Recurrent Anaplastic Astrocytoma Research Articles

A Case of a 25-year-old Male with Pituitary and Hypothalamic Extension of Recurrent Anaplastic Astrocytoma

A Case of a 25-year-old Male with Pituitary and Hypothalamic Extension of Recurrent Anaplastic Astrocytoma

10054-STMO-1 5-ALA INTENSITY ANALYSIS OF NON-NEOPLASTIC LESIONS BY IMAGE J

Abstract PURPOSE We used 5-ALA during surgery for malignant brain tumors, and analyzed the brightness using Image J for positive findings during surgery. We report on three cases that were positive for intraoperative 5-ALA and had high brightness but were diagnosed as non-tumor, including the results of brightness analysis by Image J. METHODS 5-ALA was administered according to the protocol, and intraoperative 5-ALA-positive findings were analyzed with Image J (Wayne Rasband: NIH), brightness was measured with histograms, and maximum brightness was compared. RESULTS Case 1 was suspected malignant tumor before surgery, but the diagnosis was inflammation, different from lymphoma. The intraoperative maximum brightness was as high as 239, but there was no finding of' blazing fire' characteristic of malignant tumors, and the lesion and its surroundings were uniformly red. Case 2 required differentiation between metastatic brain tumor and radiation necrosis, and case 3 required differentiation between recurrent anaplastic astrocytoma and radiation necrosis, both of which had high intraoperative brightness (113,166). CONCLUSION Measuring the brightness of 5-ALA-positive findings during surgery can help in the rapid pathological diagnosis of tumors and the determination of peripheral edema.

Low Dose Fractionated Radiation Therapy as a Chemo-Potentiator of Salvage Temozolomide (TMZ) for Recurrent Anaplastic Astrocytoma (AA) and Glioblastoma Multiforme (GBM): A Single-Arm Phase I/II Trial

Cell survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety and efficacy of low-dose fractionated radiation therapy (LDFRT) as a chemopotentiator of concurrent TMZ for patients with recurrent GBM or AA. Patients with recurrent GBM or AA s/p standard of care therapy and ≥12 months from prior RT and ≥2 months from prior TMZ were eligible to receive 0.5 Gy of RT twice daily for 10 fx with concurrent TMZ (150-200 mg/m2), both delivered in 5 consecutive days of a 28-day cycle for up to 6 cycles, followed by 6 more cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after starting therapy. Brain MRIs were obtained every 2 months, or every 1 month in cases of potential progression. Progression was defined by RANO criteria. Pseudoprogression consisted of MRI changes independent of clinical deterioration or steroid use that stabilize/reverse without oncologic intervention. The primary endpoint was 1-year overall survival (OS), with a lower bound of an 80% CI >28% deemed promising for further study based on historical data. Secondary endpoints were rates of pseudoprogression and hematologic toxicity. Thirty-one patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was seen in 8 (27%) patients. Median follow-up was 9.5 (range: 0.1-66.3) months (mos). Median and 1-yr OS were 9.6 (95% CI = 7.0-15.4) mos and 34.5% (95% CI = 20.9%-57.0%). The lower bound of the 80% CI for 1-yr OS was 24.8%. 77% of patients experienced pseudoprogression, with a median time to pseudoprogression from start of LDFRT of 1.9 (95% CI = 1.7-4.4) mos and median duration of 3.6 (95% CI = 1.6-Not estimable) mos. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 mos, HR = 0.12 [95% CI = 0.03-0.40]; P < 0.01). LDFRT in the re-irradiation setting for GBM or AA was safe. High rates of pseudoprogression were observed at strikingly low RT doses, with improved OS amongst patients with vs. without pseudoprogression. While pseudoprogression is common at definitive doses of brain RT, it is rare at palliative doses (e.g., 30 Gy/10 fx). Thus, low-dose RT hypersensitivity may be elicited by LDFRT with TMZ for patients with GBM/AA. Further study is needed to optimally apply this radiobiological property to improve patient outcomes.

Is Autophagy Inhibition in Combination with Temozolomide a Therapeutically Viable Strategy?

Temozolomide is an oral alkylating agent that is used as the first line treatment for glioblastoma multiform, and in recurrent anaplastic astrocytoma, as well as having demonstrable activity in patients with metastatic melanoma. However, as the case with other chemotherapeutic agents, the development of resistance often limits the therapeutic benefit of temozolomide, particularly in the case of glioblastoma. A number of resistance mechanisms have been proposed including the development of cytoprotective autophagy. Cytoprotective autophagy is a survival mechanism that confers upon tumor cells the ability to survive in a nutrient deficient environment as well as under external stresses, such as cancer chemotherapeutic drugs and radiation, in part through the suppression of apoptotic cell death. In this review/commentary, we explore the available literature and provide an overview of the evidence for the promotion of protective autophagy in response to temozolomide, highlighting the possibility of targeting autophagy as an adjuvant therapy to potentially increase the effectiveness of temozolomide and to overcome the development of resistance.

Hypofractionated reirradiation by conformal radiotherapy techniques in recurrent anaplastic astrocytoma and glioblastoma multiforme: An observational study at a Tertiary Care Center in North India

Aim and Objectives: The aims and objectives of the study were to assess the progression-free survival (PFS) and overall survival, local tumor control rate (response rate), effect on the quality of life, and treatment-related toxicities in all patients diagnosed with recurrent high-grade gliomas (HGGs). Methodology: The present study was conducted between September 2017 and July 2019 in the Department of Radiation Oncology, Sheri Kashmir Institute of Medical Sciences and included a total of 22 patients. The study included recurrent HGGs (Grade III/IV) Operated Cases of Grade III and Grade IV. Results: The majority of our patients were between the age group of 40–60 years (45.5%). There were 12 males (54.5%) and 10 females (45.5%). GBM was the most common diagnosis in 13 (59.1) patients and 9 (40.9%) were anaplastic astrocytoma. Sixteen patients were diagnosed as recurrent HGG radiologically. Sixteen (72.7%) patients achieved partial response and 6 (27.3%) achieved stable disease. The median PFS was 2.8 months and the median overall survival was 4.2 months. Conclusion: Reirradiation is one of the treatment options for recurrent HGGs and conformal intensity-modulated radiotherapy can be effective treatment modality for recurrent high-grade brain tumors with only mild side effects. Although survival is better in patients with good performance status and young age.

CTIM-15. RESULTS OF A PHASE IB TRIAL OF RECOMBINANT POLIO:RHINOVIRUS IMMUNOTHERAPY FOR RECURRENT PEDIATRIC HIGH GRADE GLIOMA

Abstract BACKGROUND Outcomes of recurrent pediatric high grade glioma (pHHG) are poor with a median overall survival (OS) of &amp;lt; 6 months. Viral immunotherapy such as the polio:rhinovirus chimera, PVSRIPO, is a novel treatment approach for recurrent pHHG. PVSRIPO is genetically engineered to prevent neurovirulence. In adults with recurrent glioblastoma treated with PVSRIPO, 21% survived &amp;gt; 36 months. The poliovirus receptor, CD155, is ubiquitously expressed in malignant pediatric brain tumors including pHHG. METHODS The primary objective of this Phase 1b clinical trial was to evaluate the safety and feasibility of PVSRIPO for recurrent pHGG. PVSRIPO was given at a single dose, 5x107 50% tissue-culture infectious dose (TCID50) administered by convection enhanced delivery (CED) to children with biopsy-confirmed recurrent pHHG between ≥ 1 and ≤ 5.5 in diameter. 3 mL of PVSRIPO was delivered at 0.5 mL/hr via a single catheter. RESULTS Eight patients were treated with PVSRIPO including 5 males and 3 females with a median age of 16.5 (range 9-19). Six patients had recurrent glioblastoma, 2 had recurrent anaplastic astrocytoma. The median number of previous recurrences prior to enrollment was 3.5 (range 1-5). Four patients received bevacizumab on-study for treatment-related peritumoral inflammation/edema. Six of 8 patients experienced 26 treatment related adverse events (AEs) possibly, probably, or definitely related to protocol treatment. There were no Grade 4 or 5 AEs. There were 3 Grade 3 AEs: 2 headaches and 1 seizure. There were no AEs related to biopsy or CED catheter insertion/removal. Median OS was 4.13 months (range 1.23-NA). One patient is currently alive at &amp;gt; 21 months. Monocyte and T cell inflammatory phenotypes and total CD4+ T cells were increased in peripheral blood after treatment. CONCLUSIONS CED of PVSPRIO is both safe and feasible for the treatment of recurrent pHHG. Histologic correlative results will also be presented.

Diagnostic yield of simultaneous dynamic contrast-enhanced magnetic resonance perfusion measurements and [18F]FET PET in patients with suspected recurrent anaplastic astrocytoma and glioblastoma

PurposeBoth amino acid positron emission tomography (PET) and magnetic resonance imaging (MRI) blood volume (BV) measurements are used in suspected recurrent high-grade gliomas. We compared the separate and combined diagnostic yield of simultaneously acquired dynamic contrast-enhanced (DCE) perfusion MRI and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET in patients with anaplastic astrocytoma and glioblastoma following standard therapy.MethodsA total of 76 lesions in 60 hybrid [18F]FET PET/MRI scans with DCE MRI from patients with suspected recurrence of anaplastic astrocytoma and glioblastoma were included retrospectively. BV was measured from DCE MRI employing a 2-compartment exchange model (2CXM). Diagnostic performances of maximal tumour-to-background [18F]FET uptake (TBRmax), maximal BV (BVmax) and normalised BVmax (nBVmax) were determined by ROC analysis using 6-month histopathological (n = 28) or clinical/radiographical follow-up (n = 48) as reference. Sensitivity and specificity at optimal cut-offs were determined separately for enhancing and non-enhancing lesions.ResultsIn progressive lesions, all BV and [18F]FET metrics were higher than in non-progressive lesions. ROC analyses showed higher overall ROC AUCs for TBRmax than both BVmax and nBVmax in both lesion-wise (all lesions, p = 0.04) and in patient-wise analysis (p < 0.01). Combining TBRmax with BV metrics did not increase ROC AUC. Lesion-wise positive fraction/sensitivity/specificity at optimal cut-offs were 55%/91%/84% for TBRmax, 45%/77%/84% for BVmax and 59%/84%/72% for nBVmax. Combining TBRmax and best-performing BV cut-offs yielded lesion-wise sensitivity/specificity of 75/97%. The fraction of progressive lesions was 11% in concordant negative lesions, 33% in lesions only BV positive, 64% in lesions only [18F]FET positive and 97% in concordant positive lesions.ConclusionThe overall diagnostic accuracy of DCE BV imaging is good, but lower than that of [18F]FET PET. Adding DCE BV imaging did not improve the overall diagnostic accuracy of [18F]FET PET, but may improve specificity and allow better lesion-wise risk stratification than [18F]FET PET alone.

DDRE-09. MULTI-INSTITUTION RETROSPECTIVE EXPERIENCE WITH LENVATINIB FOR PROGRESSIVE MALIGNANT GLIOMA

Abstract Despite treatment with radiation and temozolomide chemotherapy, malignant gliomas inevitably recur after treatment and have poor prognosis. Clinical trials should be offered when available, but effective treatment options for multiply recurrent tumors is sparse. In our multi-institutional retrospective cohort, we looked at recurrent malignant gliomas treated with Lenvatinib multi-kinase inhibitor. Patients consented to an IRB-approved study protocol that allows for longitudinal history review and analysis at our institution. Lenvatinib is a targeted therapy that is FDA approved for Differentiated Thyroid Cancer, Renal Cell Carcinoma, Hepatocellular Carcinoma, and Endometrial Carcinoma. Lenvatinib binds to tyrosine kinase receptors inhibiting kinase activity by VEGFR1-3, FGFR1-4, PDGFRa, FGF, KIT, and RET. In this cohort, patients received radiation and temozolomide chemotherapy, N=15, median age was 45.5, and 47% were male. At time of surgery 40% underwent biopsy, 40% had STR, and 20% had GTR. Glioblastoma was the most common tumor type at 87%, 6.7% were recurrent anaplastic astrocytoma, and 6.7% were recurrent glioma NOS. IDH mutation was seen in 13% of our cohort, and MGMT methylation was seen in 27%, all patients had available IDH and MGMT data. Patients were heavily treated, median number of recurrences was 3. Patient mean PFS was 2.7 months, and median OS was 24.0 months. Clincal Benefit Rate (PR+SD) to Lenvatinib in recurrent disease was 57%, with 29% Partial Responses and 29% Stable Disease as best radiographic response. This retrospective cohort supports further evaluation of the efficacy of Lenvatinib in recurrent malignant glioma in a clinical trial.

INNV-16. CLINICAL APPLICABILITY OF INDIVIDUALIZED DRUG RESPONSE PROFILING UTILIZING EX-VIVO TISSUE-DERIVED 3D CELL CULTURE ASSAYS IN HIGH-GRADE GLIOMA: A SINGLE INSTITUTION CASE SERIES USING 3D-PREDICT RESULTS

Abstract Recurrent high-grade glioma is a challenging disease process, without consensus on effective second-line therapy options. Individualized, patient-specific, biologically-based data is desirable in driving therapeutic decision-making. Patients with recurrent high-grade glioma and planned surgical re-resection at our institution were prospectively enrolled into the 3D-PREDICT study. Tissue was collected at the time of surgery for ex vivo 3D cell culture assays comprising a panel of agents commonly used for high-grade glioma, including chemotherapies and targeted therapies used in other solid cancers. In all cases, therapeutic agent selection was guided by the neuro-oncologist’s clinical judgement, factoring the patient’s age, performance status, comorbidities, toxicities/side effect profile of potential agents, and drug accessibility, plus ex-vivo drug response RESULTS: We present 3 cases in which the selection of agents was influenced by the tissue-derived 3D cell culture results; treatment led to clinical response observed in terms of progression free survival, quality of life, and pharmacologic tolerability. In Case 1, a patient with recurrent anaplastic astrocytoma was treated with a BRAF inhibitor for 12 months with excellent tolerability and no radiographic progression. Case 2 demonstrates the use of combination bevacizumab and irinotecan after disease progression subsequent to standard treatment. This patient had local radiographic control for 7 months, tolerating the regimen well. In Case 3, an individual with recurrent glioblastoma was treated with combination carboplatin and etoposide based on assay response prediction to both agents; treatment has been tolerated well with radiographic stability at 6 months while maintaining good performance status. This case series represents our institutional experience of utilizing patient-specific, ex-vivo tissue-derived cell drug response profiling to guide choice of therapy for recurrent high-grade glioma patients. Using individualized, tumor-specific drug sensitivity data to guide these decisions is representative of the ongoing paradigm shift into the realm of individualized medicine to improve outcomes in cancer patients.

ATIM-45. LONG TERM FOLLOW-UP OF A PHASE I/II STUDY TESTING THE TOXICITIES AND EFFICACY OF PEMBROLIZUMAB IN COMBINATION WITH MRI-GUIDED LASER INTERSTITIAL THERMAL THERAPY (LITT) IN RECURRENT MALIGNANT GLIOMAS

Abstract BACKGROUND LITT was recently demonstrated to induce temporary blood-brain barrier disruption, possibly allowing bilateral trafficking of tumor neoantigens and immune cells to induce glioma-specific immune activation - a phenomenon akin to in situ tumor vaccination. We hypothesize that combining LITT with immune checkpoint inhibition will create a synergistic therapy for recurrent GBM. METHODS The phase 1 study is a standard 3x3 design with a maximum of 18 patients with bevacizumab-naïve recurrent WHO grade 3–4 glioma. The primary endpoint is safety and toxicity of LITT plus pembrolizumab at 100, 150, or 200mg IV q3weeks. Phase 2 includes 40 patients with bevacizumab-naïve recurrent GBM, equally randomized to either pembrolizumab alone or LITT plus pembrolizumab, with progression-free survival as the primary endpoint. Serial immunophenotyping will be performed to evaluate potential positive synergy between LITT and pembrolizumab. RESULTS Phase 1 accrual was completed with 9 patients (3 at each pembrolizumab dose level). Two had recurrent anaplastic astrocytoma and 7 recurrent GBM. There was no dose-limiting toxicity with pembrolizumab 200mg IV q3weeks. The median number of doses given per patient was 9 (range 2 to 47). Severe adverse events possibly related to the study treatment included a grade 3 rash and diarrhea in 1 patient (11%) and grade 3 pneumonitis and hypotension in another patient (11%). No grade 3/4 intracranial edema deemed related to study treatment was observed. To date, four (44%) of these patients are still alive without tumor progression. Two (22%) GBM patients have not progressed for 29 and 33 months, respectively. Two (22%) anaplastic astrocytoma patient have not progressed for 23 and 24 months, respectively. CONCLUSIONS LITT plus pemprolizumab 200mg IV q3weeks is well tolerated in patients with recurrent high-grade glioma. Prolonged stable diseases were observed in almost half of patients treated. Phase 2 study is ongoing and will be updated.

ACTR-63. PHASE I DOSE ESCALATION STUDY OF PROCASPASE ACTIVATING COMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE IN PATIENTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA OR GLIOBLASTOMA

Abstract BACKGROUND Procaspase activating compound -1 (PAC-1) is a small molecule that catalyzes conversion of procaspase-3 to caspase-3 which induces apoptosis in cancer cells. Glioblastoma (GBM) is among the tumors with high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 crosses the blood brain barrier and has been shown to synergize with temozolomide (TMZ) in canine malignant glioma and meningioma that arise spontaneously. METHODS This is a multicenter phase 1 dose-escalation study to assess the maximum tolerated dose (MTD) of PAC-1 administered days 1–21 in combination with TMZ days 8–12 at a dose of 150 mg/m2 of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. A modified Fibonacci 3 + 3 design is used with up to 4 dose levels of PAC-1 (375, 500, 625 and 750 mg/day). Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. INTERIM DATA: A total of 14 subjects have been enrolled to-date. Of these, 7 at dose level 1, PAC-1 375 mg/day (6 GBM, 1 AA; median age 58y, range 25–75) and 7 at dose level 2, PAC-1 500 mg/day (5 GBM, 2 AA; median age 51y, range 35–60). Best responses to-date were 2 subjects with a partial response and 2 with stable disease. Grade 3 (hepatotoxicity) and 4 (cerebral edema) was reported as possibly related to PAC-1 in 1 patient at dose level 1. The median number of cycles received was 4 (range, 1–12+) at dose level 1 and 2 (range, 1–3) at dose level 2. Enrollment to dose level 2 has been completed and data analysis is ongoing. Updated response and toxicity as well as pharmacokinetic data will be presented.

Abstract 4771: The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose

Abstract Background: Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized yeast cytosine deaminase (CD) gene to tumors. Within infected cells, CD converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU). The combination of Toca 511 with oral extended release 5-FC (Toca FC), is currently being evaluated in a randomized phase III clinical trial for recurrent high grade glioma (glioblastoma (GBM) and anaplastic astrocytoma) (NCT02414165, Toca 5). Temozolomide (TMZ), in combination with radiation therapy, is the standard of care used for first-line chemotherapy treatment of patients with GBM, the most common and aggressive form of primary brain cancer. Previously, we have shown that: (1) Toca 511/5-FC treatment provides durable response in a syngeneic murine glioma model and supports anti-tumor immune memory; (2) The combination of TMZ and Toca 511/5-FC had synergistic efficacy in a TMZ-sensitive human glioma nude mouse model; (3) TMZ did not inhibit the efficacy of Toca 511/5-FC in a TMZ resistant murine glioma syngeneic model; (4) Toca 511/5-FC caused significant radiosensitization in a radioresistant murine glioma model. Results: To assess the interaction of TMZ with escalating doses of Toca 511 (as defined by percent of tumor transduction by RRV), an orthotopic TMZ-resistant murine glioma model, Tu-2449, was utilized. These results show that moderate levels of tumor transduction of Toca 511 (30% - 50%) with 5-FC treatment prolongs survival in the presence of TMZ compared with lower transduction rates (10%). Additionally, mice treated with Toca 511/5-FC and TMZ are being tested for the establishment of anti-tumor immune memory. Conclusion: These results demonstrate that (1) survival correlates with the transduction levels of Toca 511 when combined with temozolomide in the Tu-2449 orthotopic glioma model and (2) that this combination may support anti-tumor immune memory. These studies along with prior work support evaluation of the combination of Toca 511/5-FC with temozolomide in patients with newly diagnosed GBM (NRG-BN006). Citation Format: Maria E. Rodriguez-Aguirre, Sophie Viaud, Daniel Mendoza, Tiffany Montellano, Derek G. Ostertag, Harry Gruber, Douglas Jolly, Cornelia Bentley. The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4771.

Phase I trial of TG02 plus dose-dense or metronomic temozolomide for recurrent anaplastic astrocytoma and glioblastoma in adults.

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.

The Long-Term Progression Free Survival After the Combination of Radiotherapy with Concurrent Chemotherapy of Nimotuzumab And Temozolomide Followed Adjuvant Temozolomide In Recurrent Anaplastic Astrocytoma

The management of recurrent high-grade gliomas is highly challenging, and treatment outcome remains invariably poor. High-grade gliomas (HGGs) are highly malignant tumor, which complete surgical resection of all microscopic extensions cannot be always achieved. All high-grade gliomas nearly recur and survival following disease progression is doomed to be approximately 6 months for GBMs and 10 months for anaplastic gliomas. Therapy options for recurrent HGGs are limited and may include surgery, re-irradiation, chemotherapy and targeted therapy. We present a case of a 33-year-old male with recurrent anaplastic astrocytoma after initial surgery. The patient underwent the treatment of radiation therapy with concurrent chemotherapy of nimotuzumab and oral temozolomide for 6 weeks followed by six cycles of adjuvant temozolomide for tumor local recurrences, and the patient still do not relapse with a long-term progression free survival lasting seven years. The median survival in patients with recurrent anaplastic astrocytoma is usually 10 months after recurrence, and this unique case illustrates that comprehensive therapy can achieve long-term survival in select situations. We recommend that the treatment of each recurrent patient should be based on each clinical situation and aspire for quality of life and improved longevity.

ACTR-06. INITIAL RESULTS OF A PHASE I STUDY OF PROCASPASE ACTIVATING CCOMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE FOR RECURRENT MALIGNANT GLIOMA

Disruption of the intrinsic and extrinsic apoptotic pathways is a hallmark of neoplasia. Conversion of procaspase-3 to caspase-3 is a key reaction, as both pathways converge at this point. Procaspase activating compound -1 (PAC-1) catalyzes conversion of procaspase-3 to caspase-3 and induces apoptosis in tumor cells. Glioblastoma (GBM) is among the tumors that have high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 has anti-tumor activity in several glioma cell lines in vitro. PAC-1 crosses the blood brain barrier and its addition to alkylating chemotherapy augments anti-tumor responses in in vivo rodent models and spontaneous canine gliomas. Taken together, these findings suggest PAC-1’s potential in glioma therapy. This dose-escalation phase I study to assesses the maximum tolerated dose (MTD) of PAC-1 administered daily for 21 days with TMZ, 150 mg/m2 for 5 days of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. RANO criteria are used to assess response. A modified Fibonacci 3 + 3 design is used, expanding to 9 subjects at the MTD. Pharmacokinetics (PK) is assessed in each subject during cycle one. Secondary endpoints include pharmacodynamics and correlation of activity with procaspase-3 levels in tumor tissue. Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. 6 subjects (all GBM) enrolled at the first dose level, 375 mg PAC-1/day. The PAC-1cycles administered ranged from 1–6 (mean = 3.2). All subjects left the study due to tumor progression. The best radiographic response was stable disease. The first cohort was expanded from 3 to 6 due to CTCAE grade 4 hepatotoxicity that resolved with dose reductions in both study drugs. An update of toxicity data and results of PK and tumor procaspase levels will be discussed.

Phase I study of procaspase activating compound-1 (PAC-1) for treatment of advanced malignancies.

TPS2621 Background: Dysregulation in apoptotic pathways is a hallmark feature of cancer, offering opportunities for pharmacologic intervention in its treatment. Caspases, a family of proteases, play several roles in apoptosis. Caspase-3 catalyzes the intra-cellular proteolysis that characterizes part of the apoptotic process. Caspase-3 levels are low in many tumors including: glioblastoma; breast, colon, lung, and liver cancers: lymphoma: neuroblastoma; and melanoma. In contrast, procaspase-3, the precursor of caspase-3 is elevated in these tumors. We describe a phase I study of PAC-1, a drug that catalyzes the conversion of procaspase -3 to caspase-3. It induces apoptosis in tumor cell lines in vitro. In vivo activity has also been shown, when combined with alkylating chemotherapy, in rodent glioma models and in canines diagnosed with malignant glioma. Methods: This Phase I dose escalation study has two components: the first (C1) to determine the maximum tolerated dose (MTD) of PAC-1 in advanced malignancies; the second (C2) to determine the MTD of PAC-1 when combined with temozolomide (TMZ) in patients with recurrent anaplastic astrocytoma (AA) or glioblastoma (GBM). A modified Fibonacci 3 + 3 design is used, expanding to nine subjects at the MTD level in each component. PAC-1 pharmacokinetics is assessed in all subjects during the first cycle. Secondary objectives include pharmacodynamics and correlations of PAC-1 activity with procaspase-3 expression in tumor tissue. Neurologic toxicity is closely monitored throughout the study. Inclusion criteria: diagnoses of advanced malignancies (C1) and recurrent AA or GBM (C2), ECOG PS 0-2, adequate organ function. Exclusion criteria: prior cytotoxic therapy in the last 3-6 weeks (varying with drug class) or uncontrolled chronic illness. Administration and design: For C1, PAC-1 (orally administered) is dosed at 75-1,000 mg daily on days 1-21 of each 28 day cycle. For C 2, the first PAC-1 dose is 375 mg daily with potential for escalation to 1,000 mg daily. TMZ, PO, is dosed at 150 mg/m2 daily, days 8-12, of each cycle. Enrollment to date for C1 is 27, (dose level 6); and for C2 is 4 (dose level 1). The study is open to accrual. Clinical trial information: NCT02355535.

Extracranial bone metastases from recurrent anaplastic astrocytoma on FDG PET/CT

Objective:Extracranial bone metastases from astrocytoma are rare and frequently detected as part of multiorgan metastases. It is extremely rare for astrocytoma to have extracranial bone metastases alone. The importance of whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging in evaluating extracranial metastasis (ECMs) has not been described effectively due to the rarity of this event. The purpose of our case report is to emphasize the role of FDG PET/CT in the assessment of tumor recurrence and extracranial bone metastases from anaplastic astrocytoma.Methods and materials:A 25-year-old woman was firstly admitted with a 4-month history of progressive blurred vision, and 2-month history of intermittent headache. Presurgical MRI imaging revealed a large mass in the left trigone of lateral ventricle. Subsequently, she underwent tumor resection, radiotherapy and chemotherapy. A final pathological diagnosis of anaplastic astrocytoma (WHO III) was made. Nearly 12 months after the surgery, the follow-up brain MR imaging revealed a contrast-enhanced lesion in the site of operative region. Whole-body FDG PET/CT imaging was performed to evaluate the situation.Results:Postoperative brain FDG PET/CT showed an abnormal focal FDG uptake corresponding to the contrast-enhanced lesion in the operative area, suggesting a tumor recurrence. Whole-body FDG PET/CT also showed multiple FDG-avid osteosclerotic lesions in the body. It was highly suggestive of extracranial bone metastases. A subsequent open bone biopsy of FDG-avid lesion in right iliac crest was performed. Histopathological and immunohistochemical findings indicated characteristic of glioma. The patient died 1 month later, nearly 13 months after the initial diagnosis.Conclusions:ECMs from anaplastic astrocytoma are extremely rare but they do occur. Whole-body FDG PET/CT imaging with inclusion of brain was valuable in differentiating tumor recurrence from radiation necrosis and in detecting uncommon extracranial bone metastases from anaplastic astrocytoma, which were closely related to prognosis of this disease.

PC3 - 151 Toca 5: A Phase 2/3 Randomized, Open-Label Study of Toca 511, a Retroviral Replicating Vector, Combined with Toca FC versus Standard of Care in Patients Undergoing Planned Resection for Recurrent Glioblastoma (GBM) or Anaplastic Astrocytoma (AA) (NCT02414165)

Recurrent GBM and AA have a dismal prognosis and a high unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that encodes the transgene cytosine deaminase (CD). Toca 511 selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) by CD within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. Clinical data from phase 1 trials are consistent with this mechanism of action, and show extended survival compared to historical controls. Toca 5 is a multicenter, randomized, open-label Phase 2/3 trial of Toca 511 and Toca FC versus standard of care administered to patients undergoing resection for first or second recurrence of GBM or AA. Phase 2 will enroll 170 patients. Primary endpoint is overall survival (OS). Key secondary endpoints are safety, objective response rate, clinical benefit rate, progression-free survival, and landmark OS. Key inclusion criteria are age 18-75 years, histologically proven GBM or AA, measurable disease preoperatively of less than 5cm, candidate for equal or greater 80% resection of enhancing tumor based on pre-operative evaluation, and KPS equal or greater to 70. Assays for immune monitoring will be performed and molecular profiling of resected tumor samples will be correlated efficacy.

IMCT-04TOCA 5: PHASE 2/3 RANDOMIZED, OPEN-LABEL STUDY OF TOCA 511 WITH TOCA FC VERSUS STANDARD OF CARE IN PATIENTS UNDERGOING PLANNED RESECTION FOR RECURRENT HIGH GRADE GLIOMA (NCT02414165)

Recurrent glioblastoma and anaplastic astrocytoma have a dismal prognosis and a high unmet need for effective therapies. Toca 511 is a retroviral replicating vector derived from a cloned Moloney murine leukemia virus with the original ecotropic envelope gene replaced with an amphotropic envelope gene to enable the virus to infect human cells. A modified yeast cytosine deaminase (CD) gene has been inserted into this vector. The expressed CD enzyme catalyzes conversion of antifungal drug 5-flucytosine (administered as investigational extended-release formulation Toca FC) to antineoplastic drug 5-fluorouracil. Toca 5 is a multicenter, randomized, open-label Phase 2/3 trial of Toca 511 and Toca FC versus standard of care (Investigator's choice of single agent lomustine, temozolomide, or bevacizumab) administered to patients undergoing resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. The trial will enroll approximately 370 patients (Phase 2-170 and Phase 3-200). Primary endpoint is overall survival (OS). Key secondary endpoints are safety, objective response rate, clinical benefit rate, progression-free survival, and landmark OS. Key inclusion criteria are age 18-75 years, histologically proven glioblastoma or anaplastic astrocytoma, measurable disease preoperatively of at least 1 cm, candidate for ≥ 80% resection of enhancing tumor based on pre-operative evaluation, KPS ≥ 70. Selected exclusion criteria are enhancing tumor > 5 cm, more than two prior recurrences and prior bevacizumab other than for newly diagnosed glioma. Assays will be performed to evaluate evidence for immunologic mechanisms of disease control, including tumor reactive PBMC measurement by stimulation via ex vivo glioma antigen presentation, flow cytometry based phenotyping of PBMCs with an effector, memory, Treg, and myeloid derived suppressor cell panel. Molecular profiling of resected tumor samples will be correlated with primary and secondary endpoints to identify potential biomarkers for treatment-related response. Toca 5 is expected to begin enrollment in 3Q 2015.

Abstract 477: Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma

Abstract Patients with recurrent low-grade brain tumors or anaplastic astrocytoma may receive radiation treatment, however, the long-term sequellae from radiation treatment can be severe. For pediatric astrocytomas, low-grade tumors are associated with activation of BRAF through a tandem duplication that results in the KIAA1549-BRAF fusion (Grade 1) or through an activating point mutation of BRAF (predominantly V600E; Grade 2-4) and is the most common lesion in low- and intermediate-grade astrocytoma. Previous studies have indicated synergy between MEK inhibition and ionizing radiation therapy (XRT), although the proposed mechanisms for synergy differ. We have explored the combination of ionizing radiation with MEK inhibition in a model of BRAF-mutant anaplastic childhood astrocytoma. The regulation of TORC1 signaling by BRAF was examined in BT-40 (BRAF mutant) and BT-35 (BRAF wild type) xenografts, in a cell line derived from the BT-40 xenograft and two adult BRAF mutant (V600E) glioblastoma cell lines (DBTRG-05MG, AM380c1). The effect of MEK inhibition (selumetinib, AZD6244, ARRY-142886), XRT (2 Gy daily fractionated doses), or the combination of selumetinib and XRT was evaluated in subcutaneous BT-40 xenografts. Inhibition of MEK signaling by selumetinib, suppressed TORC1 signaling only in the context of the BRAF-mutant both in vitro and in vivo. Inhibition of MEK signaling in BT-40 cells or in xenografts lead to a complete suppression of TORC1 signaling and decreased levels of FANCD2 protein, whereas inhibition of TORC1 signaling was less in DBTRG-05MG cells and even less in AM380c1 cells. The level of TORC1 inhibition by selumetinib was associated with loss of clonogenic survival, and suppression of FANCD2 in vitro. In vivo we examined the sensitivity of BT-40 xenografts to selumetinib (75 mg/kg BID x 42 days, PO), XRT (10 Gy delivered as 2 Gy daily fractions), or selumetinib combined with XRT. For control tumors, median time to event was 17 days, whereas for XRT alone it was 80 days (P&amp;lt;0.0001). Selumetinib treatment induced complete regression of most tumors with progression starting around week 5 of the 6-week treatment period, consistent with previous data, with median time to event being 51 days (P&amp;lt;0.0001 vs control). In contrast to XRT or selumetinib as single agents, the combination caused complete regression of all tumors, with only 4 of 10 (40%) recurrent tumors within the 24 weeks observation period, and significantly better than radiation or selumetinib alone (P&amp;lt;0.0001 for both comparisons). These data add to studies that indicate synergy between XRT and MEK inhibitors, and suggest the possibility of potentiating the effect of XRT selectively in tumor cells by MEK inhibition in the context of mutant BRAF. Combining MEK inhibition with XRT may allow maintenance of tumor control at lower doses of XRT that would decrease long-term sequellae for children with BRAF-mutant brain tumors. Citation Format: Adam W. Studebaker, Kathryn Bondra, Star Seum, Justin Leasure, Christopher Chronowski, Changxian Shen, Doris Phelps, Paul D. Smith, Raushan T. Kurmasheva, Xiaokui Mo, Peter J. Houghton. Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 477. doi:10.1158/1538-7445.AM2015-477