Search

Author(s): Grossman, Stuart A; Romo, Carlos G; Rudek, Michelle A; Supko, Jeffrey; Fisher, Joy; Nabors, L Burt; Wen, Patrick Y; Peereboom, David M; Ellingson, Benjamin M; Elmquist, William; Barker, Fred G; Kamson, David; Sarkaria, Jann N; Timmer, William; Bindra, Ranjit S; Ye, Xiaobu

BACKGROUND Glioblastoma often can relapse as mesenchymal (MES) tumors, indicating a phenotypic shift during clinical progression. Glioma spheres, when they gain MES phenotypes, develop dependence on AXL for their growth both in vitro and in vivo. The first-in-class orally bioavailable AXL kinase inhibitor bemcentinib has IC50 of 14 nM and is > 100-fold selective for AXL over other kinases. Bemcentinib is currently under evaluation as a monotherapy and in combination with other treatments across various PhII trials in several oncology indications. METHODS This is an open-label, multicenter, intratumoral pharmacokinetic study of bemcentinib in patients with recurrent glioblastoma for whom a surgical resection is medically indicated. All subjects must have had histological confirmation of glioblastoma by either biopsy or resection that is progressive or recurrent following radiation therapy ± chemotherapy. Intratumoral drug levels were analyzed by LC/MS. RESULTS A planned analysis after the first 5 patients were enrolled with glioblastoma (4 IDH WT and 1 IDH-mutant), (3m, 2f, median age 57, KPS 80). Bemcentinib concentration in contrast enhancing brain tissue ranged from 3.1 to 43.0 uM with a geometric mean concentration of 11.1 uM (% CV, 132.1). The drug concentration in contrast enhancing tumor tissue exceeded the 1.0 uM threshold in all 5 patients, satisfying the criteria of the protocol to enroll an additional 15 patients into the surgical study. Total drug levels were approximately 2-fold greater in contrast enhancing tissue as compared to tissue from a non-enhancing region of the tumor (geometric mean, 5.8 uM; % CV, 187.7). The mean ratio of the drug concentration in brain tissue to plasma was 25.9 (% CV, 92.7) for contrast enhancing tissue and 13.4 (% CV, 126.8) for non-enhancing tissue. CONCLUSIONS Bemcentinib readily distributes in brain tumor tissue following oral administration. The study continues to complete accrual for the remaining 15 patients.

BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. Pamiparib (BeiGene BGB-290) is an effective PARP-trapping PARP inhibitor with demonstrated favorable brain penetration in animal models. METHODS ABTC 1801 is a study examining the safety, pharmacokinetics, and efficacy of the combination of pamiparib with low dose metronomic temozolomide in recurrent IDHmt gliomas. The Phase I component utilized a 3 + 3 design with a target DLT rate ≤ 33%. Pamiparib dose was 60 mg BID and temozolomide dose 20 mg daily, with dose de-escalation levels for anticipated hematological toxicity. RESULTS Seven patients were enrolled on the Phase I portion at dose level 1; one patient was replaced for inadequate dosing secondary to non-compliance. All patients had prior radiotherapy and temozolomide; 4/7 had received multiple lines of alkylator therapy including nitrosoureas. Median age was 45, KPS 90, and number of prior relapses 3. Four patients had anaplastic astrocytoma, 2 anaplastic oligodendroglioma, and 1 glioblastoma. One of 6 patients (16.7%) experienced DLT during the first cycle (grade 3 neutropenia and thrombocytopenia). Two additional patients had grade 2 neutropenia. Two patients remain on study treatment at 12+ and 10+ months, while a third progressed at 10.1 months (PFS-6 43%). Tumor tissue was collected from two patients in the surgical arm. In enhancing and non-enhancing tumors, the mean unbound pamiparib concentrations were 198 and 160 nmol/L (or nmol/kg), respectively, which were > 20-fold the in vitro IC50 for PARP inhibition; mean unbound tumor-to-plasma ratios were 0.65 and 0.38. CONCLUSIONS Phase I results support pamiparib 60 mg BID with temozolomide 20 mg daily as the dosages for the Phase II study. Preliminary Phase 0 data suggest that pamiparib likely achieves sufficient pharmacologically active concentrations in both enhancing and non-enhancing brain tumors.

Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28day regimen. Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24-69); median KPS 90 (60-100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4mg/kg every 2 weeks. Dose limiting toxicities at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients) (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1-16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4mg/kg every 2 weeks.

Quantitative 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has potential as a noninvasive tumor biomarker for the objective assessment of response to treatment. To guide interpretation of these quantitative data, we evaluated the repeatability of 18F-FLT PET as part of a multicenter trial involving patients with high-grade glioma. Methods:18F-FLT PET was performed on 10 patients with recurrent high-grade glioma at 5 different institutions within the Adult Brain Tumor Consortium trial ABTC1101. Data were acquired according to a double baseline protocol in which PET examinations were repeated within 2 d of each other with no intervening treatment. On each of the 2 imaging days, dedicated brain PET was performed at 2 time points, 1 and 3 h after 18F-FLT administration. Tumor SUVs and related parameters were measured at a central laboratory using various volumes of interest: isocontour at 30% of the maximum pixel (SUVmean_30%), gradient-based segmentation (SUVmean_gradient), the maximum pixel (SUVmax), and a 1-mL sphere at the region of highest uptake (SUVpeak). Repeatability coefficients (RCs) were calculated from the relative differences between corresponding SUV measurements obtained on the 2 d. Results: RCs for tumor SUVs were 22.5% (SUVmean_30%), 23.8% (SUVmean_gradient), 23.2% (SUVmax), and 18.5% (SUVpeak) at 1 h after injection. Corresponding data at 3 h were 22.4%, 25.0%, 27.3%, and 23.6%. Normalizing the tumor SUV data with reference to a background region improved repeatability, and the most stable parameter was the tumor-to-background ratio derived using SUVpeak (RC, 16.5%). Conclusion: SUV quantification of 18F-FLT uptake in glioma had an RC in the range of 18%-24% when imaging began 1 h after 18F-FLT administration. The volume-of-interest methodology had a small but not negligible influence on repeatability, with the best performance obtained using SUVpeak Although changes in 18F-FLT SUV after treatment cannot be directly interpreted as a change in tumor proliferation, we have established ranges beyond which SUV differences are likely due to legitimate biologic effects.

BACKGROUND Immune checkpoint inhibitors (ICIs) are not uniformly effective in glioblastoma treatment. Immunogenomic determinants may identify patients who are most likely to benefit from these therapies. Therefore, we compared the immunogenomic phenotype of a responder to combination anti-LAG-3 and anti-PD-1 therapy to non-responders. METHODS We performed T cell receptor (TCR) sequencing and gene expression analysis on pre-treatment, post-chemoradiation, and post-immunotherapy tumor specimens of glioblastoma patients treated with anti-LAG3 in combination with anti-PD-1 after first recurrence (NCT02658981, ongoing). We evaluated T cell clonotypes and immunophenotype of serially collected peripheral blood mononuclear cells (PBMCs) during treatment using multi-parametric flow cytometry. RESULTS To date, six patients have been enrolled in the initial anti-LAG-3 and anti-PD-1 cohort. One patient demonstrated complete response, one had stable disease, and four had progressive disease by radiographic evaluation. The responder demonstrated substantially higher TCR clonality in the resected tumor at initial diagnosis compared to non-responders (mean 0.028 vs. 0.005). Shared tumor infiltrating clonotypes with pre-immunotherapy PBMCs exhibited an increase in frequency from initial resection (6.8%) to resection at recurrence (20%). The responder’s tumor at initial resection exhibited increased gene signatures of PD1low CD8+ T cells, chemokine signaling, and interferon gamma pathways. On PBMC phenotypic analysis, the responder demonstrated significantly higher percentages of CD137+ CD8+T cells (median 8.38% vs 3.24%, p=0.02) and lower percentages of Foxp3+CD137+ CD4+T cells compared to non-responders (median 18.5% vs. 38.5%, p=0.006). Interestingly, dynamic analysis of PBMCs showed that the responder demonstrated a lower percentage of PD1+ CD8+ T cells pre-immunotherapy (median 2.5% vs.12.4%, p=0.002), with persistent decrease over the course of treatment while non-responders showed no consistent pattern. CONCLUSION Our preliminary results demonstrate significant differences in tumor and peripheral blood immunogenomic characteristics between responder and non-responders to anti-LAG3 and anti-PD-1 therapy. These immunogenomic characteristics may help stratify patients’ response to combination ICIs.

Background Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG. Methods Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB. Results Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB. Conclusions MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.

AZD1775 is an oral small molecular inhibitor of the G2/M checkpoint regulator Wee1. The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. Dose of AZD1775 was increased in a 3 + 3 design M-F during concurrent RT/TMZ and x 5d/28d cycle with adjuvant TMZ in separate cohorts. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. MTD was 200 mg for concurrent with 2/6 patients experiencing DLTs (grade 4 neutropenia, grade 3 ALT elevation). MTD for the adjuvant cohort was 425 mg with 1/6 patients experiencing DLT (grade 4 decrease in ANC). 6/12 patients experienced DLTs when cohorts were combined, however, five during the concurrent phase. Three patients had grade ≥3 ALT/AST elevation, one had grade 3 afib, and one had grade 4 neutropenia/thrombocytopenia, grade 3 dehydration/fatigue/muscle weakness. A sixth patient had grade 4 neutropenia in the first adjuvant cycle. Following amendment, an additional 6 patients were enrolled with 150 mg (concurrent) and 425 mg (adjuvant) combination and are in the observation period with one DLT currently. Drug concentration in contrast enhancing and non-enhancing brain tumor was 4–8 x and 0.5–2.6 x greater than plasma, respectively for patients on IDD portion. CONCLUSIONS: AZD1775 in combination with RT/TMZ at 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ had unacceptable DLT rate in the concurrent phase. A cohort with 150 mg concurrent/425 mg adjuvant has competed accrual with acceptable rates of toxicity currently in observation. AZD1775 has good penetration to non-enhancing and enhancing tumor areas.

Despite advances in the understanding of molecular pathways, the availability of NGS panels to identify potentially drugable mutations, the proliferation of targeted therapies, and the progress seen in other cancers, only one novel agent (temozolomide) has significantly improved the survival of patients with glioblastoma in the past three decades. A major factor distinguishing brain cancer from other malignancies is the presence of the blood-brain barrier that restricts entry into the central nervous system of over 95% of drugs currently approved by the FDA. Clinical investigators have historically justified glioblastoma efficacy trials with pharmacokinetic data documenting measurable brain concentrations in animals or in contrast enhancing brain tumor specimens from patients. However, the discovery of effective therapeutic agents (whose mechanism of action requires that the drug directly reaches the cancer) will likely require that therapeutic drug concentrations (rather than measurable levels or blood:brain ratios) be delivered to non-contrast enhancing regions of the brain. The importance of delivering therapeutic concentrations of drug to non-enhancing brain is highlighted by knowledge that a gross total resection of all enhancing portions of a glioblastoma provides no chance of cure and limited improvement in overall survival. Utilizing these more stringent emerging criteria to select novel agents for efficacy studies will encourage pre-clinical and phase I studies to define the CNS penetration of new drugs and determine a therapeutic concentration for each agent. This will aid in the rational prioritization of agents selected for phase II studies. A full report of the outcome of the ABTC workshop on this topic will be presented. This will include: 1) methods to determine “therapeutic” drug concentrations for glioblastoma, 2) methods to quantify drug concentrations in non-enhancing brain, 3) pharmacokinetic and pharmacodynamic considerations, and 4) potential shortcomings of this approach.

2017 Background: Preclinical GBM data targeting the checkpoint molecules Lag-3 and CD137 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and anti-CD137. Methods: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients at first recurrence of GBM. The primary objective is to define MTD for the mono and combinational treatment. The major secondary objective is to explore for a signal in efficacy. The key inclusion criteria are adults, first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, stable corticosteroid regimen, measurable disease, and written informed consent. Sequential allocation was used for the treatment assignment at starting dose of 80mg for anti-LAG-3 and 8mg for anti-CD137. Anti-PD-1was given at a flat dose of 240 mg in the combination treatment arms. The 3+3 design is used for the dose finding with a target DLT rate < 33%. Results: to date 44 patients were enrolled into the trial with median age at 57, median KPS at 90. Median treatment cycle was 3 and 39% tumors were MGMT methylated. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. The safe dose for anti-CD137 alone arm is 8mg with 1 DLT, and 2 grade 3 elevated serum ALT at end of cycle 2. Combination arms of Anti-LAG-3 +anti-PD-1 (160 mg/240mg as the highest dose combination) had one DLT (hypertension) and no toxicities were seen in the combination arm of Anti-CD137+Anti-PD-1 (3 mg/240 mg). mOS was 14 months for anti-CD137 alone, 8 months for Anti-Lag-3, and 7 months for Anti-Lag-3 + Anti-PD-1. Correlative data will be discussed. Conclusions: The trial is ongoing. The RP2D is 800mg for anti-LAG-3 as a monotherapy and 8mg for anti-CD137. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 and 3 mg of anti-CD137 and 240 mg antiPD-1 were the RP2D. Clinical trial information: NCT02658981.

Quantitative 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET has potential as a noninvasive tumor biomarker for the objective assessment of response to treatment. To guide interpretation of these quantitative data, we evaluated the repeatability of 18F-FLT PET as part of a multicenter trial involving patients with high-grade glioma. Methods: 18F-FLT PET was performed on 10 patients with recurrent high-grade glioma at 5 different institutions within the Adult Brain Tumor Consortium trial ABTC1101. Data were acquired according to a double baseline protocol in which PET examinations were repeated within 2 d of each other with no intervening treatment. On each of the 2 imaging days, dedicated brain PET was performed at 2 time points, 1 and 3 h after 18F-FLT administration. Tumor SUVs and related parameters were measured at a central laboratory using various volumes of interest: isocontour at 30% of the maximum pixel (SUVmean_30%), gradient-based segmentation (SUVmean_gradient), the maximum pixel (SUVmax), and a 1-mL sphere at the region of highest uptake (SUVpeak). Repeatability coefficients (RCs) were calculated from the relative differences between corresponding SUV measurements obtained on the 2 d. Results: RCs for tumor SUVs were 22.5% (SUVmean_30%), 23.8% (SUVmean_gradient), 23.2% (SUVmax), and 18.5% (SUVpeak) at 1 h after injection. Corresponding data at 3 h were 22.4%, 25.0%, 27.3%, and 23.6%. Normalizing the tumor SUV data with reference to a background region improved repeatability, and the most stable parameter was the tumor-to-background ratio derived using SUVpeak (RC, 16.5%). Conclusion: SUV quantification of 18F-FLT uptake in glioma had an RC in the range of 18%–24% when imaging began 1 h after 18F-FLT administration. The volume-of-interest methodology had a small but not negligible influence on repeatability, with the best performance obtained using SUVpeak. Although changes in 18F-FLT SUV after treatment cannot be directly interpreted as a change in tumor proliferation, we have established ranges beyond which SUV differences are likely due to legitimate biologic effects.

BACKGROUND: Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. METHODS: In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. RESULTS: Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). CONCLUSIONS: Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose. Cancer 2012. © 2012 American Cancer Society.

BACKGROUND: Others and we have shown additional checkpoint molecules are expressed in GBM and preclinical studies have shown that combining anti-Lag-3 and anti-CD137 with anti-PD-1 can induce effective antitumor immune responses. METHODS: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients with first time recurrent GBM. The primary objective was to define MTD for the mono and combination treatments with a secondary objective of OS. Using a sequential allocation, we started with doses of 80mg for anti-LAG-3 and 8mg flat for anti-CD137. Anti-PD-1 was given at a flat dose of 240 mg in the combination treatment arms. Using a 3 + 3 design our target DLT rate was < 33%. RESULTS: To date 30 patients were enrolled into the trial with median age at 56, median KPS of 90. Median treatment cycle was 3 and 43% tumors were MGMT methylated. Recruitment of the monotherapy Anti-LAG-3 and anti-CD137 arms were completed. We observed no DLT at the highest dose for Anti-LAG-3 at 800mg and only one DLT (a grade 3 elevated serum ALT at end of cycle 2) with anti-CD137 at the top dose of anti-CD137 at 8mg flat. In addition, three out of 12 patients developed elevated ALT at end of cycle 2 that was considered possibly related to anti-CD137. Another two patients had grade 1 elevated ALTs. Six patients are currently enrolled into a combination cohort of Anti-LAG-3 at160mg +anti-PD-1with no observed DLT and the combination arm of anti-CD137 with anti-PD-1 is open to accrual. CONCLUSIONS: The safe monotherapy dose is 800mg for anti-LAG-3 and 8mg flat for anti-CD137. Both Anti-LAG-3 and anti-CD137 in combination with antiPD-1 cohorts and an intratumoral surgical anti-CD137 cohort are open for accrual.

Ixabepilone is an epothilone, a novel class of non-taxane microtubule stabilizing agents. A phase I/II and pharmacokinetic trial of ixabepilone was conducted in patients with recurrent high-grade gliomas. Adult patients received ixabepilone as a 1-h infusion daily for 5 days every 3 weeks. A modified continual reassessment method was used to escalate doses, beginning at 5.0 mg/m(2), in patients stratified by use or non-use of enzyme inducing antiepileptic drugs (EIAED). In the phase I study, the maximum tolerated dose (MTD) and pharmacokinetics of ixabepilone were determined for each group. The phase II study used a two-stage design to evaluate response rate. Secondary endpoints were survival and 6-month progression free survival. In the phase I trial, 38 patients (median age 54 years) were enrolled. The MTD was 6.8 mg/m(2) for patients not taking EIAEDs and 9.6 mg/m(2) for those taking EIAEDs. The dose limiting toxicities in both groups were hematologic. Twenty-three patients (median age 54 years) were enrolled in the first stage of the phase II trial. No objective responses were observed. Median overall survival was 5.8 (95% CI, 5.0-8.6) months and 6-month PFS rate was 4% (95% CI, 0-22%). The overall mean total body clearance for ixabepilone was significantly higher (P = 0.003) in patients receiving EIAEDs (36 ± 11 l/h/m(2)) than those not (24 ± 9.2 l/h/m(2)). Patients on EIAEDs had a substantially higher MTD likely due to induction of cytochrome P450. Ixabepilone had no activity in patients with recurrent high-grade gliomas.

Purpose: Novel agents are currently combined with radiation and temozolomide (RT + TMZ) in newly diagnosed glioblastoma using overall survival as the primary end point. Results of these phase II studies are typically compared with the phase III European Organization for Research and Treatment of Cancer (EORTC) survival data that resulted in RT + TMZ becoming standard therapy. Experimental Design: The New Approaches to Brain Tumor Therapy (NABTT) Consortium assigned 365 patients with glioblastoma to four single-cohort studies with similar eligibility criteria. Patients received RT + TMZ with talampanel (n = 72), poly-ICLC (n = 97), or cilengitide (n = 112) or RT + TMZ alone with monitoring of CD4 counts (n = 84). Overall survival of those ages 18 to 70 years with glioblastoma was compared with published EORTC data. Results: NABTT and EORTC patients had comparable performance status and debulking surgery. Median, 12-month, and 24-month survival rates for the EORTC patients (n = 287) and the comparable NABTT patients receiving RT + TMZ and novel agents (n = 244) are 14.6 versus 19.6 months, 61% versus 81%, and 27% versus 37%, respectively. This represents a 37% reduction in odds of death (P < 0.0001) through 2 years of follow-up. NABTT and EORTC patients receiving only RT + TMZ had similar survival. Conclusions: Newly diagnosed glioblastoma treated recently with RT + TMZ and talampanel, poly-ICLC, or cilengitide had significantly longer survival than similar patients treated with only RT + TMZ accrued internationally from 2000 to 2002. These differences could result from the novel agents or changing patterns of care. Until the reasons for these different survival rates are clarified, comparisons of outcomes from phase II studies with published RT + TMZ survival data should be interpreted with caution. Clin Cancer Res; 16(8); 2443–9. ©2010 AACR.

Purpose Prognostic factor analyses have proven useful in predicting outcome in patients with newly diagnosed malignant glioma. Similar analyses in patients with recurrent glioma could affect the design and conduct of clinical trials substantially. Patients and Methods Between 1995 and 2002, 333 adults with recurrent gliomas were enrolled onto 10 phase I or II trials of systemic or local therapy. The studies had similar inclusion criteria and were conducted within the New Approaches to Brain Tumor Therapy CNS Consortium. Ninety-three percent of the patients have died. Cox proportional hazards (PH) regression and recursive partitioning analysis (RPA) were performed to identify prognostic factors. Results Factors associated with an increased risk of death were increased age, lower Karnofsky performance score (KPS), initial and on-study histologies of glioblastoma multiforme (GBM), corticosteroid use, shorter time from original diagnosis to recurrence, and tumor outside frontal lobe. The final PH model included initial histology of GBM (relative risk [RR] = 2.01), 10-year increase in age (RR = 1.23), KPS less than 80 (RR = 1.54), and corticosteroid use (RR = 1.49). RPA resulted in seven classes. Median survival time was poorest in non-GBM patients with KPS less than 80 or GBM patients, age ≥ 50 years, corticosteroid use (4.4 months; 95% CI, 3.6 to 5.4 months); median survival was best in patients with initial histology other than GBM with KPS ≥ 80 and tumor confined to the frontal lobe (25.7 months; 95% CI, 18.7 to 52.5), and was 7.0 months (95% CI, 6.2 to 8.0 months) for all patients. Conclusion Initial histology, age, KPS, and corticosteroid use are prognostic for survival in recurrent glioma patients. To allow comparisons across phase II trials, enrollment criteria may need to be restricted.

Purpose This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma. Patients and Methods Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration. Results A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy. Conclusion Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.

Purpose This phase I trial was designed to (1) establish the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite. Patients and Methods The first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT). Results Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4 μmol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 μmol/L. Conclusion Systemically administered O6-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.

BACKGROUND: Mibefradil (MIB) is a selective T-type calcium channel blocker that has shown preclinical impact on cell cycle activity, specifically arrest at G1/S in tumor cells, suggesting a potential chemo-sensitizing effect if given prior to chemotherapy. In our study, MIB was administered orally QID x 7 days prior to standard temozolomide (150-200 mg/m2 x 5/28d) in recurrent high-grade glioma (HGG) patients. 18F-FLT PET was used as an exploratory imaging biomarker to assess influence of MIB on overall tracer accumulation in tumor. METHODS: 18F-FLT PET was performed in 10 patients treated at the maximum tolerated dose of MIB (87.5 mg po QID) at 5 different institutions. Prior to MIB administration, 2 PET scans were performed as a double baseline to assess repeatability of PET measurements. A third scan was performed on day 7 of MIB treatment to assess 18F-FLT uptake for response. Tumor standardized uptake values (SUVs) were measured at a central laboratory by automatically positioning a 1mL sphere at the region of highest uptake (SUVpeak). RESULTS: The double baseline data indicated 95% limits of repeatability of 18.5% (6.7% within-patient coefficient of variation) for SUVpeak. Two of the 10 patients demonstrated a drop in SUVpeak after 7 days of MIB that exceeded these limits (-47% and -67%). No significant change between double baseline and day 7 of MIB was seen in the remaining 8 patients. CONCLUSIONS: In this first 18F-FLT PET imaging study within a multicenter HGG trial, 18F-FLT PET was found to be feasible and highly repeatable. The results suggest influence of MIB on tumor accumulation of the radiotracer, possibly in part due to alterations in cell cycle activity in a subset of patients, but the precise mechanism remains to be determined as tracer delivery/transport effects may also be contributing to the decline in signal observed in the two patients.

Differentiating agents may alter tumor growth and progression, slow or inhibit metastases, and/or affect response to other forms of therapy. Phenyl-butyrate (PB)4 is an aromatic fatty acid that is converted in vivo to phenylacetate (PA) by β-oxidation in liver and kidney mitochondria. The actions of PB as a differentiating agent are primarily related to its activity as an inhibitor of histone deacetylase (Carducci et al., 1996). In vitro PB concentrations required to inhibit histone deacetylase and induce apoptosis begin at 0.5 mM of PB. In solid tumor cell lines, PB induces G1/G0 arrest and induces p21waf1/cip1, a cell cycle checkpoint protein associated with differentiation and an inhibitor of histone deacetylase, within 24 h of treatment. Glioblastoma and prostate cancer cell lines exposed to PA and PB (Gore et al., 2002) at concentrations of 1 to 5 mM in vitro develop time-and dose-dependent growth arrest (Dmitrovsky et al., 1990; Samid et al., 1993). Human glioblastoma cells can undergo cell maturation and revert to a nonmalignant phenotype when exposed to these agents (Dmitrovsky et al., 1990; Hudgins et al., 1994; Sidell et al., 1995). In vivo studies exist for experimental gliomas in rats. Samid and colleagues administered PA to rats bearing intracranial glioma cells and showed suppression of tumor growth, more than 50% of the animals being rendered free of tumor when exposed to continuously administered PA (Samid et al., 1994). Phenylbutyrate had not been tested in these glioma models, but as a precursor in PA, and as a more potent agent, clinical studies of PB were warranted. A phase 1 clinical trial of continuous intravenous infusions of PB in patients with refractory solid tumors demonstrated that this agent is safe and that doses of 410 mg/kg per day for five days every 21 days are well tolerated (Carducci et al., 2001). No complete responses (CRs) were noted; however, one patient with prostate cancer did have a partial response (PR). The dose-limiting toxicity (DLT) in this study was predominantly neurocortical. A phase 1 study of oral PB in 28 patients with solid tumors also showed that this agent was well tolerated. Oral bioavailability was 78%, and the maximum tolerated dose (MTD) was 27 g/day, with nausea/vomiting, neurocortical toxicity, and hypocalcemia being dose limiting at doses ⩾45 g/day (Gilbert et al., 2001). Both of these studies excluded patients with primary CNS tumors. This study was designed to evaluate the safety, toxicity, and pharmacology of orally administered PB given three times daily to patients with recurrent high-grade gliomas until progression. In this clinical trial, we also studied the tolerability of continued exposure to oral PB, the ability to achieve plasma levels of >0.5 mM, and the impact of P450-inducing anticonvulsant drugs on the pharmacology of PB and its metabolites, and we examined preliminary evidence of therapeutic activity.

Object. In this study the authors evaluated the safety and performance of the GliaSite Radiation Therapy System (RTS) in patients with recurrent malignant brain tumors who were undergoing tumor resection. Methods. The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of tumor debulking. Low-dose-rate radiation is delivered with an aqueous solution of organically bound iodine-125 (Iotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]), which are temporarily introduced into the balloon portion of the device via a subcutaneous port. Adults with recurrent malignant glioma underwent resection and GliaSite implantation. One to 2 weeks later, the device was filled with Iotrex for 3 to 6 days, following which the device was explanted. Twenty-one patients with recurrent high-grade astrocytomas were enrolled in the study and received radiation therapy. There were two end points: 1) successful implantation and delivery of brachytherapy; and 2) safety of the device. Implantation of the device, delivery of radiation, and the explantation procedure were well tolerated. At least 40 to 60 Gy was delivered to all tissues within the target volume. There were no serious adverse device-related events during brachytherapy. One patient had a pseudomeningocele, one patient had a wound infection, and three patients had meningitis (one bacterial, one chemical, and one aseptic). No symptomatic radiation necrosis was identified during 21.8 patient-years of follow up. The median survival of previously treated patients was 12.7 months (95% confidence interval 6.9–15.3 months). Conclusions. The GliaSite RTS performs safely and efficiently. It delivers a readily quantifiable dose of radiation to tissue at the highest risk for tumor recurrence.

2005 Background: The standard of care treatment for newly diagnosed GBM is maximal safe surgical resection followed by two DNA damaging agents, RT and TMZ. Cellular response to DNA damage involves checkpoints that halt the cell cycle to allow DNA repair. AZD1775 is an oral small molecular inhibitor of a nuclear tyrosine kinase Wee1, a key regulator of the G2/M checkpoint. Abrogation of the G2/M checkpoint prevents repair and pushes cells into mitosis with unrepaired DNA damage. AZD1775 was shown to enhance TMZ and RT effects in preclinical models. Methods: The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. The dose finding portion is comprised of two arms, one with AZD1775 given Monday through Friday during concurrent RT/TMZ and a second arm given with adjuvant TMZ qd x 5d/28d cycle. Each arm had standard 3+3 design. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. Results: 51 patients enrolled in the dose finding arms. For the concurrent arm, the MTD was 200 mg. At 275 mg one patient had grade 3 fatigue and another had grade 4 thrombocytopenia and neutropenia. Two of 6 total patients enrolled at 200 mg experienced DLTs (grade 4 neutropenia and grade 3 ALT elevation). The MTD for the adjuvant arm was 425 mg as 1 of 6 patients had DLT (grade 4 decrease in ANC). At 500 mg, 2 of 3 patients experienced intolerable diarrhea despite prophylaxis. Enrollment in the combination cohort is completed and evaluation of safety is underway. The drug concentration in contrast enhancing and non-enhancing brain tumor was 4-8 x and 0.5-2.6 x greater than plasma, respectively for patients on IDD portion. Conclusions: The MTD for AZD1775 in combination with RT/TMZ is 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ. IDD and PK/PD analysis is ongoing to inform the decision to proceed to phase II testing. Clinical trial information: NCT01849146.

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

9-Aminocamptothecin (9-AC) was administered as a 72-h i.v. infusion every 2 weeks to a total of 99 adults with high-grade astrocytomas. Fifty-one patients with newly diagnosed glioblastoma multiforme received 9-AC treatment prior to radiation therapy and 48 patients with high-grade astrocytomas were treated at the time of tumor recurrence. Upon entrance into these research protocols, all patients had measurable disease that was evaluated on a monthly basis with volumetric CT or MRI scans. A partial response was defined by > or =50% reduction in the contrast enhancing volume on stable or decreasing doses of glucocorticoids. The study specified that all apparent responders would have central review of their radiologic studies and histopathology. The initial patients treated with 9-AC were also receiving anticonvulsants and were noted to have minimal myelosuppression with this chemotherapy. Thus, 9-AC doses were escalated from the previously reported maximum tolerated dose (MTD) of 850 microg/m2/24 h. We then established new MTDs for patients receiving enzyme-inducing anticonvulsants. We defined these MTDs to be 1,776 microg/m2/24 h for newly diagnosed, previously untreated patients and 1,611 microg/m2/24 h for patients with recurrent disease. Twenty-two patients with newly diagnosed glioblastoma multiforme received 9-AC at doses > or =1,776 microg/m2/24 h. Of these, 18 had evaluable disease on central review, and 0 of 18 (0%) demonstrated a partial or complete response. Twenty-one patients with recurrent high-grade astrocytomas were treated at 1,611 microg/m2/24 h; 20 had evaluable disease and 0 of 20 (0%) had a partial or complete response. Thus, the overall response rate in the 38 evaluable patients treated at the MTD was 0 of 38 (0%). Furthermore, of the 51 evaluable patients who were treated at doses less than the MTD, only one partial response was observed, yielding an overall response rate of 2%. Evidence of drug failure was rapid with tumor progression in one-half of patients after 2 drug cycles. 9-AC lacks evidence of substantial activity in patients with newly diagnosed or recurrent high-grade astrocytomas.

Background: High grade astrocytomas remain uniformly fatal despite aggressive surgery and radiotherapy. As existing chemotherapeutic agents are of limited benefit, clinical trials are underway to screen new drugs, such as 9-aminocamptothecin (9-AC), for activity in high grade astrocytomas. Purpose: This study was designed to estimate the efficacy of 9-AC in patients with newly diagnosed glioblastoma multiforme and recurrent high grade astrocytomas. The planned dose of 9-AC for this trial was 850 μg/m2 per 24 h as a 72-h continuous intravenous infusion every 2 weeks. This was the maximum tolerated dose (MTD) on this schedule in multiple phase I studies in patients with systemic malignancies. However, we found this dose subtherapeutic in our patient population. As a result, the purpose of the study was altered to determine the MTD. Methods: A group of 32 patients were studied using 850 μg/m2 per 24 h with a provision to escalate to 1000 μg/m2 per 24 h if the first three cycles of 9-AC were without significant hematologic toxicity. Once it was determined that myelosuppression did not occur in patients on anticonvulsants, dose escalations were initiated using the continual reassessment method. Dose escalations were conducted independently in newly diagnosed and recurrent patients and in those taking and not taking hepatic enzyme-inducing anticonvulsants. Pharmacologic studies were conducted during the first cycle of 9-AC. Toxicity was determined using the NCI common toxicity criteria and efficacy was assessed using serial volumetric brain scans. Results: 9-AC was administered to 59 patients, 31 with newly diagnosed glioblastoma multiforme and 28 with recurrent high grade astrocytomas. No grade III–IV myelosuppression was noted in the 29 patients (128 cycles) on phenytoin, carbamazepine, phenobarbital, and/or valproic acid who received 850 μg/m2 per 24 h. In contrast, two of three patients (five cycles) who were not taking anticonvulsants developed grade IV myelosuppression. Steady-state total 9-AC plasma levels were lower in patients on anticonvulsants (median 25.3 nM ) than in patients who were not taking anticonvulsants (median 76.5 nM ). Dose escalations performed in 27 additional patients determined the MTD in patients taking anticonvulsants to be 1776 μg/m2 per 24 h for patients with newly diagnosed tumors and 1611 μg/m2 per 24 h for patients with recurrent disease. Conclusions: We describe a new and unexpected drug interaction between 9-AC and anticonvulsants. This is similar to recent findings with paclitaxel, and suggests that higher than “usual” doses of some chemotherapeutic agents are required in patients on anticonvulsants. Prospectively defined dose escalations and pharmacologic studies are essential for the careful evaluation of new chemotherapeutic agents in patients with brain tumors.

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.

Context Bone marrow aspiration and biopsy (BMAB) is a frequently performed and painful procedure. Objectives To evaluate the efficacy of magnetic acupressure in reducing pain in cancer patients undergoing BMAB. Methods Cancer patients without previous acupuncture or acupressure experience were stratified by the number of prior BMAB and randomized to having magnetic acupressure delivered to either the large intestine 4 (LI4) acupoint or a sham site. The primary study endpoint was the patient’s pain intensity rating during the procedure using a visual analogue scale (VAS). Results Seventy-seven eligible patients received magnetic acupressure: 37 were randomized to treatment at the LI4 site arm and 40 at the designated sham site arm. There was no significant difference between the median pain scores of patients treated at the LI4 site and the sham site (P = 0.87). However, severe pain (VAS ≥ 7) was reported in only one patient (2.7%) treated at the LI4 site compared with eight patients (20%) at the sham site (P = 0.03). No patients experienced significant magnetic acupressure-related toxicities. Conclusion Magnetic acupressure at the LI4 acupoint requires minimal training and expense and is well tolerated. Although its use did not significantly reduce median pain scores in patients undergoing BMAB, it does appear to reduce the proportion of patients with severe pain associated with this invasive procedure.

Purpose Recent data suggest that the glutamatergic system is important in the proliferation and migration of glioblastoma. Talampanel is a well-tolerated, oral α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker that could be beneficial in this disease. Patients and Methods This trial was designed to estimate overall survival in adults with newly diagnosed glioblastoma treated with talampanel in addition to standard radiation (RT) and temozolomide (TMZ). A secondary purpose was to evaluate talampanel toxicity in this setting. Talampanel was initiated with RT + TMZ and discontinued for toxicity or disease progression. Survival was compared with historical controls. Results Seventy-two patients were enrolled from December 2005 to July 2006. Their median age was 60 years (range, 37 to 85 years, with 17% > 70 years), median Karnofsky performance score was 90 (range, 70 to 100), and 77% had a debulking procedure. With a median follow-up time of 18 months, 55 patients (76%) have died, yielding a median survival time of 18.3 months (95% CI, 14.6 to 22.5 months). When the 60 patients who were 18 to 70 years old were compared with the European Organisation for Research and Treatment of Cancer (EORTC) RT + TMZ data, the median survival (20.3 v 14.6 months, respectively) and percentage of patients surviving at 24 months (41.7% v 26.5%, respectively; P = .02) seemed superior. The percentage of patients methylated at O6-methylguanine–DNA methyltransferase was lower than on the EORTC study (29% v 43%, respectively). Talampanel was well tolerated and did not increase the known hematologic or nonhematologic toxicities of TMZ. Conclusion Talampanel can be added to RT + TMZ without significant additional toxicity. The encouraging survival results in methylated and unmethylated patients suggest that blocking AMPA receptors may be a useful strategy in newly diagnosed glioblastoma.

Glioblastoma multiforme (GBM) is a lethal primary malignant brain tumor in adults. R115777 (tipifarnib) is an oral agent with antiproliferative effects, being a potent and selective inhibitor of farnesyltransferase. This multicenter, open-label phase II study was designed to evaluate the efficacy and safety of R115777 given after surgery and prior to radiation in patients with newly diagnosed and residual enhancing GBM. Following surgery, an MRI confirmed the presence of residual enhancing tumor. Patients on enzyme-inducing antiseizure drugs (EIASDs) received 600 mg twice per day, and those not on EIASDs received 300 mg twice per day. One to three monthly cycles of R115777 were administered, and radiation was initiated with progression or after three cycles. A cycle consisted of 3 weeks of continuous R115777 followed by a 1-week rest. MRI was done monthly. The primary end point was overall survival; secondary end points were tumor response rate and toxicity. A total of 28 confirmed GBM patients entered the study; 15 patients (54%) were on EIASDs. The overall median time of survival was 7.7 months. There were no tumor responses. Eight patients (29%) had stable disease as the best response. The study was stopped early due to progression of the disease in 12 patients (48%). A total of 24 patients (85%) were off study before the planned treatment schedule for radiation therapy. R115777 administered prior to radiation therapy in patients with newly diagnosed GBM and residual enhancing disease did not result in any measurable responses or improvement in survival. R115777 administered prior to radiation therapy is not recommended for patients with newly diagnosed GBM.

Atrasentan is an oral selective endothelin-A receptor antagonist that may inhibit cell proliferation and interfere with angiogenesis during glioma growth. We conducted a dose-finding study to assess atrasentan’s safety and toxicity and to gather preliminary evidence of efficacy. Patients with recurrent malignant glioma received oral atrasentan at ⩾10 mg/day. We increased the dose among cohorts until the maximum tolerated dose (MTD) was defined. Patients were evaluated for response every 8 weeks and remained on the study until the tumor progressed or toxicities occurred. Twenty-five patients were enrolled, with a median age of 53 years (range, 25 – 70) and a median KPS of 90% (range, 60 – 100%). Twenty- two patients had glioblastoma multiforme (GBM), 2 had anaplastic astrocytoma, and 1 had an anaplastic oliogodendroglioma; 24 patients had received one prior chemotherapy regimen before being enrolled in the study. The most common atrasentan-related toxicities were grade 1 or 2 rhinitis, fatigue, and edema. One patient developed grade 3 hypoxia and peripheral edema at a dose of 90 mg/day. We observed no dose-limiting toxicities in an expanded cohort of 10 patients at 70 mg/day, which was declared the MTD. Two partial responses (8%) were seen in patients with GBM at the 70- and 90-mg/day dose levels, and 4 patients had stable disease before progressing. Nineteen patients have died, and median survival was 6.0 months (95% confidence interval, 4.2 – 9.5 months). We conclude that the MTD of daily oral atrasentan in patients with recurrent malignant glioma is 70 mg/day. Further study of atrasentan with radiation therapy and temozolomide in newly diagnosed GBM is warranted to evaluate the efficacy of this novel agent.

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...

Purpose: Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD). Experimental Design: Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (−) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay. Results: Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in −EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation. Conclusions: This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.

Penicillamine is an oral agent used to treat intracerebral copper overload in Wilson's disease. Copper is a known regulator of angiogenesis; copper reduction inhibits experimental glioma growth and invasiveness. This study examined the feasibility, safety, and efficacy of creating a copper deficiency in human glioblastoma multiforme. Forty eligible patients with newly diagnosed glioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) in conjunction with a low-copper diet and escalating doses of penicillamine. Serum copper was measured at baseline and monthly. The primary end point of this study was overall survival compared to historical controls within the NABTT CNS Consortium database. The 25 males and 15 females who were enrolled had a median age of 54 years and a median Karnofsky performance status of 90. Surgical resection was performed in 83% of these patients. Normal serum copper levels at baseline (median, 130 microg/dl; range, 50-227 microg/dl) fell to the target range of50 microg/dl (median, 42 microg/dl; range, 12-118 microg/dl) after two months. Penicillamine-induced hypocupremia was well tolerated for months. Drug-related myelosuppression, elevated liver function tests, and skin rash rapidly reversed with copper repletion. Median survival was 11.3 months, and progression-free survival was 7.1 months. Achievement of hypocupremia did not significantly increase survival. Although serum copper was effectively reduced by diet and penicillamine, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.

A preliminary evaluation of the efficacy of irinotecan in patients with malignant glioma demonstrated modest activity. A markedly lower than expected incidence of drug-related toxicity was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of irinotecan in this patient population was considerably greater than in colorectal cancer patients. Concomitant medications used chronically in brain cancer patients, especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in patients with recurrent malignant gliomas to independently determine the maximum tolerated dose (MTD) of irinotecan in patients stratified according to the use of enzyme-inducing anticonvulsants (EIAs).Patients with recurrent malignant gliomas received irinotecan as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m(2)/week for both groups of patients (+/-EIA). Groups of/==" BORDER="0"3 patients were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of irinotecan, its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), and the glucuronide conjugate of SN-38, SN-38 glucuronide, were determined in all patients during treatment with the first weekly dose.Forty patients were enrolled into the study and treated with a total of 135 cycles of irinotecan. The MTD was determined to be 411 mg/m(2)/week in the +EIA cohort and 117 mg/m(2)/week in the -EIA cohort for the weekly x 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of irinotecan was distinctly dose dependent in the patients receiving EIAs, decreasing from approximately 50 liters/h/m(2) at the lower dose levels (125-238 mg/m(2)) to a mean +/- SD value of 29.7 +/- 9.0 liters/h/m(2) (n = 7) at the MTD. The grand mean CL for a group of 13 patients who were not taking EIAs, 18.8 +/- 10.6 liters/h/m(2), was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of SN-38 (P = 0.4) and SN-38 glucuronide (P = 0.55) were not significantly different at the MTDs for the two cohorts of patients.The MTD of irinotecan was 3.5 times greater in patients with malignant glioma who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of irinotecan. These findings have important implications for subsequent clinical trials to further evaluate irinotecan in brain cancer patients and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.

PURPOSE: To determine the toxicity, efficacy, and pharmacology of suramin in patients with recurrent or progressive recurrent high-grade gliomas. PATIENTS AND METHODS: Fifty adults were to receive suramin. However, if no responses were seen in the first ten patients, the study was to be terminated. A total of 12 patients were enrolled onto this trial. Ten patients had glioblastoma multiforme, and 11 had received prior nitrosoureas. RESULTS: Drug-related toxicities were modest and reversible. Three patients developed grade 3 to 4 neutropenia, constipation, diarrhea, or nausea. No CNS bleeding was observed. Median time to progression was 55 days (range, 17 to 242 days) and median survival was 191 days (range, 42 to 811 days). No partial or complete responses were seen at 12 weeks. However, the clinical outcome of three patients suggests that evidence of suramin activity may be delayed. One patient who “progressed” after 12 weeks of suramin had a subsequent marked reduction in tumor size and has maintained an excellent partial response for over 2 years without other therapy. Two others had disease stabilization and lived for 16 and 27 months. Pharmacokinetics from 11 patients revealed that all reached target suramin concentrations. CONCLUSION: This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas and may have efficacy in this disease. Its pharmacology seems unaffected by anticonvulsants. As a result of this data, suramin and radiation are now being administered concurrently to patients with newly diagnosed glioblastoma multiforme, with survival as the primary outcome.

Background: Despite advances in neuro-imaging, neurosurgery, radiation therapy, and chemotherapy, limited progress has been made in the treatment of patients with high-grade astrocytomas. The National Cancer Institute has attempted to speed advances in this field by funding CNS consortia to conduct innovative clinical trials in this patient population since 1994. Methods: The NABTT CNS Consortium is composed of a consortium headquarters and nine member institutions with outstanding multidisciplinary expertise, clinical and laboratory research capabilities, and access to large numbers of patients with brain tumors. Results: The objectives of the NABTT Consortium are to improve the therapeutic outcome for adults with primary brain tumors, to conduct basic science and clinical research, and to improve the care and quality of life of adults with primary brain tumors. NABTT's clinical studies have discovered important drug interactions between anticonvulsant and antineoplastic agents, defined the activity of paclitaxel and 9-aminocamptothecin in glioblastoma multiforme, tested a novel dose escalation strategy for brain tumor trials, and established new protocol “classes” to expedite and standardize clinical research in this field. Conclusions: Significant progress in the care of patients with primary brain tumors is likely to result from the highly focused and multidisciplinary efforts of the NIH-funded CNS consortia.

Purpose: We describe a practical, reliable, efficient dose-finding design for cytotoxic drugs applied in a multi-institutional setting. Methods: The continual reassessment method (CRM) was modified for use in phase I trials conducted through the New Approaches to Brain Tumor Therapy (NABTT) Consortium. Our implementation of the CRM uses (1) a simple dose-toxicity model to guide data interpolation, (2) groups of three patients to minimize calculations and stabilize estimates, (3) investigators' clinical knowledge or opinion in the form of data to make the process easier to understand, and (4) a flexible computer program and interface to facilitate calculations. Results: The modified CRM was used in two dose-finding trials of 9-aminocamptothecin in patients with newly diagnosed and recurrent glioblastoma who were taking anticonvulsant medication. The CRM located the maximum tolerated dose (MTD) efficiently in both trials. Compared to conventional designs, the CRM required slightly more than half the number of patients expected, did not greatly overshoot the MTD (i.e. no patients were treated at dangerously high doses), and did not underestimate the MTD. Conclusions: Our experience demonstrates the feasibility of implementing this design in multi-institutional trials and the possibility of performing dose-finding studies that require fewer patients than conventional methods.

PURPOSE The purpose of this study was to determine the response rate of paclitaxel administered at maximal tolerated doses (MTD) in patients with newly diagnosed glioblastoma multiform. PATIENTS AND METHODS All patients in this multicenter study were 45 years or older and had measurable residual tumor on postoperative MRI scans. Up to 3 cycles of paclitaxel were administered as a continuous 96-hour intravenous infusion prior to radiation, provided that the tumor did not enlarge on serial MRIs. The initial 10 patients were treated with the previously recommended phase II dose of 140 mg/m2. Less than anticipated toxicity led to the development of a phase I/II study in 24 patients in which paclitaxel doses were escalated separately in patients receiving (+EIAED) or not receiving (-EIAED), concomitant enzyme-inducing antiepileptic drugs. Paclitaxel plasma steady-state concentrations (Css) were measured during the first cycle of chemotherapy. Response was the primary efficacy endpoint for this study, although survival was also assessed. RESULTS The MTD was 140 mg/m2 in the -EIAED, and 200 mg/m2 in the +EIAED patient groups. The mean Css for the -EIAED patients treated at 140 mg/m2 was 38 nM, whereas the mean Css for +EIAED patients were 17 nm at 140 mg/m2, 27 nM at 175 mg/m2, 46 nM at 200 mg/m2, and 51 nM at 230 mg/m2. One patient, who had a verified partial response, had his diagnosis changed to an anaplastic oligodendroglioma on subsequent central neuropathologic review. None of the 15 assessable glioblastoma patients treated at or above the MTD doses showed a radiographic response to paclitaxel. The median survival of eligible patients on this protocol was 355 days (95% CI, 255 to 485 days), which is similar to the survival of comparable patients treated with conventional therapy. CONCLUSIONS These results suggest that (1) paclitaxel given as a 96-hour infusion at the MTD has minimal activity in patients with untreated glioblastoma, (2) the concomitant administration of EIAEDs alters the pharmacology of paclitaxel, resulting in a lower Css, reduced systemic toxicity, and higher dose requirements, (3) this study design, in which a new agent is given prior to radiation therapy (with serial monitoring of MRI), did not adversely affect survival in this patient population.

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]

TPS2105 Background: Despite recent advances in their treatment, high-grade gliomas (HGG) carry a dismal prognosis. Treatment options at recurrence are particularly limited and a re-challenge with temozolomide (TMZ) frequently appears as the most appropriate systemic treatment option in patients whose progression occurred off TMZ. This study investigates the sequential treatment of mibefradil (MIB), a selective Cav3 calcium channel blocker, and standard dose TMZ. Preclinical data showed that Cav3 inhibitors such as MIB can slow tumor growth without significant effect on normal tissues and can induce cell cycle arrest in cancer cells at the G1/S-phase checkpoint. We hypothesize that withdrawal of MIB could synchronize and release cells into S-phase, thereby potentiating the cytotoxic effect of TMZ. Methods: This trial is an open-label, multicenter phase I study, structured into a dose escalation phase to determine the maximum tolerated dose of MIB (MTD; Primary Objective) and an expansion cohort of 10 patients at the MTD level. Adults with recurrent HGG (WHO grade 3 or 4) who have previously received standard adjuvant therapy with radiation (RT) and TMZ (last dose ≥ 3 months prior to enrollment) and who have not received other cytotoxic therapy (except for carmustine wafers) are eligible. Patients receive oral MIB for 7 days on a 4 x/day (QID) schedule, followed by standard dose TMZ at 150-200 mg/m2 for 5 days each 28-day cycle. Dose finding uses a modified 3+3 design, starting at MIB 25 mg po QID (100 mg/day) with dose increases of 25 mg/dose per dose level. The target dose-limiting toxicity (DLT) rate is ≤ 33%. Secondary Objectives: (1) safety and adverse event analysis (incl. cardiac monitoring during cycle 1), (2) pharmacokinetic profile of MIB, (3) response assessment (RANO criteria), and (4) assessment of the potential effect of MIB on tumor DNA synthesis as determined by fluorothymidine positron emission tomography (FLT PET; extension cohort). Enrollment status as of January 2013: cohort 1 completed without DLT; cohort 2 enrolling at MIB 200 mg/day. Clinical trial information: NCT01480050.

2043 Background: Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGFA, VEGF-B and placental growth factor (PlGF), depleting circulating levels of these growth factors. Methods: The Adult Brain Tumor Consortium (ABTC) conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed high-grade gliomas (HGG). Three cohorts were examined: Cohort 1: Aflibercept with radiotherapy and concomitant temozolomide; Cohort 2: Aflibercept and adjuvant temozolomide using the 5/28 regimen; and Cohort 3: Aflibercept and adjuvant temozolomide using the 21/28 day regimen. Eligibility criteria included histologically proven newly-diagnosed glioblastoma (GBM) or anaplastic glioma (AG), > 18 yrs old, KPS > 60, adequate bone marrow reserve and organ function. Patients initially received 2 mg/kg of aflibercept every 2 weeks. If no dose-...

Abstract 71 Introduction: Bone marrow aspiration and biopsy (BMAB) is one of the most frequently performed and painful procedures in cancer patients. Magnetic acupressure has been used to reduce pain in patients in China. Our study was designed to study the efficacy of magnetic acupressure in reducing pain in cancer patients undergoing BMAB. Patients and Methods: Patients eligible for this IRB approved study had cancer, had a BMAB planned, and had not previously had acupuncture or acupressure. They were stratified by the number of prior BMAB they had experienced and randomly assigned to receive either magnetic acupressure at large intestine 4 point or at a non-acupuncture point (placebo) located in the proximal fourth interosseus space of the hand. All BMAB procedures were done by one operator (JS) and all acupressure was performed by one experienced operator (TB). All patients as well as the BMAB operator and data collector were blinded to treatment assignment. A visual analog score (VAS) was used to measure the patient's baseline pre-BMAB pain and the pain associated with the BMAB procedure. The acupressure operator was blinded to baseline pain scores and the pain associated with the BMAB by having the patient complete a form which was seen only by an independent data collector. The differences in VAS associated with the BMAB in the real versus placebo acupressure cohorts were compared to determine the analgesic efficacy of magnetic acupressure. Results: From 5/08 to 6/09, 77 cancer patients (47 male, 63 Caucasian, with a median age: 56 yrs, range: 21-80) undergoing BMAB at the Johns Hopkins Kimmel Sidney Comprehensive Cancer Center were enrolled in the study. Thirty-seven patients were randomized to the intervention arm and 40 to the control arm. Thirty-one patients (84%) in the intervention arm and 30 patients (75%) in the control arm had more than 1 BMAB prior to this study (p=0.34). Gender, analgesic or anxiolytic medications intake within 12 hours of BMAB and the pain score before BMAB were well balanced between two arms. The primary outcome was patient rated VAS pain score (0 to 10) during BMAB assessed after the procedure. Only one patient (2.7%) in the intervention arm experienced severe pain (VAS≥7) compared to 8 patients (20%) in the control arm (p=0.03, two- tailed Fisher's exact test). Using a multivariate logistic regression analysis to adjust for the number of BMAB patients had prior to this study, the odds of patients experiencing severe pain during BMAB procedure was 8.4 times (95% CI: 0.98-71.9) higher in the control arm versus the intervention arm. Forty-five percent of patients in each arm requested acupressure for future BMABs. No significant side effects or discomforts related to acupressure were reported by patients in either arm. Conclusions: These results suggest that magnetic acupressure significantly reduces the proportion of patients experiencing severe pain during BMAB. As acupressure requires minimal training and expense and was not associated with adverse events, it could be readily incorporated as a treatment option in this patient population. A larger, multi-centered, randomized, placebo controlled trial is planned to confirm these observations. Disclosures: No relevant conflicts of interest to declare.

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.

2064 Background: Gadolinium texaphyrin (Gad Tex) is a putative radiosensitizer which inhibits cellular respiration resulting in the production of reactive oxygen species and induces apoptosis (Drugs R D. 2004; 5(1):52–7). Methods: The New Approaches to Brain Tumor Therapy (NABTT) consortium conducted a prospective phase I dose-escalation trial to determine the maximum tolerated dose of Gad Tex along with brain radiation therapy (RT) in newly diagnosed glioblastoma multiforme with KPS > 60. RT was 60 Gy in 30 fractions, 5 days per week over 6 weeks, to localized treatment fields. Two different dosing regimens of Gad Tex were utilized. In regimen A, the initial dose was 2.5 mg/kg with each daily fraction of RT whereas in regimen B it was 5.5 mg/kg with every fraction of RT. Gad Tex was administered 2–5 hours before each radiation treatment. Results: The initial dose in both regimen A and B was found not to be tolerable. Of three patients treated at 2.5 mg/kg/dose on regimen A (daily dosing), one completed planned therapy (30 doses of Gad Tex), one had treatment stopped after 16 doses of Gad Tex when diffuse pulmonary infiltrates with shortness of breath developed and returned after rechallenge with an additional dose of Gad Tex, and one patient developed an allergic reaction after 15 doses of Gad Tex which returned on rechallenge. Of three patients treated at 5.5 mg/kg/dose (qod dosing) on regimen B, one completed planned therapy (15 doses of Gad Tex) after a dose reduction related for skin blisters, and the other two patients discontinued treatment after 9 doses of Gad Tex for debilitating skin blisters. Conclusions: Gad Tex was poorly tolerated as administered in this small phase I study as 4 of 6 patients experienced dose limiting toxicities. As such, NABTT elected not to pursue this drug in subsequent clinical trials. However, similar or more intensive regimens utilizing Gad Tex in combination with brain RT have been successfully administered in patients with newly diagnosed glioblastoma and brain metastases. No significant financial relationships to disclose.

2063 Background: De novo purine biosynthesis entails two metabolic pathways of which one pathway is frequently impaired in cancer due to gene deletion of the rate limiting enzyme, methythioadenosine phosphorylase (MTAP). In MTAP-deficient cancers, SDX-102 inhibits purine biosynthesis by blocking the remaining synthetic pathway. This study was to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetic activity of SDX-102 in the treatment of recurrent MTAP-deficient malignant gliomas. Methods: Eligible patients had recurrent supratentorial MTAP-deficient malignant gliomas treated previously with surgery, radiation and = 2 regimens of chemotherapy. Dose escalation was conducted separately for patients taking enzyme inducing anti-seizure drugs (EIASD+) and for those not (EIASD-). The starting dose in both groups was 80 mg/m2/day continuous infusion for 5 days every 3 weeks, cycle length was 3 weeks. Dose escalation was in a stepwise fashion in cohorts of three patients, up to a maximum dose of 125 mg/m2/day. Results: 118 patients were screened of which 39 (33%) had MTAP-deficient tumors. 21 patients (14 males/7 females) were enrolled between 9/17/04 and 3/17/06. Median age was 50 years (23–76); median KPS was 90 (60–100); 16 patients (76%) had GBM. Two dose levels of SDX-102 were tested in the EIASD+ group: 80 mg/m2/day (n=4) and 100 mg/m2/day (n=3), 3/3 dose limiting toxicity (DLT) were noted with grade 3 mucositis at 100 mg/m2/day , so in the EIASD+ group the MTD was 80 mg/m2/day. Three dose levels were tested in the EIASD- group: 80 mg/m2/day (n=4), 100 mg/m2/day (n=7), 1/3 patients had DLT (Grade 4 mucositis) at 100 mg/m2/day and the cohort was expanded for additional 3 patients without DLT noted; and 125 mg/m2/day (n=3) amongst whom no DLT was observed. No MTD was determined in the EIASD- group because the MTAP assay became unavailable through the sponsor. There were a range of 1–14 cycles administered in this patient population. Conclusions: SDX-102 infusion is safe and feasible in patients with recurrent MTAP-deficient malignant gliomas. The MTD in EIASD+ patients is 80 mg/m2/day. The EIASD-group MTD has not been determined however the highest dose tested is 125 mg/m2/day. No significant financial relationships to disclose.

1518 Purpose The aim of this study was to evaluate response and survival following the administration of R115777 prior to and following radiation therapy in newly diagnosed patients with GBM who ha...

1538 Background: Significant tumor control and prolongation of survival have been demonstrated by combined use of radiosurgery and antivascular agent, Arsenic Trioxide (ATO), in rodent gliosarcoma model in rats. This agent is now undergoing clinical evaluation in the NABTT Brain Tumor Consortium in a Phase I trial with ATO dose escalation in combination with fractionated radiation therapy. Since this agent showed rapid effect on the tumor vasculature in the animal studies, MRI perfusion and diffusion studies were performed shortly following ATO administration. Methods: The patients were treated with external beam radiotherapy 60 Gy in 6 weeks with ATO at a starting dose of 0.25 mg/kg once a week during the course radiotherapy. ATO dose was escalated by 0.05 mg. The perfusion images were acquired using a Echo Planar Image (EPI) sequence. Perfusion parameters were Mean Transit Time (MTT), relative Cerebral Blood Volume (rCBV), and relative Cerebral Blood Flow (rCBF). The perfusion parameter values under reg...

1548 Background: NABTT opened trial 2106 to determine the maximum tolerated dose (MTD) of GliaSite Brachytherapy (GSBT) in the treatment of recurrent GBM. This trial closed 2004 without reaching th...