Search

Supplementary Methods. Supplementary Table S1: Baseline characteristics of PCNSL Patients. Supplementary Table S2: Baseline characteristics of SCNSL patients. Supplementary Table S3: Corticosteroid use. Supplementary Table S4: Genes with Recurrent Mutations in PCNSL (non-aSHM). Supplementary Table S5: Genes that are targeted by aSHM in PCNSL. Supplementary Table S6: Comparison of mutation prevalence in current PCNSL genomic landscape analysis (red) with prior studies in PCNSL and DLBCL. Supplementary Table S7: Gene set enrichment analysis of CD79B-mutant PCNSLs compared to CD79B-wildtype PCNSLs. Supplementary Figure S1: Ibrutinib concentrations in Cerebrospinal Fluid (CSF). Supplementary Figure S2: Comparison of mutation frequencies in PCNSL and DLBCL outside the CNS. Supplementary Figure S3: Cell-of-origin (COO) Markers in PCNSL. Supplementary Figure S4: CD79B-mutant PCNSL xenograft models. Supplementary Figure S5: Comparison of PCNSL cells with non-CNS DLBCL cell lines. Supplementary Figure S6: Inhibition of individual PI3K isoforms does not induce cell death in CD79B-mutant PCNSL cells. Supplementary Figure S7: In-vitro effects of ibrutinib on CD79B-mutant PCNSL cells.

Figure S1: Distribution of systemic therapies received. Figure S2: Number of sequenced samples per patient. Figure S3: Subgroup-defining genomic lesions in IDH-wildtype and -mutant gliomas. Figure S4: Frequency of mutations in primary tumors. Figure S5: Frequency of glioma type-defining genes. Figure S6: Outcome by enhancement and cell-cycle alteration status. Figure S7: Alteration of key functional groups in IDH-WT astrocytic tumors. Figure S8: Cell-cycle alterations and outcome in 1p19q-intact IDH WT tumors. Figure S9: Rate of alkylating therapy-induced hypermutation by WHO class. Figure S10: Frequency of actionable alterations. Figure S11: BRAF hotspot mutations in glioma. Figure S12: MR brain images for three patients receiving MAPK-directed therapy.

Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.

Supplementary Data 1 ELIGIBILITY CRITERIA. Supplementary Data 2 HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY PLANNING. Supplementary Data 3 MRI ACQUISITION PARAMETERS AND PROCESSING. Supplementary Data 4 Nanostring-based Tissue Correlates Methods. Supplementary Data 5 Number of patients experiencing Grades 3-5 treatment-related toxicities. Supplementary Data 6 Univariate analysis of DSC MR perfusion and diffusion MRI. Supplementary Data 7 NEUROPSYCHOLOGICAL TEST Z-SCORES, QUALITY OF LIFE, DEPRESSION AND FATIGUE SCORES OVER TIME.

Table S1: Patient-level clinical annotation. Table S2: Sample-level clinical annotation. Table S3: Patient-level treatment lines. Table S4: Gene panels for targeted sequencing. Table S5: Somatic mutations. Table S6: Gene-level copy number alterations. Table S7: Hotspot mutations in 3,130 sequenced glioma patients. Table S8: Pathogenic and likely pathogenic germline variants identified. Table S9: Pathways and gene content for cohort-wide pathway-level analyses.

Purpose:The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes.Results:Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context.Conclusions:These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

List of Supplementary Data

Background Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. The 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45–100), 56% (95% CI: 38–74), and 85% (95% CI: 71–99), respectively. Median time to response was 1.9 months (range 1.0–3.8 months). Duration of treatment ranged from 1.2–31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3–4 in 3 patients. No new safety signals were identified. Conclusions In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.

Objectives:To report on the tolerability and efficacy of olaparib with temozolomide (TMZ) for gliomaMethods:Single-center retrospective series of glioma patients treated with olaparib/TMZ September 2018-December 2021Results:Twenty patients (median age: 42, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH-mutant oligodendroglioma (n=5), IDH-mutant astrocytoma grade 2-3 (n=4), IDH-mutant astrocytoma grade 4 (n=7), or IDH-wildtype glioma (n=4). One patient was treated upfront and 19 at recurrence (median=3). Olaparib 150mg was administered three times/week concurrent with TMZ 50-75mg/m2 daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. 6/20 patients required dose reduction (n=4) or discontinuation (n=2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH-mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH-mutant astrocytomas (0/5) or IDH-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively.Discussion:Olaparib/TMZ resulted in objective radiographic response in 50% of evaluable patients with recurrent IDH-mutant grade 2-3 gliomas with encouraging PFS and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population.Classification of Evidence:This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma.

INTRODUCTION Treatment of brainstem tumors is often initiated without a tissue diagnosis due to the risk of biopsy. A subset of brainstem gliomas harbor an isocitrate dehydrogenase 1/2 (IDH) mutation, which predicts response to alkylator chemotherapy and IDH inhibitors; non-invasive diagnostic tests are needed to identify these mutations. METHODS We identified a cohort of patients with IDH-mutant brainstem gliomas through chart review of patients who underwent magnetic resonance spectroscopy (MRS) and/or brain biopsy. IDH mutation was established by biopsy, presence of a 2-hydroxyglutarate (2HG) peak on MRS, or identification on cerebrospinal fluid (CSF) sequencing of cell-free DNA (cfDNA). RESULTS We identified 15 patients with IDH-mutant brainstem gliomas, age range 5-48, 47% women. 15/15 were involving/abutting the brachium pontis, and 10/15 were non-enhancing at diagnosis. 13/15 patients were identified by biopsy, 1/15 by MRS and CSF, and 1/15 by MRS only. 10/13 patients with available data had a non-IDH1 R132H mutation in IDH1/2. 7/7 patients with MRS prior to radiation had a 2HG peak (MRS was concordant with tissue in all cases in which biopsy was obtained). 4/6 patients with MRS post-radiation retained a 2HG peak. 4 IDH-mutant tumors had sequencing of cfDNA and an IDH mutation was found in 2/4. Response data was available in 13/15 patients; all received radiation, 10 with concurrent temozolomide: best response was partial response in 8 and stable disease in 5. 4 patients received an IDH inhibitor: 2 patients after progression, and 2 as maintenance after radiation/temozolomide, achieving tumor control in all. For this cohort, median PFS was 71.4 months and median OS has not been reached. CONCLUSION IDH-mutant brainstem gliomas have a characteristic appearance, a high response rate to treatment, and a better overall prognosis than other brainstem tumors. MRS and CSF cfDNA sequencing allow for non-invasive diagnosis of IDH mutations in these patients.

Background Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors. Methods We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS). Results We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment–related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5–13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months. Conclusion Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.

Purpose Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well‐tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti‐tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. Methods Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. Results We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose‐limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). Conclusion Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

Purpose To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. Materials and Methods Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with Results Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2–69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. Conclusion The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

BACKGROUND Larotrectinib is a highly selective TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset. METHODS Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Responses were investigator-assessed. RESULTS As of July 2021, 38 patients with TRK fusion primary CNS tumors (median age, 10.8 [range 1.3–79.0] years) were identified: high-grade glioma (HGG; n = 23), low-grade glioma (LGG; n = 9), and other (n = 6). Sixteen (42%) patients had ≥ 2 prior systemic therapies. ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥ 24 weeks), and five progressive disease. For pediatric patients (n = 28), the ORR was 39% (95% CI 22–59). For pediatric patients with HGG and LGG, ORRs were 43% (95% CI 18–71) and 38% (95% CI 9–76), respectively. ORRs for patients with 0, 1, 2, and ≥ 3 prior therapies were 33%, 20%, 38%, and 38%, respectively. Median time to response was 1.9 months. The 24-week DCR was 73% (95% CI 56–86). Median duration of response (DoR) was not reached; 12-month DoR rate was 64%. Median progression-free survival was 16.5 months (95% CI 6.7–not estimable). Median overall survival (OS) was not reached; 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. No patients discontinued treatment due to TRAEs. CONCLUSION Larotrectinib demonstrated a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors.

Background High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). Methods Eight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. Results Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. Conclusions This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. Clinical trial registration NCT03684980 (Registration date 26/09/2018).

PURPOSE: An increased incidence in hematologic toxicity has been reported with the addition of bevacizumab to lomustine for patients with recurrent or progressive high grade gliomas (HGG). Data regarding incidence of toxicity with combination bevacizumab and carmustine is limited. The purpose of this study is to compare toxicity of single agent carmustine and carmustine plus bevacizumab for patients with HGGs. METHODS: This single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with age ≥18 years who received carmustine between January 2003 and May 2017. RESULTS: Sixty-five patients with HGGs collectively received 110 doses of BCNU during the specified time period. Sixteen patients received single agent BCNU (30 doses); 49 patients received combination bevacizumab with BCNU (80 doses). There was no significant difference in incidence or grade of toxicity between single agent and combination therapy with respect to hepatotoxicity, leukopenia, lymphopenia, neutropenia, anemia, and thrombocytopenia. Rates of grade 3 and 4 neutropenia (20% vs 13.8%, p=0.55) and thrombocytopenia (23.3% vs 23.8%, p=1) did not differ between single agent BCNU versus combination therapy. When stratified based on dose (150mg/m2), there was no statistically significant difference between the two groups with respect to grade 3 and 4 neutropenia or thrombocytopenia. CONCLUSIONS : This is the first study to report the toxicity of carmustine with or without bevacizumab for the treatment of recurrent and refractory HGG. The addition of bevacizumab to carmustine did not increase incidence or grade of hematologic toxicity when compared to single agent carmustine.

PURPOSE: Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM). METHODS: We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600mg PRF (in 4 divided doses on day 1) followed by 100mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort. RESULTS: Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n=16): the PFS6 rate was 0%, median PFS was 1.58 months [95%CI: (1.08, 1.84)], median overall survival was 3.68 months [95%CI: (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n=14). CONCLUSIONS: PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.

2010 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are known oncogenic drivers in a variety of tumor types. Larotrectinib is a highly selective, CNS-active TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset of patients. Methods: Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Larotrectinib was administered at 100 mg twice daily (BID) in adults and 100 mg/m2 (max 100 mg) BID in pediatric patients. Response was investigator-assessed. Results: As of July 2021, 38 adult and pediatric patients with TRK fusion primary CNS tumors were identified: high-grade glioma (HGG; n =23), low-grade glioma (LGG; n =9), and other (n =6; includes glioneuronal, neuroepithelial, diffuse leptomeningeal, neuroblastoma, recurrent small round blue cell, and not otherwise specified). Median age at enrollment was 10.8 years (range 1.3–79.0; 28 [74%] patients < 18 years old). The gene fusions involved NTRK2 (n = 28), NTRK1 (n = 6), and NTRK3 (n = 4). Sixteen (42%) patients received one prior line of systemic therapy and 16 (42%) received ≥2 prior lines. The ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥24 weeks), and five progressive disease. The 24-week DCR was 73% (95% CI 56–86) for all patients, 68% (95% CI 45–86) for patients with HGG, and 89% (95% CI 52–100) for patients with LGG. Twenty-five of 31 patients (81%) with measurable disease at baseline had tumor shrinkage. Median time to response was 1.9 months. Median duration of response (DoR) was not reached; median follow-up was 25.6 months. The 12-month DoR rate was 64%. Median progression-free survival (PFS) was 16.5 months (95% CI 6.7–not estimable); median follow-up was 27.4 months. Median overall survival (OS) was not reached; median follow-up was 26.7 months. The 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Twenty-two patients (58%) progressed on treatment and three continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) were reported in 21 patients (55%); the majority of these patients (18/21 [86%]) reported Grade 1 or 2 TRAEs. No Grade 3 or higher treatment-related neurological adverse events were reported. There were no treatment discontinuations due to TRAEs. Conclusions: Larotrectinib achieved a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

BACKGROUND Medical therapies for recurrent brain tumors are limited. Abemaciclib is a small molecule CDK4/6 inhibitor that has demonstrated antitumor activity in multiple cancer types and crosses the blood-brain barrier. METHODS We conducted a phase II trial of single-agent abemaciclib in patients with recurrent primary brain tumors utilizing a novel CNS basket trial design with multiple tumor types accrued to separate cohorts including patients with recurrent IDH-wildtype gliomas (Cohort A), any recurrent gliomas requiring cytoreductive surgery (Cohort B), and any other recurrent primary brain tumors (Cohort C) including IDH-mutant gliomas, meningiomas, and other tumor types. In all patients, abemaciclib was administered orally at 200mg twice daily for each 28-day cycle. In cohort B abemaciclib was administered 4-7 days prior to surgery then resumed after recovery. Neuroimaging disease assessments were performed every two cycles. Cohorts were individually assessed for efficacy, tumoral molecular characteristics, and exploratory biomarker analyses. Next generation sequencing was performed on patients who had prior surgery. RESULTS To date, a total of 61 patients have enrolled and initiated treatment with abemaciclib. Cohort A enrolled 9 patients with IDH-wildtype WHO grade II and III astrocytomas. Cohort B enrolled 10 patients with astrocytomas of varying IDH-status. Cohort C is a diverse group of 42 patients including 22 treatment-refractory meningiomas, 10 IDH-mutant gliomas (5 astrocytomas, 5 oligodendrogliomas), 3 ependymomas, 3 primary CNS lymphomas, 2 pituitary tumors, 1 glioneuronal rosette forming tumor, and 1 diffuse midline glioma. A total of 7 grade 3 toxicities occurred in 6 patients: fatigue (3), neutropenia (2), colitis (1) and seizure (1); no grade 4 toxicities occurred. CONCLUSIONS We present the results of a novel CNS basket trial looking at the efficacy of abemaciclib across multiple recurrent primary brain tumors. Efficacy results will be presented, highlighting an update on promising results in the 22 patients with recurrent meningiomas.

BACKGROUND NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for patients with TRK fusion cancer, with a 75% objective response rate (ORR) in 206 evaluable patients with various non-CNS cancers (Hong et al, ASCO 2021). We report data on patients with TRK fusion-positive primary CNS tumors. METHODS Patients with TRK fusion-positive primary CNS tumors in 2 clinical trials (NCT02637687, NCT02576431) were identified. Objective responses were investigator-assessed. RESULTS As of July 2020, 33 patients with TRK fusion-positive primary CNS tumors were identified (19 high-grade gliomas [HGG], 8 low-grade gliomas [LGG], 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, 1 small round blue cell tumor). Median age was 8.9 years (range 1.3-79.0). Patients were heavily pre-treated, with 45% having ≥ 2 prior systemic therapies. ORR was 30% (95% CI 16-49): 3 complete responses (all pediatric), 7 partial responses, 20 stable disease, and 3 progressive disease. ORR in patients with HGG and LGG were 26% (95% CI 9-51) and 38% (95% CI 9-76), respectively. Median time to response was 1.9 months. Responses were seen regardless of the number of prior systemic therapies. The 24-week disease control rate was 73% (95% CI 54-87). Median PFS was 18.3 months (95% CI 6.7-not estimable [NE]) and median overall survival (OS) was not reached (95% CI 16.9-NE) at a median follow-up of 16.5 months; 12-month OS rate was 85% (95% CI 71-99). Treatment duration ranged from 1.2 to 31.3+ months. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 3 patients (9%). There were no treatment discontinuations due to TRAEs. CONCLUSIONS In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and favorable safety regardless of age or number of prior systemic therapies.

This study explores the repeated use of glucarpidase following HD-MTX in patients with CNSL. HD-MTX requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase 50 units(u)/kg for delayed MTX clearance results in a reduction of systemic MTX levels without crossing the blood brain barrier. This study explores the use of 1000 or 2000 units of glucarpidase following repeated cycles of MTX 3–8 g/m2. Eligible adult patients had isolated CNSL, CrCl ≥ 60 mL/min, and KPS ≥ 50. Rituximab with MTX was administered for eight cycles. Glucarpidase was given 24 hours after each MTX infusion. MTX concentrations were monitored in serum and cerebrospinal fluid (CSF). Twelve patients enrolled to date and data are available for 50 doses of MTX (3 g/m2 (20), 6 g/m2 (21), 8 g/m2 (9)). Glucarpidase 1000u (14) or 2000u (36) resulted in at least a 95% reduction in serum MTX levels within 15 minutes following 49/50 doses. A 93% decrease was seen with the remaining dose. Glucarpidase was not detected in the CSF of 7 patients analyzed. Potentially cytotoxic MTX concentrations (10–6 M) were observed in CSF 1 hour (7/7) and 6 hours (4/7) after glucarpidase administration. Radiographic responses are evaluable in 9 patients: complete response (5), partial response (2), stable disease (1), and progressive disease (1). No grade 3 events were attributed to glucarpidase; one grade 4 event of anaphylaxis occurred. Anti-glucarpidase antibodies were detected in 2/5 patients analyzed. In summary, administration of low-dose glucarpidase 24 hours after MTX 3–8 g/m2 results in a reproducible rapid reduction in serum MTX levels in non-renally impaired patients. CSF MTX levels remain therapeutic and clinical response expected from MTX-based therapy does not appear compromised. Anti-glucarpidase antibodies may develop though significance remains unclear. Study is ongoing. Future directions will explore glucarpidase use for reduction of inpatient stay with HD-MTX.

Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P

BackgroundIntraparenchymal hemorrhage (IPH) is a relative contraindication to bevacizumab therapy, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody approved for the treatment of recurrent glioblastoma. However, in patients with symptomatic enhancing tumors and poor functional status, bevacizumab may be the only beneficial therapeutic option.MethodsWe retrospectively reviewed all patients with high-grade glioma who were treated between January 1, 2005 and December 31, 2014 with bevacizumab despite prior IPH.ResultsEighteen patients met our study criteria. There were 12 women and 6 men with a median age of 56 years. Tumor types were glioblastoma (n = 15), anaplastic astrocytoma (n = 2), and anaplastic oligodendroglioma (n = 1). Seventeen patients had prior spontaneous intratumoral bleed (13 grade 1–2; 4 grade 3–4); the 1 remaining patient had a grade 3 bleed due to cerebral venous thrombosis. Among them, identifiable risk factors for hemorrhage were anti-VEGF therapy, anticoagulation use, thrombocytopenia, and hypertension; seven had no identifiable risk factors. The median duration from IPH to (re-)initiation of bevacizumab was 113 days (range 13–1367). Brain imaging performed prior to bevacizumab treatment showed persistent or evolving hemorrhage in 8 patients and complete resolution in 10 patients. With a median follow-up duration of 137 days after bevacizumab re-initiation, only 1 (6%) of the 18 patients re-bled; this patient had an anaplastic oligodendroglioma and developed a grade 2 intratumoral bleed after 3 doses of bevacizumab.ConclusionsThe incidence of re-bleed is rare. Bevacizumab use was safe in patients with recurrent high-grade glioma following IPH for whom no other meaningful treatment options existed.

Leptomeningeal metastases (LM) is associated with limited survival and treatment options for patients with solid tumor malignancies. While focal radiotherapy is effective for local palliation, it lacks durability due to cerebrospinal fluid (CSF) tumor cells reseeding. Craniospinal irradiation (CSI) in contrast treats the entire central nervous system (CNS) compartment thus potentially improves disease control. We performed a phase IB study of proton CSI using 30CGE in 10 fractions for treating solid tumor LM (NCT03520504). The primary end point is dose-liming toxicity (DLT) within 1 month of treatment. Clinical outcomes and CSF circulating tumor cells (CTCs) by CellSearch® were evaluated. Overall (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates. Of the 24 patients enrolled, 4 were excluded from analysis: 3 did not complete treatment due to CNS or systemic disease progression (PD), and 1 completed treatment outside study window. The majority of patients had metastatic lung (55%) and breast (30%) malignancies. At this submission, the median follow-up was 2.8 months (0.5–9.4 months). No DLT was observed. Treatment-related grade 2+ toxicities were: fatigue (G2=43%), anorexia (G2=5%), anemia (G2=10%), thrombocytopenia (G3=5%, G2=10%), and leukopenia (G3=14%, G2=14%). Median survival is not reached with 17 patients (85%) alive with stable/improved LM including 2 with durable CNS control for >9 months, 1 patient alive with CNS and systemic PD at 3.7 months, 2 patients died at 3.6 and 5.1 months with CNS and systemic PD. At 3-month, OS and PFS were 100% and 90% (95% CI 100–72%), respectively. In the 13 patients with CSF CTCs evaluation, decreased quantifiable CTCs at 1-month after proton CSI correlated significantly with improved CNS PFS (log-rank p=0.014). These early findings suggest that proton CSI is a safe and potentially effective treatment for patients with solid tumor LM. CSF biomarkers assessment is needed to better elucidate predictors of response.

Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

2002 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types, including central nervous system (CNS) tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across 175 adult and pediatric patients with various non-CNS cancers (McDermott et al, ESMO 2020). We report data on patients with TRK fusion-positive primary CNS tumors. Methods: Patients with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified: 19 high-grade gliomas (HGG), 8 low-grade gliomas (LGG), 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, and 1 small round blue cell tumor. The patients had gene fusions involving NTRK2 (n = 24; 73%), NTRK1 (n = 5; 15%), and NTRK3 (n = 4; 12%). Median age was 8.9 years (range 1.3–79.0); 26 patients were pediatric ( < 18 years). Patients were heavily pre-treated with 45% having 2 or more prior lines of systemic therapy. The ORR in all patients was 30% (95% CI 16–49): 3 complete responses (all in pediatric patients), 7 partial responses (2 pending confirmation), 20 stable disease (including 15 pts > 6 months), and 3 progressive disease. The ORR in patients with HGG and LGG were 26% (95% CI 9–51) and 38% (95% CI 9–76), respectively. In all patients, the 24-week disease control rate was 73% (95% CI 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The median time to response was 1.9 months. Median duration of response (DoR) was not reached (95% CI 3.8–not estimable [NE]) at a median follow-up of 12.0 months. The 12-month DoR rate was 75% (95% CI 45–100). Median PFS was 18.3 months (95% CI 6.7–NE) at a median follow-up of 16.5 months. Median overall survival (OS) was not reached (95% CI 16.9–NE) at a median follow-up of 16.5 months, with a 12-month OS rate of 85% (95% CI 71–99). Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events (TRAE) were reported by 20 patients and were Grade 3–4 in 3 patients (9%). There were no treatment discontinuations due to TRAEs. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile. These results support testing for NTRK gene fusions in patients of all ages with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

Background Glioblastomas treated with bevacizumab may develop low-signal apparent diffusion coefficient (low-ADC) lesions, which may reflect increased tumor cellularity or atypical necrosis. The purpose of this study was to examine the relationship between low-ADC lesions and overall survival (OS). We hypothesized that growing low-ADC lesions would be associated with shorter OS. Methods We retrospectively identified 52 patients treated with bevacizumab for the first (n = 42, 81%) or later recurrence of primary glioblastoma, who had low-ADC lesions and 2 post-bevacizumab scans ≤90 days apart. Low-ADC lesion volumes were measured, and normalized 5th percentile histogram low-ADC values were recorded. Using OS as the primary endpoint, semiparametric Cox models were fitted to ascertain univariate and multivariate hazard ratios (HRs) with significance at P = .05. Results Median OS was 9.1 months (95% CI = 7.2-14.3). At the second post-bevacizumab scan, the volume of the low-ADC lesion (median: 12.94 cm(3)) was inversely associated with OS, with larger volumes predicting shorter OS (HR = 1.014 [95% CI = 1.003-1.025], P = .009). The percent change in low-ADC volume (median: 6.8%) trended toward increased risk of death with growing volumes (P = .08). Normalized 5th percentile low-ADC value and its percent change were not associated with OS (P > .51). Also correlated with shorter OS were the pre-bevacizumab nonenhancing volume (P = .025), the first post-bevacizumab enhancing volume (P = .040), and the second post-bevacizumab enhancing volume (P = .004). Conclusions The volume of low-ADC lesions at the second post-bevacizumab scan predicted shorter OS. This suggests that low-ADC lesions may be considered important imaging markers and included in treatment decision algorithms.

Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab. Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1. Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT. Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.

Meningioma is the most common primary brain tumor, comprising 35% of all CNS tumors in the United States.1 Approximately 80% of meningiomas are World Health Organization (WHO) grade I and may be observed expectantly or treated successfully with surgery or radiotherapy. However, the remaining 20% are either WHO grade II (atypical) or grade III (anaplastic or “malignant”) and have high recurrence rates, exceeding 50% for atypical tumors and 80% for anaplastic tumors. Despite maximal surgical resection and radiotherapy, a subset of these patients will recur and require additional treatment, but there is no proven effective chemotherapy for patients with aggressive meningiomas. Studies investigating traditional chemotherapies (temozolomide, hydroxyurea, irinotecan, and triple therapy with cyclophosphamide + doxorubicin + vincristine), hormonal therapies (progesterone and estrogen modulators, somatostatin analogues), interferon alfa-2b, and molecularly targeted therapies, including inhibitors of platelet-derived growth factor receptors (PDGFRs; imatinib) and epidermal growth factor receptor (gefitinib and erlotinib), have all been disappointing.2–19 Although the natural history of these tumors is not well established, the 6-month progression-free survival (PFS6) rate for these patients is poor. A phase II study of imatinib in recurrent meningioma demonstrated a PFS6 of 0% in the atypical/anaplastic cohort.19 PDGF is a ubiquitous growth factor driving cell proliferation in normal development as well as numerous neoplasms, including meningiomas.20–25 Administration of PDGF-BB to meningioma cells in culture results in stimulation of tumor growth, while administration of anti–PDGF-BB antibodies inhibits proliferation.26,27 Vascular endothelial growth factor (VEGF) is upregulated in almost all meningiomas and has been associated with neovascularization, tumor growth, and the development of edema.28,29 Targeting VEGF with different agents has proved effective in several different cancers, including malignant gliomas.30,31 Targeting this pathway may have therapeutic potential in meningioma. Sunitinib malate (SU011248, Sutent, Pfizer) is an orally administered tyrosine kinase inhibitor targeting VEGF receptor (VEGFR), PDGFR, and KIT.32 Inhibiting these targets represents an attractive therapeutic approach for recurrent meningiomas. The FDA-approved and recommended dose for sunitinib in renal cell carcinoma and gastrointestinal stromal tumor is 50 mg daily for 4 of every 6 weeks. We selected this dose because meningiomas are extraparenchymal tumors. Given (i) the strong preclinical rationale for targeting PDGFR and VEGFR in meningiomas, (ii) the efficacy of sunitinib cotargeting VEGFR2 and PDGFR, and (iii) its safety in adults with other solid tumors, we investigated sunitinib in this phase II study for recurrent and progressive meningiomas that had failed prior surgery and radiation.

BACKGROUND: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. This trial combines the pan-PI3K inhibitor copanlisib with Ibrutinib in patients with r/r PCNSL. METHODS: Eligible patients had r/r PCNSL, age≥18, ECOG≤2, normal end-organ function, and an unrestricted number of CNS directed prior therapies. Ibrutinib was given orally daily; copanlisib intravenously on days 1, 8, and 15 of each 28-day cycle. RESULTS: Six patients have been enrolled so far and received copanlisib at 60 mg and ibrutinib at 560 mg. Median age was 68 (range 50-77); 3 were women. Median ECOG was 1 (0: 2, 1: 3, 2: 1). All had recurrent parenchymal disease. Three had additional cerebrospinal fluid (CSF) involvement. Two had received prior single-agent ibrutinib. Initially, no prophylactic antimicrobial treatment was required. PCP prophylaxis was made mandatory after one patient developed PCP pneumonia leading to a grade 5 lung infection. Four patients are still on trial and one withdrew due to personal choice. Two grade 4 adverse events were observed in 2 patients (LFT elevation, lymphopenia); four grade 3 events in 3 patients (rash, lymphopenia, LFT elevation). The most common toxicities at any grade were transient, infusion-related hyperglycemia and hypertension. No Aspergillus infections have been observed. Enrollment into the next dose level (copanlisib 60 mg, ibrutinib 840 mg) is ongoing. After a median follow-up of 180 days (range 46-249), all patients were evaluated for response with an overall response rate of 67% with 1 CR, 3 PR, 1 SD and 1 PD as best response. CONCLUSION: Treatment with copanlisib and ibrutinib in patients with PCNSL has manageable adverse events after initiation of mandatory PCP prophylaxis. Clinical response was seen in 67% of patients. Disclosures Grommes: Squipps: Speakers Bureau; Kite: Consultancy; BTG: Consultancy. OffLabel Disclosure: The combination of the BTK inhibitor ibrutinib and the pan PI3K inhibitor copanlisib in recurrent PCNSL will be discussed

146 Background: A multidisciplinary clinic (MDC) is a pilot project in the MSK Department of Neurology designed to improve quality of care and patient satisfaction. The MDC enables the patient to receive coordinated care from multiple providers (eg a physical therapist, physiatrist, nutritionist, social worker, case manager, spiritual advisor, and neurologist) in one location in one longer visit. This approach is new, and few patients (pts) have had the opportunity to experience the MDC. We hypothesized that giving the patient information about the MDC will increase the MDC volume. Methods: This is a prospective quality improvement study from June 14, 2018 to July 20, 2018 conducted in four Neuro-Oncology clinics. Pts with primary or metastatic central nervous system (CNS) cancers were identified prior to the visits in their regular oncology clinic. Pts were asked if they were interested in receiving verbal or written information (brochure) about the MDC. For each patient, we recorded if they agreed to receive information, what information they received, and whether they scheduled an appointment at the MDC. We also recorded patient demographics, CNS cancer type, and whether they were accompanied by caregivers. Results: We approached 41 pts. Of the 41 pts, 31(74%) were accompanied by caregivers. Median patient age was 58 (range, 24-79) years. 26 (62%) were female. CNS cancers were primary brain tumors in 31 (76%) and brain metastases in 10 (24%). 27 (64%) of 41 pts agreed to receive both verbal information and a brochure. The remaining 14 (36%) pts did not want to receive more information about the MDC; of these, one patient didn’t take a brochure, 2 pts resided out of the country, and one patient said all needs had been addressed. Within 4 weeks of this pilot study four (15%) of 27 pts scheduled an appointment in the MDC clinic for upcoming dates. Conclusions: Among our pts with CNS tumors visiting their oncologists, 64% were willing to receive information about the MDC, four (15%) made an appointment with the MDC. More study is needed to facilitate education about and access to the MDC; to identify potential barriers; and to obtain longer follow-up.

Radiotherapy with concomitant temozolomide followed by adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma,1 but the optimal regimen for recurrent disease has not been defined. Clinical trials in recurrent glioblastoma have reported dismal outcomes, with objective response rates (ORRs) of 5%–6%, 6-month progression-free survival rates (PFS6) of 9%–21%, and median overall survival (OS) of 6–7 months.2–6 Treatment with numerous targeted and nontargeted agents has been attempted without success, with the exception of bevacizumab.7–9 This agent received accelerated FDA approval for recurrent glioblastoma, based on improved ORRs of 20%–26% seen in 2 phase II trials.8,9 However, responses tend to be short-lived (median: 4 months), and OS has been modest (median: 8–10 months). Metronomic temozolomide has emerged as a well-tolerated salvage approach in recurrent glioblastoma.10–15 Preclinical studies have suggested that metronomic temozolomide may result in increased activity through depletion of the O6-methylguanine-DNA methyltransferase (MGMT) protein16 and anti-angiogenic properties through targeting of endothelial cells.17,18 A phase II study19 using metronomic, daily temozolomide (50 mg/m2/d) for glioblastoma at first relapse investigated 3 pre-established cohorts: patients with progression before completion of 6 adjuvant cycles (“early” group), patients with progression after 6 cycles while still on temozolomide (“extended” group), and patients who discontinued temozolomide after completing 6 cycles without progression (“rechallenge” group). The extended group did not seem to benefit (PFS6: 7%), but the early and rechallenge groups achieved PFS6 of 27% and 36%, respectively. However, these results are difficult to interpret because there are no historical controls for either of these cohorts. Moreover, results in the early group could have represented inclusion of patients with pseudoprogression, while patients in the rechallenge group could have harbored tumors with a different biology. It is also unclear how these results apply to current treatment trends in the United States, where temozolomide tends to be continued beyond 6 cycles and the use of bevacizumab is frequent. We report a phase II trial using a similar regimen of temozolomide 50 mg/m2 daily but encompassing eligibility criteria similar to available historical controls and typical clinical trials in glioblastoma,4,20 with no restriction on timing of failure with respect to previous temozolomide use. We also performed an exploratory, comprehensive disease-specific mutational analysis to characterize the typical population of patients entering studies of recurrent malignant gliomas (MGs) from a molecular perspective.

High-grade gliomas of the spinal cord are rare tumors, traditionally managed with surgery and radiotherapy. Once patients fail standard treatment, many receive some chemotherapy, although the data supporting such is limited. We reviewed our experience treating high-grade gliomas of the spinal cord with standard intracranial regimens including temozolomide and bevacizumab. Outcomes investigated include radiographic response, clinical response, progression-free survival, and overall survival. We identified eight patients who were treated with temozolomide and six who were treated with bevacizumab. Temozolomide was administered to three patients at initial diagnosis and five patients at recurrence after failing prior radiotherapy. For the recurrent patients, the median time-to-progression was 6.6 months (range 1-40 months) and the median overall survival from initiation of temozolomide was 16.6 months (range 1.2-64.5 months). We identified six patients who received bevacizumab at the time of recurrence. MRI demonstrated a partial response in five patients which also correlated with clinical improvement. The median time to progression was 20.7 months (range 3.3-29.9 months) and median overall survival was 22.8 months (range 3.3-31.8 months). This retrospective review suggests that temozolomide and bevacizumab may be beneficial in spinal cord high-grade gliomas. The compact architecture of the spinal cord makes bevacizumab a particularly appealing agent due to the drug's effect on peritumoral edema and mass effect.

BACKGROUND The aim of this study was to assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) PET-CT and dynamic contrast-enhanced (DCE) MRI in differentiating tumor progression and radiation injury in patients with indeterminate enhancing lesions after radiation therapy (RT) for brain malignancies. METHODS Patients with indeterminate enhancing brain lesions on conventional MRI after RT underwent brain DCE-MRI and PET-CT in a prospective trial. Informed consent was obtained. Lesion outcomes were determined by histopathology and/or clinical and imaging follow-up. Metrics obtained included plasma volume (Vp) and volume transfer coefficient (K(trans)) from DCE-MRI, and maximum standardized uptake value (SUVmax) from PET-CT; lesion-to-normal brain ratios of all metrics were calculated. The Wilcoxon rank sum test and receiver operating characteristic analysis were performed. RESULTS The study included 53 patients (29 treated for 29 gliomas and 24 treated for 26 brain metastases). Progression was determined in 38/55 (69%) indeterminate lesions and radiation injury in 17 (31%). Vpratio (VP lesion/VP normal brain, P < .001), K(trans) ratio (P = .002), and SUVratio (P = .002) correlated significantly with diagnosis of progression versus radiation injury. Progressing lesions exhibited higher values of all 3 metrics compared with radiation injury. Vpratio had the highest accuracy in determining progression (area under the curve = 0.87), with 92% sensitivity and 77% specificity using the optimal, retrospectively determined threshold of 2.1. When Vpratio was combined with K(trans) ratio (optimal threshold 3.6), accuracy increased to 94%. CONCLUSIONS Vpratio was the most effective metric for distinguishing progression from radiation injury. Adding K(trans) ratio to Vpratio further improved accuracy. DCE-MRI is an effective imaging technique for evaluating nonspecific enhancing intracranial lesions after RT.

BACKGROUND: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in various B-cell malignancies. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. METHODS: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL, systemic disease needed to be absent. All patients needed to have at least one prior CNS directed therapy. RESULTS: Forty-four patients were enrolled; 3 received ibrutinib at 560mg and 41 at 840mg. Median age was 68 years (range 21-90); 20 were women. Median ECOG was 1 (0: 11, 1: 22, 2: 11); 29 had PCNSL and 15 SCNSL; 61% had recurrent disease. Twenty-four had isolated parenchymal disease, 4 isolated cerebrospinal fluid (CSF) involvement and 16 both. No grade 5 event has been observed. Eleven patients experienced 12 grade 4 adverse events: neutropenia (in 5 patients), lymphopenia (2), ALT elevation (1), combined ALT/AST elevation (1), sepsis (1), and pneumonitis (1). Seventeen patients experienced 35 grade 3 adverse events (most common: lymphopenia in 4, ALT elevation (3), hyperglycemia (3), urinary tract infection (3), decreased WBC (2), lung infection (2), and thrombocytopenia (2)). Treatment was stopped due to adverse events in 3 patients (grade 4 pulmonitis, grade 4 liver toxicity, grade 3 infectious encephalitis). Twenty-four patients did not experience ≥3 grade adverse events. The most common toxicities at any grade were thrombocytopenia (73%), hyperglycemia (55%), anemia (43%), hypercholesterolemia (43%) and hypertriglyceridemia (43%) of which most were grade 1/2. Only 1 Aspergillus infection has been observed in a patient with chronic steroid use. After a median follow-up of 22 months (range 1.5-39), 40/44 patients were evaluated for response (4 did not complete at least 15 days of drug treatment due to deteriorating clinical status or withdrawal from study). Overall response was 78% (31/40; 81% (22/27) in PCNSL; 69% (9/13) in SCNSL) with 17 CR, 14 PR, 4 SD and 5 PD as best response. The median PFS is 4 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 16.5 months). The median overall survival is 19.5 months. CONCLUSION: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 78% of CNS lymphoma patients. Disclosures No relevant conflicts of interest to declare.

BACKGROUND: Though the genomic landscape of primary gliomas has been well characterized by The Cancer Genome Atlas, the genetic determinants of malignant transformation and response to therapy remains poorly understood. MATERIAL AND METHODS: Prospective clinical sequencing was performed on 1,004 gliomas from 923 patients. This dataset includes primary and recurrent tumors and contains detailed clinical annotation, including review of the patients’ imaging. RESULTS: We investigated the germline and somatic attributes of IDH1/2-wildtype and IDH1/2-mutant tumors at the time of diagnosis and recurrence. 13% of patients harbored either a pathogenic or likely pathogenic germline mutation, whereof 29% arose in genes mediating DNA repair. In astrocytomas, agnostic of IDH status, cell cycle alterations were depleted in low-grade tumors. Moreover, mutations in effectors of the cell cycle were associated with the development of enhancing disease in IDH-mutant astrocytomas but not oligodendrogliomas. IDH-mutant astrocytomas with a cell-cycle alteration have a significantly shorter progression-free survival from recurrence compared to tumors without a cell cycle alteration (median 2. 5 vs. 35. 3 months, HR 3. 25, log-rank p-value 0. 00061). Based on our data, hypermutation appears to occur exclusively in the context of pre-existing cell cycle alterations in astrocytic tumors, regardless of IDH status. We next correlated molecular findings with clinical behavior and treatment response and defined subsets of gliomas that are uniquely susceptible to targeted treatment and have a differential prognosis. CONCLUSION: Cell-cycle alterations are lineage-specific alterations associated with aggressive disease in glioma. Targeted genomic sequencing can identify subsets of tumors with a greater sensitivity to treatment and a better prognosis.

BACKGROUND: Bevacizumab is approved for the treatment of recurrent glioblastoma (GBM) and has been associated with clinical improvement and steroid reduction. ICH is a contraindication to bevacizumab therapy. However, in patients with symptomatic enhancing tumors and poor Karnofsky performance status, bevacizumab may be the only beneficial treatment option. METHODS: We retrospectively reviewed patients with recurrent malignant glioma who were treated with bevacizumab despite prior ICH at our center. RESULTS: Five patients (3 males; 2 females) with a median age of 51 years (range 20-60 years) were identified. All patients developed intratumoral bleed (three grade 2; two grade 1); one was receiving bevacizumab and two were on anticoagulation for systemic venous thrombosis. The mean volume of ICH was 9.4 cm3 (range 0.2-39.5 cm3). After a median duration of 61 days (range 14-140 days) from the ICH, bevacizumab was started or resumed at the standard dose of 10 mg/kg every two weeks. Brain imaging performed immediately prior to bevacizumab treatment showed persistent or evolving hemorrhage in four patients and complete resolution of ICH in one patient. Following bevacizumab therapy, all patients achieved initial clinical improvement. One patient received bevacizumab while intubated, was successfully extubated but developed other systemic complications, and died 42 days after receiving bevacizumab; post-bevacizumab CT brain scan was stable without ICH progression. The other four patients were followed clinically and radiographically for a median duration of 4 months (range 1.4-22 months) and did not demonstrate any evidence of recurrent or worsening ICH on brain imaging. CONCLUSIONS: In this case series, although small, bevacizumab use was safe in patients with recurrent malignant glioma following ICH for which no other meaningful treatment options existed.

High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154.

Purpose We previously reported a series of patients treated with high-dose methotrexate (MTX) -based chemotherapy, with or without whole brain radiotherapy. The purpose of this report is to update the initial results and provide long-term data regarding overall survival, patterns of relapse, and the risk of treatment-related neurotoxicity. Patients and Methods Fifty-seven patients with an average age of 65 and median Karnofsky performance score of 70 were treated; all patients have been observed longitudinally with serial magnetic resonance imaging scans and neurologic examinations. Results The overall median survival was 51 months with a median follow-up of 115 months for surviving patients. Twenty-five patients relapsed or developed progressive disease; median progression-free survival was 129 months. Seventeen patients developed treatment-related neurotoxicity; all but one had received whole brain radiotherapy as a component of treatment. Seventy-four percent of patients younger than 60 years who received both MTX-based chemotherapy and whole brain radiotherapy were alive at last follow-up. Median survival for patients older than 60 years was 29 months regardless of whether or not they received whole brain radiotherapy. Conclusion Long-term follow-up of our initial cohort confirms the observation of excellent overall survival, particularly for those patients younger than age 60 at diagnosis. For older patients, it appears to be reasonable to defer whole brain radiotherapy in an effort to minimize treatment-related neurotoxicity.

7515 Background: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in Mantle cell lymphoma, CLL, Marginal Zone, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. Methods: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Twenty-five patients were enrolled (3 at 560 mg; 22 at 840 mg). Median age was 68 (range 21-85); 15 were women. Median ECOG was 1 (0: 2, 1: 15, 2: 8). 64% had PCNSL and 36% SCNSL; 68% had recurrent disease. Seventeen had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 5 both. Seven grade 4 adverse events were observed in 7 patients neutropenia (in 3 patients), lymphopenia (2), sepsis (1), and ALT elevation (1). Fourteen patients developed 20 grade 3 toxicities, including lymphopenia in 5 patients, hyperglycemia in 3, ALT elevation in 2, thrombocytopenia in 2, lung infection in 2, AST elevation in 1, neutropenia in 1, urinary tract infection in 1, colitis in 1, febrile neutropenia in 1 and fungal encephalitis in 1. The most common toxicities at any grade were hyperglycemia, thrombocytopenia and anemia of which most were grade 1/2. No grade 5 events have been observed. After a median follow-up of 414 days (range 289-674), 22/25 patients were evaluated for response (3 did not complete at least 15 days of drug treatment). Over all response was 68% (17/22; 77% (17/22) in patient that completed at least 15 days of drug treatment) with 10 CR, 7 PR, 2 SD and 3 PD as best response. The median PFS is 4.6 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 15.3 months). The median overall survival has not been reached. Conclusions: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 68% of CNS lymphoma patients. Clinical trial information: NCT02315326.

BACKGROUND: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range between 30-60% with a PFS of 2-5 months. Ibrutinib has shown promising clinical response in Mantel cell lymphoma, CLL, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. METHODS: Eligible patients had r/r PCNSL or Secondary CNS Lymphoma (SCNSL), age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. RESULTS: Twenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69 (range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. Five grade 4 adverse events were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (2)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1, urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 193 days, 19/20 patients were evaluated for response: 8 CR, 7 PR, 1 SD and 3 PD; 75% (15/20) ORR. The median PFS is 7.29 months (95% CI: 3.80-15.43 months (longest: 15.3 months)). The mean Ibrutinib concentration in the CSF 2h post administration at day 1 and 29 is 1.75 ng/mL (3.97 nM) and 2.51 ng/mL (5.6 nM) which is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells.An additional treatment arm has been added to the trial which will evaluate adverse events of the combination of ibrutinib and high-dose methotrexate chemotherapy. Enrollment into the combination arm is ongoing and updates will be presented at the meeting. CONCLUSION: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Drug concentrations in CSF are higher at steady state (day 29) and meaningful CSF concentrations are reached. Clinical response was seen in 75% of CNS lymphoma patients. A combination arm will assess the adverse events of ibrutinib in combination with high-dose methotrexate chemotherapy. Disclosures No relevant conflicts of interest to declare.

2064Background: CTO is an oral inhibitor of non-voltage-dependent calcium signaling that results in simultaneous modulation of several receptor-mediated calcium-dependent signaling pathways. This s...

Background. Bevacizumab, a monoclonal antibody targeting a vascular endothelial growth factor (VEGF) protein, has been reported to induce mucosal toxicities. However, the clinical characteristics of these particular toxicities have not been well characterized. We aimed at providing a detailed clinical description of signs and symptoms limited to the tongue mucosa in patients treated with bevacizumab. Methods. A retrospective review of medical records and clinical photographs was performed with specific attention to clinical presentation, evolution, associated symptoms, concomitant medications, and treatment methods. Results. In total, four patients presented to the dermatology service with clinical findings characterized by multifocal, erythematous circinate and serpiginous erosions on the dorsal tongue surrounded by white hyperkeratotic rims that were temporally related to bevacizumab therapy. Associated increased sensitivity to spicy foods was frequently observed. Conclusion. These characteristic clinical findings are consistent with geographic tongue. However, large prospective evaluations are necessary to confirm this potential relationship. If bevacizumab is indeed associated with geographic tongue, increased awareness may result in improved reporting and characterization of this particular adverse event.

Purpose Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM. Patients and Methods Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m2 days 1 to 7 and 15 to 21) or metronomic (50 mg/m2 continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status. Results Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm). Conclusion Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.

Purpose To investigate the efficacy and safety of the combination of vinorelbine and intensive temozolomide for recurrent or progressive brain metastases from solid tumors. Methods Patients ≥18 years of age and with Karnofsky performance scale (KPS) ≥ 60, adequate organ function and progressive or recurrent brain metastases were eligible. This was a phase II trial with 28-day cycles using temozolomide (150 mg/m2, days 1–7 and 15–21) and vinorelbine 25 or 30 mg/m2 on days one and eight. The primary endpoint was objective radiographic response. Results Thirty-eight patients (15 men, 23 women) with a median age of 57 years (range, 39–75) and median KPS of 80 were enrolled. The primary tumor sites were lung (n = 20), breast (n = 11), colorectal (n = 2), kidney (n = 2), bladder (n = 1), endometrium (n = 1), head and neck (n = 1). Prior therapies included chemotherapy (97%), whole-brain radiation therapy (79%), brain metastasis resection (53%) and stereotatic radiosurgery (47%). Objective radiographic response rate was 5% (one complete response and one minor response); five patients had stable disease, 29 progressive disease and two patients were not evaluable. Twenty-nine patients (76%) have died and the median follow-up of survivors was six months. Median progression-free and overall survivals were 1.9 and 5 months, respectively. Grade 3/4 toxicities were mainly hematological and two patients discontinued the study due to myelosuppression. Conclusions In this heavily pretreated population of patients with brain metastases, adding vinorelbine and increasing the intensity of temozolomide do not improve response rates compared to previous studies with single-agent temozolomide at standard doses.