Recurrent Malignant Brain Tumors Research Articles

Intra-lesion injection of activated Natural Killer (NK) cells in recurrent malignant brain tumors

Despite multi-modal therapies for patients with malignant brain tumors, their median survival is < 2 years. Recently, NK cells have provided cancer immune surveillance through their direct natural cytotoxicity and by modulating dendritic cells to enhance the presentation of tumor antigens and regulate T-cell-mediated antitumor responses. However, the success of this treatment modality in brain tumors is unclear. The main reasons are; the brain tumor microenvironment, the NK cell preparations and administration, and the donor selection. Our previous study showed that intracranial injection of activated haploidentical NK cells resulted in the eradication of glioblastoma tumor mass in the animal model without any evidence of tumor recurrence. Therefore, in the present study, we evaluated the safety of intra-surgical cavity or intra cerebrospinal fluid (CSF) Injectionofex vivoactivated haploidentical NK cells in six patients with recurrent glioblastoma multiform (GBM) and malignant brain tumors resistance to chemo/radiotherapy. Our results indicated that activated haploidentical NK cells express activator and inhibitor markers and can kill the tumor cells. However, their cytotoxic potential on patient-derived GBM (PD-GBM) was more than that of its cell line. Also, their infusion increased the overall disease control rate by about 33.3%, with a mean survival of 400 days. Moreover, we showed that local administration of the activated haploidentical NK cells in malignant brain tumors is safe, feasible, tolerated at higher doses, and cost-effective.

An open-label multi-center phase 1 safety study of BXQ-350 in children and young adults with relapsed solid tumors, including recurrent malignant brain tumors

BackgroundBXQ-350 is a novel anti-neoplastic agent composed of saposin C (SapC) and phospholipid dioleoylphosphatidyl-serine sodium (DOPS) that selectively binds tumor cell phosphatidylserine (PS), inducing apoptosis. BXQ-350 has demonstrated preclinical antitumor effects in high-grade gliomas (HGG) and clinical activity in adult patients with recurrent HGG. MethodsA phase 1 study was conducted in pediatric patients with relapsed/refractory solid tumors, including recurrent brain tumors. Primary objectives were to characterize safety and determine maximum tolerated dose (MTD) and preliminary antitumor activity. Sequential dose cohorts were assessed up to 3.2 mg/kg using an accelerated titration design. Each cycle was 28 days; dosing occurred on days 1–5, 8, 10, 12, 15, and 22 of cycle 1, and day 1 of subsequent cycles, until disease progression or toxicity. ResultsNine patients, median age 10 years (range: 4–23), were enrolled. Seven patients (78%) had central nervous system (CNS) and two (22%) had non-CNS tumors. Eight patients completed cycle 1. No dose limiting toxicity (DLT) or BXQ-350-related serious adverse events (SAEs) were observed. Six patients experienced at least one adverse event (AE) considered possibly BXQ-350-related, most were grade ≤2. One patient with diffuse intrinsic pontine glioma experienced stable disease for 5 cycles. The study was terminated after part 1 to focus development on the frontline setting. ConclusionNo DLTs or BXQ-350-related SAEs were reported, and the maximal planned dose of 3.2 mg/kg IV was tolerable. Limited safety and efficacy data support continued BXQ-350 development in pediatric HGG; however, early discontinuations for progression suggest novel therapies be assessed at earlier disease stages.

CTIM-32. FIRST-IN-CHILDREN PHASE 1 TRIAL OF INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS: ANALYSIS OF SAFETY, TOLERABILITY, AND 5-YEAR OUTCOME

Abstract BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/ METHODS Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemotherapy regimen (cyclophosphamide 2.5 mg/kg/day orally and etoposide 50 mg/m2/day orally for 21 days of each 28-day cycle). RESULTS Between December 2015 and January 2019, the study enrolled 81 brain tumor patients, including newly-diagnosed DIPG (n = 13) or recurrent ependymoma (n = 27), glioblastoma/high-grade glioma (n = 19), medulloblastoma (n = 13), or other CNS tumors ( n= 9). Median follow-up was 52 months (range 39-77 months). No dose-limiting toxicities were observed, and the pediatric indoximod dose was determined (19.2 mg/kg/dose, given twice daily). Indoximod was well tolerated and did not affect the ability to deliver chemotherapy or radiation as planned. Median overall survival was 13.6 months (n = 81). Median overall survival was 34.7 months for the subset of patients who continued indoximod with second-line chemotherapy after progression on indoximod plus temozolomide (n = 18). CONCLUSIONS Indoximod was well tolerated and could be combined with a variety of standard treatments for pediatric brain tumors. Preliminary anti-tumor activity and overall survival suggest that indoximod with standard therapy should be further evaluated in pediatric brain tumors, and potentially other pediatric solid tumors.

DDEL-05. Intraventricular therapy with topotecan is feasible and safe: Experience in 50 pediatric patients with various malignant brain tumors

BACKGROUND: Malignant brain tumors carry a high risk for leptomeningeal dissemination, but the CSF compartment is often not affected by systemic therapy. Intraventricular therapy via an Ommaya reservoir is one possibility to increase the cytotoxic drug concentration in the CSF. Unfortunately, the number of drugs that can be administered directly into the CSF is limited. We report on our experience with topotecan administered via an Ommaya reservoir. PATIENTS AND METHODS: Between 2015 and 2021, 50 patients aged 1 to 22 years (mean and median both 8 years) with various malignant brain tumors received intraventricular topotecan via an Ommaya reservoir. Topotecan was administered at 0.4mg twice a week (>1 and <2 years 0.25mg, >2 and <3 years 0.32mg). RESULTS: In total, 1168 doses of topotecan (1-87/patient, mean 23, median 18) were administered at our department. Treatment was given over a period of 0-65 months (mean and median 33 months). Intraventricular treatment with topotecan was generally well tolerated. Two patients reported side effects. One boy with multiple recurrences of an ependymoma in the posterior fossa showed increased tremor after intraventricular administration of topotecan, another girl with recurrent medulloblastoma reported fatigue. CONCLUSION: Intraventricular therapy with topotecan is feasible and generally well tolerated. Topotecan can be an important addition for patients with recurrent malignant brain tumors to increase cytotoxic drug concentrations in CSF.

IMMU-10. USE OF A SINGLE PEPTIDE CHECKPOINT INHIBITOR FOR TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS

Cancer immunotherapy has revolutionized clinical management of malignancies by generating long-term, durable control of tumors. Unfortunately, these therapies often cause serious immune-related adverse events. In addition, only a small percentage of solid tumors respond to these therapies and there is little efficacy in CNS tumors. Our research is focused on the CD200 immune checkpoint, which modulates the immune system through the inhibitory receptor (CD200R1) and activation receptors (CD200AR). We demonstrated that targeting the CD200AR with a checkpoint peptide ligand (CD200AR-L) activates the immune system and renders it impervious to the inhibitory effects of CD200. In a pre-clinical canine spontaneous high-grade glioma trial, CD200AR-L, with autologous tumor lysate vaccination, resulted in a 20% two-year progression-free survival; no toxicities or adverse effects were observed. We suggest this result was due to the ability of the CD200AR-L to modulate multiple immune checkpoints. During the characterization of the CD200AR-L, we discovered signaling molecules are shared by the CD200 and PD-1/PD-L1 checkpoint pathways, suggesting these immune checkpoints are connected. Our preliminary studies demonstrated that the inhibitory CD200R1 and PD-1 mediate immune checkpoint signaling activities through the SHIP1/2. Moreover, CD200AR-L overpowers the suppressive effects of CD200 and PD-L1, which are both shed by tumors, by downregulating the inhibitory CD200R1 and PD-1 on both antigen-presenting cells (APC) and T-cells. In addition, CD200AR-L downregulates PD-1 on APCs and inhibits the upregulation of PD-L1 and CTLA4. These studies led to the discovery that the novel peptide modulates the CD200, PD-1/PD-L1 and CTLA-4 pathways, providing the basis for the translatable development of a CD200-directed peptide for clinical use against multiple tumors including gliomas. These studies led to FDA approval of this peptide for the first in human phase I single center, open-label, dose-escalation clinical trial (NCT04642937) in adult and pediatric trial for children with recurrent malignant brain tumors.

DDEL-14. SAFETY OF INTERVENTRICULAR METHOTREXATE ADMINISTRATION FOLLOWING RADIATION IN PEDIATRIC PATIENTS WITH MALIGNANT BRAIN TUMORS

BACKGROUNDMethotrexate has been used for intrathecal administration in leukemia as well as embryonal CNS tumors in children. Concerns about neurologic side effects including leukoencephalopathy, demyelination, and seizures have limited the use of methotrexate following exposure to focal radiation.OBJECTIVETo evaluate and determine safety of Intraventricular administration of Methotrexate in pediatric patients with recurrent malignant brain tumors along with systemic Topotecan and Cyclophosphamide after exposure to prior radiation therapy. DESIGN/METHOD: Patients with recurrent cerebellar embryonal tumors after standard treatment that included radiation were enrolled on this IRB approved phase 2 study. An Ommaya reservoir was inserted in the lateral ventricle and used to administer 4 daily doses of methotrexate (2 mg/dose) along with (Topotecan [0.75mg/m2/day] and Cyclophosphamide [250 mg/m2/day]). A neurological evaluation was performed at baseline and daily during the intraventricular administration of the Methotrexate, this evaluation was repeated prior to each subsequent cycle and at completion of the protocol.RESULTSThree patients (age range 3–20) received 2–3 cycles of intra-Ommaya Methotrexate and Topotecan/Cyclophosphamide. No MRI demyelination or white matter changes were seen after completion of the intraventricular Methotrexate therapy. None of the patients enrolled on this trial had adverse effects related to the therapy regimen received. Clinical neurological status was unchanged during the entire course of the treatment and upon completion of the scheduled therapy.CONCLUSIONIntraventricular administration of daily low dose Methotrexate is well tolerated in children with recurrent embryonal CNS tumors who had prior exposure to radiation.

PEDT-02 Clinical usage of NCC Oncopanel/FoundationOne CDx for pediatric/AYA patients with recurrent malignant brain tumors

Backgrounds: Analyses of somatic mutations in malignant brain tumors have been used to make effective treatment strategies. NCC Oncopanel and FoundationOne CDx are custom targeted next-generation sequencing (NGS) panels. The cost for this analysis is 560,000 yen covered by National Health Insurance in Japan since June 2019. These methods can be applied for the solid cancers with no established therapies and relapsed after the standard therapies. Following these inclusion criteria, most malignant brain tumors, especially recurrent malignant brain tumors in pediatric/AYA generations, can be included. Object: To report the results of our initial experiences. Methods: In the last one year, we utilized these NGS panels for five patients with recurrent malignant brain tumors in this generations: 2 epithelioid glioblastomas; 1 anaplastic meningioma; 1 diffuse astrocytoma (gliomatosis cerebri); 1 atypical choroid plexus papilloma. Results: Final recommended treatments are as follows: BRAF/MEK inhibitors, bevacizumab, or anti-PD-1 antibody for one epithelioid glioblastoma; MEK inhibitor for another epithelioid glioblastoma previously treated by BRAF inhibitor and bevacizumab; ERK1/2 inhibitors for anaplastic meningioma. The diffuse astrocytoma had IDHR132H mutation. There was no clinical trial using IDH inhibitor for recurrent diffuse astrocytoma; thus, the final recommendation for this case was rechallenge of temozolomide. To date, only one NGS for a choroid plexus papilloma has been reported (Arch Pathol Lab Med, 2017). Our case had multiple actionable gene alterations, including TERT mutation and amplification of various genes. Unfortunately, there was no druggable gene alteration among them. Conclusions: Insurance-covered cancer gene panel tests could represent effective treatment options for some malignant brain tumors in pediatric/AYA generations. If the relapse is local and can be treated by repeat resections, we think the surgery is the first-line choice. But, in another situation, information from NGS panels should be obtained positively. Efforts to increase the utility of off-label use of drugs are encouraged.

CTIM-31. USE OF A SINGLE PEPTIDE CHECKPOINT INHIBITOR FOR TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS

Abstract Cancer immunotherapy has revolutionized clinical management of malignancies by generating long-term, durable control of tumors. Unfortunately, these therapies often cause serious immune-related adverse events. In addition, only a small percentage of solid tumors respond to these therapies and there is little efficacy in CNS tumors. Our research is focused on the CD200 immune checkpoint, which modulates the immune system through the inhibitory receptor (CD200R1) and activation receptors (CD200AR). We demonstrated that targeting the CD200AR with a checkpoint peptide ligand (CD200AR-L) activates the immune system and renders it impervious to the inhibitory effects of CD200. In a pre-clinical canine spontaneous high-grade glioma trial, CD200AR-L, with autologous tumor lysate vaccination, resulted in a 20% two-year progression-free survival; no toxicities or adverse effects were observed. We suggest this result was due to the ability of the CD200AR-L to modulate multiple immune checkpoints. During the characterization of the CD200AR-L, we discovered signaling molecules are shared by the CD200 and PD-1/PD-L1 checkpoint pathways, suggesting these immune checkpoints are connected. Our preliminary studies demonstrated that the inhibitory CD200R1 and PD-1 mediate immune checkpoint signaling activities through the SHIP1/2. Moreover, CD200AR-L overpowers the suppressive effects of CD200 and PD-L1, which are both shed by tumors, by downregulating the inhibitory CD200R1 and PD-1 on both antigen-presenting cells (APC) and T-cells. In addition, CD200AR-L downregulates PD-1 on APCs and inhibits the upregulation of PD-L1 and CTLA4. These studies led to the discovery that the novel peptide modulates the CD200, PD-1/PD-L1 and CTLA-4 pathways, providing the basis for the translatable development of a CD200-directed peptide for clinical use against multiple tumors including gliomas. These studies led to FDA approval of this peptide for the first in human phase I single center, open-label, dose-escalation clinical trial in adult and pediatric trial for children with recurrent malignant brain tumors.

Temozolomide and oral etoposide in children with recurrent malignant brain tumors.

Despite advances in the treatment of brain tumors, the prognosis of children with recurrent malignant brain tumors remains poor. Etoposide (VP-16), an inhibitor of nuclear enzyme deoxyribonucleic acid (DNA)-topoisomerase II, has shown activity in brain tumors. Its efficacy appears schedule dependent but, to date, the most effective schedule of administration has not been well defined. Temozolomide (TMZ), like VP-16, penetrates the blood–brain barrier and has activity against malignant brain tumors. This novel alkylating agent is rapidly absorbed and is highly bioavailable after oral administration. The antitumor activity of TMZ has been shown to be schedule dependent. Based on the evidence of different mechanisms of cytotoxicity, TMZ and VP-16 have been utilized in combination in patients with malignant brain tumors. This review evaluates the results derived from the combination use of TMZ and oral VP-16. The reported data suggest potential activity of oral VP-16 and TMZ alone or in combination. Further clinical trials are needed to explore and confirm their promising activity in relapsed brain neoplasms.

The Application of Magnetic Resonance Imaging-Deformed 11C-Methionine-Positron Emission Tomography Images in Stereotactic Radiosurgery

Background: Although ¹¹C-methionine positron emission tomography (MET-PET) images can be fused with magnetic resonance (MR) images using planning software for gamma knife radiosurgery (GKR), the stereotactic information has limited value in patients with recurrent malignant brain tumor due to the difference in imaging protocols between MET-PET and MR images. The aim of this study was to evaluate the clinical application of MR imaging (MRI)-deformed MET-PET images in GKR using a deformable registration tool. Methods: We examined the enhanced MR stereotactic images, MET-PET and MRI-deformed MET-PET images without stereotactic information for 12 newly developed metastatic brain tumors. MET-PET and MRI-deformed MET-PET images were co-registered with the MR stereotactic images using radiosurgery planning software. Visual analysis was performed to determine whether the MET-PET and MR images matched better after using the deformable registration tool. In addition, the matching volume between MR and MET-PET images was compared before and after applying this tool. The matching volume was calculated as the metabolic tumor volume on the MET-PET images, including the MR-enhanced volume. The matching percentage was calculated as the matching volume divided by the MR-enhanced volume, multiplied by 100. Results: Visual analysis revealed that the MRI-deformed MET-PET images provided the same axial plane as that of the MR images, with the same window level, enabling easy identification of the tumor with the radiosurgery planning software. The mean matching percentage of the MET-PET/MR fusion images was 61.1% (range 24.7–94.7) and that of the MRI-deformed MET-PET/MR fusion images was 63.4% (range 20.8–94.3). No significant difference was found in the matching percentage between the two types of fusion images (p = 0.754). Conclusions: The MRI-deformed MET-PET images enable utilization of the functional information when planning a treatment in GKR without significant volume change.

Stereotactic Placement of Intratumoral Catheters for Continuous Infusion Delivery of Herpes Simplex Virus -1 G207 in Pediatric Malignant Supratentorial Brain Tumors

The engineered herpes simplex virus-1 G207, is a promising therapeutic option for central nervous system tumors. The first-ever pediatric phase 1 trial of continuous-infusion delivery of G207 via intratumoral catheters for recurrent or progressive malignant brain tumors is ongoing. In this article, we describe surgical techniques for the accurate placement of catheters in multiple supratentorial locations and perioperative complications associated with such procedures. A prospective study of G207 in children with recurrent malignant supratentorial tumors is ongoing. Preoperative stereotactic protocol magnetic resonance imaging was performed, and catheter trajectories planned using StealthStation planning software. Children underwent placement of 3-4 silastic catheters using a small incision burr hole and the Vertek system. Patients had a preinfusion computed tomography scan to confirm correct placement of catheters. Six children underwent implantation of 3-4 catheters. Locations of catheter placement included frontal, temporal, parietal, and occipital lobes, and the insula and thalamus. There were no clinically significant perioperative complications. Postoperative computed tomography scans coupled with preoperative MRI scans demonstrated accurate placement of 21 of 22 catheters, with 1 misplaced catheter pulled back to an optimal location at the bedside. One patient had hemorrhage along the catheter tract that was clinically asymptomatic. Another patient had cerebrospinal fluid leak from a biopsy incision 9 days after surgery that was oversewn without complication. The placement of multiple intratumoral catheters in pediatric patients with supratentorial tumors via frameless stereotactic techniques is feasible and safe. Intratumoral catheters provide a potentially effective route for the delivery of G207 and may be employed in other trials utilizing oncolytic virotherapy for brain tumors.

Abstract CT004: Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy

Abstract BACKGROUND: In theory, combining immunotherapy with radiation (RT) and chemotherapy is an appealing therapeutic strategy that may offer potential synergistic benefits. The indoleamine 2,3-dioxygenase (IDO) pathway regulates inflammation and immune responses to apoptotic cells. Indoximod reverses the profound immunosuppression created by IDO in the tumor microenvironment. METHODS: 29 pediatric patients with recurrent or progressive malignant brain tumors were treated in two separate indoximod dose-escalation cohorts. Patients eligible for re-irradiation (re-RT) (17/29) were treated with conformal RT (15-54 Gy) in combination with indoximod, followed by indoximod with cyclic temozolomide (200 mg/m2/day for the first 5 days of each 28-day cycle). Patients not eligible for RT received indoximod plus cyclic temozolomide. After initial response or disease stabilization (at least 4 months), patients who showed progression were offered planned re-RT to escape lesions, surgical debulking where indicated, and cross-over to an alternative chemotherapy regimen (oral metronomic cyclophosphamide plus etoposide) while continuing indoximod immunotherapy. Time to Regimen Failure (TTRF) was used to capture time on study. RESULTS: In aggregate, 29 relapsed patients had a median PFS of 6.2 months, median time on study (TTRF) was 11.7 months, and 9/29 are continuing treatment. Patients given RT had median TTRF 13.5 months vs. 4.3 months for no RT. Patients not eligible for conventional full-dose re-RT (&amp;gt;50 Gy) received lower-dose RT (=&amp;lt;30 Gy) not attempting to target all disease where that would be toxic. 9 of 17 patients received lower-dose, restricted-field RT and median TTRF was 16 months versus 13 months for full-dose RT. Based on these results, a cohort of newly-diagnosed patients with diffuse intrinsic pontine glioma (DIPG) was opened using indoximod during front-line RT (54 Gy) followed by maintenance indoximod plus temozolomide. To date 6 newly-diagnosed DIPG patients have enrolled, all with bulbar signs and bulky disease on MRI at study entry. The first 3 newly-diagnosed DIPG patients have completed induction radio-immunotherapy which was well tolerated with symptomatic improvement in all patients, radiographic responses in 3/3, and near resolution of one tumor at the end of radiotherapy. An additional patient with progressive DIPG received re-RT (27 Gy) combined with indoximod, which was tolerated well with symptomatic improvement and objective tumor reduction on post-RT MRI. CONCLUSIONS: Indoximod was well-tolerated in combination with RT and chemotherapy. TTRF compares favorably with historical controls. Lower-dose, restricted-field RT may be beneficial when combined with indoximod in relapse cases. Front-line studies have begun in a cohort of DIPG patients. Citation Format: Theodore S. Johnson, Dolly Aguilera, Ahmad Al-Basheer, Robert C. Castellino, Bree R. Eaton, Natia Esiashvili, Nicholas Foreman, Ian M. Heger, Eugene P. Kennedy, Charles J. Link, William Martin, Eric K. Ring, Ramses F. Sadek, Amy Smith, Vahanian N. Vahanian, Tobey J. MacDonald, David H. Munn. Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT004.

Novel nor-monoterpenoid indole alkaloids inhibiting glioma stem cells from fruits of Alstonia scholaris

BackgroundGlioblastoma multiforme (GBM) is a highly aggressive and frequently recurrent malignant brain tumor, and to date, the clinically effective drugs against GBM remain scarce. Natural products play an important role in drug discovery, and might be the resource of antitumor agents for GSCs. Alstonia scholaris (L.) R. Br. is rich in monoterpenoid indole alkaloids (MIAs) and used extensively for treatment of tumor in the traditional medicine system of Asia. PurposeTo search for new MIAs with antitumor activity against glioma stem cells from clinical patients and explore their mechanism. MethodsCompounds were obtained from the fruits of A. scholaris by chromatographic separation, including silica gel, Sephadex LH-20 and recrystallization. Their structures were elucidated by the use of UV, IR, NMR and MS spectra. The antitumor activity of the compounds against the glioma stem cells (GSC-3#, GSC-12#, GSC-18#) were investigated by phenotypic screening and MTS assays. Cell proliferation assay by BrdU immunofluorescence staining, and apoptosis assay by cleaved-caspase-3 immunofluorescence staining and real-time PCR assay. The soft-agar clonal formation assay was performed to determine the antitumor efficacy of the compounds in vitro. ResultsTwo new nor-monoterpenoid indole alkaloids were isolated from the fruits of A. scholaris. They exhibited selective antitumor activity against glioma stem cells (GSC-3#, GSC-12#, GSC-18#) with IC50 values of 15–25 µg/ml. Furthermore, they inhibited GSCs proliferation, induced GSCs apoptosis by increasing the expression of TNF-α and cleavage of caspase-3, and significantly damaged colony forming capacity of GSCs. ConclusionNew nor-monoterpenoid indole alkaloids from the fruits of A. scholaris provide new type promising molecule for the selective killing of human glioma stem cells.

(OA12) Pulsed Reduced Dose Rate Re-Irradiation (PRDR) Using Modulated ARC (MARC) IMRT for Recurrent Gliomas: Initial Clinical Outcomes of a Novel Technique

Limited salvage options exist for patients with recurrent malignant brain tumors after standard treatment. Pulsed reduced dose rate re-irradiation (PRDR) is a biologically-unique strategy that lowers the effective dose rate, potentially decreasing toxicity by allowing for greater sublethal damage repair in normal tissue. It has been shown to be safe and effective in patients with recurrent gliomas using a 3DRT technique. We developed a novel technique using PRDR with modulated arc (mARC) IMRT delivery to further reduce the amount of normal tissue exposed. We report our initial clinical results using mARC PRDR in patients with previously-irradiated recurrent gliomas. We conducted a retrospective review of all brain tumor patients treated with mARC PRDR at our Institution. All mARC PRDR plans were generated with Monaco (Elekta Inc) using 1/10 of the total prescription dose. For each treatment fraction a total of 10 identical treatment beams were delivered with a minimum time interval of 3 min between beam initiations. This technique allows for the entire treatment volume to receive exactly 1/10 of the prescription dose every 3 min while limiting the prescription dose rate to less than 0.0667 Gy/min. A total of 34 patients were treated with mARC PRDR. Primary histology included grade 2 (n=6), grade 3 (n=10), and grade 4 (n=15) gliomas. Median dose at initial RT was 60 Gy (range 48 – 70) at 1.8 – 2 Gy per fraction. Patients were heavily pre-treated with a mean of 3 prior recurrences (range 1 – 7) before PRDR. Nineteen patients had repeat resection at recurrence including 6 just prior to PRDR. Bevacizumab was previously given to 16 patients with 26 patients receiving bevacizumab while undergoing PRDR (dose 10 mg/kg or 5 mg/kg q2 weeks). All patients had a KPS of 70 or greater. Mean age at PRDR was 53 (range 3 – 71). Median interval between initial RT and PRDR was 4.75 years (range 0.5 – 18.3). Median total dose was 54 Gy (range 30 – 60) at 2 Gy per fraction. At a mean follow-up of 9.3 months (range 0.5 - 19.3), 6-month OS was 70.5% and 1-year was OS 23.5%. Median time to progression was 6 months with 6-month PFS 47% and 1-year PFS 17.6%. Five of the 34 patients did not finish treatment due to clinical decline and/or tumor progression. No acute G3 toxicities were seen from PRDR. This is the first clinical report of mARC IMRT PRDR for recurrent gliomas. This technique appears to be safe, feasible, and well-tolerated for previously-irradiated patients with recurrent gliomas. We await long-term clinical data to better define efficacy and toxicity.

346P - Prognostic Impact of neutrophil to lymphocyte ratio (NLR) in patients (pts) with recurrent primary malignant brain tumours (PMBT) in phase I (Ph1) trials: The Royal Marsden (RMH) Experience

346P - Prognostic Impact of neutrophil to lymphocyte ratio (NLR) in patients (pts) with recurrent primary malignant brain tumours (PMBT) in phase I (Ph1) trials: The Royal Marsden (RMH) Experience

11C-methionine PET/CT findings in benign brain disease.

11C-methionine (MET) is one of the most commonly used positron emission tomography (PET) tracers for evaluation of malignant brain tumor, with MET-PET being a sensitive technique for visualization of primary and recurrent malignant brain tumors. However, previous reports have demonstrated MET uptake in lesions associated with benign brain diseases. These diseases usually show an increase in MET uptake similar to that of malignant tumors. This pitfall in MET-PET image interpretation is important not only for nuclear medicine professionals, but also for radiologists. In this review, we demonstrate the imaging characteristics of MET uptake in benign brain disease, and recommend physician interpretation of imaging findings and disease characteristics for optimal patient management. Benign uptake must be identified to prevent misdiagnosis and unnecessary surgical operations.

Rationale and Design of a Phase I Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors

Rationale and Design of a Phase I Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors

Intraventricular etoposide safety and toxicity profile in children and young adults with refractory or recurrent malignant brain tumors

Systemic administration of etoposide is effective in treating metastatic, recurrent or refractory brain tumors, but penetration into the cerebrospinal fluid is extremely poor. This study was designed to determine the safety and toxicity profile of intraventricular etoposide administration and was affiliated with the prospective, multicenter, nonblinded, nonrandomized, multi-armed HIT-REZ-97 trial. The study enrolled 68 patients, aged 1.1-34.6 (median age 11years). Adverse events that could possibly be related to intraventricular etoposide therapy were documented and analyzed. Intraventricular etoposide was simultaneously administered with either oral or intravenous chemotherapy in 426 courses according to three major schedules varying in dosing (0.25-1mg), frequency of administration (bolus injection, every 12 or 24h), course duration (5-10days) and length of interval between courses (2-5weeks). Potential treatment-related adverse effects included transient headache, seizures, infection of the reservoir, nausea and neuropsychological symptoms. Hematological side effects were not observed. One patient, with history of multiple prior therapies, who received long-term intraventricular and oral etoposide treatment developed acute myeloid leukemia as a secondary malignancy. Overall intraventricular etoposide is well tolerated. The results of this study have warranted a phase II trial to determine the effectiveness of this regimen in disease stages with very limited therapeutic options.

Ventricular access device placement in the fourth ventricle to treat malignant fourth ventricle brain tumors: technical note.

PurposeVentricular access devices (VADs) are commonly placed in the lateral ventricle but rarely placed in other ventricular compartments. This manuscript describes technical aspects of VAD placement into the fourth ventricle for the purpose of treating malignant posterior fossa brain tumors.MethodsAs part of a pilot clinical trial to treat recurrent malignant brain tumors in children, seven patients underwent posterior fossa craniotomy and placement of a ventricular catheter under direct vision into the fourth ventricle. The catheter was placed without passing through any brain parenchyma. It was then connected to a VAD placed subcutaneously at the inferior aspect of the incision. Three of the seven patients underwent simultaneous subtotal resection of recurrent tumor located in the fourth ventricle or cerebellum, and one patient underwent simultaneous tumor biopsy. The VAD was used to administer chemotherapy (methotrexate) in five of the seven patients.ResultsSix patients had no new neurological deficits after surgery, and one patient had partial left-sided facial weakness that was attributed to resection of tumor close to the floor of the fourth ventricle. No new neurological deficits were caused by VAD placement or by methotrexate infusions into the fourth ventricle.ConclusionsA VAD for chemotherapy infusion can be placed safely into the fourth ventricle without damaging the brainstem or cerebellum. Attention to anatomical details specific to the fourth ventricle are important when placing a fourth ventricle VAD and when using it to administer chemotherapy.

IMCT-21UPDATES ON PHASE 1B/2 COMBINATION STUDY OF THE IDO PATHWAY IHIBITOR INDOXIMOD WITH TEMOZOLOMIDE FOR ADULT PATIENTS WITH TEMOZOLOMIDE-REFRACTORY PRIMARY MALIGNANT BRAIN TUMORS

BACKGROUND: Indoleamine 2, 3-dioxygenase (IDO) is a key immune-modulatory enzyme within the IDO Pathway that inhibits CD8+ T cells and enhances the suppressor activity of Tregs. IDO is expressed in 50 to 90% of glioblastoma (GBM), and this high expression correlates with poor prognosis. IDO pathway inhibitors such as indoximod can improve anti-tumor T cell response slowing the tumor growth in vivo. We have demonstrated a synergistic effect of indoximod when combined with temozolomide (TMZ) and radiation in a syngeneic orthotopic brain tumor model. The purpose of this study is to determine the safety and preliminary efficacy of indoximod in combination with TMZ in recurrent refractory malignant brain tumors. METHODS: After progression on TMZ, patients are treated with indoximod (1200 mg BID orally) combined with a standard fixed dose of TMZ (150mg/m2x5 days). In the phase 2 expansion, patients are enrolled into 3 cohorts: 2a: indoximod with TMZ, 2b: indoximod with TMZ and bevacizumab (after progression on bevacizumab), 2c: indoximod with TMZ in conjunction with stereotactic radiosurgery in selected patients. Indoximod is administered for 28 days of each treatment cycle. RESULTS: 30 patients of a planned 105 are enrolled of which 12 patients completed the phase 1b cohort with no DLTs. The ready for phase 2 dose was 1200mg BID. 4 patients in phase 1b remain on study, the longest for 15 months. Best responses to date in the phase 1b component include one patient demonstrating an ongoing PR at 15 months per RANO criteria and SD in 4 patients lasting between 4 and 11 months. No severe AEs or change in TMZ dosing due to indoximod addition were documented. CONCLUSIONS: The phase 1b part has been successfully concluded with encouraging preliminary observations. Enrollment into the phase 2 portion is ongoing. Updates will be presented at the meeting. NCT02052648.