Trial Title:
MCT for the Harvard/UCSF ROBIN Center
NCT ID:
NCT06000787
Condition:
Glioma, Childhood Brainstem
Neuroblastoma
Conditions: Official terms:
Neuroblastoma
3-Iodobenzylguanidine
Conditions: Keywords:
Diffuse midline glioma
Iodine-131 meta-iodobenzylguanidine
Radiation oncology
Radiobiology
Radiopharmaceutical
Radiotherapy
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Two non-randomized cohorts with assignment based on tumor type
Primary purpose:
Basic Science
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
External beam radiotherapy
Description:
Subjects with diffuse midline glioma on PNOC023 (NCT04732065) Arm A or B receive
standard-of-care external beam radiotherapy to the brain tumor.
Arm group label:
Diffuse Midline Glioma
Intervention type:
Radiation
Intervention name:
131I-Metaiodobenzylguanidine (MIBG)
Description:
Subjects with high-risk neuroblastoma on COG ANBL1531 (NCT03126916) Arm B receive the
radiopharmaceutical 131I-Metaiodobenzylguanidine (MIBG) 15 mCi/kg via either a central or
a peripheral IV catheter over 1.5 to 2 hours at a maximum rate of 500 mCi/hour.
Arm group label:
Neuroblastoma
Summary:
The goal of the Molecular Characterization Trial (MCT) is to obtain biological specimens
and data resources from patients enrolled on prospective trials, to ensure that the
Harvard/UCSF ROBIN Center accomplishes its key objective of advancing our understanding
of the biological mechanisms that underlie how radiation treats tumors but also can cause
unwanted side effects. The MCT focuses on collection of research biospecimens before,
during, and after radiation. Also critical to the MCT is the deep annotation of these
research biospecimens with elements that complement each other to provide a holistic,
detailed view of each patient. Annotated elements include those used in the past such as
clinical and biological features but extend to factors we have so far neglected but must
incorporate in the future such as dosimetry (precise anatomical measurement of radiation
dose), artificial intelligence, computational biology, and natural language processing.
Detailed description:
The MCT is critical to testing the central hypothesis of the Harvard/UCSF ROBIN and
achieving the central goals of the Center. This hypothesis centers on recent observations
that cells within a single tumor show tremendous variability from a developmental and
biological perspective. This contrasts with how radiation oncologists usually approach
individual tumors as they plan the radiotherapy course: generally, the entire tumor is
targeted with a uniform dose of radiation albeit with efforts to keep doses to adjacent
normal tissues as low as possible. The Harvard/UCSF ROBIN Center proposes to test the
hypothesis that this marked variability within a given tumor-both in the actual tumor
cells and in the normal cells and microenvironment elements-is also reflected at the
level of biological responses to radiation. New technologies that allow deep, molecular
analyses of single cells within individual tumors, will for the first time be applied
specifically to molecular underpinnings of cellular responses to radiation.
The investigators chose to focus on pediatric cancers precisely because the iterative,
deep-dive approach of the ROBIN positions the children-focused ROBIN to transform
radiation biology for the benefit of adult and pediatric patients alike. In particular,
childhood cancers have simpler genetic landscapes that minimize potentially confounding
passenger mutations occurring with age. Accordingly, biospecimens and multiscale analyses
of pediatric cancers are more likely to yield deeper insights into causal biological
mechanisms of radiation response. Historical validation of this approach rests in the
many oncogenic drivers and tumor suppressors that were first identified in childhood
cancers, only to then prove widely relevant to adult cancers.
The pediatric cancers being studied by the Harvard/UCSF ROBIN are the two most common
solid tumors in children-glioma (specifically, diffuse midline glioma, a type of primary
brain tumor) and neuroblastoma (a tumor of the peripheral nervous system). The MCT will
centralize all of the biospecimen and data resources for the Harvard/UCSF ROBIN Center by
leveraging two international consortia studies of these pediatric tumors. In addition to
its focus on pediatric malignancies that are responsible for disproportionate
person-years lost, the Harvard/UCSF ROBIN underscores inclusion of two key radiation
modalities (i.e., external beam radiation and radiopharmaceuticals). The MCT will manage
the regulatory aspects of all biospecimen and data collection, including site protocols
for collection of protected health information (PHI) and biospecimens in institutional
biorepositories.
One cohort consists of 18-23 subjects from the Pacific Pediatric Neuro-Oncology
Consortium PNOC023: Open label Phase 1 and Target Validation study of ONC206 in Children
and Young Adults with Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and
Other Recurrent Primary Malignant Brain Tumors (NCT04732065). Blood samples will be
obtained from all subjects before, during and after RT. Cerebrospinal fluid (CSF) samples
will be obtained from all subjects before and after RT. Tumor samples will be obtained
from all subjects before RT and then at the time of autopsy, which occurs disconcertingly
soon in this uniformly deadly disease. This trial is highly innovative in that it
collects tumor tissue and molecular data on each enrolled patient as well as
longitudinally collected CSF, blood, MRI imaging, and a battery of validated quality of
life outcome measures that are so critical to the well-being of patients and their
families. This is one of the first clinical trials for DMG integrating the collection of
such a myriad of sample types and molecular data making this an ideal parent trial for
the MCT in order to support the investigators' research in the response of tumors and
normal tissues to radiation. Collection of tumor samples after RT will be essential for
studies of pre- and post-treatment paired samples. Unfortunately given the severity of
the disease, most patients die within a short interval due to disease progression.
Uniform mortality, together with the short time from diagnosis to death, enables
postmortem tumor samples to serve as a surrogate for post-therapy tissue. Postmortem
tumor samples can be paired with diagnostic biopsy tissues to create paired sample
sets--an unprecedented research tool for DMGs that are never resected, and historically
not even biopsied. Postmortem tumor samples will be collected under an established
protocol, with support from the Gift of a Child Foundation.
The second cohort within the MCT similarly supports achievement of the ROBIN overarching
goal of defining biological underpinnings of the effects of radiation on tumors and
normal tissues. For neuroblastoma, the team identified Children's Oncology Group (COG)
ANBL1531 (NCT03126916), a phase 3 study of 131I-MIBG or crizotinib added to intensive
therapy for children with newly diagnosed high-risk neuroblastoma. ANBL1531 features
unique aspects that are particularly suitable for fulfilling the aims of research on
neuroblastoma and radiopharmaceuticals, which are drugs that are preferentially taken up
by tumor cells and expose them to radiation. ANBL1531 is the current North American
randomized phase 3 trial for children with newly diagnosed high-risk neuroblastoma. It is
the largest clinical trial of 131I-MIBG ever conducted. This trial will accrue 774
patients with high-risk neuroblastoma over 5.1 years, followed by 3 years of follow-up
for clinical outcomes. Patients are eligible for ANBL1531 if they are 1-30 years of age;
and have newly diagnosed high-risk neuroblastoma without prior treatment. If the
patient's tumor takes up MIBG, the patient is randomized to either COG standard therapy
(Arm A) or to COG standard therapy with the addition of the radiopharmaceutical 131I-MIBG
(Arm B); the randomized portion of the study is comprised of 500 of the subjects in the
study. As the only difference between Arm A and Arm B is receipt of 131I-MIBG, the
investigators will be able to isolate the effects of 131I-MIBG therapy on clinical
endpoints and on key biomarkers. The endpoints documented and collected by the study are
not only relevant to tumor control and patient survival but also relevant to key quality
of life and late toxicities features, such as thyroid toxicity, impaired growth, impaired
pubertal development, and second malignancies. In addition, this study is particularly
poignant for the ROBIN Center's goals because it has embedded within it a rich array of
biospecimens and imaging studies to learn as much as possible about how
radiopharmaceuticals cure tumors but also cause unwanted side-effects. It includes
collection of tumor specimens at diagnosis prior to any therapy, and after 131I-MIBG
therapy at the time of surgery. Blood is collected at multiple timepoints for a host of
studies, including paired samples obtained just prior to 131I-MIBG therapy and again 72
hours after, in formats suitable for measuring the expression levels of genes and various
RNA molecules.
In summary, the MCT focuses on a small number of subjects (e.g., 18-23 subjects for DMG
and 24 subjects for neuroblastoma), treated with standard-of-care radiation therapy
(external beam radiation therapy for DMG and the 131IMIBG radiopharmaceutical for
neuroblastoma). The MCT is configured to isolate the effects of radiation, incorporates
longitudinal sampling (baseline, on-treatment, post-treatment), and incorporates both
invasive and non-invasive approaches such as tumor biopsies, imaging, blood and CSF
sampling, dosimetry (precise anatomical measurement of radiation dose). Patient-reported
outcomes, and other quality-of-life measures are also monitored. As a key feature,
because the subjects are being selected from trials with substantially higher numbers of
participants (e.g., N = 60-216 for PNOC023 and N = 500 for ANBL1531), findings from the
proposed ROBIN studies can be readily validated using data and biospecimens from
additional subjects participating in these trials.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Enrollment on one of the following clinical trials:
- Pacific Pediatric Neuro-Oncology Consortium PNOC023: Open label Phase 1 and
Target Validation study of ONC206 in Children and Young Adults with Newly
Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent
Primary Malignant Brain Tumors (NCT04732065) - Arm A or B (Key Eligibility
Criteria: Newly diagnosed DMG, Age ≥ 2 years, If on corticosteroids, on a
stable or decreasing dose for ≥ 3 days prior to baseline MRI scan, Karnofsky ≥
50 for age >16 or Lansky ≥ 50 for age ≤ 16, No known disorder that affects the
immune system or uncontrolled infection)
- Children's Oncology Group ANBL1531: A Phase 3 Study of
131I-Metaiodobenzylguanidine (131I-MIBG) or Crizotinib Added to Intensive
Therapy for Children with Newly Diagnosed High-Risk Neuroblastoma (NCT03126916)
- Arm B (Key Eligibility Criteria: Diagnosis of high-risk neuroblastoma (INRG
Stage M with MYCN amplification or age > 547 days, INRG Stage MS with MYCN
amplification, INRG Stage L2 with MYCN amplification, or progression to Stage M
in certain groups), Age ≥ 1 and ≤ 30 years at diagnosis, No prior systemic or
radiation therapy, with certain exceptions, No contraindication to targeted
radiopharmaceutical therapy)
- Tumor tissue confirmation of malignancy
- Adequate bone marrow, renal, liver and neurologic function
- Availability of tumor tissue, blood and/or CSF biospecimens
Exclusion Criteria:
- Pregnancy or breastfeeding
- Inability to follow the procedures of the study
Gender:
All
Minimum age:
N/A
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California, San Francisco
Address:
City:
San Francisco
Zip:
94143
Country:
United States
Status:
Recruiting
Contact:
Last name:
Sabine Mueller, MD, PhD
Facility:
Name:
Brigham and Women's Hospital
Address:
City:
Boston
Zip:
02115
Country:
United States
Status:
Recruiting
Contact:
Last name:
David Kozono, MD, PhD
Investigator:
Last name:
David Kozono, MD, PhD
Email:
Principal Investigator
Start date:
September 19, 2023
Completion date:
August 31, 2028
Lead sponsor:
Agency:
Brigham and Women's Hospital
Agency class:
Other
Collaborator:
Agency:
Dana-Farber Cancer Institute
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Collaborator:
Agency:
University of California, San Francisco
Agency class:
Other
Source:
Brigham and Women's Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06000787
