bluuebunny/crossref_metadata_2025 huggingface dataset:
COVD-15. COVIDNEUROONC: A UK MULTI-CENTRE, PROSPECTIVE COHORT STUDY OF THE IMPACT OF THE COVID-19 PANDEMIC ON THE NEURO-ONCOLOGY SERVICE
Authors: Fountain Daniel , Piper Rory , Poon Michael , Solomou Georgios , Brennan Paul M , Chowdhury Yasir , Colombo Francesca , Elmoslemany Tarek , Ewbank Frederick , Grundy Paul , Hasan Md Tanvir , Hilling Molly , Hutchinson Peter , Karabatsou Konstantina , Kolias Angelos , McSorley Nathan , Millward Christopher , Phang Isaac , Plaha Puneet , Price Stephen , Rominiyi Ola , Sage William , Shumon Syed , Silva Ines , Smith Stuart , Surash Surash , Thomson Simon , Lau Jun Yi , Watts Colin , Jenkinson Michael
Published: December 2020

BACKGROUND

The COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors.

METHODS

We performed a multi-centre prospective study of all adult patients discussed in weekly neuro-oncology and skull base MDTs who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had follow-up data at least 30-days after the index MDT date. Descriptive statistical reporting was used.

RESULTS

There were 1357 referrals for newly diagnosed or recurrent intracranial tumors across fifteen neuro-oncology centres. Of centres with all intracranial tumors, a change in initial MDT management was reported in 8.6% of cases (n=104/1210). Decisions to change the MDT management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% (n=75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy (n=20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, p >0.9).

CONCLUSIONS

Disruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival.
COVD-16. THE COVID-19 PANDEMIC FROM A NEURO-ONCOLOGY PERSPECTIVE: STRATEGIES, PROTOCOLS, AND LESSON LEARNED
Authors: Burke John , Aghi Manish , Chan Andrew , Mummaneni Praveen , Berger Mitchel
Published: December 2020

INTRODUCTION

The COVID-19 pandemic has had an incalculable impact on our national healthcare system, and elective surgical procedures have been particularly affected. Given that brain tumors often straddle the line between elective and emergent procedures, the pandemic has presented unique challenges to the neuro-oncology community. Here, we present our institutional protocols to (1) maintain an active outpatient neuro-oncology practice, (2) triage surgical cases under limited operating room availability, and (3) safely resume research efforts.

METHODS

Given the rapidly evolving nature of the pandemic, we based the development of our protocols on the Delphi system to achieve consensus across a multi-disciplinary panel of experts. Specifically, we used this system to develop (1) a standardized physical examination that could be implemented over tele-medicine and (2) a triage system for surgical cases. Research efforts were largely suspended in the early days of the pandemic, however protocols for enrollment in clinical trials as well as the resumption of benchwork were also developed.

RESULTS

From the COVID-19 shelter-in-place order (March, 2020) through May 2020, our department performed 96 surgeries for the resection of brain tumors compared to 127 such surgeries from the three months prior. During this time, using a modified Delphi procedure, we developed detailed protocols to triage tumor cases. Implementation of telemedicine outpatient visits allowed the continuation of the neuro-oncology clinic and, ultimately, the resumption of clinical trials.

CONCLUSIONS

The protocols presented here offer several strategies to continue neuro-oncological care during the pandemic, including the surgical treatment of brain tumors. As we prepare for future outbreaks, these treatment algorithms will help ensure that patients with brain tumors receive the highest level of care independent of COVID-19.
COVD-23. PLANNED-USE GLUCARPIDASE FOR OUTPATIENT HIGH DOSE METHOTREXATE (HD-MTX) ADMINISTRATION IN PATIENTS WITH CNS LYMPHOMA (CNSL) DURING THE COVID-19 PANDEMIC
Authors: Schaff Lauren , Lobbous Mina , Bozza Alexis , Carlow Dean , Nabors Louis , Grommes Christian
Published: December 2020

Infection with SARS CoV-2 virus has resulted in a global pandemic of COVID-19, a respiratory illness with a crude mortality rate of 3–4%. Risk of death is higher in the elderly and in patients with underlying comorbid conditions. When local incidence of COVID-19 is high, hospital resources are scarce and elective admissions and procedures are placed on hold. Patients with CNSL receiving first-line HD-MTX require admission for monitoring and aggressive hydration to prevent toxicity. This study explores the feasibility of planned-use glucarpidase, a recombinant bacterial enzyme that rapidly reduces serum MTX levels, to facilitate outpatient administration of HD-MTX. Eligible adult patients had isolated CNSL and had previously tolerated inpatient HD-MTX. MTX 3.5 g/m2 was administered in the outpatient setting with hydration. Patients returned 24 hours after MTX administration for glucarpidase 2000u and additional hydration. MTX level was determined by high pressure liquid chromatography (HPLC) 48 hours following MTX administration. To date, seven outpatient HD-MTX treatments have been administered to a total of three patients. In all cases, MTX levels were reduced to < 100 nmol/L at 48 hours. Three treatments resulted in grade 1 elevation of AST/ALT (two patients). One treatment resulted in a grade 2 creatinine increase. Creatinine returned to baseline following additional outpatient hydration. No patients required hospital admission. This study demonstrates feasibility of outpatient HD-MTX administration with planned-use glucarpidase during the COVID-19 pandemic. We are currently enrolling to a larger study of planned-use glucarpidase for repeated doses of outpatient HD-MTX.
CSIG-21. BAF60C/SMARCD3 REGULATES TUMOR CELL DISSEMINATION IN MEDULLOBLASTOMA
Authors: Hu Baoli , Poore Brad , Sharma Vaibhav , Guan Yongchang , Agnihotri Sameer , Pollack Ian , Hu Baoli
Published: December 2020

Medulloblastoma, the most common malignant brain tumor in children, is a diverse and heterogeneous disease. Molecular characterization of MB revealed four major subgroups, WNT, SHH, Group 3, and Group 4. Although surgical resection, radiotherapy, and chemotherapy are effective at eliminating some forms, patients with the aggressive tumors cannot be cured with conventional therapies, particularly in Group 3. Group 3 is the most aggressive subtype of this disease, accounting for about 25%-30% of cases, and characterized by frequent metastasis at diagnosis and the worst prognosis among all the subgroups. Metastatic dissemination is a major treatment challenge and strongly associated with poor prognosis in patients with medulloblastoma. However, the molecular mechanisms of tumor cell early dissemination and late metastasis remain largely unknown. Here, we found that Group 3 has elevated expression of BAF60C/SMARCD3, a subcomponent of SWI/SNF complex, which significantly mobilizes nucleosomes and remodels chromatin. Clinically, elevated SMARCD3 mRNA resulted in a poorer prognosis in medulloblastoma patients, which was further validated in 63 patient tumors by immunohistochemical staining for SMARCD3. Interestingly, tumors that had metastasized often had elevated expression of SMARCD3, in all subgroups of medulloblastomas and Group 3 only. An orthotopic mouse model further supported that SMARCD3 is highly expressed in metastatic tumors compared to primary tumors. Importantly, CRISPR-Cas9-mediated SMARCD3 deletion decreased cell migration and invasion in multiple medulloblastoma cell lines. Mechanistically, SMARCD3 deletion led to decreased H3K27me3, suggesting that SMARCD3 may cooperate with PRC2 in regulation of gene expression. Strikingly, SMARCD3 deletion downregulated Reelin signaling pathway, an essential role in neuronal positioning during neurodevelopment, which indicates that tumors with highly expressed SMARCD3 hijack a developmental signaling to promote their dissemination and aggressiveness. Together, our results suggest that inhibition of SMARCD3 controlling downstream signaling may effectively prevent tumor dissemination and improve clinical outcomes in children with medulloblastoma.
CTIM-03. PHASE II STUDY OF REGORAFENIB IN BEVACIZUMAB REFRACTORY RECURRENT GLIOBLASTOMA
Authors: Rauf Yasmeen , Schilero Cathy , Peereboom David , Ahluwalia Manmeet
Published: December 2020

BACKGROUND

Most patients with glioblastoma (GBM) receive bevacizumab as part of their treatment. There is no good therapeutic option after bevacizumab failure. Regorafenib has potent preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.

METHODS

Patients with progression of GBM after treatment with Bevacizumab will be eligible for the study. Oral administration of Regorafenib at 160 mg once daily will be administered for 3 weeks on /1 week off. Weekly dose escalation of regorafenib from 80 mg to 160 mg/day will be employed as per the Redos strategy. Patients start the treatment 80 mg/day in week 1, with weekly dose escalation to 120 mg in week 2, then 160 mg week in 3 if no significant drug-related toxicities are observed. They will be continued on treatment with Regorafenib 160 md /day till tumor progression or toxicity. They will get MRI brain every 4 weeks during the study.

RESULTS

Primary endpoint is median Overall survival. Secondary endpoints include progression free survival at 6 months and the median time to progression and objective response rate using the modified RANO criteria. The overall safety and tolerability of regorafenib by CTCAE version 5.0. will also be reported.

CONCLUSION

This is an ongoing clinical trial.
CTIM-13. CLINICAL EFFICACY OF MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, IN RECURRENT GBM DELIVERED BY CONVECTION ENHANCED DELIVERY (CED)
Authors: Sampson John , Achrol Achal , Aghi Manish , Bankiewiecz Krystof , Bexon Martin , Brem Steven , Brenner Andrew , Chandhasin Chandtip , Chowdhary Sajeel , Coello Melissa , Ellingson Benjamin , Floyd John , Han Seunggu , Kesari Santosh , Merchant Fahar , Merchant Nina , Randazzo Dina , Vogelbaum Michael , Vrionis Frank , Zabek Miroslaw , Butowski Nicholas
Published: December 2020

BACKGROUND

MDNA55 is an IL4R-targeted toxin in development for GBM, a universally fatal disease. IL4R is over-expressed in GBM, the tumor microenvironment, and high expression is associated with poor outcomes in GBM.

METHOD

MDNA55-05 is an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in rGBM patients at 1st or 2nd recurrence with an aggressive form of GBM (de novo GBM, IDH wild-type, not-resectable at recurrence, ~ 50% expressing high levels of IL4R). Primary endpoint is mOS, secondary endpoint includes impact of IL4R status on mOS. A Synthetic Control Arm (SCA) served as an external comparator constructed from patient registries at neurosurgery centers under IRB-approved protocols. Propensity score weighting corrected for imbalances in baseline characteristics between the two groups.

RESULTS

MDNA55 showed an acceptable safety profile at doses up to 240μg. In all evaluable subjects (n=44) mOS was 11.6 and OS-12 was 46%. A sub-population (n=32) consisting of all IL4RHigh subjects + only IL4RLow subjects treated with high dose (median 180µg) showed most benefit: mOS is 15 months, OS-12 is 55%. Tumor control, assessed by mRANO criteria, was seen in 81% (26/32) of this sub-population, including those that had pseudo-progression (15/26). In these subjects, tumor control was associated with longer mPFS (4.7 months) and mOS (15.0 months) than those with progressive disease (mPFS 1.0 month, mOS 7.7 months). Comparison against the SCA demonstrated > 100% increase in mOS: 15.7 months vs 7.2 months (HR 0.52, 95% CI 0.30, 0.91).

CONCLUSIONS

MDNA55 demonstrates improved survival and tumor control in this study design and has potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. There are no approved therapies for rGBM that can extend survival by 50%; the potential for MDNA55 to extend survival by > 100% is promising for this devastating disease.
CTIM-15. PRELIMINARY RESULTS OF A PHASE II STUDY OF NIVOLUMAB WITH HYPOFRACTIONATED RE-RADIATION AND BEVACIZUMAB FOR RECURRENT MGMT METHYLATED GLIOBLASTOMA
Authors: Grommes Christian , Mehta Minesh , Miller Alexandra , Daras Mariza , Piotrowski Anna , Boire Adrienne , Butler Brittany , Stone Jacqueline , Pentsova Elena , Kotecha Rupesh , Morrison Tara , Odia Yazmin , Mellinghoff Ingo , Beal Kathryn
Published: December 2020

Standard of standard of care for glioblastoma (GBM) remains unsatisfactory with universal disease recurrence and a median survival of < 2 years. Immune checkpoint inhibitors (ICI) have shown limited single-agent activity in GBM thus far. GBMs with methylated MGMT promoter and no baseline corticosteroid dependence may be most likely to derive benefit from ICI. The combination of ICIs with radiation has shown promising activity in other human cancers. Combining nivolumab and re-RT/bevacizumab in GBM may augment ICI activity through immunogenic effects of radiation, may reduce the risk of radiation necrosis by addition of bevacizumab at the time of radiation, and may reduce the need for corticosteroids. In this multicenter phase II study, nivolumab is combined with re-irradiation and optional concurrent bevacizumab followed by nivolumab in patients with first recurrence of IDH-wildtype and MGMT methylated glioblastoma. Primary objective is to improve 1-year overall survival (OS) from 33 (based on EORTC 26101) to 50%. Nine-three patients are required to show a significant finding with an α of 0.05 and 81% power. Thirteen of 93 patient (14%) have been enrolled with a median age of 59 (range 42–71) with a median KPS of 90 (range 70–90). Treatment has been tolerated well without any grade ≥ 4 toxicities and only one grade 3 (amylase elevation). The most common adverse events were pruritus and hypothyroidism in 3/13 (23%). The median progression-free survival (PFS) is 7 months with a 6months PFS of 55.6%. The 12months OS is 66.7%. Patients with recurrent MGMT methylated, IDH-wildtype glioblastoma tolerate trial treatment with acceptable toxicities. Clinical efficacy in the first patients enrolled shows a promising effect. Enrollment is ongoing.
CTIM-16. INTERSTITIAL PHOTODYNAMIC THERAPY WITH 5-ALA FOR MALIGNANT GLIOMA RECURRENCES
Authors: Lietke Stefanie , Schmutzer Michael , Schwartz Christoph , Weller Jonathan , Aumiller Maximilian , Heckl Christian , Forbrig Robert , Niyazi Maximilian , Stepp Herbert , Sroka Ronald , Tonn Joerg-Christian , Rühm Adrian , Thon Niklas
Published: December 2020

Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a cytotoxic photosensitizer has been shown to be a feasible treatment option for malignant gliomas. We present outcome measures and a risk profile analysis of salvage iPDT in a large monocentric cohort with local tumor recurrence following standard therapy. This study included consecutive adult patients undergoing salvage iPDT for small, circumscribed, biopsy-proven malignant glioma recurrences not deemed eligible for safe complete resection of contrast enhancing tumor. A modified 3-D treatment-planning software was used to calculate the treatment-volume and the position of the stereotactic light diffusers within the lesion. Outcome measurements included estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and the risk profile of iPDT. Prognostic factors were obtained from logistic regression models. The institutional review board approved the study. A total of 44 patients (median age: 49.4 years, range 33.4–87.0 years, 17 female) were included. Recurrent tumors included 37/44 glioblastomas WHO grade IV and 7/44 anaplastic astrocytomas WHO grade III. Thirty (68.2%) tumors were MGMT methylated. Median treatment volume was 3.3 ccm (range, 0.5–22.8 ccm). A median number of 4 (range: 3–8) laser fibers were used. Median illumination time was 60min (range: 60–167 min). Symptomatic edema (8/44) or intratumoral hemorrhagic imbibition (7/44) did not result in any permanent morbidity. Median TTF was 7.1 months and median PRS was 13.0 months. The 2- and 5-years PRS rates were 25.0% and 4.5%. Treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. In conclusion, iPDT was associated with promising outcome measurements in local malignant glioma recurrences in highly selected patients. Transient neurologic deterioration did not lead to any permanent morbidity. The procedure deserves further prospective evaluation particularly to identify mechanisms of favorable treatment response and prognostic factors associated with long-term survival.
CTIM-18. DENDRITIC CELL VACCINATION IN CONJUNCTION WITH ADJUVANT TLR-3 AGONIST ADMINISTRATION ENHANCES PRO-INFLAMMATORY IMMUNE RESPONSES AND IS ASSOCIATED WITH EXTENDED SURVIVAL IN MALIGNANT GLIOMA PATIENTS
Authors: Chavez Carolina , Everson Richard , Orpilla Joey , Lee Alexander , Khattab Sara , Antonios Joseph , Salazar Andres , Cloughesy Timothy , Liau Linda , Sun Lu , Hugo Willy , Prins Robert
Published: December 2020

Despite recent advances with immunotherapy in other tumor types, malignant glioma patients have not shown a therapeutic benefit, potentially due to the insufficient activation of an immune response. We and others have documented immune responses and extended survival following dendritic cell (DC) vaccination in small clinical trials. In this Phase II clinical trial, we randomized malignant glioma patients to receive autologous tumor lysate pulsed DC vaccination with and without adjuvant toll-like receptor (TLR) agonists. Treatment with TLRs in cancer patients has been shown to activate the innate immune response by inducing the expression of pro-inflammatory factors and cytokines. Twenty-three patients with WHO grade III or IV glioma received three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 in conjunction with either a placebo adjuvant, TLR-7 agonist (Resiquimod), or TLR-3 agonist (Poly ICLC). We observed a difference in survival for the DC-vaccinated patients who received adjuvant Poly ICLC treatment of 54 months over adjuvant placebo (20 months) and adjuvant Resiquimod (28 months) groups (P = 0.04). The patient cohorts were balanced for WHO grade, IDH mutation, and MGMT methylation status. Mass cytometry (CyTOF) analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of the monocyte populations CD14+CD16- and CD14dimCD16+ after Poly ICLC treatment. In addition, gene expression analysis of the PBMC populations using single cell RNA sequencing demonstrated increased expression of pro-inflammatory genes after adjuvant Poly ICLC and Resiquimod treatment. Nonetheless, a greater fold change increase and a larger pro-inflammatory repertoire was observed in the Poly ICLC group. Overall, these findings demonstrate that adjuvant Poly ICLC increases the number of circulating monocytes and induces a large pro-inflammatory response, which may account for the survival differences observed over adjuvant Resiquimod and placebo.
CTIM-22. PHASE 1 TRIAL OF OSIMERTINIB WITH STEREOTACTIC RADIOSURGERY (SRS) IN PATIENTS WITH BRAIN METASTASES FROM EGFR POSITIVE NON-SMALL-CELL LUNG CANCER (NSCLC)
Authors: Rauf Yasmeen , Kotecha Rupesh , Fadul Camilo , Evanoff Wendi , Suh John , Chao Samuel , Murphy Erin , Yu Jennifer , Angelov Lilyana , Barnett Gene , Mohammadi Alireza , Ahluwalia Manmeet
Published: December 2020

BACKGROUND

Osimertinib is an oral, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor activating mutation (EGFRm) and the resistance mutation (T790M) that is FDA approved for patients with EGFR mutant lung cancer. The synergism between Osimertinib and radiation likely enhances DNA damage, leading to increased cell apoptosis. For patients with EGFR positive NSCLC with brain metastases, we hypothesize that the combination of Osimertinib and SRS will lead to better long term control of brain metastases as well as the systemic disease.

METHODS

This is an open label, single arm, phase I multi-institution study. It will employ a 3 + 3 design. After enrollment onto the study, patients will be started on Osimertinib at the predetermined level daily for 0–7 days, after which all patients will undergo radiosurgery and then receive Osimertinib daily concurrently until disease progression, withdrawal or until unacceptable toxicity. SRS will be given in single fraction as determined by the treating radiation oncologist and neurosurgeon.

RESULTS

Primary endpoint include Safety, tolerability and maximum tolerated dose (MTD) of Osimertinib, when administered in combination with SRS in patients with EGFR positive NSCLC with brain metastases. Secondary endpoints include Six-month intra-cranial and extra-cranial progression-free survival (PFS-6), overall survival, overall response rate, both intracranial and extra cranial in patients with EGFR positive NSCLC brain metastases.

CONCLUSION

This is an ongoing clinical trial.
CTIM-29. CRUCIAL APPLICATION OF SINGLE CELL GENE EXPRESSION FOR MONITORING CHANGES IN GLIOBLASTOMA PATIENTS WITH SUSTAINED RADIOGRAPHIC RESPONSE TO CMV pp65-LAMP RNA-PULSED DENDRITIC CELL-BASED VACCINES
Authors: Yegorov Oleg , Yang Changlin , Dechkovskaia Anjelika , Rahman Maryam , Ghiaseddin Ashley , Mitchell Duane
Published: December 2020

BACKGROUND

The application of single cell sequencing as a novel immune monitoring platform can be used to identify the molecular mechanisms of immune response to dendritic cell- based vaccines, trace the cell types and states involved, and uncover novel biomarkers for immunotherapy. We applied single-cell RNA Seq analysis of longitudinal peripheral blood mononuclear cells (PBMCs) in patients with newly-diagnosed GBM enrolled on the ATTAC II clinical trial (FDA IND BB-16530; Clinicaltrials.gov # NCT02465268) who experienced a sustained radiographic response to autologous CMV pp65-LAMP RNA-pulsed DC vaccines plus GM-CSF and tetanus-diphtheria booster administered during adjuvant cycles of dose-intensified temozolomide.

METHODS

We constructed 5’ gene expression libraries and T cell receptor enriched libraries for 10x Genomics single-cell 5’ and VDJ sequencing, generated from PBMCs collected prior to and during patient immunization using dendritic cells loaded with messenger ribonucleic acid encoding the human cytomegalovirus (CMV) matrix protein pp65 conjugated with the lysosomal associated membrane protein (LAMP) sequence.

RESULTS

Overall, we sequenced a total of 189,808 single-cell transcriptomes from 5 patients. We leveraged these transcriptome-wide features to distinguish 15 peripheral immune cell subtypes in tested PBMCs. Analysis revealed dynamic changes in immune cell subsets over the course of first three vaccines, including increases in cytotoxic CD8 T cells, CD4 T cells, and NK cell subsets. Increased markers of T cell activation were observed during vaccination. Surprisingly, we observed a very high-level frequency of natural killer T (NKT) cells in the patient with a complete durable response compared to other patients. After three DC vaccines, the level of NKT cells in PBMC of this patient increased up to 10%.

CONCLUSIONS

These results emphasize the importance of subset specific profiling to achieve higher resolution in monitoring immune responses compared with bulk expression profiling in patients receiving immunotherapeutic treatment.
CTNI-02. TBCRC049: A PHASE II STUDY TO ASSESS THE SAFETY AND EFFICACY OF THE COMBINATION OF TUCATINIB, TRASTUZUMAB AND CAPECITABINE FOR THE TREATMENT OF LEPTOMENINGEAL METASTASIS IN HER2 POSITIVE BR1AST CANCER
Authors: Murthy Rashmi , O’Brien Barbara , Berry Donald , Navin Nicholas , Johnson Jason , Gule-Monroe Maria , Leone Jose , Specht Jennifer , Melisko Michelle , Morikawa Aki , Storniolo Anna , Brufsky Adam , Pohlmann Paula , Park Deric , Park Ben , Krop Ian , Lin Nancy , Rimawi Mothaffar , Wolff Antonio , Forero-Torres Andres , Stringer-Reasor Erica
Published: December 2020

Treatment options for patients with leptomeningeal metastasis (LM) from HER2-positive breast cancer (HER2+ BC) are limited and prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and combinatory anti-tumor activity, including partial responses in heavily treated patients and those with brain metastases (BM). This is a phase 2 single-arm study to evaluate the efficacy of tucatinib, trastuzumab and capecitabine in HER2+ BC with newly-diagnosed LM. CNS disease will be evaluated at screening and every 6 weeks by neuroaxis MRI, CSF cytology, and neurological assessments per RANO-LMD (adapted) and RANO-BM criteria. Extra-CNS disease will be evaluated at screening and every 12 weeks by CT scan per RECIST criteria. All patients will be followed for survival. Symptom burden and quality of life assessments, as well as correlative blood and CSF samples, will be collected. Eligible patients include adults with HER2+ BC, KPS > 50, and newly-diagnosed, untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM, plus clinical signs/symptoms). Patients with treated or concurrent/new BM are allowed. Patients treated with capecitabine within the last 12 months are excluded. This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, success is defined as CNS PFS for 12 weeks. Enrollment will end if fewer than two successes are observed in the first 15 patients. Secondary endpoints include safety, CNS PFS at 12 weeks, RR in CNS and extra-CNS, and symptom burden/quality of life. The regimen will be considered worthy of future study if the median OS is > 4.4 months. Fourteen of 30 patients have accrued thus far. The study is active at multiple Translational Breast Cancer Research Consortium sites around the country.
CTNI-08. A PHASE 1–2 CLINICAL TRIAL OF EO1001, A NOVEL IRREVERSIBLE PAN-ErbB INHIBITOR WITH PROMISING BRAIN PENETRATION
Authors: Wheeler Helen , Bacha Jeffrey , Brown Dennis , Kanekal Sarath , Sankar Neil , Nisbet Ian , Skoff Kathy , Shen Wang , ZhenZhong Wang , Pedersen Harry
Published: December 2020

Mutations causing errant ErbB activation are implicated in many cancers, including tumors correlated with high incidence of CNS metastasis. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs, particularly in advanced disease. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. EO1001 is being advanced into first-in-man studies under the Australia Clinical Trials Notification (CTN) scheme (ANZCTR Reg.#ACTRN12320000589343p). METHODS: Adult patients with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. Toxicity is assessed by NCI CCTCAEv5 and tumor response is assessed by RECISTv1.1. CNS exposure is evaluated in in select patients with confirmed CNS disease involvement via CSF collection. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥ G2) is observed, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). DOSE ESCALATION: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD EXPANSION: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). An update on the progress of this trial will be presented.
CTNI-22. RETROSPECTIVE ANALYSIS OF THE COMBINED TREATMENT OF VINCRISTINE, ACNU, CARBOPLATIN AND INTERFERON-β PLUS RADIOTHERAPY (VAC-FERON-R)IN PATIENTS WITH DIFFUSE ASTROCYTOMA
Authors: Arakawa Yoshiki , Makino Yasuhide , Kawauchi Takeshi , Tanji Masaharu , Mineharu Yohei , Kanemura Yonehiro , Miyamoto Susumu
Published: December 2020

OBJECTIVE

Diffuse astrocytomas are classified as WHO grade II and its median overall survival (mOS) is 10 to 11 years. The efficacy of chemoradiation in the high-risk feature has been reported. The prognosis is associated with IDH and TERT promoter (TERTp) mutations. Here, we retrospectively analyzed the patients with diffuse astrocytoma treated with vincristine, ACNU, carboplatin and interferon-β plus radiotherapy (VAC-feron-R)in our institute.

PATIENTS AND METHODS

Between December 2003 to January 2016, 44 patients were diagnosed as diffuse astrocytoma with integrated diagnosis of histological and molecular analysis. The average age was 43.1 years (22–71 years). They received VAC-feron-R as initial treatment in our institute. We analyzed the IDH1/2 and the TERTp mutation using Sangar sequencing and determined the 1p/19q codeletion by the fluorescence in situ hybridization or the multiplex ligation-dependent probe amplification.

RESULTS

Median follow-up period was 76.5 months, mPFS was 126 months, mOS did not reach, and 10-year survival rate was 60%.IDH status was determined in 29 patients, 9 mutant and 20 wild types. There was no significant difference in PFS and OS between the two groups. TERTp status was determined in 18 patients with IDH wild type, 6 mutant and 12 wild types. mPFS of patients with TERTp wild type did not reach, but that with TERTp mutant type was 34.5 months (p = 0.0356).

CONCLUSION

Compared with previous clinical studies, VAC-feron-R showed a favorable clinical outcome in diffuse astrocytoma. The impact of TERTp status on prognosis was identified but not IDH status in this cohort.
CTNI-26. ACCELERATOR-BASED BNCT IN RESCUE TREATMENT OF PATIENTS WITH RECURRENT GBM: A MULTICENTER PHASE II STUDY
Authors: Miyatake Shin-Ichi , Kawabata Shinji , Goto Hiromi , Narita Yoshitaka , Suzuki Minoru , Hirose Katsumi , Takai Yoshihiro , Ono Koji , Ohnishi Takanori , Tanaka Hiroki , Kato Takahiro
Published: December 2020

BACKGROUND

Boron neutron capture therapy (BNCT) is tumor-selective particle　radiation and theoretically efficacious especially for tumors with infiltrative nature, such as glioblastoma (GBM). The aim of this study is to assess safety and efficacy of accelerator-based BNCT (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent malignant gliomas, chiefly GBM.

METHODS

The multi-institutional open-label, phase II clinical trial for recurrent 27 cases of malignant gliomas (MG) (24 cases were GBM) was conducted with above AB-BNCT system, using 500mg/kg of SPM-011 (study code, JG002). The patients were enrolled from February 2016 to June 2018. The inclusion criteria are bevacizumab-naïve MG, recurrent after standard treatment composed of XRT and chemotherapy with TMZ. Neutron-irradiation time were determined not to exceed to 8.5 Gy-Eq for scalp dose. Primary endpoint was 1-year survival rate and secondary ones were median overall survival (mOS), median progression free survival (mPFS). The results were compared to previous Japanese domestic bevacizumab trial for recurrent GBM (JO22506) which had the similar inclusion criteria with JG002.

RESULTS

1-year survival rate and mOS of recurrent GBM cases in JG002 was 79.2% (95% CI:57.0–90.8) and 18.7 months (95% CI:12.9–23.4) respectively, while those of JO22506 was 34.5% (90% CI:20.0–49.0) and 10.5 months (95% CI:8.2–12.4), respectively. Median PFS of JG002 and JO22506 were 0.9 and 3.3 months, respectively. Most important adverse event in JG002 was brain edema. Brain edema in 21 out of 27 cases was treated with bevacizumab after progress disease.

CONCLUSIONS

AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG chiefly GBM. AB-BNCT might produce brain edema somewhat after the treatment, which might be the unavoidable adverse event of re-irradiation for recurrent MG, however that seemed to be controlled well with bevacizumab.
CTNI-51. NEUROCOGNITIVE FUNCTION (NCF) OUTCOMES OF RTOG FOUNDATION 3508: A PHASE 3 TRIAL OF ABT-414 WITH CONCURRENT CHEMORADIATION AND ADJUVANT TEMOZOLOMIDE IN PATIENTS WITH EGFR-AMPLIFIED NEWLY DIAGNOSED GBM
Authors: Wefel Jeffrey S , Won Minhee , Lassman Andrew , Stern Yaakov , Wang Tony , Aldape Kenneth , Armstrong Terri , Vogelbaum Michael , Sulman Erik , Moazami Golnaz , Macsai Marian , Gilbert Mark , Bain Earle , Blot Vincent , Gan Hui , Preusser Matthias , Ansell Peter , Samanta Suvajit , Kundu Madan , Seidel Clemens , de Vos Filip , Hsu Sigmund , Cardona Andres , Lombardi Giuseppe , Bentsion Dmitry , Peterson Richard , Gedye Craig , Lebrun-Frenay Christine , Wick Antje , Pugh Stephanie , Curran Walter , Mehta Minesh
Published: December 2020

RTOG 3508/AbbVie M13-813/INTELLANCE-1 was a phase 3 trial of depatuximab-mafodotin (depatux-m, formerly ABT-414) that accrued 639 patients with EGFR-amplified newly diagnosed GBM. At the pre-specified interim OS analysis, the futility criteria were met and there was no survival benefit from adding depatux-m to SOC. Pre-specified secondary NCF analyses included time to decline in verbal learning and memory as assessed by the HVLT-R Total Recall based on the reliable change index. Exploratory NCF analyses examined changes in other HVLT-R outcomes over time. As corneal epitheliopathy causing visual impairment is a known toxicity of depatux-m, NCF tests that did not depend on visual acuity were employed. NCF testing occurred at baseline, day 1 of the first cycle of adjuvant depatux-m, every other cycle (i.e., 8 weeks) thereafter, and at progression. Compliance with test completion was 95% at screening and 80%, 70%, 58%, 51%, 47% thereafter through cycle 9. The most common reasons for missing data was site error. Time to HVLT-R Total Recall decline trended worse in the depatux-m arm compared to placebo but the difference was not significant (12 month deterioration: 41.2%, 95% CI: 3.50–47.2 vs 32.4%, 95% CI: 26.6- 38.4, p=0.052). The depatux-m arm, in comparison to the placebo arm, showed greater decline from baseline on the HVLT-R at the following time points: cycle 3 (Total Recall: mean= -1.8, SD=5.7 vs mean= -0.5, SD=5.5, respectively, p=0.046; Delayed Recall: mean= -1.1, SD=3.0 vs. mean= -0.2, SD=2.7, respectively, p=0.01), cycle 7 (Total Recall: mean= -0.6, SD=5.1 vs mean= 1.4, SD=5.0, respectively, p=0.009; Delayed Recall: mean -0.6, SD=3.0 vs. mean= 0.5, SD=2.7, respectively, p=0.01), and cycle 9 (Delayed Recall: mean=-0.4, SD=2.7 vs. mean= 0.8, SD=2.4, respectively, p=0.003). Depatux-m added to concurrent chemoradiation and adjuvant temozolomide was associated with faster time to deterioration and worse episodic learning and memory over time than placebo.
CTNI-55. PREDICTIVE FACTORS FOR HIGH GRADE TRANSFORMATION IN BENIGN MENINGIOMAS
Authors: Hoon Kim Jeong , Yoo Hee Jun
Published: December 2020

OBJECT

Meningiomas are generally slow-growing, benign tumors, most of which are classified as WHO Grade I. Rarely, benign meningiomas may recur after surgery with transformation into WHO Grade II atypical meningiomas. As atypical meningiomas are different from benign meningiomas in terms of clinical course, and prognosis, predicting the transformation is important for patient management. The purpose of the study was to investigate the radiological and pathological factors that predict the risk of tumor progression from benign to atypical meningioma.

METHOD

All patients treated with recurrent meningiomas in whom the tumor showed histopathologically confirmed high grade transformation between 2001 and 2017 were included. To evaluate the predictors for transformation, patients’ medical records for previous benign meningioma before transformation were collected. Each patient was matched with 4 age and sex-matched controls treated with benign meningioma, and were analyzed.

RESULTS

Fourteen patients with high grade transformation were included. The median time interval of transformation was 63 months (range of 19 – 132). Multivariate analysis indicated that increased mitotic index (OR, 10.409, 95% CI, 1.297–83.549, p=0.027) was significant predictive factor of transformation. And prominent peritumoral edema (OR, 33.822, 95% CI, 0.935–223.688, p=0.054) showed relative risk for transformation.

CONCLUSION

Increased mitotic index and prominent peritumoral edema may be predictors for high grade transformation of benign meningiomas. Although these tumors do not meet the criteria for atypical meningioma, they may be required more attentive observation and management than other benign meningiomas.
CTNI-63. PROGNOSTIC FACTORS IN PATIENTS WITH BASAL GANGLIA GERM-CELL TUMORS: A RETROSPECTIVE ANALYSIS OF THE SINGLE CHINESE INSTITUTE EXPERIENCE FROM 2009 TO 2019
Authors: Hu Qingjun , Li Juan , Lai Mingyao , Zhou Cheng , Zhou Zhaoming , Shan Changguo , Cai Linbo
Published: December 2020

OBJECTIVE

To evaluate the clinical factors related to the prognosis of basal ganglia germ cell tumors.

METHODS

A retrospective analysis of 52 cases of the basal ganglia germ cell tumors treated from January 2009 to January 2019 in the department of oncology of Guangdong Sanjiu Brain Hospital. The median age: 12 years (range: 5–32), The median course of disease: 11.7 months (range: 1–54). Thirteen cases were diagnosed by biopsy and 39 cases were diagnosed by elevated tumor markers. There were 31 patients (59.6%) diagnosed with germinomas and 21 patients (40.4%) with non-germ germ cell tumors. Univariate and multivariate survival analysis was performed.

RESULTS

To October 15, 2019, the median follow-up time was 30.4 months (range 2–124 months). The 5-year survival rate was 85%, and the 5-year progression-free survival rate was 84%. Multivariate analysis found whether serum AFP was greater than 100mIU / ml, (with HR: 11.441,95% CI: 2.09–47.66, P = 0.005),the degree of surgical resection(with HR 5.323 (1.19–23.812), P = 0.029), PD as the effect of radiotherapy (HR: 16.53, (1.19–23.81), P = 0.001) were independent prognostic factor affecting survival.

CONCLUSION

The pathological type, degree of surgical resection, and response to initial treatment can all affect survival.
CTNI-64. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY DIFFUSE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM
Authors: Green Richard , Thornton Colleen
Published: December 2020

We report our experience treating 16 patients with newly diagnosed primary diffuse B-cell lymphoma of the central nervous system with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 66 years (y); 8 patients were men and 8 were women. Fourteen had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 4 X 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 12 patients completed initial chemotherapy. Eleven of these 12 went on to transplantation; one patient had early disease progression and did not proceed to transplantation. All 4 patients over 70 y died early after 1–2 cycles; the median age of these was 80 y, and the causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia; the other 11 experienced no serious acute toxicity. One patient had late disease progression; one developed symptomatic leukoencephalopathy. Nine of the 16 patients remain alive. At a median follow-up of 23 months, median time to progression was 421 days and overall survival 564 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 70 y suggests that the regimen may be too toxic for elderly individuals.
CTNI-66. ONE-YEAR FOLLOW-UP DATA OF PHASE I/II STUDY OF TIRABRUTINIB IN PATIENTS WITH RELAPSED OR REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Mishima Kazuhiko , Narita Yoshitaka , Nagane Motoo , Terui Yasuhito , Arakawa Yoshiki , Yonezawa Hajime , Asai Katsunori , Fukuhara Noriko , Sugiyama Kazuhiko , Shinojima Naoki , Aoi Arata , Nishikawa Ryo
Published: December 2020

Primary central nervous system lymphoma (PCNSL) is known as one of the incurable brain tumors. In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the indication of relapsed or refractory PCNSL (rrPCNSL) based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646). In this study, 44 Japanese patients with rrPCNSL were treated with TIR QD at 320 mg, 480 mg, or 480 mg in the fasted condition (480 mg fasted QD). The primary endpoint was overall response rate (ORR) assessed by an independent review committee according to International PCNSL Collaborative Group criteria. We previously reported the results of this study with data cutoff on June 13, 2019 (Nagane et al., the 61st American Society of Hematology Annual Meeting and Exposition in 2019). In the report, 17 of 44 patients were treated with TIR at 480 mg fasted QD which is an approved dose, and had ORR of 52.9%, median progression-free survival of 5.8 months, and median overall survival of not reached (median follow-up: 3.8 months). In 44 patients, ORR was similar among patients harboring either of the oncogenic mutants CARD11, MYD88, CD79B, or wild type. Throughout the whole patients, most common adverse events (AEs) at any grade were rash (32%), neutropenia (23%), leukopenia (18%), and lymphopenia (16%), and grade ≥3 AEs were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). We will present one-year follow-up data of this study at the meeting. As of data cutoff (February 25, 2020), 11 of 44 patients continued to receive TIR, including 6 patients with 480 mg fasted QD. Updated data for OS, duration of response, and time to onset of AEs will also be presented.
CTNI-71. TTFIELDS IN ROUTINE CLINICAL CARE OF NEWLY DIAGNOSED GBM PATIENTS IN GERMANY – FIRST REPORT ON THE FULLY ENROLLED TIGER STUDY POPULATION
Authors: Bähr Oliver , Tabatabai Ghazaleh , Fietkau Rainer , Goldbrunner Roland , Glas Martin
Published: December 2020

OBJECTIVE

Glioblastoma (GBM) is widely treated with surgery, chemoradiation and TTFields in combination with chemotherapy. Since the introduction of TTFields to first-line GBM treatment, prescribing physicians in Germany are interested to gain additional knowledge on the use in clinical practice. The TIGER study was designed to assess the therapy decision making process, safety and efficacy of TTFields in clinical routine, as well as evaluating quality of life (QoL) within 4 months after start of therapy, treatment compliance and duration.

METHODS

This multi-center prospective non-interventional study in Germany (NCT03258021) included newly diagnosed GBM patients eligible for TTFields therapy. Within the study, after receiving introduction to TTFields therapy, patients could decide for or against receiving TTFields. The study was designed to recruit 500 patients for each group, with and without TTFields. Demographic data, QoL and reasons for therapy decision 2–4 months after treatment start are assessed using the EORTC-QLQ-C30/BN-20 and a TTFields questionnaire, respectively, with 18 months follow-up.

RESULTS

At the last data cut-off (31st March, 2020), the median follow-up was 11 months (range: 0–28 months) and 581 (82%) of the 710 recruited patients in the trial had decided for TTFields therapy. According to preliminary analysis, this patient population represents a typical GBM population regarding median age (59 years, range: 19.0–85.0), gender (37 % female), median KPS (90, range: 40–100) and MGMT promoter methylation status (44% methylated). In this population 49 % received complete resection, 33 % partial resection and 19 % biopsy.

CONCLUSION

The TIGER study allows prospective and systematic analysis of TTFields treatment decision making and use of typical GBM patient population in routine clinical care. In addition, the study allows the evaluation of compliance and treatment duration. Here, we will present an updated analysis of the TIGER study.