bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-25. PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTION-ENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA
Authors: Bruce Jeffrey , Spinazzi Eleonora , Lassman Andrew , Iwamoto Fabio , Welch Mary , Banu Matei , Argenziano Michael , Upadhyayula Pavan , Agar Nathalie Y R , Humala Nelson , Marie Tamara , Pereira Brianna , Sudhakar Tejaswi , Mahajan Aayushi , Neira Justin , Lignelli-Dipple Angela , Grinband Jack , Sims Peter , D’Amico Randy , Canoll Peter 
Published: December 2020

Abstract

OBJECTIVES
Convection-enhanced delivery (CED) provides pharmacokinetic advantages over systemic delivery for achieving cytotoxic drug levels into targeted regions of the brain. A major shortcoming of CED has been the need to limit treatment duration because of infection risks associated with external pumps. We engineered a subcutaneously implanted catheter-pump construct for prolonged CED which was successfully tested in a large animal model and then approved by the FDA for a Phase Ib clinical trial with topotecan in patients with refractory glioblastoma (IND 131889).

METHODS
Five patients with recurrent glioblastoma underwent surgical implantation of a subcutaneous pump and catheter that infused intracerebral topotecan over 30 days. Gadolinium was co-infused as a surrogate tracer and advanced non-invasive radiographic imaging was used to monitor drug distribution and pharmacological effects. Tissue from multiple radiographically-localized regions of each tumor and surrounding brain was procured pre-treatment at the time of catheter implantation and then post-treatment when tumors were surgically resected. Tissue was used for drug level measurements and advanced molecular, genomic and cellular analysis of treatment effects.

RESULTS
Treatments were successfully completed in all five patients without significant complications. The safety and tolerability of treatment was validated by quality-of-life measures and neurological assessments. Noninvasive imaging demonstrated large and stable drug distribution volumes. Comprehensive tissue analysis demonstrated effective targeting of mitotically active tumor cells while sparing neurons.

CONCLUSIONS
We engineered a subcutaneously implanted catheter-pump construct for chronic CED that was successfully tested in a Phase Ib clinical trial with topotecan in recurrent glioblastoma patients. Analysis of pre- and post-treatment tissue showed significant anti-tumor activity from topotecan that was not harmful to normal brain. Chronic CED combined with non-invasive real time drug distribution monitoring provides a safe and effective glioma strategy suitable for clinical use.
CTNI-32. PHASE I/II STUDY OF TEMOZOLOMIDE PLUS NIMUSTINE CHEMOTHERAPY FOR RECURRENT MALIGNANT GLIOMAS: KYOTO NEURO-ONCOLOGY GROUP
Authors: Aoki Tomokazu , Arakawa Yoshiki , Ueba Tetsuya , Oda Masashi , Nishida Namiko , Akiyama Yukinori , Aoki Tomokazu , Iwasaki Koichi , Mikuni Nobuhiro , Miyamoto Susumu 
Published: December 2020

Abstract
The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.
CTNI-35. SURVIVAL OUTCOME AND PROGNOSTIC FACTORS IN ANAPLASTIC OLIGODENDROGLIOMA: A SINGLE-INSTITUTION STUDY OF 95 CASES
Authors: Shin Dongwon , Kim Young Hoon 
Published: December 2020

Abstract

OBJECTIVE
Anaplastic oligodendroglioma (AO) is a rare intracranial malignant neoplasm and its treatment remains challenging. The aim of this study was to evaluate prognostic factors including surgical, radiographic, and histopathologic analyses in AO patients.

METHODS
We reviewed the electronic records of 95 consecutive patients who underwent surgical procedures and were diagnosed with AO from 1998 to 2018. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Univariate and multivariable analyses included clinical, histopathological, and radiographic prognostic factors. Subgroup analysis was performed in isocitrate dehydrogenase (IDH1/2)-mutant and 1p/19q-codeleted patients.

RESULTS
The median PFS and OS were 24.7 months and 50.8 months, respectively. The progression-free 1-, 3-, 5-, and 10-year survival were 75.8%, 42.9%, 32.4%, and 16.4%, respectively. Furthermore, the overall 1-, 3-, 5-, and 10-year survival were 98.9%, 76.9%, 42.9%, and 29.7%, respectively. The median PFS and OS of the IDH1/2-mutant and 1p/19q-codeleted patients were 54.2 and 57.8 months, respectively. Age under 60, frontal lobe location, weak enhancement, gross total resection (GTR), lower Ki-67 index, 1p/19q codeletion, and IDH1/2 mutations were associated with a favorable outcome. Among them, IDH1/2 mutation was the only variable related to better PFS and OS in multivariable analysis. GTR was associated with favorable outcomes in the subgroup analysis.

CONCLUSIONS
IDH1/2 mutation status was the most important prognostic factor in AO patients. Additionally, in the subgroup analysis, GTR showed better prognosis for IDH1/2-mutant and 1p/19q-codeleted patients.
CTNI-41. 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: December 2020

Abstract

BACKGROUND
Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells.

METHODS
Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm I. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 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 and level -1 was 5 mg twice daily. Arm two was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT 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 over 6 weeks.

RESULTS
30 patients were randomized to Arm I and 16 to arm II. There was one partial response in the methylated Arm and one partial response in the unmethylated arm. The maximum tolerated dose of Ruxolitinib was 20 mg BID in both methylated and unmethylated arm. There were 14 incidences of Grade 3 toxicity including respiratory distress, seizure, gait disturbance, weakness, thrombocytopenia, cognitive disturbance, urinary retention, and bacterial meningitis. There were 4 incidences of Grade 4 toxicity including seizure, respiratory distress, somnolence and thromboembolic events.

CONCLUSION
This is an ongoing clinical trial and final results will be presented once the trial is complete. We will perform single cell sequencing on good and poor responders, that data will be presented in the meeting.
CTNI-46. A PHASE II TRIAL OF TUMOR TREATING FIELDS (TTFIELDS) CONCOMITANT WITH RADIOSURGERY FOR THE TREATMENT OF RECURRENT, BEVACIZUMAB-NAÏVE GLIOBLASTOMA
Authors: Harat Maciej , Blok Maciej , Adamczak-Sobczak Magda , Szymanski Pawel , Miechowicz Iza , Malkowski Bogdan 
Published: December 2020

Abstract

BACKGROUND
Almost all GBM patients experience recurrent disease, and median survival after recurrence is 6 months. A phase III trial conducted to test safety and efficacy of TTFields alone versus chemotherapy (including bevacizumab) in recurrent GBM showed improved PFS at six months and one-year survival was 20% in both treatment arms. Stereotactic radiosurgery (SRS), another treatment option recommended at recurrence, has limitations due to the invasive nature of glioblastoma. TTFields may decrease the tumor aggressiveness outside the target area potentially by multiple pathways, including immunogenic cell death and DNA repair inhibition sensitizing to radiation. We hypothesize that combined SRS and TTFields will be complementary, improving outcomes with minimal toxicity.

METHODS
In this open-label, phase II trial 40 participants with recurrence will be treated with SRS and TTFields, starting in 2020. Recurrence will be defined on FET-PET or MRI using RANO criteria. At least 6 months between the end of the first course of radiotherapy and SRS is mandatory with recurrent tumor visible on FET-PET and/or MRI, with the maximum diameter &lt; 5 cm by either technique. SRS must be delivered within 7 days of TTFields start. A 5-day SRS regimen is allowed. TTFields should be interrupted only during SRS. The sample size of the study was calculated for the comparison of survival against a historical control. With 40 patients followed until death, there is at least an 80% ability to detect a 19% difference in one-year survival rate and 17% difference in ORR (p=0.05) compared to the EF-11 clinical trial. The one-year survival and ORR rate were seen in 20% and 14% of TTFields patients in the historical control. Overall survival will be stratified by volume, PET-based treatment, SVZ invasion, MGMT methylation status, time to first progression, and TTFields compliance. Estimated study primary completion date is July 2023.
CTNI-49. PHASE I STUDY OF MGMT-P140K TRANSFECTED HEMATOPOETIC PROGENITOR CELLS COMBINED WITH TMZ/O6BG DOSE ESCALATION FOR NEWLY DIAGNOSED, UNMETHYLATED GLIOBLASTOMA: TOLERANCE AND EVIDENCE OF SURVIVAL BENEFIT
Authors: Sloan Andrew E , Fung Hua , Reese Jane , Rgers Lisa , Murphy Christopher , Lazarus Hillard , Dropulic Boro , Gerson Stanton 
Published: December 2020

Abstract

INTRODUCTION
GBM has median survival of 12 months despite current SOC therapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene. The MGMT inhibitor O6-benzylguanine (BG) demonstrated efficacy in depleting MGMT but approach led to unacceptable bone marrow toxicity and has thus been abandoned. We hypothesized that chemoprotection of hematopoietic HPC with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity, coupled with low affinity for BG would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. A phase I trial was performed to test this hypothesis.

METHODS
10 adults with newly diagnosed MGMT unmethylated, IDH-1 WT, GBM underwent standard surgery and radiation, followed by transplantation with autologous CD34+ HPC transfected with MGMT-P140K using a lentiviral vector. We tested tolerance and efficacy of three different paradigms for conditioning bone marrow and re-infusion of HPC.

RESULTS
Treatment was moderately toxic with 3/10 patients suffering grade 3–4 hematologic toxicity; no high grade non-hematologic toxicity was observed. Viral transduction rates ranged from 3–75% and were clearly improved in Arm III utilizing BCNU conditioning and intra-patient dose escalation of TMZ/O6GB. In patients tolerating 3 cycles or more, P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2–3) myelosuppression consistent with chemo-protection as hypothesized. Median PFS and OS was 24 and 33 months respectfully, and three patients in Arm III were progression free at 36 months with one progression free at 48 months. OS exceeded RPA & Nomogram predicted survival by 3.6-fold, suggesting clinical benefit. Viral insertion site analysis demonstrate no clonal dominance.

CONCLUSIONS
P140K-MGMT transfected HPC enables TMZ/ BG dose escalation with acceptable toxicity and increased survival in a small cohort of selected patients. A U-01 funded phase II study is ongoing at UH and NIH.
CTNI-50. NEUROCOGNITIVE FUNCTION (NCF) OF THE PHOTON COHORT IN NRG-BN001
Authors: Wefel Jeffrey S , DeMora Lyudmila , Gondi Vinai , Tsien Christina , Chenevert Thomas , Gilbert Mark , Omuro Antonio , Cao Yue , Srinivasan Ashok , Rogers Leland , Shi Wenyin , Nedzi Lucien , Chan Michael , Suh John , Battiste James , Mishra Mark , Shivnani Anand , Movsas Benjamin , Mehta Minesh 
Published: December 2020

Abstract
NRG BN001 is an ongoing randomized phase II trial of dose-intense (DI-RT) versus standard dose photon-based radiation therapy (SD-RT) with temozolomide (TMZ) for newly diagnosed glioblastoma. We report preliminary results of Group 1, DI-RT delivered with IMRT while SD-RT could be 3DCRT or IMRT. Group 2, DI-RT delivered with proton therapy, continues to accrue. From 10/2014 to 7/2018, 229 patients were eligible and randomized. Differences in overall survival following DI-RT versus SD-RT were not significant. Patients were scheduled to complete NCF testing at baseline, cycle 3 (within 7 days of cycle 4), and cycle 12 (day 22–28 of cycle 12, or 60 weeks from completion of chemoradiation). At baseline, 93–94% of eligible patients completed NCF testing. Compliance for evaluable patients at cycle 3 and cycle 12 was 66–68% and 51–54%, respectively, across the battery of NCF tests. The most common reasons for missing data were patient refusal (cycle 3: 14%, cycle 12: 22–23%) and institutional error (cycle 3: 9–10%, cycle 12: 14–15%). A prespecified secondary endpoint analysis was conducted to evaluate differences in NCF between SD-RT and DI-RT based on the Clinical Trial Battery Composite (CTB COMP), which is the mean of the standardized scores from the NCF test battery (HVLT-R, TMT, COWA). There was no statistically significant between arm difference in change from baseline on the CTB COMP at cycle 3 (DI-RT vs SD-RT mean/SD, 0.0 +/- 1.3 vs -0.3 +/- 1.5, p=0.370, Cohen’s d=0.22) or cycle 12 (DI-RT vs SD-RT mean/SD, 0.2 +/- 1.7 vs 0.2 +/- 1.1, p=0.977, Cohen’s d=0.01). A mixed effects longitudinal model of the CTB COMP yielded a non-significant time by treatment effect interaction (p=0.216). There were no significant differences in change scores between arms on any NCF test at cycles 3 or 12. NCF outcomes were similar for photon-based SD-RT and DI-RT.
CTNI-52. PHASE II STUDY OF EVEROLIMUS (AFINITOR®) FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA
Authors: Bowers Daniel , Karajannis Matthias , Gardner Sharon , Su Jack , Baxter Patricia , Partap Sonia , Klesse Laura 
Published: December 2020

Abstract
Preclinical studies suggested that the mTOR signaling pathway could be a potential therapeutic target in childhood ependymomas. As a result, a phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis that inhibition of the mTOR pathway would result in tumor responses for children with recurrent and/or progressive ependymoma. Eleven patients [sex: 4 females (36.4%); median age: 8 years (range: 2 – 15 years); race: 9 white and 2 other; prior therapies: median 6 (range: 3 – 9)] were enrolled on the study. The primary tumor location for 10 participants was the posterior fossa; the primary location of the remaining tumor was the cervical spine. All patients were treated with oral everolimus 4.5 mg/m2/day (each cycle = 28 days) that was titrated to achieve serum trough levels of 5 – 15 ng/mL. Overall, everolimus was well tolerated; adverse events were grade 1 – 2 and consistent with its previously established safety profile in children. No objective tumor responses were observed. All patients discontinued therapy due to tumor progression after a median of 2 cycles of therapy (1 cycle = 2; 2 cycles = 6; 3, 4, and 8 cycles = 1 each). This study does not support the use of everolimus for children with recurrent or progressive ependymoma.
CTNI-57. LOW-RISK MENINGIOMA: OUTCOMES FROM NRG ONCOLOGY/RTOG 0539
Authors: Rogers Leland , Pugh Stephanie , Vogelbaum Michael , Perry Arie , Ashby Lynn , Modi Jignesh , Alleman Anthony , Youssef Emad , Braunstein Steve , Bovi Joseph , de Groot John , Whitton Anthony , Lindhorst Scott , Taylor Nicholas , Shrieve Dennis , Shu Hui-Kuo , Machtay Mitchell , Mishra Mark , Robinson Clifford , Mehta Minesh 
Published: December 2020

Abstract

PURPOSE/OBJECTIVE(S)
Outcomes of low-risk meningioma from NRG/RTOG-0539.

MATERIALS/METHODS
Outcomes of the intermediate and high-risk cohorts from this phase II trial have been previously reported. Low-risk (Group 1: new WHO grade 1) patients were observed after gross total (GTR) or subtotal resection (STR). Progression-free (PFS) and overall (OS) were estimated using Kaplan-Meier. CTCAE v3 AE grading was employed.

RESULTS
Group 1 enrolled 65 patients. 56/60 (93.4%) evaluable patients had investigator-reported GTR. Sufficient imaging for central confirmation was available for 48: GTR in 35 and STR in 13. Median follow-up for living patients was 9.1 years (y). For all evaluable patients 5 and 10 y PFS and OS rates were 89.4 and 85.0%, and 98.3 and 93.8%, respectively. For patients with centrally-confirmed STR, 5/10 y PFS rates were 72.7/72.7%, with 100% 10 y OS. For patients with centrally-confirmed GTR, 5/10 y PFS and OS rates were 94.3/87.6 and 97.1/90.4%, respectively. For combined study cohorts (Groups 1–3) with central-review (n=104), the median centrally-measured largest pre-operative tumor dimension was 4.3 cm (range 0.4 - 14.4); this was significantly associated with OS (hazard ratio [HR]=1.03, p=0.021) and PFS (HR=1.03, p=0.003). No grade 4 or 5 protocol-related adverse events were reported. There were 1 grade 3 (infection), 4 grade 2 (neurologic, pulmonary, gastrointestinal, and pain), and 5 grade 1 (3 neurologic, 1 occulovisual, 1 constitutional) events from 5 patients.

CONCLUSION
These results prospectively validate high OS and PFS outcomes for low-risk meningioma managed with surgery followed by observation, but raise questions regarding optimal management following STR (5 y PFS 72.7%), a subcohort that could potentially benefit from adjuvant therapy. However, we identified considerable discordance between local and central assessments of resection extent. Pre-operative tumor size has a significant impact on OS and PFS. Supported by: U10CA180868 and U10CA180822 from the National Cancer Institute (NCI)
CTNI-60. NEOAJUVANT CHEMOTHERAPY FOLLOWED BY CRANIOSPINAL IRRADIATION FOR INTRACRANIAL NGGCTS: CLINICAL OUTCOMES AND AGE-STRATIFIED TOXICITIES IN A COHORT OF 111 PATIENTS
Authors: Wen Lei , Li Juan , Lai Mingyao , Zhou Zhaoming , Hu Qingjun , Shan Changguo , Cai Linbo , Zhou Cheng 
Published: December 2020

Abstract

BACKGROUND
Intracranial non-germinomatous germ cell tumors (NGGCTs) are rare tumors with limited studies available worldwide. Despite significantly improved survivals, there are still approximately 30% of patients experience relapse and require salvage treatment. This study aimed to access the clinical-pathological features and prognostic factors with specific interests to recurrence as well as adverse effects.

METHODS
From June 2005 and December 2018, 111 consecutive intracranial NGGCTs patients (87 localized stage and 24 metastatic stage) diagnosed based on histological confirmation, or alternatively by clinical presentation, radiological outcomes and elevated tumor markers were retrospectively analyzed.

RESULTS
After a median follow-up of 46.2 months, Three- and five- year OS were 83.5% ± 3.9% and 78.6% ± 5.1%, respectively. Three- and five- year EFS were 71.0% ± 4.8% and 64.7% ± 5.7%, respectively. Patients received craniospinal irradiation (CSI) integrated combined treatment yielded superior 3-year OS (P=0.007), EFS (P=0.002), and relapse rate (P=0.004) compared to those without CSI. A combination of minimum 4 cycles of induction chemotherapy and CSI integrated approach was the independent prognostic factor (P=0.007) conferring favorable 3-year OS and EFS of 93.9%±3.5% and 84.0%±5.4%, respectively. Poor prognosis of histological subtypes were particularly benefit from this treatment modality (P&lt; 0.001). Age-thresholds for risking therapy-related thrombocytopenia and growth impairment by ROC analysis were 14 (AUC=0.752, P&lt; 0.0001) and 11.5 (AUC=0.806, P&lt; 0.01) yr., respectively.

CONCLUSIONS
Our study suggested that multimodal approach consisting of ≥4 cycles of induction chemotherapy and CSI plus focal boost with or without second-look surgery was recommended for NGGCTs. However, CSI should be used with caution when patients &lt; 11.5-yr due to growth impairment. More precise risk stratifications are highly demanded for delivery of the most appropriate management in the future.