bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological targeting of CD133 in recurrent glioblastoma: A multi-center phase I translational and clinical study of autologous CD133 dendritic cell immunotherapy.
Authors: Rudnick Jeremy David , Fink Karen L. , Landolfi Joseph C. , Markert James , Piccioni David Eric , Glantz Michael J. , Swanson Steven J. , Gringeri Anthony , Yu John 
Published: September 2018

2059 Background: A hallmark of glioblastoma is the high incidence of tumor recurrence, thought to be triggered by cancer stem cells. These tumorigenic cells are resistant to irradiation and chemotherapeutic agents. The target antigen, CD-133, was chosen because it has been reported as a cancer stem cell antigen overexpressed in glioblastoma tumors and associated with shorter survival. Recent clinical trials suggest that the mean overall survival for these patients is roughly 5-9 months, emphasizing the important unmet medical need in this disease requiring additional strategic approaches. Dendritic cell immunotherapies such as ICT-121 could provide benefit to patients by educating their immune systems to induce the formation of cytotoxic T cells that attack tumor cells bearing the target antigen. In addition to immediate attack on tumor cells present at dosing, a long-term memory response effective against tumor recurrence might be induced. Immunotherapy, such as ICT-121, that targets cancer stem cells could be an important treatment for this disease. Methods: This Phase I multi-center trial of ICT-121 targeting CD133 was designed to assess safety and tolerability (primary endpoint) and to monitor overall survival and progression-free survival (secondary endpoints). ICT-121 is comprised of autologous dendritic cells that are loaded with two HLA-A2 restricted epitopes of the CD133 antigen. CD133 is overexpressed on glioblastoma cancer stem cells. The HLA-A2 patients that had undergone resection for recurrence of glioblastoma were treated with ICT-121 once a week for 4 weeks during the induction phase and then once every 2 months during the maintenance phase until disease progression, death, ICT-121 depletion or discontinuation. Results: A total of 20 patients were treated and eight of these patients are still alive. Immune response data with cytokine mRNA expression demonstrated a response to the CD133 epitopes. A total of 20 patients were treated and eight of these patients are still alive. Conclusions: The results from this Phase I trial suggest that ICT-121 is both safe and well-tolerated with an immune response seen in a subset of patients. Clinical trial information: NCT02049489.
Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma multiforme.
Authors: Shafer Danielle A. , Chen Zhi-jian , Harris Timothy , Tombes Mary Beth , Shrader Ellen , Strickler Kathryn , Ryan Alison A. , Dent Paul , Malkin Mark Gordon 
Published: September 2018

2060 Background: Evidence is increasing for altered immune responses in malignant gliomas. Tumor-associated microglia/macrophages infiltrate human glioma tissue and produce cytokines that promote glioma growth, invasion and angiogenesis. Dimethyl fumarate (DMF), approved for relapsing-remitting multiple sclerosis, is toxic to in vitro activated microglial cells. Based on pre-clinical data demonstrating synergism with radiation (RT) and temozolomide (TMZ), we conducted a phase I study of DMF in patients with newly-diagnosed glioblastoma (GBM) in combination with RT and TMZ. Methods: Using a standard 3+3 dose escalation design (3 dose levels: 120 mg bid, 240 mg bid and 240 mg tid), newly-diagnosed GBM patients received daily DMF with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant DMF (continuously) and TMZ for up 6 maintenance cycles (150-200 mg/m2 on days 1-5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤ 1/6 dose-limiting toxicities (DLT). The MTD was determined by evaluation of DLTs during the first 6 weeks of therapy. Results: Twelve patients were treated at the three dose levels, and no DLT was identified. There were no unexpected toxicities. The most common toxicities were lymphopenia (11 grade 3/4 events) and thrombocytopenia (2 grade 3/4 events). The only grade 3/4 non-heme toxicity was a grade 3 hemorrhoid event. Of the 12 evaluable patients, one remains on active treatment in maintenance phase. Three patients completed all treatment (concurrent and maintenance) with stable disease. Two patients had a partial response (RANO criteria) but then experienced disease progression during maintenance. Five patients had disease progression during study treatment and one patient chose to withdraw from the study during maintenance. Conclusions: These data suggest that DMF may be safely combined with RT and TMZ in GBM patients. A phase II study is under consideration. Clinical trial information: NCT02337426.
VXM01 phase I study in patients with resectable progression of a glioblastoma.
Authors: Wick Wolfgang , Wick Antje , Nowosielski Martha , Sahm Felix , Riehl Dennis , Arzt Marlene , von Deimling Andreas , Bendszus Martin , Kickingereder Philipp , Bonekamp David , Beckhove Philipp , Schmitz-Winnenthal Friedrich Hubertus , Jungk Christine , Wieckowski Sébastien , Herold-Mende Christel , Lubenau Heinz , Unterberg Andreas , Platten Michael 
Published: September 2018

2061 Background: VXM01 consists of an attenuated Salmonella typhi Ty21a carrying a plasmid encoding for VEGFR-2. The bacterium is serving as a vector via the oral route of administration carrying the plasmid into the Peyer’s plaques. The vaccine construct elicits a systemic T-cell response targeting VEGFR-2. This trial was set up to examine safety and tolerability, clinical and immunogenic response to VXM01 after treatment with at least four vaccinations [106 or 107colony-forming units (CFU)] in patients with recurrent glioblastoma who have failed at least radiochemotherapy with temozolomide. Methods: Patients with progressive resctable glioblastoma were subjected to single oral administration of VXM01 each on day 1, 3, 5, and 7. In addition, VXM01 was allowed to be administered in 4-weekly single doses every 4 weeks during the tumor follow-up period after reoperation. Follow-up was done by weekly safety laboratories and physical examinations in the treatment period and 4-weekly thereafter, MRI including perfusion maps (days 15 and 30 and six-weekly thereafter), 12-weekly T-cell immunomonitoring in the peripheral blood, and brain tumor immunohistochemistry. Results: Eight patients have been treated according to the schedule and surgery has been performed in seven of them. Under VXM01 treatment 47 adverse events, mostly unrelated to VXM01, were observed after a median of 7 doses per patient. Four out of eight patients (50%) showed a VEGFR-2 specific T cell response. In four patients there was a relevant increase in cerebral blood volume and apparent diffusion coefficient on post-vaccination MRI. In one patient there was an objective and durable T1 response, whereas three further patients remained stable prior to surgery and thereafter. Evaluation of infiltrating T cells in the tissue from re-operation revealed an increase in CD8+ T-cells in 5 out of 7 patients relative to the primary tumor tissue. Conclusions: VXM01 was safe and produces specific peripheral immune responses as well as enumeration of tumor-infiltrating T-cells in post-vaccine tumor tissue. Post treatment MRI imply vascular normalization and there was one patient with an objective response. As a consequence of this data, an expansion cohort of this trial has been launched. Clinical trial information: NCT02718443.
Apparent diffusion coefficient (ADC) decrease to predict longer survival in glioblastoma patients treated by dendritic cell immunotherapy plus standard of care.
Authors: Eoli Marica , Cuccarini Valeria , Aquino Domenico , Anghileri Elena , Servida Maura , Schettino Carla , Pellegatta Serena , Bruzzone Maria Grazie , Finocchiaro Gaetano 
Published: September 2018

2065 Background: The MRI follow –up of patients affected by glioblastoma (GBM) and treated with immunotherapy may be difficult, as immune responses may mimic tumor progression. To explore the potential contribution of quantitative MRI to the identification of patients with clinical benefit benefit, we used advanced MRI to study GBM patients treated with dendritic cell (DC) immunotherapy added to standard treatment (surgery, radiotherapy with concomitant temozolomide (TMZ) followed by adjuvant TMZ; DENDR1 trial, EUDRACT N° 2008-005035-15). Methods: A retrospective analysis was performed on longitudinal MRIs obtained soon after radiotherapy, within two days before the first vaccination (basal MRI) and every two months, in 22 patients enrolled in DENDR1. The following parameters were collected: tumor volume of contrast–enhanced lesions, mean rCBV, maximal rCBV, mean ADC, minimal ADC, ADC skewness. Receiver Operating Characteristic (ROC) curves were used to determine optimal sensitivity and specificity in differentiating patients as responder or not responder. Association with PFS (as per RANO criteria) and OS was analyzed using log-rank test and Cox regression. Results: Ten patients with PFS > 12 months were defined as responders Their basal mean ADC was significantly higher than in non responders (1.34 ± 0.17 vs 1.14 ± 0.34, p = 0.03). After four DC vaccinations mean ADC significantly decreased in responders only from 1.34 ± 0.17 to 1.23 ±0.23 (p = 0.028); the decrease persisted during immunotherapy. A basal mean ADC value ≥ 1.07 and a decrease in mean ADC value ≥ 0.13 were significant predictors of longer PFS (15.4 vs 9 m p = 0.0006; 17.2 vs 10.2 p = 0.04) and OS (29 vs 12.5 mo p = 0.002; 33 vs 19.9 p = 0.04 No significant correlations between the other parameters and the outcome were observed. Conclusions: Association with prolonged survival may suggest that in DENDR1responders decreased ADC is partly contributed by immune cells infiltrating the tumor.
Detection of tumor-derived DNA mutations in cerebrospinal fluid of patients with primary or metastatic brain tumors.
Authors: Wang Jianfei , Han Wenbo , Tian Chen , Hu Ying , Chen Yanhui , Li Xiangru , Guo Ruihan , Wang Haibo , Zhang Henghui 
Published: September 2018

2070 Background: Because detecting tumor-derived cell free DNA (cfDNA) in the blood of patients with primary or metastatic brain tumors is challenging, here we studied whether cerebrospinal fluid (CSF) could be serve as an alternative “liquid biopsy” by enabling measurement of circulating DNA within CSF to characterize tumor specific mutations. Methods: The paired cfDNA in CSF and plasma were collected from 20 patients with brain tumors and was subjected to enrichment for a 1.15M size panel cover exon regions from 1,086 genes. Followed by next generation sequencing on an Illumina X10 platform, the captured sequencing data was further processed using bioinformatics analysis to identify somatic mutations, including single nucleotide variants (SNV) and short insertions/deletions (indels). Results: The mutation profiles of 48 tumor associated genes in cfDNA were compared between the CSF and plasma. Our results showed that both average somatic mutation number and frequency identified in the cerebrospinal fluid was much higher than that in the corresponding plasma samples (25 vs. 18 & 1.39% vs. 0.55%). Among the twenty cases, one more potential actionable mutation, EGFR exon 19 deletion mutation with a 25.38% allele frequency variation, was only detected in the CSF cfDNA of a patient with brain metastasis lung cancer. Conclusions: Tumor mutations were detectable in CSF cfDNA of patients with different primary and metastatic brain tumors. Thus cerebrospinal fluid cell free DNA analysis could be a potential alternative analysis for patients with primary or metastatic brain tumors.
Linac-based radiosurgery for multiple brain metastases: A quality assurance and feasibility study.
Authors: Pfeffer Raphael M. , Levin Daphne , Spiegelmann Roberto 
Published: September 2018

2077 Background: The classical treatment for multiple brain metastases is whole brain radiotherapy (WBRT). For patients with 1-3 brain metastases stereotactic radiosurgery (SRS) results in better response, similar survival and less short and long term toxicity such as neurocognitive dysfunction than WBRT. For patients with > 3 metastases there is little prospective data of SRS partly due to the technical and logistic difficulties of delivering SRS to multiple metastases. We present a new SRS planning program (MMM) that allows the planning and delivery of linac-based SRS to up to 10 brain metastases simultaneously in less overall time than for WBRT. Methods: Between August 2014 and August 2016, patients referred for RT with 2 or more brain metastases were offered treatment with MMM. System QA included ArcCheck diode array and film dosimetry and gel dosimetry based on a patient derived phantom. Individual QA included replanting treatment arcs on an independent system. Results: 94 patients with 2-10 (median 5) metastases and a combined volume of 0.01-8.64 cc were treated. Planning time including image fusion, target delineation and RT plan generation required on average 20 minutes minutes. SRS was delivered using 4-5 (is more 7-10 since return arcs do not address the same targets) non-coplanar arcs and a single isocenter at the center of mass of the metastases. Treatment time to deliver 18-24 Gy to all metastases was 25 mins (beam on time ~6 minutes) for a total time of 45 minutes. This is the same as the time for each individual metastasis on earlier planning systems and compares to 20 minutes planning time and 12 mins delivery time for each of 10 fractions for a conventional 2 field WBRT plan WBRT (total 140 minutes). At 6 months follow up, 88% of treated metastases had decreased in size, 10% were stable and 2% grew. Acute toxicity was mild except for one patient with intractable seizures. Conclusions: Linac based SRS for multiple brain metastases is efficient, requiring the same resources as for treatment of a single metastasis and less resources than for WBRT, with a high rate of local control. Appropriate equipment is available in most radiotherapy departments which will allow more prospective studies of SRS for multiple metastases.
Debio 1347, an oral FGFR inhibitor: Results from a first-in-human, phase I dose-escalation study in patients with FGFR genomically activated advanced solid tumors.
Authors: Voss Martin Henner , Hierro Cinta , Heist Rebecca Suk , Cleary James M. , Meric-Bernstam Funda , Gandhi Leena , Ishii Nobuya , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Purcea Daniela , Vaslin Anne , Moulon Corinne , Zanna Claudio , Flaherty Keith , Tabernero Josep , Baselga Jose 
Published: September 2018

2500 Background: Oncogenic alterations in fibroblast growth factor receptors (FGFR) are seen across multiple solid tumor malignancies. Debio 1347 is an orally available, highly selective panFGFR inhibitor with potent antitumor effect in preclinical models bearing FGFR1-3 genetic alterations. Methods: Patients harboring defined FGFR 1, 2 or 3 alterations received escalating doses of Debio 1347 starting from 10 mg once daily. Dose escalation followed a 3+3+3 algorithm based on a modified Fibonacci sequence. The MTD was defined as the level where ≥ 3/9 patients suffer a DLT. Pharmacokinetics (PK) and pharmacodynamic were serially evaluated in blood, skin and/or tumor tissue. Results: Fifty-six patients were enrolled, including patients with mutations (n = 17), amplifications (n = 28) and fusions (n = 11). The dose was escalated up to 150 mg over 8 cohorts. DLTs were experienced by 4/56 patients, including G2 intolerable dry mouth + eyes at 60 mg, G3 hypercalcemia + hyperamylasemia at 80 mg, and G3 bilirubin increase at 110 mg. At data cut-off, the most common treatment-emergent adverse events (TEAE) were hyperphosphatemia (73%), fatigue (41%), diarrhea (39%), nausea (37%), and inappetence (32%). Fifteen patients (27%) experienced a grade ≥ 3 related TEAE. Twenty-five patients (47%) required dose modification, primarily due to hyperphosphatemia and cutaneous toxicity. An MTD has not been reached. PK appeared overall linear, with a half-life of 14 hours; hyperphosphatemia was dose-dependent. Among the 54 response-evaluable patients, 4 confirmed and 1 unconfirmed partial responses were observed in patients with cholangiocarcinoma (FGFR2 mutant), uterine (FGFR2 and FGFR1 amplified), colon (FGFR2 fusion), and urothelial cancer (FGFR3 fusion); an additional 10 patients had target regression < 30%. Conclusions: Debio 1347 had a tolerable and manageable safety profile. Encouraging antitumor activity was seen in several tumor types, mainly in patients with FGFR2 or 3 gene alterations, including fusion events, treated at 80 mg and 110 mg daily. Efficacy will be further explored in disease-specific and molecularly defined expansion cohorts. Clinical trial information: NCT1948297.
Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma.
Authors: Chenard-Poirier Maxime , Kaiser Martin , Boyd Kevin , Sriskandarajah Priya , Constantinidou Anastasia , Harris Samuel John , Serrano Fandos Sonia , Ryan Alison , Witt Karolina , Dawes Joanna C , Parmar Mona , Turner Alison Joanne , Tovey Holly , Hall Emma , Perez Lopez Raquel , Tunariu Nina , Lopez Juanita Suzanne , De Bono Johann S. , Banerji Udai 
Published: September 2018

2506 Background: RO5126766 is a potent RAF and MEK inhibitor with activity in xenografts models of RAS and RAF-mutated cancers. We present data from the RAS/RAF-mutated advanced solid tumor cohort and the initial results for the multiple myeloma (MM) cohort. Methods: Patients with KRAS, NRAS or BRAF-mutant tumours were treated with RO5127566 using a novel schedule:4mg twice weekly in 4-week cycles. For MM patients, it was given 3 weeks out of 4 and co-administration of weekly dexamethasone was authorised. Response assessment was completed using RECIST 1.1 criteria for solid tumours and the International Myeloma Working Group (IMWG) criteria were used for MM. Results: A total of 20 patients with solid tumours (10 NSCLC, 5 gynaecological cancers and 5 miscellaneous cancers) and 1 MM patients were evaluable. Among the 10 KRAS-mutant NSCLC patients, tumour regression was seen in 6/10 (60 %), of which 3/10 (30 %) were partial responses. Two of these patients had maintained response for over 1 year and one patient is still on study after 30 cycles. Of the gynaecological cancers, 3/5 patients (60%) achieved a partial response ( KRAS-mutant endometrial and ovarian cancer and BRAF-mutant ovarian). Of these patients, 1 of the KRAS mutants had received 2 previous lines of MEK inhibitors and the BRAF mutant had previously received a BRAF inhibitor. In the miscellaneous group, 4 patients with colorectal cancer (2 BRAF and 2 NRAS) and 1 patient with NRAS-mutant melanoma were treated and none responded. Two patients with MM have been treated so far (1 KRAS, 1 KRAS+NRAS). The one evaluable patient has had an IMWG partial response (PR) after 1 cycle (FLC-λ from 324 mg/L to 161mg/L, ratio 0.03 to 0.08) without concomittant dexamethasone. This patient was previously treated with an immunomodulatory drug, a proteasome inhibitor and two ASCTs. Conclusions: RO5126766 has shown exciting preliminary activity across a wide range of RAS- and RAF-mutated malignancies, with significant response rates in lung and gynaecological cancers. To our knowledge, the PR seen in our MM patient represents one of the first responses to a single-agent RAF/MEK inhibitor in multiple myeloma in a trial context. Clinical trial information: NCT02407509.
First-in-human phase 1/2 study of MCLA-128, a full length IgG1 bispecific antibody targeting HER2 and HER3: Final phase 1 data and preliminary activity in HER2+ metastatic breast cancer (MBC).
Authors: Alsina Maria , Boni Valentina , Schellens Jan H.M. , Moreno Victor , Bol Kees , Westendorp Martine , Sirulnik L. Andres , Tabernero Josep , Calvo Emiliano 
Published: September 2018

2522 Background: MCLA-128 is a novel IgG1 bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity targeting HER2 and HER3 receptors. We report final phase 1 single agent escalation data, and safety and preliminary activity at the recommended phase 2 dose (RP2D). Methods: In the phase 1 part, patients (pts) with advanced solid tumors received MCLA-128 every 3 weeks (q3w) IV over 1-2 hr from 40 to 900 mg. In the phase 2 part, pts with selected metastatic indications were treated at the RP2D. Antitumor activity was assessed as per RECIST 1.1. Clinical benefit rate (CBR) was defined as CR + PR + SD ≥12 weeks. Results: As of January 2017, 28 advanced solid tumor pts were treated in the escalation part. No dose limiting toxicities were seen. The RP2D was established as 750 mg q3w (flat dose, corticosteroid premedication) based on safety and PK data. Fifteen pts with HER2 amplified tumors were treated at the RP2D (8 MBC, 4 gastric, 2 ovarian, 1 colorectal). Median age was 52 years (range 33-71), ECOG PS 0/1: 3/12, all ≥2 metastatic sites. The safety profile at the RP2D confirmed dose escalation data; the most common AEs were infusion related reactions in 6 pts (40%; G1-2 in 5 pts, G4 in 1 pt), and G1-2 diarrhea, rash, fatigue in 2 pts each (13%). No congestive heart failure or significant LVEF decreases occurred. The 8 MBC pts had a median 5.5 prior lines of metastatic therapy (range 4-14), all had progressed on 3 prior Her2 inhibitor therapies and received a median of 4.5 MCLA-128 cycles (range 2-12); 1 had a confirmed PR, 5 had SD (including 2 sustained, 11 and 12 cycles). SD was also seen in 2 evaluable MBC pts treated at 480 mg in the phase 1 part (7 and 4 cycles). Overall, CBR in these 10 MBC pts was 70%. Evaluation of other indications is ongoing. Conclusions: MCLA-128 showed a well tolerated safety profile. Consistent antitumor activity was seen in heavily pretreated MBC patients progressing on HER2 therapies. Further exploration of MCLA-128 based combinations with chemotherapy or trastuzumab in less pretreated MBC patients progressing after ≥2 prior Her2 inhibitors including TDM-1 is planned. Clinical trial information: NCT02912949.