bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-16. SAFETY AND PRELIMINARY EFFICACY OF AZD1390 + RADIATION THERAPY FOR GLIOBLASTOMA
Authors: Wen Patrick , Yang Jonathan T , Imber Brandon S , Drappatz Jan , Jena Rajesh , Forst Deborah , Zukas Alicia , Short Susan C , Fan Chunling , Trigg William , Milner Alvin , Polanska Urszula M , Glover Colin , Stavraka Chara , Dalal Darshan , Karanovic Djuro , Chalmers Anthony J
Published: November 2024

BACKGROUND

Glioblastoma is an aggressive cancer; intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide is the first-line standard of care. AZD1390, an ataxia telangiectasia mutated kinase inhibitor, aims to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood–brain barrier penetration, confirmed in healthy volunteers (NCT03215381) and patients with glioblastoma (Phase 0; NCT05182905). This Phase 1, open-label study (NCT03423628) evaluated safety and efficacy of AZD1390 and IMRT in patients with glioblastoma.

METHODS

Adult patients received escalating once-daily AZD1390 doses with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent glioblastoma) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly-diagnosed O-6-methylguanine-DNA methyltransferase unmethylated glioblastoma). Patients received 2 additional weeks of adjuvant AZD1390 post-IMRT. Primary objective was safety; secondary objectives included efficacy and pharmacokinetics.

RESULTS

As of Feb 6, 2024, 115 patients (Arm A=75; Arm C=40) received AZD1390 10–900 mg/day. Pharmacokinetics were linear, with a slightly more-than dose-proportional increase and mean elimination half-life ~9–11 hours. Most patients had ≥1 treatment-emergent adverse event (AE), most commonly fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade ≥3 AZD1390-related AEs occurred in 18/115 patients. The maximum tolerated dose was 400 mg (Arm A) and 300 mg (Arm C). Dose-limiting toxicities included creatinine kinase elevation (Arm A) and radiation skin injury (Arm C). AEs led to AZD1390 discontinuation in 15/115 patients. Safety profiles were mostly consistent across Arms despite different radiation schedules. At target-engaging doses, median overall survival was 12.7 months (95% CI: 10.7–18.9; Arm A) and still maturing (Arm C).

CONCLUSIONS

Concurrent AZD1390 and IMRT demonstrated manageable safety at doses with known target engagement. Preliminary efficacy is encouraging (Arm A). AZD1390 can potentially act as a radiosensitizer for glioblastoma treatment. Clinical investigation is ongoing.
CTIM-17. INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY (IMI) FOR ADULTS WITH DIFFUSE MIDLINE GLIOMA OR DIFFUSE HEMISPHERIC GLIOMA
Authors: Van Gool Stefaan , Kosmal Jennifer , Van de Vliet Peter , Kampers Linde , Stücker Wilfried
Published: November 2024

Diffuse Midline Glioma (DMG, H3K27 mutant) and Diffuse Hemispheric Glioma (DHG, H3G34 mutant) are rare malignant CNS tumors with dismal prognosis. We retrospectively searched in our database for adults (>18y) with molecularly define DMG/DHG, treated between May 2015 and 2024 with IMI as part of first-line treatment. Amongst 157 IMI-treated malignant glioma patients, four patients fit these restrictions, pointing to scarce experience of IMI for DMG/DHG adult patients. HM (M, 29y) was diagnosed with a DMG in the pons. He received radiochemotherapy, and continued after 2x TMZm with BRAF-MEK-inhibition therapy. He received one IO-Vac® dendritic cell vaccine but showed fast progression thereafter. He died 9 months after diagnosis. GJE (F, 28y) had a DMG at the corpus callosum. She received radiochemotherapy and 6x TMZm, followed by 2x IO-Vac® and 3x maintenance immunogenic cell death (ICD) immunotherapy (NDV injections, sessions of modulated electrohyperthermia), combined with WT1 and H3K27M long-peptide vaccines. She progressed after 20 months, for which a new IO-Vac® and an H3K27M short- and long-peptide vaccine were given. She died 5 months later. Overall Survival (OS) was 26 months after initial diagnosis. JD (F, 27y) was diagnosed with a DMG in C2-C6. She received radiochemotherapy followed by IMI alone, including 2x IO-Vac®, one ICD immunotherapy, and four doses of anti-PD1. She died 17 months later, making OS 27 months after diagnosis. VJ (F, 21y) had a DHG in the left cerebrum. She received radiochemotherapy and 12 cycles of maintenance TMZ (TMZm), between which ICD immunotherapy was inserted each time. Afterwards, she received two IO-Vac®. Finally, she received ICD immunotherapy (6x) combined with checkpoint inhibitors (4x anti-CTLA4, 10x anti-PD1). Thirty months after diagnosis, she is in remission with a stable Health Utility Index of 0.72. IMI might have contributed to a better OS in three out of four DMG/DHG patients, and should be explored further as part of the treatment for these patients.
CTIM-24. PHASE II TRIAL OF RHIL-7-HYFC IN PATIENTS WITH HIGH-GRADE GLIOMA DEMONSTRATED ACCEPTABLE SAFETY PROFILE AND REDUCED LYMPHOPENIA
Authors: Derek Li Yuping , Luo Jingqin Rosy , Grote Cierra , Nehring Leslie , Katumba Ruth , Etter Kelsey , Barozinsky Kaiden , Ferrando-Martinez Sara , Stermer Kristina , Lee Byung Ha , Johanns Tanner , Butt Omar , Huang Jiayi , Campian Jian L , Chheda Milan G
Published: November 2024

BACKGROUND

Lymphopenia, a common finding in patients with high-grade gliomas (HGGs), is associated with poor outcomes including worse survival, fatigue, and in some cases, increased opportunistic infections. Interleukin-7 (IL-7) is a cytokine crucial for lymphocyte survival and proliferation. We previously demonstrated long-acting IL-7 (rhIL-7-hyFc, efineptakin alfa, NT-I7) increases absolute lymphocyte counts (ALCs) and extends survival in preclinical murine models of HGG. Here, we report results using rhIL-7-hyFc to effectively reduce lymphopenia in patients with HGG.

METHODS

We performed a phase II randomized, placebo-controlled, double-blind study of rhIL-7-hyFc in patients with newly diagnosed HGGs (82% IDH-wildtype glioblastoma in both groups). Patients received rhIL-7-hyFc (720mcg/kg) or placebo one-week post-radiation and temozolomide, with subsequent doses at weeks 13, 25, and 37. The primary endpoint was ALC four weeks post-initial administration; exploratory endpoints included CD4 count, progression-free survival (PFS), and overall survival (OS).

RESULTS

We enrolled 22 patients (median age 59.5 years, range 33-74; 40.9% female) with HGG. Both groups exhibited comparable demographics, including MGMT methylation status, and received a median of 2 doses of rhIL-7-hyFc or placebo. At 4 weeks, the pre-specified primary endpoint, ALC significantly increased relative to baseline in the treatment group, compared to placebo (median percent change=148% vs. 16.7%, p=0.007), as did CD4 count (121% vs. 10.5%, p=0.011). There were no treatment-related grade 4/5 adverse events. Exploratory endpoints of PFS and OS will be reported at time of conference.

CONCLUSIONS

rhIL-7-hyFc is safe and effective in improving ALC and CD4 count in patients with newly diagnosed HGG undergoing temozolomide and concurrent radiation therapy. This study was powered to meet the primary endpoint; larger trials will likely be required to demonstrate clinical efficacy. Nevertheless, these data support the continued exploration of rhIL-7-hyFc as an adjunct to standard therapy to mitigate lymphopenia and potentially extend survival for patients with HGG.
CTIM-28. NEOADJUVANT ANTI-PD1 IMMUNOTHERAPY FOR SURGICALLY ACCESSIBLE RECURRENT GLIOBLASTOMA: CLINICAL AND MOLECULAR OUTCOMES OF A STAGE 2 SINGLE-ARM EXPANSION COHORT
Authors: Ricardo McFaline-Figueroa J , Sun Lu , Youssef Gilbert , Huang Raymond , Li Gang , Kim Jiyoon , Lee Eudocia , Nayak Lakshmi , Chukwueke Ugonma , Beroukhim Rameen , Batchelor Tracy , Chiocca E Antonio , Everson Richard , Doherty Lisa , Stefanik Jennifer , Partridge Kathryn , Spearman Amanda , Myers Alexa , Westergaard Catharina , Russ Alyssa , Lavallee Maria , Smokovich Anna , LaForest-Roys Corey , Fox Rachel Garcia , McCluskey Christine , Bi Wenya Linda , Arnaout Omar , Peruzzi PierPaolo , Cosgrove G Rees , Ligon Keith , Romany Isabel Arrillaga , Clarke Jennifer , Reardon David , Cloughesy Timothy , Prins Robert , Wen Patrick
Published: November 2024

Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we performed bulk-RNA seq on resected tumor tissue from an additional 25 patients with recurrent glioblastoma treated with neoadjuvant pembrolizumab. Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. PF6 for the stage 2 expansion cohort was 0%, while overall survival and progression-free survival were similar to historical controls at 6.8 months and 2.5 months, respectively. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not observe a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma in our expansion cohort. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.
CTIM-33. IMMUNE BIOMARKERS OF TREATMENT RELATED IMAGING CHANGES IN GLIOBLASTOMA PATIENTS TREATED WITH STANDARD OF CARE PLUS PEMBROLIZUMAB
Authors: Claunch Cheryl , Barajas Ramon , Ambady Prakash
Published: November 2024

Pseudoprogression is a post-treatment imaging phenomenon in glioblastoma (GBM) that mimics true progression. Immune checkpoint inhibition with pembrolizumab has shown clinical benefits in multiple cancers and is a burgeoning treatment in GBM. Discerning pseudoprogression, or treatment-related imaging changes, from true progression is essential for appropriate treatment recommendations. However, there are no reliable biomarkers that can differentiate between pseudoprogression and true progression. Our prospective single-arm study (NCT 03347617) evaluated immune cell sub-populations (B-cells, T-cells, NK cells, monocytes, and myeloid cells) in newly diagnosed GBM patients who received standard-of-care chemoradiation plus concurrent pembrolizumab after maximal safe resection. Flow cytometry was performed on blood collected at predetermined timepoints (pre-treatment, post-radiation, suspected progression, and confirmed progression) and immune cell sub-populations were evaluated as covariates in univariable and multivariable logistic regression analysis. Of the 56 patients enrolled in this trial, 51 completed blood collection. Median survival was 13.84 months. Fifteen (29%) patients had pseudoprogression by modified RANO criteria and 36 (70.5%) had suspected or confirmed progression. Univariable analysis identified the following serum derived immune populations as being significantly associated with pseudoprogression: cytotoxic T-cell percentage (CD3+CD8+; HR: 1.10; p=0.045); total NK Cells percentage (CD3+CD56+; HR:0.912; p=0.0.053); IGD+CD27-naïve B-cells of B-cell percentage (HR: 0.976; p=0.014); IGD+CD27+non-switched B of B-cell percentage (HR:1.07; p=0.036). Backward selection multivariable logistic regression analysis confirmed the significant association of cytotoxic T-cell percentage (CD3+CD8+; HR:1.02; p=0.049) with pseudoprogression while controlling for IGD+CD27+non-switched B of B-cell percentage (HR:1.01, p=0.116). Increasing levels of serum cytotoxic T-cells in GBM patients treated with standard-of-care plus pembrolizumab is associated with pseudoprogression and may be used to differentiate between true progression. Validation of results is needed in a control population treated with standard-of-care prior to clinical implementation. Future studies will utilize serum immune biomarkers coupled with radiomic features to better characterize the pseudoprogression signature in GBM.
CTNI-05. A PROSPECTIVE STUDY OF TUMOR-TREATING FIELDS COMBINED WITH SYSTEMIC THERAPY IN RECURRENT GLIOBLASTOMA
Authors: Guo Chengcheng , Yang Qunying , He Zhenqiang , Duan Hao , Lu Jie , Cao Xi , Sai Ke , Ke Chao , Chen Zhenghe , Liu Ruhua , Zhang Xiangheng , Mou Yonggao
Published: November 2024

BACKGROUND

Tumor-treating Fields (TTFields) monotherapy was approved for recurrent glioblastoma. However, TTFields combined with systemic therapy has not been well studied in China. This study aims to explore the efficacy and safety of such combination therapy for recurrent GBM.

METHOD

This study is a prospective, single-arm, open-label clinical trial (NCT04689087) planning to enroll 40 recurrent supratentorial GBM patients and use TTFields combined with physician chose systemic therapy. Kaplan-Meier survival curve was used to estimate PFS, OS and survival rate. The primary endpoint was 6-months OS rate (OS6). Secondary endpoints were PFS, PFS6 and safety. OS and PFS were computed from the day of initiating TTFields.

RESULT

Fourty recurrent supratentorial GBM patients was enrolled from July 2020 to May 2023. The average age was 51 and median KPS score was 80. Sixty-eight percent (27/40) of them underwent total resection surgery and 5% (2/40) only experienced biopsy as their newly diagnosed GBM surgery. Eighty-eight percent (35/40) of patients started TTFields when they were first diagnosed as recurrence, while 12.5% (5/40) patients started TTFields at their second-time recurrence or latter. Median time from diagnosis of recurrence to initiating TTFields was 27 days. Median duration time of TTFields was 8.7 months and average compliance of TTFields was 87% (20.9 hours/day). As for molecular biomarkers, 50% (20/40) patients were MGMT protein positive and 32.5% (13/40) were TERT mutant. Chemotherapy was included in the systemic therapy in 80% (32/40) patients, antiangiogenic therapy in 60% (24/40) patients, BRAF inhibitor therapy in one patient and immune checkpoint inhibitor therapy in one patient. At data cut-off date of March 20, 2024, the median follow-up period was 20.8 months. The primary endpoint OS6 was 87.2%, the median OS was 20.2 months (95%CI 11.9-NR). Median PFS was 8.5months (95%CI 6.2-NR). PFS6 was 67.5% while the historical reference of physician’s best choice of active chemotherapy from EF-11 study showed a PFS6 of 15%. Scalp adverse events were the most common AE. Seventy-eight (31/40) of patients experienced grade 1 or 2 scalp adverse events which can be relieved by topical corticosteroids.

CONCLUSION

TTFields combined with systemic therapy showed favorable efficacy and safety in Chinese recurrent GBM patients. Key words: Recurrent GBM, TTFields, prospective study, systemic therapy
CTNI-12. TIRABRUTINIB FOR RECURRENT/REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA –A SINGLE-INSTITUTION RETROSPECTIVE ANALYSIS–
Authors: Yamasaki Fumiyuki , Yonezawa Ushio , Taguchi Akira , Onishi Shumpei , Ozono Iori , Khairunnisa Novita Ikbar , Horie Nobutaka
Published: November 2024

BACKGROUND

Tirabrutinib is a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor and approved for the treatment of recurrent/refractory primary central nervous system lymphoma (PCNSL) in Japan. We reviewed our single institution experiments of tirabrutinib.

MATERIALS AND METHODS

Our institutional review board approved this retrospective study. Twenty-eight patients with recurrent or refractory PCNSL treated with tirabrutinib at our institution between 2020 and 2024 were included. Information regarding the patient’s age, gender, imaging findings, pathological results, including immunostaining findings, and treatment information, including chemotherapy and radiation therapy, was obtained from medical records.

RESULTS

Tirabrutinib was administered to 14 patients with recurrent cases (20-85 years old, median 69.5 years old, 9 males and 5 females), 14 with refractory cases (59-87 years old, median 74 years old, 9 males and 5 females). Three male patients received rechallenge with tirabrutinib against re-relapsed. We assessed the effectiveness of tirabrutinib and observed complete response (CR) in 12 cases, partial response (PR) in 1 case, and progressive disease (PD) in 1 case among refractory patients. In recurrent cases, we observed CR in 8 cases, PR in 1 case, stable disease (SD) in 3 cases, and PD in 2 cases. In rechallenge for re-relapsed cases, we observed CR in 2 cases and PD in 1 case. The progression-free survival following beginning of tirabrutinib was 12.95 months for refractory cases and 8.2 months for recurrent cases. The overall survival was 25 months for refractory cases and 12.8 months for recurrent cases. One patient each experienced CTCAE grade 3 interstitial pneumonia or liver failure, both of which improved after discontinuing the medication. Four patients exhibited grade 1-2 skin rashes.

CONCLUSIONS

Tirabrutinib demonstrates efficacy and high tolerability for the treatment of recurrent/refractory PCNSL in real-world settings.
CTNI-16. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA
Authors: Kirton Laura , Apps John , Lawson Anna , Arvanitis Theodoros , Mitra Dipayan , Gagan Richard , Patel Hiten , Peet Andrew , Fern Lorna , Williams Emma , Coleman Nicholas , Ajithkumar Thankamma , Bison Brigitte , Veal Gareth , Stark Daniel , Morana Giovanni , Nicholson James , Billingham Lucinda , Murray Matthew
Published: November 2024

BACKGROUND

Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely.

METHODS

Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440).

RESULTS

MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (<30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design.

CONCLUSION

MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.
CTNI-26. A PHASE II STUDY OF SACITUZUMAB GOVITECAN IN RECURRENT GLIOBLASTOMA
Authors: Kelly William , Cordova Christine , Vaillant Brian , Balinda Henriette , Michalek Joel , Gilbert Andrea , Floyd John , Brenner Andrew
Published: November 2024

BACKGROUND

Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer. GBM expresses trophoblast cell-surface antigen 2 (Trop2) which correlates with proliferation rate, microvessel density, histological grade and clinical survival. Sacituzumab Govitecan (SG) is an antibody-drug conjugate targeting Trop2 with a chemotherapy payload, SN-38. This drug has been approved for triple-negative and hormone-receptor positive metastatic breast cancer.

METHODS

We conducted multi-center (UT Health San Antonio, Cleveland Clinic, Texas Oncology in Austin), open-label, single-arm phase 2 study using a 2-stage adaptive Bayesian design. Patients with recurrent GBM (rGBM), IDH wild-type, following standard-of-care chemoradiation, received SG (10mg/kg IV, days 1 and 8 every 21 days). Patients were assessed by RANO and CTCAE v5. The primary endpoint was PFS of patients on SG as compared to a historical control of lomustine.

RESULTS

As of interim analysis cutoff, 24 patients have been screened with 20 patients enrolled. The average age was 58.8 years. 65% of patients identified as male. 95% were Caucasian with 20% identifying as Spanish, Hispanic or Latino. Adverse events (AE) include lymphopenia (40%), neutropenia (40%), hypokalemia (35%), elevated alkaline phosphatase (30%), anemia (30%) with most AE being grade ≤ and no grade 5 observed. 4 patients had grade ≥3 neutropenia attributable to SG. 20% had stable disease as best response with the rest being progressive disease. The mean PFS and OS were 7.0 and 2.0 months, respectively. Of 19 evaluable samples, 63% had positive Trop2 expression (H-Score ≥100, mean 123.6±74 [0.6, 269.2]). A post-hoc analysis of OS log survival time vs H-Score (n=19) using an accelerated failure time model showed that survival correlated with H-Score (p=0.0361).

CONCLUSIONS

In the interim analysis of this study of patients with rGBM, Sacituzumab was found to be well-tolerated. Further study of those patients bearing tumors with elevated H-scores may be warranted.
CTNI-33. EARLY COMPLETE RESPONSE MIGHT NOT BE AN INDICATOR OF LONGER PROGRESSION-FREE SURVIVAL IN NEWLY-DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH A COMPLETE RESPONSE BY MTX-BASED INDUCTION THERAPY
Authors: Nagane Motoo , Sasaki Nobuyoshi , Saito Kuniaki , Kobayashi Keiichi , Kugasawa Kazuha , Onoda Ryo , Nakatomi Hirofumi
Published: November 2024

Primary central nervous system lymphoma (PCNSL) is an extra-nodal non-Hodgkin lymphoma solely arising from the central nervous system including eyes. While 70% of patients with newly-diagnosed PCNSL achieve a complete response (CR) after R-MPV, the current standard of care MTX-based induction therapy, recurrence yet frequently occurs (~50%) and clinical factors related to failure are not well defined. Early complete response is associated with lower recurrence rate in various cancers. In this study, we conducted a retrospective, single-institution study to investigate whether early complete response was associated with recurrence in PCNSL. Newly-diagnosed PCNSL patients treated with R-MPV at the authors’ institution between 2011 and 2022 were identified, and progression-free survival (PFS), overall survival (OS) were analyzed along with number of chemotherapy cycles required to achieve a CR or CR unconfirmed (CRu). In total of 92 patients treated with R-MPV identified, 68 (75%) patients achieved a CR or CRu. Among patients who achieved CR or CRu, a median total of seven (1-8) R-MPV cycles were delivered. The median cycle required to achieve CR or CRu was five (1-8). Consolidation whole brain radiation therapy (WBRT) was given to 29 younger patients (median age: 63), while 39 older patients (median age: 74) were treated without WBRT. The number of chemotherapy cycles required to achieve CR or CRu was not associated with PFS or OS in all ages. However, requiring six or more chemotherapy cycles to achieve CR or CRu was associated with longer PFS (p=0.046) in patients treated without WBRT. These data suggest that early complete response might not be indicative of superior survival outcome in newly-diagnosed PCNSL treated without consolidation WBRT. Persisting enhancing lesions during chemotherapy could lead to treatment intensification through delivering greater number of chemotherapy cycles, which might have conferred longer PFS in these patients.
CTNI-35. EVALUATE THE SAFETY AND PRELIMINARY EFFICACY OF THE COMBINATION OF NAVIFUS SYSTEM WITH RE-IRRADIATION FOR RGBM PATIENTS
Authors: Wei Kuochen , Chen Koting , Huang Chiungyin
Published: November 2024

The blood-brain barrier (BBB) remains the major obstacle in treating patients with malignant brain tumors. Radiation therapy (RT) is the mainstay adjuvant modality regardless of the BBB, but its effectiveness is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown to open the BBB and potentially increase regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). Here, we report an interim analysis of an ongoing single-arm, prospective, pilot study (NCT04988750) combining RT-FUS for recurrent malignant high-grade glioma patients, where re-RT was considered for disease control. FUS-BBB opening was conducted within 2 hours before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression-free survival, overall survival, and adverse events (AEs). In this pilot clinical trial, an interim analysis of six recurrent malignant high-grade glioma patients who underwent a total of 24 RT-FUS treatments was presented. Three patients experienced rapid disease progression after RT-FUS, while the other three patients had at least stable disease after RT-FUS, with or without salvage chemotherapy or targeted therapy. There were no FUS-related AEs, but re-RT-related grade three radiation necrosis was observed. The interim analysis of this ongoing clinical trial showed that the combination of RT-FUS was safe, with no FUS-related adverse effects. Two more cases will be recruited in this trial. A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.
CTNI-36. THE FEASIBILITY OF USING BORTEZOMIB WITH CHEMOTHERAPY IN ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Ho Wan-Ling , Hsieh Ming-Yun , Liao Yu-Mei , Chiou Shyh-Shin , Shiah Her-Shyong , Chiang Chang-Hsu , Jou Shiann-Tarng , Yen Hsu-Ju , Lee Yi-Yen , Liang Muh-Lii , Yeh Ting-Chi , Chou Yu-Cheng , Huang Fang-Liang , Chen Shu-Huey , Lee Hsin-Lun , Kuo Chia-Chun , Chen Shu-Mei , Tsai Min-Lan , Chang Hsi , Hsieh Kevin Li-Chun , Fang Chia-Lang , Chang Chia-Yau , Wang Jinn-Li , Chen Chu-Chin , Loh Joon-Khim , Lin Pei-Chin , Lin Tzu-Chin , Wang Shih-Chung , Tu Yi-Fang , Cheng Chao-Neng , Chuang Ming-Jung , Tran Huy Minh , Sung Shian-Ying , Lai Irving , Wu Kuo-Sheng , Miser James S , Liu Yen-Lin , Wong Tai-Tong
Published: November 2024

Atypical teratoid/rhabdoid tumors (ATRTs) are highly aggressive pediatric brain tumors with sensitivity to proteasome inhibitors in preclinical models. We evaluated the feasibility of combining the proteasome inhibitor bortezomib with chemotherapy. Patients aged 0-20 years with newly diagnosed ATRT were enrolled from January 2022 through December 2023. A modified Medical University of Vienna (MUV)-ATRT regimen was used. They were treated with bortezomib of 1.3 mg/m2/dose given intravenously or subcutaneously twice a week for 2 weeks concurrently with 6 cycles of chemotherapy and 2 additional cycles after high-dose chemotherapy. Radiation therapy was given prior to or at the end of chemotherapy. A total of 36 chemotherapy cycles with bortezomib in 6 patients were evaluated. The primary endpoint was grade 3 or higher non-hematologic toxicities. Numbers of cycles with grade 3+ toxicities included: AST/ALT elevation (1), hypokalemia (2), peripheral neuropathy (1), subdural hemorrhage (2), vomiting (2), oral mucositis (3), lung infection (2), urinary tract infection (8), sepsis (3), febrile neutropenia (20). No grade 3+ toxicities were considered bortezomib-related. Three patients completed 8 cycles of bortezomib treatment; 2 patients discontinued the study due to progressive disease after 2 and 4 cycles respectively; 1 patient completed 6 cycles of bortezomib and died of septic shock in complete remission after high-dose chemotherapy. Two patients had a surgical complete resection. Three patients were evaluable for response after bortezomib: 1 partial response and 2 stable disease. Two patients had progression-free survival for 16+ and 22+ months after diagnosis, respectively. Among the 3 patients with progressive disease, 2 had metastatic relapse and 1 had primary and metastatic relapse. There were 4 deaths due to metastatic PD (n=2), septic shock after high-dose chemotherapy (n=1), and septic shock after 2nd line treatment for PD (n=1). We conclude that adding bortezomib to standard and high-dose chemotherapy of ATRT was feasible with the occurrence of grade 3/4 toxicities no more than what was expected with chemotherapy alone. Metastatic relapse remains the major challenge of ATRT treatment.
CTNI-38. SINGLE-CENTER COMPARATIVE ANALYSIS ABOUT OUTCOMES OF MULTI-AGENTS CHEMOTHERAPY FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA; R-MPV SHOWED A FAVOR RESULT
Authors: Makino Yasuhide , Yamamoto Etsuko , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Arakawa Yoshiki
Published: November 2024

BACKGROUND

Primary central nervous system lymphoma (PCNSL) is a malignant tumor in the brain, spinal cord, and eyes. Radiotherapy may cause delayed leukoencephalopathy so that the first-line treatment is methotrexate (MTX)-based multi-agent chemotherapy. We had used the Bonn protocol based on MTX and cytarabine, but since 2020, we have adopted the R-MPV protocol. This study analyzes the outcomes of patients treated initially at our institution.

METHODS AND RESULTS

We reviewed 57 out of 88 newly diagnosed PCNSL patients treated with chemotherapy alone between December 2005 and January 2023. Initial treatments included the Bonn protocol in 25 patients (12 with rituximab, forming R-Bonn) and R-MPV in 26 patients. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) was given as consolidation in 4 Bonn and 9 R-MPV patients. The Bonn protocol was completed by 20 patients (80%) with a complete response (CR) in 19 (76%). The R-MPV protocol was completed by 23 patients (88%) with CR in 22 (85%). Post-treatment outcomes were compared using survival analysis. Median progression-free survival (mPFS) had not been reached in the R-MPV group and was significantly better than 33.1 months in the Bonn protocol and 58.6 months in the R-Bonn protocol (log-rank test; p=0.0296, 0.0036). Overall survival (OS) did not show significant differences. PBSCT’s impact on outcomes suggested improvement in PFS and OS after R-MPV, but this was not statistically significant.

DISCUSSION

We examined the efficacy of different chemotherapy regimens for PCNSL at our institution. The R-MPV protocol showed superior completion rates, response rates, and treatment efficacy. Consolidation with PBSCT may improve outcomes, though further investigation with more cases and longer observation is necessary.
CTNI-47. A PHASE 1, RANDOMIZED, PERIOPERATIVE TRIAL OF VORASIDENIB AND IVOSIDENIB IN IDH1-MUTANT DIFFUSE GLIOMA: UPDATED RESULTS
Authors: Mellinghoff Ingo , Wen Patrick , Taylor Jennie , Taylor Elizabeth , Arrillaga-Romany Isabel , Ellingson Benjamin , Mahboub-Johnson Paria , Baron Eric , Hassan Islam , Steelman Lori , Clarke Jennifer , Cloughesy Timothy
Published: November 2024

BACKGROUND

Vorasidenib (VOR) and ivosidenib (IVO) showed clinical activity in subjects with isocitrate dehydrogenase mutant (mIDH) gliomas. We evaluated both agents in a phase 1, randomized, open-label perioperative trial (NCT03343197). Pharmacodynamics, pharmacokinetics, and preliminary objective response rate (ORR) data as of 29-April-2020 were previously reported (Mellinghoff et al. Nat Med. 2023). Progression-free survival (PFS) data were not mature at publication time. We report here longer-term follow-up results, including mature PFS.

METHODS

Participants with grade 2/3 non-enhancing mIDH1 R132H mutant gliomas were randomized to VOR (50 or 10 mg QD), IVO (500 or 250 mg BID), or no treatment (control) for 4 weeks prior to planned surgery, with the option to continue treatment with VOR or IVO post-surgery. Secondary objectives included PFS, ORR assessed by Investigator in the post-surgery period, and safety profile of VOR and IVO.

RESULTS

Enrollment completed in April-2019. 49 participants were randomized, of which 46 participants (24 oligodendroglioma, 20 astrocytoma, 1 anaplastic oligodendroglioma, 1 anaplastic oligoastrocytoma) received treatment with either VOR (N=24) or IVO (N=22) after surgery. As of 23-September-2023 data cutoff, 11 (46%) and 5 (20%) participants remain on treatment for VOR and IVO, respectively. Median (range) post-operative treatment duration was 44.7 months (0.9–62.7) for VOR, 23.9 months (0–62.7) for IVO. Median (95% CI) PFS was 41.4 months (9.3, NE) for VOR and 38.6 months (18.3, NE) for IVO. ORR per Response Assessment in Neuro-Oncology in low-grade gliomas (RANO-LGG) was 46% for VOR and 27% for IVO. Longer safety follow up will also be presented.

CONCLUSION

These results provide further evidence of prolonged response using IVO and VOR immediately following surgery in predominantly non-enhancing gliomas. This longer-term follow-up is consistent with Phase 3 INDIGO study results where VOR demonstrated PFS benefit with manageable safety compared with placebo in participants with non-enhancing mIDH gliomas.
CTNI-60. SAFETY LEAD-IN RESULTS FOR QBS10072S IN THE INDIVIDUAL SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT) TRIAL, A RANDOMIZED ADAPTIVE PLATFORM TRIAL FOR NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA
Authors: Rahman Rifaquat , Trippa Lorenzo , Aquilanti Elisa , Lee Eudocia , Arrillaga-Romany Isabel , Wiley Jennifer , Chukwueke Ugonma , McFaline-Figueroa Jose , Partridge Kathryn , Beroukhim Rameen , Nayak Lakshmi , Batchelor Tracy , Lu-Emerson Christine , Drappatz Jan , Lassman Andy , Welch Mary , Ahluwalia Manmeet , Bi Wenya , Arnaout Omar , Haas-Kogan Daphne , Tanguturi Shyam , Aizer Ayal , Doherty Lisa , Fell Geoffrey , Lavallee Maria , Smokovich Anna , Peabody Shannon , Westergaard Catharina , Bhutani Vasvi , Russ Alyssa , Barlow Brooke , Chiocca Ennio , Ringold Gordon , Weitzman Ron , Holland Jaymes , Reardon David , Ligon Keith , Wen Patrick
Published: November 2024

BACKGROUND

QBS10072S, is a L-type amino acid transporter 1 (LAT-1) targeted alkylating agent that utilizes LAT1 as both a transport and targeting mechanism. QBS10072S can cross the blood-brain barrier, exhibits potential for cytotoxicity with a mechanism distinct from temozolomide and has low off-target effects. QBS10072S is being evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial (NCT02977780), a randomized phase 2 adaptive multi-arm platform trial.

METHODS

Adult patients with newly diagnosed MGMT-unmethylated glioblastoma are eligible for INSIGhT. Since there is no safety data available for QBS10072S in combination with radiotherapy, a safety lead-in evaluation was conducted utilizing a 3 + 3 design. Starting dose for QBS10072S was 12mg/m2 in combination with radiation therapy and adjuvantly as monotherapy in 28 day cycles. Patients were monitored for dose-limiting toxicities (DLTs) to identify the maximum tolerated dose and recommended phase 2 dose (RP2D).

RESULTS

Nine patients were enrolled December 2022 to October 2023 for safety lead-in testing, and median age was 57 years (41-67) with 6 (66%) males, 6 (66%) patients with gross total resection, and median KPS 90 (range 80-100). Pharmacokinetic studies indicated that drug exposure was lower than prior studies, and three patients received 12mg/m2, 15mg/m2, and 18mg/m2, respectively, per dose escalation protocol. No DLTs nor adverse events leading to study drug discontinuation were reported during the evaluation period. Four patients had possible treatment-related CTCAE grade ≥ 3 toxicity including lymphopenia (n=3) and fatigue (n=1). The RP2D was determined to be 18mg/m2. Seven patients were discontinued from study treatment due to progressive disease and two patients remain on treatment.

CONCLUSION

QBS10072S, concurrent and adjuvant to radiation therapy, was well-tolerated in patients with newly diagnosed unmethylated MGMT glioblastoma. QBS10072S 18mg/m2 is being evaluated as a treatment arm in phase 2 testing in the ongoing INSIGhT trial.
CTNI-62. EVALUATION OF SAFER-SEQS CTDNA ASSAY OPTIMIZED FOR DETECTING LOW CTDNA COUNTS FROM CSF AND PLASMA: ASSESSING SENSITIVITY AND FEASIBILITY FOR CLINICAL IMPLEMENTATION
Authors: Tobin Grace , Bettegowda Chetan , Huang Peng , Iacoboni Michaella , Fisher Joy , Dailey Erin , Schreck Karisa
Published: November 2024

BACKGROUND

Gliomas with BRAF alterations are often difficult to treat in the recurrent setting due to emergent resistance to FDA-approved targeted therapies. Additionally, it is difficult to assess response to therapy given the limitations of radiographic techniques and the infeasibility of serial tissue sampling. This protocol will serve as a prototype for determining the feasibility of using CSF and plasma circulating tumor DNA (ctDNA) as biomarkers for response to a novel-BRAF inhibitor, plixorafenib. Plixorafenib is a small-molecule selective inhibitor of Class 1 and 2 BRAF mutations that does not induce paradoxical reactivation of MAPK signaling.

METHODS

This clinical trial is designed as a single institution, signal-finding study to demonstrate the feasibility and sensitivity of detecting ctDNA at baseline and after one month of treatment with plixorafenib (primary endpoint). In addition, we will evaluate the correlation of ctDNA with disease status over time and response rate to plixorafenib. Patients aged 18 years or older with measurable recurrent BRAF-V600 mutant glioma (by RANO 2.0), who have received prior BRAF and/or MEK inhibitor therapy will be screened and consented for the study prior to surgery. Leptomeningeal disease allowed. A total of 12 evaluable patients will be enrolled. Patients will undergo clinically-indicated resection or biopsy for confirmation of disease progression and characterization of putative resistance alterations. All patients will have a ventricular reservoir placed at time of surgery with CSF and plasma sampling. Patients will initiate the study drug (oral plixorafenib 900mg daily with cobicistat 150mg daily) when clinically recovered from surgery. Patients will take the drug continuously for 28-day cycles. MRI, CSF, and plasma assessments will occur approximately every two months to evaluate disease status. Enrollment is planned to begin November, 2024.
CTNI-73. ASSESSMENT OF MOLECULAR ALTERATIONS IN NEWLY DIAGNOSED GBM MGMT-UNMETHYLATED PATIENTS TREATED WITH VAL-083
Authors: Kamiya-Matsuoka Carlos , Weathers Shaio-Pei , Yung Alfred , Login Monica , Majd Nazanin , Brown Dennis , Langlands John , Schwartz Richard , Knight Stephanie , Puduvalli Vinay , de Groot John , O’Brien Barbara
Published: November 2024

Glioblastoma (GBM) commonly features molecular alterations in the TERT, EGFR, PTEN, and TP53 genes, which contributes to uncontrolled cell growth, evasion of apoptosis, and enhanced tumor cell survival. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7 and O6-guanine inducing double-strand breaks causing cell death independently of MGMT DNA repair and DNA mismatch repair deficiency. VAL-083 was evaluated in an open-label, biomarker-driven, phase 2 trial in MGMT-unmethylated, bevacizumab-naïve GBM patients. The molecular profile of tumors from a newly diagnosed GBM patient subgroup who received VAL-083 alone after chemo-radiation with concurrent TMZ, was determined in order to correlate with clinical outcomes. Thirty-four (34/36, 94.4%) patients who received 30 mg/m2 VAL-083 (days 1-3 of 21-day cycle) had available next-generation sequencing data on their primary tissue. Patient median age was 54.8 years (5-95pth: 29.8-66.0), median KPS was 90 (5-95pth: 80-100) and 58.8% were males. The median number of cycles of VAL-083 was 7.5 (5-95pth: 1-12). There were 5 dose reductions due to toxicity. The median time to progression (PFS) and overall survival (OS) were 9.2 mo (95%CI: 7.6-10.2) and 16.5 mo (95%CI: 13.3-19.0), respectively. The mean number of molecular alterations was 3.9 (5-95pth 1-8). Six (17.6%) patients had gene fusions. The most common molecular alterations were TERT promoter (91.2%), EGFR amplification (amp) (52.9%), PTEN (50.0%), EGFR (20.6%), and TP53 (20.6%). Additional alterations (in ≥2 patients; 6%) included EGFR-EGFR (EGFRvIII), BRCA2, CDKN2A/B, CDK4/6 amp, MDM2/4 amp, NF1, NOTCH1, PIK3R1 and RB1. While TP53 mutations showed a trend as predictors for time to progression (P 0.027), this was not observed with OS. None of the molecular alterations were predictors of number of treatment cycles or dose reductions. No specific molecular alterations were identified that predicted either improved or poorer patient outcome, during treatment with VAL-083. Clinicaltrials.gov identifier: NCT02717962.
CTNI-76. A PHASE 1/2 DOSE ESCALATION AND EXPANSION STUDY OF SONODYNAMIC THERAPY WITH SONALA-001 IN COMBINATION WITH NON-ABLATIVE MR-GUIDED FOCUSED ULTRASOUND IN SUBJECTS WITH PROGRESSIVE OR RECURRENT GLIOBLASTOMA
Authors: Placantonakis Dimitris , Grabowski Mathew , Burns Terry , Butowski Nicholas , Clanton Ryan , Henry Lenora , Potter Wyatt , Marcus Stuart , Benaim Ely
Published: November 2024

Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective standard of care option and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination therapy that utilizes a drug, aminolevulinic acid HCL (SONALA-001, ALA), and a device, the Exablate 4000 Type 2.0 to deliver MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that SDT activates protoporphyrin IX (PpIX) to generate reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that ALA SDT was well-tolerated and not associated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of iv SONALA-001 (ALA) in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Dose escalation will include an initial drug and energy dose escalation of ALA SDT utilizing an accelerated titration design with single subject cohorts for dose level cohorts 1 and 2, followed by cohort 3 with 3 + 3 design for additional dose escalation. SONALA-001 is administered 6 to 9 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of ALA SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Preliminary PK and safety results will be presented.
DDEL-10. MICROBUBBLE-ENHANCED FOCUSED ULTRASOUND REGULATES THE ENRICHMENT OF INFLAMMATORY PATHWAYS IN THE BLOOD-BRAIN BARRIER AND IMPROVES CAR T CELL ACCUMULATION IN GLIOMAS
Authors: Arvanitis Costas , Guo Yutong , Lee Hohyun , Kim Chulyong , Park Christian , Yamamichi Akane , Chuntova Pavlina , Gallus Marco , Bernabeu Miguel O , Jo Hanjoong , Okada Hideho , Kim Chulyong
Published: November 2024

A major challenge to brain cancer immunotherapy is posed by the rate-limiting obstacles to the systemic delivery of cytotoxic T cells, such as chimeric antigen receptor (CAR) T cells, in brain tumors posed by the blood brain barrier (BBB). Although the BBB can be bypassed by direct infusion of CAR-T cells in brain tumors, these approaches offer only short-term benefits, since they cannot affect distant tumor cell infiltrations, as evidenced by tumor relapse. Circulating microbubbles (MB) upon ultrasound (US) exposure (sonication) can exert mechanical stress in brain vessels to trigger a range of responses, including local increase in the BBB permeability and activation of inflammatory signaling and phenotypes. We hypothesize that ultrasound frequency tuned at MB resonance inside brain capillaries can transiently modulate the BBB signaling and function to improve CAR-T cell trafficking in glioma tumors. RNAseq and immunostaining of protein expression reveal that at frequencies just above microbubble resonance inside vessels (1.5MHz for 2µm MB), where maximum vessel wall shear stress is observed, there is a marked enrichment of inflammatory markers in the endothelial cells of brain vessels, including P-selectin and ICAM-1. Consistent with these findings, we observed that under high frequency excitation (1.5MHz), there is a 5-fold increase in the accumulation of EGFRvIII CAR-T cells in orthotopic EGFRvIII murine glioma tumors as compared not sonicated controls. We also found that over 85% of the tumor-infiltrating CAR-T cells express PSGL-1 and LFA-1 receptors, which interact with P-selectin and ICAM-1 to facilitate T cell extravasation. Together, these findings demonstrate that tuning the US frequency can improve CAR-T cell trafficking, potentially through upregulation of cell adhesion molecules in the glioma tumor microenvironment, and further support the functional relevance and potential clinical significance of the observed immuno-mechano-biological changes.