bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-13. A BIOLOGIC EQUIVALENT DOSE COMPARISON BETWEEN RADIOSURGERY AND COLLAGEN TILE BRACHYTHERAPY FOR POST-OPERATIVE TREATMENT OF A BRAIN METASTASIS RESECTION CAVITY
Authors: Turner Adam , Garcia Michael
Published: November 2023

INTRODUCTION

Recurrence of a previously irradiated brain metastasis represents a challenging clinical scenario. Repeat radiosurgery results in sub-optimal local control (LC). Two independently published prospective cohort studies demonstrated durable LC in this setting with collagen tile brachytherapy (CTBT), a novel Cesium-131 carrier. Here we compare biologically equivalent dosimetric parameters of CTBT to radiosurgery to understand dose metrics that may underlie durable LC from CTBT.

METHODS

A patient was selected from the multi-institutional prospective CTBT registry (NCT04427384) with a brain metastasis resection cavity near brainstem. Planning was performed for radiosurgery (30Gy in 5 fractions, BED of 48Gy) and CTBT (Cs-131, activity of 3.5U). To directly compare dosimetric parameters between radiosurgery and CTBT, biologic equivalent doses (BED) were calculated for brainstem(α/β of 3, BED3) and oncologically at-risk tissue(α/β of 10, BED10). TG101 brainstem dose-constraints were referenced, and respective BED were calculated.

RESULTS

The resection cavity was 4mm away from brainstem and contained 7 CTBT tiles (28 Cs131 seeds). Gradient index (GI) (24Gy BED10 volume/48Gy BED10 volume) was 3.8 for radiosurgery and 2.2 for CTBT. Conformality index (CI) (48Gy BED10 volume/CTV volume) was 1.2 for radiosurgery and 2.6 for CTBT. BED10 to 90% of the cavity wall (2mm rim around the resection cavity) was 49.6Gy for radiosurgery and 92.6Gy for CTBT. BED3 dose limit goals (max dose 31Gy in 5 fractions, BED3 95.1Gy and threshold dose 23Gy in 5 fractions, BED3 of 58.3Gy to 0.5cc) were met for both radiosurgery and CTBT.

CONCLUSION

BED comparisons demonstrate that CTBT leads to higher CI, lower GI, and higher dose to the cavity wall than radiosurgery while meeting BED3 dose limit goals to an adjacent organ at risk. These dose characteristics might underlie durable LC seen in the recurrent brain metastasis setting, though larger scale analyses are being performed with with clinical outcomes on NCT04427384.
RADT-14. ROLE OF CHEMOTHERAPY AFTER RADIATION THERAPY FOR GYNECOLOGIC METASTASES TO THE BRAIN
Authors: Chen Eric , Aquino-Michaels Todd , Batra Sadhvi , Lochner Riley , Rizzo Anthony , Chapman Graham , Kyasaram Ravi , Harris Eleanor , Hodges Tiffany , Ferguson Lindsay , Choi Serah
Published: November 2023

BACKGROUND

Brain metastasis from gynecologic malignancy is rare, and the optimal treatment is undetermined.

METHODS

Retrospective data was collected at a single institution from 2001-2021 on 66 patients with brain metastasis from gynecologic malignancy who underwent brain radiation therapy (RT). Kaplan-Meier survival analyses, long-rank tests, and a multivariate proportional hazards model were performed.

RESULTS

Median overall survival (OS) and intracranial progression-free survival (PFS) were 4.3 and 3.6 months, respectively. 25 (38%) patients started chemotherapy after RT in a median 32.5 days (IQR 12-53). Compared to those who did not start chemotherapy after RT, those who did had a longer median OS (9.8 vs 2.6 months, p < 0.01) and PFS (5.0 vs 2.5 months, p = 0.01). On univariate analysis, factors associated with worse survival included >10 brain metastases (p = 0.09), leptomeningeal involvement (p < 0.01), presence of extracranial disease (p = 0.01), no receipt of surgery (p = 0.05), receipt of whole brain RT (p < 0.01), and no receipt of chemotherapy after RT (p < 0.01). On multivariate analysis including above factors and age-adjusted Charlson Comorbidity Index, only receipt of chemotherapy after RT was significantly associated with improved survival (HR 0.32, CI 0.16-0.64). The most common chemotherapy was platinum-based agents in 10 (40%) patients, with no difference in survival (p = 0.74) between those treated with platinum-based versus other agents. More patients who started chemotherapy after RT compared to those who didn’t had ovarian cancer (56 vs 22%, p = 0.02), underwent surgery (52 vs 29%, p = 0.07), and underwent stereotactic radiosurgery (SRS) (64 vs 27%, p < 0.01). For patients who did vs did not receive chemotherapy after SRS, median OS was 11.3 vs 4.3 months (p = 0.01), and after WBRT 4.5 vs 2.2 months (p = 0.10).

CONCLUSION

Patients treated with chemotherapy after SRS in this population may have improved outcomes, though prognosis remains poor.
RADT-17. SINGLE INSTITUTION REVIEW OF OUTCOMES FOLLOWING STEREOTACTIC RADIOSURGERY FOR SIX TO EIGHTEEN BRAIN METASTASES: INTRACRANIAL FAILURE RATES AND NEED FOR FURTHER CRANIAL RADIOTHERAPY
Authors: Lynch Sophie , Chia Kazumi , Manik Vishal , Brazil Lucy , Forner Samantha , Venkatasai Jeyaanth , Hassan Sheila , Akhtar Yasmin , Blythe Kirsty , Al-Salihi Omar
Published: November 2023

BACKGROUND

A single centre retrospective review of outcomes following linear accelerator - based stereotactic radiosurgery (SRS) for patients with 6 to 18 brain metastases was conducted.

METHODS

Patients receiving SRS to multiple metastatic sites were identified from our institutional database and subsequently stratified into those with 6-9 metastases (group 1) and 10 or more metastases (group 2).

RESULTS

45 patients were evaluated in total with a mean number of metastases of 7 for group 1 and 14 for group 2. Mean total GTV volumes for each SRS treatment were 1.92cc (group 1) and 2.70cc (group 2). Median overall survival was 8 months for group 1 (0 -51 months) and 7 months (3-36 months) for group 2 . Following SRS, median time to intracranial progression was 3 months for both groups, occurring in 59% and 64% of group 1 and group 2 patients respectively. Following relapse, more patients in group 2 received whole brain/posterior fossa radiotherapy rather than SRS when compared with those in group 1 (80% vs 40%). The majority of patients surviving more than 1 year following SRS for ≥6 brain metastases had a targetable mutation (defined as any of ALK/EGFR/ROS1/BRAF mutation, ER+, HER 2+, PDL1 expression ≥ 1) in their primary tumour; 75% of group 1 and 100% of group 2.

CONCLUSIONS

Although this study represents small patient numbers, we show that long term survival can be achieved for some patients following SRS for more than 5 brain metastases. However, many patients with more than 10 brain metastases develop intracranial relapse shortly after SRS and require whole brain/posterior fossa radiotherapy, indicating these patients are less likely to benefit from SRS. The presence of a targetable mutation in the primary tumour may indicate a better outcome following SRS for more than 5 brain metastases and warrants further investigation.
RADT-22. STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMA WITH RADIOGRAPHIC BRAINSTEM COMPRESSION
Authors: Shah Anjay , De Leo Alexandra , Li Jonathan , Bova Frank , Friedman William , Amdur Robert
Published: November 2023

BACKGROUND

The safety of single treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression- but without motor deficit- is controversial. Data on linac-based SRS in this setting are scarce. We address this deficit in the literature with a report of outcome of an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS our institution.

METHODS

We included patients with unilateral VS of any size with radiographic brainstem compression at the time of SRS. All patients were without serious brainstem neurologic deficits at the time of SRS. The SRS prescription dose was 12.5 Gy in a single fraction using 6MV photon beams produced by a linear accelerator and delivered with a multiple arc technique. Inclusion in this study required at least 1 year of radiographic follow-up with magnetic resonance imaging (MRI). The primary endpoint was freedom from serious brainstem toxicity (CTCAEv5 grade >3); secondary endpoint was freedom from tumor enlargement considered to represent tumor progression, or any type of enlargement requiring surgical intervention. We also assessed serious cranial nerve complications, excluding hearing loss, defined as CTCAEv5 grade 3 toxicity.

RESULTS

Among 139 patients, the median MRI follow-up time was 5 years and the median tumor size was 2.5 cm greatest axial dimension and 5cc in volume. The median brainstem D0.03cc = 12.6 Gy, and the median brainstem V10Gy = 0.4cc. At 5 years, the actuarial freedom from serious brainstem toxicity was 100% (zero cases), and freedom from tumor enlargement, either requiring surgery or due to progression, was 90%. The rate of grade 3 facial nerve damage in patients without tumor enlargement was 0.9% (1/113).

CONCLUSION

Linac-based SRS as delivered in our series for VS with radiographic brainstem compression is safe and effective.
RADT-31. OPTIMAL TIMING OF CHEMORADIATION AFTER RESECTION OR BIOPSY OF GLIOBLASTOMAS: A NATIONWIDE POPULATION-BASED STUDY
Authors: Roh Tae Hoon , Lee Yeonhu , Kim Se-Hyuk
Published: November 2023

BACKGROUND

The optimal time interval of concomitant chemoradiotherapy (CCRT) after surgery for newly diagnosed glioblastoma (GBM) patients remains controversial. This study was aimed to assess whether the interval between surgery and CCRT leads to a survival difference.

METHODS

Using the Korean National Health Insurance Research Database, 3,586 patients diagnosed with GBM in South Korea from 2008 to 2021 were retrospectively reviewed. The eligibility criteria were GBM-diagnosed patients who underwent surgical resection or biopsy and received CCRT (with temozolomide (TMZ)) within 6 weeks thereafter. Patients were divided into two groups based on interval between surgery and CCRT initiation: early radiotherapy (RT) within 21 days and late RT > 21 days. Patients were separately examined by the type of surgery – biopsy alone or resective surgery. Overall survival (OS) was estimated using the Kaplan-Meier method and log-rank tests. Univariable and Multivariable Cox regression analyses were performed to assess the impact of the covariables on OS.

RESULTS

The median OS for early RT group was 20.47 months compared to 17.94 months of late RT group (Log rank P value of 0.0002). Early RT was associated with prolonged OS in multivariable analysis adjusting age, sex, length of stay in hospital after surgery, and the procedure type of biopsy or tumor resection. On the contrary, subgroup analysis showed that patients who received early RT after biopsy showed higher OS than the patients who received late RT (15.93 months vs. 11.83 months).

CONCLUSION

Patients who received CCRT after 21 days of operation showed better OS than those with earlier CCRT initiation. In contrast, in the group patients who received biopsy alone showed better outcomes when started RT within 21 days. This result suggests that optimal timing of initiation of CCRT after surgery for glioblastoma may be different according to the remnant tumors.
RADT-37. INTERIM RESULTS OF ACCELERATOR-BASED BORON NEUTRON CAPTURE THERAPY, RANDOMIZED CONTROLLED TRIAL FOR RECURRENT AND REFRACTORY HIGH-GRADE MENINGIOMAS
Authors: Miyatake Shin-Ichi , Wanibuchi Masahiko , Kawabata Shinji , Furuse Motomasa , Nonoguchi Naosuke , Nihei Keiji , Fu Naonori , Ono Koji
Published: November 2023

BACKGROUND

High-grade meningiomas (HGMs) recurred after X-ray treatment showed 5.2 months as median progression free survival (mPFS) and only 24.6 months as median overall survival (mOS) from the literatures. Recently, we showed much more excellent OS and PFS using reactor-based boron neutron capture therapy (BNCT) (Neuro-Oncology 24:90-98, 2022). Based on these data, we started “A phase II investigator-lead RCT using accelerator-based BNCT system for refractory recurrent high-grade meningioma”, with the aid of Japanese governmental financial support.

METHODS

We prepared 2 study arms, BNCT test treatment arm (12 subjects) and control best supportive care arm (6 subjects) in RCT fashion. PFS judged by third party committee was set-up as primary endpoint and PFS judged by investigators themselves and OS of BNCT arm were set-up as secondary endpoints. To diminish ethical problems of this RCT, rescue BNCT is permitted for control group patients, if they showed progress disease during the observation period. Macdonald criteria was adopted for assessment. The first patient-in was August 2019 and the last patient-in was August 2021. Interim results of this trial: Three and two grade 3 subjects were included in BNCT and control arm, respectively. Others were grade 2 subjects. As of April 20, 2023, mPFS judged by investigators showed 90 weeks and 8 weeks for BNCT and control arm, respectively (P = 0.0004). OS-2 year rates of BNCT and control arms are 91.7% and 25%, respectively (p = 0.01)

CONCLUSION

Primary endpoint, mPFS judged by third party committee is still being closed and unknown, so far, until the end of the trial (August 2024). With regard to secondary endpoints, there are marked differences in both arms in mPFS judged by investigators. Also, OS in BNCT arm is extremely excellent in comparison with EORTC RCT of “trabectedine” and PD-1 blockade reports, just recently appeared.
RADT-49. A SYSTEMATIC REVIEW AND META-ANALYSIS OF HIPPOCAMPAL AVOIDANCE IN WHOLE BRAIN RADIOTHERAPY AND PROPHYLACTIC CRANIAL IRRADIATION
Authors: Leskinen Sandra , Shah Harshal , Yaffe Beril , Schneider Shonna , Ben-Shalom Netanel , Boockvar John , D'Amico Randy , Wernicke A Gabriella
Published: November 2023

PURPOSE: Hippocampal-avoidance radiotherapy has been under investigation as a technique to improve neurocognitive function in patients undergoing whole brain radiotherapy (WBRT) for intracerebral tumor treatment and control. To understand the effectiveness of hippocampal-avoidance radiotherapy compared to conventional radiotherapy, we systematically reviewed hippocampal-avoidance WBRT (HAWBRT) and hippocampal-avoidance prophylactic cranial irradiation (HAPCI). METHODS: We searched the PubMed database for studies involving hippocampal-avoidance radiation therapy, adhering to PRISMA guidelines. Included studies were analyzed for median overall survival, progression-free survival, hippocampal relapse rates, and neurocognitive function testing. RESULTS: Our initial search identified 3709 results, of which 22 studies were ultimately included and a total of 1749 patients analyzed. Seven of the included studies were randomized controlled trials, five were prospective cohort studies, and ten were retrospective cohort studies. Brain metastases were the most commonly treated tumor. There were 19 studies (86.4%) that evaluated HAWBRT and/or HAPCI in patients with brain metastases. Rates of hippocampal relapse were low (overall effect size = 0.04; 95% confidence interval [0.03, 0.05]) and there was no significant difference in risk of relapse between HAWBRT and conventional WBRT (n=5 studies; risk difference = 0.01; 95% confidence interval [-0.02, 0.03]; p = 0.63). Among the thirteen studies that assessed changes in neurocognitive function, significant differences were identified in overall cognitive function and memory/verbal learning 3-24 months post-RT. Significant differences in processing speed and executive function were reported by some studies at 4 and 6 months. No studies reported differences in verbal fluency, visual learning, concentration, and psychomotor speed at any timepoint. CONCLUSION: Analyzed studies in HA-WBRT/HA-PCI showed low hippocampal relapse or metastasis rates. Significant differences in neurocognitive testing were most prominent in overall cognitive function, memory, and verbal learning. Studies were often hampered by loss to follow-up. Further studies into the effectiveness of HA-WBRT are warranted.
CTIM-06. A PHASE 2 STUDY OF A NOVEL IMMUNOTHERAPY SL-701 IN ADULTS WITH RECURRENT GLIOBLASTOMA: EXPLORING THE PROGNOSTIC VALUE OF TREATMENT-INDUCED CD8+CD57+ T-CELLS AS A MARKER FOR SURVIVAL
Authors: Peereboom David , Lindsay Ross , Badruddoja Michael , Nabors L Burt , Kumthekar Priya , Lieberman Frank , Schiff David , Sherman Jonathan , Butowski Nicholas , Dunbar Erin , Fink Karen , Iwamoto Fabio , Moertel Christopher , Schulder Michael , Walbert Tobias , Chattopadhyay Pratip , Habboubi Nassir , Grzegorzewski Krzysztof , Brooks Christopher , Reardon David
Published: November 2023

Recurrent glioblastoma (GBM) remains a challenging disease with limited therapeutic options and poor prognosis. SL-701 is a novel immunotherapy composed of synthetic peptides designed to elicit an anti-tumor immune response against the overexpressed GBM antigens IL-13Rα2, ephrinA2, and survivin. In this study, we present updated findings from a phase 2 clinical trial (NCT02078648) evaluating SL-701+poly-ICLC+bevacizumab, where the 12-month overall survival (OS) was 50%. Using high-parameter flow cytometry, we compared the quality of the treatment induced T-cell response in patients with an OS < 12m (n = 15) versus OS >12m (n = 12). Among the patients assessed, 89% exhibited heterogeneous T-cell responses against SL-701, with no discernible correlation between the response to a specific peptide and survival. Consequently, we focused on identifying other characteristics of the pan-SL701-specific T-cell response with an association to survival. Assessing all time points collected, patients with an OS >12m generated a significantly higher frequency of SL-701-specific CD8 T-cells (79% increase, P < 0.005) and a lower frequency of CD4+ T-cells (36% decrease, P < 0.05) compared to patients with a lower OS. Moreover, the ratio of CD8:CD4 T-cells was 2-fold higher in patients with an OS >12m indicating a CD8-enriched response, whereas patients with an OS < 12m had a lower ratio of CD8:CD4 associated with CD4 enriched responses. Notably, patients with an OS >12m, expressed CD57 (identifying highly cytotoxic, differentiated memory T-cells) on 40% of their T-cells compared to 18% in patients with an OS < 12m (P < 0.05). Furthermore, the ratio of SL-701 specific CD57:CD107A expressing cells trended 20% lower in patients with an OS >12m, indicative of a replicating, cytotoxic T-cell response that is not terminally differentiated. These qualitative differences in the immune response, detectable as early as week 8 post treatment, may serve as biomarkers for monitoring and predicting survival. Deep sequencing of SL-701-specific T-cells is planned.
CTIM-14. PHASE 1 SAFETY LEAD-IN AND RANDOMIZED OPEN-LABEL PERIOPERATIVE STUDY OF VORASIDENIB COMBINED WITH PEMBROLIZUMAB IN RECURRENT OR PROGRESSIVE ENHANCING IDH1-MUTANT ASTROCYTOMAS: SAFETY LEAD-IN RESULTS
Authors: Wen Patrick , Peters Katherine , de la Fuente Macarena , Mellinghoff Ingo , Arrillaga-Romany Isabel , Kumthekar Priya , Clarke Jennifer , Puduvalli Vinay , de Groot John , Zhang Xiangmin , Chisamore Michael , Abshire Michelle , Mahboub Paria , Hassan Islam , Knipstein Jeffrey , Cloughesy Timothy
Published: November 2023

Isocitrate dehydrogenase 1 mutations (mIDH1) occur in ~80% of grade 2/3 gliomas. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mIDH1/2 enzymes, is an investigational treatment for mIDH gliomas. A neoadjuvant perioperative study in grade 2/3 mIDH gliomas suggested VOR renders the tumor immune microenvironment amenable to immune checkpoint blockade. This study (NCT05484622) evaluates safety/tolerability of VOR plus pembrolizumab to determine the recommended combination dose (RCD) (safety lead-in phase), and CD3+ T-cell infiltration in tumors following preoperative treatment (perioperative phase). Seven patients with recurrent or progressive enhancing grade 2/3 astrocytoma with an IDH1-R132H mutation were dosed in the safety lead-in phase: median age 39 (range, 34–60) years, 3 (43%) female, 6 (86%) grade 3 at screening. Patients received VOR 40 mg orally once daily (QD) plus pembrolizumab 200 mg intravenously once every 3 weeks (Q3W). As of April 29, 2023, patients received a median of 2 (range, 2–5) cycles with six (86%) ongoing; one (14%) discontinued due to disease progression. No dose-limiting toxicities (DLTs), adverse events (AEs) leading to study drug discontinuation, or AEs of special interest (AESI, elevated liver transaminases) were reported during the DLT evaluation period. Six (86%) patients experienced a treatment-related AE, none of which were grade ≥ 3. One (14%) patient experienced a serious, related AE of dysphasia (leading to VOR and pembrolizumab interruption) that subsequently resolved; both drugs were resumed. After the data cut-off, one patient (14%) experienced a grade 2 AESI. Based on safety review committee evaluation, VOR 40 mg QD + pembrolizumab 200 mg Q3W was confirmed as the RCD for the recently initiated perioperative phase. In this phase, ~60 patients will be randomized 1:1:1 to the RCD, VOR 40 mg QD alone, or no treatment prior to surgery. All patients can receive the RCD post-surgery. Funding: Servier and Merck & Co., Inc.
CTIM-17. ADDITIONAL RESULTS FROM A PHASE 1B STUDY OF IGV-001 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Perez-Olle Raul , Pennock Gregory , Scott Charles , Hooper D Craig , Judy Kevin , Andrews David
Published: November 2023

Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed glioblastoma (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM (Andrews et al., 2021), including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). Here we report additional data from the Phase 1b study. We identified two different outcome groups in the ITT population with 14 (42.4%) patients with good outcome (OS ≥ 22.0 months) and 19 (57.6%) with poor outcome (OS < 22.0 months). We also observed a significant correlation between PFS and OS in the ITT population. Five of 33 patients (15.2%) had an OS of at least 60 months. The safety of the biodiffusion chamber implantation and explantation procedures is further supported by data from four patients that were reimplanted upon progression in the Phase 1b study. The neutrophil:lymphocyte (N:L) ratio emerged as a potential marker of good response that will be explored further in the ongoing Phase 2b study. Overall, these data support the ongoing Phase 2b randomized study designed to assess the efficacy and safety of IGV-001 in patients with ndGBM.
CTIM-19. ONCOLYTIC DNX-2401 VIROTHERAPY PLUS PEMBROLIZUMAB IN RECURRENT GLIOBLASTOMA: A PHASE 1/2 TRIAL
Authors: Nassiri Farshad , Patil Vikas , Yefet Leeor , Singh Olivia , Liu Jeff , Dang Rachel , Yamaguchi Takafumi , Daras Mariza , Cloughesy Timothy , Colman Howard , Kumthekar Priya , Chen Clark , Aiken Robert , Groves Morris , Ong Shirley , Ramakrishna Rohan , Vogelbaum Michael A , Khagi Simon , Kaley Thomas , Melear Jason , Peereboom David , Rodriguez Analiz , Yankelevich Maxim , Nair Suresh , Puduvalli Vinay , Aldape Kenneth , Gao Andrew , Lopez-Janeiro Alvaro , de Andrea Carlos , Alonso Marta , Boutros Paul , Robbins Joan , Mason Warren , Sonaben Adam , Stupp Roger , Fueyo-Margareto Juan , Gomez-Manzano Candelaria , Lang Frederick , Zadeh Gelareh
Published: November 2023

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5months (10.7–13.5months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
CTIM-22. PHASE I STUDY RESULTS OF THE ANTIBODY-CYTOKINE FUSION PROTEIN L19TNF IN COMBINATION WITH LOMUSTINE FOR PATIENTS WITH RECURRENT GLIOBLASTOMA REVEAL PROMISING SAFETY AND DURABLE TUMOR RESPONSES
Authors: Weiss Tobias , Puca Emanuele , Covelli Alfredo , Gramatzki Dorothee , Roth Patrick , Neri Dario , Hemmerle Teresa , Weller Michael
Published: November 2023

Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. Recently, we showed synergistic preclinical anti-tumor activity of the immunocytokine L19TNF in combination with lomustine in orthotopic immunocompetent glioma mouse models. L19TNF is an antibody-cytokine fusion protein, comprising the pro-inflammatory cytokine tumor necrosis factor (TNF) fused to the antibody L19 that binds to a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows a targeted delivery of therapeutically relevant doses of TNF to the tumor site through intravenous administration while sparing healthy tissues. Here, we present results of the completed phase I part of a phase I/II open label, multicenter, randomized study to investigate L19TNF in combination with lomustine for patients with recurrent glioblastoma (NCT04573192). Fifteen patients were enrolled from February 2021 – January 2023 and treated at three different dose levels of L19TNF in combination with lomustine. Overall, the treatment was well tolerated. The most common adverse events were asymptomatic increase of liver function tests and a decrease of white blood cells and platelets. Serial MRI assessments revealed near-complete responses in 3 patients (20%) and stable disease in 8 (53%) patients. The median progression-free survival was 4.2 months, progression-free survival rate at 6 months was 46% (7/15 patients), and median overall survival has not been reached after a median follow-up of 11 months. Serial blood assessments demonstrated a treatment-associated increase in C-reactive protein, a peripheral marker for inflammation, which correlated with progression-free survival. A patient, who showed a near-complete response that lasted 12 months relapsed at a different location. Subsequent re-challenge with L19TNF and lomustine again led to a partial response. These encouraging results justify further investigations within the phase II part of the clinical trial that is recruiting patients in four countries.
CTIM-34. JACOB: JOINT ADMINISTRATION OF CDNA FOR TP53, CHECKPOINT INHIBITION, AND BOOST/HYPO FRACTIONATED RADIATION. A PHASE 0/1 STUDY IN CHILDREN WITH RECURRENT, PROGRESSIVE, OR REFRACTORY CNS MALIGNANCIES
Authors: Fonseca Adriana , Kim Sang Soo , Cruz Russell , Ladra Matthew , Pirollo Kathleen , Chang Esther , Packer Roger , Hwang Eugene
Published: November 2023

BACKGROUND

Pediatric patients with recurrent, progressive, or refractory brain tumors have dismal prognoses and few therapeutic options. Due to the complex biological mechanisms of resistance in these tumors, targeted agents and immunotherapeutic approaches in isolation have yielded disappointing results. The combination of SGT-53, anti-PD-1, and hypofractionated radiation has shown encouraging results in preclinical studies. SGT-53 is a novel nanoparticle carrying cDNA encoding human wild-type human TP53; the nanoparticle uses a single-chain antibody fragment recognizing the human transferrin receptor, leading to excellent blood-brain barrier penetrance and anti-tumor targeting. TP53 therapy work synergistically with immune checkpoint inhibitors like anti-PD-1. Hypofractionated radiation provides additional synergy, increasing vascular access, cytokine production and activating tumor-specific T-cells.

METHODS

JACOB is a prospective, phase 0/1 clinical trial to evaluate the safety and efficacy of SGT-53 in combination with hypofractionated radiation and anti-PD-1 in children with recurrent, progressive, or refractory CNS malignancies. Inclusion criteria: patients age ≥ 3 and ≤ 21 years, measurable disease, performance status >50 and adequate organ function. The 3 + 3 de-escalation design will be used to determine the maximum tolerated dose (MTD) of SGT-53 in combination with ICI and radiation. Dose limiting toxicities will be evaluated. SGT-53 will be administered two times per week. Hypofractionated radiation will be given in week 2, and anti-PD-1 (once in 2 weeks) will begin on the second week of treatment. A maintenance phase of SGT-53 and anti-PD-1 will be continued for up to 12 months. Primary endpoints evaluate toxicities related to SGT-53 and plasma pharmacokinetics. Secondary and exploratory endpoints include best radiological response, and immunobiological markers. Twelve patients will be treated in the phase I/dose de-escalation cohort. After the MTD has been identified, a target validation/ phase 0 cohort will include up to 4 patients receiving 2 doses of SGT-53 prior to undergoing surgical resection to determine tissue-specific response.
CTNI-03. EFFICACY OF WSD0922-FU IN OSIMERTINIB-RESISTANT NSCLC WITH CENTRAL NERVOUS SYSTEM (CNS) METASTASES – UPDATES FROM THE DOSE ESCALATION COHORT OF A FIRST-IN-HUMAN PHASE 1 CLINICAL TRIAL (MC1914)
Authors: Kizilbash Sani H , Jaeckle Kurt , Mrugala Maciej , Allred Jacob , Safgren Stephanie , McGovern Renee , Remick Adam , Reid Joel , Lammers Anita , Zhong Wei , Leventakos Konstantinos , Mansfield Aaron , Shanshal Mohamed , Ma Wen , Uhm Joon , Campian Jian , Ruff Michael , Sener Ugur , Galanis Evanthia , Burns Terry , Parney Ian , Raghunathan Aditya , Vaubel Rachael , Jentoft Mark , Roden Anja , Giannini Caterina , Sarkaria Jann , Adjei Alex
Published: November 2023

WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to >279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.
CTNI-08. TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL
Authors: Ahluwalia Manmeet , Ozair Ahmad , Khosla Atulya , Bellur Shreyas , Kotecha Rupesh , McDermott Michael , Mehta Minesh , Sandoval-Leon Ana , Mahtani Reshma , Peereboom David
Published: November 2023

BACKGROUND

20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), which are frequently tackled with stereotactic radiosurgery (SRS). Tucatinib, an oral HER-2 selective tyrosine kinase inhibitor (TKI), has demonstrated efficacy for HER-2-positive breast cancer in combination with capecitabine and trastuzumab. We hypothesize that a combinatorial approach for HER-2 positive breast cancer BMs (BCBM) will lead to better long-term control of BMs and systemic disease.

METHODS

This is an in-progress, prospective, single-arm, multicenter, phase 1 clinical trial that aims to determine the safety of combination of tucatinib, capecitabine, and trastuzumab with SRS in patients with HER-2 positive BCBM. Patients with age 18-80 years, ECOG 0-2, normal organ function, and up to 10 newly-diagnosed BMs are enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. The primary endpoint of the study is the maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg BID. Dose level -1 is 250 mg BID and level -2 is 200 mg BID. Upto 40 patients will be enrolled based on a 3 + 3 design. We plan to expand the cohort at MTD to 40 patients to assess the safety and efficacy of the combination. Secondary endpoints include efficacy as determined by response rate, intracranial PFS, extracranial PFS, and overall survival. Patients are administered oral tucatinib with SRS, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). The trial started enrollment in February 2023. Trial Information: NCT05553522.
CTNI-10. SACITUZUMAB GOVITECAN FOR BREAST CANCER BRAIN METASTASIS
Authors: Balinda Henriette , Kelly William , Ghamasaee Pegah , Gilbert Andrea , Michalek Joel , Kaklamani Virginia , Lathrop Kate , Surapaneni Prathibha , Floyd John , Brenner Andrew
Published: November 2023

Breast cancer brain metastasis (BCBM) is a challenge that significantly impacts patient prognosis and quality of life. Sacituzumab govitecan (SG), an antibody-drug conjugate, has demonstrated antitumor activity and is approved for triple negative and HR+/HER2 negative metastatic breast cancer. It consists of a humanized anti-Trop-2 monoclonal antibody linked to a potent topoisomerase I inhibitor, SN-38. SG activity was tested in a breast cancer intracranial mouse model. We conducted a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SN-38 in patients undergoing craniotomy for breast cancer brain metastases (n = 13). We enrolled patients aged ≥18 years diagnosed with brain metastatic breast cancer to receive a single intravenous dose of SG at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38. Following recovery, patients resumed SG treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were assessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria. Trop-2 and carbonic anhydrase IX (CAIX) expression was investigated by IHC. SG significantly inhibited tumor growth and increased overall survival in mice. An average of 1953.79 ng/ml in serum and 134.3 ng/g in tissue of SN-38 was quantified in patient samples. Trop-2 expression was observed in 100% of patient tumors. 41% of the samples showed high expression of CAIX. A positive correlation between the tissue:serum [SN-38], Trop-2 and gH2AX staining was observed. Median overall survival of 34.5 months (5.7 - 35.6 months) and progression free survival of 7.4 months (2 – 24.4 months) were observed. Our data suggest that SG has therapeutic potential in patients with breast cancer brain metastasis. A prospective multicenter cooperative trial of SG for BCBM, S2007, is ongoing and an update on accrual will be provided.
CTNI-41. PHASE II AND PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS
Authors: Schiff David , Bindra Ranjit S , Li Jing , Ye Xiaobu , Ellingson Benjamin , Walbert Tobias , Campian Jian , Nabors Burt , Lieberman Frank , Ozer Byram , Desai Arati , Omuro Antonio , Wen Patrick , Desideri Serena , Danda Neeraja , Grossman Stuart
Published: November 2023

BACKGROUND

Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity.

METHODS

The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR).

RESULTS

39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were >20-fold the in vitro IC50 for PARP inhibition.

CONCLUSIONS

While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.
CTNI-45. UPFRONT CHEMOTHERAPY AND SUBSEQUENT RESECTION UTILIZING NEOADJUVANT STRATEGY FOR OLIGODENDROGLIOMAS
Authors: Sasaki Hikaru , Kitamura Yohei , Toda Masahiro , Hirose Yuichi
Published: November 2023

Although both of functional preservation and higher extent of resection are required in glioma surgery, maximal resection with the risk of functional sequela is uniformly performed regardless of tumor pathology and treatment sensitivity in the current practice. Oligodendrogliomas are known to be associated with relatively favorable prognosis, however, many patients still eventually succumb to death due to tumors. Improvement in the long-term survival rate and functional preservation would be the next step to be achieved. In our hospital, patients with 1p/19q-codeleted glioma have been treated by upfront chemotherapy, if deemed in need of adjuvant treatment after initial resection, since 2006. If the initial resection was incomplete, the second surgery was intended following tumor volume decrease by chemotherapy (second-look resection, SLR). Intentional staged resection was performed in several cases for whom presence of 1p/19q codeletion was strongly suggested based on preoperative imaging characteristics. Utility of this strategy was evaluated. Forty-one patients with 1p/19q-codeleted glioma have been treated with the strategy. Of these, 30 were grade 2, and 11 were grade 3 tumors. In 9 of the 41 cases, radiotherapy was prescribed immediately after chemotherapy or SLR. Median tumor volume decrease rate by chemotherapy in the cases with initial incomplete resection was -35%. SLR following tumor volume decrease was performed in 22 cases. Median progression-free survival and overall survival after the initiation of chemotherapy were 81 months and 175 months for each in both of the total 41 cases and 32 cases for whom radiotherapy was deferred. Most of the recurrence occurred in the residual FLAIR high intensity. Upfront chemotherapy and subsequent resection strategy utilizing chemotherapeutic response provides more precise resection as well as reduction of resection volume as compared with one-time maximal safe resection. Radiotherapy may be indicated for the cases with residual FLAIR abnormality after chemotherapy or SLR.
CTNI-50. UPDATE REPORT OF THE RESPECT-GBM PHASE I/IIA DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA [RGBM] VIA CONVECTION ENHANCED DELIVERY (CED)
Authors: Brenner Andrew , Michalek Joel , Moore Melissa , Hedrick Marc , Bao Ande , Phillips William , Patel Toral , Weinberg Jeffrey , Floyd John , Youssef Michael , Huang Shiliang , LaFrance Norman
Published: November 2023

BACKGROUND

A Phase1/2a dose-escalation trial was initiated to determine the safety and recommended phase2 186RNL-dose(RP2D). Liposomal-rhenium-186(186RNL) is a source of high-energy beta-particles with gamma-photons representing attractive brain CED properties.

METHODS

A 3 + 3 Phase1 design was implemented per protocol [modified-Fibonacci dosing sequence]. We report safety and overall survival (OS) in 27 patients assigned to cohorts1-8. Patients with biopsy proven recurrent glioma had computerized treatment planning and placement of up to 5 intracranial catheter(s) single CED-186RNL administration. Whole body planar and SPECT/CT imaging through ~1 week following treatment was performed. Patients were followed for safety, sufficiency of delivery and OS. The significance of variation in OS was assessed with a 2-sided logrank test with α = 0.05.

RESULTS

Cohorts dosing ranged from 1mCi-in-0.6mL to 41.5mCi-in-16.3ml, MTD not reached, and no CED failures. No dose limiting toxicities were observed. Most common AEs were pre-existing GBM related signs/symptoms [weakness, fatigue, headache, seizure, scalp discomfort after CED] and >80% of AEs unrelated/unlikely relationship. Median absorbed radiation dose to the tumor (MARDT) was 308.4 Gy (8.9 Gy to 739.5 Gy). Patients were stratified by MARDT (< 100 Gy, ≥100 Gy). In all patients (N = 27), the median overall survival (OS) was 8 months (m), 95% CI 5 m to 13 m). In those receiving <100 Gy (N = 10), the median OS was 5 m (95% CI 1 m to 11 m) and in those with ≥ 100 Gy (N = 17) the median was 12 m (95% CI 5 m to 30 m), p < 0.001.

CONCLUSION

A single administration of 186RNL by CED in recurrent glioma patients is feasible, safe, and potentially effective in increasing overall survival when >100Gy radiation is delivered to the tumor. A RP2D of 22.3mCi in 8.8mL was selected for patients with tumor size of ≤20mL in the planned Phase 2B.
CTNI-51. A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF VORASIDENIB VS PLACEBO IN PATIENTS WITH MUTANT IDH1/2 DIFFUSE GLIOMA (INDIGO): EXPLORATORY ANALYSIS OF VARIANT ALLELE FREQUENCY AND PROGRESSION-FREE SURVIVAL
Authors: Cloughesy Timothy , Mellinghoff Ingo , van den Bent Martin , Blumenthal Deborah , Touat Mehdi , Peters Katherine , Clarke Jennifer , Mendez Joe , Yust-Katz Shlomit , Mason Warren , Ducray Francois , Umemura Yoshie , Nabors L Burt , Holdhoff Matthias , Hottinger Andreas , Arakawa Yoshiki , Sepúlveda Juan , Wick Wolfgang , Soffietti Riccardo , Perry James , Giglio Pierre , de la Fuente Macarena , Maher Elizabeth , Choe Sung , Zhao Dan , Pandya Shuchi , Steelman Lori , Hassan Islam , Tron Adriana , Wen Patrick
Published: November 2023

INTRODUCTION

Vorasidenib is an oral, brain-penetrant, inhibitor of mutant isocitrate dehydrogenase (mIDH) 1/2 enzymes. The INDIGO study (NCT04164901) showed significantly improved radiographic progression-free survival (PFS) by blinded independent review committee (BIRC) with vorasidenib, compared with placebo, in patients with mIDH1/2 adulttype diffuse glioma (hazard ratio [HR] 0.39, 95% CI 0.27–0.56; one-sided P = 0.000000067 [Mellinghoff N Engl J Med 2023]). The key secondary endpoint of time-to-next-intervention was also met.

METHODS

In this double-blind Phase 3 study, patients aged ≥ 12 years with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma, measurable non-enhancing disease, and no prior treatment for glioma were randomized 1:1 to receive vorasidenib 40 mg or placebo daily in 28-day cycles. An investigational clinical trial assay centrally confirmed IDH1 R132H/C/G/S/L or IDH2 R172K/M/W/S/G mutation variants. Pretreatment (archival) tumor tissue was analyzed by next-generation sequencing for CDKN2A/B homozygous deletion and other co-mutations (ACE Extended Cancer Panel).

RESULTS

As of Sep 6, 2022 (preplanned second interim analysis), 168 patients were randomized to vorasidenib and 163 to placebo (median age, 40.0 years; Karnofsky performance scale = 100, 53.5%; oligodendroglioma, 172; astrocytoma, 159; mIDH1, 315; mIDH2, 16). Two patient subgroups were defined by baseline IDH1/2 variant allele frequency (VAF): lower/higher than the median value (0.377). The median PFS results favored vorasidenib over placebo in both subgroups (low VAF, one-sided P = 0.0116; high VAF, one-sided P < 0.0001). Vorasidenib and placebo groups had similar and a low number of co-mutations in known/likely oncogenic genes at baseline (median number of co-mutations across both groups was 4). CDKN2A homozygous deletion was detected in only two participants (both in the placebo group). Additional data will be presented.

CONCLUSION

In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.