bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of SBP-101, in combination with gemcitabine and nab-paclitaxel, in first-line treatment of metastatic pancreatic ductal adenocarcinoma.
Authors: Kotasek Dusan , Nagrial Adnan , Lumba Sumit , Tebbutt Niall C. , George Thomas J. , Smith Sheri Lynn , Gagnon Suzanne , Cullen Michael T. , Walker Michael J. 
Published: February 2020

710 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens, N=4) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the safety, tolerability, PK, and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. Safety and tolerability were evaluated by clinical and laboratory assessments. PK was evaluated on day 1 of cycle 1. Efficacy was assessed by CA19-9 levels, objective response as assessed by RECIST criteria, progression-free survival (PFS) and overall survival (OS). Results: Fifteen patients have been enrolled in 3 cohorts (1: N=4, 2: N=7, 3: N=4) and received up to 6 cycles of treatment (7 subjects are ongoing in cohorts 2 and 3). The most common adverse events related to SBP-101 are fatigue (N=4), nausea (N=2) and injection site pain (N=2). There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. One patient in cohort 2 developed grade 3-4 reversible liver enzyme elevation. PK parameters in cohort 1 were below the limits of detection at most time points, but plasma Cmax and AUC0-t were measurable in cohorts 2 and 3. In those cohorts, CA19-9 levels decreased 76-95% in 7 of 8 evaluable subjects (1 additional subject TBD), with 5 patients achieving partial responses (4 ongoing) and 1 achieving stable disease. Median PFS and OS have not yet been reached. Conclusions: Preliminary results suggest SBP-101 is well tolerated when administered with G and A. Signals of efficacy support continued development of SBP-101 in combination first-line treatment for PDA. Clinical trial information: NCT03412799.
Modified FOLFIRINOX versus sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced pancreatic adenocarcinoma: A real-world analysis.
Authors: Tezuka Shun , Ueno Makoto , Kobayashi Satoshi , Morimoto Manabu , Nagashima Shuhei , Sano Yusuke , Asama Hiroyuki , Kawano Kuniyuki , Tanaka Satoshi , Fukushima Taito 
Published: February 2020

711 Background: Therapy options for second-line treatment of advanced pancreatic adenocarcinoma (PDAC) are limited and preferred regimens have not been established. This study compared the efficacy and safety of modified FOLFIRINOX (mFFX) and sequential chemotherapy (FOLFIRI/FOLFOX) as second-line treatment for advanced PDAC. Methods: This was a retrospective single-center analysis of all patients who received mFFX or sequential chemotherapy between December 2014 and May 2019 as second-line treatment for advanced PDAC. The sequential arm included all patients intended to be treated with sequential chemotherapy even if finished with either FOLFIRI or FOLFOX. For efficacy analysis, progression-free survival (PFS), overall survival (OS), and response rate (RR)of all the patients, excluding those with locally advanced pancreatic cancer (LAPC), were evaluated. For safety analysis, we evaluated the incidence of grade ≥3 adverse events in all the patients. Results: Seventy-four patients (mFFX 44; sequential 30) were included.The patients characteristics (mFFX/sequential) are as follows:median age 64/67 years, performance status (ECOG) 0 50%/53%, and LAPC 16%/13%. In contrast to sequential therapy, the mFFX group showed better OS and RR. However, there was no significant difference between mFFX and sequential therapy in PFS (median 4.4 [95% confidence interval (CI) 1.8-7.9] vs. 4.6 [95% CI 2.0-6.2] months; hazard ratio [HR] 0.88 [95% CI 0.51-1.56]; p = 0.657), OS (median 10.6 [95% CI 5.9-13.8] vs. 8.5 [95% CI 5.0-12.2] months; HR 0.71 [95% CI 0.37-1.41]; p = 0.318), and RR (8.1% vs. 3.8%; odds ratio 1.94 [95% CI 0.19-19.87]; p = 1.000). In the safety analysis, grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 36.4%, 6.8%, and 16.0%, respectively, with mFFX and 0%, 0% and 3.3%, respectively, with sequential chemotherapy. Conclusions: Whereas certain trends were observed, there were no significant differences in efficacy between mFFX and sequential chemotherapy. Considering the incidence of grade ≥3 adverse events with mFFX, sequential chemotherapy could be considered as one of the second-line treatment options for advanced PDAC.
A phase I/II study combining a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus and nab-paclitaxel/gemcitabine chemotherapy in advanced pancreatic cancer: An interim report.
Authors: Musher Benjamin Leon , Smaglo Brandon George , Abidi Wasif , Othman Mohamed , Patel Kalpesh , Jing James , Stanietzky Nir , Lu Jinyu (Jim) , Brisco Amanda , Wenthe Jessica , Brenner Benjamin , Eriksson Emma , Leen Ann M. , Hilsenbeck Susan G. , Ullenhag Gustav J. , Rowinsky Eric Keith , Grilley Bambj , Loskog Angelica Sara Ingrid 
Published: February 2020

716 Background: Pancreatic ductal adenocarcinoma (PDAC) has been highly resistant to immunotherapeutics to date. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, has been shown to lyse tumor cells selectively, induce anti-tumor cytotoxic T-cell responses, reduce myeloid-derived suppressor cell (MDSC) infiltration, and induce tumor regression in preclinical studies. Methods: In this phase I/II trial, patients with unresectable or metastatic PDAC are treated with LOAd703 intratumoral injections and standard nab-paclitaxel/gemcitabine (nab-P/G) chemotherapy. Starting on cycle 1 day 15 of nab-P/G, LOAd703 is injected with image guidance into the primary pancreatic tumor or a metastasis every 2 weeks for 6 injections. In the event of sustained tumor control, subjects are eligible to receive 6 more injections. Three dose levels of LOAd703 are being investigated using a BOIN dose escalation design. Primary endpoints are safety and feasibility. Secondary endpoints include response rate and overall survival. Results: To date, 13 subjects are evaluable for safety and feasibility. Three patients were treated at dose 1 (5x10e10 VP), 4 subjects at dose 2 (1x10e11 VP), and 6 subjects at dose 3 (5x10e11 VP). The most common adverse events (AEs) attributed to LOAd703 have been fever, chills, nausea, and increased transaminases. AEs have been transient and grade 1-2, with the exception of a grade 3 transaminase elevation in 1 subject receiving dose 3 (the only dose-limiting toxicity observed thus far). During protocol treatment, circulating MDSCs decreased in 8/13 subjects while effector memory T-cells increased in 10/13. ELISPOT analyses showed a rise in tumor antigen-specific T-cells in 10/13 subjects. At the lowest dose level, best response was stable disease, and 6/10 patients who received higher LOAd703 doses have had partial responses. Only 1 patient has had progressive disease as best response. Conclusions: Adding LOAd703 to nab-P/G has been safe and feasible. Treatment-emergent immune responses have been demonstrated in most subjects, with a notable proportion having objective anti-tumor responses. Clinical trial information: NCT02705196.
Clinical and pathologic characteristics of early-onset colorectal cancer (EoCRC).
Authors: Arif Arif Ahmad , Chahal Daljeet , Speers Caroline , Gill Sharlene , Donnellan Fergal , Loree Jonathan M. 
Published: February 2020

72 Background: Although CRC incidence continues to fall in patients over 50 due to adoption of screening programs, there has been an increasing incidence in patients < 50 where screening does not occur. We investigated the clinical and pathologic characteristics of EoCRC in BC. Methods: We retrospectively analyzed 27612 patients diagnosed with CRC and referred to BC Cancer between 1990-2016. Patients < 50 were classified as early onset CRC and analyzed for baseline and disease characteristics. Results: In the 2540/27612 (9.2%) of patients < 50, patients were more likely to be female (OR 1.33, 95% CI 0.61-1.44, P < 0.0001), have left sided tumors (OR 1.50, 95% CI 1.35-2.01, P < 0.0001), have poorly differentiated tumors (OR 1.24, 95% CI 1.10-1.34, P = 0.0003), and more patients presented with metastatic disease (OR 1.26, 95% CI 1.15-1.38, P < 0.0001) compared to patients ≥50. At diagnosis, patients < 50 were more likely to have a significant complication related to the primary tumor (OR 1.18, 95% CI 1.06-1.32, P = 0.0041), specifically, greater rates of perforation (OR 1.84, 95% CI 1.47-2.31, P < 0.0001). Although high risk features used to guide adjuvant therapy decisions in patients < 50 with stage II CRC were not higher, with similar T4 prevalence, poor differentiation, lymphovascular and perineural invasion, and less inadequate lymph node harvesting (≤12) (all p > 0.05), rates of adjuvant therapy were higher (OR 2.39, 95% CI 1.91-3.00, P < 0.0001). This was also noted in stage III CRC (OR 4.11 95% CI 3.07-5.48, P < 0.0001). Age impacted overall survival, with younger patients of all stages living longer (HR 0.72, 95% CI 0.68-0.76, P < 0.0001). Similar findings were noted for stage I-III CRC (HR 0.54 0.50-0.58, P < 0.0001) and for patients once they became metastatic (HR 0.84 95% CI 0.75-0.93, P = 0.0025). To control for competing causes of death, we looked at disease specific survival, which continued to show improved outcomes for patients age < 50 in stage I-III (HR 0.88 95% CI 0.81-0.97, P = 0.0016) and stage IV (HR 0.77 95% CI 0.72-0.84, P < 0.0001) CRC. Conclusions: EoCRC patients present with unique clinical and pathologic characteristics which may impact outcome. While the population < 50 has comparable outcomes, they may undergo increased rates of treatment.
Efficacy and safety of mFOLFIRINOX in patients with borderline resectable and locally advanced unresectable pancreatic cancer: Intention-to-treat population analysis.
Authors: Hwang Inhwan , Yoo Changhoon , Kim Kyu-Pyo , Byun Jae Ho , Jeong Jae Ho , Chang Heung-Moon , Ryoo Baek-Yeol 
Published: February 2020

720 Background: Borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAUPC) are heterogeneous disease entity with various prognosis. Based on the phase III PRODIGE trial, (m)FOLFIRINOX has been widely used for the management of patients with BRPC and LAUPC. Considering the lack of large phase 3 trial of (m)FOLFIRINOX for BRPC and LAUPC, real-life evidences of (m)FOLFIRINOX are needed. Methods: In this retrospective analysis, 199 patients who received at least one dose of (m)FOLFIRINOX between February 2013 and January 2017 were included. Endpoints of this study were objective response rates (ORR), surgical resection rate, progression-free survival (PFS) and overall survival (OS). Results: Median age was 60 years (range, 33-79) and 62.3% of patients were male. Pancreas head (n=112, 56.3%) was the most common primary tumor site, followed by body (n=42, 21.1%) and multifocal (n=34, 17.1%). By an independent radiology review, patients were classified to BRPC (n=75, 37.7%) and LAUPC (n=124, 62.3%). With median 40.3 months (95% CI, 36.7-43.8) of follow-up duration in surviving patients, ORR was 26.6% (n=53), median PFS and OS were 10.6 months (95% CI, 9.5-11.7) and 17.1 months (95% CI, 13.2-20.9), respectively. There was no difference in PFS and OS between BRPC and LAUPC (median PFS, 11.1 months [95% CI, 8.8-13.5] vs. 10.1 months [95% CI, 8.4-11.8], p=0.47); (median OS, 18.4 months [95% CI, 16.1-20.8] vs. 17.1 months [95% CI, 13.2-20.9], p=0.50). Curative-intent surgery (R0 and R1) was done in 63 patients (33.2%, 49 for R0 and 14 for R1) after treatment with (m)FOLFIRINOX. Resection rates were 58.2% in BRPC patients and 19.4% in LAUPC patients (p<0.001). In patients who underwent curative-intent surgery, median disease-free survival since surgery was 10.4 months (95% CI, 8.3-12.5 ) and there was no difference according to the baseline disease extent (BRPC vs. LAUPC): 10.0 months (95% CI, 7.5-12.5) vs. 12.0 months (95% CI, 3.7-20.3), p=0.37. Conclusions: (m)FOLFIRINOX is effective therapy for BRPC and LAUPC patients. Significant proportion of patients could receive curative-intent surgery.
Phase II trial of BPM31510-IV plus gemcitabine in advanced pancreatic ductal adenocarcinomas (PDAC).
Authors: Kundranda Madappa N. , Propper David , Ritch Paul S. , Strauss James , Hidalgo Manuel , Gillmore Roopinder , Sarangarajan Rangaprasad , Narain Niven R. , Kiebish Michael A. , Rodrigues Leonardo O , Granger Elder , Ramanathan Ramesh , Alistar Angela Tatiana , Bui Lynne A. , Chawla Sant P. , Niewiarowska Anna A. 
Published: February 2020

723 Background: BPM31510-IV is an Ubidecarenone (CoQ10) drug-lipid conjugate nanodispersion targeting metabolic machinery in cancer, shifting bioenergetics from lactate dependency towards mitochondrial OxPhos to generate ROS and activate apoptosis. An MTD of BPM31510-IV in combination with gemcitabine was established at 110mg/kg in a Phase I clinical trial, which determined the dose for the Phase 2 investigation. Methods: Eligible patients (aged ≥ 18 y) with relapsed/refractory PDAC to standard treatment (ST) and met inclusion/exclusion criteria were recruited. Patients received 110mg/kg IV BPM31510 in combination with gemcitabine in a 144-hour infusion. Tumor response was evaluated at week 10 and then every 8 weeks. Study endpoints assessed were Overall Response Rate (ORR), Overall Survival (OS), Progression-Free Survival (PFS), Time to Progression (TTP), Tumor Response using Adaptive Molecular Responses (multi-omic molecular profiling), changes in CA 19-9 levels and patient reported Quality of Life (QOL) using the validated FACT-HEP PRO. A comprehensive multi-omic profiling for identification of biomarkers for patient stratification was explored. Results: Of the 35 patients enrolled to receive therapy, 18 patients met criteria of an adequately treated cohort (ATC- received BPM31510-IV + gemcitabine for 30 days over 2 cycles and had a RECIST 1.1 evaluation) while remaining (n = 17) had progressive disease (PD). Half of the ATC population (n = 9/18, 50%) achieved best ORR of stable disease (SD); 10/18 (55 %) demonstrated SD as best response at target lesions and 8/18 demonstrated SD at end of Cycle 2. The mTTP was 121 days (70 – 147, 95% CI); PFS 118 days (70 – 131, 95% CI) and OS 218 days (131 – 228, 95% CI), respectively. Overall, BPM31510-IV was well tolerated; the most common AE’s were GI related. Conclusions: The efficacy signal observed in this heavily pretreated population in addition to the toxicity profile warrants further clinical investigation of BPM31510-IV + gemcitabine in advanced PDAC. Clinical trial information: NCT02650804 . [Table: see text]
A prospective trial of elemental enteral feeding in patients with pancreatic cancer cachexia (PANCAX-1).
Authors: Hendifar Andrew Eugene , Gresham Gillian , Kim Haesoo , Guan Michelle , Liu Jar-Yee , Minton Brian , Bhuiyan Diane , Langeslay Ruby , Rogatko Andre , Gong Jun , Placencio-Hickok Veronica 
Published: February 2020

726 Background: Unintentional weight loss affecting > 85% of pancreatic cancer (PC) patients contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Optimal treatment approaches have not been developed. We hypothesize that peptide-based enteral nutritional support in cachectic advanced PC patients, receiving palliative chemotherapy, results in improved weight, lean body mass (LBM), and hand-grip strength. Methods: Pancreatic adenocarcinoma patients with cachexia (> 5% unintentional weight loss within the previous 6 months) were provided a jejunal tube peptide-based diet for 3 months. Primary outcome was weight stability (0.1kg/BMI unit decrease). Secondary outcomes included changes from baseline in LBM, bone mineral density (BMD), total body fat mass (BFM), handgrip strength, physical activity (Fitbit), and CA19-9 and CRP. Planned interim analysis was performed after 14 patients completed treatment. Results: From 31 consenting patients, 16 were evaluable for the primary outcome. Patients receiving enteral therapy were 39% male, median age 69 (Range: 41 to 89 years), and 74% ECOG 1. A summary of change in outcomes at 3 months from baseline is shown in Table. The primary endpoint of weight stability in 10 (62.5%) patients was met, thus completing study. Overall survival was 6.5 months (n=31) and 9.9 months for evaluable patients (n=16). Weight stability was statistically associated with LBM (Pearson’s correlation: 0.87, p<0.001), but not survival (HR: 0.94, 95% CI 0.32, 2.83, p=0.92). Conclusions: Peptide-based enteral feeding resulted in weight stability and improvements in lean body mass and physical function. Further randomized trials assessing nutritional support in advanced patients are warranted. NIH/NCATS Grant # UL1TR000124. Clinical trial information: NCT02400398 . [Table: see text]
Prognostic and predictive value of circulating tumour DNA (ctDNA) by amplicon-based next generation sequencing (NGS) of advanced pancreatic cancer (APC) in a phase I trial of oxaliplatin capecitabine and irinotecan (OXIRI) triplet chemotherapy.
Authors: Seet Amanda Oon Lim , Choo Su Pin , Tai David Wai-Meng , Lam Justina Yick Ching , Tan Tira Jing Ying , Tan Daniel Shao-Weng , Tan Aaron C. , Chang Yvonne , Chowbay Balram , Ng Matthew C.H. 
Published: February 2020

730 Background: Tumoral KRAS mutations (KRAS mt) are detected in ~80% of APC and associated with a negative prognosis. Digital droplet PCR (ddPCR) has high sensitivity for circulating KRASmtbut narrower gene coverage. NGS using hybrid-capture methods has reported ctDNA KRASmtin ~30% of patients (pt). We previously presented clinical results of the Phase I trial of OXIRI (GI ASCO 18 #411). We now present the first prospective evaluation of ctDNA in APC by an amplicon-based NGS approach in this Phase I trial. Methods: Paired ctDNA and CA19-9 samples were taken at baseline, C2D1, C3D1 and end of trial. A targeted panel with error-correction (Lucence Diagnostics) was used to detect for mtin KRAS, TP53, SMAD4, CDKN2A, CTNNB1, GNAS, APC and MYC. CT scans were performed every 2 cycles. Survival curves by Kaplan Meier were compared by mutational status, ctDNA and CA19-9 response using the log-rank test. Spearman correlation of ctDNA and CA19-9 changes was performed. Results: ctDNA mtwas detected at baseline in 19/23 (83%) samples, comprising KRAS 17/23 (73%), TP53 (61%), SMAD4 (48%) and CDKN2A (30%). KRAS mtand SMAD4 mt conferred a negative prognosis for overall survival with a hazard ratio of 4.2 (CI: 1.6-10.4; p = 0.01) and 2.8 (CI: 0.9-8.65; p = 0.01) respectively. Drop in ctDNA and CA19-9 was associated with a trend for longer progression free survival at C2D1 (both) and C3D1 (ctDNA only). Radiological partial response (PR) was associated with lower ctDNA in 5/5 pt and CA 19-9 in 4/5 pt. Decrease in ctDNA and CA19-9 was associated with disease control (PR/SD) at C2D1 in 11/14 pt and 10/10 pt; at C3D1 in 11/12 pt and 6/7 respectively. No significant correlation between the amplitude of CA19-9 and ctDNA changes was found. Conclusions: ctDNA could be detected in 83% of pts of whom KRAS mtrates were similar to reports using tissue NGS. Determination of RAS mtand SMAD4 mtin ctDNA may aid in the prognostication of pts and decrease in ctDNA levels may predict for treatment benefit, similar in extent to CA 19-9. This may be particularly useful in non-CA19-9 secreting APC as an adjunct to imaging. Clinical trial information: NCT02368860.
Loss of Rnf43 to accelerate KRAS-mediated neoplasia in a clinically relevant genetically engineered mouse model of pancreatic adenocarcinoma.
Authors: Hosein Abdel Nasser , Dangol Gita , Okumura Takashi , Abou-Elkacem Lotfi , Maitra Anirban 
Published: February 2020

733 Background: The genetic heterogeneity of pancreatic ductal adenocarcinoma (PDAC) demands a personalized molecular-targeted treatment approach. While activating KRAS mutations are a near ubiquitous event in PDAC pathogenesis, 5-10% of cases display deleterious driver mutations in the Wnt-signaling negative regulator, ring finger 43 (RNF43). Despite this characterization there are no personalized treatment options for this subset of patients. Methods: We have developed a genetically engineered mouse model (GEMM) of PDAC, driven by an activating mutation in Kras and deletion of Rnf43 under control of a pancreas specific promoter (KRC). Mice were followed for survival outcomes and histological changes which were compared to a Kras driven PDAC GEMM (KC). Mice underwent serial magnetic resonance imaging (MRI), with and without dynamic contrast enhanced (DCE) imaging, to evaluate cystic tumor morphology and contrast enhancement during tumor progression. Single cell RNA sequencing (scRNAseq) was also performed to assess changes in single cell populations during tumor progression. Lastly, we established ex vivo cultures from KRC and KC tumors and performed bulk RNA-sequencing (RNAseq) and in vitro pharmacology studies. Results: KRC mice displayed a decrease in overall survival and higher incidence of both high grade pre-neoplastic lesions and invasive PDAC compared to KC mice. Serial MRI revealed increased cystic morphology of KRC mice during tumor progression with increasing DCE intensity. scRNAseq of KRC tumors from moribund mice displayed two distinct populations of both macrophages and fibroblasts, similar to our previous report of Kras/Tp53 and Kras/Ink4a driven GEMMs. Lastly, primary cultures from KRC tumors demonstrated increased expression of Wnt-related genes by RNAseq and increased sensitivity to small molecule porcupine inhibition relative to KC cell lines, demonstrating functional Wnt dependence of the KRC system. Conclusions: Rnf43 is a bona fide tumor suppressor gene in PDAC. This GEMM is a novel platform for drug discovery in RNF43-mutated PDAC with the eventual goal of implementing a precision oncology approach in these patients.