bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-20. SINGLE INSTITUTION REVIEW OF LARGE VOLUME HIGH GRADE GLIOMA PATIENTS TREATED WITH RADIOTHERAPY
Authors: Manik Vishal , Swampillai Angela , Al-Salihi Omar , Chia Kazumi , Brazil Lucy
Published: November 2021

AIM

Not uncommonly, we come across significantly large high grade glioma cases (HGGs). With standard delineation protocols, we end up irradiating a large volume of normal brain. Emami & QUANTEC data define normal brain tolerance doses, however they are often of limited use in clinic practice. Thus, we reviewed our patients with significant tumor volumes to derive a safe dose/ volume level for brain.

METHODOLOGY

Patients with HGGs over the last 3 years were extracted from Mosaiq™ information system. The output was sorted with respect to clinical target volumes from lowest to highest. The top 25 percentile i.e. patients with a CTV of > 412cc (n=53) were identified for this study. Data was collected with respect to clinical, tumor characteristics and radiotherapy parameters.

RESULTS

Median age of population was 53 and majority (n=38) were males. Nine patients had multi-focal tumors while six had bilateral extension. Majority of the study group had Glioblastoma Multiforme (n=44), whereas 6 had Grade 3 tumors. Most of the patients could only have a biopsy (n=27). Molecular profile showed 42 were Isocitrate-Dehydrogenase negative and 26 were unmethylated tumors. Stupp’s & Perry’s regimen were the commonly used protocols, however patients (n=7) with significant volumes near critical structures were treated with doses in the range of 50.4 – 55Gy in 30 fractions. The CTV volumes in the population ranged from 412 – 1223 cc while total brain volume range was 1112 – 1667 cc. Median of 43.5% of brain volume was covered in the PTV, while median of 5% of brain volume outside the PTV was treated to BED2 of 100Gy. Median survival was 12.4 months.

CONCLUSION

Our study shows reasonable tolerance of radiotherapy doses of > 50 Gy to larger volumes of brain. We propose a multi-center collaborative study to derive a new standardized dose volume tolerance.
RADT-21. DUAL FET PET-GUIDED SIB IN RADIOTHERAPY OF NEWLY DIAGNOSED GLIOBLASTOMA - A PILOT STUDY
Authors: Harat Maciej , Blok Maciej , Wiatrowska Izabela , Furtak Jacek , Małkowski Bogdan
Published: November 2021

BACKGROUND

PET using FET is a valuable tool to determine the actual glioblastoma infiltration.The FET-PET examination can be performed using the dual-time point acquisition of FET . Infiltration defined in dual FET PET corresponds to the location and shape of the recurrence. The aim of this study was to evaluate safety and efficacy of simultaneous integrated boost based on dual FET PET combined with temozolomide TMZ for the postoperative treatment of GBM.

METHODS AND MATERIALS

In a prospective pilot study, 17 patients were enrolled. All patient presented an active tumor in postoperative PET imaging. The radiotherapy was performed as an FET-PET-based integrated-boost IMRT. The prescribed dose was 78 and 60 Gy (single dose 2.6 and 2.0 Gy, respectively). The progression-free survival (PFS) and overall survival (OS), toxicities and radiation necrosis rate were evaluated.

RESULTS

The median follow up was 37 months.Two patients were found to have uncontrolled seizures during radiation treatment and were not able to received treatment per protocol. Patients treated per protocol presented new or increased neurological deficits in 7/15 cases in a month after irradiation. In 4 patients radiation necrosis was confirmed in pathological report after re-surgery. Three patients were still alive after 26,28 and 38 months of follow up without progression and any signs of treatment related late toxicity. The 2-year survival rate was 43% in all patients treated per protocol. Median overall survival (OS) and disease-free survival (DFS) were 20 and 12 months, respectively. In a subgroup of MGMT methylated and unmethylated the median survival was 25 and 12 months.

CONCLUSIONS

Our dose escalation concept with a total dose of 78 Gy, based on FET-PET, have lead to promising survival results even within MGMT unmethylated subgroup. However rate of early toxicity and radiation necrosis is high.
RADT-31. TREATMENT TRENDS AND SURVIVAL OUTCOMES IN ATYPICAL MENINGIOMA
Authors: Syed Yusef , Rupji Manali , Switchenko Jeffrey , Eaton Bree , Olson Jeffrey , Kimberly Hoang , Bray David , Shu Hiu-Kuo , Zhong Jim
Published: November 2021

BACKGROUND

WHO grade II (atypical) meningiomas are treated with surgical resection, often followed by adjuvant fractionated radiation therapy (FRT). The increased availability of frameless stereotactic radiosurgery (SRS) presents an opportunity to offer patients a high biological effective dose over fewer fractions. Here we study the patterns of care and outcomes of these two forms of adjuvant RT.

METHODS

Patients with atypical meningioma were abstracted from the National Cancer Database (NCDB). Descriptive statistics were reported, and differences between treatment groups were assessed using either a chi-square test or ANOVA. Patients were grouped by treatment type and Kaplan Meier (KM) analysis was performed to compare overall survival (OS) using a log rank test. Univariable (UVA) and multivariable (MVA) cox regression analyses were completed.

RESULTS

Of 10,015 cases diagnosed from 2004-2016, 7,153 received surgery alone, 2,059 received surgery and adjuvant FRT (S+RT), and 362 received adjuvant SRS (S+SRS). The use of adjuvant RT increased by 71.8% for S+RT and 97.8% for S+SRS. In 2004, 15.1% of 443 registered patients received S+RT and 2.26% received S+SRS, while in 2016 these figures were 26.0% and 4.47%, respectively, for the 1051 registered patients (p< 0.001 and 0.022, respectively). For the 8,636 patients with survival data there was no significant difference in median OS between S+RT and S+SRS (130 months vs. 125 months, log rank p=0.935). On UVA, S+RT conferred better survival compared to surgery alone (HR 0.81 [0.72-0.91], p< 0.001) while S+SRS trended towards better survival (HR 0.82 [0.64-1.06], p=0.124). On MVA, no significant OS benefit was seen with S+RT (HR 0.96 [0.85-1.08], p=0.491) or S+SRS (HR 0.90 [0.69-1.16], p=0.413) versus surgery alone.

CONCLUSIONS

While the use of adjuvant RT for atypical meningioma has increased substantially since 2004, OS is comparable between FRT and SRS. The data presented here support further prospective investigation of adjuvant SRS.
CTIM-02. PHASE II STUDY OF IPILIMUMAB AND NIVOLUMAB IN LEPTOMENINGEAL CARCINOMATOSIS
Authors: Strickland Matthew , Lee Eudocia Quant , Wang Nancy , Cohen Justine , Chukwueke Ugonma , Forst Deborah , Eichler April , Overmoyer Beth , Lin Nancy , Chen Wendy , Bardia Aditya , Juric Dejan , Dagogo-Jack Ibiayi , White Michael , Dietrich Jorg , Nayyar Naema , Kim Albert , Alvarez-Breckenridge Christopher , Mahar Maura , Mora Joana , Nahed Brian , Jones Pamela , Shih Helen , Gerstner Elizabeth , Giobbie-Hurder Anita , Carter Scott , Oh Kevin , Cahill Daniel , Sullivan Ryan , Brastianos Priscilla
Published: November 2021

Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.
CTIM-05. A PHASE 1/2 STUDY OF THE COMBINATION OF INDOXIMOD AND TEMOZOLOMIDE FOR ADULT PATIENTS WITH TEMOZOLOMIDE-REFRACTORY PRIMARY HIGH-GRADE GLIOMAS
Authors: Lukas Rimas , Phuphanich Surasak , Rudnick Jeremy , Colman Howard , Cohen Adam , Monga Varun , Milham Mohammed , Sahebajam Solmaz , Kennedy Eugene , Smith Christopher , Rixe Olivier
Published: November 2021

BACKGROUND

Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG.

METHODS

A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity.

RESULTS

33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation.

CONCLUSIONS

The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.
CTIM-07. A PHASE I/II STUDY EVALUATING THE SAFETY AND EFFICACY OF A NOVEL LONG-ACTING INTERLEUKIN-7, NT-I7, FOR PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMAS AFTER CHEMORADIOTHERAPY
Authors: Campian Jian , Butt Omar , Luo Jingqin , Avvaru Chandini , Katumba Ruth , Zhou Alice , Kim Albert , Dunn Gavin , Abraham Christopher , Yang Se Hwan , Fan Jean , Lee Byung Ha , Ranjitkar Sunita , Le NgocDiep , Ansstas George , Johanns Tanner , Rettig Michael , Chheda Milan , Huang Jiayi
Published: November 2021

BACKGROUND

Lymphopenia is common after standard radiation therapy (RT) and temozolomide (TMZ) in high-grade gliomas (HGG) and correlates with shorter survival. Interleukin-7 (IL-7), a T-cell proliferation cytokine, is inappropriately low in HGG patients. Our previous preclinical studies demonstrated that NT-I7 (efineptakin alfa), a recombinant human IL-7, corrects lymphopenia and improves survival in murine glioma models. This study examines the safety and absolute lymphocyte counts (ALCs) following administration of NT-I7 patients with newly diagnosed HGG.

METHODS

Patients with HGG receiving RT/TMZ with ALC ≥600 were eligible. NT-I7 was administered intramuscularly within 1 week after completion of concurrent RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I examined 6 dose levels (60, 120, 240, 540, 720, and 960 mcg/kg) using the accelerated-titration design for the first 2 doses and 3 + 3 design thereafter to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 HGG patients per arm comparing changes in ALC. Immune profiling will be performed with CyTOF and cytokine analysis.

RESULTS

Phase I is complete, with 19 patients (89% GBM, median age: 58 (range: 25-78), median baseline ALC: 1000 cells/mm3, median dexamethasone: 0 mg/day (range: 0-12)). The median number of NT-I7 doses administered was 2 (range: 2-4). The most common treatment-related adverse event was grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 mcg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting selection of 720 mcg/kg for phase II. Dose-dependent increases in ALC were observed at 4 weeks ranging from 1.3x to 4.1x. Phase II enrollment is ongoing.

CONCLUSIONS

NT-I7 is well tolerated when administered after chemoradiotherapy for HGG patients with MTD of 720 mcg/kg and demonstrates dose-dependent increase of ALC. Phase II and immune profiling are ongoing. Clinical Trial ID: NCT03687957.
CTIM-19. TEM-GBM: A PHASE I-IIA DOSE-ESCALATION STUDY DELIVERING IFN-Α WITHIN GLIOBLASTOMA MULTIFORME TUMOR MICROENVIRONMENT BY GENETICALLY MODIFIED TIE-2 EXPRESSING MONOCYTES
Authors: Finocchiaro Gaetano , Gentner Bernhard , Marica Eoli , Francesca Farina , Capotondo Alessia , Ferla Valeria , Carrabba Matteo , Cuccarini Valeria , Meco Francesco Di , Legnani Federico , Pollo Bianca , Saini Marco , Ferroli Paolo , Pallini Roberto , D'Alessandris Giorgio , Patanè Monica , Paterra Rosina , Garramone Mariagrazia , Antonarelli Gabriele , Naldini Matteo , Barcella Matteo , Brambilla Valentina , Magnani Tiziana , Mazzoleni Stefania , Bashir Zahid , Olivi Alessandro , Bruzzone Mariagrazia , Russo Carlo , Naldini Luigi , Ciceri Fabio
Published: November 2021

Temferon is an ex vivo gene therapy consisting of autologous HSPCs genetically modified to deliver IFN-α2 within the tumor microenvironment (TME) by Tie-2 expressing macrophages. TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed GBM patients with unmethylated MGMT. Autologous HSPCs are transduced with a LVV encoding for IFN-a2 gene. As of 30th April 2021, 18 patients have been enrolled; 13 received Temferon (D+0) with follow-up of 8 – 662 days. After conditioning and Temferon infusion, a rapid engraftment and hematological recovery occurred, with median neutrophil and platelet engraftment at D+13 and D+12, respectively. No dose limiting toxicities were reported. Temferon-derived cells were found within 14 days post treatment and persisted albeit at lower levels in the long-term. Five deaths occurred: one at +478, three at +322, +340 and +402 days due to PD, and the fourth at +60 due to complications following the conditioning regimen. Eight patients had PD (-12 to +239). SAEs include respiratory tract infections, pulmonary embolism, CMV and C.Diff infections, febrile neutropenia, hemiparesis, seizure, brain abscess, worsening of performance status and respiratory failure compatible with ASCT, concomitant medications and PD. Four patients underwent second surgery. Recurrent tumors had gene-marked cells present and increased expression of ISGs compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased IFN-response signature than in a progressing lesion. Characterization of T-cell immune repertoire suggests the expansion of tumor-associated clones. TME characterization by scRNA and TCR sequencing is ongoing. Interim results show that Temferon is well tolerated, with no dose limiting toxicities identified to date and provide initial evidence of potential immune system activation within the TME.
CTNI-07. ABTC-1701: PILOT SURGICAL PK STUDY OF BGB324 (BEMCENTINIB) IN RECURRENT GLIOBLASTOMA PATIENTS – RESULTS FROM INTERIM FUTILITY ANALYSIS
Authors: Burt Nabors L , Nakano Ichiro , Supko Jeff , Lobbous Mina , Grossman Stuart , Ye Xiaobu , Desideri Serena , Danda Neeraja , Fisher Joy , Strowd Roy , Walbert Tobias
Published: November 2021

BACKGROUND

Glioblastoma often can relapse as mesenchymal (MES) tumors, indicating a phenotypic shift during clinical progression. Glioma spheres, when they gain MES phenotypes, develop dependence on AXL for their growth both in vitro and in vivo. The first-in-class orally bioavailable AXL kinase inhibitor bemcentinib has IC50 of 14 nM and is > 100-fold selective for AXL over other kinases. Bemcentinib is currently under evaluation as a monotherapy and in combination with other treatments across various PhII trials in several oncology indications.

METHODS

This is an open-label, multicenter, intratumoral pharmacokinetic study of bemcentinib in patients with recurrent glioblastoma for whom a surgical resection is medically indicated. All subjects must have had histological confirmation of glioblastoma by either biopsy or resection that is progressive or recurrent following radiation therapy ± chemotherapy. Intratumoral drug levels were analyzed by LC/MS.

RESULTS

A planned analysis after the first 5 patients were enrolled with glioblastoma (4 IDH WT and 1 IDH-mutant), (3m, 2f, median age 57, KPS 80). Bemcentinib concentration in contrast enhancing brain tissue ranged from 3.1 to 43.0 uM with a geometric mean concentration of 11.1 uM (% CV, 132.1). The drug concentration in contrast enhancing tumor tissue exceeded the 1.0 uM threshold in all 5 patients, satisfying the criteria of the protocol to enroll an additional 15 patients into the surgical study. Total drug levels were approximately 2-fold greater in contrast enhancing tissue as compared to tissue from a non-enhancing region of the tumor (geometric mean, 5.8 uM; % CV, 187.7). The mean ratio of the drug concentration in brain tissue to plasma was 25.9 (% CV, 92.7) for contrast enhancing tissue and 13.4 (% CV, 126.8) for non-enhancing tissue.

CONCLUSIONS

Bemcentinib readily distributes in brain tumor tissue following oral administration. The study continues to complete accrual for the remaining 15 patients.
CTNI-14. EVALUATING METABOLIC ALTERATIONS IN PATIENTS WITH EGFR ACTIVATED RECURRENT GLIOBLASTOMA (RGBM) BY INHIBITING EGFR WITH OSIMERTINIB
Authors: Cloughesy Timothy , Ellingson Benjamin , Gafita Andrei , Chun Saewon , Filka Emese , Nghiemphu Phioanh , Lai Albert , Green Stacey , Tsang Jonathan , Jingwen Yao , Calais Jeremie , Sonni Ida , Li Gang , Nathanson David
Published: November 2021

BACKGROUND

EGFR activated GBM is highly metabolically active and effective targeting with EGFR TKis in human-tumor models rapidly attenuates glucose metabolism engaging apoptotic machinery. Rapid changes in glucose uptake using 18F-FDG-PET is an effective predictive biomarker of therapeutic response in these models. Clinical 18F-FDG-PET may allow investigators to obtain early readout on EGFR TKi in this patient population. We explore this approach using osimertinib in EGFRamp/p53wt rGBM.

METHODS

EGFRamp/p53wt rGBM patients were treated with oral osimertinib 240mg for three days followed by 160mg/day until progression. F18-FDG-PET scan was obtained as a double baseline, 24 hours apart, prior to dosing with osimertinib. Third scan was obtained after 3 doses of 240mg. Primary objective defines test-retest variance of tumor FDG uptake before osimertinib and to evaluate if osimertinib significantly decreases glucose utilization after three doses. Study-drug and funding provided by AstraZeneca.

RESULTS

12 pts were evaluated, 10 female, median age 57.5 years (44-61). Volumetric mRANO showed no responses, 6 SD, 5 PD, and one NE. Median PFS was 31 days, no patient achieved 6-month-PFS and median OS was 5.5 months. No new adverse event signal appeared. Double baseline PET SUV mean was 0.97 (normalized to whole cerebellum) with upward trend from first to second scan with mean percent change of 2.8 and 95% CI(0.7,5.1). Change in PET from 2nd to 3rd showed mean percent change -3.2 with 95% CI (-11.1,4.8). Preclinical models suggest 15-20% attenuation is needed to predict improved outcomes in patients treated with EGFR-TKi.

CONCLUSION

F18-FDG-PET has little variance with test-retest showing upward trend with second scan. Post osimertinib F18-FDG-PET shows limited attenuation of tumor FDG uptake. No clinical signal was seen in study. Deeper attenuation of FDG uptake may be needed to show clinical effect from EGFR inhibitors. F18-FDG-PET can be used to evaluate change in tumor glucose utilization.
CTNI-16. TROTABRESIB (CC-90010, BMS-986378), A REVERSIBLE, POTENT ORAL BROMODOMAIN AND EXTRATERMINAL INHIBITOR (BETi) IN PATIENTS WITH HIGH-GRADE GLIOMAS: A PHASE 1 OPEN-LABEL ‘WINDOW OF OPPORTUNITY’ STUDY
Authors: Vogelbaum Michael , Sepulveda Juan Manuel , Reardon David , Hanna Bishoy , Filvaroff Ellen , Aronchik Ida , Amoroso Barbara , Zuraek Marlene , Sanchez-Perez Tania , Mendez Cristina , Nikolova Zariana , Moreno Victor
Published: November 2021

Trotabresib is a potent, reversible oral BETi with antitumor activity in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270). The CC-90010-GBM-001 study (NCT04047303) enrolled patients with progressive or recurrent astrocytoma or recurrent glioblastoma scheduled for salvage resection. Patients were treated with trotabresib 30 mg daily for 4 days before surgery, then trotabresib 45 mg daily 4 days on/24 days off after recovery. Primary objectives were trotabresib tumor tissue concentration and plasma pharmacokinetics (PK). Secondary and exploratory objectives included safety, antitumor activity, cerebrospinal fluid concentration, and pharmacodynamics (PD). Twenty patients were enrolled; blood PK, blood PD, and tumor PD data were available for 14, 12, and 11 patients, respectively. Geometric mean peak trotabresib plasma concentration on day 4 was 1.92 μM; median time to peak concentration was 1.5 hours. At the time of resection, geometric mean trotabresib concentrations in plasma and brain tumor tissue were 1.01 and 0.68 μM, respectively. Blood CCR1 mRNA was reduced ≥ 50% from baseline after dose 4. Blood HEXIM1 mRNA increased at 72–96 hours following first dose, and at the time of surgery the percentage increase was related to plasma trotabresib concentration. Tumor HEXIM1 RNA increased in 10 of 11 patients. Eighteen patients (90%) had ≥ 1 treatment-related adverse event (TRAE). Nine patients (45%) had grade 3/4 TRAEs, most frequently thrombocytopenia (5 patients [25%]). Only 1 patient had serious TRAEs (hemiparesis and lethargy). Two patients died of intracranial hemorrhage unrelated to study drug. Of 16 patients evaluable for antitumor response, 7 had stable disease per RANO criteria, with 3 ongoing beyond data cutoff at cycles 4–11. Median progression-free survival was 1.9 months (95% CI, 1.4–3.3). Overall, trotabresib showed good tumor tissue penetration, with PD signals of response, and was well tolerated. A study of trotabresib + temozolomide in first-line glioblastoma is ongoing (NCT04324840).
CTNI-21. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Chen Zhong-ping , Guo Cheng-Cheng , Qun-ying Yang , Li Jia-Wei , Wu Shao-xiong , Bacha Jeffrey , Johnson Gregory , Langlands John , Kwan Claire , Kanekal Sarath , Schwartz Richard , Steino Anne , Brown Dennis
Published: November 2021

Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been conducted to evaluate efficacy and safety of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. The study was conducted in 2 stages: Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). At the end of this stage, 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. All patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. All 29 patients have completed treatment and patients are in the follow-up phase of the study. Consistent with our prior experience, myelosuppression was the most common adverse event. As of March 2021, 22/29 (75.9%) subjects had disease progression. The median progression free survival for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Sixteen (16/29; 55.2%) patients had died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.
CTNI-24. A PHASE 1/2 STUDY OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Chi Susan , Hsieh Antony , Foley Megan , Shi Hongliang , Swamy Preethi , Rodstrom Jill , Rudoltz Marc
Published: November 2021

Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; response rates are only ~15% with targeted therapies. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT alterations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) alterations. H3K27M gliomas are dependent on PDGFRA signaling and patients have an overall survival of ~1 year. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid or CNS tumors, or H3K27M gliomas. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 < 2 nM), and PDGFRA activation-loop (D842V) mutants (IC50 = 0.24 nM); cellular IC50 of PDGFRA wild-type was 95 nM. CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for CNS antitumor activity. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. Objectives of this 2-part phase 1/2, multicenter, open-label study are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients aged 2 to < 18 years with solid R/R tumors dependent on KIT or PDGFRA signaling, including H3K27M gliomas and no alternative treatment options. Part 1 will enroll ≥ 6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥ 25 patients at the recommended avapritinib dose from Part 1; primary endpoint is objective response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.
CTNI-42. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA
Authors: Rauf Yasmeen , Hufsey Rachel , robinson Kathy , Suh John , Chao Samuel , Murphy Erin , Yu Jennifer , Peereboom David , Ahluwalia Manmeet
Published: November 2021

BACKGROUND

Ruxolitinib is a novel, potent, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

METHODS

Newly diagnosed patients with MGMT not hypermethylated, Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily. Patients with MGMT hypermethylated glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks.

RESULTS

45 patients had survival data, 25 patients were in Arm I and 20 arm in II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p=0.01 and p= 0.002), respectively. 9 patients had partial response, 16 patients were stable, and 28 patients had progression.

CONCLUSION

Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone..
CTNI-46. PHASE I OPEN-LABEL, SINGLE-CENTER, DOSE ESCALATION STUDY (NCT02423525) OF PULSATILE AFATINIB IN PATIENTS WITH BRAIN CANCER
Authors: Wagle Naveed , Juarez Tiffany , Carrillo Jose , Heng Annie , Gill Jaya , Nguyen Minhdan , Truong Judy , Boucher Najee , Archer Ashley , Nguyen Hanh , Nomura Natsuko , Yenugonda Venkata , Allnutt Annamarie , Barkhoudarian Garni , Kelly Daniel , Kesari Santosh
Published: November 2021

Afatinib is a small molecule, selective and irreversible ErbB family blocker. In preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in tumor growth inhibition and is approved for the treatment of EGFR-mutated metastatic non-small cell lung carcinoma and metastatic squamous cell lung carcinoma. Pulse dosing afatinib could potentially increase CNS exposure to reach therapeutic levels while allowing a recovery period to mitigate toxicities. We are reporting the results of a Phase I open-label, single-center, ‘3 + 3’ dose escalation study to determine the safety and tolerability of pulsatile Afatinib in patients with brain cancer and to define a recommended phase 2 dose. The study assessed the exposure of Afatinib in cerebrospinal fluid and serum, objective tumor response according to RANO criteria, progression-free survival, and overall survival, and will explore the association between molecular phenotypes and patient response. In total, 26 patients were screened and 24 were enrolled (median age 60, 78% male, 87.5% Caucasian, glioblastoma N=16, chordoma N=3, brain metastases N=2, meningioma N=1, anaplastic mixed oligoastrocytoma N=1). Patients had received a median of 2.5 prior treatments. The study proceeded through the 4 dosing cohorts without reaching dose-limiting toxicity: Cohort 1 (80mg every 4 days) N=3; Cohort 2 (120mg every 4 days) N=3; Cohort 3 (180mg every 4 days) N=7, including replacement patients; Cohort 4 (280mg every 7 days) N=11. Diarrhea (75%), rash (75%), nausea/vomiting (37.5%), fatigue (29.2%), anorexia (25%), and limb edema (16.7%) were the most common side effects. There were no CTCAE defined grade 4 toxicities. Grade 3 side effects infrequently occurred in the highest dosing cohort and once in each cohort 2 and 3. These results demonstrate that pulsatile Afatinib at a dose of 280mg every 7 days is safe and tolerable for patients with brain involving cancers.
CTNI-52. RETROSPECTIVE ANALYSIS OF USING RADIOTHERAPY WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATING FIELDS FOR CHINESE PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Wang Yang , Wu Jingsong , Qin Zhiyong , Wang Enmin , Yao Yu , Zhuang Dongxiao , Liang Lipin , Ni chunxia , Lu peijiang , Chen Shu , Li Chao
Published: November 2021

OBJECTIVES

Tumor Treating Fields (TTFields) has been shown to improve the overall survival of newly diagnosed GBM (ndGBM) when combined with Temozolomide (TMZ) in the EF-14 trial. Preclinical studies suggested synergistic effects between TTFields and radiotherapy. This study is aimed to examine the safety and efficacy of combination therapy (chemoradiation concurrent with TTFields treatment) for ndGBM patients in China.

METHODS

From July 2020 to May 2021, 33 ndGBM patients were treated with combination therapy (radiation target volume following NCCN guidelines). Eight patients had transducer array removed during radiotherapy, others retained transducer array on scalp. All patients had assessment every two months by MRI scan. The adverse reactions and monthly compliance data for TTFields treatment were recorded.

RESULTS

Twenty-five patients have completed the combination therapy. Three patients retained transducer array during radiotherapy but did not limit the scalp dose (mean: 21.7Gy). As a result, Grade 2 cutaneous adverse reactions developed, and TTFields treatment was suspended. Four patients suspended TTFields treatment due to other adverse reactions. The remaining patients who had limited scalp doses (mean < 20Gy) had no suspension or delay in combination therapy due to cutaneous adverse reactions. The median time of TTFields treatment during radiotherapy is 21.24 hours/day (IQR:19.26,22.08). Two patients had progressive disease, 1 died of pulmonary infection, and 30 had stable disease. The incidence of cutaneous AE was 48.5% (16/33), Grade1: 27.2% (9/33), Grade 2: 21.2% (7/33), and Grade 3: 3% (1/33).

CONCLUSIONS

The combination therapy was well tolerated in Chinese patients with ndGBM. Removing transducer array during radiotherapy may increase the frequency of array replacement while reducing the patient's daily treatment time. However, retaining transducer array will increase cutaneous adverse reactions. Scalp dose limitation is required yet it allows a maximum duration of TTFields. Further follow-ups are ongoing.
DDRE-05. LONG-TERM OUTCOME OF INTRATHECAL CHEMOTHERAPY WITH PEMETREXED IN LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER WITH EGFR-MUTATION: A CASE REPORT
Authors: Wang hui , Zhou Jiangfen , Wen Lei , Hong Weiping , Cai Linbo
Published: November 2021

Leptomeningeal metastasis (LM) is fatal complication of non-small cell lung cancer (NSCLC) ,which has a poor prognosis and lacks effective treatments. Pemetrexed, a multitargeted antifolate agent, has demonstrated antitumor activity, a few studies have shown intrathecal pemetrexed (IP) controllable toxicities and potential promising efficacy for LM from NSCLC patients. We report a patient who diagnosed with LM from NSCLC harboring epidermal growth factor receptor (EGFR) mutation in exons 21 via typical neurological symptoms, magnetic resonance imaging (MRI) and positive cerebrospinal fluid (CSF) cytology. The curative effect of tyrosine kinase inhibitor (TKI) targeted drugs was maintained for a short time, the first-generation TKI icotinib was 4 months, and the third-generation osimertinib was 4 months. Then the patient received IP, and osimertinib continued. 30 mg of pemetrexed were implemented on day 1 every weeks for 8 weeks via lumbar puncture, then 50 mg of pemetrexed on day 1 every 4 week for 8 times. This treatment regimen resulted in the alleviation of the neurological symptoms, the CSF level of carcinoembryonic antigen also decresed without obvious side effects. At the time of this manuscript’s submission, she had maintained stable disease (SD) for more than 11 months. To our knowledge, this study provides the first clinical evidence that longterm intrathecal chemotherapy with pemetrexed providing a therapeutic approach against LM from NSCLC.
DDRE-10. SCREENING OF EPIGENETIC COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS FOR THEIR POTENTIAL TREATMENT
Authors: Tatman Philip , Wroblewski Tadeusz , Fringuello Anthony , Scherer Sam , Foreman William , Damek Denise , Youssef Samy , Lillehei Kevin , Ormond David , Graner Michael
Published: November 2021

BACKGROUND

28% of primary central nervous system tumors are glioma and glioblastoma. These tumors are responsible for 80% of malignant brain neoplasms and most brain tumor related deaths. Despite modern therapies, patients with grade II gliomas have an average survival of 8-15 years, while patients with grade III tumors have an average survival of 3-5 years, and patients with glioblastoma have an average survival of 12-15 months. The lack of a curative treatment for this group of tumors supports additional research and novel approaches to identify more effective therapies.

METHODS

In this study, we developed a high-throughput drug screen and culture system to identify epigenetic inhibitor compounds with the potential to reduce glioma and glioblastoma viability.

RESULTS

We screened 33 tumors: 18 glioblastoma, 8 oligodendroglioma, and 7 astrocytoma. The top three most effective compounds across the full glioma cohort were all HDAC inhibitors; in order from most effective: panobinostat (average tumor viability = 52.5% +/-14.1SD; p=2.16x10-61), LAQ824 (average tumor viability = 58.1% +/-18SD; p=1.48x10-45), and HC Toxin (average tumor viability = 64% +/-21.1SD; p= 1.16x10-33). Additionally, HDAC inhibition was also the most effective across each histopathological glioma type: astrocytoma, oligodendroglioma, and glioblastoma. UNC0631(G9a inhibitor) and JIB-04(KDM inhibitor) were the most effective compounds in the six recurrent tumors, though HDAC inhibition was still significantly effective in this group. We also evaluated drug sensitivity with respect to tumor grade, prior treatment, de novo vs progressive etiology, EGFR amplification, IDH mutation, MGMT methylation, and patient gender.

CONCLUSIONS

After screening a large glioma cohort against a panel of epigenetic inhibitors, we found HDAC inhibition most effectively reduced tumor viability across all histopathological types and grades. These findings require further in vivo validation.
DDRE-14. OPTIMIZING MDM2 INHIBITION FOR THE TREATMENT OF HIGH-GRADE GLIOMA
Authors: Rendo Veronica , Lupien Leslie , Khuu Nicholas , Pelton Kristine , Elcavage Lara , Lu Sophie , Khadka Prasidda , Langhnoja Jaldeep , Phoenix Tim , Ligon Keith , Bandopadhayay Pratiti , Beroukhim Rameen
Published: November 2021

A majority of high grade gliomas retain a wild-type TP53 gene and are amenable to strategies for activation of the pathway to inhibit tumor growth. The interaction between p53 and MDM2 has served as target for such strategies currently in clinical trials for glioblastoma. As the effects and resistance mechanisms of MDM2 inhibition (MDM2i) remain poorly understood in glioma, we performed genomic and transcriptomic analyses in patient-derived models to better characterize sensitive tumors and identify putative biomarkers of drug response. Treatment with an MDM2 inhibitor (KRT232/AMG232) impaired the growth of cell lines with wild-type TP53 status, particularly in tumors with amplification of MDM2/4 or PPM1D activating mutations. Treatment with KRT232 upregulated both cell cycle arrest and apoptotic cellular responses, with unique temporal and transcriptional differences correlated with MDM2/4 or PPM1D status. In other tumors resistance to MDM2i is mainly mediated by TP53 mutations, but in a subset of chronic KRT232-treated glioma models we noted lack of TP53 mutations and identified cell state and transcriptional changes as potentially more treatable mediators of resistance.
DDRE-21. LOMUSTINE AND TARGETED-CYTOKINE THERAPY: A BENEFICIAL LIAISON FOR RECURRENT GLIOBLASTOMA
Authors: Weiss Tobias , Look Thomas , Puca Emanuele , De Luca Roberto , Hemmerle Teresa , Roth Patrick , Neri Dario , Weller Michael
Published: November 2021

Treatment options for recurrent glioblastoma are limited and except from regorafenib (potentially), no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma.

We investigated the combination of lomustine or bevacizumab that are frequently used for recurrent glioblastoma with L19TNF (onfekafusp alfa), a systemically administered tumor-stroma targeting antibody-cytokine fusion protein that enables a targeted delivery of tumor-necrosis factor (TNF)a to the tumor. In immunocompetent orthotopic glioma mouse models, the combination of lomustine and L19TNF demonstrated the strongest anti-tumor activity, acted in synergy and cured a majority of tumor-bearing mice, whereas lomustine or L19TNF monotherapy only had only very limited anti-tumor activity. Ex vivo profiling of the tumors and tumor-infiltrating immune cells from immunocompetent or immunodeficient hosts demonstrated immune-dependent cytotoxic and cytostatic effects on the glioma cells, and a strong increase of tumor-infiltrating immune cells upon combination therapy in immunocompetent models. Based on these encouraging results, we translate this combinatorial therapy to patients with recurrent glioblastoma. For the first patients, the treatment with lomustine and L19TNF was well tolerated and led to stable disease with a reduction in tumor perfusion. More patients are recruited in an ongoing phase I/II clinical trial with lomustine and L19TNF for patients with recurrent glioblastoma (NCT04573192).
DDRE-22. DISRUPTING REDOX BALANCE VIA THE TETRAHYDROBIOPTERIN PATHWAY IN GLIOBLASTOMA
Authors: Tuy Kaysaw , GC Sajina , Chen Wei , Harrison David , Aleman John , Hjelmeland Anita
Published: November 2021

Aberrant redox statuses are observed in glioblastoma (GBM), and we previously identified GTP cyclohydrolase I (GCH1) to be a redox regulator upregulated in brain tumor initiating cells (BTICs). GCH1 is a rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin (BH4), a cofactor that produces catecholamine precursors and nitric oxide (NO) and, once used, becomes 7,8-dihydrobiopterin (BH2). Regeneration of BH2 into BH4 by dihydrofolate reductase (DHFR) helps to maintain proper BH4/BH2 ratios for redox balance. Although the BH4 pathway has traditionally been studied in the vasculature system for its regulation of NO, our previous work and that of others suggests the GCH1/BH4 pathway plays a critical redox role including in neoplastic cells. In silico analysis of primary and recurrent gliomas indicate high expression of BH4 related enzymes that correlated with worse patient survival in both primary and recurrent gliomas. The observed elevation of the BH4 pathway not only emphasizes its importance, but a therapeutic opportunity for improving survival in glioma patients. By repurposing FDA approved drugs known to cross the blood brain barrier and previously suggested as anti-glioma therapies, combining inhibitors for the de novo synthesis (sulfasalazine) and regeneration (pyrimethamine) of BH4 could prove to be an effective strategy for targeting the GCH1/BH4 through redox disruption. Preliminary data BTICs isolated from patient derived xenografts (PDXs) indicated reduced viability when treated with sulfasalazine (SASP) and pyrimethamine (PYR). Furthermore, we observed lower/depleted levels of BH4 relative to BH2 when BTICs were treated with SASP and PYR. Lastly, there is an increase in mitochondrial ROS upon SASP and PYR treatment, suggesting dysregulated redox states. Importantly, temozolomide resistant GBM cells remained sensitive to SASP and PYR. Taken together, our preliminary data suggests the plausibility of targeting the GCH1/BH4 pathway with SASP and PYR to disrupt redox balance in glioma through the depletion of BH4.
DDRE-31. MITOCHONDRIAL TRAFFICKING AS A TARGET FOR GBM THERAPY
Authors: Lepe Javier , Douglas Christopher , Lomeli Naomi , Di Kaijun , Das Bhaskar , Bota Daniela
Published: November 2021

Glioblastoma (WHO Grade IV glioma) is the most aggressive brain cancer. The current standard of care treatment includes surgery, radiation, and chemotherapy. Tumor recurrence is almost inevitable as less than 50% of patients survive more than two years. The low survival rate poses a dire need to develop an effective therapy for GBM patients. GBM cells are resistant to treatment, as they activate their DNA damage response mechanisms to overcome the effects of radiation and temozolomide (TMZ) treatments. Recurrent tumors can arise from slow cycling and self-renewing stem/tumor-initiating cells resistant to radiation and TMZ. No second-line therapy was proven to prolong survival after TMZ failure. Magmas (Mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a subunit of the TIM23 complex regulating precursor protein trafficking into the mitochondrial matrix. Magmas is encoded by pam16, known to be upregulated in human pituitary adenomas, prostate cancer and GBM. Previous studies have demonstrated that Magmas negatively regulates the stimulatory activity of Pam18, which in turn stimulates the ATPase activity of mitochondrial heat shock protein 70 (mtHsp70). No small molecules targeting Magmas are in clinical use. We developed a novel small molecule inhibitor (BT9) that has been specifically designed to inhibit Magmas binding to Pam18. BT9 induces apoptosis through cleavage of caspase-3, reduced mitochondrial respiration and glycolysis. Our recent findings also demonstrate that BT9 treatment reduced protein trafficking of Lon protease into the mitochondrial matrix. Pretreatment of glioma cells with BT9 sensitizes cells to radiation treatment and enhances the TMZ activity. BT9 can cross the blood-brain-barrier and improve survival in intracranial glioma PDX models. BT9 has potential therapeutic value by directly dysregulating mitochondrial function in GBM, enhancing radiation and chemotherapy response, and improving survival in a relevant animal model.