MCT for the Harvard/UCSF ROBIN Center

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.