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. 2011 Nov;13(Suppl 3):iii85–iii91. doi: 10.1093/neuonc/nor154

ONGOING CLINICAL TRIALS

PMCID: PMC3199166
Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-01. IMPROVING LOW-GRADE GLIOMA EXTENT OF RESECTION: INTRAOPERATIVE CONFOCAL MICROSCOPY ENABLES VISUALIZATION OF 5-AMINOLEVULINIC ACID FLUORESCENCE

Laura A Snyder 1, Norissa Honea 1, Stephen W Coons 1, Jennifer Eschbacher 1, Kris A Smith 1, Robert F Spetzler 1, Nader Sanai 1

Abstract

INTRODUCTION: Greater extent of resection for low-grade glioma patients corresponds with improved clinical outcome, yet remains a central challenge to the neurosurgical oncologist. Although 5-aminolevulinic acid (5-ALA)-induced tumor fluorescence is a strategy that can improve glioma extent of resection, only glioblastomas routinely fluoresce following 5-ALA administration. Intraoperative confocal microscopy adapts conventional confocal technology to a hand-held probe that provides real-time fluorescent imaging at up to 1000-fold magnification. We report a combined approach using intraoperative confocal microscopy to visualize 5-ALA tumor fluorescence in low-grade gliomas during the course of microsurgical resection. METHODS: Following 5-ALA administration, newly diagnosed low-grade glioma patients underwent microsurgical resection. Intraoperative confocal microscopy was conducted at (1) the initial encounter with the tumor, (2) the midpoint of tumor resection, and (3) the presumed brain-tumor interface. Histopathological analysis of these sites correlated tumor infiltration with intraoperative cellular tumor fluorescence. RESULTS: Ten consecutive patients with World Health Organization (WHO) grades I and II gliomas underwent microsurgical resection with 5-ALA and intraoperative confocal microscopy. Macroscopic tumor fluorescence was not evident in any patient. However, in each case, intraoperative confocal microscopy identified tumor fluorescence at a cellular level, a finding that corresponded to tumor infiltration on matched histological analyses. CONCLUSIONS: Intraoperative confocal microscopy can visualize cellular 5-ALA-induced tumor fluorescence within WHO grades I and II low-grade gliomas and at the brain-tumor interface. To assess the clinical value of 5-ALA for high-grade gliomas in conjunction with neuronavigation and for low-grade gliomas in combination with intraoperative confocal microscopy and neuronavigation, a phase IIIa randomized, placebo-controlled trial (BALANCE) is underway at our institution.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-02. A PILOT STUDY OF SYSTEMICALLY ADMINISTERED BEVACIZUMAB IN PATIENTS WITH NEOPLASTIC MENINGITIS: IMAGING, CLINICAL, CSF, AND BIOMARKER OUTCOMES

Morris D Groves 1, John DeGroot 1, Ivo Tremont 1, Arthur Forman 1, Sanghee Kang 1, Be-Lian Pei 1, Walker Julie 1, Diana Schultz 1, Ying Yuan 1, Nandita Guha 1, Wen-Jen Hwu 1, Nicholas Papadopoulos 1, Kevin Camphausen 2, WK Alfred Yung 1

Abstract

INTRODUCTION: Roughly 75% of patients with neoplastic meningitis (NM) due to breast cancer, lung cancer, or melanoma have elevated VEGF levels in their CSF. We administered intravenous (IV) bevacizumab to such patients to evaluate clinical, imaging, CSF, and various other biomarker outcomes. METHODS: Patients with NM were treated with IV bevacizumab 10 mg/kg every 2 weeks, and underwent clinical and MRI examinations, and CSF, plasma, and urine collection before treatment, then every 2 weeks x 3, then every 6 weeks thereafter. Collected samples are to be analyzed for VEGF, soluble VEGF receptors, bFGF, and other circulating soluble and cellular biomarkers of angiogenesis and anti-angiogenesis treatment resistance. RESULTS: Fifteen patients (11 females) were enrolled. Median age was 40 years (range, 21-72 years) and median KPS was 80 (range, 60-100). Cancers were breast (9), lung (3), and melanoma (3). MRI showed NM in the brain in 12 of 15 patients (80%) and in the spine in 7 of 15 patients (47%). CSF was positive for tumor cells in 14 of 15 patients (93%). Four patients remain on protocol; 9 patients have died. Safety data review is pending. Median PFS is 6 weeks (range, 2-28 weeks-4 censored). Median OS is 14 weeks (range, 2-70 weeks-6 censored). Best protocol responses were CR (1), SD (6), PD (7), and TE (1). CSF responses were CR (2), SD-remained positive or negative (6), and TE/no data (7). MRI responses were PR (3), SD (6), PD (2), and TE/no data (4). Clinical responses were PR (1), SD (7), PD (6), and TE (1). Correlative biomarker data from CSF, plasma, and urine are pending. CONCLUSIONS: In patients with NM, IV bevacizumab results in some response or stable disease. Survival, in this small sample, appears noninferior to other treatments for NM. The study is ongoing. Changes in CSF, plasma, and urine VEGF and other experimental biomarkers of angiogenesis as well as more complete outcomes and safety data will be presented.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-03. PROSPECTIVE MULTIMODALITY THERAPY FOR NEWLY DIAGNOSED GLIOBLASTOMA WITH SURGICAL RESECTION, IMPLANTABLE BCNU CHEMOTHERAPY AND COMBINATION RADIOTHERAPY AND TEMOZOLOMIDE: LONG-TERM FOLLOW-UP

Timothy Ryken 1

Abstract

INTRODUCTION: This study prospectively evaluated the safety and long-term survival of surgical resection with implantable BCNU, oral temozolomide, and radiotherapy for newly diagnosed glioblastoma. METHODS: Patients undergoing resective surgery for glioblastoma received implantable BCNU chemotherapy and concomitant temozolomide with external-beam radiotherapy, followed by temozolomide for 12 months. Toxicities and long-term survival were monitored. RESULTS: Twenty-one patients were included with a median age of 60 years (range, 49 to 78 years) including 9 females and 12 males. Overall average survival for the group was 18.2 months. One patient died of postoperative cardiopulmonary complications and was excluded from the subsequent survival analysis. Of the remaining 20 patients, the average survival was 18.9 months, 25.6 months in patients 65 years and younger, and 22.4 months in patients age 70 years and younger. There were 9 grade 3 to 5 toxicities in 5 patients: grade 5 death (1; cardiopulmonary collapse and multi-organ system failure); grade 4 nausea, vomiting, seizure, pulmonary embolus; and grade 3 liver toxicity (2) and thrombocytopenia. None appeared related specifically to combination implantable BCNU and combination radiotherapy/temozolomide. CONCLUSIONS: The combination of cytoreductive surgery with implantable BCNU combined with concomitant temozolomide and radiotherapy does not appear to increase the toxicity of treatment above what would be expected with either alone. Although a phase II design, the potential for an additive or synergistic effect is suggested by the 19 to 26 month survival.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-04. SALVAGE THERAPY WITH SINGLE-AGENT BENDAMUSTINE FOR RECURRENT ANAPLASTIC GLIOMA

Sandra K Johnston 1, Carrie Graham 1, Sean Grimm 2, Howard Colman 3, Jeff Raizer 2, Marc C Chamberlain 1

Abstract

BACKGROUND: We conducted a prospective multi-institution phase II study of the novel alkylator, bendamustine, in adult patients with recurrent temozolomide-refractory anaplastic gliomas (AG) with a primary objective of evaluating 6-month progression free survival (PFS). METHODS: Ten patients (4 men; 6 women), ages 31-59 years (median, 38 years), with recurrent AG were treated. All patients had previously been treated with surgery, involved-field radiotherapy, and temozolomide chemotherapy. Three patients were treated at first recurrence following re-operation, and 7 patients were treated at second recurrence (3 previous bevacizumab treatment). Bendamustine was administered intravenously on 2 consecutive days (100 mg/m2/day) every 4 weeks (operationally defined as a single cycle). Neurological evaluation was performed every 4 weeks; neuroradiographic evaluation was performed every 8 weeks; laboratory assessments were performed on days 21 and 28 of each cycle. RESULTS: All patients were evaluable. A total of 32 cycles of bendamustine (median, 2 cycles; range, 1-6) was administered. Grade 3 or higher bendamustine-related toxicity included lymphopenia (6/10 patients, 60%) and clinically significant nausea and vomiting (1, 10%). One patient required a dose reduction to 75 mg/m2/day due to prolonged grade 2 neutropenia. No patient required transfusion or developed neutropenic fever. Best response was stable disease in 3 patients (30%). No treatment-related deaths occurred. Time-to-tumor progression ranged from 1–12+ months (median, 1+ month). Survival ranged from 2-14+ months (median, 6+ months). Six patients are alive, 4 with radiographic stable disease (3 receiving alternative salvage therapy] and 2 with known disease progression (none receiving alternative therapy). Six-month PFS was 30%. CONCLUSIONS: Bendamustine demonstrated sufficient efficacy with acceptable toxicity in this initial cohort of adult patients with recurrent AG that prespecified study expansion is planned and actively enrolling. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Cephalon, Inc.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-05. HOW TO OVERCOME DOSE-LIMITING TOXICITY IN TREATING GLIOBLASTOMA PATIENTS WITH O6-BENZYLGUANINE AND TEMOZOLOMIDE

Maciej M Mrugala 1, Jennifer E Adair 2, Brian C Beard 2, Daniel L Silbergeld 3, Jason K Rockhill 3, Hans-Peter Kiem 1

Abstract

BACKGROUND: Glioblastoma, confers poor prognosis despite aggressive treatment. Patients with unmethylated MGMT promoter tend to have shorter survival. Combination chemotherapy including carmustine (BCNU) or temozolomide (TMZ) with the MGMT inhibitor O6-benzylguanine (O6BG) has been used, but hematopoietic toxicity allows for only very few cycles at full dose. OBJECTIVE: To assess safety and efficacy of a retroviral vector encoding the O6BG-resistant MGMTP140K gene for transduction and autologous transplantation of hematopoietic stem cells (HSCs) in MGMT unmethylated, newly diagnosed glioblastoma patients in an attempt to protect bone marrow during combination O6BG/TMZ therapy. METHODS: Five patients have been enrolled in this phase I/II study. Patients underwent tumor resection, standard radiation therapy without TMZ followed by G-CSF mobilization, apheresis, and conditioning with 600 mg/m2 BCNU prior to infusion of gene-modified cells. Posttransplant, patients were treated with 28-day cycles of single-dose TMZ (472 mg/m2) paired with 48-hour intravenous O6BG (120 mg/m2 bolus, then 30 mg/m2/day). RESULTS: The BCNU dose was nonmyeloablative with ANC below 100/µL for ≤ 2 days and nadir thrombocytopenia of 28,000/µL. Within 31 days following transplant, gene-modified white blood cells represented between 38.6% and 60.0% of peripheral blood white blood cells and 51% to 60% of peripheral blood granulocytes. Patients have received up to 9 cycles of O6BG/TMZ, with evidence for chemoprotection and selection of gene-modified cells. No extra-hematopoietic toxicity has been observed. Long-term analysis is available for 3 patients, 2 of whom are alive at more than 22 months since diagnosis. CONCLUSIONS: These data demonstrate feasibility of achieving significant engraftment of MGMTP140K- modified cells with a well-tolerated dose of BCNU, allowing for more efficient administration of TMZ with O6BG. The results obtained thus far provide a platform for further optimization of combination therapy with O6BG and TMZ. In addition, survival has been favorable in all 3 patients with follow-up of more than 1 year.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-06. PRELIMINARY DATA FROM A MULTICENTER, PHASE II, RANDOMIZED, NONCOMPARATIVE CLINICAL TRIAL OF RADIATION THERAPY AND TEMOZOLOMIDE WITH OR WITHOUT VANDETANIB IN NEWLY-DIAGNOSED GLIOBLASTOMA

Eudocia Quant Lee 1, Tracy T Batchelor 2, Andrew B Lassman 3, David S Schiff 4, Thomas J Kaley 3, Eric T Wong 5, Tom Mikkelsen 6, Benjamin W Purow 4, Jan Drappatz 1, Andrew D Norden 1, Rameen Beroukhim 1, Stephanie Weiss 7, Brian M Alexander 7, Christine Sceppa 8, Mary Gerard 8, Stephen D Hallisey 8, Caelainn A Bochacki 8, Katrina H Smith 8, Alona M Muzikansky 2, Patrick Y Wen 1

Abstract

EGFR and VEGFR signaling have been implicated in the development and growth of glioblastoma (GBM). In addition, angiogenesis inhibitors may enhance radiation sensitivity. Vandetanib is an inhibitor of VEGFR-2 and EGFR tyrosine kinase activities. We conducted a randomized phase II study of vandetanib in patients with newly diagnosed GBM in combination with radiation therapy (RT) and temozolomide (TMZ). A total of 114 newly diagnosed GBM patients (pts) were planned to be randomized in a ratio of 1:2 to Arm A: RT/TMZ (38 pts) or Arm B: vandetanib 100 mg daily (76 pts) + RT/TMZ. All pts receive RT (60 Gy) and concurrent TMZ (75 mg/m2 daily), followed by adjuvant TMZ for up to 12 cycles (150-200 mg/m2 on days 1-5 of each 28-day cycle). Pts with age ≥ 18, Karnofsky performance status ≥ 60, and not on enzyme-inducing antiepileptic drugs are eligible. Primary endpoint is overall survival (OS) from the date of randomization. Secondary endpoints include median progression-free survival (PFS) and safety. To date, we have enrolled 98 pts (33 in Arm A and 65 in Arm B) with median age of 55 years (range, 23-73 years) in Arm A and 59 years (range, 23-83 years) in Arm B. Median KPS is 90 (range, 60-100) in both arms. Most frequent Gr ≥ 3 AEs in the vandetanib arm were lymphopenia (20%), thrombosis (12.5%), transaminitis (8%), and leukopenia (5%). Preliminary median OS is 487 days with 95% CI (350, NR) in Arm A and 503 days with 95% CI (451, 634) in Arm B. Median PFS is 141 days with 95% CI (104, 252) in Arm A and 127 days with 95% CI (93, 165) in Arm B. Although reasonably well tolerated, the addition of vandetanib to standard chemoradiation in newly diagnosed GBM may not significantly prolong overall survival compared to historical controls. Updated efficacy and toxicity data will be presented.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-07. A PHASE II AND PHARMACODYNAMIC TRIAL OF RO4929097 FOR PATIENTS WITH RECURRENT/PROGRESSIVE GLIOBLASTOMA

David M Peereboom 1, Tom Mikkelson 2, Andrew E Sloan 3, Jeremy N Rich 1, Jeffrey G Supko 4, Xiaobu Ye 5, Cathy Brewer 1, Kathleen Lamborn 6, Michael Prados 6, Stuart A Grossman 5

Abstract

INTRODUCTION: Cancer stem-like cells (CSCs) are capable of self renewal and differentiation within a tumor. These properties are likely a major cause of resistance to chemotherapy and radiotherapy. Therefore, CSCs are an attractive target for therapy of GBM. Proliferation of CSCs occurs via several signaling pathways. One of the major pathways is Notch. Expression of Notch is critical for survival and proliferation of human gliomas. Gamma secretase (GS) is a critical enzyme in the Notch pathway. Therefore, disruption of the Notch pathway by inhibition of GS is a logical treatment strategy for patients with GBM. RO4929097 is an oral small molecule inhibitor of GS. This phase II and pharmacodynamic study assesses the efficacy of RO4929097 against rGBM and includes biomarker assays on freshly resected GBM samples from patients receiving this agent. METHODS: Two groups of adults with contrast-enhancing rGBMs and unlimited prior chemotherapy regimens (except GS inhibitors) are eligible. Group A will consist of 40 patients who receive RO4929097 only, and Group B will consist of 20 patients who receive the drug before and after resection of rGBM. The primary endpoint is 6-month progression-free survival. Secondary endpoints include biomarker studies on fresh tumor from Group B patients that is assayed for neurosphere generation, expression of Notch pathway components and downstream targets, and survival of mice bearing orthotopic xenografts. A 25% reduction of neurosphere generation compared to a contemporaneous group of rGBM patients will be considered significant. RESULTS: To date, 11 patients (all in Group A) have enrolled in the study, although the follow-up is very short (< 3 months). Correlative biology and clinical data will be presented at the meeting. CONCLUSION: This study is designed to provide preliminary information on drug effects in patients (Group A) and in tumor samples resected from patients and studied in neurospheres and implanted in mice (Group B).

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-08. PHASE II STUDY USING THE RESPONSE ASSESSMENT IN NEURO-ONCOLOGY (RANO) CRITERIA TO EVALUATE THE EFFICACY OF VERUBULIN WITH RADIATION THERAPY AND TEMOZOLOMIDE IN SUBJECTS NEWLY DIAGNOSED WITH GLIOBLASTOMA MULTIFORME: PART A SAFETY AND TOLERABILITY RESULTS

Jay-Jiguang Zhu 1, Lawrence D Recht 2, Howard Colman 3, Santosh Kesari 4, Lyndon J Kim 5, Alfred H Balch 6, Cathy C Pope 6, Maryse Brulotte 6, Andrew P Beelen 6, Marc C Chamberlain 7

Abstract

BACKGROUND: Verubulin is a microtubule destabilizer and vascular disrupting agent that achieves high brain concentrations in animals. Combining verubulin with standard-of-care therapy may improve survival rates of patients with glioblastoma (GBM). METHODS: This study was designed to establish the safety, tolerability, and efficacy of verubulin when combined with radiation therapy (RT) and temozolomide (TMZ) in adult patients with newly diagnosed GBM. Part A is an open-label, standard 3 + 3 dose-finding design to establish the MTD of IV verubulin (doses 2.2, 3.3, or 2.8 mg/m2) when combined with RT/TMZ. Part B is an open-label, randomized, 2-arm comparative trial. Subjects in Part B will receive either RT/TMZ alone or in combination with verubulin at the MTD dose established in Part A. Treatment consists of an initial 6-week period of RT (200 cGy x 30 doses; 5 days/week), TMZ (75 mg/m2 QD for 42 days), +/− verubulin (weekly for 3 weeks, 1 week off, then weekly for 2 weeks) followed by a 28-day treatment rest, then 28-day cycles of TMZ (150-200 mg/m2 QD for 5 days/cycle), +/− verubulin (weekly for 3 weeks/cycle). The primary endpoint is 9-month progression-free survival (PFS-9). Study entry criteria include adults with histologically proven GBM who have not received any treatment other than tumor resection, KPS ≥ 70, and free of active cardiovascular disease or uncontrolled hypertension. Response will be assessed using the Response Assessment in Neuro-Oncology (RANO) criteria. Tumor samples will be collected to assess the relationship between tumor biomarkers/subtype and clinical outcome. RESULTS: Safety and tolerability data from Part A (ongoing) will be presented. CONCLUSION: This phase II trial will determine if PFS is prolonged by the addition of verubulin to RT/TMZ in adults with newly diagnosed GBM.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-09. UPDATED SURVIVAL DATA OF THE PHASE III CLINICAL TRIAL OF NOVOTTF-100A VERSUS BEST STANDARD CHEMOTHERAPY FOR RECURRENT GLIOBLASTOMA

Eric T Wong 1, Zvi Ram 2, Philip H Gutin 3, Roger Stupp 4

Abstract

NovoTTF-100A (TTF) is a portable device delivering low-intensity, intermediate-frequency, alternating electric fields using noninvasive, disposable scalp electrodes. TTF interferes with tumor cell division, and it has been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent glioblastoma (rGBM) based on data from a phase III trial. This presentation describes the updated survival data 2 years after completing recruitment. Adults with rGBM (KPS ≥ 70) were randomized (stratified by surgery and center) to either continuous TTF (20-24 h/day, 7 days/week) or efficacious chemotherapy based on best physician choice (BPC). The primary endpoint was overall survival (OS), and secondary endpoints were PFS6, 1-year survival, and QOL. Patients were randomized (28 US and European centers) to either TTF alone (n = 120) or BPC (n = 117). Patient characteristics were balanced, median age was 54 years (range, 23-80 years), and median KPS was 80 (range, 50-100). One quarter of the patients had debulking surgery, and over half of the patients were at their second or later recurrence. OS in the intent-to-treat (ITT) population was equivalent in TTF versus BPC patients (median OS, 6.6vs. 6.0 months; n = 237; p = 0.26; HR = 0.86). With a median follow-up of 33.6 months, long-term survival in the TTF group was higher than that in the BPC group at 2, 3, and 4 years of follow-up (9.3% vs. 6.6%; 8.4% vs. 1.4%; 8.4% vs. 0.0%, respectively). Analysis of patients who received at least one treatment course demonstrated a survival benefit for TTF patients compared to BPC patients (median OS, 7.8 vs. 6.0 months; n = 93 vs. n = 117; p = 0.012; HR = 0.69). In this group, 1-year survival was 28% vs. 20%, and PFS6 was 26.2% vs. 15.2% (p = 0.034). TTF, a noninvasive, novel cancer treatment modality shows significant therapeutic efficacy with promising long-term survival results. The impact of TTF was more pronounced when comparing only patients who received the minimal treatment course. A large-scale phase III trial in newly diagnosed GBM is ongoing.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-10. AUSTRALIAN GENOMICS AND CLINICAL OUTCOMES OF GLIOMA: CHARACTERIZING A RESEARCH POPULATION

Julie Marsh 1, Kerrie McDonald 2, Helen Wheeler 3, Charles Teo 4, Lauren Martin 1, Lyle Palmer 5, Michael Rodriguez 6, Michael Buckland 7, Eng-Siew Koh 8, Michael Back 9, Bruce Robinson 7, David Joseph 10, Anna K Nowak 1

Abstract

The Australian Genomics and Outcomes of Glioma (AGOG) study is a comprehensive bio-banking and clinical data resource to promote collaborative research use. We aimed to clinically characterize the current AGOG population. Consecutive consenting patients with a pre- or postoperative diagnosis of a glioma were enrolled from 5 Australian sites with a high neuro-oncology case load from January 2008, and recruitment is ongoing. Patients donate biospecimens (fresh tumor, genomic DNA, RNA, and serum), complete an epidemiological questionnaire, and have lifetime follow-up for treatment received and survival. Five hundred fifty-nine patients have consented; 61% are male. The percentage of patients with grades 1, 2, 3, and 4 glioma are 2%,12%,19%, and 67%, respectively. Mean patient age increased with grade of tumor. Of patients with grade 4 glioma, 25% had biopsy alone, 18% had partial resection, and 56% had total resection with or without lobectomy as the primary surgical procedure. Of patients with grade 4 glioma receiving radiotherapy, 83% received 60 Gy in 30 fractions, of whom 99% completed treatment. However, 11% of those prescribed < 60 Gy did not complete radiotherapy. Ninety-five percent of patients treated with 60 Gy radiotherapy also received concurrent treatment with temozolomide chemotherapy, with 92% of these completing planned treatment. Median survival for patients with grade 4 glioma was 13.5 months from first surgical episode. Additional treatment data will be presented. In conclusion, these data characterize the clinical management received by AGOG individuals. While most patients with grade 4 glioma received best practice care, this study revealed a proportion of patients who are not fit for radiotherapy to 60 Gy or do not receive combined chemoradiotherapy. The AGOG biospecimen resource captures biospecimens and clinical data from individuals often considered ineligible for clinical trials and thus provides a representative study population for collaborative research.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-11. SAFETY AND FEASIBILITY OF MRI-GUIDED CONVECTION-ENHANCED DELIVERY OF NIMUSTINE HYDROCHLORIDE AGAINST RECURRENT GLIOMA AFFECTING BRAINSTEM

Ryuta Saito 1, Yukihiko Sonoda 1, Yoji Yamashita 1, Masayuki Kanamori 1, Toshihiro Kumabe 1, Teiji Tominaga 1

Abstract

Treatment of gliomas affecting brainstem such as diffuse brainstem gliomas represents a challenge. We have been working to develop novel convection-enhanced delivery (CED)-based strategy to overcome this disease. The chemotherapeutic agent, nimustine hydrochloride (ACNU), was infused by the method of CED. As monitoring the drug distribution during CED will be necessary, especially when infusing chemotherapeutic agents into brainstem lesions, we mixed chelated gadolinium into the infusion solution. In this study, we report 4 cases of recurrent glioma that affected brainstem regions and were treated with CED of ACNU aided by MRI monitoring to detect the co-infused gadolinium chelate (Gd-DOTA). Patients underwent stereotactic insertion of the catheter and received CED infusion. Although moderate aggravations in neurological symptoms were observed during and immediately after infusion, these disappeared later leaving no additional disability in patients. MRI successfully monitored the infusion during CED. In one patient who was suffering recurrence of glioblastoma infiltrating the brainstem, the lesion disappeared after CED (reported in J Neurosurg Pediatr). In another patient suffering recurrence of brainstem glioma, this treatment attenuated the rapid enlargement of the recurrent tumor. The presented strategy was safe and feasible, and it worked in patients suffering recurrent glioma at brainstem. We are now continuing the phase I study to treat recurrent brain stem gliomas with the presented strategy.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-12. PHASE I STUDY OF THE SMOOTHENED (SMO) ANTAGONIST LDE225 IN PATIENTS WITH ADVANCED SOLID TUMORS: PRELIMINARY SAFETY, PHARMACOKINETICS (PK), PHARMACODYNAMICS (PD), AND ANTITUMOR ACTIVITY IN MEDULLOBLASTOMA

Jordi Rodon 1, Hussein A Tawbi 2, Anne L Thomas 3, Dereck D Amakye 4, Camille Granvil 4, Yaping Shou 4, Jyotirmoy Dey 4, Silvia Buonamici 5, Rodrigo Dienstmann 1, Alain C Mita 6, Reinhard Dummer 7

Abstract

INTRODUCTION: Aberrant activation of the Hedgehog pathway is implicated in the pathogenesis of many cancers, including a subset of medulloblastomas. LDE225 is a potent and selective inhibitor of Smo-dependent Hedgehog activity. In preclinical efficacy studies in Patched mutant medulloblastoma models, LDE225 exhibited dose-dependent tumor growth inhibition. Updated results of safety, PK, PD, and antitumor activity of LDE225 in patients with advanced solid tumors are presented. METHODS: Patients (n = 89) received oral doses of LDE225, ranging from 100 to 3000 mg QD and 250 to 750 mg BID, on a continuous 28-day schedule, with a single dose PK run-in period. Dose escalations were guided by Bayesian logistic regression. Study assessments included safety, PK, tumor response, and PD analyses in skin and tumor biopsies. RESULTS: LDE225 800 mg QD is well tolerated with no DLTs. QD doses ≥1000 mg and BID doses ≥400 mg caused DLTs characterized by reversible grade 3/4 increases in creatine kinase (CK) associated with muscle pain. DLTs occurred after ∼4-6 weeks of daily treatment and resolved completely following LDE225 discontinuation. High systemic drug exposure (day 15 AUC >40 µM hr) has been identified as a risk factor for DLTs. Grade 1/2 treatment-related toxicities (≥10% of patients) include nausea, vomiting, dysgeusia, anorexia, myalgia/muscle spasms, increased CK, and fatigue. Exposure-dependent target inhibition, measured by reduction in Gli1 mRNA expression, was observed in skin and tumor biopsies. Two of 8 heavily pretreated medulloblastoma patients experienced partial RECIST and PET responses (4 and ∼10 months, respectively). Correlative analysis demonstrates a link between Hh target gene expression and antitumor activity. CONCLUSIONS: The MTD for LDE225 is 800 mg QD PO. The principal DLT is grade 3/4 CK elevation. LDE225 exhibits exposure-dependent target inhibition and clinically relevant antitumor activity in tumors characterized by activated Hh signaling. These promising results support further development of LDE225 in medulloblastoma.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-13. PHASE II TRIAL OF CONTINUOUS SUNITINIB IN PATIENTS WITH RECURRENT OR PROGRESSIVE GLIOBLASTOMA (SURGE 01-07)

Markus Hutterer 1, Nowosielski Martha 2, Embacher Sabine 2, Gotwald Thaddäus 2, Stockhammer Florian 3, Marosi Christine 4, Oberndorfer Stefan 5, Greil Richard 1, Moik Martin 1, Buchroithner Johanna 6, Tüttenberg Jochen 7, Herrlinger Ullrich 8, Wick Wolfgang 9, Vajkoczy Peter 3, Stockhammer Günther 2

Abstract

PURPOSE: The purpose of our study was to determine the safety and efficacy of a continuous treatment regimen of sunitinib in patients with recurrent or progressive glioblastoma. PATIENTS AND METHODS: We conducted a multicenter prospective single-arm phase II study including 40 patients with histologically confirmed supratentorial primary glioblastoma at first progression after standard treatment. Inclusion criteria were age (range, 18-80 years), ECOG ≤ 2, and adequate organ functions. Only nonenzyme-inducing antiepileptic drugs were permitted. All patients received a starting dose of continuous 37.5 mg sunitinib daily. Depending on drug tolerability, the sunitinib dose was escalated to 50 mg or reduced to 25 mg. Treatment response and tolerability were assessed in 8-week intervals (clinical follow-up, MRI RANO-criteria). The histopathological findings and MRI readings were centrally reviewed. Primary study endpoint for efficacy was 6-month progression-free survival (PFS6). RESULTS: By May 2011, 36 patients (9 females, 27 males) with a median age of 57 years (range, 36-79 years) and a median ECOG 0.5 are evaluable for interim analysis. PFS6 was 11.1% (median PFS, 1.9 months). We observed 4 responding patients (11.1%) with stable diseases clinically and on MRI after 8 weeks and a median PFS of 16.5 months (range, 7.3-30.1 months; P<0.0001, t-test; 1 patient is still under treatment after >30 months). The most common toxicities were fatigue (47.2%), mucositis (30.6%), dysesthesias (30.6%), diarrhea (25.0%), leukocytopenia (27.8%), and thrombocytopenia (27.8%). Grade 3/4 toxicities (10/36 patients, 27.8%) included deep vein thrombosis (in one case with pulmonary embolism), mucositis, diarrhea, hand-foot syndrome, thrombocytopenia, sinus bradycardia, pneumonia and sepsis, in particular when treated with 50 mg sunitinib daily. CONCLUSION: Continuous sunitinib treatment in patients with first recurrence/progress of a glioblastoma was not effective in the majority of patients but associated with several and frequent toxicities impairing the patients quality of life. A subgroup of responsive patients, however, showed stable diseases lasting between 7-30 months. Ongoing translational studies aim to identify this sunitinib-responsive subgroup of glioblastoma patients.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-14. A RANDOMIZED PHASE II STUDY OF CARBOPLATIN AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA MULTIFORME (CABARET STUDY)

Kathryn M Field 1, Lawrence Cher 2, Helen Wheeler 3, Elizabeth Hovey 4, Anna K Nowak 5, John Simes 6, Kate Sawkins 6, Trevor France 6, Chris Brown 6; CABARET COGNO Investigators7

Abstract

Glioblastoma multiforme (GBM) is the most aggressive malignant glial tumor, and relapse is almost inevitable. There is no accepted standard management after disease progression. The CABARET clinical trial is a sequential stratified randomized phase II study that commenced in November 2010 and has recruited 11 of 120 patients. Patients must have recurrent GBM after radiotherapy and temozolomide, have had no other chemotherapy for GBM, have ECOG performance status of 0-2, and have measurable disease or resected recurrence. At least 3 months must have elapsed since radiotherapy. In part 1 of the study, patients are randomized 1:1 to intravenous bevacizumab 10 mg/kg 2-weekly and carboplatin AUC5 4-weekly or to bevacizumab monotherapy. In part 2, on progression, patients suitable for continuing treatment will be randomized to continue or cease bevacizumab. The primary objective is to determine the effect of bevacizumab plus carboplatin versus bevacizumab alone on progression-free survival according to modified Response Assessment in Neuro-Oncology (RANO) criteria. Secondary endpoints are response rates (both RANO and MacDonald criteria), cognitive function, quality of life, steroid dose toxicity, and overall survival. CogState, a validated neurocognitive testing tool, will be used prospectively for the first time in a brain tumor trial and compared with mini-mental state examination. An early MRI at 4 weeks will assess if early radiological response is predictive of benefit. Patients are stratified by center, age, sex, and performance status. The combination of carboplatin and bevacizumab for recurrent GBM has not been studied prospectively before. Much remains unknown about the optimal use of bevacizumab, including the role of continuing beyond radiological disease progression and patterns of progression during and after bevacizumab use. Additionally, the new RANO criteria have yet to be prospectively validated. As of May 10, 2011, no serious adverse events have been reported. The trial is expected to complete recruitment in 2012.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-15. AVASTIN AND TEMOZOLOMIDE FOLLOWING RADIATION AND CHEMOTHERAPY FOR NEWLY DIAGNOSED GLIOBLASTOMA: RESULTS OF A PHASE II STUDY

MK Nicholas 1, S Chmura 1, Nina Paleologos 2, Hendrikus Krouwer 3, Mark Malkin 4, Larry Junck 5, Nicholas A Vick 6, Rimas V Lukas 1

Abstract

INTRODUCTION: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Standard treatment includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy. Bevacizumab (BEV) is used at recurrence. We report results of a clinical trial that brings BEV into the adjuvant setting for newly diagnosed GBM. METHODS: Sixty-two subjects with newly diagnosed GBM were enrolled between May 17, 2007 and June 26, 2010, and all began treatment with RT (60 Gy in 30 fractions) and TMZ (75 mg/m2/day) within 5 weeks of surgery. Four weeks after completing RT/TMZ, subjects began monthly TMZ (150-200 mg/m2) for 5 of 28 days and BEV (10 mg/kg) every 14 days. Treatment could continue until disease progression or unacceptable toxicity. Response was assessed using the MacDonald criteria and included consideration of steroid dose and change in clinical examination. We report progression-free survival (PFS) and median overall survival (OS), objective response (OR), and toxicities using a cutoff date 6 months following enrollment of the last subject. RESULTS: PFS was 35.7 weeks. OS was 54.3 weeks. OR (defined as the percentage of patients with partial or complete radiographic responses) was 43.5%, as determined by the investigators. Grade III-IV toxicities (CTCAE v3.0) of special interest, listed by type and grade (III/IV),included: wound dehiscence = 0/0; deep venous thrombosis = 4/1; pulmonary embolus = 0/1; stroke = 1/1, gastrointestinal bleed = 0/2; hypertension = 2/0; proteinuria = 0/2; myelosuppression = 18/8. CONCLUSIONS: These data indicate that the addition of BEV following chemoradiation to the accepted standard of care for newly diagnosed GBM is well tolerated. PFS and OS did not differ significantly from the randomized phase III clinical trial that resulted in FDA approval for TMZ for newly diagnosed patients (Stupp et al, NEJM. 2005, 352(10):987-96). The impact of MGMT promoter methylation on these results and radiographic patterns of progression will be discussed.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-16. NCCTG N0272: PHASE II TRIAL OF IMATINIB MESYLATE; (GLEEVEC; STI571) IN TREATMENT OF RECURRENT OLIGODENDROGLIOMA AND MIXED OLIGOASTROCYTOMA: A NORTH CENTRAL CANCER TREATMENT GROUP STUDY

Kurt A Jaeckle 1, SK Anderson 2, Matt Kosel 2, Jann Sarkaria 2, Paul Brown 2, PJ Flynn 3, Jann C Buckner 2, Eva Galanis 2

Abstract

BACKGROUND: PDGFR is overexpressed in oligodendroglioma, and PDGFR phosphorylation and PDGF-dependent MAP-K activation is inhibited by imatinib. We conducted a phase II trial of imatinib in patients with recurrent oligodendroglioma. METHODS: Patients with recurrent AO, AOA, O, or OA not receiving EIAC were eligible. Patients received imatinib 600 mg PO, a dose that produces blood concentrations of imatinib and its active metabolite CGP74588, which inhibits proliferation of glioma lines and xenografts. Patients must have failed prior RT + TMZ and could have received any number of prior regimens. The primary endpoint was PFS6; secondary endpoints were OS, TTP, and ORR. Toxicity (TOX) was assessed using CTC over 2.0. The study used a 2-stage Fleming version of Simon's MinMax design, powered to detect an increase in PFS6 from 25% to 45%, requiring 39 evaluable patients. RESULTS: At interim efficacy analysis, the study successfully met the decision rule, and full accrual ensued. To date, median TTP is 4.0months (95% CI: 1.8 - 7.4), median OS is 16.6 months (95% CI: 8.7-39.4), and overall confirmed response is 5.3% (2/38; PR = 1; REGR = 1). Eleven patients are alive; 5 have not yet progressed (median F/U 8.4 months; max, 57.6 months). Data for the primary endpoint analysis (PFS6) matures in July 2011. Grade 3+ nonhematologic TOX was observed in 33% (13/39 of evaluable patients; hypophosphatemia =6, hemorrhage = 4, fatigue = 3, dehydration = 2, and thrombosis = 2). Grade 4 hematologic TOX occurred in 8% (3/39 evaluable patients; neutropenia = 2, leukopenia = 1, and thrombocytopenia =1). There were 14.3% (5/35) of patients that went off treatment due to AE, and 71.4% (25/35) went off treatment because of disease progression. CONCLUSION: Single agent imatinib showed limited but definite activity in heavily pretreated recurrent O/OA patients, but with moderate toxicity. Supported by NCI CA-25224.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-17. FEASIBILITY AND PHASE I/II TRIAL OF TANDUTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Tracy Batchelor 1, Stuart Grossman 2, Steve Brem 3, Glenn Lesser 4, Alfredo Voloschin 5, Louis B Nabors 6, Tom Mikkelsen 7, Serena Desideri 2, Jeffrey Supko 1, David Peereboom 8

Abstract

INTRODUCTION: Platelet-derived growth factor signaling is important in gliomagenesis, and PDGFR-β is expressed on > 90% of endothelial cells in glioblastoma. METHODS: We report results from a feasibility, phase I/II 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 recurrent glioblastoma patients conducted by the Adult Brain Tumor Consortium (ABTC). RESULTS: In the feasibility study, 6 recurrent glioblastoma patients scheduled for resection received tandutinib 500 mg BID for 7 days prior to craniotomy. The mean ( SD) concentration of tandutinib in tumor tissue, measured by LC/MS was 7.2 3.2 µg/mL, and the mean brain to plasma ratio was 9.6 7.7. In the phase I study, 18 patients were enrolled to determine the maximum tolerated dose (MTD). Three dose levels (500 mg BID, 600 mg BID, 700 mg BID) were assessed. Four patients were replaced owing to early withdrawal unrelated to toxicity. Dose-limiting toxicity (DLT) was observed in 1 of 6 patients at 500 mg BID (grade 3 phosphorous, grade 3 fatigue, and grade 3 somnolence in one patient); 1 of 6 patients at 600 mg BID (grade 3 phosphorous); 2 of 3 patients at 700 mg BID (grade 3 fatigue and grade 3 weakness). The 600 mg BID dose was declared the MTD. In the 2-stage phase II design, the primary objective was the radiographic response (RR) proportion, and the coprimary objective was the progression-free survival at 6 months (PFS6). Thirty patients were enrolled in the phase II study. After the conclusion of the first stage, it was determined that the study would not meet prespecified efficacy thresholds for RR and PFS6, and the study was terminated. CONCLUSION: Although the target of tandutinib is highly expressed on glioblastoma endothelium and the drug achieves adequate blood-brain tumor penetration, there is no apparent efficacy in the recurrent glioblastoma patient population.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-18. INTERIM ANALYSIS OF A PHASE III TRIAL WITH ANTI-EGF-R MONOCLONAL ANTIBODY (NIMOTUZUMAB, OSAG-101) IN COMBINATION WITH RADIO-CHEMOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA

Manfred Westphal 1, Torsten Pietsch 2, Ferdinand Bach 3, Oliver Heese 1; OSAG-101 Study Group4

Abstract

The epidermal growth factor receptor (EGF-R) is still an elusive target for the treatment of malignant glioma. Genomic amplification and an array of mutations point toward a crucial role in glioma biology. Antibodies, targeted toxins, and small molecule tyrosine kinase inhibitors have not met expectations yet. Stringent analysis of the experiences with different therapeutic agents in clinical trials with correlative biology may define the collateral conditions required for efficacy of anti-EGF-R therapy. In this context, we report on a clinical phase III multicenter trial with an anti-EGF-R antibody for newly diagnosed glioblastoma (nimotuzumab, OSAG-101) added to the standard chemo-radiotherapy regimen. After completion of recruitment of the targeted 150 patients, 75 patients have reached the study's endpoint (disease progression) and are currently available for efficacy evaluation and correlative molecular analysis. In the overall group (irrespective of resection status), progression-free survival at 12 months (PFS 12, primary endpoint) for the non-MGMT methylated patients was 5.6 months in the control group and 8.3 months in the treatment arm. Overall survival (secondary endpoint) was almost identical, with 14.5 months vs. 13.8 months. In respect to EGF-R amplification, there is a tendency for prolonged time to progression in the treatment arm for patients with amplification. Because of multiple strata of extent of resection, MGMT status and EGF-R amplification status, and presence of the vIII variant of the EGF-R, the analysis of the complete cohort will be required for statistical analysis and will be available within 6 months. As for safety, no issues were identified, and none of the possible side effects such as rash, mucositis, or conjunctivitis were reported, indicating excellent tolerability. From the current analysis, it appears that signals for efficacy will be obtained in subgroups only.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-19. THE ADDITION OF BEVACIZUMAB TO TEMOZOLOMIDE AND RADIATION THERAPY FOLLOWED BY BEVACIZUMAB, TEMOZOLOMIDE, AND ORAL TOPOTECAN FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME

James J Vredenburgh 1, Annick Desjardins 1, David A Reardon 1, Katherine B Peters 1, John P Kirkpatrick 1, James E Herndon II 1, April D Coan 1, Leighann Bailey 1, Dorothea Janney 1, Cynthia Lu 1, Henry S Friedman 1

Abstract

The prognosis for newly-diagnosed glioblastoma multiforme (GBM) remains poor. The addition of temozolomide to radiation therapy improved the median overall survival to 14.6 months. GBMs have the highest level of vascular endothelial growth factor (VEGF). Hypoxia-inducing factor-1 alpha (HIF-1 alpha) is an important regulator of VEGF, and topotecan may inhibit HIF-1 alpha. We performed a phase II trial in newly diagnosed GBM by adding bevacizumab and topotecan to standard therapy. Eighty newly diagnosed GBM patients were enrolled between January 2010 and January 2011. Patients received standard radiation therapy and temozolomide. Bevacizumab at 10 mg/kg every 14 days was added a minimum of 4 weeks after surgery. Two weeks after radiation therapy was completed, patients began 12 monthly cycles of temozolomide at 150 mg/m2/d for days 1-5, oral topotecan at 1.5 mg/m2 for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 2.0 mg/m2 for patients on an EIAED for days 2-6, and bevacizumab at 10 mg/kg on days 1 and 15. The addition of bevacizumab to standard radiation therapy and daily temozolomide was safe. Of the 80 patients, 76 completed radiation therapy. Four patients did not complete radiation, 2 with clinical decline, and 1 each with a bone flap infection and a pulmonary embolus. There have been 19 progressions and 12 deaths, all due to progressive disease. Nine other patients came off study, 6 with recurrent grade IV thrombocytopenia, and 1 each with grade 2 CNS hemorrhage, wound dehiscence requiring surgery, and a GI perforation. The median PFS and OS have not been reached at a median follow-up of 8 months. The 6-month EFS is 83%. The addition of bevacizumab to temozolomide and radiation followed by temozolomide, bevacizumab, and oral topotecan is tolerable. The 6-month EFS is encouraging. Randomized phase III trials with bevacizumab for newly diagnosed GBM patients are essential.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-20. PHASE II STUDY OF PANITUMUMAB IN COMBINATION WITH IRINOTECAN FOR MALIGNANT GLIOMA PATIENTS

Annick Desjardins 1, David A Reardon 1, Katherine B Peters 1, James E Herndon II 1, Sridharan Gururangan 1, Julie Norfleet 1, Henry S Friedman 1, James J Vredenburgh 1

Abstract

BACKGROUND: The epidermal growth factor receptor (EGFR) plays an important role in the tumorigenicity of malignant glioma (MG). Panitumumab is a high affinity, fully human IgG2 monoclonal antibody directed against EGFR, extensively studied in colorectal cancer in combination with irinotecan. The need for effective therapies for recurrent MG lead to this phase II study. METHODS: Adult patients with measurable recurrent WHO grade IV MG, ≥ 12 weeks after radiation therapy, ≥ 4 weeks after chemotherapy, with adequate organ function and KPS ≥ 70%, were eligible. Excluded were patients homozygous for the 7/7 UGT1A1 genotype or previously treated with anti-EGFR therapy. Panitumumab and irinotecan were administered intravenously every 14 days. Panitumumab was dosed at 6 mg/kg. Irinotecan was dosed at 125 mg/m2 for patients not on enzyme inducing anti-epileptic drug (EIAED) and 340 mg/m2 for patients on EIAED. Physical exam and brain MRI were performed every 6 weeks (one cycle). RESULTS: Sixteen patients were enrolled on study (14 not on EIAED and 2 on EIAED); 13 were male. Median age was 49 years (range, 22-81 years), and median KPS was 80%. Three patients withdrew consent after less than one cycle of therapy due to side effects. One patient had an intracranial bleed after only one infusion. One patient is too early for evaluation. Of the 11 patients who completed one cycle of therapy, 7 patients had disease progression at the first MRI. One patient completed 1 year of therapy with stable disease. Median PFS was 6 weeks, and median OS was 20 weeks. Grade 3-4 toxicities included: grade 4 neutropenia (n= 1), grade 3 constipation (n = 1), and 2 patients each with grade 3 nausea, grade 3 rash, and grade 3 paronychia. Seven patients experienced grade 2 fatigue, and 9 patients had grade 2 rash. CONCLUSION: The combination of panitumumab and irinotecan has limited efficacy and moderate toxicity.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-21. PHASE I TRIAL OF TEMSIROLIMUS AND PERIFOSINE FOR RECURRENT OR PROGRESSIVE MALIGNANT GLIOMA

Andrew B Lassman 1, Thomas J Kaley 1, Lisa M DeAngelis 1, Adilia Hormigo 1, Ingo K Mellinghoff 1, Daniel D Otap 1, Jennifer Seger 1, LA Doyle 2, Emmy Ludwig 1, Mario E Lacouture 1, Katherine S Panageas 1

Abstract

BACKGROUND: PI3K/AKT/mTOR signaling is an important therapeutic target in malignant glioma (MG). The mTOR inhibitor, temsirolimus, and the AKT inhibitor, perifosine, are well tolerated as single agents but have limited activity. Preclinical data from genetically engineered mouse models of MGs demonstrated synergistic antitumor effects during combined therapy, including extensive tumor cell death, cell-cycle arrest among surviving cells, and inhibition of AKT and mTOR. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs. METHODS: Adults with recurrent MG, KPS ≥ 60, normal organ function who were not taking enzyme inducing anti-epileptic drugs were enrolled. There was no limitation on the number or type of prior therapies except that prior radiotherapy and temozolomide were mandatory. The dose of temsirolimus was escalated in each cohort using a standard 3 + 3 design. The dose of perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly thereafter (the single MTD). RESULTS: Fourteen patients (9 men and 5 women) were enrolled, with a median age of 52 years (range, 22-66 years) and median KPS of 80 (range, 60-100). Diagnoses included GBM (7), anaplastic astrocytoma (3), or anaplastic oligodendroglioma (4). Twelve had received bevacizumab previously. There was one dose-limiting toxicity (DLT, grade 2 thrombocytopenia) at dose level 3 (50 mg temsirolimus), which was expanded to 6 patients without additional DLTs. Dose level 4 (75 mg temsirolimus) is currently accruing. Other tolerable treatment related toxicities included anemia, neutropenia, ALT elevation, hyperglycemia, hypophosphatemia, hypercholesterolemia, rash, and diarrhea. The MTD has not been reached. CONCLUSION: Concurrent administration of temsirolimus (≥ 50 mg weekly) and perifosine (100 mg daily, following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs. Accrual continues, and updated results will be presented. A phase II trial will commence after determining the MTD.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-22. A PHASE II STUDY OF MULTIMODAL THERAPY EMPLOYING SURGERY, CARMUSTINE (BCNU) WAFER, CONCOMITANT TEMOZOLOMIDE AND RADIATION, FOLLOWED BY DOSE DENSE THERAPY WITH TEMOZOLOMIDE PLUS BEVACIZUMAB FOR NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

Arash Rezazadeh 1, Renato V LaRocca 1, Todd W Vitaz 2, Wayne G Villanueva 2, Jonathan Hodes 3, Leslie Haysley 1

Abstract

INTRODUCTION: Previous studies in management of newly diagnosed glioblastoma (GBM) demonstrated the efficacy of both carmustine (BCNU) wafer and temozolomide as part of multimodal therapy with resection and RT. Bevacizumab has been shown to have activity in combination with chemotherapy in subjects with recurrent malignant gliomas This phase II trial assessed the safety and efficacy of using BCNU wafer, TMZ, and bevacizumab within a multimodal regimen. METHODS: Eligible patients were aged 18-75 years. Subjects had resection of the tumor with BCNU wafer implantation followed by concomitant XRT with daily temozolomide (75 mg/m2) followed by temozolomide at 150 mg/m2 on days 1-7 and 15-21 of a 28 day cycle, with bevacizumab 10mg/kg IV every other week for up to 12 weeks. Endpoints include safety, median survival (MS), and progression-free survival (PFS). RESULTS: A total of 10 patients have thus far entered the study (7 male and 3 female). Median age was 52.5 years (range, 41-70 years), and median KPS was 95 (range, 70-100). One, 7, and 2 patients were RPA class III, IV, and V, respectively. Six patients had adequate tissue for MGMT analysis (methylated n = 2; unmethylated n = 4). Median follow-up was 9 months (range, 3-19 months). Six patients experienced progressive disease. Adverse events included deep vein thrombosis (n = 2), pulmonary embolism (n = 1), intracranial hemorrhage (n = 2), sepsis (n = 1), neutropenic fever (n = 1), fungal infection(n = 1), acute renal failure (n = 2), and acute lung injury (n = 1). Cause of death included disease progression (n = 4), renal failure (n = 1), and unknown (n = 1). CONCLUSION: These data suggest that multimodal therapy with surgery, BCNU wafer, concomitant daily temozolomide, and radiation, followed by dose-dense temozolomide and bevacizumab is feasible. Patients are still being enrolled in the study, and the efficacy of this penta-modality regimen will be reported when the data becomes available.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-23. A PHASE I ASCENDING DOSE TRIAL OF THE SAFETY AND TOLERABILITY OF TOCA 511 IN SUBJECTS WITH RECURRENT HIGH-GRADE GLIOMA

Daniel Pertschuk 1, Timothy F Cloughesy 2, Susan M Chang 3, Manish K Aghi 3, Michael A Vogelbaum 4, Linda M Liau 2, Bob Shafa 2, Douglas J Jolly 1, Carlos E Ibañez 1, Omar D Perez 1, Joan M Robbins 1, Harry E Gruber 1

Abstract

Toca 511 is a retroviral replicating vector (RRV) expressing a modified cytosine deaminase (CD) gene. Unlike oncolytic viruses whose life-cycle requires cell lysis, RRVs reproduce by budding off from the intact host cell. In animal models of brain cancer, Toca 511 can selectively infect tumor cells. When exposed to 5-fluorocytosine (5-FC), tumor cells expressing the CD gene convert 5-FC into 5-fluorouracil (5-FU). In these models, a single intratumoral injection of Toca 511 followed by cyclic treatment with 5-FC has resulted in dramatic prolongation of survival and clearance of tumors. Until now, RRVs have not been explored clinically as a potential cancer therapy. This first in-human ascending dose study will evaluate the safety and tolerability of a single dose of Toca 511 injected transcranially into recurrent high-grade gliomas and followed by monthly 6-day courses of oral 5-FC. Subjects must be ≥18, have failed surgery and chemoradiation, and have a single, supratentorial recurrence that measures ≤9cm^2 in its greatest cross-sectional area. This study uses a standard 3 + 3 dose escalation design. After a single injection, Toca 511 is then allowed to spread through the tumor for 4 weeks at which time 5-FC is administered. If tolerated, courses of 5-FC are repeated monthly for up to 6 cycles. Three subjects have been enrolled in the first dosing cohort. No dose-limiting toxicities (DLTs) have been identified in this group. There have been no grade 3 or 4 AEs considered related to either Toca 511 or 5-FC. This clinical study is the first one known to use an RRV to achieve gene transfer to human brain tumors. Intratumoral injection of Toca 511 followed by cyclic treatment with 5-FC was safe and well tolerated at the first dose of Toca 511 studied. These data support enrollment of subjects at higher doses of Toca 511.

Neuro Oncol. 2011 Nov;13(Suppl 3):iii85–iii91.

OT-24. NEOADJUVANT ADMINISTRATION OF THE POTENT PDGFR INHIBITOR, CRENOLANIB, TO MALIGNANT GLIOMAS AT INITIAL DIAGNOSIS: DOES IT HIT THE TARGET?

Elizabeth A Maher 1, Clinton Stewart 2, Kimmo Hatanpaa 1, Jack Raisanen 1, Tomoyuki Mashimo 1, Xiao-Li Yang 1, Chaitanya Muralidhara 3, Christopher Madden 1, Abhijit Ramachandran 3, Bruce Mickey 1, Robert Bachoo 1

Abstract

PDGFRalpha is frequently amplified, mutated, and/or overexpressed in malignant gliomas and has been shown to play a role in driving glioma growth. Previous attempts to block PDGFRalpha in patients with high-grade gliomas has been largely unsuccessful. Whether the poor outcome was owing to lack of efficacy of the drug or failure to effectively block PDGFR signaling is unknown. Crenolanib, a novel orally bioavailable selective inhibitor of PDGFR receptor tyrosine kinase with IC50s of 0.9 nM and 1.8 nM for PDGFRalpha and PDGFRbeta, respectively, has superior specificity and affinity than prior agents. Phase I trials of crenolanib in nonbrain tumor patients have shown a favorable safety profile and serum concentrations up to 2000 nM. Prior to initiation of phase II studies of crenolanib in glioma, we designed a neoadjuvant study to determine whether crenolanib penetrates the blood-brain barrier and blood-tumor barrier and accumulates in the tumor at a concentration capable of blocking PDGFR signaling. Patients with radiographic evidence of grade II, III, or IV glioma who require surgical resection are eligible. Crenolanib is administered for a minimum of 3 days preoperatively, and the final dose is given on the morning of surgery. Detailed pharmacokinetics are performed over the first 24 hours of drug administration, and a final serum drug level is obtained intraoperatively at the time of tumor resection. To date, 2 glioblastoma patients have been enrolled and treated with crenolanib (300 mg daily). Serum drug concentration at the time of resection was 388 nM and 286 nM, and tumor tissue concentration was 9.31 nmoles/g and 19.6 nmoles/g, respectively. In the second case, surrounding brain, histologically verified to be free of tumor cells, was analyzed, and crenolanib concentration was 2.14 nmoles/g. PK data, intratumoral drug concentration,s and PDGFR signaling analysis from additional patients in this study will be presented.

Articles from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Oxford University Press

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