Lay Summary

Medulloblastoma is the second most common malignant brain tumor of childhood. Treatment consists of a combined-modality approach including surgery, radiotherapy and chemotherapy in most patients. Medulloblastoma relapse (rMB) occurs in approximately 30% of patients, is universally fatal and accounts for 10% of all childhood cancer deaths. Thus, there is a clear need to develop more effective therapies. This study is being undertaken by the Pediatric Brain Tumor Consortium (PBTC) which comprises 16 children's hospitals in the USA and Canada dedicated to improving treatment options for childhood brain tumors.

A novel modality of treatment involves intraventricular radio-immunotherapy (RIT) wherein radiolabeled monoclonal antibodies (MoAbs) are injected into the cerebrospinal fluid (CSF). CSF is the liquid around the brain and spinal cord which is made in the ventricles (hollow spaces) of the brain. Medulloblastoma cancer cells usually spread through the CSF. A radiolabeled monoclonal antibody (MoAb) is an antibody that’s made in a lab and specially designed to attach to cancer cells. The antibody has liquid radiation attached to it. 131I-Omburtamab is a monoclonal antibody that targets B7H3, a protein that is highly abundant in medulloblastoma tumor cells but is not present in normal brain and spinal tissue. This radiation kills the cancer cells directly without damaging normal tissue.

PBTC-058 is a phase II clinical trial using an investigational drug called 131I-omburtamab to see if it is safe for children when added to standard chemotherapy. The research will also investigate whether the addition of 131I-omburtamab lowers the chance of tumor growth and improves survival compared to patients in the past who only received chemotherapy and/or radiotherapy. Patients will receive 2 courses of induction chemotherapy (Irinotecan + temozolomide + bevacizumab) before receiving 131I-omburtamab. The induction chemotherapy will be followed by 4-6 weeks of observation during which the patient will undergo a surgery to place an intraventricular access device (i.e., Ommaya or programmable ventriculoperitoneal shunt). Following the observation period, patients who meet criteria to start treatment will proceed to radioimmunotherapy (56 days in length) which consists of two therapeutic doses of 131I-omburtamab. Following radioimmunotherapy, patients will continue to receive maintenance chemotherapy for up to 12 total courses.

The FDA has previously granted the drug Breakthrough Therapy Designation for the treatment of neuroblastoma with CNS metastases (the primary cancer has spread to the brain and/or spinal cord). The Breakthrough Therapy Designation means that early evidence has shown that 131I-omburtamab may help people who have neuroblastoma with CNS metastases, and the FDA is speeding up the review process. However, upon FDA review of the existing data from early-phase clinical trials in 2022, the FDA has requested additional data from the company before considering approval for this indication. The company therefore decided to prioritize its resources to study the drug in a clinical trial for children with CNS neuroblastoma. As a result, the drug manufacturer discontinued the radiolabeling of omburtamab for children with relapsed MB being treated on the PBTC-058 study, but instead offered to provide the “naked” (unlabeled) antibody. Accordingly, we are modifying the study to allow the radiopharmacy department at Memorial Sloan Kettering Cancer Center to assume the responsibility for drug manufacturing (i.e., radiolabeling of omburtamab). The current proposal seeks funding to support the radiolabeling costs for the drug (omburtamab) for the treatment of patients with relapsed MB on the PBTC-058 study.

If the combination of RIT with 131I-omburtamab is safe and results in a cure or longer survival for children with rMB, this will represent a significant achievement in the fight against this aggressive deadly cancer. Given the lack of any curative therapies at relapse, the current PBTC study remains quite appealing because it is a phase 2 combination study utilizing a novel treatment paradigm (cRIT) together with a standard chemotherapy backbone, thereby minimizing harm/burden to patients relative to other early phase trials which test novel treatments alone to ascertain safety signals. If successful, the study results would help support potential FDA approval and eventually commercialization of the drug for widespread use. Even if the results fall short of expectations, the study results can inform physician investigators regarding the best way in which to incorporate RIT including for the upfront treatment of specific subgroups of patients with medulloblastoma. For instance, RIT may help reduce the dose of craniospinal (whole brain and spine) radiotherapy in patients with ‘low risk’ subgroups of medulloblastoma (meaning low risk of relapse and death such as WNT subgroup) because craniospinal radiotherapy is associated with multiple long term side effects including lower IQ scores and poor cognitive development in survivors which can be mitigated with reduced radiotherapy doses. RIT can also be added to the therapy for patients with ‘high risk’ medulloblastoma (such as those patients with metastases in spine) after completion of all planned treatment to help reduce the risk of relapse and improve survival.

Executive Summary

Background

Relapsed medulloblastoma (rMB) occurs in approximately 30% of all patients despite intensive multi-modal standard upfront treatment comprising maximal safe resection, craniospinal irradiation (CSI) and chemotherapy. Prognosis following relapse is dismal, with less than 5% of patients surviving. Relapsed MB accounts for a significant proportion of childhood cancer deaths (~10%) and remains an urgent area of clinical unmet need. Novel therapeutic strategies are urgently required.

Clinical significance

This trial has the possibility of having a significant impact on a population that desperately needs new therapeutic strategies. It combines the current best known chemotherapy regimen (irinotecan, temozolomide and bevacizumab) used frequently at first relapse of MB, with an innovative therapeutic strategy termed compartmental radioimmunotherapy (cRIT) that has been well tolerated and demonstrated evidence of efficacy in other pediatric patient populations with CNS metastases. Pediatric brain tumors are the most common cause of cancer-related death in children. Despite molecular heterogeneity, relapsed medulloblastoma patients have homogenously dismal outcomes. This trial has the possibility of having a significant impact on a population that desperately needs novel therapeutic strategies.  It combines the current best known chemotherapy regimen, with an innovative radioimmunotherapy that has been well tolerated in other heavily pre-treated pediatric patient populations with CNS metastases.

Successful completion of this trial may result in a paradigm shift in MB treatment supporting the incorporation of cRIT with 131I-omburtamab in treating patients with medulloblastoma at first recurrence. Even if the study does not meet its primary endpoint, the results from this study will help inform the design of future clinical trials. Understanding the best way to utilize this innovative therapeutic strategy designed to eliminate micro-metastatic and leptomeningeal disease will be essential. Completion of this trial may provide an avenue for future studies to confirm efficacy or to design new ways to integrate this therapy upfront into combination strategies. The results of the current study can inform and support the incorporation of cRIT with radiolabeled MoAbs to standard of care therapies in the upfront setting for patients with medulloblastoma. Once the logistics of multi-center administration are in place and depending on preliminary data from this trial, an upfront trial for molecularly stratified high-risk medulloblastoma may be pursued. Such studies could include radiotherapy dose reduction trials for ‘low risk’ medulloblastoma subgroups (non-metastatic WNT or group 4 with chromosome 11 gain) to avoid/mitigate the neurocognitive sequelae of CSI. Conversely, addition of cRIT as ‘maintenance therapy’ for patients with high risk medulloblastoma who achieve a complete remission post upfront CSI and adjuvant chemotherapy may contribute to improved survival outcomes and reduce risk of recurrence. Importantly, addressing which patients might benefit and the best ways to utilize this innovative therapeutic strategy will be essential. 

Since patients will have an intraventricular access device placed for therapy administration, serial CSF samples will be collected for research purposes. As such, the translational aspects of this study will enable the evaluation and validation of CSF (and plasma) cell free DNA (cfDNA) and exosomes as non-invasive biomarkers of disease response and relapse in a uniformly treated cohort of patients with recurrent MB.

 

Hypothesis

Prior studies suggest that cRIT with 131I-omburtamab is safe, with no increased risk of radiation necrosis. The studies showed favorable dosimetry to the CSF versus blood, and when added to salvage therapy using conventional modalities may have clinical utility in maintaining remission among patients with high-risk or recurrent CNS tumors, particularly when used in the setting of targeting minimal residual disease. Borrowing on the model of eradicating CNS deposits for NB, this study will investigate the role of cRIT 131I-omburtamab for pediatric patients with recurrent medulloblastoma. We propose a phase 2 efficacy trial and hypothesize that addition of cRIT with 131I-omburtamab to a chemotherapy backbone of irinotecan/temozolomide/bevacizumab (ACNS0821) will provide therapeutic benefit to patients with recurrent medulloblastoma and prolong event free survival (EFS) without increasing toxicity. Our results will be compared to historical controls who received irinotecan/temozolomide/bevacizumab chemotherapy only on the completed ACNS0821 therapeutic study.

 

Goals

 

Aim 1

To perform a ‘first in kids’ multi-center phase 2 study evaluating the combination of irinotecan/temozolomide/bevacizumab chemotherapy with compartmental radioimmunotherapy (cRIT) using intraventricular radiolabeled monoclonal antibody therapy (131I-omburtamab) targeting B7H3 in patients with refractory or recurrent medulloblastoma. The study will assess efficacy as measured by 2 year event free survival (primary objective) compared to a matched historical cohort treated with chemotherapy alone on a prior children’s oncology group (COG) study ACNS0821 and overall survival (secondary objective) and acute as well as cumulative toxicities associated with the combination treatment (secondary objective).

 

Aim 2

To explore the utility of cell free DNA (cfDNA) and exosomes in plasma and CSF in assessing minimal residual disease and identify biomarkers of response and resistance.

 

Methods

This study is being undertaken by the Pediatric Brain Tumor Consortium (PBTC) which comprises 16 academic centers and children's hospitals in the United States dedicated to improving treatment options for childhood brain tumors. This is a phase 2 single-arm open-label study.

Study population

Inclusion criteria: Patients < 22 years of age with a histologically confirmed diagnosis of medulloblastoma that is recurrent (no more than 2 recurrences), progressive, or refractory to standard therapy. Patients must have either measurable disease OR diffuse leptomeningeal disease OR clear MRI evidence of disease that may not be measurable in two perpendicular diameters OR positive CSF cytology. Protocol treatment with radioimmunotherapy (131I-omburtamab) will require the presence of an appropriate intraventricular access device (e.g., programmable ventriculoperitoneal [VP] shunt or Ommaya reservoir). Washout periods for prior therapy include 21 days (3 weeks) for myelosuppressive anticancer therapy; ≥ 7 days for biological agents, ≥ 21 days for monoclonal antibody treatment; 24 weeks for craniospinal irradiation, whole brain radiation, total body irradiation, or radiation to >50% of pelvis or spine; 14 days for focal radiation to areas of symptomatic metastatic disease and ≥ 3 months after stem cell transplant. Performance Status must be ≥ 50%. Patients must have adequate bone marrow, hepatic and renal function including absence of severe proteinuria and normal blood pressure.

Patients who have previously received the combination of bevacizumab, irinotecan, and temozolomide therapy are ineligible. Patients with a serious or non-healing wound, ulcer, or bone fracture, a history of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess, a known bleeding diathesis or coagulopathy or significant vascular disease, a known thrombophilic condition, a history of stroke, myocardial infarction, transient ischemic attack (TIA), severe or unstable angina, peripheral vascular disease, or grade II or greater congestive heart failure within the past 6 months are ineligible. Patients with evidence of new CNS hemorrhage on baseline MRI obtained within 14 days prior to study enrollment are ineligible.

Study design:

Patients with recurrent medulloblastoma will receive Induction Chemotherapy with irinotecan, temozolomide, and bevacizumab on study as per the Children’s Oncology Group (COG) trial ACNS0821. Following 2 or 4 courses of chemotherapy and if radiographic disease status is stable or improved, patients may continue to Radioimmunotherapy to receive 2 therapeutic doses (50 mCi each) of cRIT 131I-omburtamab. Following Radioimmunotherapy, patients may resume to Maintenance Chemotherapy with irinotecan, temozolomide, and bevacizumab for up to 12 total courses of chemotherapy or until disease progression, whichever occurs sooner. The primary comparison for this study will be the recurrent medulloblastoma cohort treated on ACNS0821 on the irinotecan + temozolomide + bevacizumab arm (N=52). 

Statistical considerations

Sample size/accrual rate:

Through a data use agreement, the PBTC was given access to the patient level data from the temozolomide, irinotecan, bevacizumab arm of ACNS0821, which will serve as the control cohort.  The EFS for 40 medulloblastoma patients on that study arm was 10.9 months, with a 2 year EFS rate of 15% (95% CI: 7.2%-31.4%). The primary efficacy comparison will be between the cohort which enrolls on this study and the medulloblastoma cohort treated on ACNS0821 with temozolomide, irinotecan, bevacizumab (N=40).

We will power the study for a HR=0.625 which translates to approximately 15% improvement in EFS (15% vs. 30%) at 2-years in the overall cohort. Using the approach proposed by Wu and Xiong,²⁸ the design proposed here requires 33 patients all of whom will be followed until progressive disease (PD) or at least 2 years post accrual completion to achieve approximately 80% power at 10% type 1 error using a 1-sided log-rank test. The estimated accrual duration is 2.5-3 years. All eligible patients who initiate treatment with induction chemotherapy will be evaluable for the primary efficacy assessment in this stratum and will be counted towards this accrual goal. A 1-sided log-rank test will be used for the primary efficacy analysis in Stratum 1 with a significance threshold of 10%. The design also incorporates 1 interim analysis for futility assessed when 10 events are observed in the omburtamab-treated cohort. If the estimated HR > 1 at the time of the futility analysis, then the study will stop for inadequate evidence of efficacy.

Analysis of secondary endpoints

All patients will be evaluable for toxicity from the time of their first treatment with induction chemotherapy. Toxicities will be summarized by grade and attribution.
As a secondary endpoint, we will estimate OS using a Kaplan-Meier approach. If an adequate number of patients are available to make such analyses informative, we will include Kaplan-Meier estimates of these outcomes for patients who were treated with omburtamab vs. those who were not. We will estimate response rates as well as duration of response in patients with measurable or evaluable disease at the time of enrollment.  Exact confidence intervals will be provided for response rates and duration of response will be measured from the earliest date of documentation of an objective response (PR or CR) until disease progression (on or off treatment) or last follow-up with disease assessment, whichever is earlier.

Statistical Analysis of Exploratory Objectives

Analysis of CSF and plasma exosomal microRNA and protein signature will be performed for the identification of potentially targetable oncogenic pathways and for monitoring disease status following treatment. Longitudinal measurements of tumor-specific exosomal microRNA and protein profiles from plasma and CSF will be described using summary statistics and plots. Pairwise change estimates will be provided for various timepoints (e.g., baseline vs. end of Induction Chemotherapy, before and after Radioimmunotherapy, etc.). We will correlate these results with radiographic findings (such as PR or PD) and PFS. These analyses will be exploratory in nature.

The FDA has previously granted 131I-omburtamab Breakthrough Therapy Designation for the treatment of neuroblastoma with CNS metastases which means that early evidence has shown that 131I-omburtamab may help people who have neuroblastoma with CNS metastases. Subsequently, in 2022, the FDA did not approve 131I-omburtamab to treat CNS metastatic neuroblastoma. The FDA’s decision was predicated on the fact that the results from the single arm, single center study (03-133) were compared to a poorly matched external control population. Therefore, the FDA has requested additional data be collected prior to re-evaluating approval status. The sponsor/drug manufacturer (Ymabs) is now focusing primarily on the ongoing multi-center study in CNS/leptomeningeal neuroblastoma which is ongoing to acquire the additional data requested by the FDA. As such, the sponsor decided to discontinue the contract with the third party that was contracted to perform radiolabeling of omburtamab leading to a temporary interruption of drug supply of 131I-omburtamab for the ongoing PBTC-058 study. Given there remains substantial interest in this novel treatment model using cRIT with 131I-omburtamab in recurrent MB, the PBTC-058 study was amended to permit MSK radiopharmacy to assume the responsibility for radiolabeling of omburtamab thereby enabling resumption of drug supply. We are seeking funding to primarily help support the costs associated with radiolabeling Omburtamab to enable this study to reopen to accrual.

In summary, there remains a viable path to potential FDA approval including commercialization for widespread use of 131I-omburtamab should the current PBTC study meet its defined primary endpoint. Given the lack of any curative therapies at relapse, the current PBTC study remains quite appealing because it is a phase 2 combination study utilizing a novel treatment paradigm (cRIT) together with a standard COG chemotherapy backbone, thereby minimizing harm and burden to patients relative to other early phase trials which often test novel treatments alone to ascertain safety signals.

Description of Research Proposal

Budget

Collaborations and Conflicts of Interest