bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATIM-16. VALIDATION OF RESPONSE TO NEOADJUVANT ANTI-PD-1 IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA
Authors: Chow Frances , Mochizuki Aaron , Lee Alexander , Galvez Mildred , Orpilla Joey , Everson Richard , Liau Linda , Cloughesy Timothy , Prins Robert 
Published: November 2019

Abstract

BACKGROUND
Recurrent glioblastoma has a poor median overall survival despite multimodal treatment. The use of pembrolizumab, an anti-PD-1 monoclonal antibody, demonstrates promise, including improved overall survival and increased immune response, when used in the neoadjuvant setting.

METHODS
We evaluated 13 patients with surgically accessible recurrent glioblastoma who were treated at the University of California, Los Angeles with neoadjuvant checkpoint inhibition prior to tumor resection. Combining data with our previously published multi-center study, we followed this cohort prospectively, performing tumor gene expression to validate the immune response and improved survival following neoadjuvant therapy with pembrolizumab.

RESULTS
When combined with findings from our prior study, patients in the neoadjuvant group (n = 27) had an overall survival of 400 days, whereas those in the adjuvant-only group (n = 19) had a median overall survival of 228 days by Kaplan-Meier estimator (P = 0.029, log-rank test). Progression-free survival in the neoadjuvant group was 108 days, whereas in the adjuvant-only group it was 72.5 days (P = 0.017, log-rank test). In elastic net penalized Cox proportional hazards regression, neoadjuvant anti-PD-1 blockade continued to be associated with improved overall survival, with a hazard ratio of 0.11 (P=0.003, log-rank test). Bulk tumor gene expression corroborates our previously described pattern of increased T-cell- and IFN-g-related gene expression, decreased cell-cycle-related signatures and their association with clinical response. Additionally, epigenetic regulation inversely correlated with clinical response.

CONCLUSIONS
Our findings support the neoadjuvant timing of PD-1 blockade in enhancing local immune responses and prolonging overall- and progression-free-survival. Correlative biological studies suggest a potential role for cell-cycle-related gene expression as a biomarker to predict response to therapy. Continued data collection and the addition of patients to the neoadjuvant arm of the trial, will be crucial to determine the potential role of checkpoint inhibition in the treatment of this deadly disease.
ATIM-20. A RETROSPECTIVE STUDY EVALUATING THE SAFETY AND SURVIVAL OF THE COMBINATION OF PD-1 IMMUNE CHECKPOINT BLOCKADE AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA
Authors: Friedman Joshua , Hormigo Adilia 
Published: November 2019

Abstract

INTRODUCTION
Immune checkpoint inhibitors (ICI) have demonstrated clinical efficacy in a variety of cancers. It is known that cancer including glioblastoma (GBM) induces an immunosuppression. Bevacizumab by normalizing blood vessels in the tumor can facilitate immune surveillance and potentially improve the efficacy of ICI in GBM patients. We analyze GBM patients with recurrent disease treated with ICI and bevacizumab.

METHODS
We retrospectively review records of patients diagnosed with recurrent GBM treated at our institution with Pembrolizumab or Nivolumab and bevacizumab and evaluate for tolerance and outcomes.

RESULTS
Twenty-one patients, 12 men and 9 women with median age 62 (range 36–78) and KPS 70 (range 60–90) were treated with a median of 10 ICI cycles (range 4–29) and 5 of bevacizumab (range 0–21). A total of 8 patients (38%) had immune-related adverse events (IRAE): 3 grade 1, 3 grade 2 and 2 grade 3. A patient with pneumonitis required cessation of ICI. Median OS for the 21 patients was 22 months (range 6–41). The 7 patients that had MGMT detected in their tumors had a median OS of 27 months (range 23–41) compared to a survival of 21 months (range 6–24) for the 13 patients that had MGMT undetected. One had undetermined MGMT and her OS was 21 months. The median survival for all the patients from onset of ICI was 10 months (range 1–25) and 10 of them (47.6%) survived > 12 months.

DISCUSSION
The development of IRAE was common but self-limiting, allowing continuation of the treatment in all but one patient. The combination of ICI and bevacizumab increased survival. Our data needs to be interpreted with caution, as it is a retrospective analysis of a small group of patients. However, these results warrant prospective studies using the combination of ICI and bevacizumab to treat recurrent GBM.
ATIM-36. TEM-GBM-001 STUDY: AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2 & ADMINISTERED TO PATIENTS WITH GLIOBLASTOMA & AN UNMETHYLATED MGMT PROMOTER
Authors: Finocchiaro Gaetano , Gentner Bernhard , Ciceri Fabio , DiMeco Francesco , Legnani Federico , Eoli Marica , Pollo Bianca , Farina Francesca , Zambanini Andrew , Mazzoleni Stefania , Russo Carlo , Naldini Luigi 
Published: November 2019

Abstract

BACKGROUND
Most patients with GBM & an unmethylated O-6-methylguanine-DNA methylase (MGMT) gene promoter, have a poor prognosis with approximately 20% of patients surviving to 2 years. Poor prognosis is likely related to factors including a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) & microglia. A subset of tumor-infiltrating macrophages characterized by expression of the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis & are infrequently found in normal organs. Tie2 is significantly upregulated upon homing to tumors. Gene therapy technology has allowed TEMs to be used as carriers for the local and tumor restricted release of interferon-α (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Cell-based delivery of IFN into the TME by TEMs is expected to provide efficacy, taking advantage of pleiotropic anti-tumor effects & avoiding tolerability issues associated with systemic IFN treatment. We are currently conducting a Phase I/IIa clinical study in Milan (INCB & OSR) to evaluate this therapeutic approach (Temferon) in 21 patients with GBM & unmethylated MGMT promoter (EudraCT Number 2018-001404-11). Eligible patients are identified immediately after first surgical resection. After screening, harvesting of HSPCs occurs followed by 6 weeks of radiotherapy. Non-myeloablative conditioning consists of BCNU & thiotepa followed by administration of non-manipulated HSPCs and Temferon.

RESULTS
In Part A of the study, 3 cohorts of 3 patients will receive escalating doses of Temferon. After Part A, a single dose of Temferon will be studied in a further 12 patients (Part B). Criteria for study eligibility are the same for both Part A and Part B. Part A is ongoing with the first 2 patients recruited (June 2019) and Temferon is scheduled for administration. An update on the status and progress of the study will be provided.
ATIM-39. PHASE 2 OPEN-LABELED STUDY OF ADJUVANT TEMOZOLOMIDE PLUS TUMOR TREATING FIELDS PLUS PEMBROLIZUMAB IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (2-THE-TOP)
Authors: Tran David , Warren Sonisha , Allen Anne , Sampson Deborah , Chen Dongjiang , Thomas Nagheme , Greene Valerie , Rahman Maryam , Ghiaseddin Ashley 
Published: November 2019

Abstract

BACKGROUND/OBJECTIVE
Tumor treating Fields (TTFields) plus maintenance temozolomide is an approved standard treatment for newly diagnosed Glioblastoma (GBM). TTFields are alternating electric fields of low intensity and intermediate frequency delivered non-invasively via transducer arrays to tumor region. Immune checkpoints have not been studied widely in newly diagnosed GBM patients. TTFields combined with temozolomide elicit anti-mitotic effects on proliferative cancer cells and augment recruitment of immune effector cells specific for glioma cells to the tumor microenvironment where pembrolizumab further potentiates the immune reaction to achieve a synergistic therapeutic effect. This study [NCT03405792] will determine if adding pembrolizumab to TTFields and maintenance temozolomide (triple combination) increases progression-free survival (PFS) in patients with newly diagnosed GBM versus historical control (EF-14).

METHODS
This study will enroll patients (N=24) with pathologic diagnosis of newly diagnosed GBM WHO grade 4, > 18 years after maximal surgery or biopsy followed by radiation therapy with adjuvant temozolomide (Stupp protocol). The primary endpoint is increases in PFS compared to historical control data (EF-14). Secondary endpoints include: toxicity and tolerability of the triple combination; overall survival and response rates versus historical data; augmentation of TTFields-initiated glioma-specific immune reaction by pembrolizumab. Exploratory endpoints include: metabolomics signature of immune activation by TTFields and TTFields plus pembrolizumab in serum and urine, and correlation of mutation burden in primary tumor samples with response to pembrolizumab plus TTFields. We assumed an accrual period of 12 months, an accrual rate of 2 patients per month, an additional 18 months of follow-up, and proportional hazards. Per shape parameter estimate of k=0.88 with empirical 95% confidence interval (0.82, 0.95) obtained via simulation of historical control data, a sample size of 24 patients should detect an improvement in PFS of 6 to 8 months with 80% power and a 1-sided significance level of 0.05 (Wu and Xiong, 2014).
ATIM-42. DOUBLE-BLINDED, PLACEBO CONTROLLED PHASE 2 STUDY OF ERC1671 IN RECURRENT GLIOBLASTOMA: OS CORRELATIONS WITH INITIAL AND MAXIMUM CD4+T LYMPHOCYTE COUNT IN THE PERIPHERAL BLOOD
Authors: Bota Daniela , Taylor Thomas , Xiao-Tang Kong , Fu Beverly , Alsharif Mohamad , Pretto Chrystel , Strik Ankie , Schijns Virgil , Stathopoulos Apostolos 
Published: November 2019

Abstract
Standard therapy for recurrent GBM is bevacizumab, a monoclonal VEGF inhibitor that targets tumor vascularization. The response to bevacizumab is transient and short-lived (4–6 months) after which patients typically develop progressive physical and mental debilitation culminating in death. ERC1671 is an allogeneic/autologous therapeutic vaccine – composed of whole, inactivated tumor cells mixed with tumor- cell lysates. The hypothesized action of ERC1671 is to potentiate the patients’ immune system against the tumor. Goals of this ongoing, phase 2 study are to to determine the safety and effectiveness (over-all survival) of ERC1671 in combination with GM-CSF and cyclophosphamide as an add-on treatment to bevacizumab at the time of GBM recurrence. To date 16 recurrent bevacizumab-naïve GBM patients have been randomized to ERC1671/GM-CSF/Cyclophosphamide + Bevacizumab or Placebo + Bevacizumab. Median age is 56.5 (39–74), 5 patients (31%) are female, and average KPS is 83 (70–100). Thirteen patients are deceased and were unblinded at the time of further progression: 5 received vaccine, 7 received placebo, and 1 is non-evaluable due to discontinuation before completing 1 cycle. Median overall survival of the deceased patients treated with ERC1671 + Bevacizumab was 328 days (10.9 months), compared to 245 days (8.2 months) for patients treated with Placebo + Bevacizumab. While sparse, the data to date suggest pre-treatment and maximal CD4+T lymphocyte count in the peripheral blood correlate with OS more strongly in the ERC1671 group than in the placebo group. First clinical results for toxicity show no difference in the distribution of AEs between the Vaccine and Placebo groups, with no Gr4/Gr5 AEs in either group. The phase 2 randomized, double-blinded study is ongoing with the addition of 2 subsites.
ATIM-46. A MULTICENTER, PHASE I, TRIAL OF RADIATION, TEMOZOLOMIDE AND RRx-001 FOLLOWED BY MAINTENANCE TEMOZOLOMIDE WITH OR WITHOUT RRx-001 IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Aiken Robert , Fine Howard , Butowski Nicholas 
Published: November 2019

Abstract

BACKGROUND
RRx-001 is an aerospace-derived radiochemosensitizer with minimal toxicity. The purpose of this trial was to establish the safety of RRx-001 plus radiotherapy and temozolomide and to look for signals of enhanced anti-tumor activity in patients with newly diagnosed glioblastoma.

METHODS
In this non-randomized trial called G-FORCE-1 (NCT02871843), 18 newly diagnosed, histologically verified glioblastoma patients were enrolled. The treatment plan included 6 weeks of temozolomide and radiotherapy with RRx-001 followed by maintenance temozolomide with or without RRx-001. Four cohorts of 3 patients received intravenous RRx-001 at doses of 0.5,1,2, or 4 mg/week during radiotherapy only. An additional two cohorts of 3 patients received 4 mg/week of RRx-001 during radiotherapy and 0.5 mg/week of RRx-001 during temozolomide maintenance.

RESULTS
There were no grade 3 or 4 dose-limiting toxicity events (DLT) that appeared related to RRx-001 for the dose range of 0.5 to 4 mg/week. A maximum tolerated dose was not defined. The main adverse event related to RRx-001 was injection-site reaction. The overall response rate was 16.7% (3 PR out of 18) pending confirmation since pseudoprogression was prevalent, and the disease control rate was 61.1% (3 PR, 8 SD out of 18). The median time to tumor progression (95% confidence interval lower limit of 9.2 months to NR) and the median overall survival time (95% confidence interval lower limit of 12.9 months to NR) have not been reached after a median follow-up time of 10.3 months (range: 2.7 to 25 months.).

CONCLUSION
RRx-001 was well tolerated with concurrent temozolomide and radiotherapy and with temozolomide maintenance in 18 newly diagnosed glioblastoma patients. The primary objective to determine the MTD of RRx-001 was not met, since no DLTs occurred. The median time to progression and overall survival time have not been met after a median follow up time of 10.3 months.
ACTR-04. BIOMARK: A PHASE II STUDY OF BEVACIZUMAB BEYOND PROGRESSION FOR NEWLY DIAGNOSED GLIOBLASTOMA: SAFETY, EFFICACY AND PROSPECTIVE BIOMARKER ANALYSIS
Authors: Ichimura Koichi , Nagane Motoo , Kato Mamoru , Narita Yoshitaka , Aoki Tomokazu , Tanaka Shota , Mukasa Akitake , Wakabayashi Toshihiko , Uzuka Takeo , Nakamura Hideo , Arakawa Yoshiki , Suehiro Satoshi , Nakada Mitsutoshi , Kitahara Mai , Hibiya Yuko , Narushima Daichi , Onuki Ritsuko , Morita Satoshi , Nishikawa Ryo 
Published: November 2019

Abstract

BACKGROUND
Clinical benefit of continuing bevacizumab beyond progression is unknown in glioblastomas. A biomarker analysis of the AVAglio trial suggested that proneural subtype of IDH-wildtype glioblastoma patients may receive an OS benefit from a first-line bevacizumab. This study explored biomarkers that may predict survival of glioblastoma patients treated with concurrent irradiation, temozolomide (TMZ) and bevacizumab (BEV) followed by BEV beyond progression (BBP).

METHODS
In the primary protocol, newly diagnosed GBM patients aged 20–75 received concurrent TMZ (75 mg/m2, D1-42), irradiation (2 Gy x 5 QW x6) and BEV (10 mg/kg Q2W x 3) followed by ≤12 4-week cycles of TMZ (150–200 mg/m2, D1-5) plus BEV (10 mg/kg, D1 and 15) and then 2 or 3-week cycles of BEV monotherapy (15 or 10 mg/kg). Upon PD/recurrence during the primary protocol, the patients were subjected to the secondary protocol with 2-3-week cycles of BEV monotherapy with or without other chemotherapeutic agents (BBP). The primary endpoint was 2-year survival rate in patients receiving BBP. Fresh-frozen tumor specimen were subjected to genome-wide methylation, copy number, expression and mutation analysis. A subset of the control cohort of the AVAglio study was used as BEV-negative control.

RESULTS
A total of 94 GBM patients were enrolled at 39 centers between June 2015 and January 2017. Efficacy analyses were based on the full analysis set (FAS) cohort (N=90), excluding non-GBM diagnosis by central review. The median time to PD/recurrence was 453 days in the FAS and 348 days in patients receiving BBP (N=27). The 2-year survival rate (90% CI) was 52.4% (43.3–60.8%) and 28.8% (15.4–43.7%), respectively. The 2-year survival rate in GBM patients receiving BBP was lower than expected (50%). That of proneural and mesenchymal IDH-wt GBM in the biomarker cohort (n=83) were 52.9% (31.7–70.3%) and 56.6% (41.6–69.1%), respectively. A full biomarker analysis will be presented.
ACTR-26. SAFETY AND EFFICACY OF BEVACIZUMAB PLUS TTFIELDS IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM): DATA FROM A PHASE II CLINICAL TRIAL
Authors: Fallah Jaleh , Chaudhary Rekha , Rogers Lisa , (Auston) Wei Wei , Brewer Cathy , Peereboom David , Ahluwalia Manmeet 
Published: November 2019

Abstract

BACKGROUND
Studies of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients with recurrent GBM. In an open label, single-arm, phase 2 clinical trial, the safety and efficacy of the combination of bevacizumab and TTFields was studied in patients with recurrent GBM.

METHOD
Bevacizumab-naïve patients with histologically confirmed GBM or other grade IV glioma, with recurrent disease after radiotherapy and temozolomide chemotherapy, were eligible. Bevacizumab dose was 10mg/kg intravenously every 2 weeks and TTFields was worn at least 18 hours daily. The primary endpoint was safety, progression-free survival at 6 months (PFS6) and overall survival at 12 months (OS12). Treatment was continued until disease progression or unacceptable toxicity. Survival outcomes were assessed using the Kaplan-Meier method. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria.

RESULTS
25 patients were enrolled and 23 were eligible for data analysis: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 patients were Caucasian, 1 was African American and 1 of unknown race. Median follow-up was 6.0 months (range 2.4–22). Seven patients (30 %) had disease progression. Median PFS was 9.9 (95% CI: 6.7-NA) months. PFS rate at 6 months (PFS6) was 71% (95% CI: 0.54–0.94). Median overall survival was 9.9 (95%CI 7.3-NA) months. OS rate at 12 months (OS12) was 42% (95%CI 0.24–0.74). 7 patients (30%) had grade 3 toxicity (cough, dysphagia, muscle weakness, hyperglycemia, hypertension, psychosis, seizure, lymphopenia, transaminitis). 1 patient developed grade 4 muscle weakness in the lower extremities.

CONCLUSION
Treatment with the combination of bevacizumab and TTFields in patients with recurrent GBM is safe and feasible and has shown clinical efficacy.
ACTR-30. UPDATED EFFICACY AND SAFETY OF DABRAFENIB PLUS TRAMETINIB IN PATIENTS WITH RECURRENT/REFRACTORY BRAF V600E–MUTATED HIGH-GRADE GLIOMA (HGG) AND LOW-GRADE GLIOMA (LGG)
Authors: Wen Patrick , Stein Alexander , van den Bent Martin , De Greve Jacques , Dietrich Sascha , De Vos Filip , von Bubnoff Nikolas , van Linde Myra , Lai Albert , Prager Gerald , Campone Mario , Fasolo Angelica , Lopez-Martin Jose , Min Kim Tae , Mason Warren , Hofheinz Ralf-Dieter , Blay Jean-Yves , Cho Daniel , Gazzah Anas , Gomez-Roca Carlos , Yachnin Jeffrey , Boran Aislyn , Burgess Paul , Palanichamy Ilan , Gasal Eduard , Subbiah Vivek 
Published: November 2019

Abstract

BACKGROUND
There is a lack of treatment options for HGG and LGG patients. BRAFV600E mutations are uncommon in glioma, with a poor long-term prognosis. Combined BRAF/MEK inhibition extends progression-free survival (PFS) and overall survival (OS) in BRAF V600E–mutated melanoma, non small-cell lung cancer, and anaplastic thyroid cancer.

METHODS
This phase 2, open-label trial (NCT02034110) evaluated dabrafenib (BRAF inhibitor, 150mg BID) plus trametinib (MEK inhibitor, 2mg QD) in patients with BRAF V600E mutations in 9 rare tumor types, including HGG and LGG. Eligible patients had histologically-confirmed recurrent or progressive glioma (LGG:WHO grade 1 or 2; HGG:WHO grade 3 or 4), with HGG patients required to have received radiotherapy and first-line chemotherapy, or concurrent chemoradiation. Treatment continued until unacceptable toxicity, disease progression, or death. Primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety.

RESULTS
Interim analysis (IA) #14 (data cutoff: April 2, 2018) reported additional 3 months follow-up, with 49 patients enrolled (HGG, n=39; LGG, n=10) and 3 patients not evaluable for response. In HGG patients, ORR was 27% (10/37; 95%CI: 13.8%-44.1%), including CR (n=1), PR (n=9), and SD (n=11), with 16 patients currently ongoing treatment. In LGG patients, ORR was 56% (5/9; 95%CI: 26.8%-79.3%), including PR (n=5) and SD (n=4), with 6 patients currently ongoing treatment. OS, PFS, and DOR will be presented (IA#15). In HGG patients, adverse events (AEs) included fatigue (33%), headache (31%), rash (28%), and pyrexia (23%); grade 3/4 AEs included neutropenia (8%) and fatigue (5%). In LGG patients, AEs included headache (70%), fatigue, pyrexia (60% each), nausea, and arthralgia (50% each); grade 3/4 AEs included fatigue (20%).

CONCLUSIONS
Dabrafenib plus trametinib demonstrated promising efficacy in patients with recurrent or refractory BRAF V600E‒mutated HGG or LGG, with manageable AEs and no new safety signals.
ACTR-32. NRG ONCOLOGY RTOG 1205: RANDOMIZED PHASE II TRIAL OF CONCURRENT BEVACIZUMAB AND RE-IRRADIATION VS. BEVACIZUMAB ALONE AS TREATMENT FOR RECURRENT GLIOBLASTOMA
Authors: Tsien Christina , Pugh Stephanie , Dicker adam , Raizer Jeffrey , Matuszak Martha , Lallana Enrico , Huang Jiayi , algan ozer , Taylor Nicholas , Portelance Lorraine , Villano John , T Hamm John , S Oh Kevin , N Ali Arif , Kim Michelle , Lindhorst Scott , Mehta Minesh 
Published: November 2019

Abstract
This study sought to determine whether re-irradiation (ReRT) and concurrent bevacizumab (BEV) improves overall survival (OS) compared to BEV alone in recurrent glioblastoma (GBM). Patients (pts) were randomized 1:1 to ReRT (35 Gy/10 fractions) plus BEV (IV 10 mg/kg q2 wks) vs. BEV alone. With 160 pts, there was 80% power to detect a 31% reduction in death hazard for BEV+RT at a one-sided significance level of 0.10 using a log rank test. OS and PFS were estimated by Kaplan-Meier and HRs estimated by exact binomial distribution. Objective response was assessed using MacDonald and RANO criteria. From 11/2012 to 4/2016, 182 pts were randomized, with 170 eligible, analyzable pts. 11 pts did not receive protocol treatment. Patient characteristics (age, KPS, re-resection rates) were balanced between arms. Median f/u for censored pts was 12.8 months (mos; min-max, 0.03–52.8). BEV+ReRT did not improve OS vs BEV alone, with median OS of 10.1 vs 9.7 mos, (HR=0.98, 95% CI=0.70–1.38, p=0.46). Median PFS for BEV+RT and BEV was 7.1 vs. 3.8 mos, respectively (HR=0.73, 95% CI=0.53–1.0, p=0.051). BEV+ReRT improved 6-mo PFS rate (PFS6): 54 vs. 29%, (HR=0.42, 95% CI=0.34–0.5, p=0.001). Overall, treatment was well tolerated: 5% acute and 0% delayed grade 3+ treatment-related AE. Most patients died from recurrent GBM. CONCLUSION: RTOG 1205 is the first, prospective, randomized multi-institutional study to evaluate the safety and efficacy of ReRT in recurrent GBM using modern RT techniques. Overall, ReRT was shown to be safe and well tolerated. BEV+ReRT did not demonstrate a benefit in OS but an improved PFS6, and clinically meaningful PFS improvement. Molecular correlates of response analyses are ongoing. Funded by U10CA180868, U10CA180822 from the National Cancer Institute.