Participants Who Have Undergone Tumor Analysis | 2 years | Participant tumor analysis for potential associations between primary tumor tissue molecular markers and tumor response. |
| Event Free Survival | up to 12 months | — |
| Number of Participant Tumors Analyzed for Potential Association Between Histology (Grade) With Protein and ELISA Measurements of Those Proteins. | 2 years | — |
| Percentage of Participants With Development of Rash, Either Acneiform and/or Desquamation | 2 years | The purpose is to investigate whether the rash associated with cetuximab is secondary to an inflammatory pathway initiated and mediated by the action of cetuximab on host cells. |
| Number of Samples Demonstrating EGFR Copy Number Gain | 2 years | Identify gene transcripts for putative cetuximab |
| Overall Survival | Up to 43 months | — |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pts With High-grade Astrocytoma This is a 2-group parallel (high-grade astrocytoma, diffuse pontine tumor), single stage study investigating cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan in pediatric and young adult patients. Optional exploratory components of the study include (1) correlation of tumor molecular markers with outcome, (2) CSF proteomics, and (3) assay of serum cytokine levels in patients who develop a cetuximab-associated rash.
cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan: External beam radiation therapy (5940 cGy in 180 cGy fractions) with weekly cetuximab (250 mg/m2/dose).4-8 weeks rest, 10 cycles of irinotecan (16 mg/m2/day x 5 consecutive days x 2 weeks) with weekly cetuximab (250 mg/m2/dose) at about 21 day intervals. Research biological evaluations will be performed in consenting patients as an optional portion of the study. Cetuximab is to be given every 7 days (+/- 2 days). Cetuximab does not need to be given on Day 1 of each week. | 21 |
| Pts With Diffuse Pontine Tumor This is a 2-group parallel (high-grade astrocytoma, diffuse pontine tumor), single stage study investigating cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan in pediatric and young adult patients. Optional exploratory components of the study include (1) correlation of tumor molecular markers with outcome, (2) CSF proteomics, and (3) assay of serum cytokine levels in patients who develop a cetuximab-associated rash.
cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan: External beam radiation therapy (5940 cGy in 180 cGy fractions) with weekly cetuximab (250 mg/m2/dose).4-8 weeks rest, 10 cycles of irinotecan (16 mg/m2/day x 5 consecutive days x 2 weeks) with weekly cetuximab (250 mg/m2/dose) at about 21 day intervals. Research biological evaluations will be performed in consenting patients as an optional portion of the study. Cetuximab is to be given every 7 days (+/- 2 days). Cetuximab does not need to be given on Day 1 of each week. | 26 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Pts With High-grade Astrocytoma | Total | Pts With Diffuse Pontine Tumor |
|---|---|---|---|
| Age, Continuous | 10.7 years | 8.3 years | 6.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 12 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 35 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 16 Participants | 35 Participants | 19 Participants |
| Region of Enrollment United States | 21 Participants | 47 Participants | 26 Participants |
| Sex: Female, Male Female | 8 Participants | 24 Participants | 16 Participants |
| Sex: Female, Male Male | 13 Participants | 23 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 21 | 24 / 26 |
| other Total, other adverse events | 21 / 21 | 26 / 26 |
| serious Total, serious adverse events | 16 / 21 | 17 / 26 |
Outcome results
Primary
Number of Participants Experiencing Toxicity
To determine the safety of cetuximab administered weekly in conjunction with involved field external beam radiation therapy for diffuse pontine tumors and high-grade astrocytomas, toxicities will be assessed via the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 3.0)
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pts With High-grade Astrocytoma | Number of Participants Experiencing Toxicity | 20 Participants |
| Pts With Diffuse Pontine Tumor | Number of Participants Experiencing Toxicity | 25 Participants |
Primary
Number of Participants With High-grade Astrocytoma and Diffuse Pontine Tumors Achieving One Year Progression Free Survival.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pts With High-grade Astrocytoma | Number of Participants With High-grade Astrocytoma and Diffuse Pontine Tumors Achieving One Year Progression Free Survival. | 5 Participants |
| Pts With Diffuse Pontine Tumor | Number of Participants With High-grade Astrocytoma and Diffuse Pontine Tumors Achieving One Year Progression Free Survival. | 6 Participants |
Secondary
Event Free Survival
Time frame: up to 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pts With High-grade Astrocytoma | Event Free Survival | 8.9 months |
| Pts With Diffuse Pontine Tumor | Event Free Survival | 6.9 months |
Secondary
Number of Participants Who Have Undergone Tumor Analysis
Participant tumor analysis for potential associations between primary tumor tissue molecular markers and tumor response.
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pts With High-grade Astrocytoma | Number of Participants Who Have Undergone Tumor Analysis | Tumor Analyzed | 18 Participants |
| Pts With High-grade Astrocytoma | Number of Participants Who Have Undergone Tumor Analysis | Tumor Did Not Undergo Analysis | 2 Participants |
| Pts With Diffuse Pontine Tumor | Number of Participants Who Have Undergone Tumor Analysis | Tumor Analyzed | 1 Participants |
| Pts With Diffuse Pontine Tumor | Number of Participants Who Have Undergone Tumor Analysis | Tumor Did Not Undergo Analysis | 24 Participants |
Secondary
Number of Participant Tumors Analyzed for Potential Association Between Histology (Grade) With Protein and ELISA Measurements of Those Proteins.
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pts With High-grade Astrocytoma | Number of Participant Tumors Analyzed for Potential Association Between Histology (Grade) With Protein and ELISA Measurements of Those Proteins. | Tumor tissue analysis completed | 18 Participants |
| Pts With High-grade Astrocytoma | Number of Participant Tumors Analyzed for Potential Association Between Histology (Grade) With Protein and ELISA Measurements of Those Proteins. | Tumor tissue analysis Not Done | 2 Participants |
| Pts With Diffuse Pontine Tumor | Number of Participant Tumors Analyzed for Potential Association Between Histology (Grade) With Protein and ELISA Measurements of Those Proteins. | Tumor tissue analysis completed | 1 Participants |
| Pts With Diffuse Pontine Tumor | Number of Participant Tumors Analyzed for Potential Association Between Histology (Grade) With Protein and ELISA Measurements of Those Proteins. | Tumor tissue analysis Not Done | 24 Participants |
Secondary
Number of Samples Demonstrating EGFR Copy Number Gain
Identify gene transcripts for putative cetuximab
Time frame: 2 years
Population: Paraffin-embedded tumor sections were obtained from 19 of 23 patients who underwent surgery (18 HGA and one DIPG). Because only 1 DIPG sample was available and based on the number of available samples per arm it was pre-specified to pool data for this Outcome Measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pts With High-grade Astrocytoma | Number of Samples Demonstrating EGFR Copy Number Gain | With GFR copy number gain | 18 samples |
| Pts With High-grade Astrocytoma | Number of Samples Demonstrating EGFR Copy Number Gain | No GFR copy number gain | 1 samples |
Secondary
Overall Survival
Time frame: Up to 43 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pts With High-grade Astrocytoma | Overall Survival | 17.4 months |
| Pts With Diffuse Pontine Tumor | Overall Survival | 12.1 months |
Secondary
Percentage of Participants With Development of Rash, Either Acneiform and/or Desquamation
The purpose is to investigate whether the rash associated with cetuximab is secondary to an inflammatory pathway initiated and mediated by the action of cetuximab on host cells.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pts With High-grade Astrocytoma | Percentage of Participants With Development of Rash, Either Acneiform and/or Desquamation | 60 percentage of participants |
| Pts With Diffuse Pontine Tumor | Percentage of Participants With Development of Rash, Either Acneiform and/or Desquamation | 53.3 percentage of participants |
Secondary
Time to Progression
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pts With High-grade Astrocytoma | Time to Progression | 9.02 months |
| Pts With Diffuse Pontine Tumor | Time to Progression | 7.12 months |