bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-42. INB-200: PHASE 1 STUDY OF GENE MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)
Authors: Lobbous Mina , Goswami Trishna , Lamb Lawrence , Rochlin Kate , Pillay Thiumaine , Youngblood Samantha , ter Haak Mariska , Nabors Burt
Published: November 2023

γδ T cells target NKG2D ligands that are upregulated on tumor cells after chemotherapy exposure. IN8bio’s DeltEx drug resistant immunotherapy (DRI) are γδ T cells genetically engineered to express MGMT, conveying TMZ resistance to allow concomitant therapy. We present updated results from this Phase 1 trial, which enrolled adult newly diagnosed glioblastoma patients with adequate organ function, KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107) of DRI cells intratumorally with 150 mg/m2 of TMZ on Day (D) 1 of Stupp maintenance. The primary endpoint is safety and secondary endpoints include survival; immunologic and genomic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. 21 patients were enrolled, with 11 dosing (57% male; median age 68 (range: 21-76); 86% IDH-WT, 52% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS) or neurotoxicity (ICANS) reported. Most common adverse events were WBC/platelet count decreased, asthenia, headache, hydrocephalus, decreased appetite and balance disorder. C1 pts had PFS of 8.3, 11.9, 7.4 months (m) and OS of 15.6, 17.7 and 9.6m, respectively. In C2, 1 pt remains progression free at 26.4m, while one progressed at 22m and another died without relapse at 8.7m. C3 pt had a PFS of 7.1 and OS of 13.11m with other pts in dosing. γδ T cells successfully infused with peripheral TMZ-based lymphodepletion evidenced with near or below normal range T, B, and NK subsets for up to 1 year. DRI T cells have manageable toxicity with encouraging trend in PFS with enriched γδ T cell remaining despite peripheral lymphodepletion.
CTNI-06. RHENIUM (RE-186) OBISBEMEDA{RE-186-NANOLIPOSOME (186RNL)} IN LEPTOMENINGEAL METASTASES [LM] PHASE 1/2A DOSE ESCALATION TRIAL: INITIAL SAFETY AND FEASIBILITY
Authors: Brenner Andrew , Youssef Michael , Kumthekar Priya , Michalek Joel , Hedrick Marc , Bao Ande , Phillips William , Patel Toral , Weinberg Jeffrey , Floyd John , LaFrance Norman
Published: November 2023

CONCLUSIONS: Adjuvant MHT may induce tumor radio-sensitization, immune cell recruitment, and survival benefit when combined with CRT. Optimization of the combination therapy treatment scheme is required.
CTNI-12. GENOMIC ANALYSIS OF HUMAN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY UNDER THE PHASE-II CLINICAL TRIAL (NCT03398694) REVEALS DNA DAMAGE REPAIR AT THE PERIPHERAL TUMOR EDGE
Authors: Shireman Jack , White Quinn , Agrawal Namita , Ni Zijan , Chen Grace , Mohanty Chitrasen , Zhao Lei , Wang Xiaohu , Ahmed Atique , Miller James , Kulwin Charles , Cohen-Gadol Aaron , Payner Troy , Lin Chih-Ta , Savage Jesse , Lane Brandon , Shiue Kevin , Kamer Aaron , Shah Mitesh , Iyer Gopal , Watson Gordon , Zang Yong , Boyd LaKesha , Lautenschlaeger Tim , Kendziorski Christian , Dey Mahua
Published: November 2023

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are also significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.
CTNI-16. USE OF PREDICTIVE SCORE-BASED HISTORICAL CONTROL DATA IN SINGLE-ARM TRIALS
Authors: Yoo Wonsuk , Kennedy William , Hong Amy , Sanai Nader
Published: November 2023

Even though the randomized controlled trials (RCTs) are still the preferred approach to evaluate the effects of treatments, single-arm study designs have been traditionally used in Phase II oncology clinical trials. The single-arm studies using historical control or external control might be inevitable and even fatal when concurrent controls are impractical or unethical in rare and high-risk diseases. Due to recruiting difficulty, ethical and economic reasons, the single-arm trials can be a good option to test the experimental efficacy with the external control data of historical control rates for early efficacy phase 2 trials in glioblastoma. The FDA guidelines on external control data focus on the use of patient-level data from other clinical trials or real-world data (RWD), and so there is no guidance for summary-level historical control. Furthermore, there exist methodological issues to use historical data like identification of relevant data, amount of discounting (time difference and dissimilarity), prior robustness or operating characteristics. In this study, we propose a synthetic data based predictive scoring method optimally to match the historical control data with the characteristic conditions of the experimental studies. We consider both a binary (PFS on six months) and survival (median PFS) endpoints as surrogates for Phase 2 single-arm trials in newly diagnosed and recurrent glioblastoma patients. We perform meta-analysis to summarize the endpoints and the related socio-demographic, treatment and genetic factors from the summary-level historical data. Then we generate the synthetic patients based on the meta-summarized data. The generalized boosted regression models will be used to identify significant characteristics affecting the survival of GBM patients using the synthetic data. Finally the predictive score-based historical data model will be developed to provide the optimal matching with the characteristics of the experimental studies. This study will be validated using existing patient-level data as well as cross-validation methods.
CTNI-19. RESECTION AND CESIUM-131 RADIATION SOURCES IMBEDDED IN BIO-RESORBABLE COLLAGEN TILES (GAMMATILE™) FOLLOWED BY THE STUPP PROTOCOL IN NEWLY-DIAGNOSED GLIOBLASTOMA: GESTALT TRIAL-IN-PROGRESS UPDATE
Authors: Dunbar Erin , Nowlan Adam , McCracken David , Fink Karen , Lewis Luke , Hoeprich Mark , Lee Stuart , Paravati Anthony , Tuncer Tolga , David John , Mella Divya , Aboud Orwa , Fragoso Ruben , Bloch Orin , Ferreira Clara , Dusenbery Kathryn , Peach Matthew Sean , Chang Eric , Brachman David , Campbell Lisa , Chen Clark
Published: November 2023

OBJECTIVE

To evaluate the safety and feasibility of combining resection with immediate initiation of radiation and subsequent Stupp protocol in newly-diagnosed glioblastoma (GBM).

BACKGROUND

Rapid early local progression (REP) after resection, prior to the initiation of EBRT+/-chemotherapy, occurs in 25-50%. This high-rate of REP supports initiation of an effective postoperative treatment as early as safely possible. Bio-resorbable collagen tiles with imbedded cesium-131 radiation sources (Gammatiles™) are FDA cleared for this use. Intraoperatively, tiles are placed within the resection bed, thus achieving an immediate initiation of surgically targeted radiation therapy (STaRT). DESIGN/

METHODS

GESTALT is a single-arm 61 patient multi-center trial. Consented adults with suspected or confirmed GBM undergo a maximum safe resection with Gammatile™ (STaRT). Patients with molecular GBM (WHO 2021 criteria) start concurrent EBRT/Temozolomide beginning 25±4 days post-surgery. Subsequent EBRT (20 fractions, 4 weeks) to low and high-risk PTV takes Gammatile™ dose into account to a combined biologically equivalent dose of 46 and 60 Gy delivered in 2Gy/fraction, respectively. Adjuvant TMZ (6 cycles) begins 28±7 days after EBRT/Temozolomide. TTF is allowed. IDH-mutated gliomas are followed for safety. Outcomes include feasibility of incorporating Gammatile™ without delay of Stupp protocol, consent/attrition rates, safety, performance status trajectory (ECOG, KPS), immune competence (absolute lymphocyte counts), local control, PFS, and OS.

RESULTS

The trial opened in Fall 2022 at 4 sites. 12 additional sites are onboarding (NCT05342883). 16 patients are on trial as of abstract submission. Currently, this trial appears feasible and without any unexpected intolerances/toxicities.

CONCLUSIONS

This is the first trial in newly diagnosed GBM patients to combine resection, Gammatile™, and the Stupp protocol, in an attempt to reduce REP, as well as possibly, improve other outcomes.

RESULTS

will inform the routine and investigational use of Gammatile™, and if suggestive, will form the basis for a subsequent randomized trial.
CTNI-20. NIMOTUZUMAB COMBINED WITH CONCURRENT CHEMORADIOTHERAPY IN THE TREATMENT OF NEWLY DIAGNOSED PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Qiu Xiaoguang , Jiang Mawei , Liu Chao , Wang Gang , Tao Rongjie , Xu Jiankun , Shen Liangfang , Liu Yanwei , Wang Heling , Zhu Chuanying , Zhang Hui , Zeng Gao , Hong Jidong , Chen Baoshi , Wang Shujun , Bao Wenlan , Yang Jia , Lin Qingtang , Li Huan , Liu Shuai , Zhang Wei , Chen Shuxian , Zhao Yongrui , Tang Jianbing , Kou Zhen , Su Jun , Sun Peng , Wang Longyun , Sun Xiaoyang , Ju Yan , Ma Wenbin , Wang Yu
Published: November 2023

BACKGROUND

Newly diagnosed pediatric DIPG is a fetal disease with a poor prognosis and lacks of effective treatments. Multiple studies have demonstrated that the median survival time for patients is less than one year. A single-armed, prospective, multicenter study was conducted to evaluate the efficacy and safety of adding nimotuzumab to concurrent chemoradiotherapy for the treatment of newly diagnosed pediatric DIPG.

METHODS

Patients were 3-15 years old, histologically or imaging confirmed newly diagnosed DIPG, Lansky score ≥ 60, and at least one measurable lesion. Totally 48 patients were enrolled. Nimotuzumab (150mg/m2/w) concurrent chemoradiotherapy (Temozolomide: 75mg/m2 per day. Radiotherapy: 54Gy/30f) were administered for 6 weeks following a maintenance treatment (Nimotuzumab: 150mg/m2 biweekly. Temozolomide: 150-200mg/m2 per day for 5 days every 28 day). The primary endpoint was ORR, with secondary endpoints including 1-year OS rate, PFS and safety.

RESULTS

Between Apr 3, 2021 and Apr 13, 2023, a total of 48 patients were enrolled with a median age of 7 years old, in which 20 patients radiologically diagnosed DIPG, 28 patients histopathologically confirmed DIPG with 25 (89.3%) had H3K27M mutation. The median follow-up was 15.2 months. The ORR was 31.3% (95%CI, 18.66%-46.25%), mOS was 10.35 months, 1-year OS rate was 27.4% (95%CI, 14.73%-41.73%), mPFS was 6.93 months, and 1-year PFS was 9.5% (95%CI, 2.46%-22.56%). Eight patients (16.7%) experienced grade 3 or above ADRs. The most common toxicities were neutropenia (40%), leukopenia (25.0%), thrombocytopenia (25.0%). anemia (5.0%), flank pain (5.0%).

CONCLUSIONS

Nimotuzumab combined with concurrent chemoradiotherapy showed survival benifit for newly diagnosed pediatric DIPG patients with tolerable toxicity.
CTNI-22. A PHASE 0/2 ‘TRIGGER’ TRIAL OF NIRAPARIB IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Sanai Nader , Margaryan Tigran , Molloy Jennifer , Zhang Hualin , Knight William , Harmon Jocelyn , Hong Amy , Wanebo John , Kennedy William , Braun Kelly , Garcia Michael , Barani Igor , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal
Published: November 2023

BACKGROUND

Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met.

METHODS

Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors and positive PK were eligible for phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib.

RESULTS

All phase 0 patients (n = 44) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 226.7 nM (n = 38). PAR suppression after ex vivo radiation was observed in 71% of the patients (20/28). Eighteen out of 26 patients with unmethylated tumors enrolled in phase 2. Five of the 18 initial patients in phase 2 experienced grade 4 thrombocytopenia related to niraparib. All adverse events were resolved without sequelae. For patients who completed at least 6 months of follow-up, PFS6 was 64% (n = 11) with 9.2-month median follow-up. Median follow-up for all patients (n = 18) was 4.2 months with 8 patients remaining on treatment and 2 patients ongoing PFS6 follow-up.

CONCLUSIONS

Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.
CTNI-31. TREATMENT BENEFIT IN PATIENTS AGED 80 YEARS OR OLDER WITH BIOPSY-PROVEN AND NON-RESECTED GLIOBLASTOMA IS DEPENDENT ON MGMT PROMOTER METHYLATION STATUS
Authors: Weller Jonathan , Katzendobler Sophie , Niedermeyer Sebastian , Harter Patrick , Herms Jochen , Trumm Christoph , Niyazi Maximilian , Thon Niklas , Tonn Joerg-Christian , Stoecklein Veit
Published: November 2023

PURPOSE

Glioblastoma is associated with especially poor outcome in the elderly. It is unclear if patients aged ≥ 80 years benefit from tumor-specific therapy as opposed to receiving best supportive care (BSC) only.

METHODS

Patients with IDH-wildtype glioblastoma (WHO 2021), aged ≥ 80 years, and diagnosed by biopsy between 2010 and 2022 were included. Patient characteristics and clinical parameters were assessed. Uni- and multivariate analyses were performed.

RESULTS

76 patients with a median age of 82 (range 80–89) and a median initial KPS of 80 (range 50–90) were included. Tumor-specific therapy was initiated in 52 patients (68%). 22 patients (29%) received temozolomide monotherapy, 23 patients (30%) were treated with radiotherapy (RT) alone and 7 patients (9%) received combination therapies. In 24 patients (32%), tumor-specific therapy was omitted in lieu of BSC. Overall survival (OS) was longer in patients receiving tumor-specific therapy (5.4 vs. 3.3 months, p<0.001). Molecular stratification showed that the survival benefit was owed to patients with MGMT promoter methylation (MGMTpos) who received tumor-specific therapy as opposed to BSC (6.2 vs. 2.6 months, p<0.001), especially to those with better clinical status and no initial polypharmacy. Patients with unmethylated MGMT promoter (MGMTneg) did not benefit from tumor-specific therapy (3.6 vs. 3.7 months, p=0.18). In multivariate analyses, better clinical status and MGMT promoter methylation were associated with prolonged survival (p<0.01 and p=0.01).

CONCLUSION

Benefit from tumor-specific treatment in patients with newly diagnosed glioblastoma aged ≥ 80 years might be restricted to MGMTpos patients, especially to those with good clinical status and no polypharmacy.
CTNI-43. A PHASE 1/2 STUDY OF LOW DOSE FRACTIONATED RADIATION THERAPY AS A CHEMOPOTENTIATOR OF SALVAGE TEMOZOLOMIDE FOR HIGH-GRADE GLIOMA
Authors: Lin Timothy , Ke Suqi , Hu Chen , Mukherjee Debraj , Weingart Jon , Kleinberg Lawrence , Huang James , Assadi Ryan , Holdhoff Matthias , Grossman Stuart , Ahmed Mansoor , Redmond Kristin
Published: November 2023

Cell-survival curves demonstrate low-dose radiation hypersensitivity, with steepest cell kill at 0.3-0.5 Gy/fx. This phase 1/2 study assessed the safety/efficacy of low-dose fractionated radiotherapy (LDFRT) as a chemopotentiator of TMZ in recurrent glioblastoma or anaplastic astrocytoma (AA) patients. Patients with recurrent glioblastoma/AA following standard-of-care therapy, > 12 months from prior RT and >2 months from prior TMZ were eligible for 0.5 Gy RT twice daily x10 fractions with concurrent TMZ (150-200 mg/m2), both delivered in 5 days of a 28-day cycle up to 6 cycles, followed by 6 cycles of adjuvant TMZ. In phase 1, hematologic toxicity was assessed 1 month after initiating therapy. Brain MRIs were obtained every 2 months, or monthly when concerned for progression (defined by RANO criteria). Pseudoprogression consisted of MRI changes irrespective of clinical deterioration/steroid use that stabilized/reversed without oncologic intervention. The primary endpoint, 1-year overall survival (OS), would be considered for future investigation with a lower bound of 80% CI > 28%, chosen from historical data. Secondary endpoints included rates of pseudoprogression and hematologic toxicity. 31 patients were enrolled/analyzed. Grade 3-4 acute hematologic toxicity was observed in 8(27%) patients. Median follow-up was 9.5(range:0.1-66.3) months. Median OS was 9.6(95%CI 7.0-15.4) months. 1-year OS was 34.5%(95%CI 20.9%-57.0%; lower bound of 80%CI = 24.8%). 77% of patients experienced pseudoprogression, with a median time from start of LDFRT of 1.9(95%CI 1.7-4.4) months and median duration of 3.6(95%CI 1.6-Not estimable) months. Patients with pseudoprogression had improved OS vs. those without (N = 6; median 10.6 vs 3.9 months, HR = .12[95%CI .03-.40];P < .01). LDFRT for recurrent glioblastoma/AA was safe. High pseudoprogression rates were observed at low RT doses, with improved OS amongst patients with pseudoprogression. LDFRT with TMZ may elicit low-dose RT hypersensitivity in patients with glioblastoma/AA. Further study is needed to optimally apply this radiobiological property to improve clinical outcomes.
CTNI-47. DOSE ESCALATION OF ASTX727 IN ADULT PATIENTS WITH RECURRENT/PROGRESSIVE NON-ENHANCING IDH MUTANT GLIOMAS
Authors: Arrillaga-Romany Isabel , Miller Julie , Dietrich Jorg , Plotkin Scott R , Gerstner Elizabeth , Jordan Justin T , Forst Deborah , Lee Eudocia , Wen Patrick , Reardon David , Nayak Lakshmi , Batchelor Tracy , Chukwueke Ugonma , Rivera Miguel , Agar Nathalie , Cahill Daniel , Bernstein Bradley
Published: November 2023

BACKGROUND

IDH mutant gliomas typically display a hypermethylation pattern known as the glioma CpG island methylator phenotype (G-CIMP) which results in gene activation that promotes gliomagenesis. This study aims to reverse this methylation signature and disrupt tumor growth via treatment with an oral demethylating agent.

METHODS

This is 2-stage clinical trial investigating oral ASTX727 (decitabine + cedazuridine, a cytidine deaminase inhibitor, as a combination tablet) in patients with recurrent primarily non-enhancing IDH mutant gliomas. The Dose Escalation Stage consisted of a single arm 3 + 3 design. The primary objective was to establish the MTD and assess safety in this patient population.

RESULTS

Eleven pts (F = 45%, M = 55%) with a median age of 44 yrs (range 26-61 yrs) were enrolled. Two DLTs (grade 4 neutropenia for >72 hrs) were observed in 5 pts enrolled at the starting dose (35 mg decitabine/ 100 mg cedazuridine for 5 consecutive days). Six additional patients were enrolled at dose level -1 (35 mg decitabine/100 mg cedazuridine for 4 consecutive days). There were no DLTs at dose level -1 and this was declared the MTD. Grade ≥ 3 AEs included neutropenia (5 pts), leukopenia (1 pt), lymphopenia (1 pt), hyponatremia (1 pt) and increased ALT (1 pt). Best treatment response was SD in 11 patients. At the time of last follow-up (5/15/23) 10 pts have discontinued treatment (8 for PD, and 2 based on physician decision), 2 pts (18%) have died due to disease progression, 8 pts remain alive and in follow-up, and 1 patient remains on treatment. Median duration on treatment was 212 days (range 36 days – not reached).

CONCLUSIONS

ASTX727 was well tolerated in patients with recurrent non-enhancing IDH mutant glioma at dose level -1 with no DLTs . A surgical expansion cohort is currently enrolling to confirm drug target engagement and explore pharmacodynamics.
CTNI-49. RHENIUM-(RE-186)-OBISBEMEDA [RE-186-NANOLIPOSOME] (186RNL) PHASE 2 FOR RECURRENT GLIOBLASTOMA (RGBM) VIA CONVECTION ENHANCE DELIVERY [CED]
Authors: Brenner Andrew , Michalek Joel , Moore Melissa , Hedrick Marc , Bao Ande , Phillips William , Patel Toral , Weinberg Jeffrey , Floyd John
Published: November 2023

BACKGROUND

The Phase 1 ReSPECT-GBM trial observed a relative improvement in overall survival(OS) in rGBM with absorbed doses >100 Gray[Gy] compared to lower doses and historical controls. Statistical modeling was employed to understand the dose response relationship in planning the Phase2 trial.

METHODS

Phase1 data from cohorts1-6 of the 3 + 3 dose-escalation trial[N = 21] were utilized. Longitudinal MRI and SPECT/CT imaging were performed to assess treatment outcomes. SPECT/CT images were used to find the treatment volume. Variation in survival significance was assessed with log rank tests and an accelerated failure time (AFT) model. All statistical testing was 2-sided with a 5% significance level.

RESULTS

MTD/DLT was not reached in the first 6 cohorts. The 3 + 3 dosing (ml&mCurie) by cohort was 1: 0.66&1.0, 2: 1.32&2.0, 3: 2.63&4.0, 4: 5.28&8.0, 5: 5.28&13.4, 6: 8.8&22.3. Unadjusted for covariate information, median OS was 11.0 months(m) [95% Confidence Interval (CI) 5.0 m to 17 m]. Median OS varied significantly with absorbed dose; < 100 Gy: n = 9, median OS = 6.0 m, 95% CI 1.0m to 11m), ≥100 Gy: n = 12, median OS = 17.0 m (95% CI 8.0 m to 35.0 m), p < 0.001. After adjustment for age, baseline ECOG performance status, and baseline tumor volume, the AFT model predicted the OS to fold increase by 1.3 (95% CI 1.1 to 1.5)/100Gy increase in the absorbed dose (p < 0.001) and by 1.28 (95% CI 1.21 to 1.35 m)/10% increase in the treated to total tumor volume ratio (p < 0.001). The phase 2 trial, utilizing Cohort6 administered dose 22.3mCi in 8.8mL for tumor volumes ≤20mL [average absorbed dose of 374.5Gy], is ongoing--n = 5 accrued as of May 2023.

CONCLUSION

186RNL therapy resulted in a dose and volume dependent impact on OS without significant toxicity. Based on these data, the Cohort 6 non-DLT dose advanced to Phase 2. Study progress will be reported.
CTNI-53. ESTABLISHING A PHASE I AND RANDOMIZED PHASE II TRIAL OF SELINEXOR AND TEMOZOLOMIDE IN GLIOBLASTOMA
Authors: Chow Frances , Berens Michael , Tamir Sharon , Landesman Yosef , Walker Christopher , Palmer Joycelynne , Porter Alyx , Piccioni David , Ney Douglas , de la Fuente Macarena , Kizilbash Sani H , Bojanowski-Hoang Kimberly , Lipinski Lindsay , Strowd Roy , Giglio Pierre , Hrachova Maya , Mantica Megan , Schiff David , Gore Steven , Portnow Jana
Published: November 2023

BACKGROUND

Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ).

METHODS

We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL.

RESULTS

Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p < 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented.

CONCLUSION

Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).
CTNI-78. EVALUATION OF POST-PROGRESSION TREATMENTS AFTER VAL-083 IN RECURRENT AND NEWLY DIAGNOSED GBM MGMT-UNMETHYLATED PATIENTS
Authors: Kamiya-Matsuoka Carlos , Weathers Shiao-Pei , Yung W K Alfred , Loghin Monica , Majd Nazanin , Brown Dennis , Langlands John , Schwartz Richard , Knight Stephanie , Puduvalli Vinay , de Groot John , O'Brien Barbara
Published: November 2023

Almost all GBM patients experience recurrent disease following up-front standard of care treatment, with a median survival of 3-9 months after recurrence. Challenges with salvage therapies include the potential for side-effects, which may limit further treatment. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7-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 two-arm biomarker-driven phase 2 trial in MGMT-unmethylated bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-radiation with TMZ (Group 2). Post-progression, patients were followed for survival status, and any post-VAL-083 treatments. Here we review treatments received by patients following participation in this clinical trial, and their outcomes. Patients were excluded from the review if no data had been collected or if they had undergone subsequent surgery. Group 1(n=42) and Group 2(n=31) who received 30 mg/m2 VAL-083 (days 1-3 of 21-day cycle) were evaluated. In Group 1 and Group 2, 17/42 (40.5%) and 20/31 (64.5%), respectively, received an alkylating agent post-VAL-083. Receiving more than the median number of cycles of VAL-083 in either group didn’t limit patients from receiving alkylating agents such as CCNU and TMZ after VAL-083. No hematologic complications were identified. Furthermore, receiving ≥5 cycles of adjuvant TMZ prior to VAL-083 in Group 1 didn’t affect patient’s ability to receive alkylating agents. For both groups, mOS and OS-6 from the last dose of VAL-083 were greater for those receiving alkylating agent post VAL-083, compared to those who didn’t. These data demonstrate that alkylating agents may be administered safely to patients who have progressed following therapy with VAL-083, and patients who have received an alkylating agent after VAL-083 therapy have a better outcome compared to those receiving other treatments.
CTNI-80. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NF2-RELATED SCHWANNOMATOSIS PATIENTS WITH PROGRESSIVE SCHWANNOMAS, MENINGIOMAS, AND EPENDYMOMAS: PRIMARY OUTCOME OF THE BRIGATINIB TREATMENT ARM
Authors: Plotkin Scott R , Babovic-Vuksanovic Dusica , Dinh Christine , Fell Geoffrey , Merker Vanessa , Nghiemphu Phioanh , Trippa Lorenzo , Yohay Kaley , Blakeley Jaishri
Published: November 2023

INTRODUCTION

NF2-related schwannomatosis (NF2-SWN) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. The rarity of NF2-SWN and the presence of multiple tumor types has impeded clinical trials. We conducted a multi-center, adaptive, platform-basket trial to screen multiple drugs against progressive NF2-SWN tumors. We report the final analysis of the first treatment arm with brigatinib, an oral ALK inhibitor that inhibits multiple tyrosine kinases.

METHODS

This study enrolled participants ≥ 12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma Radiographic response (RR) was defined as ≥ 20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Secondary outcomes included safety, hearing response, and RR in non-target tumors. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. In stage 1, 20 participants received brigatinib 180 mg daily. Interim analysis suggested activity in NVS and meningioma. Thus, an additional 20 participants with progressive meningioma or NVS were enrolled in stage 2.

RESULTS

Forty participants (median age 26 years, 12 pediatric, 28 female) were treated. Prior treatment included surgery (90%), radiation therapy (20%) and chemotherapy (55%). Target tumors included 10 VS, 9 NVS, 19 meningiomas, and 2 ependymomas. Overall RR rate was 10% for all target tumors (22% for non-VS, 11% for meningioma, 0% for VS, and 0% for ependymomas). There were no grade 4 or 5 treatment-related adverse events (AEs). The most common AEs were diarrhea (63%), nausea (40%), muscle cramps (33%), increased LDH (35%), increased AST (33%), and increased ALT (23%).

CONCLUSION

Brigatinib treatment was associated with RR in NVS and meningiomas in a heavily pretreated cohort of participants with progressing NF2-SWN tumors. This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.
DNAR-01. PAR-MEDIATED DNA DAMAGE SIGNALING IN IDH MUTANT GLIOMAS: COMBINING PARG INHIBITION AND RADIATION FOR SELECTIVE CYTOTOXICITY
Authors: Kitagawa Yosuke , Nasser Ali , Chang Chia , Melamed Lisa , Miller Julie , Wakimoto Hiroaki , Cahill Daniel
Published: November 2023

Isocitrate dehydrogenase (IDH) 1 or 2 mutant gliomas have unique metabolic characteristics and DNA damage response. Radiotherapy and chemotherapy have been proven to be effective treatments for IDH mutant gliomas. Poly (ADP-ribose) (PAR) mediates DNA damage response and is regulated by opposing enzymes: poly (ADP-ribose) polymerases (PARPs) synthesize PAR, while poly (ADP-ribose) glycohydrolase (PARG) breaks it down. Combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells leads to imbalanced NAD sequestration into PAR, causing metabolic lethality. This study characterizes the combination of PARGi and radiation. PARGi monotherapy showed no difference between IDH mutant and wild-type cells. However, we found that combining PARGi with radiation significantly increased cytotoxicity in IDH mutant glioma models, similar to PARPi and radiation. (Wang et al, ACi.Adv. 2020) Our findings showed that unlike TMZ+PARGi, PARGi and radiation did not consume and deplete NAD. Cytotoxicity was partially reversed by IDH inhibitor, highlighting the contribution of PAR-mediated DNA damage signaling in IDH mutant contexts. This convergence of vulnerabilities in IDH mutant cells identifies PAR-mediated DNA repair mechanisms that operate independently of NAD metabolism. IDH mutant enzyme generates 2 hydroxyglutarate (2HG), which is critical early in tumor development. However, the effect of 2HG on radiation sensitivity varies across cellular contexts. In this study, we found that IDH1 mutation and 2HG production enhance radiosensitivity in glioma cells both in vivo and in in vitro models, facilitated by PAR-dependent mechanisms. This augmentation of radiosensitivity is associated with S-phase blockage of the cell cycle, unveiling a vulnerability in the replication process of these cancer cells. In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways, augmenting cytotoxicity specifically in IDH mutant gliomas. Targeting PAR during radiation holds promise for treating IDH mutant gliomas, tailoring therapy to maximize durability while minimizing impact on normal cells.
DNAR-04. MICRORNA DEGRADATION ENHANCES GLIOBLASTOMA INTRA-TUMORAL HETEROGENEITY TO AUGMENT ACQUIRED TEMOZOLOMIDE RESISTANCE
Authors: Ramakrishnan Valya , Singh Gatikrushna , Xu Beibei , Ackers Johnny , Chen Clark
Published: November 2023

INTRODUCTION

O6 methyl-guanine methyltransferase (MGMT) restores alkylated DNA to its undamaged form and dictates clonal evolution in response to chemotherapy. As such, MGMT is a major determinant of glioblastoma resistance to the standard-of-care chemotherapy temozolomide. miR-181d is a MGMT suppressing microRNA, whose expression inversely correlate with survival expectation after temozolomide treatment. Here, we characterize the expression of miR-181d and MGMT in response to temozolomide treatment. Method: Laboratory characterization, single cell analysis, and murine modeling

RESULTS

Treatment of glioblastoma cells with temozolomide (TMZ) induced a feed-forward cascade resulting in an ataxia telangiectasia and Rad3 (ATR) and polyribonucleotide nucleotidyl transferase 1 (PNPT1) dependent degradation of miR-181d. Single-cell analyses revealed such miR-181d degradation: 1) increased mean level of MGMT expression in a cell population and 2) enhanced cell-to-cell variability in MGMT expression to increase intra-tumoral heterogeneity in DNA repair capacity. This increased intra-tumoral heterogeneity enhanced glioblastoma resistance to temozolomide through a mechanism distinct from lowering the mean MGMT expression of the tumor population. Suppression of this heterogeneity by exogenous miR-181d over-expression enhanced the tumoricidal activity of temozolomide against glioblastomas.

CONCLUSION

We identified an interface between DNA damage response and miRNA degradation that mediate intra-tumoral heterogeneity and subsequent temozolomide resistance. This resistance mechanism is distinct from modulation of the mean MGMT expression of the population.
DDEL-09. SATURATED FATTY ACID EMULSION OPENS THE BLOOD-BRAIN BARRIERS AND ENHANCES DRUG DELIVERY
Authors: Sung Kyoung Su , Cho Won-Ho , Kim Hak Jin
Published: November 2023

PURPOSE

To evaluate whether saturated fatty acid (SFA) emulsion affects the BBB and whether drug delivery is promoted with the aid of SFA in the brain.

MATERIAL AND METHODS

Each SFA (butyric, valeric, caproic, enantic and caprylic acid) emulsion was infused into the right common carotid artery in a rat model. Trypan blue staining for qualitative and semiquantitative analysis of the BBB opening was performed. A transmission electron microscopic (TEM) exam with the contrast media for morphologic evaluation of the tight junction was obtained. Delivery of doxorubicin in the brain was determined by fluorometric analysis. Delivery of temozolomide (TMZ) through the BBB was studied by desorption electrospray ionization (DESI)-MS imaging.

RESULTS

The ipsilateral hemisphere revealed positive trypan blue staining in all five SFA emulsion groups. Ratios of the ipsilateral to the contralateral hemisphere of in trypan blue permeability with hue analysis was above 1.0. As the carbon number in the used SFA increased, the ratio of trypan blue permeability increased and was statistically significant (P < 0.05). The tight junction and neural interstitium were filled with the contrast media in all five SFA emulsion groups. Delivery of doxorubicin (P < 0.05) and TMZ were significantly high in the ipsilateral hemisphere compared to the contralateral hemisphere. In the caprylic acid group, the BBB opening and drug delivery were highest among the five SFA groups.

CONCLUSION

SFA emulsion with intraarterial infusion opened the BBB and drug delivery was enhanced consequently. Thus, SFA emulsion might be another strategy for the research of BBB opening and promotion of drug delivery in the brain.
DDDR-31. TARGETING CANCER STEM CELLS WITH A CDK2 INHIBITOR IN GLIOBLASTOMA
Authors: Mahmoudian Elham , Qu Dianbo , Jahani-Asl Arezu
Published: November 2023

Glioblastoma (GB) is the most common and aggressive adult brain tumor with no cure. Brain tumor stem cells (BTSCs) are a rare population of self-renewing multipotent stem cells in GB that contribute to tumorigenesis, therapeutic resistance and tumour recurrence. Here, we report a CDK2 inhibitor that suppresses BTSCs via OSM/OSMR/STAT3 signalling pathway. To begin with we performed high throughput screening (HTS) of ~8400 compounds including FDA-approved drugs in patient derived human BTSCs that naturally harbour EGFRvIII mutation and elevated STAT3 phosphorylation, in search of compounds that can suppress EGFRvIII/OSMR/STAT3 oncogenic pathway. The screen led to the identification of a panel of CDK inhibitors that possessed important characteristics including a) ability to cross the blood-brain barrier with mall molecular weights of 277-566 kDa, b) low Topological Polar Surface Area (TPSA) of 76-115 A°, c) a low number of Hydrogen Bond Donors (HBDs) (1-4), and d) cLogP values ranging from 2-4. Following counter screens, we focused on a CDK2 inhibitor that significantly and most efficiently reduced OSM/OSMR signalling and STAT3 activation. Importantly, we found that the compound inhibited the self-renewal and growth of BTSCs in EGFRvIII subtype of BTSCs. This research has led to future investigation on in vivo assessment of this CDK2 inhibitor in combination with ionizing radiation and chemotherapy in preclinical models of GB.
DDDR-33. TNG908, A BRAIN-PENETRANT MTA-COOPERATIVE PRMT5 INHIBITOR, IS EFFICACIOUS IN PRECLINICAL MTAP-DELETED MODELS INCLUDING GLIOBLASTOMA
Authors: Zhang Minjie , Tsai Alice , Cottrell Kevin , Wilker Erik , Davis Charles , DiBenedetto Heather , Weitzman Ron , Huang Alan , Maxwell John , Briggs Kimberly
Published: November 2023

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) with standard of care therapies, demonstrating the significant need for the development of novel therapeutics. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that is selectively active in MTAP-deleted cells by leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors have MTAP loss due to a co-deletion event with the proximal tumor suppressor gene, CDKN2A. In preclinical in vitro studies, TNG908 was 15-fold more potent in MTAP-deleted cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is neither a substrate for P-glycoprotein nor Breast Cancer Resistant Protein (BCRP) efflux transporters. Consistent with these favorable attributes, TNG908 demonstrated in vivo brain penetration in multiple preclinical models, including non-human primates and mice. TNG908 on-target pharmacodynamic activity was determined by dose-dependent decreases in SDMA-modified protein levels in a GBM subcutaneous xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite 6-fold reduced Kpuu in rodents (Kpuu ~0.15) relative to non-human primates (Kpuu 0.9), oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).
EPID-03. SEX DIFFERENCES IN ODDS OF BRAIN METASTASIS AND OUTCOMES BY BRAIN METASTASIS STATUS AFTER ADVANCED MELANOMA DIAGNOSIS
Authors: Cioffi Gino , Ascha Mustafa , Dmukauskas Mantas , Waite Kristin , Wang Xiaoliang , Royce Trevor , Calip Gregroy , Waxweiler Timothy , Rusthoven Chad , Kavanagh Brian , Barnholtz-Sloan Jill
Published: November 2023

Sex differences in cancer are well-established. However, less is known about sex differences in diagnosis of brain metastasis and outcomes among individuals with advanced melanoma. Using the nationwide Flatiron Health electronic health record-derived deidentified database, we evaluated individuals diagnosed with advanced melanomafrom 1/1/11-07/30/22 who received oncologist-defined rule-based first line of therapy (N = 7,969, 33% female according to EHR, 35% w/ documentation of brain metastases). Odds of documented brain metastasis diagnosis were calculated using multivariable logistic regression adjusted for age, practice type, diagnosis period (pre/post-2017), ECOG performance status, anatomic site of melanoma, group stage, documentation of non-brain metastases prior to first-line of treatment, and BRAF positive status. Real-world overall survival (rwOS) and progression-free survival (rwPFS) starting from first-line initiation were assessed by sex, accounting for brain metastasis diagnosis as a time-varying covariate using the Cox proportional hazards model, with the same adjustments as the logistic model, excluding group stage, also adjusting for race, socioeconomic status, and insurance status. Adjusted analysis revealed males with advanced melanoma were 22% more likely to receive a brain metastasis diagnosis compared to females (aOR: 1.22, 95% CI:1.09, 1.36). Males with brain metastases had worse rwOS (aHR: 1.15, 95% CI:1.04, 1.28) but not rwPFS (aHR: 1.04, 95% CI: 0.95, 1.14) following first-line treatment initiation. Among individuals with advanced melanoma not diagnosed with brain metastases, survival was not different by sex (rwOS aHR: 1.06 [95% CI: 0.97, 1.16], rwPFS aHR: 1.02 [95% CI: 0.94, 1.1]). This study showed that males had greater odds of brain metastasis and, among those with brain metastasis poorer rwOS compared to females, while there were no sex differences in clinical outcomes for those with advanced melanoma without brain metastasis.
EPID-10. CNSONTRK STUDY: CLINICAL CHARACTERISTICS AND OUTCOME OF CENTRAL NERVOUS SYSTEM TUMORS HARBORING NTRK GENE FUSIONS
Authors: Lamoureux Audrey-Anne , Fisher Michael , Lemelle Lauriane , Pfaff Elke , De Wilde Bram , Pfister Stefan , Sturm Dominik , Orbach Daniel , Raskin Scott , Drilon Alexander , Zapotocky Michal , Barritault Marc , Leblond Pierre , Tabori Uri , Hawkins Cynthia , Hansford Jordan , Erker Craig , Gottardo Nicholas , Nørøxe Dorte , Goto Hiroaki , Ziegler David , Liu Yen-Lin , Hwang Eugene , Aguilar-Bonilla Ana , Cheng Sylvia , Cacciotti Chantel , Massimino Maura , Wood Paul , Hoffman Lindsey , Lassaletta Alvaro , Gerber Nicolas , Ceruso Mariella Spalato , Bendel Anne , Abadi Christina Coleman , Mueller Sabine , Aguilera Dolly , Robison Nathan , O’Halloran Katrina , Abbou Samuel , Geoerger Birgit , Øra Ingrid , Moertel Christopher , Razis Evangelia , Seizeur Romuald , Clarke Matthew , Doz François , Laetsch Theodore , Perreault Sébastien , Ellezam Benjamin , Alves Mélanie
Published: November 2023

BACKGROUND

TRK fusions are detected in less than 2% of central nervous system (CNS) tumors. There are limited data on the clinical course of affected patients.

METHODS

We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, TRK gene fusion, treatment modalities and outcomes. The growth modulation index (GMI) was calculated as a ratio of time to progression with TRK inhibitors to time to progression with the prior line of therapy.

RESULTS

119 patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 4.5 years (range 0.0–78.3); 101 (85.6%) were < 18 and 45.3% were < 3 years of age. The most frequent tumor location was hemispheric (63.8%). Tumor types included 68 high-grade gliomas (HGG; 57.1%), 33 low-grade gliomas (LGG; 27.7%), 5 embryonal tumors (4.2%) and 13 others (10.9%). Median follow-up was 38.5 months (range 0.03–229.3). Pediatric patients had a better prognosis with a median OS of 185.5 months compared to 24.8 months in adults (p< .0001). Patients with LGG also had a better outcome with median OS that was not reached for LGG compared to 99.5 months for HGG and 38.5 months for embryonal tumors (p=0.0012). Out of 16 evaluable treatment regimens with larotrectinib an objective response was reported in 11 (11/16 (68.8%)-4 CR, 5 PR and 2 MR) compared to 38.1% for non-targeted treatment regimens (24/63 (38.1%)-10 CR, 13 PR and 1 MR). The GMI was 2.11 for pediatric patients treated with larotrectinib.

CONCLUSIONS

We report a large cohort of patients with TRK fusion-driven primary CNS tumors. Children with LGG glioma had a favorable outcome compared to adult and HGG. Larotrectinib appears to be associated with a better response rate and longer duration of response compared to non-targeted therapy.