Diffuse Intrinsic Pontine Glioma
Conditions
Keywords
Molecularly Determined Treatment
Brief summary
Diagnosis of diffuse intrinsic pontine glioma (DIPG) for decades has relied on imaging studies and clinical findings. Histologic confirmation has been absent with surgical biopsy of brainstem tumors not believed to have acceptable safety. The prognosis of DIPG has remained quite poor and novel therapeutic strategies are needed. This DIPG Biology and Treatment Study (DIPG-BATS) study incorporates a surgical biopsy at presentation using strict preoperative neurosurgical planning and stratifies participants to receive FDA-approved agents chosen on the basis of specific biologic targets. This is the first prospective national clinical trial to examine the feasibility and safety of incorporating surgical biopsy into potential treatment strategies for children with DIPG.
Detailed description
The primary objective of this study is to estimate the overall survival of children and young adults with DIPG in the context of a molecularly based treatment strategy, compared to historical controls (COG ACNS0126). Secondary objectives were to determine the safety and potential morbidity associated with biopsy of classic DIPGs based on imaging and clinical history as well as ability to perform biologic analyses on the biopsy material obtained to guide therapy. At study entry, a MRI-guided frameless or frame-based stereotactic biopsy will be performed approaching the pontine termentum through a trans-cerebellar or trans-frontal route. The exact biopsy location will be determined by the treating neurosurgeon at the designated participating site with the goal of minimizing procedural risk. Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O\^6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive).
Interventions
DRUGBevacizumab
DRUGErlotinib
DRUGTemozolomide
RADIATIONRadiation
Sponsors
Boston Children's Hospital
University of California, San Francisco
Ann & Robert H Lurie Children's Hospital of Chicago
Children's Healthcare of Atlanta
Children's Hospital Colorado
Children's Hospital Los Angeles
Children's Hospital of Michigan
Children's Hospitals and Clinics of Minnesota
Cook Children's Medical Center
OHSU Doernbecher Children's Hospital
Duke University
Johns Hopkins University
Nicklaus Children's Hospital f/k/a Miami Children's Hospital
Nemours Children's Clinic
New York University
Milton S. Hershey Medical Center
Seattle Children's Hospital
Lucile Packard Children's Hospital
University of Louisville
Children's National Research Institute
Washington University School of Medicine
Phoenix Children's Hospital
Medical University of South Carolina
Karen D. Wright MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is not a randomized trial rather participants are classified and therapy is directed based on molecular profile obtained from surgical biopsy.
Eligibility
Sex/Gender
ALL
Age
3 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
Participants must meet the following criteria on screening examination to be eligible to participate in the study: 1. Tumor: Newly diagnosed non-disseminated diffuse intrinsic pontine glioma based on classic clinical AND radiographic finding. 2. No prior radiation therapy or chemotherapy. 3. Age: Patient must be 3 to \< 18 years of age at the time of diagnosis. 4. Performance Score: Karnofsky Performance Scale \> 12 y/o \>/= 50 or Lansky Performance Score for patients \< 12y/o 50 assessed within two-weeks prior to enrollment. 5. Participants must have normal organ and marrow function as defined below within two week s prior to enrollment: * Absolute neutrophil count \> 1,000/mcL * Platelets \> 100,000/mcL (transfusion independent) * Hemoglobin \> 8gm/dL (can be transfused) * Hepatic: Total bilirubin \< 1.5 times the upper limit of normal; alanine aminotransferase \[SGPT (ALT)\] and aspartate aminotransferase \[SGOT (AST)\] \< 5 times the institutional upper limit of normal. * Renal: Serum creatinine which is less than 1.5x the upper limit of institutional normal for age or Glomerular Filtration Rate (GFR) \> 70 ml/min/1.73m2. 6. Female patients of childbearing potential must have negative serum or urine pregnancy test. Patient must not be pregnant or breast feeding. 7. Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study. 8. Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
1. Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy. 2. Patients receiving any other anticancer or experimental drug therapy. 3. Patients with disseminated intrinsic diffuse brainstem gliomas in either brain or spine (can be based on clinical evaluation). 4. Participants receiving any medications or substances that are strong/intermediate inhibitors or inducers of Cytochrome P450 (CYP450), Cytochrome P3A4(CYP3A4) or Cytochrome 1A2 (CYP1A2) are ineligible. Lists including medications and substances known or with the potential to interact with the CYP450 CYP3A4 or CYP1A2 isoenzymes are provided in Appendix I. 5. Use of hematopoietic growth factors within the 2 weeks prior to initiation of therapy. 6. Patients with evidence of spontaneous hemorrhage greater than 0.5cm unrelated to surgery. 7. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 8. Pregnant women are excluded from this study because bevacizumab, temozolomide and erlotinib can have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 9-month Overall Survival (OS) Rate | 9 months | 9-month overall survival is the percentage of participants remaining alive 9 months from registration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate | 2 weeks | Grade 3-4 post-procedural surgery-related toxicity rate is the percentage of participants experiencing at least one grade 3-4 adverse event (AE) during the post-procedural time frame of 14 days attributable to the surgical procedure based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4). |
| Delay in Radiation Therapy Start | 3 weeks | The number of participants delaying the start of radiation therapy by more than 3 weeks due to complications as a result of surgical biopsy to obtain diagnostic tumor sample. |
| Rate of Lethal Complications From Surgery | 2 weeks | The rate of lethal complications from surgery is the percentage of participants dying as a result of surgery. |
| Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy | Adverse events were routinely throughout treatment. Treatment duration was a median of 6.4 months (range 0.4-13.4 months) in this study cohort. | Counts any participant experiencing at least one treatment-related grade 3 or 4 adverse event (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) over chemoradiation therapy as reported on case report forms. |
| Median Progression Free Survival (PFS) | Disease assessments using a standard CNS imaging protocol occurred chemoradiation cycles 1 and 2, every other maintenance cycle, every 3 months post-treatment year 1 then annually until PD or therapy change; In this study cohort, follow-up was up to 34m. | PFS based on the Kaplan-Meier method is defined as the duration of time \[months (m)\] from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at the date of last disease assessment. For intrinsic pontine brainstem gliomas, only one lesion/mass is present at diagnosis. Comparisons of maximal 2-dimensional measurements, TxW (product of the longest diameter \[width (W)\] and its longest perpendicular diameter \[transverse (T)\]) are used to assess response for this target lesion. PD is 25% or more increase, taking as reference the smallest product observed since the start of treatment, or the appearance of one or more new lesions. |
| Feasibility Rate of Molecular Approach to Therapy | 3 weeks | Feasibility rate of the molecular strategy is based on the percentage of participants either with inadequate tissue from surgical biopsy to confirm DIPG diagnosis and/or with uninterpretable results for identification of EGFR overexpression and MGMT methylation status. |
Countries
United States
Participant flow
Recruitment details
Study screening procedures were conducted at 23 sites in the United States. Eligible participants enrolled between September 2011 and September 2015.
Participants by arm
| Arm | Count |
|---|---|
| All Biopsied Participants Protocol treatment lasts approximately 52 weeks including a 4-week interim period once radiation therapy is completed and a maintenance phase (cycle duration=28 days).
Treatment directed based on tumor biopsy results requires classification of patients into 1 of 4 potential cohorts: O\^6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status (negative versus positive) and epidermal growth factor receptor (EGFR) overexpression status (negative versus positive). | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 | 0 | 0 | 0 |
| Overall Study | Alternative Therapy | 2 | 0 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Disease Progression | 15 | 12 | 0 | 1 | 0 |
| Overall Study | Travel Issue/Prefer Treatment at Home | 2 | 0 | 1 | 1 | 0 |
| Overall Study | Unevaluable for Biopsy | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Biopsied Participants |
|---|---|
| Age, Continuous | 6.3 years |
| Molecular Classification MGMT-/EGFR- | 30 Participants |
| Molecular Classification MGMT-/EGFR+ | 14 Participants |
| Molecular Classification MGMT+/EGFR- | 3 Participants |
| Molecular Classification MGMT+/EGFR+ | 3 Participants |
| Region of Enrollment United States | 50 Participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 29 / 30 | 14 / 14 | 3 / 3 | 2 / 3 |
| other Total, other adverse events | 30 / 30 | 14 / 14 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 8 / 30 | 9 / 14 | 1 / 3 | 2 / 3 |
Outcome results
Primary
9-month Overall Survival (OS) Rate
9-month overall survival is the percentage of participants remaining alive 9 months from registration.
Time frame: 9 months
Population: The analysis population is comprised of the subset of participants who underwent biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | 9-month Overall Survival (OS) Rate | 64.4 percentage of participants |
Secondary
Delay in Radiation Therapy Start
The number of participants delaying the start of radiation therapy by more than 3 weeks due to complications as a result of surgical biopsy to obtain diagnostic tumor sample.
Time frame: 3 weeks
Population: The analysis dataset is comprised of all enrolled participants who underwent stereotactic biopsy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | Delay in Radiation Therapy Start | 1 Participants |
Secondary
Feasibility Rate of Molecular Approach to Therapy
Feasibility rate of the molecular strategy is based on the percentage of participants either with inadequate tissue from surgical biopsy to confirm DIPG diagnosis and/or with uninterpretable results for identification of EGFR overexpression and MGMT methylation status.
Time frame: 3 weeks
Population: The analysis dataset is comprised of all enrolled participants who underwent stereotactic biopsy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | Feasibility Rate of Molecular Approach to Therapy | 92.0 percentage of participants |
Secondary
Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate
Grade 3-4 post-procedural surgery-related toxicity rate is the percentage of participants experiencing at least one grade 3-4 adverse event (AE) during the post-procedural time frame of 14 days attributable to the surgical procedure based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4).
Time frame: 2 weeks
Population: The analysis dataset is comprised of all enrolled participants who underwent stereotactic biopsy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | Grade 3-4 Post-Procedural Surgery-Related Toxicity Rate | 10.0 percentage of participants |
Secondary
Median Progression Free Survival (PFS)
PFS based on the Kaplan-Meier method is defined as the duration of time \[months (m)\] from study entry to documented disease progression (PD) or death. Participants alive without PD are censored at the date of last disease assessment. For intrinsic pontine brainstem gliomas, only one lesion/mass is present at diagnosis. Comparisons of maximal 2-dimensional measurements, TxW (product of the longest diameter \[width (W)\] and its longest perpendicular diameter \[transverse (T)\]) are used to assess response for this target lesion. PD is 25% or more increase, taking as reference the smallest product observed since the start of treatment, or the appearance of one or more new lesions.
Time frame: Disease assessments using a standard CNS imaging protocol occurred chemoradiation cycles 1 and 2, every other maintenance cycle, every 3 months post-treatment year 1 then annually until PD or therapy change; In this study cohort, follow-up was up to 34m.
Population: The analysis population is comprised of the subset of participants who underwent surgical biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy. The PFS was aggregated across cohorts per statistical analysis plan to evaluate the effect of the molecular strategy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | Median Progression Free Survival (PFS) | 8 months |
Secondary
Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy
Counts any participant experiencing at least one treatment-related grade 3 or 4 adverse event (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 4 (CTCAEv4) over chemoradiation therapy as reported on case report forms.
Time frame: Adverse events were routinely throughout treatment. Treatment duration was a median of 6.4 months (range 0.4-13.4 months) in this study cohort.
Population: The analysis population is comprised of the subset of participants who underwent surgical biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy | 5 Participants |
| Cohort 2 MGMT-/EGFR+ | Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy | 5 Participants |
| Cohort 3: MGMT+/EGFR- | Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy | 0 Participants |
| Cohort 4. MGMT+/EGFR+ | Number of Participants With Grade 3-4 Treatment-Related Toxicity Over Chemoradiation Therapy | 0 Participants |
Secondary
Rate of Lethal Complications From Surgery
The rate of lethal complications from surgery is the percentage of participants dying as a result of surgery.
Time frame: 2 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | Rate of Lethal Complications From Surgery | 0.0 percentage of participants |
Post Hoc
9-month Overall Survival (OS) Rate by Molecular Cohort
9-month OS rate is the percentage of participants alive at 9 months from registration.
Time frame: 9 months
Population: The analysis population is comprised of the subset of participants who underwent surgical biopsy, obtained a molecularly-based treatment assignment and started assigned chemoradiation therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients Starting Assigned Chemoradiation | 9-month Overall Survival (OS) Rate by Molecular Cohort | 66.7 percentage of participants |
| Cohort 2 MGMT-/EGFR+ | 9-month Overall Survival (OS) Rate by Molecular Cohort | 57.1 percentage of participants |
| Cohort 3: MGMT+/EGFR- | 9-month Overall Survival (OS) Rate by Molecular Cohort | 50.0 percentage of participants |
| Cohort 4. MGMT+/EGFR+ | 9-month Overall Survival (OS) Rate by Molecular Cohort | 100 percentage of participants |