Treatment Of Advanced Pancreatic Cancer Research Articles

Abstract 4436: Metformin upregulates hENT1 expression and enhances gemcitabine efficacy in pancreatic cancer cells

Abstract Pancreatic cancer is the 4th leading cause of cancer death and is normally diagnosed at a late stage due to the lack of symptoms and early detection. Pancreatic cancer patients have one of the worst prognoses among all cancer types with a 5 year survival rate of less than 5%. Despite significant improvement in understanding molecular and epigenetic changes of this disease, the prognosis and management remained unchanged. The golden standard of advanced pancreatic cancer treatment is gemcitabine or gemcitabine with more targeted therapy. Patients treated with gemcitabine can, however, eventually develop resistance to this drug. Previously published data from our laboratory demonstrated enhanced efficacy of gemcitabine with the dietary agent, indole-3-carbinol (I3C) though up-regulation of the human equilibrative nucleoside transporter (hENT1). hENT1 is the major drug transporter for gemcitabine. One of the drugs currently being investigated for treatment of pancreatic cancer is metformin. Metformin is one of the most widely prescribed drugs for the treatment of type 2 diabetes mellitus. Metformin has exhibited both chemopreventive and chemotherapeutic activities in preclinical human pancreatic cancer cells and animal models. Currently this drug is in clinical trial for pancreatic cancer. Metformin has been found to be transported by a member of the equilibrative nucleoside transporter (ENT) family named ENT4.The current study examined the potential efficacy and regulation of hENT1 in pancreatic cancer cells when treated with gemcitabine and/or metformin. Several pancreatic cell lines (Mia PaCa-2, AsPC-1, Su86.86 and PANC-1) were examined for modulation of hENT1 expression when treated with gemcitabine or metformin or in combination for 24h and 72h. The results varied for each of the cell lines. After 24 h treatment, hENT1 expression analysis of Su86.86 and PANC-1 gemcitabine resistant cell lines showed no change in hENT1 expression levels. After 72h of treatment with gemcitabine and/or metformin hENT1 expression was up-regulated (p<0.05); however, metformin did not enhance the efficacy of gemcitabine. In AsPC-1, a cell line with moderate gemcitabine resistance, hENT1 expression was down-regulated (p<0.05) after 24 h treatment with gemcitabine and/or metformin; however, after 72h of treatment with gemcitabine and metformin, metformin increase the efficacy of gemcitabine (p<0.05). In MIA Paca-2, a gemcitabine sensitive cell line, the expression of hENT1 was up-regulated (p<0.05) after 24h treatment with gemcitabine. Metformin and combination with gemcitabine treatments also upregulated the expression of hENT1 (p<0.05) but metformin did not increase the efficacy of gemcitabine. There was no change in expression for MIA Paca-2 cells treated for 72h. Based on initial studies, the sensitivity of pancreatic cancer cell lines to gemcitabine/metformin combination is through up-regulation of hENT1. Citation Format: Stancy J. Joseph, Taylor Osborne, Beverly Word, Beverly Lyn-Cook. Metformin upregulates hENT1 expression and enhances gemcitabine efficacy in pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4436. doi:10.1158/1538-7445.AM2015-4436

Abstract B102: A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation

Abstract Background: Despite the recent progress made with front-line treatment for advanced pancreatic cancer (PC), most patients (pts) will either relapse or be refractory to treatment. Others may not even be eligible due to the toxicity profile of the available options or due to clinical deterioration. Once the disease progresses following front-line treatment, there is no accepted standard of care. Treatment options are clearly needed for patients with refractory disease. Approximately 5% of unselected PC pts, 10% of PC patients of Ashkenazi Jewish descent, and up to 19% of familial PC cases, harbor a germline BRCA mutation. Though less well characterized to date, somatic BRCA mutations also appear to play a significant role in PC. Clinical data have shown that pts with BRCA-mutant (BRCAmut) tumors, including those with PC, respond to treatment with a PARP inhibitor (PARPi). Early data suggest that other genomic characteristics may be surrogate biomarkers of homologous recombination deficiency (HRD) and define a larger group of responders than just BRCA mutation(s) alone. Rucaparib, an oral PARPi, is being developed for treatment of cancers associated with HRD due to a BRCA mutation or other homologous recombination pathway defect. Rucaparib has a desirable PK profile, is well tolerated, and has demonstrated clinical activity (RECIST and/or CA-125 responses) in patients with BRCAmut pancreatic, ovarian, or breast cancer in an ongoing Phase 1/2 study (NCT01482715). Three studies are currently ongoing in ovarian cancer and a trial in BRCAmut pancreatic cancer is now planned. The clinical activity of PARPi, including rucaparib, in BRCAmut PC, combined with the paucity of active 2nd-line therapies, support evaluation of rucaparib in PC pts with a BRCA mutation. Methods: Study CO-338-023 (NCT02042378) is a single-arm, open-label Phase 2 trial of continuous monotherapy rucaparib in up to 100 pts with pancreatic ductal adenocarcinoma (or related subtype) who are known to harbor a deleterious BRCA mutation (germline or somatic). Pts must have received at least 1, but no more than 2, prior regimens for locally advanced or metastatic disease and have relapsed / progressive disease confirmed by radiologic assessment, or are no longer able to tolerate chemotherapy due to toxicity, and radiologic assessment confirms stable or progressive disease. Other key inclusion criteria include measurable disease, ECOG Performance Status 0 or 1, and adequate organ function. Pts with endocrine tumors or who received prior PARPi treatment are excluded. Pts will take 600 mg BID rucaparib continuously and be evaluated for safety every 2–4 wks, disease status (CT scans, CA19–9) every 4–8 wks until disease progression, and then for survival every 4 wks. Blood and archival tumor tissue (if available) will be collected from all pts. The primary endpoint is ORR by RECIST v1.1. Key secondary endpoints include duration of response, PFS, OS, and safety. Exploratory analyses include gene sequence and structural rearrangements of tumor DNA and evaluation of circulating tumor DNA. A group sequential interim monitoring plan will be implemented to stop the study early for either superior efficacy or futility. Interim analyses will occur after every 10th patient enrolled has sufficient disease assessment data available. If robust activity is observed in the BRCAmut PC population, the trial may be broadened to include PC pts with HRD due to other than a BRCA mutation. The trial will be open to enrollment at clinical sites in the US and Israel in 2Q 2014. Citation Format: Susan M. Domchek, Robert McWilliams, Andrew Hendifar, Rachna T. Shroff, Lawrence Leichman, Ron Epelbaum, Ravit Geva, George Kim, Steven R. Alberts, Robert A. Wolff, Andrew Allen, Heidi Giordano, Mitch Raponi, Jeff Isaacson, Lindsey Rolfe, Andrew Biankin, Robert H. Vonderheide. A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B102.

Abstract B90: Hapten enhanced personalized chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmuno-therapy: UMIPIC-therapy in advanced pancreatic cancer

Abstract Backgound: To evaluate the clinical effectiveness of hapten enhanced chemoimmunotherapy in the treatment of advanced pancreatic cancer by ultra-minimum incision personalized intratumoral chemoimmuno-Therapy (UMIPIC-Therapy) and to further analyze its role as an immune adjuvant. Method: Patients with late stage pancreatic cancer (92 cases) were treated with UMIPIC-Therapy or just intratumoral Chemotherapy (ITCT) , UMIPIC-Therapy is a proprietary therapeutic regimen which is composed of three components (i.e. an oxidant, a cytotoxic drug and a hapten) that is utilized in chemotherapeutic modulation. The patients (at end of study, 47 patients with complete response analysis data and 45 patients with complete survival data were in the randomly divided two groups: Control group of ITCT alone with an oxidant and a cytotoxic drug without hapten and the experimental group receiving UMIPIC-Therapy with an oxidant, a cytotoxic drug plus hapten. Result: In the ITCT (control) and UMIPIC (experimental) groups, the clinical response rates were 92.86% and 82.88% respectively; the median survival time and 6-month survival rate were 4.98 months vs 6.45 months and 45% vs 64%, respectively. While all of above mentioned showed no statistical difference (P>0.05), 1-year survival rate of the ITCT group was 5% while those of the ITCIT group was 28% and statistically significant (P<0.05). Conclusion: The hapten enhanced immunotherapy by ultra-minimum incision personalized intratuoral chemoimmuno-therapy (UMIPIC-Therapy) is shown to be effective in the pancreatic cancer. Our data suggests that the hapten plays an important role in prolonging the patient survival time is could be very valuable in future clinic applications. Citation Format: Baofa Yu, Feng Gao, Wei Han, Zhenlu Ma. Hapten enhanced personalized chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmuno-therapy: UMIPIC-therapy in advanced pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B90.

Introduction to Irreversible Electroporation—Principles and Techniques

Irreversible electroporation (IRE) is a novel nonthermal focal ablation technique that uses a series of brief but intense electric pulses delivered by paired electrodes into a targeted region of tissue, killing the cells by irreversibly disrupting cellular membrane integrity. Unlike other ablation methods, IRE has relatively little effect on connective tissues and nerves and has a low patient effect. The ability of IRE to achieve cell death immediately adjacent to large vessels without effect on the vessels themselves has raised the possibility of better treatment of advanced pancreatic cancer. Because of the low effect on the patient, IRE is well suited for use in conjunction with chemotherapeutic agents. The IRE effect is not uniform and is dependent on the intrinsic conductivity of the tissue, the number of pulses delivered, the current flow achieved, and the total time for the treatment. It is currently under investigation for a wide range of solid tumors and prostate cancer in humans and in animals in the breast, brain, and spinal cord. In clinical practice, IRE can be administered either percutaneously under imaging guidance or at open operation under direct vision. In animals there is some evidence of an immune response presumably due to exposure of the intracellular target material, resulting in a greater therapeutic effect. Unlike many other cancer treatments, IRE has been introduced for human clinical use at a very early stage of development of the technique and much of the basic understanding of how and when to use IRE is still under investigation.

A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. ClinicalTrials.gov:NCT00789633.

Clinical study of S-1 alone compared to gemcitabine combined with S-1 in treatment of patients with advanced pancreatic cancer

Objective To value the clinical efficacy and toxicity of S-1 compared to gemcitabine combined with S-1 in treatment of patients with advanced pancreatic cancer. Methods From January 2011 to December 2013, the data of 46 patients with advanced pancreatic cancer were analyzed retrospectively, including 24 patients receiving S-1 alone (group A) and 22 patients who received gemcitabine combined with S-1 (group B). The results were evaluated by objective response rate (ORR), disease control rate (DCR), survival time and safety. Results In group A the ORR was 20.8 % (5/24), DCR was 66.7 % (16/24), median progression-free survival was 4.8 months, median overall survival was 9.6 months, and 1 year survival was 12.5 %. In group B the ORR was 27.3 % (6/22), DCR was 72.7 % (16/22), median progression-free survival was 5.9 months, median overall survival was 10.3 months, and 1 year survival was 22.7 %. There was no significant difference between the two groups (P>0.05). The incidence rates of leukopenia, neutropenia and thrombopenia in group A were significantly lower than those in group B (P<0.05). Conclusion S-1 alone and gemcitabine combined with S-1 have similar effects in the treatment of advanced pancreatic cancer, but the toxicity of S-1 is mild and tolerable. Key words: Pancreatic neoplasms; S-1; Gemcitabine

Phase I trial of enzalutamide, gemcitabine, and nab-paclitaxel as a first-line treatment for advanced pancreatic cancer.

e15250 Background: Sex steroid hormones may play an important role in the growth and progression of pancreatic cancer. In the Phase Ia portion of this trial, we evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel in pts with metastatic pancreatic cancer as a first-line treatment. Methods: Standard 3+3 dose escalation design was used to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg daily. Gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) was administered IV on days 1, 8 and 15 of a 28-day cycle. The dose limiting toxicity (DLT) period was 28-days or until the beginning of the second cycle. A full PK profile was evaluated for nab-paclitaxel after the initial dose through 48 hours post dose while enzalutamide was tested on day 1 at 1 and 2 hours post dose along with levels every 7 days to follow achievement of steady state by day 29 (C2D1). Results: Twelve patients with stage IV pancreatic can...

Modified FOLFIRINOX as initial treatment of advanced pancreatic cancer: A single cancer center experience.

e15228 Background: The FOLFIRINOX regimen has been shown to significantly increase both overall (OS) and progression free (PFS) survival in metastatic pancreas cancer (MPC), compared to gemcitabine...

Dendritic cells generated with PDL-1 checkpoint blockade for treatment of advanced pancreatic cancer.

4128 Background: The efficacy of immunotherapy with monocyte derived dendritic cells (MoDC) is controlled via immune checkpoints, among them the PD-1/PDL-1 pathway. PDL-1 expressed on DC delivers an inhibitory signal to T-cells upon binding to PD-1 expressed on activated T-cells. Blocking of PDL-1 on DC may lead to improved efficacy of DC therapy for pancreatic cancer. Methods: After isolating monocytes from peripheral blood of n = 44 patients with stage IV pancreatic cancer, who failed first-line chemotherapy, antigen primed MoDC were generated using standard protocols. Patients included in the follow-up analysis received a minimum of 3 vaccines. 10 patients received MoDC modified by PDL-1 blockade after failure of previous DC therapy. PDL-1 blockade was performed by adding soluble CD80 or anti-PDL-1 to MoDC. Cytokine release and T-cell activity were measured exemplary using a mixed lymphocyte culture (MLC). Results: Median survival after onset of DC-therapy was 8 months with MoDC alone (18 months after primary diagnosis) with longest follow up of 36 months (49 months after primary diagnosis). We could induce a secondary stabilisation (4 to 8 months) in 5 from 10 patients, who failed to respond to previous DC therapy by using MoDC modified by PDL-1 blockade. Cytokine measurement using MLC, which was exemplarily performed, shows a change in the cytokine release upon PDL-1 blockade. Conclusions: An effective immune response requires both the inhibition of inhibitory signals and the activation of an antigen specific T-cell response. The efficacy of dendritic-cell based therapy may be improved by blockade of PDL-1 on dendritic cells to avoid an inhibitory signal and thus improve the T-cell specific response. Further investigations are necessary to ascertain whether the combination of systemic anti PD1-therapy with DC therapy using MoDC modified with PDL-1 blockade may further enhance therapeutic efficacy in solid tumors.

The Impact of Diabetes Mellitus and Metformin Treatment on Survival of Patients with Advanced Pancreatic Cancer Undergoing Chemotherapy.

PurposeA causal relationship between diabetes mellitus (DM) and pancreatic cancer is well established. However, in patients with advanced pancreatic cancer (APC) who receive palliative chemotherapy, the impact of DM on the prognosis of APC is unclear.Materials and MethodsWe retrospectively enrolled APC patients who received palliative chemotherapy between 2003 and 2010. The patients were stratified according to the status of DM, in accordance with 2010 DM criteria (American Heart Association/American Diabetes Association). DM at least 2 years’ duration prior to diagnosis of APC was defined as remote-onset DM (vs. recent-onset).ResultsOf the 349 APC patients, 183 (52.4%) had DM. Among the patients with DM, 160 patients had DM at the time of diagnosis of APC (remote-onset, 87; recent-onset, 73) and the remaining 23 patients developed DM during treatment of APC. Ultimately, 73.2% of patients (134/183) with DM received antidiabetic medication, including metformin (56 patients, 41.8%), sulfonylurea (62, 45.5%), and insulin (43, 32.1%). In multivariate analysis, cancer extent (hazard ratio [HR], 1.792; 95% confidence interval [CI], 1.313 to 2.445; p < 0.001) showed association with decreased overall survival (OS), whereas a diagnosis of DM (HR, 0.788; 95% CI, 0.615 to 1.009; p=0.059) conferred positive tendency on the OS. Metformin treatment itself conferred better OS in comparison within DM patients (HR 0.693; 95% CI, 0.492 to 0.977; p=0.036) and even in all APC patients (adjusted HR, 0.697; 95% CI, 0.491 to 1.990; p=0.044).ConclusionFor APC patients receiving palliative chemotherapy, metformin treatment is associated with longer OS. Patients with DM tend to survive longer than those without DM.

BRCA-associated pancreatic cancer: the evolving management.

Pancreatic cancer is one of the deadliest cancers. While BRCA-associated pancreatic cancers are uncommon, the distinctive phenotype of this malignancy may offer unique therapeutic targets. At the 2013 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, a review of the characteristics and outcomes of one large case series (Abstract #278), however, did not reveal a benefit to first-line platinum chemotherapy in the treatment of advanced pancreatic cancer. In another study (Abstract #147), substantial responses were observed in both patients with BRCA2-associated pancreatic cancer treated with the poly-(ADP-ribose) polymerase (PARP) inhibitor ABT-888 (veliparib). We will review these abstracts and our current knowledge of the treatment for patients with BRCA-associated pancreatic cancer. In this group of patients, these new results continue to shape our understanding of this disease.

Phase I trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer.

467 Background: Despite recent advances, patients with metastatic pancreatic cancer have a very poor prognosis with a median survival of less than 1 year. Sex steroid hormones may play an important role in the growth and progression of pancreatic cancer. Anti-androgen drugs have demonstrated to have activity in pre-clinical pancreatic cancer models. In this Phase 1a/Ib trial, we evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel. Methods: Pts with histologically confirmed metastatic pancreatic adenocarcinoma were included in this trial as a first-line treatment. Standard 3+3 dose escalation design was used to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg daily. Gemcitabine 1,000 mg/m2 was administered IV on days 1, 8 and 15 of 28-day cycle. The dose of nab-paclitaxel was 125 mg/m2 IV on days 1, 8 and 15. The DLT period was 28-days or until the beginning of the second cycle. Imaging studies were performed every 2 cycles. Results: Eight pts with stage IV pancreatic cancer have been enrolled in this trial, 5 pts at the first dose level and 3 pts at the second dose level. The median age was 64 years (50-80 years). All pts were male with an ECOG performance status of 1. Five pts had liver metastases. One patient was non-evaluable for DLT. No DLTs have been observed. Grade 3 treatment related AEs include febrile neutropenia (n=1), Neutropenia (n=1), ALT elevation (n=1). Grade 2 anemia and thrombocytopenia was seen in one patient. Grade 1 AEs included anemia (n=2), neutropenia (n=4), thrombocytopenia (n=3), diarrhea (n=1), fatigue (n=2), pruritis (n=1), nausea (n=1), hyponatremia (n=1) and AST elevation (n=1). Three pts had restaging studies performed and all had stable disease by RECIST criteria. There were decreases in size of target lesions in all the 3 patients along with a decrease in CA 19-9 levels. Conclusions: Enzalutamide at the dose of 160 mg daily is safe to administer in combination with gemcitabine and nab-paclitaxel. No unexpected toxicity has been observed. Cytopenias secondary to chemotherapy is common. Preliminary signals of efficacy were observed with this combination. Clinical trial information: NCT02138383.

Phase Ib study of PGG beta glucan in combination with anti-MUC1 antibody (BTH1704) and gemcitabine for the treatment of advanced pancreatic cancer.

TPS493 Background: Mucin 1 (MUC1) is a tumor associated membrane-bound glycoprotein that promotes oncogenesis through promotion of epithelial cell polarity loss, anti-apoptosis, and hypoxia driven angiogenesis. MUC1 overexpression is associated with aggressive behavior and poor outcomes in pancreatic ductal adenocarcinoma (PDAC), and increased resistance to gemcitabine (G) in vitro. BTH1704 (BTH) is a humanized monoclonal antibody (MAb) targeting aberrantly glycosylated MUC1. Imprime PGG (PGG) is a soluble yeast-derived b 1,3/1,6 glucan that binds complement receptor 3 (CR3) on innate immune cells priming them to exert anti-tumor activity against complement (iC3b) opsonized tumor cells. Following incubation of PGG with whole blood from healthy subjects, variability in PGG binding to neutrophils and monocytes has been observed, with higher binding and functional changes correlating with higher levels of endogenous anti-b glucan antibodies. BTH binds to antigens (MUC1), leading to iC3b opsonization of tumor cells thus, allowing PGG-primed leukocytes to kill the iC3b-opsonized tumor cells. This forms the rationale for testing BTH1704 combined with G + PGG. Methods: This is a single institution Phase 1b dose escalation study with a standard 3x3 design to determine the maximal administered dose (MAD) of BTH combined with G + PGG in patients with previously treated advanced PDAC.Each dose cohort includes at least one subject with high and one low PGG binding capability. Primary objectives: establish MAD of BTH combined with G + PGG. Secondary objectives: characterize adverse effects, clinical response, time to progression, progression free and overall survival. Correlative objectives: quantify PGG binding, MDSC phenotyping of PBMC, anti b glucan antibody levels, MUC1 IHC. Inclusion criteria: confirmed advanced PDAC, ECOG PS 0-2, rest period 2-6 weeks from prior first- or second-line treatment. Exclusion criteria: uncontrolled chronic illness. Administration and design: BTH and PGG are administered on days 1, 8, 15, and 22 of a 28-day cycle; G is administered on days 1, 8, and 15. The study is currently enrolling patients. Clinical trial information: NCT02132403. Clinical trial information: NCT02132403.

FOLFIRINOX for the treatment of advanced pancreatic cancer: U.K. West Midlands experience.

450 Background: The PRODIGE 4/ACCORD 11 trial demonstrated that FOLFIRINOX significantly improved response rates and survival in patients with metastatic pancreatic cancer, compared to gemcitabine. However this regimen is associated with significant toxicity. We have thus analysed the safety, tolerability and efficacy of FOLFIRINOX given outside a clinical trial setting. Methods: A retrospective analysis was conducted on all patients treated with FOLFIRINOX for advanced pancreatic cancer between July 2012 and July 2014, within the West Midlands region in the UK. Data was collected on baseline demographics, disease stage, toxicity and response to chemotherapy. Results: A total of 60 patients were identified (28 locally advanced, 32 metastatic). The median age was 59 (range 34-74) and 12% of patients were aged 70 or over. The primary tumour was located in the head of the pancreas in 68% of patients and 38% of patients had a biliary stent. All patients had an ECOG performance status of 0 or 1 (45% and 55% respectively), and had received no prior chemotherapy for advanced pancreatic cancer. FOLFIRINOX was commenced at reduced doses in 79% of patients, and subsequent dose reductions were required in 81% of patients. The median number of FOLFIRINOX cycles administered was 6 (range 1-14) but 33% of patients currently remain on treatment. Hospital admissions were required in 58% of patients but only 22% of hospital admissions were for neutropenic sepsis. FOLFIRINOX was discontinued in 30% of patients due to toxicity. There were no treatment related deaths. Of 40 patients who were eligible for assessment of response, 38% achieved a partial response and a further 45% achieved stable disease. Four patients with LA pancreatic cancer became suitable for curative surgical resection following chemotherapy; 2 of these also received chemoradiotherapy. The median overall survival for patients with metastatic disease was 12 months and the median overall survival for patients with locally advanced disease has not been reached. Conclusions: Our data shows that FOLFIRINOX can be safely delivered in a real world setting. Even with reduced doses, the response rates and survival outcomes are comparable with the results from the PRODIGE 4/ACCORD 11 trial.

Therapeutic Effects of SB Natural Anticancer Drug in 50 Patients with Stage IV Pancreatic Cancer

Purpose: Pancreatic cancers are still difficult in early dection and progression is rapid that can be hardly cured. Surgical therapy is limited by its hypervascularity, poor responses of radiational therapy and anticancer drugs. Root extract of Pulsatilla Koreana, SB365 has shown apoptotic effect by Pulsatilla saponin D component, and inhibition of angiogenesis by deoxypodophyllotoxin element as well as c-Met signal pathway inhibition in the pancreatic cancer. We present its therapeutic effect in 50 patients with stage IV pancreatic cancer for the first time in Korea. Materials and Methods From March 2013 to May 2014, there were 50 patients with stage IV pancreatic cancers admitted to Sahmyook Seoul Hospital for SB anticancer treatments with 24 control patient who did not get SB anticancer treatments in the same time interval.SB anticancer drug were administrated directly intratumoral injections using radiofrequent ablation techniques by interventional radiologist and intravenously by physician. Results Total 50 patients received SB anticancer therapy, male 25, female 25, and age ranged from 27 to 86 years with median age of 57 years with liver, lung, peritoneum and/or bone metastases, Control 24 patients, male 10, female 14, age ranged from 36 to 90 years with median age of 69 years. There was no significant side effect clinically as well as by laboratory measurement after every SB injections. Number of survived patients in SB study group was 27cases (54.0%), but only 2 cases(8.3%) in SB not treated control group ( p<0.01 with statistical significance). The total survival duration after diagnosis in SB treated group was 7 months, but 4 months in SB not treated control group. The interval from initial diagnosis to SB treatment in survived group was 2 month, less than 1 month in 12(44.4%) patients while in death group 5 months, and less than 1 month in only 3(14.3%) cases (p< 0.01 with statistical significance).The follow up duration and progression free estimate after SB treatment in survived group was median 5 months each, while in control group, median 2 months. Conclusion: SB natural anticancer drug administration is safe and increases survival rate and duration compared with control group, especially when treated within 1 month after diagnosis of stage IV pancreatic cancer. Long term follow up study with more numbers of patients are needed for accurate efficacy of SB treatment for advanced pancreatic cancer.

Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer.

BackgroundPancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena.MethodsWe examined the ability of cellular arginine depletion through treatment with PEG-ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined.ResultsCombination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2.ConclusionThe ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer.

Meeting report: the 1st BRG-training school in Asia, a first step in the building of an ASEAN encapsulation network.

The 6th training school on bioencapsulation of the Bioencapsulation Research Group (BRG http://bioencapsulation.net/2014_Nha_Trang/index1.html) took place in Nha Trang, Vietnam, in March 2014. This event, organised by AgroSup Dijon, Nha Trang University and the BRG with the support of the Agency of French‐Speaking Universities (Agence Universitaire de la Francophonie, AUF) and Buchi was the first BRG‐event organised in Asia. The success of this school, which brought together bioencapsulation researchers from eight countries of the Association of Southeast Asian Nations (ASEAN) along with those from Europe, Japan, Australia and many other countries, shows that bioencapsulation is a growing field in Southeast Asia. After a brief presentation of bibliometric data showing the dynamism and the specificities of encapsulation research in Southeast Asia, a presentation of the achievements and needs in some countries is given showing the interest in building a network in this region.

33. Irreversible electroporation in the treatment of advanced pancreatic cancer

33. Irreversible electroporation in the treatment of advanced pancreatic cancer

EL12 - Novel Combination Chemotherapy for Pancreatic Cancer

Gemcitabine (GEM) has long been the standard treatment for advanced pancreatic cancer (APC). Multiple phase III trials have failed to show survival benefit over GEM alone. The combination of GEM plus erlotinib showed a statistical improvement in survival, but this difference was not considered clinically significant.Recently, new cytotoxic combination therapies achieved a significant survival benefit compared to GEM alone. In 2010, ACCORD 11 trial demonstrated that FOLFIRINOX, a combination of 5-fluorouracil, irinotecan and oxaliplatin, improved survival from 6.8 to 11.1 months (HR 0.57). However, there were significantly more grade 3-4 adverse events, including neutropenia (45.7%), thrombocytopenia (9.1%), febrile neutropenia (FN) (5.4%), diarrhea (12.7%), and neuropathy (9.0%). Phase II study conducted in Japan also showed similar efficacy of FOLFIRINOX regimen, but grade 3-4 neutropenia and FN were more frequent (77.8% and 22.2% respectively). In 2013, MPACT study showed that GEM plus nab-paclitaxel improved survival from 6.7 to 8.5 months (HR 0.72). Common grade 3 or higher adverse events were neutropenia (38%), thrombocytopenia (13%), FN (3%), fatigue (17%), neuropathy (17%), and diarrhea (6%).There is a need to identify which regimen should be chosen for first-line treatment. It is difficult to draw any conclusions since these two regimens were not compared directly in the same trial. But cross-trial comparison suggested that FOLFIRINOX seemed to be the most effective regimen, while GEM plus nab-paclitaxel was likely a better tolerated regimen. Therefore, at present, patients with the highest performance status (PS) and no liver dysfunction are likely to receive FOLFIRINOX, and those with slightly depressed PS maybe be offered GEM plus nab-paclitaxel. Patients with poorer PS will likely be offered treatment with GEM (plus erlotinib) or oral fluoropyrimidine. Predictive biomarkers are needed to select the most effective regimen for individual patients with APC.

Abstract CT218: Wilms′ tumor gene 1 (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer

Abstract Wilms′ tumor gene 1 (WT1) protein is an attractive target for cancer immunotherapy. To investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide for patients with advanced pancreatic cancer, 32 HLA-A*24:02-positive patients were enrolled. HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) was injected intradermally biweekly. Moreover, gemcitabine (1,000 mg/m2) was administrated on days 1, 8, and 15 of a 28-day cycle. Median survival time and one-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity (DTH) to WT1 peptide alone was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T-lymphocytes (CTLs) before and during treatment. In conclusion, the combination therapy was well-tolerated and promising treatment for advanced pancreatic cancer. DTH-positivity to WT1 peptide alone and a higher frequency of memory-phenotype WT1-specific CTLs could be useful predictive markers for clinical efficacy. Citation Format: Shigeo Koido, Sumiyuki Nishida, Sadamu Homma, Yutaka Takeda, Hideo Komita, Satoshi Morita, Toshinori Ito, Soyoko Morimoto, Yoshihiro Oka, Satoru Yanagisawa, Yoichi Toyama, Masahiro Ikegami, Hiroaki Nagano, Toshifumi Ohkusa, Hisao Tajiri, Haruo Sugiyama. Wilms′ tumor gene 1 (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT218. doi:10.1158/1538-7445.AM2014-CT218