bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-29. PHASE 2 STUDY OF A NOVEL IMMUNOTHERAPY SL-701 IN ADULTS WITH RECURRENT GBM: IDENTIFICATION OF TREATMENT-INDUCED CD8+CD107A+ CD57+ PD-1- MEMORY T-CELLS THAT ARE ASSOCIATED WITH INCREASED SURVIVAL
Authors: Peereboom David , Lindsay Ross , Badruddoja Michael , Nabors L Burt , Kumthekar Priya , Lieberman Frank , Tran David , Phuphanich Surasak , Schiff David , Sherman Jonathan , Butowski Nicholas , Dunbar Erin , Fink Karen , Iwamoto Fabio , Moertel Christopher , Schulder Michael , Walbert Tobias , Habboubi Nassir , Grzegorzewski Krzysztof , Brooks Christopher , Reardon David A
Published: November 2022

Recurrent glioblastoma (GBM) is an aggressive disease with poor survival and limited treatment options. SL-701 is a novel immunotherapy comprised of synthetic peptides designed to elicit an anti-tumor immune response against GBM antigens IL-13Rα2, ephrinA2, and survivin. Here we describe an 18-color flow cytometry analysis from stage 2 of a Ph2 clinical trial of SL-701+poly-ICLC+bevacizumab (NCT02078648), in which 12-month overall survival (OS) was 50%. Of the 27 patients in stage 2, 24 (89%) developed heterogeneous T-cell responses against 1, 2, or 3 of the SL-701 CD8 peptides. Magnitude and kinetics of peptide responses were variable among these patients with no clear relationship to OS. Therefore, a phenotypic analysis of the T-cell response in all 27 patients was conducted using terraFlow, a unique data analysis approach utilizing machine learning to identify T-cell phenotypes associated with clinical response from all possible combinations of markers. In total, 10,184 unique SL-701 induced phenotypes were measured, including 223 phenotypes (P < 0.05) and 16 core phenotypes that uniquely represent differences between patients with OS above or below 12 months (P < 0.05). 50% of the core phenotypes were CD8+ CD57+ CD107a+ PD-1- SL-701-specific T-cells, which are highly-differentiated memory T-cells primed for cytotoxicity. The frequency of the CD57+ core phenotypes (8%-18%) was enhanced 1.6- to 2.3-fold in patients with an OS > 12 months (P < 0.05). Similarly, 2 core phenotypes identified cytotoxic CD4+ and CD8+ T cells, which were enhanced 1.9- and 2.5-fold in patients with an OS >12 months. The final 6 core phenotypes identified activated CD4+ CD154+ SL-701-specific T-cells (5%-19%) that were enhanced 0.3- to 0.5-fold in patients with an OS < 12 months (P < 0.05), suggesting helper T-cell responses in the absence of cytotoxic T-cell responses are associated with an OS < 12 months. Deep sequencing of SL-701-specific T-cells using whole transcriptome-based molecular cytometry is planned.
CTIM-34. PRELIMINARY SAFETY AND EFFICACY DATA ON TWO PATIENTS WITH RELAPSED/REFRACTORY CNS LYMPHOMA TREATED WITH EMAVUSERTIB (CA-4948) AND IBRUTINIB COMBINATION: A SUBSET ANALYSIS OF TAKEAIM LYMPHOMA TRIAL
Authors: Iqbal Madiha , Tun Han , Joffe Erel , Grommes Christian , Nowakowski Grzegorz , Lunning Matthew , Ramchandren Radhakrishnan , Li Chia-Cheng , Zhao Wanying , Martinez Elizabeth , von Roemeling Reinhard , Earhart Robert , McMahon Meaghan , Isufi Iris , Leslie Lori , Rosenthal Allison
Published: November 2022

BACKGROUND

Emavusertib, an oral interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, targets toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathway in B-cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of NF-κB, causing inflammation and tumor growth. Emavusertib has been reported to be well tolerated and active as monotherapy in heavily pretreated relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). In a murine PDX model of primary CNS lymphoma (PCNSL), emavusertib crossed the blood-brain barrier, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, emavusertib showed in vivo anti-cancer synergy in B-cell NHL.

METHODS

This is an ongoing open-label trial (NCT03328078) in patients with R/R NHL. Currently, we are in the dose escalation portion of combination therapy to evaluate safety and efficacy following treatment of emavusertib at dose levels of 200 or 300mg BID with ibrutinib at full prescribed dose. As of May 6th, 2022, 13 patients have been treated with emavusertib+ibrutinib combination therapy.

RESULTS

Among the 13 patients, two were diagnosed with R/R PCNSL and had several prior lines of anti-cancer therapy. Emavusertib in combination with ibrutinib (560 mg daily) appeared to be well tolerated in these two subjects. One patient experienced Gr3 treatment-related adverse events (thrombocytopenia, muscle weakness, pain). The preliminary efficacy data demonstrated one CR and one SD. The patient who achieved CR after the combination therapy was originally intolerant to high-dose methotrexate based chemoimmunotherapy and did not achieve complete remission after switching to ibrutinib, providing early clinical evidence of CNS penetration and anti-tumor activity of emavusertib.

CONCLUSION

In R/R PCNSL, these preliminary data suggest that combination therapy has a tolerable safety profile with promising anti-cancer activity and may overcome ibrutinib resistance.
CTIM-35. A PHASE II STUDY OF GITR AGONIST INCAGN01876 AND PD-1 INHIBITOR RETIFANLIMAB IN COMBINATION WITH STEREOTACTIC RADIOTHERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Bagley Stephen , Shabason Jacob , Mathew Divij , Kothari Shawn , Oldridge Derek , Desai Arati , Lustig Robert , Kurtz Goldie , Alonso-Basanta Michelle , Chen Kan , Long Qi , Harsch Jessica , Salman Muhammad , Fernandez Peter , Monsour Maikel , Prior Timothy , Maloney Eileen , MacMurtrie Eileen , Angeloni Natalie , O’Neill Meghan , Albright Karen , Caturla Maria , Ignatowski Melissa , Frangos Suzanne , Blessing Caroline , Phillips Richard , Nabavizadeh Ali , Mohan Suyash , Nasrallah MacLean , Jackson Christina , Brem Steven , Amankulor Nduka , Binder Zev , O’Rourke Donald , Wherry E John
Published: November 2022

BACKGROUND

We evaluated the combination of retifanlimab, INCAGN01876, and FSRT in patients with recurrent GBM.

METHODS

Phase II, single-center, 2 cohort study (A: single-arm non-surgical cohort; B, two-arm neoadjuvant/surgical cohort). Cohort A patients received pre-FSRT one-time doses of retifanlimab (500mg) and INCAGN01876 (300mg), FSRT (8 Gy x 3 fractions), and post-FSRT 28-day treatment cycles (retifanlimab, day 1; INCAGN01876, days 1, 15). Cohort B patients received pre-surgery doses of retifanlimab + INCAGN01876; subsequently, patients either went directly to resection (Sub-Arm 1) or to FSRT followed by resection (Sub-Arm 2). All patients resumed immunotherapy post-operatively. Primary endpoint: ORR in Cohort A. Data cut-off for this analysis was June 30, 2022.

RESULTS

Thirty-two evaluable patients: Cohort A, n=16; Cohort B, n=16 (Sub-Arm 1, n=8, Sub-Arm 2, n=8). Median follow-up time: Cohort A, 13.6 months; Cohort B, 8.8 months. Forty-four percent women, median age 64 (IQR, 55–65), 56% MGMT unmethylated. Most common grade 3/4 treatment-related AEs included cerebral edema (25%), lymphopenia (16%), and cognitive disturbance (13%). Efficacy in Cohort A: no objective responses observed, best response of stable disease achieved in 9/16 patients (56%), median PFS 3.9 months (95% CI 2.1 – 6.2 months), median OS 9.8 months (95% CI 8.3 months – not reached [NR]). Efficacy in Cohort B: median PFS NR, median OS 15.1 months (95% CI 8.5 months – NR). Median PFS and OS are longer in Cohort B Sub-Arm 2 compared to Cohort B Sub-Arm 1 (PFS, NR vs. 2.2 months, p = 0.009; OS, NR vs. 8.5 months, p=0.026). Results of tissue and blood-based immune correlative analyses will be presented.

CONCLUSIONS

The combination of retifanlimab, INCAGN01876, and FSRT is generally well-tolerated in patients with recurrent GBM when administered with or without surgical resection. Survival outcomes in the neoadjuvant cohort are encouraging, largely driven by patients that received neoadjuvant FSRT.
CTNI-10. RANDOMIZED PIVOTAL STUDY OF BLOOD-BRAIN BARRIER (BBB) DISRUPTION USING EXABLATE MODEL 4000 WITH STANDARD OF CARE (SOC) THERAPY IN NON-SMALL CELL LUNG CANCER (NSCLC) BRAIN METASTASES: LIMITLESS TRIAL
Authors: Ahluwalia Manmeet , McDermott Michael , Khosla Atulya , Sahgal Arjun , Mishra Mark , Achrol Achal S , Woodworth Graeme , Lipsman Nir
Published: November 2022

BACKGROUND

NSCLC is the most common cause of brain metastases. The Exablate focused ultrasound with circulating microbubble resonators uses the concept of real-time imaging to treat small target spots focusing energy through the skull in noninvasive manner, thereby disrupting the BBB. There is preclinical evidence of synergy of FUS-mediated BBB with immunotherapy beyond improved drug delivery due to BBB disruption (BBBD).

METHODS

LIMITLESS is a prospective, multi-center, randomized, two-arm, controlled, pivotal clinical trial to evaluate the safety and efficacy of additional targeted BBB disruption using Exablate Model 4000 for the treatment of NSCLC brain metastases in subjects who are undergoing planned pembrolizumab monotherapy compared to Pembrolizumab alone in 2:1 randomization. The inclusion criteria include age ≥ 18 years, KPS ≥ 70, NSCLC (EGFR and ALK negative) with up to 3 brain metastases, one of which meets the RANO-BM criteria for measurable Disease (1 cm x 1 cm) with normal organ function. The primary endpoint is to test superiority of Exablate BBBD targeted to their brain metastases over the standard of care without Exablate BBBD as determined by Objective Response Rate (ORR) based on RANO- BM by 6 months. The secondary endpoints include best objective response rate and time to response for brain metastases by treatment arm. Other end points include progression-free survival (PFS), overall survival (OS), Intracranial and extracranial PFS, quality of life assessments. The Bayesian design statistical analysis will assume superior ORR of 60% in Exablate group compared to 30% in SOC group for a total sample size of 96 subjects (64 subjects in Exablate and 32 in SOC) for 80% power using a two-sided Pearson's Chi-Square test with alpha = 0.05. For the upper-bound estimate ORR of 45% in Exablate group and 30% in SOC group will need 369 subjects (246 subjects in Exablate and 123 in SOC).
CTNI-13. A FIRST-IN-HUMAN PHASE 0/1 TRIAL OF 5-AMINOLEVULINIC ACID SONODYNAMIC THERAPY (5-ALA SDT) IN RECURRENT GLIOBLASTOMA
Authors: Sanai Nader , Tien An-Chi , Tovmasyan Artak , Chang Yu-Wei , Margaryan Tigran , Hendrickson Kristen , Eschbacher Jennifer , Yoo Wonsuk , Harmon Jocelyn , Hong Amy , Quarles Christopher , Barani Igor , Alhilali Lea , Mirzadeh Zaman , Mehta Shwetal
Published: November 2022

BACKGROUND

5-ALA SDT is not a blood-brain barrier disruption technique, but rather a first-in-class drug-device therapy exploiting the heme synthesis pathway in recurrent glioblastoma (rGBM). Following IV 5-ALA administration, aberrant tumor metabolism results in protoporphyrin-IX (PpIX) accumulation. Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in rGBM patients.

METHODS

Six hours prior to SDT, adult patients with rGBM were administered 10mg/kg of an IV formulation of 5-ALA (SONALA-001). Patients were assigned to one of three ascending acoustic energy levels of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval prior to planned tumor resection. In each patient, 50% of the enhancing and nonenhancing tumor volume was targeted with MRgFUS with the untreated tumor serving as an internal control. The Optimal Biological Dose (OBD) associated with 5-ALA SDT is the energy level associated with greatest tumor cell death.

RESULTS

8 patients were accrued across all energy levels, and none demonstrated drug- or device-related adverse events. Compared to internal control tissue, the apoptosis biomarker, cleaved caspase-3, was elevated in all patients, but most prominently at the 200J energy level. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were elevated in treated vs. control tissues at all energy levels. The mean Cmax for 5-ALA and PpIX in plasma were 305 µM and 65 nM, respectively. No off-target histological or radiographic alterations were detected in any patient.

CONCLUSIONS

This first-in-human Phase 0/1 study of a new therapeutic modality for rGBM patients demonstrates that 5-ALA SDT is safe at 200 to 800J and likely induces targeted cell death in rGBM patients via oxidative stress. At 10mg/kg of 5-ALA, the OBD is at or lower than 200J.
CTNI-15. REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2)
Authors: Padovan Marta , De Salvo Gian Luca , D'Avolio Antonio , Caccese Mario , Zagonel Vittorina , Lombardi Giuseppe
Published: November 2022

Glioblastoma (GBM) has activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneously xenografts. This phase I open-label multicentric study will evaluate the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ+RT as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in those two cohorts. Secondary objectives are: assessment of pharmacokinetics of REG, TMZ and possible pharmacokinetic interactions between TMZ and REG (cohort A); assessment of preliminary antitumor activity; evaluation of quality of life during the treatment. The dose escalation will be explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg; level -1 40 mg will be evaluated in case of Dose-Limiting Toxicity (DLT) during REG 80 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ+RT (60 Gy/30 fractions); in the adjuvant phase of cohort B, REG will be given (in association to TMZ) at MTD shown in the prior adjuvant phase dose escalation.The DLT evaluation period will be two cycles from the start of cycle 1 of adjuvant or from day 1 to last day of the concomitant phase. Approximately 36 subjects will be enrolled.
CTNI-16. NRG-RTOG 9802 OBSERVATION ARM - LONG TERM RESULT
Authors: Iwamoto Fabio , Polley Mei-Yin , Shaw Edward , Buckner Jan , Barger Geoffrey , Coons Stephen , Ricci Peter , Gilbert Mark , Brown Paul , Stelzer Keith , Rogers C Leland , Suh John , Schultz Christopher , Howard Steven , Fisher Barbara , Kim Michelle , Huang Jiayi , Haddock Michael , Won Minhee , Mehta Minesh
Published: November 2022

BACKGROUND

Radiation Therapy Oncology Group 9802 was a phase III trial for patients with centrally confirmed LGG (WHO grade II). Participants ³ 40 years or those with neurosurgeon defined less than gross total resection (GTR) were randomized to radiotherapy (RT) +/- PCV. In a separate cohort, adults age < 40 years with neurosurgeon defined GTR were observed by MRI every 6 months without adjuvant therapy. At last report, outcome for the observation cohort was immature with median follow-up of only 4.4 years. Here, we present mature outcomes for the observation arm.

METHODS

Eligible adults (as above) were observed by MRI every 6 months. OS and PFS were estimated by Kaplan-Meier method and estimated hazard ratios to characterize the prognostic variables.

RESULTS

There were 111 eligible patients (median age 30; median KPS = 100). Median follow-up was 16.1 years with 71 (64%) alive at the last follow-up. 79 patients (71%) had progressed with median PFS of 6.9 years. 5, 10, and 15 year-PFS and OS rates were 54%, 39%, 28% and 94%, 77%, and 65%. 1p19q status was codeleted in 32%, IDH1/2 mutant in 78% and MGMT promoter methylated in 39% of tested cases. Multivariate Cox analyses showed that preoperative tumor size ³ 4 cm (HR = 2.43 for PFS, p = 0.001; HR = 2.58 for death, p = 0.016) and residual disease on imaging ³ 1 cm (HR = 2.97 for PFS, P < 0.001; HR = 2.02 for death, p = 0.05) were associated with worse outcomes. Analyses based on molecular results will be presented.

CONCLUSION

A subset of low-grade gliomas can be observed after the initial resection based on younger age, smaller tumor size, and no residual disease on neuroimaging. This can likely be further refined by prognostic molecular markers. Patients with the most favorable prognostic factors can avoid or delay the acute and long-term side effects of RT and chemotherapy for several years.
CTNI-37. REPEATED OPENING OF THE BLOOD-BRAIN BARRIER WITH THE SKULL-IMPLANTABLE SONOCLOUD-9 (SC9) DEVICE: PHASE 1 TRIAL OF NAB-PACLITAXEL AND SC9 IN RECURRENT GLIOBLASTOMA
Authors: Sonabend Adam M , Gould Andrew , Luan Yu , Hou Ye , Kobayashi Mikoto A , Castro Brandyn , Zhang Daniel Y , Chen Li , Korobova Farida , Amidei Christina , Youngblood Mark , Bebawy John Patrick F , Liu Benjamin , Horbinski Craig , Desseaux Carole , Helenowski Irene B , Zhang Hui , Muzzio Miguel , Yue Feng , Canney Michael , Stupp Roger
Published: November 2022

BACKGROUND

The blood-brain barrier (BBB) is a major impediment to pharmacological treatment of gliomas. Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU/MB), temporarily opens the BBB. Here we investigate the pharmacokinetics and safety of this approach of repeated delivery of albumin-bound paclitaxel (Abraxane®, ABX) to the peri-tumoral brain. To perform LIPU/MB-based BBB opening prior to ABX infusions, we used a novel 6 x 6 cm device with 9 ultrasound emitters (SC9) that is implanted in a skull window after tumor resection.

METHODS

A Phase 1 dose-escalation trial using Bayesian adaptive design was conducted (NCT04528680). Patients with recurrent operable glioblastoma, a WHO PS ≤ 2 and adequate bone marrow and organ function were eligible. After tumor resection and implantation of SC9, repeated cycles of BBB opening by LIPU/MB immediately followed by ABX, was performed every 3 weeks. Intraoperative LIPU/MB and low dose ABX was given prior to tumor resection allowed for investigation tissue concentrations and pharmacokinetics.

RESULTS

Seventeen patients have been treated at six escalating ABX dose levels (40-260 mg/m2). At dose of 260 mg/m2, a grade 3 reversible taxane-associated dose limiting encephalopathy was observed in one patient. The patient continued treatment at a lower dose in subsequent cycles. A second patient exhibited encephalopathy on cycle 2. One patient developed grade 2 cumulative peripheral neuropathy. Intraoperative pharmacokinetic studies showed that ABX tissue concentrations in non-enhancing peri-tumoral brain were increased 3.7-fold after LIPU/MB. sc-RNA-sequencing showed transcriptional dysregulation of membrane transporters, pathways related to trans-cytosis as well as cell-cell and cell-matrix adhesion.

CONCLUSIONS

The LIPU/MB using skull-implantable ultrasound enhances the penetration of ABX in large regions of the brain. The procedure can be performed repeatedly and safely. LIPU-based BBB opening leads to transcriptional alterations in brain endothelium. Funding: NIH/NCI 1R01CA245969-01A1, CarThera (SC9 devices), BMS/Celgene (Abraxane®).
CTNI-60. PRELIMINARY RESULTS OF BINIMETINIB AND ENCORAFENIB IN ADULTS WITH RECURRENT BRAF V600E-MUTATED HIGH-GRADE GLIOMA
Authors: Schreck Karisa , Strowd Roy , Nabors L Burt , Ellingson Ben , Fisher Joy , Desideri Serena , Danda Neeraja , Rudek Michelle , Grossman Stuart , Ye Xiaobu
Published: November 2022

BACKGROUND

Although < 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are being identified more frequently as genetic testing increases in gliomas. Given the treatment-refractory nature HGG, RAF-targeted therapy is of special interest. The combination of encorafenib (BRAF inhibitor) with binimetinib (MEK inhibitor) was evaluated in adults with recurrent BRAFV600-mutated HGG.

METHODS

In this phase 2, open-label, Adult Brain Tumor Consortium trial(NCT03973918) encorafenib (450mg daily) and binimetinib (45mg twice daily) were administered continuously until disease progression, unacceptable toxicity, or death. Eligible patients had a histologically-confirmed HGG with BRAF-V600E mutation identified by PCR or next generation sequencing, and had progressed after radiation and any number of prior medical therapies. The primary endpoint was radiographic response rate by RANO criteria. Plasma was collected at baseline, on-study, and at progression for correlatives.

RESULTS

Five patients enrolled between January 2020 and November 2021. All patients had at least one prior recurrence (range 1-4) and received radiation one or more times. Median age was 27 years(range 22-77). Histopathologic diagnosis was glioblastoma(n = 2), anaplastic PXA(aPXA; n = 2), and anaplastic ganglioglioma(aGG; n = 1). Patients received treatment for 2-28months; currently 2/5 patients remain on treatment (8 and 30 months). Radiographic response rate was 60%(3/5): CR in two (glioblastoma, treated 10months; glioblastoma, 8months treatment ongoing), PR in one (aPXA, 28months treatment ongoing), SD in one (aGG, treated 3months), and PD in one (aPXA, treated 2months). Likely attributable adverse events (CTCAE grade ≥ 3) included cilioretinal artery occlusion (came off study) and asymptomatic elevated CPK. Analysis of paired plasma samples and correlation with response is ongoing.

CONCLUSIONS

Encorafenib and binimetinib demonstrate promising tumor responses in patients with recurrent BRAFV600E-mutated HGG with sustained responses in all GBM and 50% of aPXA in this small series, warranting careful consideration in this rare tumor subgroup. This Phase 2 study has closed due to enrollment issues
CTNI-65. INTUITT-NF2, AN ADAPTIVE PLATFORM-BASKET TRIAL FOR NEUROFIBROMATOSIS 2 PATIENTS WITH PROGRESSIVE TUMORS: INTERIM RESULTS OF THE BRIGATINIB TREATMENT ARM
Authors: Plotkin Scott , Allen Jeffrey , Babovic-Vuksanovic Dusica , Dinh Christine , Nghiemphu Leia , Trippa Lorenzo , Yohay Kaleb , Blakeley Jaishri
Published: November 2022

Neurofibromatosis type 2 (NF2) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. We developed an adaptive platform-basket trial to screen multiple drugs against any type of progressive NF2-related tumor. We report the interim analysis of the first treatment arm with brigatinib, an ALK inhibitor that inhibits multiple tyrosine kinases. We conducted a multicenter, phase II, open-label study for subjects ≥12 years old with NF2 and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Up to 5 non-target tumors were followed in each participant. In stage 1, 20 participants (minimum of 2 participants per basket) were treated with brigatinib 180 mg daily. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. Radiographic response (RR) was defined as ≥20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Per protocol, the brigatinib arm would be discontinued if no target tumor achieved a RR at interim analysis. Twenty subjects (median age=25 years, 7 pediatric, 12 females) were treated. Target tumors included 10 VS, 3 NVS, 5 meningiomas, and 2 ependymomas; non-target tumors included 18 VS, 36 NVS, and 14 meningiomas. RR rate for target and non-target tumors was 5% and 22%, respectively. By tumor basket, RR was 28% for meningioma, 26% for non-VS, 4% for VS, and 0% for ependymomas. Annualized tumor growth rates decreased for VS, NVS, and meningioma during treatment. Brigatinib was well tolerated with one dose reduction and one discontinuation due to grade 2 diarrhea. Brigatinib treatment was associated with RR in meningiomas, VS, and NVS. In stage 2, the study will enroll 20 participants in the two most promising baskets (meningioma and NVS). This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.
CTNI-66. THE PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG) STUDY: A NOVEL TREATMENT PARADIGM TO IMPROVE OUTCOMES?
Authors: Borst Gerben , Waqar Mueez , McBain Catherine , Beasley William , Golby Christopher , Hamerlik Petra , Karabatsou Tina , Bailey Matthew , D’Urso Pietro , Djoukhadar Ibrahim , Akkari Leila , Richardson Jenny , Hewitt Lauren , DuPlessis Daniel , O’Leary Claire , Jackson Richard , Coope David , Roncaroli Federico
Published: November 2022

OBJECTIVE

The Preoperative Brain Irradiation in Glioblastoma (POBIG) study evaluates for the first time the safety, feasibility, and impact of single fraction preoperative radiotherapy in newly diagnosed glioblastoma patients.

METHODS

Operable patients with a radiological diagnosis of glioblastoma, by consensus of a multidisciplinary tumor board including two dedicated neuro-radiologists, are screened for the study. Anatomical and functional MRI sequences are acquired for further tumor characterization and preoperative radiotherapy planning. Radiotherapy is delivered approximately two weeks after the initial screening. Radiation targets the macroscopic and microscopic tumor region at risk of being left behind during surgery and spares at least 2cc tumor volume being debulked to safeguard unperturbed and clinically relevant tissue examination and molecular profiling. The study dose-escalates (from 8Gy to 14Gy) based on the time-to-event Continual Reassessment Methodology. Subsequently, patients undergo surgical debulking followed by postoperative fractionated radiotherapy 60Gy/30fr with concurrent temozolomide.

RESULTS

The first POBIG study patient underwent preoperative radiotherapy followed by a subtotal resection of a left posterior fronto-opercular tumor and completed the postoperative chemoradiotherapy. Screening, study consent, MRI imaging and analysis, radiotherapy planning and delivery until surgery can be achieved within three weeks from screening while maintaining adequate and personalized patient communication. There were no surgical or radiotherapy delays or complications. During surgery, we successfully sampled unirradiated and irradiated tumor regions. The radiotherapy field covered the whole remnant tumor, and image-guided obtained tumor samples and imaging analysis showed clear evidence of differential radiation-induced changes.

CONCLUSION

We successfully initiated a new treatment strategy of preoperative radiotherapy for glioblastoma patients. The first patient completed the treatment, and the study is now open for further recruitment. Paired tumor sampling and advanced imaging analysis showed promising results. The POBIG study offers a unique opportunity for a paradigm shift towards personalized treatment regimens, hopefully leading to better outcomes.
CTNI-68. FIREFLY-1 (PNOC026): PHASE 2 STUDY OF PAN-RAF INHIBITOR TOVORAFENIB IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RAF-ALTERED RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA OR ADVANCED SOLID TUMORS
Authors: Kilburn Lindsay , Landi Daniel , Leary Sarah , Ziegler David , Baxter Patricia , Franson Andrea , McCowage Geoffrey , Waanders Angela , Van der Lugt Jasper , Oren Michal Yalon , Gerber Nicolas , Gottardo Nicholas , Khuong-Quang Dong-Anh , Nysom Karsten , Bailey Simon , Driever Pablo Hernáiz , Perreault Sebastien , Witt Olaf , Hahn Seungmin , Hargrave Darren , Hassall Timothy , Jabado Nada , Kang Hyoung Jin , Larouche Valerie , Toledano Helen , Kline Cassie , Abdelbaki Mohamed , Chi Susan , Gardner Sharon , Whipple Nicholas , Mueller Sabine , Blackman Samuel , Zhao Xin , Da Costa Daniel , Cox Michael , Packer Roger , Hansford Jordan
Published: November 2022

BACKGROUND

RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor.

METHODS

FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring an activating BRAF alteration. Patients aged 6 months–25 years who progressed following ≥ 1 prior line of systemic therapy were eligible. Tovorafenib 420 mg/m2 (≤ 600 mg) was administered weekly (tablet or liquid suspension formulation) until progression or for ≥ 26, 28-day cycles. The primary endpoint (arm 1) was overall response rate, as defined by RANO criteria, per independent review.

RESULTS

As of April 14, 2022, 25 patients were enrolled to arm 1 and had ≥ 6 months of follow-up. Median age at enrollment was 8 years (range 3–18). Most patients had astrocytomas (92%), 48% with optic pathway involvement. Patients were heavily pretreated (56% with ≥ 3 prior lines of therapy), and 72% previously received MAPK pathway-targeted agents. Tumors harbored BRAF fusions (84%) or BRAF V600E mutations (16%). Per independent assessment, partial responses (1 unconfirmed) were seen in 14 (64%) of 22 evaluable patients, with 6 additional patients having stable disease, and a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations. Most treatment-emergent adverse events (AEs) were grade 1 or 2 (96%). The most common grade ≥ 3 AEs were anemia (12%), vomiting, increased blood creatinine phosphokinase and maculopapular rash (8% each). Seven patients (28%) required dose modification for treatment-related AEs; no patients discontinued tovorafenib due to AEs. Updated results, including efficacy per RAPNO assessments will be presented.

CONCLUSIONS

Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children with pretreated BRAF-altered LGG.
DDEL-09. FRACTIONATED INTRACAVITARY RADIOIMMUNOTHERAPY WITH LU-177 LABELED 6A10 FAB FRAGMENTS IN PATIENTS WITH GLIOBLASTOMA
Authors: Müther Michael , Roll Wolfgang , Böning Guido , Delker Astrid , Zeidler Reinhard , Gildehaus Franz Josef , Stegger Lars , Schäfers Michael , Reulen Hans-Jürgen , Stummer Walter
Published: November 2022

Background

Radio-immunotherapy (RIT) with Lu- 177 labeled 6A10-Fab fragments, targeting tumor-associated carbonic anhydrase XII (CA12) and applied directly into the resection cavity, offers a promising strategy to address hibernating tumor burden after resection and completion of adjuvant treatment for glioblastoma. We report on the first in human applications.

METHODS

Three patients underwent microsurgical resection of glioblastoma. After completion of adjuvant radio- and chemotherapy, RIT was offered in a compassionate use setting. After implantation of an injection reservoir into the tumor cavity, three consecutive doses of Lu-177 labeled 6A10 Fab fragments were administered over three months, corresponding to 25% - 50% - 25% of the total activity. The injected dose was adapted to the size of the resection cavity. Dosimetry was performed with planar whole-body scintigraphy and SPECT/CT 12h, 24h, 48h, 76h and 5-7 days after injection.

RESULTS

Patient 1 (IDH1-Mutation) received three doses of RIT (total of 592 MBq) with stable disease 12 months after therapy and 26 months after initial diagnosis. Patient 2(IDH-Wildtype) had histologically proven tumor progression after the second cycle (total of 526 MBq). Patient 3 (IDH-Wildtype) has so far received one cycle of RIT (327 MBq of a planned total of 1300 MBq). No toxicity according to CTCAE version 6.0 or other adverse events related to RIT were observed. Dosimetry did not reveal absorbed doses above the upper dose limits for organs at risk.

Conclusions

Intracavitary radioimmunotherapy with Lu-177 labeled 6A10-Fab fragments appears to be a safe maintenance therapy for glioblastoma patients, albeit only assessed in three compassionate use situations far. A multicenter confirmatory phase-I-trial will be was initiated in May 2022 (EudraCT-No: 2015-004417-25) to determine the maximum tolerated dose and safety of adjuvant RIT with Lu-177 labeled 6A10-Fab fragments.
DDDR-03. DEVELOPMENT OF NOVEL ANTI-BRAIN METASTASIS INHIBITORS
Authors: Kieliszek Agata , Mobilio Daniel , Bassey-Archibong Blessing , Johnson Jarrod , Venugopal Chitra , Magolan Jakob , Singh Sheila
Published: November 2022

The current standard of care for (surgery and radiation) for brain metastases (BM) is inadequate as BM have a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need. The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Connectivity Map analysis was applied to the gene expression signatures of pre-metastatic BM cells to identity a compound (Drug A) which selectively inhibits BM cell proliferation but is not blood-brain barrier (BBB) penetrant and has not been previously considered in the context of brain metastasis. We synthesized a BBB-penetrant analogue of Drug A and found, using our patient-derived xenograft (PDX) models, that it increased survival benefit relative to both placebo and Drug A. Beginning with this promising scaffold, we will conduct structure-activity hypothesis-driven medicinal chemistry campaigns to optimize this scaffold for brain permeation while maintaining selective anti-BM activity. Development of novel small molecules that target premetastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.
DDDR-39. IDENTIFICATION OF A NOVEL THERAPEUTIC TARGET THAT IS SYNTHETICALLY LETHAL WITH MUTANT IDH INHIBITOR IN GLIOMA USING THE CRISPR/CAS9 GENOME EDITING TECHNOLOGY
Authors: Maeda Sachi , Aoki Kosuke , Hinohara Kunihiko , Yamaguchi Junya , Ohka Fumiharu , Motomura Kazuya , Kibe Yuji , Natsume Atsushi , Saito Ryuta
Published: November 2022

Diffuse glioma is the most frequent and malignant neuroepithelial tumor in the central nervous system. IDH mutations are the most frequent genetic mutations in adult gliomas. The WHO Classification of Tumors, 5th edition, volume 6: Central Nervous System Tumours revised in 2021, defines the presence of IDH mutations in gliomas as astrocytoma IDH-mutant and oligodendroglioma IDH-mutant and 1p/19q-codeleted. In addition, more than 90% of IDH mutations found in gliomas are IDH1 R132H mutation. Several clinical trials of mutant IDH1 inhibitors targeting the IDH1 R132H mutation have shown their efficacy, but it has also been reported that IDH1 inhibitors alone may not provide sufficient tumor suppression. In this study, we performed genome-wide knockout screening using CRISPR/Cas9 genome editing technology to search for new drug targets that are synergistic with the mutant IDH1 inhibitor DS-1001b. The results of CRISPR screening and RNA sequence analysis revealed that several metabolism-related genes are factors that define resistance to mutant IDH inhibitor. In a tumor suppression study, treatment of two IDH1 R132H mutant glioma cell lines (MGG152 and BT142) with mutant IDH1 inhibitor suppressed production of the oncometabolite D2-HG, but did not significantly alter cell growth. However, when mutant IDH1 inhibitor were combined with inhibitor for metabolism-related genes, cell survival was significantly reduced, and the effects were synergistic. In this study, we found that administration of mutant IDH inhibitors to IDH mutant gliomas significantly altered intratumor metabolism using various molecular approaches. We then identified targets that, when combined with mutant IDH inhibitor, provide synergistic tumor suppression. These results are expected to provide a new therapeutic approach for a subset of patients who have difficulty responding to mutant IDH1 inhibitors.
EOLP-04. A CALL TO ACTION TO INCREASE ACCESS TO POST-MORTEM BRAIN TUMOR DONATIONS: GIFT FROM A CHILD
Authors: Lyons Nicole , Waanders Angela , Williams Melissa , Nazarian Javad , Eze Augustine , Bornhorst Miriam , Frenkel Elizabeth , Mason Jennifer , Minturn Jane E , Koptyra Mateusz , Monje Michelle , Hysinger Jared , Souweidane Mark , Greenfield Jeffery P , Campbell Cindy , Uceda Esteban , Smith Amy , Hegert Julia , Campion Stephani , McLean Ginny , Gustafson Patti , Gustafson Allen
Published: November 2022

Implementation of access to donate post mortem tissue among pediatric brain tumor patients remains a challenge[DSM1] . Previous attempts to develop a post-mortem network have been jeopardized by barriers such as a lack of education, logistical coordination of donation, and difficulties effectively communicating the benefit of post-mortem donations to families. [CC2] Utilizing feedback from patients’ families, clinicians, and researchers, standard operating procedures (SOP) were developed and utilized by six “tissue navigators” (TN) working across institutions. Tissue navigators are critical in implementation of access to donate as they serve as a liaison between patients’ families and clinical team to ensure post-mortem tissue is procured correctly and respectfully. From 2018 through 2021, there has been an increase in donations, which has led to establishment of tumor cell cultures translating rapidly to clinical development, and a growing network of centers participating in GFAC procedures. Donations have been facilitated at over 75 institutions. GFAC has coordinated 146 donations in this 3-year launch timeframe, with nearly half from families outside GFAC’s primary institutional network. Barriers to implementation were addressed with the design of GFAC’s SOPs, which lead to the successful implementation of access to donation. GFAC is developing CME training for clinicians and researchers to address communication of post-mortem donation, continuing awareness campaigns with collaborators in the field, advocating for families to receive feedback on the donation, and expanding on the SOPs as more is learned from clinicians and families.
EPID-08. AGE-STRATIFIED SURVIVAL ANALYSES OF PHARMACOLOGICAL TREATMENTS IN PATIENTS WITH GLIOBLASTOMA
Authors: Rabin Erik , Mi Xinlei , Huang Jonathan , Kim Miri , Mozny Andreas , Amidei Christina , Sieg Erica , Bell April , Zhai Lijie , Bommi Prashant , Lauing Kristen , Lukas Rimas , Wainwright Derek
Published: November 2022

Glioblastoma is the most common primary malignant brain tumor in adults. Age is a prognostic factor for grade IV glioma (GIV) survival, where older adults 65 and older, tend to have quicker mortality compared to adults 18-64. This may be due to intrinsic aspects of the aged host, including age-dependent changes to the brain and immune systems. We studied pharmacologic management of GIV patients treated with medications affecting the brain, immune, and other systems for associations with age and survival. Electronic records for 1,208 GIV patients were collected at a single institution from 1/1/2000 to 9/8/2021 and used to construct a multivariable time-dependent cox model that examined intra-cohort hazards associated with 14 different categories of outpatient medications. Date of diagnosis was identified as the start-time and subject death was used to define the event-time. Patients who were alive or lost to follow-up were censored to last recorded date. Survival time was calculated as the difference between diagnosis date and event time or censorship. For positive control, we confirmed that younger and older patients experienced an improved hazard with temozolomide. Strikingly, younger, but not older patients, experienced increased hazard with a steroid prescription (1.46 [1.12,1.90], **). In contrast, older, but not younger patients experienced improvements in hazard with prescription of neurological medications including benzodiazepines (0.47 [0.27, 0.80] **) and anti-convulsants (0.28 [0.08, 0.90] *), in addition to heart failure treatments including angiotensin II inhibitors (0.48 [0.27, 0.85] *) and diuretics (0.30 [0.15, 0.87] *). Patients prescribed antidepressants didn’t show improved hazard across younger and older GIV patients, which consistent with our previously published work. These data indicate novel associative benefits due to prescription of select pharmacologic agents that vary with patient age. This work may be used to better understand therapeutic approaches that selectively benefit younger vs. older adults with GIV.
EPID-17. CENTRAL NEUROCYTOMA: RESEARCH TRENDS, MOST CITED PAPERS, AND SCIENTOMETRICS ANALYSIS TO DATE
Authors: Durrani Sulaman , Qamar Mohammad Aadil , Tebha Sameer Saleem , Nathani Karim , Bydon Mohamad
Published: November 2022

INTRODUCTION

Central neurocytoma is the most common primary intra-ventricular tumor in adults being classified by the World Health Organization (WHO) as a benign grade II tumor with a good prognosis. Given the recent advances with regards to this tumor, a bibliometric analysis was due to study the change in research interest and patterns to identify the future direction of research for neurocytomas. MATERIALS AND

METHODS

A comprehensive Elsevier’s Scopus database search was performed to capture all published and indexed studies to date using the keywords "neurocytoma" and "central neurocytoma". A discrete set of validated bibliometric parameters were extracted and analyzed. All statistical analyses were performed on R 4.1.2.

RESULTS

A total of 1,002 documents were included in our analysis covering a period between 1910-2021 (111 years). Around 98.5% of the documents were multi-author publications with a collaboration index (CI) of 4.21. Acta Neuropathologica, The American Journal of Surgical Pathology, and Cancer were the journals to include the most number of top ten cited articles (2 out of 10 most cited articles, 20%). Switzerland (4 out of 10, 40%) accounted for the country to have the most number of top 10 most cited articles. The United States of America (5588 out of 16395 citations, 34.1%) had the most number of citations. Lastly, our analysis reported an annual growth rate of 6.9% for the number of papers produced by year.

CONCLUSION

This is the first bibliometric analysis to study the top 10 most cited articles with regard to neurocytomas. A shift from histopathologic and clinical symptoms toward treatment and management of the tumor was observed in our analysis. These findings highlight the need for investigation into treatment modalities for future research.
DISP-03. FEMALE-SPECIFIC CANCER METASTASES TO THE BRAIN: OUTCOMES IN A MEDICALLY UNDERSERVED AREA
Authors: Shaffer Annabelle , Krist David , Smith Emily , Naik Anant , Mittal Anisha , Smith Alexander , Janbahan Mika , Najafali Daniel , Hassaneen Wael
Published: November 2022

INTRODUCTION

Cancer care in medically underserved areas (MUA) is challenging and not widely reported. This report seeks to characterize the outcomes of female patients with brain metastases from breast, ovarian, cervical, and endometrial cancer who underwent surgical resection in an MUA.

METHODS

Our institution’s electronic medical record was queried for patients who underwent a craniotomy from 2013-2022. All female patients with brain metastasis from breast, ovarian, cervical, or endometrial cancer were included. The following variables were collected: alive or deceased, survival time, demographics, past medical history, metastasis location and number, extent of resection, time to metastasis, and time to recurrence. MUA was defined by the Health Resources & Services Administration’s database (data.hrsa.gov).

RESULTS

Nine patients had metastases from breast, four from endometrial, one from ovarian, and one from cervical cancers. Metastases were most commonly located in the posterior fossa. The median age at surgery was 65 years. The median time from primary cancer diagnosis to brain metastasis diagnosis was 2.1 years. Gross total resection (GTR) was achieved in 15/21 metastases. Recurrence occurred in 7/15 patients after a median of 10 months. At the conclusion of the study, eight patients were deceased (53%), two patients were alive with no known new metastases (13%), four were alive with new metastases (27%), and one (6.7%) was lost to follow-up. In patients who died during the study, the median survival was 9.4 months, the median age at death was 65.7 years, and 7/8 had GTR of the metastasis(es).

CONCLUSION

To our knowledge, this is the first report of female-specific cancer brain metastases in an MUA. The median survival time was approximately nine months, which is similar to survival reported in multi-center studies. Further studies are recommended to identify and manage cancer care disparities in MUAs.
IMMU-39. NANOPARTICLE TREATMENT REBALANCES IMMUNODOMINANCE OF ANTI-VIRUS IMMUNITY TO ENHANCE ANTI-TUMOR IMMUNITY DURING ONCOLYTIC ADENOVIRUS THERAPY IN SOLID TUMORS
Authors: Shin Dong Ho , Jiang Hong , Gillard Andrew , Kim Debora , Nguyen Teresa , Fan Xuejun , Yi Yanhua , Ban Kechen , Alemany Ramon , Alonso Marta M , Lang Frederick , Gomez-Manzano Candelaria , Ozpolat Bulent , Fueyo Juan
Published: November 2022

Oncolytic virotherapy shows great potential for treating brain tumors and other solid tumors that metastasize to the brain. A phase I clinical trial testing the oncolytic adenovirus Delta-24-RGD (DNX-2401) in patients with recurrent malignant gliomas demonstrated significant clinical benefits for a subset of patients, and another phase I trial testing Delta-24-RGD in patients with pediatric brain tumors also indicated similar clinical benefits. However, virus injection in tumors initiates both anti-virus and anti-tumor immune responses by activating respective clones of CD8+ T-cells, which compete for limited resources for clonal expansion. Expansion of T-cells against highly immunogenic viral antigens might limit the expansion of subdominant clones against tumor antigens. We hypothesized that inducing immune tolerance for the dominant viral antigens will allow the expansion of previously subdominant tumor-specific T-cells. In this work, we observed that nanoparticles encapsulating adenoviral antigens successfully induced immune tolerance for viral antigens. These nanoparticles were taken up by liver resident macrophages, which are involved in maintaining peripheral immune tolerance. RNA-sequencing revealed that T-cells recognizing the encapsulated antigens had unique transcriptome signatures with upregulation of genes specifically involved in peripheral immune tolerance, including immune coinhibitory molecules. Virus-specific immune tolerance using nanoparticles redirected the focus of the immune response towards antigens for melanoma as measured by interferon-gamma secretion (P < 0.0001). Reduction of virus-specific T-cells and simultaneous expansion of tumor-specific T-cell clones were confirmed with tetramer staining (P < 0.05). Importantly, virotherapy in combination with nanoparticle-induced immune tolerance towards viral antigens increased the percentage of long-term survivors compared to virus treatment alone (100% versus 50%). Our data provide the basis to develop future clinical trials that aim to maximize the potential of cancer virotherapy in solid tumors.