Pancreatic Ca Research Articles

A phase I study of PT-112 in advanced solid tumors.

2519 Background: PT-112 is a novel platinum-pyrophosphate agent designed to avoid the toxicity and drug resistance mechanisms of conventional chemotherapy. Pre-clinical models show effects on multiple cell signaling components: p16 mediated G1/S cell cycle arrest; modulation of MDM2/p53 expression; extrinsic apoptosis initiation; and immunogenic cell death (ICD) induction. This Phase I first-in-human, multicenter, open label study assesses PT-112’s safety and pharmacokinetic (PK) profile in advanced solid tumor patients (pts), to determine the RP2D and signals of activity. Methods: Pts with advanced solid tumors and acceptable marrow / organ function received PT-112 IV over 1-hr on days 1, 8, and 15 every 4 wks in a 3+3 dose escalation design. Intra-subject escalation was allowed. PK samples from cycles 1-2 were analyzed by ICP-MS and LC-MS/MS. Results: 44 pts have been treated across dose levels (DL) from 12-300mg/m2. Cumulative dosing ranged from 1 to 60 infusions, and cumulative exposure from 96 to 5,244 mg/m2. PK parameters were dose proportional. Target Cmax and AUC levels were achieved, with constant VD. DLTs were observed at 150mg/m2 (G3 pancytopenia); 250mg/m2 (G2 renal injury in a cervical ca pt with hydro-nephrosis); and 300mg/m2 (G3 rash). The most common treatment-related AEs were G1-2 fatigue (26% pts), nausea (23%), vomiting (14%), constipation (12%), and diarrhea (12%). Numerous signals of activity were observed at DLs ≥ 125mg/m2. These include a confirmed PR in a NSCLC pt with 6 prior lines of therapy and no response to TKI inhibition or PD-1 blockade; PFS > 6 months (7-18 months) in 3 pts; metabolic response via PET scan in bone and liver mets (basal cell and pancreatic ca.); biomarker responses in ovarian and prostate ca.; and nodal/metastatic volumetric reduction in 3 pts. Conclusions: PT-112 is a well-tolerated novel agent with a pleiotropic mode of action and feasibility for long-term and combination treatment. Numerous signals of anti-cancer efficacy in heavily pre-treated pts suggest lack of cross-resistance with conventional agents. MTD has not yet been reached. PT-112’s profile makes it an attractive candidate for further development, including in combination with immunotherapy. Clinical trial information: NCT02266745.

Characterization of cancer family history among patients with PCa cancer.

272 Background: Family history (FH) is a well-documented risk factor for prostate cancer (PCa). Certain cancers (Ca) are also shown to co-segregate in families. This study evaluated Ca FH in PCa patients (pts) and the impact of FH on clinical covariates. Methods: FHs were collected from 535 PCa pts at Tulane Hospital between 2015 and 2016. Incidence rates of familial Cas were analyzed. Age at diagnosis (dx), Gleason score, and the presence of metastases at any time were documented. Chi-square and the Mann-Whitney U tests were performed to identify correlations between clinical parameters and FH. Results: 435 pts (81.3%) had a Ca FH. 281 pts (52.5%) had ≥2 relatives with Ca. Rates of breast, lung, colorectal, pancreatic Ca, and leukemia FH did not vary between pts diagnosed at ≤55 and those diagnosed over 55. Pts with PCa FH were more likely than pts with no PCa FH to have an age of dx ≤55 (p= 0.0169). Median age at dx was 59 for pts with PCa FH and 64 for pts with no PCa FH. PCa FH did not affect Gleason score or the presence of metastases. Conclusions: PCa, breast, lung, and colorectal were the most common familial Cas reported. Pts with PCa FH were younger at dx than those without PCa FH. Further studies are needed to understand the co-segregation of PCa with other Cas and genetic studies are needed to clarify the mechanisms of these trends. [Table: see text]

Endoscopic Hemostasis for Cancer Specific Bleeding Is Safe and Effective: A Single Center Experience

Introduction: Gastrointestinal bleeding (GIB) specifically from cancers (Ca) involving the gastrointestinal tract (GI) is rare representing 5% of GIB. Endoscopy (endo) plays an important role in diagnosis of tumor related bleeding and occasionally in treatment. There is very little data published on this topic especially on methods of hemostasis(HMS) and thus there are currently no guidelines specifically addressing this issue. HMS in the past has been mostly attempted with electrocautery including Argon Plasma Coagulation (APC), epinephrine injection (Epi) or mechanical such as clipping. Initial HMS is thought to be often successful however rebleeding (RBL) rate is reported to occur in 16 to 80% of the cases. Newer methods such as Hemospray (HS) and Cryotherapy (cryo) has been reported in selected cases to be effective. This data shows the outcome of endoscopic HMS at a tertiary Ca Center including outcomes of cryo and HS.Figure 1Figure 2Methods: This is a retrospective review of all endoscopic HMS procedures performed at a tertiary care Ca center for malignancy related bleeding between July 2013 and November 2015. Data obtained include CA type, presentation, site of bleeding, HMS method used, adverse events, immediate success, time to RBL and long term outcome. Early RBL was defined as occurring in less than 30 days. Results: 13 procedures were performed with immediate HMS achieved in all cases. Most patients presented with overt bleeding. Ca types included esophageal, colorectal, pancreatic Ca with gastric involvement and Large B cell lymphoma with gastroduodenal involvement. HMS methods included APC, Dual therapy with Epi/APC, endoscopic clipping, cryo and HS. Early RBL occurred in 3 cases. Delayed RBL requiring another intervention occurred in 6 cases. All RBL cases occurred after treatment with APC. Patients treated with clipping, cryo or HS did not require any further interventions. There were no adverse events noted. Data is shown in table 1. Endoscopic videos are available. Conclusion: GIB from Ca is rare. Endo plays a very important role in diagnosis and treatment. Endoscopic HMS was found to be safe in this series with no adverse events. It was very effective in achieving immediate HMS. Long term HMS was achieved in 53% of the cases. HMS methods which are well established include electrocautery and mechanical based methods. Cryo and HS are promising option but further studies are needed. Endoscopic HMS should be considered for Ca related GIB due to its efficacy and safety.

The Role of CA19-9 in Predicting Tumour Resectability in Carcinoma Head of Pancreas

Carbohydrate antigen 19-9 (CA 19-9) is a tumour associated antigen. Blood levels may be elevated in benign as well as malignant conditions. Its sensitivity (70-90%) and specificity (68-91%) are inadequate for accurate diagnosis. It can be used to predict the extent of disease and outcome after resection. The aim of the present study was to assess the role of CA 19-9 in predicting the resectability of the tumour in the head of pancreas. This was a prospective study which included 30 patients and study period was from May 2012 to October 2014. Data collected from all patients with carcinoma of the head of pancreas on the basis of contrast enhanced computed tomography/Magnetic resonance cholangiopancreaticography. CA 19-9 levels were measured and recorded. Patients who were medically unfit for surgery or those who didn't warrant palliative surgery were excluded from the study. During surgery the operative findings on operability were documented and tabulated against corresponding CA 19-9 levels. Of the 30 patients who were operated, 13(43.3%) patients had operable tumours and underwent Whipple's procedure and 17(56.7%) underwent palliative bypass procedure. Of the 30, CA 19-9 levels were elevated in 9(30.0%) and were normal in 21(70.0%). Among 13(43.3%) who had operable tumours, CA 19-9 was elevated in 4(13.3) and was normal in 9(30.0%). Of the 17(56.7%) who had inoperable tumours CA 19-9 was elevated in 5(16.7%) and was normal in 12(40.0%). Among the 17 who had inoperable tumours, 8(47.1%) were diagnosed preoperatively and of them CA 19-9 levels were raised in 2(11.8%) and normal in 6(35.3%). In the group of 9(52.9%) who had inoperable tumours diagnosed intraoperatively, CA 19-9 was raised in 3(17.6%) of them and was normal in the remaining 6(35.3%) of them. Based on the study findings, it can be stated that there is no significant correlation with resectability of pancreatic adenocarcinoma and CA 19-9 and it doesn't predict vascular involvement and liver metastasis.

Gremlin1 and chronic pancreatitis: a new clinical target and biomarker?

Chronic pancreatitis (CP) is a progressive inflammatory condition triggered by the loss of exocrine pancreatic acini and fibrosis or scarring of pancreas tissue [1]. The exocrine pancreas comprises about 90 % of total pancreas and releases digestive enzymes such as chymotrypsin, amylase and lipase in response to a meal. CP develops in 16 % of patients presenting with acute pancreatitis, a number which increases to 38 % upon second admission. The most common symptom of CP is abdominal pain, which can be both intermittent and persistent. Furthermore, 95 % of CP patients present with alcoholic or idiopathic disease [1]; however, excessive consumption of alcohol alone may not be the cause of CP. Additional causes of CP include gallstones, exposure to volatile hydrocarbons, viral infection and genetic mutations [2]. There are various genetic forms of CP including gain-of-function mutations in genes such as Prss1 which results in a form of trypsin that is resistant to degradation and can lead to an autosomal-dominant hereditary form of CP [1]. In contrast, loss-of-function mutations in genes such as Spink1 and Cftr, which is involved in the inactivation of pancreatic trypsin, are also associated with CP. The overall survival rate for CP patients is only 50 % at 20–25 years from diagnosis [3], and CP patients also have an increased risk of developing pancreatic cancer [4]. Current treatments for CP involve pain management with paracetamol and non-steroid anti-inflammatory drugs as first line, followed by mild opioids such as tramadol. An important clinical feature of CP is steatorrhea, caused by reduced absorption of fat in the intestine. Supplementation of pancreatic enzymes such as lipase, together with H2 histamine antagonists, is used to reduce this malabsorption of lipids [1]. Micronutrient therapy containing antioxidants such as Antox® (containing methyl and thiol moieties, as well as methionine and vitamin C) is now being tested, as it has been shown to control the pain and attacks associated with CP [1]. The pathogenesis of CP is believed to be associated with inappropriate pancreatic enzyme activation and clearance from the acinar cells. Increased pancreatic Ca levels as a result of excessive consumption of alcohol or other causes is common in CP, with calcifying protein deposits implicated in the blockage of the acinar ducts, leading to digestive enzyme accumulation and subsequent inflammation. Other evidence suggests that noxious agents such as alcohol are directly toxic to the acinar cells and may also trigger the activation of pancreatic stellate cells [5]. An important element of the pathogenesis of CP is fibrosis, which can occur via sustained activation of pancreatic stellate cells that migrate to sites of tissue damage and secrete excess extracellular matrix proteins, causing fibrosis or scarring [6]. Factors that drive this fibrotic response include lipid peroxidation products released by acinar cells and TGF-β1 release by reactive oxygen species (ROS)-activated mast cells that infiltrate the pancreas as part of the inflammatory response to CP [1]. Progression of fibrosis in CP is associated with the loss of acinar and islet cells, leading to both exocrine and endocrine pancreas dysfunction. There are currently no effective therapies to prevent or reverse CP [7]. Given the insidious nature of CP, together with the increased mortality rate and pancreas cancer risk, improved treatment options for reversing the progressive fibrosis associated with this disease are urgently needed. To this end, new molecular targets that are involved in the onset and progression of fibrosis associated with CP need to be identified. * Derek P. Brazil d.brazil@qub.ac.uk

Tumor markers in pancreatic cancer: 2013.

Amongst the tumor markers for pancreatic cancer CA 19-9 is being used most widely and newer clinically useful applications of this tumor marker are being researched. We will discuss four abstracts presented at the American Society of Clinical Oncology (ASCO) Annual Meeting which contribute to expanding the application of CA 19-9 measurement (Abstracts #4042, #4058, #e15082, #e15146).

Phase I/II trial of IMMU-132 (isactuzumab govitecan), an anti-Trop-2-SN-38 antibody drug conjugate (ADC): Results in patients with metastatic gastrointestinal (GI) cancers.

703 Background: Trop-2 is a tumor-associated glycoprotein highly expressed in many epithelial cancers. Elevated expression has been linked to more aggressive disease and a poorer prognosis. IMMU-132 is an ADC comprising a humanized mAb binding to Trop-2 and conjugated to SN-38 (drug: Ab ratio = 7.6), the active metabolite of irinotecan. After finding potent activity in human tumor xenografts, a phase I/II trial was undertaken (NCT01631552). Methods: Pts with relapsed/refractory metastatic cancers were enrolled, starting at a dose of 8 mg/kg given on days 1 and 8 of a 3-week cycle. Dose levels of 8 and 10 mg/kg were chosen for phase II (N=47). Results: Sixty pts with advanced GI cancers were enrolled in phase I/II. Neutropenia was the principal dose-limiting toxicity, with fatigue, diarrhea, nausea, and vomiting as other reported toxicities. In the phase II pts with median prior therapies of 3 (range 1-7), the following moderate/severe drug-related toxicities occurred: neutropenia (Gr 3, 18.8%; Gr 4, 10.4%); fatigue (Gr 3, 14.6%; Gr 4, 0%), anemia (Gr 3, 10.4%; Gr 4, 0%); diarrhea (Gr 3, 4.2%; Gr 4, 0%). Of 29 CRC pts (10 mg/kg [N=9], 8 mg/kg [N=20]), 1 had a PR and 14 had SD as the best response by RECIST, with a time to progression (TTP) of 11.5+ months (mo) for the PR (65% shrinkage) and a median of 4.8+ mo for the SD pts (5 ongoing). This is a disease control rate (DCR) of 51.7%. Thirteen CRC pts had KRAS mutations, 7 with SD (median TTP = 4.4+ mo [range, 2.8-7.8 mo; 3 ongoing]). Of 15 pts with pancreatic ca, 8 had SD as best RECIST response (median TTP = 3.4 mo); DCR=53.3%. Among 11 pts with esophageal ca, 7 had CT assessments with 1 PR (TTP, 6.9+ mo), and 4 SD (TTP, 4.0+, 5.0, 6.0, and 6.9 mo) as best response; DCR=62.5%. Of 5 gastric ca pts, only 3 had post-baseline CT assessments, all with SD (1 with 19% target lesion reduction and an ongoing TTP of 6.7+ mo). Conclusions: IMMU-132 is a novel anti-cancer therapeutic, conjugating a topoisomerase I inhibitor to an internalizing, cancer-selective mAb. This ADC can be given safely and repeatedly over many months to heavily pretreated patients. Encouraging activity in pts with several metastatic gastrointestinal tumors has been observed. Clinical trial information: NCT01631552.

The Nature and Function of Immunogenic Tumor Proteins That Characterize Pancreatic and Colorectal Cancer: A Review

The use of immunotherapy as it relates to the treatment of solid tumor malignancies appears to be an effective approach for managing many patients who present with both recurrent and metastatic disease. This holds true, especially in those cases where patients have failed current chemotherapeutic protocols and evidence of tumor progression is noted. In such instances, the delivery of the proper immunotherapeutic agents may be effective either alone or in combination with chemotherapy. The ideal approach would be in the identification of an immunogenic protein that characterized and was specific for the tumor system to be treated. One of the first attempts to utilize specific active immunotherapy for treating cancer patients with advanced disease was by Ariel Hollinshead. She produced several vaccine preparations composed of tumor associated antigen (TAA) derived from pooled allogeneic tumor membrane preparations. These vaccines, obtained from operative specimens were shown to exhibit varying degrees of improvement in the overall survival of such patients. They were employed in treating patients with advanced malignancies including those having lung cancer, colon cancer and malignant melanoma. For most who received the vaccine following resection of an advanced disease process, survival results demonstrating 80-90% freedom of disease at 5 years could be achieved. These results were considered significant when compared to other therapeutic protocols available at the time. Further use in clinical trials were held back at the suggestion of the FDA due to possible viral contamination in the next set of vaccine preparations if any tumor specimen used contained the possible presence virulent strains of virus such as hepatitis, AIDS and HPV. At this point recombinant vaccines were felt to be essential if such vaccines were to be used in future clinical trials. Monoclonal antibodies were therefore developed against each of the pooled vaccine preparations and used for affinity purification and sequencing of the antigens. In reviewing our survival data results it became apparent that those who failed therapy were patients unable to mount an effective IgG1 response and not related to the presence of CD8 T cells. The mAbs were now produced in GMP format and clinical trials as such were initiated for patients with recurrent colon and pancreatic Ca having failed standard chemotherapy.

Abstract CT314: “Multi-metronomic” algorithms for targeted therapy to improve value of response and “failed drugs” for “resistant” women's cancers

Abstract The use of Bevacizumab (Bev) for ovarian cancer (OC) has been impeded by adverse events (AEs), long maintenance therapy (T) and tumor rebound. Eligibility, requirements and limits, as well as ideal time(s) and length of use remain unknowns. Drug interactions and algorithms offer testable solutions. Multi-metronomic Ts provide Bev with 5-6 synergistic integrated partners. Bruckner HW ASCO 06 gastric ca, ASCO 01,04,08,12 pancreatic ca; Hirschfeld A ASCO 12 cholangioca and Loupakis F ASCO GI 2013 colon ca Methods: For resistant OC Bev 10mg/kg day 1, Cyclophosphamide 250 150mg/m2 day 1 day 2 were combined with GFLIC - (D); Gemzar ° 500mg/m2, Fluorouracil ° 1500mg/m2, Irinotecan ° 80mg/m2, day1 , (Docetaxel (D) 25mg/m2) and Carboplatin ° AUC 2, day 2. (° reduced 20% on addition of D and then increased). D was added at complete response, plateau or any Bev stop. When Bev was resumed the use of D continued. GFLIC, core drugs were never stopped. Bev was briefly held for Gr 1-2 GI and other Gr 2-3 AEs. Exclusions: Helsinki criteria PS4 urgent surgery or 4 weeks survival. Sequential T at best response (CR or plateau) was evaluated for rapid response, and potential value for research, low tumor volume, Ts. Results: 30 OC patients pts had no severe clinical AEs, Bev could be resumed, stop-go (all but once) after Gr 2-3 AEs. None had rebound. RECIST response rates were > 80% and 12% SD after 3-8, median 5, lines had failed, 5 had failed Bev. Primary PACLITAXEL and carboplatin resistant ROC, had 5 of 5 CRs p 0.03-0.008 after either early- plateau or 2nd line retreatment recurrence, Multi line ROC > 4cm, size reduction was 60% to less than 2cm, 40% to less than 0.5cm; <4cm ROCs were “all” downsized, p 0.03. Post neuropathy resumption of D was safe and improved responses for half the pts. PFS for PS 0-2 multi-line ROC was not reached at 1 year; for performance status 3 pts it was 6 mos. Conclusions: The sequential multi drug cores give cytotoxic and targeted drugs second chances to help achieve symptom free small tumor status and, in high risk subsets, improve survival: 1, a second time after AEs ; 2, 6-24 mos after Bev failed; 3, as a possible multimetronomic T ; with unconventional low doses for Gemzar, Irinotecan, Docetaxel and Carboplatin; 4, replace maintenance, T to progression with either 4a, neoadjuvant or 4b, stop-go Ts. T creates 5, many ideal pts for research; 6, testable algorithms to reduce Bev's duration of use, 7, cost and 8, AEs by 50-75% and 9, selectively expand eligibility to PS3 pts. It is safer to use 5-6 drug cores than to use many 1-2 drug Ts. Cores are suitable for integration algorithms and drug development. Rapid sequential T to low volume OC, creates ideal pts for crossover immunoT and other targeted Ts for stable disease. These add value to response and biochemical modulation and second chances for both used drugs and “unnecessary” failures due to one Phase III, all or none, single drug survival tests of $50 million investments. Citation Format: Howard W. Bruckner, Azriel Hirschfeld, Jeanetta Stega, Peter Dottino. “Multi-metronomic” algorithms for targeted therapy to improve value of response and “failed drugs” for “resistant” women's cancers. [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 CT314. doi:10.1158/1538-7445.AM2014-CT314

A Phase I Multi-Arm Dose-Expansion Study of the Anti-Programmed Cell Death-Ligand-1 (Pd-L1) Antibody Medi4736: Preliminary Data

ABSTRACT Aim: MEDI4736 is a human IgG1 mAb, engineered to prevent antibody-dependent cell-mediated cytotoxicity (ADCC) activity, that blocks PD-L1 binding to PD-1 and CD-80. This expansion study (NCT01693562) assessed MEDI4736 in pts with NSCLC, melanoma (cutaneous and uveal), hepatocellular carcinoma (ca), squamous cell ca of the head and neck (SCCHN), gastroesophageal ca, pancreatic ca, and triple negative breast ca. Methods: 10–20 pts (performance status [PS] 0–1) were initially enrolled per tumor type/study arm, with expansion allowed upon observation of clinical activity. MEDI4736 was administered as 10 mg/kg IV every 2 wks (q2w) for up to 12 months, with retreatment permitted for progression during follow-up. Response was assessed by RECIST v1.1. Results: This multi-arm dose expansion study was initiated in Sep 2013. As of 14 April 2014, 288 pts median age 61y (20–96), 57% male, PS 0/1/unknown (31%/65%/4%), median 3 (1–11) prior treatments, had received a median of 3 (1–20) doses of MEDI4736 10 mg/kg q2w and were evaluable for safety. Safety profile appeared to be consistent across tumor types and with previous reports. Treatment-related adverse events (AE) in 34% of pts (any Grade [Gr]); Gr ≥3 in 5.6%; no Gr 4–5); AEs led to discontinuation of study drug in 5.8% (drug-related in 1 pt). Most frequent treatment-related AEs were fatigue (14%), nausea (8.7%), and rash (5%). Gr 2 pneumonitis (resolved with drug interruption/steroids) was seen in 1 pt (0.4%). No colitis reported. No immunogenicity detected at the 10 mg/kg dose; 1/89 with antidrug antibodies impacting PK. Tumor shrinkage has been seen across all histologies, with responses as early as 6 wks and after initial progression in some pts. Clinical activity to date appears durable (maintained ≥ 48 wks in 5 pts). Analysis of correlation between activity and clinical attributes or biomarkers including PD-L1 expression is ongoing. Conclusions: Results indicate that MEDI4736 has a manageable safety profile even in heavily pretreated pts. Evidence of clinical activity has been seen across all 9 tumor types; other tumor types will be evaluated. Current experience supports development of MEDI4736 as monotherapy and in combination with other anti-cancer therapies for multiple tumor types. Disclosure: N.H. Segal: Ad Board participation with MedImmune, Alkermes Scientific and Imugene. Research funding from BMS and Pfizer. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; O. Hamid: My only conflict here is the research funding that I received from Medimmune. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; W. Hwu: No financial interest in MedI4736,process involved in the research.I dont own stock,serve on ad board,board of director or other substantive relationship with research sponsor who consider research fund rec'd for conduct of Medi-sponsored study a COI; C. Massard: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Received financial support from MedImmune Inc. to cover the costs of conducting MedImmune-sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Antonia: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins: Employee of MedImmune and owns stock/stock options in AstraZeneca; P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; X. Li: Employee of MedImmune and owns stock/stock options in AstraZeneca; J. Vasselli: Employee of MedImmune and owns stock/stock options in AstraZeneca; S. Khleif: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I also function as a clinical advisor.

P-0004 - The Evaluation of Cellular and Humoral Immunity Characteristics in Gastrointestinal and Hepatocellular Cancers

Introduction: Gastrointestinal cancers (GI Ca) are a global health problem leading to high morbidity and mortality all over the world. Human organism presents a well organised defense mechanism against cancer cells by humoral and cellular immune system. Nowadays, cancer immunotherapy is an essential and promising research field of modern immunology. In this study, we aimed to evaluate the characteristics of the humoral and cellular immune systems in gastrointestinal and hepatocellular cancers (HCC) patients. Methods: Cellular and humoral immune parameters (CD3, CD4, CD8, CD16 / CD56 and CD 19 lymphocytes respectively) were investigated in the peripheral blood samples of 71 gastric Ca, 50 pancreatic Ca, 27 colorectal Ca, 50 HCC patients and of 30 healthy persons as control group by flow cytometry method. One way Anova and post hoc Dunnett tests were used to compare mean lymphocyte values of cancer groups with the control group. Significance level is determined as p: 0.05. Results: CD3 and CD4 lymphocyte levels were not significantly different in all cancer groups compared to the control group (Table-1). CD8 lymphocyte levels were significantly increased in pancreatic and colorectal cancer groups (p < 0.05) whereas CD19 lymphocytes were significantly lower in the same groups (p < 0.01-0.05). Natural killer (CD16 / CD56) lymphocytes were significantly higher in gastric Ca, colorectal Ca and HCC patients compared to the control group (p < 0.01-0.05). Conclusion: Cellular immunity is not weakened, even activated in the course of gastrointestinal carcinogenesis possibly related to malign stimulation. Interestingly, we observed the decline of the humoral immunity in gastrointestinal cancers. Strengthening humoral immune system by humoral immune methods (specific monoclonal antibodies etc.) must be considered as an adjunct to the cellular immune therapies (dendritic vaccines etc.).

Paraduodenal Pancreatitis: Clinical Performance of MR Imaging in Distinguishing from Carcinoma

To evaluate the diagnostic performance of contrast material-enhanced magnetic resonance (MR) imaging for distinguishing paraduodenal pancreatitis (PDP) from pancreatic head duct adenocarcinoma (CA) in patients with diagnoses confirmed by histopathologic analysis. This retrospective study was approved by the institutional review board and is HIPAA compliant. Between July 2007 and July 2010, 47 patients who underwent Whipple procedure and MR imaging less than 60 days before surgery were identified retrospectively. Two relatively inexperienced fellowship trainees with 9 months of body fellowship training were asked to record the presence or absence of three MR imaging features: focal thickening of the second portion of the duodenum; abnormal enhancement of the second portion of the duodenum; and cystic focus in the expected region of the accessory pancreatic duct. Strict criteria for diagnosis of PDP included presence of all three imaging features. Any case that did not fulfill the criteria was classified as CA. Sensitivity, specificity, positive predictive value, and negative predictive value for characterization of PDP was calculated for each reader with 95% confidence intervals. A κ test assessed level of agreement between readers. Each reader correctly categorized 15 of 17 (88.2%) PDP cases when all three imaging criteria were met. Alternatively, 26 of 30 (86.7%) pancreatic duct CA were correctly categorized as inconsistent with PDP. Four patients with histopathologic diagnosis of CA were incorrectly classified as PDP by each reader. Agreement between the two readers showed substantial κ agreement for the diagnosis of PDP and differentiation from pancreatic duct CA. Contrast-enhanced MR imaging may help accurately identify PDP and distinguish it from CA when strict diagnostic criteria are followed. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13112056/-/DC1.

Paraduodenal Pancreatitis: Clinical Performance of MR Imaging in Distinguishing from Carcinoma

To evaluate the diagnostic performance of contrast material-enhanced magnetic resonance (MR) imaging for distinguishing paraduodenal pancreatitis (PDP) from pancreatic head duct adenocarcinoma (CA) in patients with diagnoses confirmed by histopathologic analysis. This retrospective study was approved by the institutional review board and is HIPAA compliant. Between July 2007 and July 2010, 47 patients who underwent Whipple procedure and MR imaging less than 60 days before surgery were identified retrospectively. Two relatively inexperienced fellowship trainees with 9 months of body fellowship training were asked to record the presence or absence of three MR imaging features: focal thickening of the second portion of the duodenum; abnormal enhancement of the second portion of the duodenum; and cystic focus in the expected region of the accessory pancreatic duct. Strict criteria for diagnosis of PDP included presence of all three imaging features. Any case that did not fulfill the criteria was classified as CA. Sensitivity, specificity, positive predictive value, and negative predictive value for characterization of PDP was calculated for each reader with 95% confidence intervals. A κ test assessed level of agreement between readers. Each reader correctly categorized 15 of 17 (88.2%) PDP cases when all three imaging criteria were met. Alternatively, 26 of 30 (86.7%) pancreatic duct CA were correctly categorized as inconsistent with PDP. Four patients with histopathologic diagnosis of CA were incorrectly classified as PDP by each reader. Agreement between the two readers showed substantial κ agreement for the diagnosis of PDP and differentiation from pancreatic duct CA. Contrast-enhanced MR imaging may help accurately identify PDP and distinguish it from CA when strict diagnostic criteria are followed. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13112056/-/DC1.

A phase II study of Recchia's immunomodulatory schedule (RIS) as a maintenance therapy in high-risk tumors after a response.

3074 Background: F. Recchia et al. (Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: A phase II study. Int J Oncol. 20: 1275-1282, 2002) previously defined the possibility of achieving a chronic immune stimulation through a prolonged low dose sc interleukin 2 (IL2)-based schedule, leading to a prolongation of PFS in advanced cancer patients (pts). A confirmatory phase II study was started. Methods: Pts diagnosed of high risk solid tumors in response to chemotherapy were included. RIS consisted in low dose IL2 (1.8 MU sc per day, 5 days per week, 3 weeks per month) plus oral isotreonin (CRA, 0.5 mg/kg) the same days of IL2 and/or sc PEG-interferon (50 µg per week of treatment). No Chx was allowed with RIS, but concurrent maintenance with TKI or Hx was permitted. Results: Since 08/2007 to 01/2013, 69 pts (39 M/30 F, median age 60 y, range 31-78) were included. 51 pts were treated with stage IV disease. 36 pts entered in complete response (CR), 29 in partial response (PR), 1 with progressive disease, 3 adjuvant. 4/69 grade 3/4 toxicity, (6%): 1 fatal poliserositis resistant to cortisone after 20 months of RIS, 1 stopped RIS for reaction requiring steroids, 1 for multiinfarction dementia, 1 for grade 3 liver toxicity. 3 pts presented other alterations managed along the course of the RIS (1 PVT, 1 ITP, 1 angina resolved after stent placement). Grade 1-2 fever, fatigue and joint pain were commonly observed but usually controlled with NSAIDs. Among the 68 pts evaluable for response, one pt progressed, 26 presented stable disease (median TTP 3 mo, range 2-28), 3 presented PR (1 melanoma, 1 prostatic ca, 1 ovarian ca; 9, 11 and 28 mo respectively), and 38 maintained or presented CR (median TTP 19 mo, range 2-62+). Three pts in PR were converted to a CR during RIS (1 pancreatic ca, 1 ovarian ca, 1 larynx ca). Conclusions: In this study we confirm the previous results reported by F. Recchia et al. RIS represents a good alternative for high risk pts with solid tumors after systemic chemotherapy induced response with acceptable tolerability and offers in selected pts a possibility of obtaining a CR after a PR. Further validation and randomized studies are warranted.

Cumulative impact of algorithm-integrated multidisciplinary treatments for cholangiocarcinoma.

e14732 Background: Pancreatic Ca (PC) treatments (rxs) are often applied to patients (pts) with cholangioC (CC). Analyses support parallel "testing" of neoadjuvant (NeoA) and adjuvant (A) rx for CC pts. The rxs below “doubled” phase II objective response (OR) and survival (OS) vs PC. Methods: With pre-registration and IRB consent over ten years: GFLIP&gt;GFLIO &gt;GFLIO docetaxel (D) -/+mitomycin -C (MM-C) (Bruckner ASCO 01, 05, 08, 11) were applied to pts with PC and CC; stage adjusted, “possible best" choices for PC rxs were applied as NeoA and A rxs for high risk CC pts. Risk was defined by: margin, +; size, large; location, surgical difficulty, central; LNs, involved (or suspect), number of sites (and distance); pathology, atypical, high virulence and relapse (second surgery). These are the worst half of resected pts. Pts with unresectable (U) and metastatic (IV) CC were eligible with or without prior failure of some of the rx drugs. Targeted rx (TT) was briefly added, bevacizumab (B) 5mg/kg or cetuximab (C), as needed, to convert stable disease (SD) to NeoA eligible OR. Gallbladder Ca (GBC) pts were also treated. The algorithm's goal was to both optimize surgery for tumor reduction to improve rx and to select “timely” drug partners to reduce tumor size and allow further surgery. Results: No fatal AEs; Of 16 high risk, Adjuvant, resected pts, at 18 mos, 14 are alive, 10/11at 2 yrs, 6/7 (86%) at 3 yrs, 1 lost contact CC U/ IV, N=28, 4 lost contact 16/19 (84%) alive at 18 mos; 12/16 alive at 2yrs; 8/12 alive at 3 yrs. This vs. 50% (18mo) MST (ASCO 11). Of 7 NeoA, 4/4 were alive at 3 yrs, 3 others alive &lt; 3 yrs. (3 had best R with TT). *RR GFLIO ~ 60% add DMM-C ~ 60% € ~84% add TT ~20% €~ 87%. Conclusions: Rxs are safe, economical and well tolerated. € RR and OS adding (FI, D, D-MMC and selectively TT) are testworthy. Both 12 mos OS and NeoA/A are testworthy for GBC pts. B and C are individually active, safe and cost effective in brief NeoA usage applications. Low dose multi drug rxs are ideal safe platforms for TT. High serial € RR encourage 1° and 2° attempts at both debulking - strategic palliative and definitive surgery, ideally in trials to optimize (pt conditioning, eligibility) and compare NeoA vs A rxs.

Serial application and development of a new treatment paradigm for pancreatic cancer.

e14729 Background: New "paradigm driven" treatments (rx) “doubled” phase II survival (S) for 250 pts (ASCO, Bruckner 01, 04, 05, 08, 11). Addition or repartnering of drugs which failed trials or individual use (all in cost saving doses) produced synergism and reversed drug resistance. New rxs and safer doses were rapidly discovered by application of game theory to models of rxs, testing human pancreatic ca (PC) in vitro. Some measures of response (R) and extreme drug resistance as selection criteria were downgraded. Priority went to disease specific in vitro “R” rate (RR), increased number of simultaneously impacted drugs, activity at low doses and avoiding both duplication of targeting and antagonism. Clinical objectives now included wider eligibility, safety and 50% cost saving. Methods: With prospective registration and IRB consent rxs evolved: GFLIP&gt;GFLIO&gt;GFLIO -/+ docetaxel (D) -/+Mitoymcin-C (M). GFLIO and on progression GFLIO-D-M was the rx for 107 new tests (biopsy high risk ductal PC, PS 0-2, no active obstruction). Pts: unresectable (U) or metastatic (IV), G1; failing prior rx with some rx drugs, G2 or resected PC +/- margin G3 (G1, G2 all with progressive disease). Serial findings were compared (ASCO 05, 08). Results: OS for U/IV (G1 and G2) adding D-MMC to GFLIO was: n=70, at 24 mos 22/38 (S) (61%) alive; at 36 mos 8/20 (40%) vs prior 32 and 21%. Adjuvant, G3: n=37 at 18 mos 15, (50%) PFS, 28/30 S; alive S at 24 mos 10, (43%) PFS 20/23 S; at 36 mos 6, 40% PFS 14/15 S. Cumulative RR depending on R criteria meet models for 40-60% R per treatment with benefit rx (61-84%). Rxs were safe, no induction hospital AEs. Conclusions: This 350 pt prospective Phase II further supports testing of low dose rx; use of D-MMC as additions and adjuvant GFLIO rx (see Reni, Fine, Isakoff). The pts large N and long OS have testworthy practice changing: consent, reimbursement and trial (algorithm) “design” implications. Cost of drugs per unit of survival (S) can often be saved, safely while possibly improving QL and OS. Palliative applications of dose intensity, drug efficacy, tumor resistance and one drug at a time testing as rx concepts are (sometimes) questionable. improving QL and OS.

Phase I dose-escalation study of talimogene laherparepvec (T-VEC) for advanced pancreatic cancer (ca).

e14546 Background: T-VEC is an investigational, immune-enhanced oncolytic herpes simplex virus type I that selectively replicates in solid tumors. This was an open-label, dose-escalation study of T-VEC administered by endoscopic ultrasound (EUS)-guided fine needle injection (FNI) for advanced pancreatic ca. Methods: Eligibility criteria included ≥ 18 yrs old, ECOG 0-2, pathologically confirmed pancreatic ca with measurable disease (tumors ≥ 1 cm dia), and failure or unable to receive standard tx. T-VEC was administered at wks 6, 12, 18 to a single pancreatic tumor in 4 cohorts (C), 3 pts each enrolled sequentially (extended dosing allowed in pts thought to have benefit): C 1: 1 dose of 104 PFU/mL then 2 of 105 PFU/mL; C 2: 1 dose of 105 PFU/mL then 2 of 106 PFU/mL; C 3: 1 dose of 106 PFU/mL then 2 of 107 PFU/mL; C 4: 1 dose of 106 PFU/mL then 2 of 108 PFU/mL. 2 doses/pt were required for enrollment to the next C. A C could be expanded to 6 if 1 related DLT occurred. If 2 DLTs occurred, dose escalation was stopped. Endpoints were safety and activity as assessed by CT tumor dia changes from screening. Results: 17 pts were enrolled in C 1-3 given at least 1 dose of T-VEC; 65% were men; median age 54; 76% white, ECOG 0-1 82%. C 4 was not opened because of early study termination (not related to safety). 7/17 (41%) received all 3 planned doses and 8 (47%) had at least 1 post-dose CT scan. Only C 3 showed a median decrease in injected tumor dia with 2/4 pts achieving substantial tumor reductions (-36% and -33%). 3 pts (in C 1and C 3) showed decreases in the dia of ≥ 1 uninjected tumors (in liver, pancreas, kidney, and chest); 1 pt had disappearance of a nonmeasurable tumor in the liver. A dose trend was not observed for reductions of uninjected tumors. Most common AEs were ascites (47%), dehydration (41%), anemia, abdominal pain, constipation, and nausea (each 35%), and vomiting (29%). 2 pts (12%) had a grade 5 AE, both considered unrelated to T-VEC. Conclusions: EUS-guided FNI of T-VEC in advanced pancreatic ca, at initial doses of 104 to 106 PFU/mL followed by up to 107 PFU/mL, was feasible and tolerable. Evidence of biologic activity was observed. Future studies should be conducted in pts with less advanced disease, to allow sufficient time to receive multiple doses before PD.

Celiac plexus block in patients with nonpancreatic GI malignancies: Experience from a single institution.

e19551 Background: Celiac plexus block (CPB) has been well described in the treatment of pancreatic cancer pain. A recent Cochrane Library review of the subject concluded that CPB often resulted in fewer adverse effects when compared to chronic opioid use. CPB has not been well described in non-pancreatic GI malignancies. This study sought to determine the effectiveness of CPB in non-pancreatic GI malignancies. Methods: The Virginia Commonwealth University Massey Cancer Center database was queried for all patients who had undergone celiac plexus block, 2001-2010, using specific CPT billing codes. In addition, VCU Radiology Department records were also examined. Diagnosis, physician assessment of effectiveness, pre and post procedure pain scores, complications of procedure, and pain medication dosage pre and post procedure were all assessed. Results: 68 total patients were identified. 12 patients underwent a CPB for non-pancreatic GI malignancies and 56 for pancreatic cancer patients. The most common non-pancreatic GI malignancies were colorectal cancer (50%), hepatocellular carcinoma (8%), carcinoid (8%), duodenal cancer (8%), and gastric cancer (8%). By study criteria, 7 of the 12 patients had sufficient data for exploratory analysis. By physician assessment, CPB resulted in pain relief in 5 (71%) of 7 patients. Furthermore, the post procedure pain score improved but the usage of pain medications did not change. By comparison, 26 of 56 patients with pancreatic CA had sufficient data and 15(58%) has pain relief by physician assessment. Conclusions: CPB appears to provide some pain relief for patients with non-pancreatic GI malignancies. However, the retrospective design revealed missing data including: pre and post procedure pain scores, complications of procedure and patient assessments of pain. A prospective study is being considered.

A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.

2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.

Pancreatic Ca Risk Not Confined to Target Cyst

Pancreatic Ca Risk Not Confined to Target Cyst