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Purpose: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. Experimental Design: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green–Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. Results: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. Conclusions: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma. Clin Cancer Res; 19(4); 900–8. ©2012 AACR.

2055Background: Microtubule inhibitors have demonstrated efficacy in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by subtherapeutic dose delivery. Designed to overcome this limitation, TPI 287 is a third-generation taxane that readily penetrates the blood brain barrier and evades mechanisms of P-glycoprotein mediated efflux. CB-017 is a multi-center phase 1/2 trial designed to determine the maximum tolerated dose and potential efficacy in patients treated with TPI 287 plus bevacizumab (BEV) for treatment of recurrent GBM. Results of the recently completed dose escalation stage of the trial are reported. Methods: GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks via IV infusion. MRIs were obtained every six weeks with response assessed via RANO. TPI-287 dose escalation was based upon a standard 3+3 design....

Introduction Primary angiosarcoma of the brain is extremely rare; only 15 cases have been reported in adults over the last 25 years. Case presentations We describe two cases of primary angiosarcoma of the brain that are well characterized by imaging, histopathology, and immunohistochemistry. Case 1: our first patient was a 35-year-old woman who developed exophthalmos. Subtotal resection of a left extra-axial retro-orbital mass was performed. Case 2: our second patient was a 47-year-old man who presented to our facility with acute visual loss, word-finding difficulty and subtle memory loss. A heterogeneously-enhancing left sphenoid wing mass was removed. We also review the literature aiming at developing a rational approach to diagnosis and treatment, given the rarity of this entity. Conclusions Gross total resection is the standard of care for primary angiosarcoma of the brain. Adjuvant radiation and chemotherapy are playing increasingly recognized roles in the therapy of these rare tumors.

Cilengitide, a cyclicized arginine–glycine–aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor–stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

To analyse patterns of failure in patients with glioblastoma multiforme treated with concurrent radiation and temozolomide.A retrospective review of patients treated with concurrent radiation and temozolomide was performed. Twenty patients treated at the University of Alabama at Birmingham, with biopsy-proven disease, documented disease progression after treatment, and adequate radiation dosimetry and imaging records were included in the study. Patients generally received 46 Gy to the primary tumour and surrounding oedema plus 1 cm, and 60 Gy to the enhancing tumour plus 1 cm. MRIs documenting failure after therapy were fused to the original treatment plans. Contours of post-treatment tumour volumes were generated from MRIs showing tumour failure and were overlaid onto the original isodose curves. The recurrent tumours were classified as in-field, marginal or regional. Recurrences were also evaluated for distant failure.Of the 20 documented failures, all patients had some component of failure at the primary site. Eighteen patients (90%) failed in-field, 2 patients (10%) had marginal failures, and no regional failures occurred. Four patients (20%) had a component of distant failure in which an independent satellite lesion was located completely outside of the 95% isodose curve.Radiation concurrent with temozolomide appears to be associated with a moderate risk of distant brain failure in addition to the high rate of local failure. The risk of distant failure was consistent with that observed with radiation alone, suggesting that temozolomide does not act to reduce distant brain failure but to improve local control.

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.

Objective To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Design Phase 1 dose-escalation clinical trial. Setting Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Interventions Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Main Outcome Measures Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. Results There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. Conclusions ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

Objective: Patients with malignant glioma (MG) must make ongoing medical treatment decisions concerning a progressive disease that erodes cognition. We prospectively assessed medical decision-making capacity (MDC) in patients with MG using a standardized psychometric instrument. Methods: Participants were 22 healthy controls and 26 patients with histologically verified MG. Group performance was compared on the Capacity to Consent to Treatment Instrument (CCTI), a psychometric measure of MDC incorporating 4 standards (choice, understanding, reasoning, and appreciation), and on neuropsychological and demographic variables. Capacity outcomes (capable, marginally capable, or incapable) on the CCTI standards were identified for the MG group. Within the MG group, scores on demographic, clinical, and neuropsychological variables were correlated with scores on each CCTI standard, and significant bivariate correlates were subsequently entered into exploratory stepwise regression analyses to identify multivariate cognitive predictors of the CCTI standards. Results: Patients with MG performed significantly below controls on consent standards of understanding and reasoning, and showed a trend on appreciation. Relative to controls, more than 50% of the patients with MG demonstrated capacity compromise (marginally capable or incapable outcomes) in MDC. In the MG group, cognitive measures of verbal acquisition/recall and, to a lesser extent, semantic fluency predicted performance on the appreciation, reasoning, and understanding standards. Karnofsky score was also associated with CCTI performance. Conclusions: Soon after diagnosis, patients with malignant glioma (MG) have impaired capacity to make treatment decisions relative to controls. Medical decision-making capacity (MDC) impairment in MG seems to be primarily related to the effects of short-term verbal memory deficits. Ongoing assessment of MDC in patients with MG is strongly recommended.

We have previously demonstrated safety of G207, a doubly mutated (deletion of both gamma(1)34.5 loci, insertional inactivation of U(L)39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky scoreor=70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 x 10(9) plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.

2033 Background: Mibefradil (MIB) is a selective T-type calcium channel blocker that had previously been approved for treatment of hypertension. MIB has shown significant preclinical activity in ma...

2009 Background: EGFRvIII, a constitutively active EGFR deletion driver mutation, is associated with poor long-term survival in glioblastoma (GB). The investigational vaccine rindopepimut consists ...

Pleomorphic xanthoastrocytoma (PXA) is an uncommon low grade astrocytic tumor and molecular alterations commonly observed in other WHO grade II gliomas, such as TP53 mutation, EGFR amplification, 1p19q deletion, are rarely seen. A 25-year-old woman experienced generalized seizures; a left temporal lesion in was identified in 2001. Resections were performed in 2004 and 2011 with a diagnosis of PXA, WHO grade II. The patient was treated with radiation and chemotherapy, but recurrence was found in 2013. The pathology of the craniotomy resection showed tumor necrosis and increased proliferation index (25% by Ki-67), and the diagnosis of PXA with anaplastic features exhibiting leptomeningeal infiltration was rendered, which likely represented malignant transformation. Targeted next-generation sequencing analysis was performed at Genomic Pathology Service (Washington University). A potentially actionable BRAF gene mutation (p.V600E) as well as potentially relevant TP53 gene p.R158H mutation was identified. The patient is on Vemurafenib and the lesion is stable on MRI. PXA has been shown to have BRAF mutations in 60–70% of cases. PXA with anaplastic features is a rare entity and has significantly worse prognosis. Vemurafenib is suggested to cross the blood-brain barrier and the patients with BRAF mutated brain tumors would benefit from BRAF targeted therapies.

Tumor-associated seizures and epilepsy in patients with primary malignant brain tumors constitute a major healthcare challenge. Seizures and antiepileptic drugs (AEDs) used in their management significantly impact patients' quality of life; there is a dearth of information regarding the actual effects of AEDs on cortical irritability, as measured by electroencephalograms (EEGs). Herein, we investigated the effects of various AEDs on the presence or absence of epileptiform discharges (EDs) in glioma patients. METHODS: We identified 210 patients with a pathologically confirmed diagnosis of primary glioma and who had at least 1 EEG at our institution from 01/01/2009 to 12/31/2013. EEGs were independently reviewed and scored for the presence of EDs and current AEDs were recorded. RESULTS: "Last available" EEGs were reviewed on 149 patients (M = 75, F = 74, mean age at time of EEG = 51 SD-14.2). Eighty-five percent of patients had high-grade glioma (HGG) and 15% had low-grade glioma (LGG). EDs were identified in 34.2% of all patients; in 27.3% of those with LGG and in 35.8% of those with HGG. We noted that patients with HGG had a higher incidence of EDs in the EEG than those with LGG, however this difference was not significant (35.8% vs. 27.3%, p = 0.44). Further, we did not observe a specific effect of any of the AEDs used on the presence/absence of EDs (p > 0.05 for levetiracetam, phenytoin, valproate, lacosamide, zonisamide, or topiramate). CONCLUSIONS: Our retrospective data indicate that there is no correlation between AED(s) used and cortical irritability as measured by EEG in patients with gliomas. This is an interesting and important observation. Prospective clinical trials are needed to assess the role of EEG in guiding treatment decisions, as related to AED therapy and choice in this population and the value of pre-treatment EEG as a possible biomarker for the development of tumor-related epilepsy needs to be evaluated.

BACKGROUND: The RNA-binding protein, HuR is over-expressed in glioma and controls mRNA stabilization and translation in centrosomes. Alterations in HuR phosphorylation promote centrosomal abnormalities. METHODS: Primary and established glioma cell lines were utilized. Subcellular fractionation and immunofluorescence techniques were used to confirm localization of HuR in the PCM. Immunoprecipitation and kinase assays were used to document HuR interaction with and phosphorylation by SRC and ABL1. RESULTS: HuR association with the pericentriolar matrix (PCM) is growth factor dependent and facilitates centrosome amplification and genomic instability in glioma. The SRC and ABL1 kinases are possible regulators of the HuR association with pericentriolar matrix and phosphorylate HuR. CONCLUSIONS: HuR is involved in the regulation of genomic instability through growth factor and centrosome dependent pathways in glioma. We provide the evidence of HuR regulation by SRC and ABL1 kinases in U251 cells and discuss molecular and cellular consequences of this interaction. SECONDARY CATEGORY: n/a.

A 52-year-old woman presented with a clinical picture consistent with bacterial meningitis 3 years after functional endoscopic sinus surgery. Diagnosis of a cerebrospinal fluid (CSF) fistula was made clinically, and the site of the fistula was confirmed using magnetic resonance cisternography. The utilization of this technique in the diagnosis of CSF disorders is gaining popularity. Its usefulness in the context of other imaging modalities is discussed.

LBA2009 Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). Methods: This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. Results: 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. Conclusions: CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. Clinical trial information: NCT00689221.

LBA2009 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

2044 Background: VEGF and PDGF receptors are overexpressed in glioblastoma (GBM). Both receptor families may be important therapeutic targets. We explored early biologic markers of VEGFR-2 or PDGFRa inhibition with functional MRI. Methods: A subset of patients (pts) from a multicenter phase II study of monoclonal antibodies to VEGFR-2 (ramucirumab 8mg/kg IV q2wks) or PDGFRa (olaratumab 20mg/kg IV q2wks) in adult patients with recurrent GBM underwent a standardized MRI brain protocol with dynamic contrast enhanced (CE); diffusion tensor; perfusion weighted and routine sequences at -1d, +1d, +28d and every +56d from treatment initiation. ACRIN performed site qualification and imaging QA. Regions of CE and T2w hyperintensity were manually defined; percent change in volumes and change in normalized image intensities was calculated. Results: 28 patients were evaluable. Pts receiving ramucirumab (n=11; 7 male) had a median age of 54 (43-67), KPS 90 (70-100) and Dex dose 2mg (0-8). Pts receiving olaratumab (n=17; 14male) had a median age of 58 (24-72), KPS 80 (70-100) and Dex dose 2mg (0-4mg). KPS and Dex were stable over time. Conclusions: Preliminary results show that within 1 day of ramucirumab, CE volume, relative CE intensity and blood volume decreased and by 28 days, T2 volume and ADC decreased suggesting a potent antiangiogeneic effect. PDGFRa inhibition had no effect on lesion volume, but reduced relative CE intensity and blood volume at 28 days. Clinical efficacy results are anticipated in mid-2013. Clinical trial information: NCT00895180. [Table: see text]

2054 Background: Despite high vascularity, duration of response of glioblastoma (GBM) to anti-angiogenic therapy is short. One proposed mechanism of resistance is via co-option of native brain blood vessels and tumor infiltration into normal appearing brain. We designed a Phase I study of cediranib, a VEGFR tyrosine kinase inhibitor, in combination with cilengitide, an integrin inhibitor, to block this infiltrative relapse. Methods: A phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent GBM. Once the MTD was determined, 40 patients enrolled in a dose expansion cohort. Standard eligibility criteria were included and all patients needed to have at least 1 cm of residual disease to assess tumor response. In the dose expansion cohort, 20 patients had received prior anti-VEGF therapy and 20 had never received anti-VEGF therapy. The primary endpoint was the safety of cediranib with cilengitide. Secondary endpoints were overall survival, the proportion of patients alive and progression free at 6 months (APF6), radiographic response (RR), and exploratory analyses of advanced MRI (perfusion, permeability, diffusion imaging) and blood biomarkers. Results: Forty-five patients were enrolled with a median age of 54 (23-80) and a median KPS 80 (60-100). No DLTs were observed and the MTD was cediranib 30mg daily and cilengitide 2000 mg twice weekly. There were no unexpected Grade 3 or 4 toxicities. Thirty patients experienced disease progression, 8 patients went off study for toxicity, and 5 patients withdrew from the study. Thirty nine patients have died. Partial response was seen in 2 patients, stable disease in 13, progression in 21, and 7 patients were not evaluable for RR. Median OS was 6.4 months, median PFS was 2.4 months, and APF6 was 7.5%. Conclusions: Combination cediranib/cilengitide was well tolerated but the median PFS/OS, APF6, and RR were not very promising. Ongoing analysis of the correlative imaging and blood biomarkers may shed light on a subset of patients who might benefit from this regimen and if anti-VEGF therapy blocked the penetration of cilengitide into the tumor. Clinical trial information: NCT00979862.

Experimental and clinical evidence suggest that vitamin D protects against several types of cancer by promoting cell differentiation and apoptosis and by inhibiting cell proliferation and angiogenesis. In vitro evidence supports a similar protective function in glioma; however, no study has examined whether common genetic variants in the vitamin D pathway are related to glioma risk or patient outcome. We evaluated these potential associations in a clinic-based case-control study conducted at medical centers in the southeastern US. Genotyping was performed in 623 newly diagnosed (eg. nonrecurrent) glioma cases (including 343 WHO grade IV glioblastomas (GBM); 148 WHO grade II or III astrocytomas, 95 oligoastrocytomas and oligodendrogliomas, and 37 gliomas with unspecified histology) and 631 healthy controls with no history of brain tumors. A total of 7 candidate tagging single nucleotide polymorphisms (SNPs) were genotyped in the vitamin D receptor (VDR at 12q13) including rs2107301, rs2238135, rs4516035, rs731236 (Taq1), rs1544410 (Bsm1), rs11568820 (Cdx2), and rs2228570 (Fok1). SNPs associated with serum concentrations of 25-hydroxy vitamin D in genome-wide association studies (GWAS) were also evaluated including rs1155563, rs12512631, rs2282679, and rs7041 in GC (4q12-q13), rs10741657 in CYP2R1 (11p15), rs6013897 in CYP24A1 (20q13), rs3829251 in NADSYN1 (11q13), and rs6599638 at C10orf88 (10q26). Genotyping was performed in oral DNA samples using Illumina GoldenGate and Taqman OpenArray assays. Logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to vitamin D genotypes. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for glioma-related death among 439 patients with high grade tumors including GBM and high grade astrocytomas (331 deaths; median Kaplan-Meier survival: 15.0 months). GWAS SNPs in NADSYN1, GC, and C10ORF88 were not associated with glioma risk or patient survival. Risk associations limited to GBM were observed for rs2238135 in the VDR (G>C; minor allele frequency (MAF) = 0.20) (per variant allele OR = 1.31; 95% CI: 1.01 to 1.71; p for trend = 0.04) and for GWAS SNP rs10741657 located near CYP2R1 (G>A; MAF = 0.40) (per variant allele OR = 0.79; 95% CI: 0.63 to 0.98; p for trend = 0.03). The variant allele in CYP24A1 rs6013897 (T>A; MAF = 0.20) was associated with prolonged survival among patients with high grade tumors (per variant allele HR = 0.79; 95% CI: 0.59 to 0.97; p for trend = 0.03) in patients uniformly treated with the current standard of care (surgery, radiation and temozolomide). To our knowledge this is the first report suggesting that genetic variation in vitamin D related genes may be a determinant of glioma risk and outcome. Further studies are needed to confirm these results and identify the putative causal variant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2629. doi:1538-7445.AM2012-2629

2010 Background: Epidermal growth factor receptor (EGFR) is over-expressed in ~50% of glioblastoma (GBM); approximately half express the constitutively active mutant receptor EGFRvIII. Afatinib (A)...

2010 Background: Prognosis of patients with recurrent glioblastoma multiforme (GBM) is poor. Cilengitide is an investigational selective αvβ3/5 integrin inhibitor with multiple anti-tumor effects. ...

2012 Background: TMZ and radiotherapy (RT) improve survival in patients with glioblastoma multiforme. However, DNA repair mechanisms confer resistance to these therapies. Inhibition of PARP1, a cri...

TPS151 Background: Expected median survival is poor for patients with glioblastoma multiforme (GBM). Cilengitide, an investigational selective αvβ3/5 integrin inhibitor, has demonstrated antitumor activity against GBM in previous phase II studies. CORE (cilengitide in combination with temozolomide [TMZ] and radiotherapy [RTX]) will assess the efficacy and safety of 2 regimens of cilengitide in GBM patients with an unmethylated MGMT promoter. The study is a companion trial to CENTRIC, which includes patients with newly diagnosed GBM with methylated MGMT promoter. Methods: CORE is a phase II, randomized, multicenter, open-label, controlled, trial investigating 2 regimens of i.v. cilengitide in combination with standard therapy [RTX/TMZ then TMZ; Stupp et al NEJM 2005] vs standard therapy alone (2:2:1 ratio). The 2 cilengitide regimens compare 2,000 mg twice weekly vs. 2,000 mg 5 times weekly on each day of RTX during 6 weeks of RTX/TMZ, followed by cilengitide 2,000 mg twice-weekly combined with TMZ, follow...

e14507 Background: Pre-clinical studies demonstrate TM601 binding to glioblastoma, melanoma, and other tumor types in vitro and in vivo (human xenograft tumors in mice). Here we report imaging and safety data from a Phase I clinical trial in patients with recurrent metastatic somatic and/or cerebral solid tumors that received IV 131I-TM601. Methods: Patients received an IV imaging test dose of 10 mCi/0.2mg 131I-TM601. Subjects not showing tumor localization, received a second imaging test dose of 20 mC/0.4mg 131I-TM601. Subjects without localization at either dose were dropped from study; patients showing tumor localization without toxicity then received a 30 mCi/0.6mg 131I-TM601 IV injection. The primary objectives were to: 1) determine whole body localization and dosimetry, 2) estimate the maximum tolerated dose based on normal tissue dosimetry and 3) determine the acute toxicity of IV 131I-TM601. Results: A total of 44 evaluable patients received IV doses of 131I-TM601 without dose-limiting toxicity. 31/44 (70%) showed tumor specific uptake on follow-up gamma camera or SPECT imaging. Tumor-specific uptake was observed in patients with malignant glioma (7/8), metastatic melanoma (7/7), non-small cell lung cancer (3/4), colon cancer (6/7), pancreatic cancer (2/3), prostate cancer (2/2), breast cancer (1/4) and in one evaluable patient each with transitional cell carcinoma, pleomorphic xanthoastrocytoma and metastatic paraganglioma. Notably, all patients with metastatic cerebral disease showed tumor-specific uptake of systemically injected 131I-TM601. No uptake was seen in CNS lymphoma (n=1), ovarian (n=2), small cell lung (n=2), or medulllary thyroid cancers (n=1). Conclusions: Tumor-specific uptake of IV 131I-TM601 in primary and metastatic (including brain) solid tumors suggests that further dose escalation is warranted. Notably, IV injected 131I-TM601 crossed the blood brain barrier. Based on normal tissue dosimetry from this study, future clinical trials will evaluate safety and therapeutic efficacy in patients with recurrent glioma and metastatic melanoma at doses up to 100 mCi 131I-TM601 (maximum single dose). [Table: see text]

2010 Background: R-(-)-gossypol (AT-101) is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of racemic gossypol demonstrated objective responses in patients with malignant glioma. The objectives of this trial were to determine the efficacy and safety of the more active (-) enantiomer of gossypol (AT-101) in patients with recurrent GBM. Methods: Fifty-six patients with recurrent GBM were enrolled in this multi-institution phase II clinical trial through the NABTT CNS consortium designed to detect a 33% increase in overall survival (OS, primary endpoint) from 5 to 6.65 months with Power/Alpha 80%/0.01. All patients had received prior radiation and none had received more than two prior treatments. Patients taking P450-inducing anticonvulsants were not eligible. AT-101 was administered at 20 mg PO per day for 21 of 28 days in repeated cycles. Radiographic assessment of tumor response was made at q 8-week intervals. Results: Fifty-six patients were enrolled with a median age of 59 (range 34–79) and KPS of 80 (range 60–100). Grade 3 or greater adverse events possibly or probably related to AT-101 included fatigue (n = 2), ileus (n = 1), elevated cardiac troponin T levels (n = 1), elevated GGT (n = 1), and thrombocytopenia (n = 1). Response data is available for 43 patients. OS determination is ongoing. Seven patients (16%) had stable disease as the best response. One partial response (centrally reviewed) was observed. No complete responses were observed. Although treatment is ongoing, two patients are without progression after more than 7 months of therapy. Conclusions: AT-101 is well tolerated and without unique toxicities in patients with recurrent GBM. Further follow-up will determine the impact of AT-101 on OS and whether any tissue correlate is predictive of efficacy. No significant financial relationships to disclose.

e13006 Background: Postoperative radiotherapy for glioma has been shown to improve survival with increased radiation doses. Dose escalation of external beam radiotherapy or brachytherapy is limited by normal brain radionecrosis. Radiolabeled targeting molecules can deliver localized radiation to tumor and reduce normal brain radionecrosis. TM601, or synthetic Chlorotoxin, is a peptide derived from scorpion venom that specifically binds to tumor cells. Here we report dosimetry results of an imaging sub-study of a phase II trial, in which weekly doses of 131I-TM601 were infused into surgically created tumor resection cavities for 3 or 6 weeks. Methods: Five out of 76 patients treated in a phase II trial were imaged after receiving 1, 3, or 6 doses of 40 mCi/0.8 mg 131I-TM601 intracavitarily. For each imaging study, 5 sequential SPECT images (1–168 hour) were registered with MRI to determine the 131I-TM601 radiation dose to the 2-cm tumor cavity margin. Five sequential body scans were also acquired to determine 131I-TM601 radiation dose to extra-cranial organs. Results: 131I-TM601 is a rapidly penetrating and clearing radiolabeled peptide. The median residual activity in the cavity at 7 days post injection was 8.4%. Median radiation dose to the cavity margin was 121 cGy/mCi and ranged 52- 338 cGy/mCi in 5 subjects. The median coefficient of variation (intra-patient inter-fraction) for the 2-cm margin dose was 14.7% and ranged 7.1–18.9%. Median tumor cavity volume was 11.4 mL, and ranged 5.2 - 35.5 mL. There was no observed correlation between the 2-cm margin dose and the cavity volume. Median radiation dose to thyroid, kidneys, red marrow, and body was 8.3, 1.3, 0.4, and 0.6 cGy/mCi, respectively. Conclusions: Radiation dose ratio for 2-cm cavity margin-to-normal tissues was quite high. While intra-patient reproducibility was relatively good, cumulative effect of the residual activity was only meaningful within a week. These results support the multi-dose fractionation scheme for 131I-TM601 to minimize normal tissue toxicity, including radiation necrosis, and extend continuous irradiation to clinical or sub-clinical residual tumor cells after surgery. [Table: see text]

2023 Background: ABT-510 (Abbott Laboratories, Abbott Park, IL, USA) is a Thrombospondin-1 (TSP-1) mimetic drug with anti-angiogenic properties. This phase I dose escalation trial was designed to study the maximum tolerated dose (MTD) of ABT 510 when used concurrently with temozolomide (TMZ) and radiotherapy (RT) in patients with newly diagnosed glioblastoma multiforme (GBM). Methods: A total of 23 patients with newly diagnosed, histologically verified GBM were enrolled between April 2005 and January 2007, after obtaining written consent. The study was approved by the University of Alabama at Birmingham (UAB) Institutional Review Board. Four cohorts with three patients in each, receiving subcutaneous ABT 510 injection at doses of 20, 50, 100, and 200 mg/day were studied. The starting dose was primarily based on preclinical findings from animal studies and phase I studies on healthy subjects and cancer patients. Treatment plan included 10 weeks of induction phase (TMZ and RT with ABT 510) followed by a maintenance phase (ABT 510 and TMZ) of 14 cycles each consisting of 28 days. Patients were monitored with brain MRI along with laboratory values for dose limiting toxicities (DLT) defined as grades 3–4 non-hematological toxicities and grade 4 hematological toxicities (neutropenia or thrombocytopenia). In the absence of a DLT in at least two of the three patients, the dose was increased by 50% in the next cohort of patients. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression and survival statistics were analyzed. Results: During this trial, grade 3/4 DLT were not observed even after the dose was increased to 200 mg/day, hence, the last cohort was expanded to include 14 patients. A MTD was not defined. The median time to tumor progression (TTP) was 220 days and the median overall survival was 422 days. Gene expression analysis of the tumor pathology will be performed to evaluate the relationship between the expression of TSP-1, TSP-2, and patient response to the drug. Conclusions: ABT 510, at subcutaneous doses up to 200 mg/day, is tolerated well with concurrent TMZ and RT in patients with newly diagnosed GBM. No significant financial relationships to disclose.

2039 Background: Platelet-derived growth factor signaling is important in gliomagenesis and PDGFR-β is expressed on >90% of endothelial cells in glioblastoma specimens. Methods: We report the results of a feasibility and phase I study of tandutinib (MLN518), an orally bioavailable, quinazoline-based inhibitor of type III receptor tyrosine kinases including PDGFR-β, FLT-3, and c-Kit, in patients with recurrent glioblastoma (GBM) conducted in the New Approaches to Brain Tumor Therapy (NABTT) consortium. Results: A feasibility study was conducted in 6 recurrent GBM patients in whom resection was clinically indicated. These patients received tandutinib 500-mg BID for 7 days prior to resection. In these patients, the drug was measured in tumor tissue and plasma samples obtained shortly before and after the resection by LC/MS. The mean ± SD concentration of tandutinib in tumor tissue was 7.2 ± 3.2 μg/mL and the mean ratio of its concentration in brain tumor-to-plasma was 9.6 ± 7.7. A phase I study was conducted in 19 patients to determine the MTD in this recurrent GBM population with sequential assessment of the following dose levels: 500-, 600-, and 700-mg BID. Four patients were replaced due to early withdrawal unrelated to toxicity. Dose limiting toxicities were observed in 1/6 patients at 500-mg BID (grade 3 phosphorous, grade 3 fatigue, grade 3 somnolence in 1 patient); 1/6 patients at 600-mg BID (grade 3 phosphorous); 2/3 patients at 700-mg BID (grade 3 fatigue, grade 3 weakness). 600-mg BID was declared the MTD and a phase II study has been initiated at this dose level. Conclusions: The mean brain tumor tissue-to-plasma ratio of tandutinib in GBM patients receiving 500-mg BID exceeded the estimated threshold ratio of 0.33 that was considered as being necessary to achieve local cytotoxic concentrations in brain tumors. The MTD of tandutinib in the recurrent GBM population is 600-mg BID. A phase II trial has been initiated at this dose level. [Table: see text]

2001 Background: EMD 121974 (cilengitide) is a selective integrin receptor inhibitor that is well tolerated and has demonstrated biological activity in patients with malignant glioma. The objectives of this phase II trial were to determine safety when combined with chemoradiation and estimate the overall survival for two different doses in newly diagnosed GBM. Methods: A total of 112 patients were accrued onto the trial through the NABTT CNS consortium. Cilengitide was administered by one-hour infusion twice a week with 18 patients treated in a safety run-in phase of 6 patients at the tested dose levels of 500 mg, 1000 mg, and 2000 mg. After safety completion, 94 patients were randomly assigned to either 500 mg or 2000 mg groups. To date, 55 out of 112 (49%) patients have died. Overall survival was estimated using all patients in this trial regardless of their treating dose. Results: The median age was 55 years old (range: 22–88) and the median KPS was 90 (range: 60–100). 86 out of the 112 (76.8%) had a craniotomy as their initial surgical procedure and 25 patients (22%) had a biopsy. There were no DLTs during the safety run-in phase. The estimated median survival time is 18.9 months (95% CI: 16.3 -30.0 months) for patients treated with RT+TMZ+EMD. The trial was closed to accrual on December 31, 2007. To date, 89 out of 112 patients were alive 12 months from their initial diagnosis. The overall survival at 12 months for all patients is 79.5% (95% CI: 71–87%). MGMT methylation status and survival based on dose levels received are not currently available. Conclusions: EMD 121974 (cilengitide) is well-tolerated when combined with standard chemoradiation (TMZ+RT) and may improve survival for patients newly diagnosed with GBM given the substantial differences between the estimated median survival and that seen in the EORTC study (Stupp, N Engl J Med, 2005). [Table: see text]

2041 Background: TM601, a synthetic chlorotoxin, is a peptide derived from scorpion venom. In vitro data demonstrate binding to vascular endothelial cells, and blockage of endothelial cell invasion. In vivo, intravenous infusion of TM601 decreases neovascularization. Based on this work and previous clinical trials demonstrating tumor-specific uptake of 131I-TM601 in malignant glioma after IV delivery, a phase I trial was initiated with intravenous unlabeled TM-601. Methods: Six patients with recurrent glioblastoma have been enrolled. All patients received a test dose of 10 mCi 131I-TM601 to demonstrate tumor-specific uptake prior to TM601 treatment at doses of 0.04 mg/kg IV weekly for 3 weeks in a 4 week cycle. Treatment continued until tumor progression. Patients were evaluated at week 4 of each cycle with conventional and dynamic susceptibility contrast MRI (DSC-MRI) to assess perfusion. Anatomic and perfusion MRI evaluations were performed at baseline, 1 day after the initiation of TM601 therapy, and 21 days after initiation of each treatment cycle. MRI data were post-processed to yield an arterial input function and parametric hemodynamic maps. Results: With respect to safety, there has been one intratumoral hemorrhage that was considered to be possibly related to therapy. Three other serious adverse events considered to be unrelated to therapy included disease progression on therapy, a hip fracture and renal calculi in a patient with a history of renal calculi. Two of six patients in the first dosing cohort have demonstrated a greater than 25% reduction in relative cerebral blood flow (rCBF) and/or relative cerebral blood volume (rCBV) compared to baseline. Both patients with improvement in perfusion MRI had extended response to intravenous TM601. Conclusions: Intravenous unlabeled TM601 at the initial dose schedule produces measurable changes in perfusion MRI parameters which correlate with clinical response. Perfusion MRI parameters appear to correlate with clinical response to TM601 and are consistent with angiogenic inhibition. [Table: see text]

2042 Background: G207 is a doubly mutated (deletion of both γ134.5 loci, insertional inactivation of UL39) herpes simplex virus (HSV)-1. Safety and efficacy of intracerebral inoculations of G207 to patients suffering from recurrent malignant gliomas have been demonstrated in previous clinical trials. Methods: In this phase I clinical trial, a total of 1 x 109 plaque forming units (pfu) G207 were administered by five stereotactic injections of 0.2 mL each into regions of recurrent malignant glioma defined by MRI, followed by focal radiation therapy 24 hours post injection. Included patients suffered from inoperable pathologically proven recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) which was progressive despite radiotherapy or chemotherapy and failed external beam radiotherapy > 5 Gray prior to study enrolment. Results: 9 patients were treated in this phase I study. 5 patients were suffering from relapsed GBM, 4 patients were suffering from relapsed AA. 1 month after treatment, 3 patients (3xGBM) showed SD, 2 patients (1xGBM, 1xAA) PR, and 4 patients (1xGBM, 3xAA) PD. The 2 patients with initial PR (1xGBM, 1xAA) were re-treated with G207/Irradiation at time point of tumor recurrence, showing PR one month after re-treatment again. Median overall survival time for all 9 patients was 229 days (7.6 months), with one patient still alive at time of abstract submission. In patients suffering from relapsed GBM, mOS was 7.4 months, in patients suffering from relapsed AA, mOS was 9.25 months. 20 serious adverse events occurred in this study, only 3 were possible/probable related to G207/irradiation. Within persistent areas of tumor, HSV staining was present by using a polyclonal antibody for HSV, indicating intratumoral G207 replication (proof of concept). Conclusions: In 9 patients suffering from relapsed GBM or AA, stereotactic intracerebral G207 inoculation followed by radiation therapy was feasible, safe, and induced clinically relevant responses. G207/Irradiation re-treatment was possible and induced anew clinical responses. Median overall survival is superior to published data in this patient population. Therefore, further clinical development of G207 in GBM is medically reasonable. [Table: see text]

2003 Background: Many novel agents are being studied in combination with radiation and temozolomide (RT+TMZ) in newly diagnosed glioblastoma using survival as the primary endpoint. These single arm phase II studies generally plan to compare their results with those reported from the phase III EORTC RT+TMZ study (Stupp, NEJM, 2005). Methods: The NABTT CNS Consortium has completed accrual to three RT+TMZ+ novel agent studies using the same eligibility criteria. A total of 281 patients with newly diagnosed glioblastoma were enrolled. The novel agents included talampanel (72 pts), poly ICLC (97 pts), and cilengitide (112 pts). The survival data emerging from these three single arm phase II studies was compared with the published EORTC data. Results: The median age, KPS, and percent undergoing debulking surgery for EORTC patients was 56, 86% (WHO 0–1), and 84% and for NABTT patients receiving talampanel 60, 90, and 77%, poly ICLC 56, 90, 86%, and cilengitide 55, 90, and 76%. A total of 247 patients (88%) were ages 18–70 making them comparable to the EORTC patient population. Currently available survival data for these NABTT and EORTC studies are provided below. MGMT methylation status and survival based on dose levels are not currently available. Conclusions: Survival of newly diagnosed glioblastoma patients treated with RT+TMZ + novel agents at 9 NABTT institutions accruing from 2005 to 2008 appears increased compared to RT+TMZ at 85 EORTC institutions accruing from 2000 to 2002. These results do not appear related to a specific effective agent. As a result, caution should be exercised when comparing outcomes from recently conducted Phase II studies in this patient population to published EORTC data. [Table: see text] No significant financial relationships to disclose.

2058 Background: Sorafenib (BAY 43–9006) is a small molecule inhibitor of multiple kinases to include raf, VEGF receptors, and PDGF receptors. The molecule has demonstrated anti-proliferative and anti-angiogenic activity in a number of in vitro and in vivo model systems. Methods: In this multi-institutional trial, we have conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Cohorts of 3 patients, stratified based on the use of enzyme inducing anticonvulsants (EIAC) or not (non-EIAC), have completed enrollment through the following dose levels: 200 mg, 400 mg, 600 mg, and 800 mg. Therapy has been given as a twice daily oral administration with cycles of 28 day duration. Results: A total of 35 patients have been enrolled and are evaluable for toxicity. Treatment related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematological toxicity, and grade 4 hematological toxicity (platlets and ANC) or febrile neutropenia of any duration. The following DLTs were observed: one grade 3 hand-foot-syndrome at the 400 mg BID (EIAC), one grade 3 puritis 400 mg BID (non-EIAC) dose level, grade 3 hand/foot syndrome 800 mg BID (EIAC and non-EIAC arms), grade 3 hypophosphatemia 800 mg BID (EIAC), and grade 3 joint pain 800 mg BID (EIAC). A MTD of 600 mg BID has been defined for the EIAC arm with 3/6 DLTs at 800 mg BID. A MTD has not been defined and enrollment has been completed through the 800 mg BID dose level for the non-EIAC. Of the enrolled patients, 20 are with glioblastoma multiforme (GBM), 8 with anaplastic astrocytoma (AA), and 7 with anaplastic oligodendroglioma (AO). Conclusions: The MTD for sorafenib is 600 mg BID for patients on EIAC. Sorafenib is well tolerated with limited toxicities to doses of 800 mg twice daily in patients with recurrent malignant glioma not on EIAC (non-EIAC arm). No significant financial relationships to disclose.

2048 Background: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1–4 brain metastases treated with radiosurgery without whole brain radiation therapy. Methods: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase II trial of radiosurgery (15–24 Gy) and adjuvant temozolomide. Temozolomide was started within 14 days of radiosurgery and was administered 150–200 mg/m2 p.o. q day x 5 days in 28 day cycles. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. If more than 4 metastases were identified on the MRI performed on the day of radiosurgery, then the patient could still be treated on the clinical trial if all tumors could be treated with radiosurgery. In addition to clinical and radiographic follow-up, QOL was assessed utilizing the FACT-Br questionnaire. Results: Twenty-five patients were enrolled 2002–2005; three were not evaluable for determining DBF. Of the remaining twenty-two patients, tumor types included NSCLC (n=8), melanoma (n=7), other (n=7). Extracranial disease was present in ten (45%) patients. The median number of tumors was 3 (range 1–6). The median overall survival was 31 weeks. The median radiographic follow-up for patients that did not develop DBF was 33 weeks. Six patients developed DBF. The one year actuarial risk of DBF was 37%. Patients with melanoma had a higher risk of DBF than other patients (p No significant financial relationships to disclose.

1555 Background: 131I-chlorotoxin is a peptide originally derived from scorpion venom that will specifically bind to tumor cells targeting lamellipodia and produces a variety of secondary messenger effects through phosphatidyl inositol signaling. Preclinical studies suggest it is both a radiation and chemotherapy sensitizer. A previous phase I/II clinical trial defined the distribution and dosimetry of single injection intracavitary 131I-chlorotoxin and suggested clinical activity in patients with recurrent glioma. Methods: 15 patients with recurrent GBM after prior treatment (radiation therapy), were enrolled in this sequential, multiple-dose escalation study with re-resection and implantation of a ventricular access device (VAD) into the resection cavity. Dose limiting toxicity was defined as any grade 3 or greater toxicity judged probably related to study drug and occurring within 7–11 days of the last dose. Dosing cohorts of 3–5 patients were entered at each of the listed dose levels designed to maintain a constant drug specific activity. Results: One subject did not complete treatment due to thrombocytopenia possibly related to a VAD infection necessitating removal of the VAD following the initial dose of study drug. Eight serious adverse events (SAEs) were observed in 15 patients after study drug administration. These included seizure, cerebral edema, and gait disturbances. None were judged to be both unexpected and related to study drug. No dose limiting toxicity was observed. Two subjects experienced Grade 1/2 CTC 3.0 neutropenia. Conclusions: The safety profile of weekly intracavitary injections of 131I-chlorotoxin was acceptable. Dose limiting toxicity was not reached at the final planned dose level D (6 x 40 mCi/0.8 mg peptide, total 240 mCi), which is the maximum practical dose. Accrual to the randomized phase II portion of this trial comparing three vs. six weekly injections began 12/2005. [Table: see text] [Table: see text]

1567 Background: Bortezomib is a selective inhibitor of the proteasome that has been approved for the treatment of multiple myeloma and has also shown promising evidence of clinical activity against solid tumors. This study was undertaken to determine the maximum tolerated dose (MTD), toxicity profile, and biologic activity of bortezomib for the treatment of recurrent malignant glioma (MG). Methods: Eligible patients (pts) had supratentorial progressive MG upon radiotherapy and ≤ 1 prior regimen of chemotherapy. Dose escalation was conducted separately for pts taking enzyme inducing antiseizure drugs (EIASD+) and for those not (EIASD-). Bortezomib was given by bolus iv injection on weeks 1 and 2 of each 3 week cycle of therapy. The starting dose in both groups was 0.9 mg/m2. Cohorts of at least 3 patients were evaluated at each dose level. 20S proteasome activity was determined in whole blood lysates before and at 1 and 24 h after the first dose. Results: Fifty-nine evaluable pts (41 male/18 female) with a median age of 51 years and median KPS of 90% have been enrolled. All but 2 pts had received 1 prior chemotherapy regimen. In the EIASD- group, the weekly dose was escalated from 0.9 to 1.9 mg/m2 through 3 intermediate dose levels, with 1.7 mg/m2 established as the MTD. DLT experienced by 2 of 6 pts in the 1.90 mg/m2 dose level were grade 3 thrombocytopenia and grade 3 fatigue plus neurosensory toxicities. In the EIASD+ group, the dose has been escalated to 2.3 mg/m2 without the occurrence of any DLT. Ten additional EIASD- pts were treated at 1.7 mg/m2, with the most common adverse events being thrombocytopenia and peripheral neuropathy. The extent of proteasome inhibition in whole blood increased in a dose-dependent manner in both treatment groups. Mean proteasome inhibition in EIASD+ pts 1 h after receiving 2.1 mg/m2 of bortezomib (77 ± 12%) was similar to the 1.7 mg/m2 dose in EIASD- pts (79 ± 6%). Conclusions: The MTD for the weekly x 2 schedule of bortezomib in EIASD- patients, 1.7 mg/m2, is higher than the approved dose of 1.3 mg/m2 for the treatment of multiple myeloma. The enhanced tolerability of the drug when given together with EIASDs, for which the MTD is at least 2.1 mg/m2, is consistent with the diminished inhibition of 20S proteasome activity in these pts. No significant financial relationships to disclose.

1513 Background: EGFR inhibitors may potentiate the therapeutic efficacy of RT in GBM patients. To evaluate the toxicity and maximum tolerated dose (MTD) of erlotinib plus RT in patients with GBM, we performed the following phase I trial. Methods: Patients were stratified based upon the use of enzyme-inducing anticonvulsants (EIACs). Patients with resected or biopsied GBM were treated with erlotinib for a week prior to concurrent erlotinib and 6 weeks (60 Gy) of RT and maintained on erlotinib until progression. The erlotinib dose was escalated in cohorts of 3 with a starting dose of 100mg/day. Intrapatient dose escalation was not allowed. Response was evaluated by MRI and clinical assessment of neurological status every two months. Results: 20 patients were enrolled; 19 are evaluable. There were 14 males/5 females, median age 54 years; 7 had undergone biopsy only/ 5 subtotal resections/ 7 gross total resections. Current dose level is 150mg/day erlotinib for patients not on EIACs (group 1) and 200mg/day fo...

Primary Central Nervous System NHL (PCNSL) has increased in incidence across all age groups over the past decades. 90% are B-cell NHL. Resection has not been shown to improve survival and standard chemotherapy is not effective. While radiation therapy (RT) was formerly the standard therapy, high-dose methotrexate (Mtx) is the single most active agent. High-dose Mtx alone or in combination with RT has resulted in response rates of 100% and median survival ranging between 30–60 months, although the risk of relapse is 50%. The prognosis at relapse is poor; clearly, new strategies are needed for these patients. There are no previous cases or clinical trials to evaluate the efficacy of Zevalin in PCNSL. We report a single patient with PCNSL treated with Zevalin. A 26YO male with a CD20+/CD19+ PCNSL was diagnosed in 05/01 when he presented with a left frontal mass. The patient underwent surgical resection (pathology: pleomorphic xanthoastrocytoma). By 09/01 local progression was documented and a second excision was done. Pathology showed a CD20+/CD19+, PCNSL (previous pathology was reviewed and the diagnosis was confirmed). No systemic disease was found and the patient was HIV negative. While the patient was waiting to start RT, the lesion progressed and a third resection was done, followed by RT. By 01/03 progression was documented by imaging studies but the lesion was found in the right frontal lobe, just across the previous lesion in the left side; diagnosis was confirmed with a stereotactic biopsy. Systemic disease was not documented. PET scan showed area of increased uptake in the right frontal lobe of the brain consistent with active lymphoma with no areas of abnormally increased F-18 uptake in the rest of the body. It was decided to treat the patient with Zevalin RIT. The study utilized the standard Zevalin kit and the preparation, administration and storage were followed in the drug labeling directions. On day 1 he received Rituxan 250 mg/m2 followed by 5.0 mCi of 111In-2B8 for biodistribution evaluation. Whole body scintogram planar images were obtained 24 and 48 hours after the infusion of the 111In-2B8 and they showed increased activity in the right frontal lobe consistent with the patients known lymphoma. Otherwise, there was normal blood pool and organ distribution of the radiolabeled antibody. On day 8 the patient received Rituxan 250 mg/m2 followed by 29.1 mCi of Zevalin (0.4 mCi/Kg). Tumor localization of radioactivity was evident at 24 hours. The estimated localization per gram of tumor at 24 hours was 0.21% of the injected dose (marrow 0.0042%, liver 0.0069%, kidney 0.0065%, spleen 0.015%). The anticipated hematologic toxicity nadired on week 5 and recovered by week 7. MRI was performed on weeks 6, 14, 20 indicating stable disease with an interval decrease in the right frontal abnormal T2 hyperintensity. PET scan performed on week 20 indicating interval decrease in the right frontal lobe uptake. On week 32, an MRI of the brain and a PET scan showed progression. This report is the first description in humans using Zevalin in PCNSL, and serves as a proof-of-principle. We have proposed a hypothesis-driven pilot study to confirm our observation that Zevalin binds to the PCNSL and it is able to deliver local radiation. If positive, a more definitive design would be pursued. Images (MRI, PET, Indium Scans) will be presented in the meeting.

2568 Background: Wee1 is a key regulator of the G2/M checkpoint and is frequently overexpressed in glioblastoma (GB). Adavosertib is a first-in-class oral, small molecule inhibitor of Wee1 that acts primarily as a DNA damage sensitizer. A phase I clinical trial was conducted to evaluate its safety and establish the recommended phase II dosing. Studies were undertaken to evaluate whether potentially therapeutic concentrations of the drug are achieved in recurrent tumor and adjacent non-enhancing brain regions with presumed intact blood-brain barrier (BBB). Methods: Twelve patients received five daily doses of adavosertib pre-operatively at either the maximum tolerated dose (MTD) for concurrent radiation or adjuvant temozolomide. Tissue from contrast enhancing (CE) and non-enhancing (NE) brain regions was obtained for analysis during surgical resection. A second stage is being conducted using microdialysis (MD) to facilitate continuous sampling of extracellular fluid (ECF) and measuring free drug concentrations in: normal-appearing brain, contrast enhancing tumor, and a peritumoral T2 hyperintense area. The concentration of total adavosertib in plasma and tissue homogenates and free drug in ECF were determined by validated LC/MS/MS methods. Results: Geometric mean concentrations of adavosertib after a 200 mg dose were 644 ng/mL and 119 ng/mL in CE and NE tissue specimens, respectively (6 patients). At the 425 mg dose, the mean concentrations were 3,576 ng/mL in CE tissue and 885 ng/mL in NE tissue (6 patients). MD was performed in 2 patients. Samples from functional MD catheters were collected from NE brain in patient no. 1 and from two NE areas and a FLAIR hyperintense region in patient no. 2, with the following results in the table. Conclusions: The total drug concentration in tissue samples was notably lower in regions of the brain with a relatively intact BBB as compared to contrast enhancing tissue. Concentrations of adavosertib measured by MD vary markedly depending on catheter location. Free drug levels in ECF within brain with a functional BBB, although considerably lower than total drug levels in tissue, were 2-10 times below the previously reported IC50 for antiproliferative activity against sensitive GB cell lines (127 ng/mL). Whether or not the target of the drug is effectively inhibited at these concentrations remains to be demonstrated. Clinical trial information: NCT01849146 . [Table: see text]

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.

2012 Background: Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. We report on the feasibility and conduct of this approach. Methods: Tumor genotyping was performed prior to treatment assignment on eligible participants with newly diagnosed MGMT-unmethylated glioblastoma to identify biomarker signatures. Initial randomization was 1:1:1:1 between control (temozolomide) and 3 experimental arms (abemaciclib, CC-115, and neratinib). Subsequent randomization was adapted based on Bayesian estimation of biomarker-naïve and biomarker-specific probabilities of treatment impact on progression-free survival (PFS). Ineffective or toxic arms were discontinued by protocol amendment. The primary endpoint was overall survival (OS). Results: INSIGhT randomized 71 patients to the control arm, 73 patients to the abemaciclib arm, 12 patients to the CC-115 arm, and 81 patients to the neratinib arm between 2/9/2017 and 5/14/2021. Following the initial equal randomization period, early data were repeatedly analyzed during the study to capture early signals of treatment effects across the enrolled population or in specific biomarker subgroups. The results of these interim analyses influenced the randomization probability for future enrolled patients. In total, 77% of the participants were randomized before assessing their biomarker profile and 23% were biomarker randomized. The CC-115 arm opened and closed three times during the safety lead-in. The randomization probability to the CC-115 arm decreased based on poor early PFS results and the arm eventually closed after 12 patients due to toxicity. The randomization probability to the abemacicilb arm increased based on promising early PFS results. After the completion of accrual into the abemaciclib arm, the trial switched to block randomization to finish enrolling into the remaining neratinib and control arms. A total of 28 interim analyses and 32 randomization tables were created throughout the course of the trial with 4 adjustments (3 due to CC-115 closures and 1 due to completion of the abemaciclib arm). Biomarker association trends for neratinib and abemaciclib were similar to those seen in preclinical modeling of the trial. Conclusions: Relative to a standard randomization design, the adaptive platform design facilitated more efficient and economical testing of experimental arms by sharing a control arm, decreasing the probability of enrollment to potentially ineffective arms, and increasing the probability of enrollment to potentially effective arms. Additional future arms are planned on INSIGhT. Clinical trial information: NCT02977780.