bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) patients (pts).
Authors: Mercade Teresa Macarulla , Moreno Victor , John Binu , Morris John Charles , Sawyer Michael B. , Yong Wei Peng , Gutierrez Martin , Karasic Thomas Benjamin , Sangro Bruno , Sheng-Shun Yang , Gentry Carleen , Kim Amy , Kumar Pavan , MacKenzie Crystal , Rioux Nathalie , Schindler Joanne , Selvaraj Anand , Finn Richard S. 
Published: May 2019

4095 Background: FGF19 overexpression is hypothesized to hyperactivate FGFR4 and its downstream signaling pathway leading to enhanced tumor growth in HCC/ICC. Targeting FGFR4 may have therapeutic benefit in HCC/ICC with altered FGF19 signaling. A phase 1 study (NCT02834780) was initiated to assess H3B-6527, an investigational highly selective covalent FGFR4 inhibitor. Methods: Adult pts with advanced HCC or ICC, ECOG PS 0-1, well compensated liver function, and who progressed after at least one prior therapy, were administered H3B-6527 orally QD (once daily) on a 21-day cycle following a 3+3 design. Patients in the dose escalation phase were treated regardless of FGF19 status. Adverse events (AEs), pharmacokinetics (PK), and pharmacodynamics (PD) were assessed. Response was determined by RECIST 1.1 or modified RECIST every 6 weeks. Results: As of 06-Jan-2019, 37 pts have been treated with H3B-6527 at doses of 300 to 1400 mg QD (23 pts in escalation; 14 in expansion). In dose escalation, a total of 17 patients with HCC, Child-Pugh A received prior systemic therapy including 100% with prior TKI and 35% with prior IO. 12% had hepatitis B virus and 47% had hepatitis C virus. H3B-6527 plasma levels increased with dose from 300 to 1000 mg QD and plateaued. H3B-6527 was rapidly absorbed with a tmax of ~2-3 h and showed a terminal half-life of ~4-5 h, following administration of 1000 mg (fasted). No dose-limiting toxicities or ≥ Grade 3 treatment-related AEs (TRAE) have been observed in escalation. Most common TRAEs (≥ 10%) were diarrhea, nausea, and vomiting. Based on safety, PK, and PD, 1000 mg QD was the recommended phase 2 dose. Durable stable disease and partial responses (PR) have been observed on the once daily fasted schedule; 2 of 17 pts with HCC achieved PRs and an additional 7 with stable disease were on treatment for ≥ 5 months. Conclusions: H3B-6527 is well tolerated and demonstrates early signs of clinical activity. Dose expansion on QD schedule and exploration of BID (twice daily) schedule is ongoing. Clinical trial information: NCT02834780.
A phase II, open label, multicenter trial of avelumab in patients with advanced, metastatic high-grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after first-line chemotherapy (AVENEC).
Authors: Fottner Christian , Apostolidis Leonidas , Ferrata Martina , Krug Sebastian , Michl Patrick , Schad Arno , Roth Wilfried , Jaeger Dirk , Galle Peter R. , Weber Matthias M. 
Published: May 2019

4103 Background: High grade Neuroendocrine Neoplasias (NEN) are rare tumors with a poor prognosis and no established second line therapy when progressive after first line platinum-based chemotherapy resulting in a median overall survival (OS) of 5 months. This study aims to evaluate the efficacy and safety of the anti-programmed death ligand-1 (PD-L1) antibody Avelumab in patients (pts) with NEN G3 progressing after first-line chemotherapy. Methods: In a multicenter, national, single-arm, open-label, phase II trial the efficacy and safety of Avelumab was evaluated in patients with metastatic progressive Neuroendocrine Carcinomas (NEC G3) according to WHO 2010, excluding Merkel cell carcinoma and small cell lung cancer. Results: From 12/2017-11/2018 a total of 29 pts (20 male, 69%), were enrolled (16 NEC G3 and 11 moderately differentiated NETG3). Mean age was 59.2±10.2 ys (range 33-75), median follow up 16.5 weeks (3-48). Median Ki67 was 60% (range 20-95%). Site of origin included pancreas (12), genito-urinary tract (4), stomach-esophagus (3), colo-rectum (3), lung (2), ear-nose-throat (2), papilla of Vater (1). In an interim analysis the DCR (stable disease or partial remission according to irRECIST) after 8 weeks was 32% (4 SD, 2 PR). In responders, mean duration of disease control was 20 (±13.8) weeks, with 4 pts. showing stable disease or partial remission ≥6 months. Median OS was 4.2 months (range 1- >12). Treatment-related adverse events occurred in 11 of 29 pts (38%) and were mainly mild to moderate (CTCAE-grade 1 [52%], 2 [44%] and 3 [4%]) and included fatigue (n=6; 20.6%), diarrhea (n=4; 13.7%), fever/chills after infusion (n=4; 13.7%), loss of appetite and nausea (n=4; 13.7%), skin rash (n=1; 3%), deterioration of preexisting psoriasis (n=1; 3%) and abdominal pain (n=1; 3%). Conclusions: Immune checkpoint blockade with avelumab in pretreated high grade NEN shows relevant activity in a subset of patients with excellent tolerability. Clinical trial information: NCT03352934.
Oxaliplatin and 5-fluorouracil (FOLFOX) in advanced well-differentiated digestive neuroendocrine tumors: A multicenter national retrospective study from the French Group of Endocrine Tumors (GTE).
Authors: Girot Paul , Baudin Eric , Senellart Helene , Bouarioua Nadia , Hentic Olivia , Guimbaud Rosine , Walter Thomas , Ferru Aurelie , Roquin Guillaume , Cadiot Guillaume , Pracht Marc , Girot Jean-Baptiste , Malka David , Ducreux Michel , Hadoux Julien , Matysiak-Budnik Tamara , Touchefeu Yann ,   French Group of Endocrine Tumors (GTE)
Published: May 2019

4104 Background: Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs.Oxaliplatin-based regimens have shown promising antitumor activity in digestive neuroendocrine tumors (NETs), however the available data are limited. Our aim was to assess the tumor response and survival in a large series of patients treated with oxaliplatin and 5-fluorouracil (FOLFOX) for advanced digestive NETs. Methods: All patients with advanced well-differentiated digestive NETs treated with at least 3 cycles of FOLFOX between 2004 and 2018 in 12 centers of the French GTE, were retrospectively included. Best response according to the RECIST 1.1 criteria, progression-free survival (PFS) and overall survival (OS) were evaluated. The prognostic factors for PFS were investigated by multivariate analysis using a Cox proportional hazard model including variables with a p value ⩽ 0.20 in univariate analysis. Results: One hundred and forty-nine patients were included. Primary tumor location was pancreas (n = 88), small intestine (n = 37), stomach (n = 7), rectum (n = 4) and unknown without lung tumor at CT scan (n = 13). Partial response rate was of 31% for pancreatic NETs, 13% for small intestine NETs, 14% for gastric NETs, 25% for rectal NETs and 38% for unknown primary NETs. Median PFS were, respectively, 9, 9, 14, 4 and 6 months, and median OS were 30, 28, 31, 25 and 15 months. Significant poor prognostic factors for PFS after FOLFOX in digestive NETs were: progressive disease (HR = 2.5, p = 0.018), hepatic involvement > 50% (HR = 1.8, p = 0.009), prior targeted therapy (HR = 1.5, p = 0.048) and rectal primary tumor (HR = 4.2, p = 0.01). Among pancreatic NETs, the 9 insulinomas had a 22 months PFS versus 9 months for the others (p = 0.025), and serum glucose normalization was obtained in 8 out of 9 cases. Conclusions: FOLFOX has a promising clinical activity for gastroenteropancreatic NETs, especially in insulinomas.
Impact of gender on multikinase inhibitors (MKIs) toxicity in patients (pts) with advanced pancreatic and gastrointestinal neuroendocrine tumors (NETs): A pooled analysis of two phase II trials with pazopanib and lenvatinib.
Authors: Hernando-Cubero Jorge , Grande Enrique , Castellano Daniel E. , Ibrahim Toni , Fazio Nicola , Lopez Carlos , Teule Alex , Valle Juan W. , Garcia-Carbonero Rocio , Diez Marc , Acosta Daniel , Roca Maria , Capdevila Jaume 
Published: May 2019

4109 Background: Retrospective data in some cancer types suggested a possible different toxicity profile with chemotherapy and targeted therapies according to gender. However, data from prospective studies are still very limited, especially in infrequent tumors such as NETs. Methods: Pts with advanced pancreatic and gastrointestinal NETs treated with pazopanib or lenvatinib in the multicenter open-label phase II studies PAZONET and TALENT respectively, were included in the analysis. Both studies were performed by Spanish Task Force Group for Neuroendocrine Tumors (GETNE). All toxicity grades with an incidence higher than 5% were considered for univariate review. Additionally, all grade 3-4 toxicities were analyzed separately. Results: 155 pts (47.7% female) with 1213 adverse events (AEs) (20% G3-4) divided in 121 categories were included. In female patients, liver toxicity, headache, pyrexia, nausea/vomiting, hair/skin disorders and dizziness were significantly more common (table). The only toxicity with higher incidence in men was dysphonia (OR 0.42, 95% CI 0.2-0.9, p 0.02). There were no gender differences in grade 3-4 toxicities. Conclusions: We observed significant differences in toxicity AEs by gender in two prospective phase II studies with MKIs in NETs patients. Potential different approach to manage toxicity may be adopted based on gender. [Table: see text]
Blood-based next-generation sequencing analysis of neuroendocrine tumors.
Authors: Shaib Walid Labib , Roberts Ali , Zakka Katerina Mary , Akce Mehmet , Wu Christina , Alese Olatunji B. , El-Rayes Bassel F. , Kasi Pashtoon Murtaza , Starr Jason Scott 
Published: May 2019

4110 Background: Neuroendocrine tumors (NET) comprise around 2% of all malignant tumors of the gastrointestinal system. The genomic landscape of NET has not been well studied. The aim of this study was to confirm the feasibility of next generation sequencing (NGS) using ctDNA in NET and characterize common alterations in the genomic profile. Methods: Molecular alterations in 114 plasma samples from 114 patients with NET using clinical-grade NGS of ctDNA (Guardant360Ò) across multiple institutions were evaluated. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 114 NET patients were evaluated, of which 64 (56.1%) were female. Mean age was 59.7 years with a range between 23-89 years. ctDNA NGS testing was performed on 114 plasma samples; 1 patient had testing performed twice. Genomic alterations were defined in 94 (n = 94/114, 82.5%) samples with a total of 289 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Alterations were identified in at least one sample from 83 patients; TP53 associated genes were most commonly altered (n = 83/289, 28.7%), followed by KRAS (n = 22, 7.6%), PI3CA (n = 15, 5.2%), CCNE1 (n = 15, 5.2%), BRAF (n = 13, 4.5%), MYC (n = 12, 4.1%), ERBB2 (n = 11, 3.8%), APC (n = 10, 3.5%), EGFR (n = 10, 3.5%), MET (n = 10, 3.5%), PTEN (n = 9, 3.1%), RB1 (n = 9, 3.1%), CDK6 (n = 7, 2.4%), AR (n = 5, 1.7%), ARID1A (n = 5, 1.7%), FGFR1 (n = 5, 1.7%), and PDGFRA (n = 5, 1.7%). Other genomic alterations of low frequency, but clinical relevance included: CDK4 (n = 4, 1.3%), NF1 (n = 4, 1.3%), RAF1 (n = 4, 1.3%), GNAS (n = 3, 1.0%), KIT (n = 3, 1.3%), BRCA2 (n = 2, 0.7%), CCND2 (n = 2, 0.7%), CTNNB1 (n = 2, 0.7%), JAK2 (n = 2, 0.7%), NRAS (n = 2, 0.7%), SMAD4 (n = 2, 0.7%), and TERT (n = 2, 0.7%). Alterations in AKT1, ALK, ATM, BRCA1, CCND1, CDKN2A, FGFR2, MTOR, RHOA, SMO and STK11 were all reported once (n = 1, 0.3%). Conclusions: Evaluation of ctDNA is feasible among individuals with NET. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in NET patients.
Clinical efficacy and toxicity data on phase I study of fosbretabulin in combination with everolimus in neuroendocrine tumors.
Authors: Chauhan Aman , Arnold Susanne M. , Wu Jianrong , Nair Rashmi T , Slone Stacey A. , Dressler Emily Van Meter , Flynn Heather , Adams Val R. , Weiss Heidi , Evers Mark , Anthony Lowell Brian 
Published: May 2019

4114 Background: Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs). Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D), safety data and early clinical efficacy in metastatic GEPNET patients was conducted. Methods: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. RECIST 1.1 was used to evaluate radiological responses at 3 month. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had > 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Conclusions: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Clinical trial information: NCT0301429.
Antitumor efficacy of concurrent everolimus with hepatic transarterial bland embolization (evero-embo) in patients with metastatic well differentiated neuroendocrine tumor (NET).
Authors: Anthony Lowell Brian , Chauhan Aman , Wu Jianrong , Krohmer Steven J , Gabriel Gaby , Adams Val R. , Evers Mark , Arnold Susanne M. , Khouli Riham 
Published: May 2019

4115 Background: Hepatic transarterial embolization (HAE) is an effective loco-regional therapy for neuroendocrine tumor (NET) management. Systemic targeted therapies, such as everolimus and sunitinib, are typically held 2-4 weeks prior to and after procedures. The safety of concurrent use of everolimus with HAE has been previously reported (GI-ASCO). HAE induces anoxic injury while everolimus effects cell growth, proliferation and survival. Combining these two modalities may result in clinical synthetic lethality effectively debulking significant hepatic disease and/or delay progression. Historically bland HAE has a median hepatic PFS of ~9 months. In this study, the clinical efficacy of evero-embo is examined. Methods: A review of clinical and radiographic data was conducted for all sequential patients who underwent evero-embo between September 2016 and April 2018 at the University of Kentucky Markey Cancer Center. An independent radiologist performed RECIST measurements. Patients were required to have had systemic everolimus for ≥ 1 month prior to embolization in order to be included in this study and be on everolimus immediately post procedure. Patients with at least 12 months post procedure follow up were included for efficacy review. Results: A total of 51 HAEs with concurrent systemic everolimus were performed in 34 NET patients. Twenty one of 24 patients were noted to have a partial response. Rest had stable disease. Hepatic progression was not observed. Twenty-one of the 34 patients have had 12 or more months of follow up post procedure (median of 17 months). None of these 21 patients have had hepatic progression. Conclusions: Evero-embo results in a partial response rate of 62% and may have significant antitumor activity when compared to bland hepatic artery embolization in NET patients. With a median follow-up of 17 mos, hepatic progression has not occurred in any patient. Additional follow up is necessary to compare the median hepatic PFS of evero-embo to the historical drug-eluting bead HAE PFS.
Paclitaxel/carboplatin with or without cetuximab for treatment of carcinoma with unknown primary (PACET-CUP): Results of a multi-center randomized phase II AIO trial.
Authors: Krämer Alwin , Stein Alexander , Huebner Gerdt , Stahl Michael , Kasper Stefan , Kretzschmar Albrecht , Kohne Claus-Henning , Grünwald Viktor , Hofheinz Ralf , Schütte Katharina , Löffler Harald , Bokemeyer Carsten , Folprecht Gunnar ,   Arbeitsgemeinschaft Internistische Onkologie (AIO) - CUP group
Published: May 2019

4120 Background: Paclitaxel/carboplatin is one of the standard regimens for empiric treatment of patients (pts) with carcinoma with unknown primary (CUP) when a specific therapy is not available. The EGFR antibody cetuximab demonstrated efficacy in several cancer types. Methods: Pts with newly diagnosed non-resectable, undifferentiated or adeno-CUP were randomized to 6 cycles paclitaxel 175 mg/m² and carboplatin AUC 5 every three weeks (arm A) or the same chemotherapy plus cetuximab (400 mg/m², then 250 mg/m² weekly; arm B) at 13 German centres. CUP pts belonging to favorable prognosis groups [i.e. women with isolated peritoneal carcinomatosis or axillary lymph node metastases, men with retroperitoneal lymph nodes, pts with specific tumor entities according to histology / immunohistochemistry] were excluded from the trial. The primary endpoint was progression-free survival (PFS), secondary endpoints were response rate (RR) and overall survival (OS). Results: Between 03/2010 and 03/2017, 72 pts were randomized to arm A and 78 pts to arm B. The median age was 61 years, 84 pts were male (40 and 44 pts in arm A and B). 58 pts had a performance status (PS) of 0 (24 and 34 pts), 89 pts a PS of 1 (47 and 42 pts in arm A and B), and one patient in arm A had a PS of 2. PFS and OS did not differ between arms. The median PFS was 3.7 [95%CI: 3.0 - 4.4] and 4.6 [95%CI: 2.9 - 6.2] months in arms A and B (HR 0.98 [95%CI: 0.70-1.37]), the median OS 8.1 [95%CI: 6.5 - 9.8] and 7.4 [95%CI: 5.1 - 9.6] months in arms A and B, respectively (HR 1.10 [95%CI: 0.77 - 1.56]). There was a statistically non-significant trend towards a higher RR with cetuximab: 11 pts had a partial response in arm A (15% [95%CI: 7.9 - 26%]), and 17 pts in arm B (22% [95%CI: 13%-33%], p = 0.30). Twenty-five pts in each arm had stable disease, and 36 pts in each arm had progressive disease or were not evaluable for response. Conclusions: This study represents one of the largest trials in pts with CUP and demonstrates that randomized trials are feasible in this disorder with high medical need. The outcome of CUP pts in the unfavorable prognosis group was not improved by adding cetuximab to empiric therapy paclitaxel/carboplatin. Clinical trial information: NCT00894569.
PanCO: An open-label, single-arm pilot study of phosphorus-32 (P-32; Oncosil) microparticles in patients with unresectable locally advanced pancreatic adenocarcinoma (LAPC) in combination with FOLFIRINOX or gemcitabine + nab-paclitaxel (GNP) chemotherapies.
Authors: Ross Paul J. , Croagh Daniel , Aghmesheh Morteza , Nagrial Adnan , Nguyen Nam , Nikfarjam Mehrdad , Wasan Harpreet Singh , Ajithkumar Thankamma V. , Iwuji Chinenye , Hendlisz Alain , Maher Thomas , Kraszewski Anna , Harris Marion 
Published: May 2019

4125 Background: LAPC is associated with a poor prognosis. Current standard treatment is limited to chemotherapy or chemo-radiotherapy. P-32 Microparticles is a brachytherapy device that implants a predetermined dose of P-32 into pancreatic tumours via endoscopic ultrasound (EUS) guidance. This reports the initial results of a pilot study in combination with chemotherapy. Methods: Eligible patients were permitted to receive either GNP or FOLFIRINOX. P-32 was implanted at week 4 or 5. The dose of P-32 was calculated from tumour volume to deliver an absorbed dose of 100 Gy. Diffusion pattern of the P-32 suspension was assessed by EUS and bremsstrahlung SPECT/CT imaging. Safety data was graded using CTCAE v4.0 criteria. Response was assessed according to RECIST 1.1 with CT scans every 8 weeks and FDG-PET scans at baseline and week 12. Results: 50 patients were enrolled (Intent-to-Treat population (ITT)) of which 42 were implanted with the device (Per Protocol population (PP)). 10 received FOLFIRINOX and 40 GNP. Median age was 65, 28 were male and all had a PS 0/1. 1070 adverse events (ITT) were reported; 153 (80% of patients) were ≥ Grade 3. The most common AEs of ≥ Grade 3 were haematological (39, 46%) and gastrointestinal disorders (30, 34%). No serious device- or radiation-related toxicities have been reported. PP Local Disease Control Rate at Week 16 was 90%; 95% CI: 77-97% and at Week 24 was 71%; 95% CI: 55-84%. Overall Response Rate (ORR) was 31%; 95% CI: 18-47%. Median change in tumour volume from Baseline to Week 16 and to Week 24 was -38% (range +89% to -90%) and -27.5% (range +139% to -79%). Ten (24%) patients underwent surgical resection following repeat staging. Eight patients had R0 margin. Conclusions: The use of EUS-guided implantation of P-32 is feasible, with an acceptable safety profile in combination with first-line chemotherapy for LAPC patients. Encouraging OR and DCR are observed. Further follow-up to inform results of local progression free survival and progression free survival is warranted. Acknowledgement: Nab-paclitaxel was supported by Specialised Therapeutics Australia Pty Ltd. Clinical trial information: NCT03003078.