Faculty Bibliography

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant tumors represent a distinct subtype among diffuse gliomas, with improved prognosis compared to grade-matched IDH wild-type tumors. As a basis for clinical trial design of IDH-targeting drugs, we sought to describe outcomes exclusively within the glioma subgroup defined by IDH1 mutation.
METHOD(S): We retrospectively analyzed 275 IDH mutant glioma patients (48.7% grade II and 51.3% grade III tumors; 65.5% astrocytic and 34.5% oligodendroglial tumors) treated at our institution. We calculated progression and survival statistics, including median time to second progression event following first episode of recurrence, using the method of Kaplan-Meier. Estimated survival proportions were correlated with molecular, histologic and clinical factors.
RESULT(S): During a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression events (54.1%) were observed, with estimated median PFS of 5.7 years (95% CI 4.7-6.4) and median OS of 18.7 years (95% CI 12.2 years - not reached). We validated the effect of grade, molecular diagnosis and treatment paradigms on PFS in our cohort and found results consistent with existing literature. Following the first episode of progressive disease, 79 second progression events occurred during a median follow-up period of 4.1 years. The estimated PFS following first progressive event (PFS-2nd) is 3.0 years (95% CI 2.1-4.1).
CONCLUSION(S): This well-characterized cohort of IDH mutant glioma patients demonstrate progression and survival outcomes reflecting published literature and serves as a reasonable historical control population. Notably, the PFS interval accelerates during disease course, with interval between first to second recurrence (3.0 years) shorter than time from diagnosis to first recurrence (5.7 years). The novel survival statistic PFS-2nd offers an accurate and relevant surrogate outcome for the design of clinical trials investigating experimental drug efficacy at recurrence. These findings highlight that inappropriate comparison to historical baseline PFS may result in prematurely abandoning promising agents

BACKGROUND: Current treatment outcomes for patients with recurrent HGG are poor, with median progression-free survival (PFS) and overall survival (OS) of 2.5 and 7.5 months, respectively. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) resulted in an intracranial overall response rate (ORR) of 58% in BRAF V600-mutated melanoma brain metastases. Dabrafenib + trametinib was evaluated as treatment for patients with BRAF V600E-mutated HGG.
METHOD(S): In this phase 2, open-label trial (NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HGG, received continuous dabrafenib (150 mg BID) + trametinib (2 mg QD) until unacceptable toxicity, disease progression, or death. For the HGG cohort, eligible patients had histologically confirmed recurrent or progressive WHO grade 3 or 4 glioma and had prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiation therapy. The primary endpoint was investigatorassessed ORR by RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety.
RESULT(S): Thirty-seven patients with HGG had enrolled at data cutoff (3 January 2018). Median age was 42 years, 31 of 37 patients were evaluable for response. Investigatorassessed confirmed ORR was 26% (8/31; 95% CI, 12%-45%), including 1 complete response (CR). Six of 8 responses were ongoing at data cutoff. Five of 8 responding patients had a DOR of >= 12 months. Median PFS was 1.9 months (95% CI, 1.7-18.5). Median OS was 11.7 months (95% CI, 6.4-not reached). Adverse events (AEs) in patients with HGG included fatigue (35%), headache (30%), and rash (24%). Grade 3/4 AEs included neutropenia (8%) and fatigue (5%). Biomarker analyses are ongoing and will be presented.
CONCLUSION(S): Dabrafenib + trametinib demonstrated promising efficacy in patients with BRAF V600E-mutated recurrent/ refractory HGG, as 1 patient had a CR, and most responders had a prolonged DOR

The imipridone ONC201 is the first selective antagonist of DRD2 for clinical oncology. Several Phase 1, Phase 1/2 and Phase 2 studies in patients with advanced cancers have established the single agent recommended Phase 2 dose (RP2D) of 625mg ONC201 administered orally once a week in adults. ONC201 induces p53-independent apoptosis in newly diagnosed and recurrent high-grade glioma in vitro, ex vivo and in vivo. Furthermore, radiographic regressions in adult recurrent H3 K27M-mutant glioblastoma patients in response to single agent ONC201 have been reported. Based on this adult experience and complementary preclinical results demonstrating the increased susceptibility of H3 K27M-mutant gliomas to ONC201, we initiated the first Phase 1 pediatric clinical trial of ONC201 January 30, 2018. This trial will determine the safety and RP2D of ONC201 in pediatric postradiation H3 K27M-mutant glioma patients as a single agent and in newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients in combination with radiation (NCT03416530). Patients without known H3 K27M-mutation status by a CLIA-lab can enroll with commitment to post-term biopsy. This is a multicenter, open-label, 2 arm, dose-escalation and dose-expansion study. Ten children with H3 K27M-mutant gliomas ages 5-18 years have been treated post-radiation: 3 at dose level 1; 3 at dose level 2; 4 as part of the dose expansion cohort on dose level 2. Patients have received 2-12 doses (median= 5). The ONC201 has been tolerated very well. Grade III/IV events include: decreased neutrophil count grade III (n=1) spontaneously resolved without dose modification and elevated AST grade III (n=1) returned to grade II after holding 1 dose. Additional safety data as well as pharmacokinetics, pharmacodynamics, and progression-free survival results from this trial will be reported

BACKGROUND: Up to 20% of meningiomas are aggressive tumors with high recurrence rates and poor prognosis. Biomarkers predicting the risk of an unfavorable clinical course are lacking although aberrations in NF2, increased copy number variations and a hypomethylated phenotype have been associated with more aggressive behavior. Mutational signatures (MS) are characteristic patterns of somatic mutations seen in cancer genomes associated with aging, exposure to certain mutagens, or defective DNA repair. We aimed to identify MS patterns in clinically aggressive meningiomas.
METHOD(S): We performed whole exome sequencing of 18 de novo meningiomas (locally invasive and recurrent WHO I, n=6; atypical WHO II, n=4; anaplastic WHO III, n=8). Median PFS was 18.9 months. Copy numbers and DNA methylation phenotype were assessed by DNA methylation array analysis. Mutational signatures were identified using published signature algorithms (COSMIC).
RESULT(S): MS1 and MS5 (aging) were found in 18 (100%) cases. MS associated with defective DNA MMR were highly prevalent: MS20 and MS26 were detected in 18 (100%) and MS6 in 2 (12%) cases. MS12 (unknown etiology) was present in 14 (82%) cases. Despite the association with defective DNA MMR, none (0%) of the MS6 cases harbored somatic mutations associated with DNA MMR while MS12 tumors were enriched for mutations in DNA MMR (43%), chromatin remodeling (36%) and other cancer-associated genes (7%). MS6 tumors had significantly lower indels compared to non-MS6 tumors (p=0.01). Tumors with mutations in chromatin remodeling genes had a significantly higher rate of single nucleotide variants (SNVs) compared to cases without such mutations (p=0.02).
CONCLUSION(S): MS associated with defective DNA MMR were highly prevalent in this set of aggressive meningiomas. However, despite the association with DNA MMR, MS6 meningiomas harbored no somatic mutations associated with DNA MMR while MS12 tumors were enriched for mutations in DNA MMR, chromatin remodeling and cancerassociated genes

Oligodendroglioma (OD) is a subtype of adult diffuse glioma defined by IDH1/2 gene mutation and co-deletion of chromosomal arms 1p and 19q. Although prognosis in OD tumors is initially relatively favorable, the majority of OD develop outgrowth of a subclone that has undergone malignant transformation. Modeling the molecular mechanisms of this tumor progression is crucial to identify therapeutic targets for malignant disease. However, there are few available patient-derived OD xenograft models, which limit preclinical investigations. Here, we present novel patient derived anaplastic oligodendroglioma (AOD) xenograft models. In a panel of OD at different stages of disease, we harvested two distinct cell samples: those with and without PIK3CA mutation. From the tumor that subsequently rapidly progressed and had a PIK3CA mutation, we established a xenograft model that was lethal to the mouse and retained the PIK3CA mutation. In contrast, xenograft did not form from the other tumor that was clinically stable after resection and had wild-type PIK3CA. We confirmed AOD phenotype and the presence of IDH1 mutation and 1p/19q co-deletion in xenograft tissue, indicating successful capture of these signature OD genetic alterations. We also tested to see if PI3K/AKT/mTOR gene mutation could induce patientderived OD xenograft formation. In our attempts to establish xenograft models, the presence of activating mutations in PI3K/AKT/mTOR pathway was consistently associated with successful xenograft establishment. OD/ AOD tumors that did not form xenograft did not have mutation in the PI3K/ AKT/mTOR pathway Importantly, we found progressive tumor cells that harbor mutant PIK3CA were vulnerable to alkylating agents and PIK/AKT/ mTOR pathway inhibitors. These findings suggest there is a critical role of PI3K/AKT/mTOR pathway activation in driving progression and xenograft formation in oligodendroglial tumors. Our xenograft models will facilitate dissection of the mechanism of malignant transformation, contributing to the identification of optimal therapeutic strategies for patients with oligodendroglial tumors

BACKGROUND: H3 K27M-mutant gliomas have a dismal clinical prognosis and no proven curative therapy. We report the updated clinical experience with ONC201, the first cancer-specific DRD2 antagonist, in adult and pediatric H3 K27M-mutant gliomas.
METHOD(S): As of May 28, 2018, 26 patients with H3 K27M-mutant glioma have been treated with ONC201: 9 pediatric (<18 years old) and 17 adult patients (>18 years old). Twelve patients had recurrent disease and 14 had previously-treated stable disease prior to initiating ONC201. Patients had 1-4 prior lines of therapy and all received prior radiation. Ten adult patients were enrolled on clinical trials and the other 16 were on compassionate use. ONC201 was orally administered at 625 mg to adults and scaled by body weight for pediatric patients. All patients, except one, were dosed weekly.
RESULT(S): Fourteen of 26 patients (54%) remain progression-free on ONC201 with a median follow up of 3.6 (range 1.6-24.5) months. No dose modifications or discontinuation due to toxicity have occurred. Among the 12 adult patients with recurrent disease who received single agent ONC201, the estimated PFS6 is 36.5%. Seven patients have experienced radiographic and/or clinical benefit (neurological stabilization or improvement). Among the 5 adults with recurrent thalamic glioma, three have experienced durable complete regression of their thalamic tumors, including the first H3 K27M-mutant glioma patient treated with ONC201 who has experienced 96% regression of her recurrent disease and continues single agent ONC201 for >2 years. Two DIPG pediatric patients who initiated single agent ONC201 6-8 weeks after radiation have experienced radiographic and neurological improvements and exhibited PFS of >13 months from diagnosis.
CONCLUSION(S): Emerging clinical data suggest that ONC201 exhibits clinical activity for some patients with H3 K27M-mutant glioma

BACKGROUND AND PURPOSE/OBJECTIVE:Few studies have shown MR imaging features and ADC correlating with molecular markers and survival in patients with glioma. Our purpose was to correlate MR imaging features and ADC with molecular subtyping and survival in adult diffuse gliomas. MATERIALS AND METHODS/METHODS:promoter methylation, and overall survival. RESULTS:wild-type glioma. Other MR imaging features were not statistically significant predictors of survival. CONCLUSIONS:wild-type gliomas.

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.

PURPOSE/OBJECTIVE:Recent advances in sodium brain MRI have allowed for increased signal-to-noise ratio, faster imaging, and the ability of differentiating intracellular from extracellular sodium concentration, opening a new window of opportunity for clinical application. In gliomas, there are significant alterations in sodium metabolism, including increase in the total sodium concentration and extracellular volume fraction. The purpose of this study is to assess the feasibility of using sodium MRI quantitative measurements to evaluate gliomas. METHODS:), apparent intracellular sodium concentration (aISC), and apparent total sodium concentration (aTSC). Measurements were made within the contralateral normal-appearing putamen, contralateral normal-appearing white matter (NAWM), and solid tumor regions (area of T2-FLAIR abnormality, excluding highly likely areas of edema, cysts, or necrosis). Paired samples t test were performed comparing NAWM and putamen and between NAWM and solid tumor. RESULTS:(p = 0.19). CONCLUSION/CONCLUSIONS:Quantitative sodium measurements can be done in glioma patients and also has provided further evidence that total sodium and extracellular volume fraction are increased in gliomas.