Award: $400,000 over 2 years (2020 – 2022)
Principal Investigators: Dr. Peter de Blank, Cincinnati Children’s Hospital, Dr. Heather Conklin, St. Jude Children’s Research Hospital

In order to comprehensively compare CV and selumetinib treatment regimens, we will evaluate quality of life, cognitive, functional, and behavioral outcomes in children with newly diagnosed low-grade glioma. Because overall survival for low-grade glioma is typically excellent, understanding the impact of treatment regimens on quality of life and function is essential. Aim 1: Compare the change in quality of life, measured by the PedsQL generic module, following treatment with either selumetinib or carboplatin/vincristine in children with previously untreated low-grade glioma. Aim 2: Prospectively evaluate and compare the change in cognitive function measured by the BRIEF Cognitive Regulation Index between baseline and 12 months in children treated with either therapy. Aim 3: Determine whether visual acuity in children with previously untreated OPG is better after treatment with selumetinib or carboplatin/vincristine, using Teller Acuity Cards and HOTV letter acuity testing. Aim 4: Compare the improvement in motor function as measured by the Vineland Scale in children with previously-untreated LGG treated with either therapy that have motor deficits at enrollment.

Award: $300,000 over 2 years (2020 – 2022)
Principal Investigators: Dr. Lindsay Kilburn, Children’s National Medical Center, Dr. Angela Waanders, Lurie Children’s Hospital of Chicago, Dr. Mohamed AbdelBaki, Nationwide Children’s Hospital

Although preclinical and clinical data support the use of single agent MEK or mTOR inhibitors in the treatment of pediatric LGGs, there are anecdotal reports of tumor progression or rapid regrowth following cessation of therapy. Development of tumor resistance to single-targeted agents is inevitable, one mechanism being upregulation of parallel pathways. [10] Both preclinical and clinical studies have demonstrated additive or synergistic responses to therapy with trametinib and other MEK inhibitors when used in combination with both targeted and conventional chemotherapeutics. Therefore, further evaluation of rationale combination therapies is indicated in pediatric patients with gliomas, which may provide improved efficacy and or durability of response in these patients. Given the available preclinical data suggesting synergy with the combination of MEK and mTOR inhibition as well as demonstrated safety and efficacy of trametinib and everolimus in children with LGGs, we are proposing to evaluate the combination of trametinib and everolimus in children with recurrent or refractory LGGs.

Award: $250,000 over 2 years (2020 – 2022)
Principal Investigators: Dr. Nathan Robison, Pediatric Neuro-Oncology Attending, Children’s Hospital Los Angeles, Dr. Mariella Gruber, Department of Pediatric Neuro-Oncology, Dana-Farber Cancer Institute, Dr. Karen Wright, Pediatric Neuro-Oncologist, Dana-Farber Cancer Institute
Funding Partners: Taylor Matthews Foundation, WhyNotMe? Foundation, Making Headway

Phase I of this trial was rolled out in 2016 with support from PLGA Fund and had a target validation component to determine the ability of MEK162 to penetrate into the tumor as well as assess the ability of MEK162 to affect its target. A short course pharmacokinetics and pharmacodynamic evaluation on these patients for correlation was performed to evaluate the following criteria: To quantify concentration of investigational compound in tumor tissue after treatment with MEK162 for 7-21 days and correlate with PK assessment in blood; to assess RAS-RAF-MEK-ERK pathway inhibition, as measured by ERK phosphorylation, in LGG after treatment with MEK162 for 7-21 days. Blood pharmacodynamic assessment will also be performed and correlated with tumor results. MEK162 demonstrated a positive response; with such promising initial results, researchers expanded the enrollment by 33% (from 75 patients to 100) and allowed current patients to remain on the trial for an additional year.

Award: $428,000 over 2 years (2019 – 2021)
Principal Investigators: Dr. David Jones and Dr. Stefan Pfister, Heidelberg German Cancer Institute

The principle aim of the trial is to identify the optimum treatment regimen with respect to efficacy, improvement of visual and neurological function, reduction of neurotoxicity as well as treatment duration using a randomized comparison of vinblastine (VBL) versus vincristine (VCR) in a carboplatin-based chemotherapy regimen, also randomizing 18 versus 12 months treatment duration. An additional novel point of the planned trial is the adaptive design and interim analyses (from year 3 onwards), which will allow for the timely investigation of novel targeted agents, once a chemotherapy standard of care ‘winner’ has been established (VCR vs VBL, 12 vs 18 months). The overarching aim of this proposed funding application will be to provide a comprehensive molecular characterization of all patient tumor samples collected during the course of the SIOP‐LGG 201X trial as well as an associated registry study for all newly-diagnosed pediatric LGG (see Appendix B). This is a pan-European, population-based study, with an expected recruitment of >90% of all newly diagnosed LGGs in the 19 participating countries. Since LGG patients often suffer from significant damage to important functional structures of the brain, particularly for tumors located in central midline structures, the current trial for the first time includes assessment of acute and long-term morbidities to visual and neurological function as a primary outcome measure. We will therefore have access to tumor and germline material from a very large, uniformly-treated cohort with very detailed and standardized clinical annotation and careful follow-up.

Award: $350,000 over 2 years (2019 – 2021)
Principal Investigators: Dr. Arzu Onar-Thomas, St. Jude Children’s Research Hospital

The development of MAP kinase-specific targeted inhibitors is the shifting therapeutic strategy for pediatric LGGs and offers many of these children new treatment options. Early phase investigations of RAF and MEK inhibitors in pediatric gliomas have demonstrated reasonable tolerability and superior responses in some patients compared to conventional chemotherapy. However, a significant subset of patients maintains either stable disease or progresses on targeted therapy, suggesting potential benefit from combining RAF or MEK inhibitors with agents targeting other active pathways.

Autophagy is a process by which components of a cell are recycled to promote cell survival, particularly in times of stress. Dr. Mulcahy Levy’s laboratory has generated preclinical data demonstrating specific upregulation of autophagy in BRAF-mutant compared to wild-type glioma cells and has shown that autophagy inhibition can effectively overcome intrinsic and acquired resistance to RAF inhibition. Based on these data and early clinical experience at the University of Colorado, we have proposed a phase I/II trial with dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) + hydroxychloroquine (autophagy inhibitor; HCQ) in BRAF V600E-mutant gliomas and a combination of trametinib + HCQ in BRAF fusion or NF1-driven gliomas in children.

The primary aims of this trial are to demonstrate safety and early efficacy of the proposed combinations. Only children whose tumors have failed MEK and/or RAF inhibitors previously will be eligible; thus, we are selecting a specific group of children for whom other therapeutic options are limited and who are most likely to benefit.

This trial will aid understanding of tumor biology that drives response or resistance to targeted therapies through evaluation of the genetics and expression profiles of pre- and post-therapy tumor samples. Knowledge gained will be broadly relevant to other patients with LGG, particularly as more are being treated with targeted agents earlier in their treatment course. We will also use ddPCR to very sensitively track BRAFV600E transcript levels (in patients with known mutation) while on protocol therapy. If as a proof-of-principle, there is a correlation between BRAFV600E transcripts and tumor burden on MRI and/or outcome, this study would strongly support greater utilization of ddPCR to define and track minimal residual disease in pediatric CNS tumors.

Award: $300,000 over 2 years
Principal Investigators: Dr. Karen Wright, Director of Neuro-Oncology, Assistant Professor-Pediatrics, Dana-Farber Cancer Institute, Dr. Daphne Haas-Kogan, Chair-Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, and Sabine Mueller, Associate Professor of Oncology, University of California, San Francisco
Funding Partners: Thea’s Star of Hope, Starry Night Knoxville, Think Fit for Kids

Oncogenic dysregulation of the RAS/RAF/MEK/ERK pathway has been described in a number of diverse malignancies, including low grade gliomas. Furthermore, mutations in BRAF, which occur in both monomeric and dimeric forms, drive the majority of pediatric LGG. Yet, only ten percent of pediatric LGGs possess BRAF V600E mutations, some of which are targetable by current type I inhibitors (dabrafenib, vemurafenib), which bind the activation site of the V600E mutation to prevent downstream signaling. The application of type I inhibitors to the majority of patients whose tumors do not possess V600E mutations was met with disappointment and in many cases deleterious results due to the unexpected acceleration of tumor growth in treated patients – a result brought about by paradoxical ERK activation in a process termed negative cooperativity. Current therapies for this patient group now target the downstream MEK and MTOR signaling molecules but have yielded responses in only a small subset of patients likely due to poor CNS penetration and downstream location. A promising new class of inhibitors, however, targets all mutations of BRAF, including the much more common dimerizing forms of mutant BRAF, as exemplified by the common KIAA1549:BRAF fusion duplication. This class of BRAF inhibitor (called type II) functions via a completely different mechanism of action via stabilization of the BRAF/MEK complex. Our preclinical results supported by our Brain SPORE grant (Project 4; PIs Kieran and Eck) demonstrated that this inhibitor has excellent CNS penetration as demonstrated by scanning MALDI-TOF analysis, is effective on all BRAF point mutations (not just BRAF V600E) as well as all truncated fusion forms of BRAF and that by virtue of the RAF/MEK complex stabilization, prevents the paradoxical activation that occurs with all type I inhibitors currently available. Clinical trials of these drugs in adults have laid the foundation for moving forward with testing in children, thereby positioning us to design the first trial to test such a novel pathway inhibitor for the most common pediatric brain tumor. TAK-580, a type II inhibitor with excellent CNS penetration and documented activity demonstrated in a number of LGG models based on the work done at our institution, is the focus of our upcoming trial. The trial design includes phase 1, 2 and target validation arms, the latter providing the opportunity to verify CNS penetration in patient tumors and evaluate pre- and post-treatment biopsy samples to study pathway inhibition and possible resistance among unresponsive tumors. This drug has the potential to transform treatment for the majority of patients with the most common pediatric tumor, a tumor for which surgery is often not possible and treatment morbidity high.

Funded in 2018.

Funding Partners: WhyNotMe? Foundation, Team Jack Foundation

With the discovery of new targets, the pipeline for PLGA clinical trials is ramping up to be more productive than ever before. The newest PLGA clinical trial, entitled Phase 1/II Study of MEK162 for Children with Ras/Raf Pathway Activated Tumors, opened for recruitment in June 2016. The main purpose of the phase I study is to determine the most effective dosage of the drug for children and adolescents with tumors that have recurred despite standard chemotherapy treatment, and to identify the most common side effects. Spearheaded by Dr. Nathan Robison at the Children’s Hospital of Los Angeles, the trial has already enrolled the first 2 cohorts of patients to evaluate optimal drug dosage and will continue to move forward. The phase II objectives will determine whether MEK162 causes NF1 patents and other tumors thought to be caused by abnormal activation of the Ras/Raf/MAP molecular pathway tumors in the pediatric population to shrink and/or stop growing. The study is projected to span 2 years for patient enrollment and will include 15 different institutions across the country.

Update: November 17, 2016

We’re excited to report that at the European Society for Medical Oncology (ESMO) 2016 Congress, held October 7–11 in Copenhagen, Denmark, Dr. Mark Kieran discussed the results of a phase I/II trial of dabrafenib therapy, which demonstrated higher response and lower toxicity in pediatric brain tumors. In this video clip, he discusses how the BRAF inhibitor has significant impact on gliomas in children, with none of the side effects seen in adult melanoma patients and introduces upcoming doublet trials alongside a MEK inhibitor. There are additional findings presented at ESMO 2016 about the effectiveness of targeted combination therapy for children with certain types of low-grade glioma brain tumors.

Funded in 2016.

With the collaboration of 3 major medical institutions in Germany, Italy and France, this European partnership has combined forces to create the largest clinical trial for PLGA children ever. Set to open in the second half of 2015, the trial is expected to enroll 3000 patients from 19 different European countries over the course of 5 years.

The focus of this trial, titled “Prospective assessment of predictive/prognostic molecular biomarkers in the SIOP-LGG 201X adaptive phase III clinical trial cohort” is to identify the optimum treatment regimen with respect to efficacy, improvement of visual and neurological function, reduction of neurotoxicity as well as treatment duration using a randomized comparison of vinblastine (VBL) versus vincristine (VCR) in a carboplatin-based chemotherapy regimen.

An additional novel point of the planned trial is the adaptive design and interim analyses (from year 3 onward), which will allow for the timely investigation of novel targeted agents, once a chemotherapy standard of care ‘winner’ has been established. This trial will establish new precedents for treating children with these two ‘gold standard’ treatments and make room for comparative studies as new targeted drug therapies are developed.

PLGA fund at PBTF is a proud sponsor of this unprecedented clinical trial.

Funded in 2015.

This proposal fills a critical unmet need for a pediatric population with few other therapeutic alternatives and addresses an important problem in PLGG therapy, namely, how to best target dysregulated components within signaling pathways. This study (PNOC001) will elucidate mechanisms by which the most common genetic aberrations in PLGGs influence responses to novel, promising, translatable agents and will enable the next generation of clinical trials in which rational drug combinations are administered to appropriate patients in hypothesis-driven studies. This proposal steps beyond the usual approach of testing agents empirically in response-based trials. It utilizes a novel clinical trial statistical design to establish if specific molecular features are predictive markers of response to a targeted agent and establishes a new paradigm for PLGGs in which tumor tissue is acquired from each child in order to identify biomarkers of response. Funding support for the trial provides for the trial’s implementation and continued patient accrual across PNOC’s 15 member clinical trial consortium. Funding for the trial by PLGA fund at PBTF thus supports the robust accrual into an important clinical trial and enables children from all areas of the country to have access to a novel, directed treatment for PLGGs.

Funded in 2013.

Low-grade gliomas are the most common brain tumor in children. While a portion of patients are effectively cured with surgery alone, for a significant majority, especially those without neurofibromatosis type 1, recurrences are common. These patients often require repeated resections, chemotherapy and radiation therapy.

The damage caused by these therapies has a significant impact in the lives of these children. More targeted and less toxic therapies in this population are therefore required. An important pathway that has been implicated in pediatric low-grade gliomas is mTOR, a central relay site within the cell that when activated, results in increased proliferation, cell migration and angiogenesis.

Our preliminary work has demonstrated the presence and activation of this pathway in LGGs samples from children without NF1. RAD001 is a new oral mTOR inhibitor that has demonstrated excellent inhibition of this pathway at clinically achievable doses. The drug is exceedingly well tolerated and is currently used to reduce the risk of solid organ transplant rejection. We are now proposing a formal multi-institutional clinical trial of RAD001 in non-NF1 children with recurrent or progressive LGGs after standard treatment.

Funded in 2008.