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Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium. Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum. Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.

Biliary tract cancers (BTC) comprise a group of uncommon malignancies in which the standard therapies are minimally effective and evolve slowly. Like the majority of gastrointestinal cancers, with some notable exceptions, the impact of immune-based approaches has yet to be seen. However, the etiological background of BTC-overlapping in almost every known causative or associated factor with inflammation-provides a strong clue that these approaches may have an impact in this group of diseases. This review covers what we currently know about the role of the immune system in the etiology of BTC, highlighting differences by subtype, and pointing to the therapeutic opportunities currently entering the clinic or about to do so. (Hepatology 2016;64:1785-1791).

BACKGROUND Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. METHODS Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. RESULTS Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. CONCLUSIONS Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Cancer 2016;122:1757-65. Published 2016. This article is a U.S. Government work and is in the public domain in the USA..

People living with HIV (PLWH) are diagnosed with cancer at an increased rate over the general population and generally have a higher mortality due to delayed diagnoses, advanced cancer stage, comorbidities, immunosuppression, and cancer treatment disparities. Lack of guidelines and provider education has led to substandard cancer care being offered to PLWH. To fill that gap, the NCCN Guidelines for Cancer in PLWH were developed; they provide treatment recommendations for PLWH who develop non-small cell lung cancer, anal cancer, Hodgkin lymphoma, and cervical cancer. In addition, the NCCN Guidelines outline advice regarding HIV management during cancer therapy; drug-drug interactions between antiretroviral treatments and cancer therapies; and workup, radiation therapy, surgical management, and supportive care in PLWH who have cancer.

SUMMARY Biliary tract carcinoma is a rare malignancy. We performed a comprehensive analysis of published prospective clinical trials in advanced biliary tract carcinoma in an attempt to identify active regimens in this setting. We searched PubMed and abstracts presented at the American Society of Clinical Oncology, Gastrointestinal Cancer Symposium, European Society of Medical Oncology and European Cancer Organization conferences for clinical trials in this disease. We found 83 trials. The effect of gemcitabine on overall survival benefit showed a strong trend (p = 0.014) and an improvement in progression-free survival (p = 0.003). Gemcitabine-based regimens containing 5-fluorouracil showed a trend toward an improved overall survival (p = 0.047) relative to platinum agents. Our findings support gemcitabine as the chemotherapy backbone for the treatment of patients with cholangiocarcinoma. Gemcitabine plus 5-fluorouracil combinations warrant further investigations.

Squamous metaplasia is commonly detected in pancreatic parenchyma; however, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis.Surveillance, Epidemiology, and End Results (SEER) registries were examined identifying pancreatic SCC and adenocarcinoma cases from 2000 to 2012. Age-adjusted incidence rates were calculated. Patients with SCC versus adenocarcinoma were compared by clinical features and relative survival outcomes.We identified 214 patients with SCC and 72,860 with adenocarcinoma. For SCC, incidence rates tripled between 2000 and 2012. Significantly higher SCC incidence rates were observed in older age groups, blacks, and males. Greater proportion of patients with SCC than those with adenocarcinoma had poorly differentiated histology (73.0% vs 43.7%, P0.001). In both subtypes, majority of patients had stage IV disease, 59.0% for adenocarcinoma versus 62.6% for SCC. The 1- and 2-year relative survival rate was significantly lower in patients with SCC versus adenocarcinoma. The 1-year relative survival was 14.0% (95% confidence interval, 9.5%-19.4%) for SCC, compared with 24.5% (95% confidence interval, 24.2%-24.8%) for adenocarcinoma.Although primary pancreatic SCC is a rare neoplasm, incidence rates for this subtype are increasing. Relative to adenocarcinoma, pancreatic SCC is characterized by poorly differentiated histology and worse survival.

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors.The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib.Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105.A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study.TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.

SummaryCurrent systemic treatment options for patients with hepatocellular carcinoma (HCC) are limited to sorafenib. With the recent FDA approval of the second PD1-PD-L1 pathway inhibitor, immunotherapy has gained even more interest as a potential novel treatment option for patients with HCC. This is due not only because of the failure of other treatment approaches in the past, but also because immunological mechanisms have been shown to play an important role during tumor development, growth, and treatment. Here we present a review of immunological mechanisms in the liver relevant for tumor progression and treatment. We summarize our current knowledge on immune activating and immune suppressing mechanisms during tumor initiation, development, and treatment. We try to explain the paradox of how inflammatory responses in a setting of chronic infection promote tumor development, while the primary aim of immunotherapy is to activate immunity. Finally we summarize recent advances in addition to providing an outlook for the immunotherapy of HCC.

Background: Signet ring carcinoma (SRC) is a distinct histological phenotype of adenocarcinoma. There are only a few published studies specifying the epidemiology of SRC with extragastric presentation. The purpose of our study was to define the most common primary sites of extragastric SRC, determine the incidence, and to compare survival by primary site and disease stage. Methods: The Surveillance Epidemiology and End Result (SEER) database was examined from 2000 to 2012 in order to identify SRC histology (8490) and determine its most common primary sites, incidence, and survival by site and stage. The five most common primary extragastric sites were identified by utilizing ICD-0-3/WHO 2008 classification. Age-adjusted incidence rates for extragastric SRC were calculated and compared to gastric SRC. Relative survival (RS) and overall survival (OS) at 1 and 3 years were analyzed by primary site and stage using Kaplan-Meier method. Chi-square test was used for categorical variables. Results: A total of 24,522 histologically confirmed cases of SRC were identified, and SRC comprised 0.5% of all malignant neoplasms. Among cases with known histological grade, 89.7% had poorly differentiated tumors. Overall, digestive system origin was recorded for 90% of SRC cases. Approximately half (44.2%) of primary SRC tumors were detected outside of the stomach. The most common primary sites for extragastric SRC were colon (40.5%), esophagus (11.9%), rectum (9.8%), lung/bronchus (7.3%), and pancreas (4.7%). The incidence rates for common extragastric SRC were much lower than for gastric SRC, and were higher for males than females (p Conclusion: Our study indicated that extragastric SRC most commonly occurs in the colorectum, esophagus and lung/bronchus. We confirmed that the primary site substantially impacts survival. Thus, development of unique molecular or histologic markers may help to identify the organ of origin and thereby determine prognosis in these phenotypically similar neoplasms. Citation Format: Chul Kim, Susanna Ulahannan, Julius Strauss, Jaydira Del Rivero, Austin Duffy, Tim F. Greten, Oxana V. Makarova-Rusher. Epidemiology and survival in patients with extragastric signet ring carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3421.

TPS470 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. MEDI4736 is a human monoclonal antibody directed against PD-L1. Blockage of ligation between PD-L1 and PD1 induces local immune activation and prevents anergy and exhaustion of effector T-cells. Several studies have documented an increase in peripheral antitumor immunity following radiation. This effect is evidently too weak to be clinically relevant, but has the potential to be boosted by immune modulation. The underlying hypothesis of this study is that the effect of immune checkpoint inhibition (accomplished via tremelimumab and/or MEDI4736) treatment can be enhanced by radiation in patients with advanced pancreatic carcinoma. Whilst radiation treatment in pancreas cancer is commonly employed in limited or early stage disease, if radiation can enhance the effect of immune checkpoint inhibition to produce systemic anti-tumor effects the combination could become an effective treatment modality for patients with advanced disease. Methods: Patients with histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-recurrent) disease are being enrolled to this pilot study. The primary objectives are to determine the safety, tolerability and feasibility of immune checkpoint inhibition [comprising either MEDI4736 alone (Cohort A), Tremelimumab (Cohort B) or combined MEDI4736 and Tremelimumab (Cohort C)] in combination with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic cancer. Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 criteria and accessible for biopsy. No prior radiation therapy to the pancreas allowed. There is no limit to the number of prior chemotherapy regimens received; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: NCT02311361.

270 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA) have been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced HCC. Methods: Patients with HCC [Childs Pugh A/B7; BCLC B/C; ECOG 0/1; post-sorafenib (BCLC stage C only)] or refractory BTC were enrolled in a study of Tremelimumab combined with subtotal TACE, RFA or CA performed on week 6. All BTC patients received RFA as the immune-stimulant in combination with tremelimumab. Tumor biopsies were performed at baseline and at time of RF/TACE. Results: 34 pts enrolled (28 HCC, 6 BTC). Characteristics: M:F 26:8; Median age 54(range 42-76); In HCC pts cirrhosis present in 17pts, BCLC Stage B/C: 9/19; Hepatitis B/C/neg: 4/15/9. 13 pts received TACE, 16 underwent RFA (inc 6 BTC pts), 3 CA during week 6 of tremelimumab therapy. 2 pts did not receive an ablative procedure. No DLT encountered. Most common toxicity was pruritus. One patient developed pulmonitis and was taken off study but remained disease-free at 16m. Of N = 17 pts evaluable for response outside of TACE/RFA-treated lesion 4 (23.5%) achieved confirmed partial responses. 8 of 9 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed immune cell infiltration on all evaluable patients. Median PFS for the evaluable HCC population (N = 25) was 5.7m. Conclusions: Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and feasible. Obtaining tumor biopsies at baseline and at the time of RFA/TACE is safe. Evidence of immune cell infiltration was seen on evaluable patients. Encouraging clinical activity seen with objective confirmed responses, PFS 5.7m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618.

220 Background: Although squamous metaplasia is commonly detected in pancreatic parenchyma, primary pancreatic squamous cell carcinoma (SCC) is a rare malignancy with unknown incidence and unclear prognosis. Methods: Using SEER-18 database primary code C25 in conjunction with histology codes for SCC (8052-8053, 8070-8078, 8083-8084) and for adenocarcinoma (AC) (8052-8053, 807-8078, 8083-8084), we identified cases diagnosed from 2000 to 2012. Age-adjusted incidence rates and trends over time were calculated. Patients with SCC were compared with AC by clinical features (TNM categories and histological differentiation), and 1-year and 2-year relative survival (RS) outcomes. Chi-square tests for categorical variables and t-tests for continuous variables were conducted. Kaplan-Meier method was used to estimate RS and Z-test was used to compare RS rates. SEERStat and GraphPad were used for analysis. Results: We identified 214 patients with microscopically confirmed SCC and 72,860 patients with AC. SCC constituted less than 1% of all cases of primary pancreatic cancer; however, age-adjusted incidence rates for this subtype tripled between 2000 and 2012. The annual percent increase of SCC incidence rate was 5.5%. Significant differences were observed by age, gender and race: older age groups, blacks and males had higher SCC incidence rates. Compared to AC, a greater proportion of patients with SCC had poorly differentiated histology (15.8% vs. 30.4%, p < 0.01). Similar to AC, the majority of patients with SCC had stage IV disease at diagnosis, 54.3% for AC vs. 56.4% SCC. The 1-year and 2-year relative survival rates were significantly lower in patients with SCC than AC. The 1-year relative survival rate was 15.8% (95%CI = 10.4-22.3) for SCC, compared with 24.7% (95%CI = 24.3-25.1) for AC, p < 0.001. Conclusions: Although primary squamous pancreatic carcinoma is a rare neoplasm, incidence rates for this subtype are markedly rising. Relative to adenocarcinoma, pancreatic squamous cell carcinoma is characterized by poorly differentiated histology and worse survival.

Introduction: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Patients with advanced hepatocellular carcinoma, who progressed on standard of care, were treated with tremelimumab and tumor ablation (radiofrequency ablation and transcatheter arterial chemoembolization) to augment anti-tumor immunity. Treatment was safe and feasible. Encouraging clinical activity has been seen with objective confirmed partial responses in 4/12 (33%) evaluable patients and a time to progression of 7.4 months. Here we report first results from immunoanalysis evaluating tumor biopsies, immune cell subsets in peripheral blood and serum viral loads in patients with chronic HBV or HCV infection. Methods: 20 Patients with HCC were treated with tremelimumab and tumor ablation on clinical trial NCT01853618. Tumor biopsies were taken at the time of ablation and peripheral blood mononuclear cells (PBMC) were collected before and during treatment in a subset of patients. Serum samples were tested for viral load (quantitative HCV RNA). Serum HBsAg titers were measured by chemiluminescent microparticle immunoassay (CMIA) using the ARCHITECT platform (Abbott Laboratories, Chicago, IL), as per the manufacturer's instructions. Tumor biopsies with analyzed by immunohistochemistry for CD3, CD4, CD8, CD20 and Granzyme B. Eleven-color flow cytometry was performed to study PBMC using the following antibodies: CD4, CD3, CD4, CD8, CD11c, CD14, CD19, CD20, CD25, CD38, CD45RA, CD56, CD123, CD127, CCR7, CCR4, CXCR3, PD-1, 4-1BB, TIM3, CTLA4, PD-L1, ICOS, HLA-DR. Statistical analysis was done using the Wilcoxon signed rank test. Results presented are preliminary and update data will be presented at meeting. Results: Immunohistochemical analysis of tumor biopsies demonstrated an increase in the CD3+CD8+ T cell population in tumors. CD8+ T cells stained positive for Granzyme A. No changes in the number of CD68+ macrophages were seen. Multi-color flow cytotometry PBMC revealed statistically significant changes after the 1st cycle of activated CD4+ and CD8+ T cells. There was a trend towards a reduction in CD4+ Tregs. Activated CD8+ T cells remained elevated for more than three months. Eight of 9 patients with quantifiable HCV experienced a marked reduction in viral load. Four of 4 HBV patients experienced a reduction in quantitative HepBsAg. Analysis of immune cell phenotype and more in depth analysis of tumor samples is ongoing and will be reported. Conclusions: Tremelimumab in combination with subtotal TACE or RFA leads to an accumulation of intratumoral CD8+ T cells, an activation of CD4+ and CD8+ T cells in peripheral blood and reductions in HCV viral load and HBsAg. Citation Format: Firouzeh Korangy, Mei ElGindi, Drew Pratt, David Venzon, Austin Duffy, Oxana Makarova-Rusher, Sid Kerkar, David Kleiner, Bradford Wood, Tim Greten. Tremelimimab activates CD4 and CD8+ T cells in patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A195.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Primary liver cancer is the sixth most common cancer worldwide, with HCC representing the majority of the cases. In the U.S., HCC rates are higher among Hispanics, Asians and blacks than among whites. Whether the higher risks are due to different distributions of risk factors is not clear. Thus, we conducted an analysis of HCC risk factors by race/ethnicity in the SEER-Medicare database for the years 2000-2009. Methods: HCC cases (n = 8,116), identified by ICD-O morphology codes 8170-8175, were compared to a 5% random sample of cancer-free persons in the SEER areas (n = 313,525). Risk factors examined included type II diabetes (DM II), obesity, hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-related disorders. Multivariate logistic regression analyses, which adjusted for age, location, gender, income and date of diagnosis as well as the other risk factors were used to compare risk factors by racial/ethnic group. Results: Risk factors by race/ethnicity | Risk factor | White | Black | Asians | Hispanics | |:----------------- | ------- | ---------------- | ------ | ---------------- | ---- | | | N 6,120 | N 668 | N 971 | N 357 | | | % | OR (95% CI) | % | OR (95% CI) | % | OR (95% CI) | % | OR (95% CI) | | Obesity | 6.3 | 1.06 (0.9-1.2) | 5.5 | 1.0 (0.7-1.5) | 0.7 | 0.2 (0.1-0.8) | 7.8 | 1.2 (0.7-1.9) | | DM II | 44.5 | 2.9 (2.8-3.1) | 41.8 | 1.3 (1.1-1.6) | 38.1 | 1.8 (1.5-2.1) | 54.6 | 2.0 (1.5-2.7) | | HBV | 1.8 | 3.8 (2.6-5.7) | 3.6 | 1.6 (0.7-3.7) | 17.7 | 17.1 (11.8-25.0) | 2.0 | 1.4 (0.2-11.1) | | HCV | 16.8 | 19.7 (17.1-22.6) | 34.0 | 36.8 (28.0-48.6) | 31.1 | 21.4 (15.4-29.9) | 22.7 | 16.0 (9.2-28.1) | | Alcohol cirrhosis | 11.4 | 4.7 (3.7-5.8) | 7.6 | 4.5 (2.4-8.5) | 4.0 | 3.8 (1.3-11.7) | 17.1 | 3.3 (1.7-6.8) | | Alcohol NOS | 13.1 | 2.7 (2.2-2.9) | 13.2 | 1.6 (1.1-2.4) | 3.7 | 2.0 (1.0-4.1) | 14.8 | 1.6 (0.8-3.0) | | Cirrhosis NOS | 33.3 | 45.5 (41.2-50.4) | 24.1 | 17.9 (12.3-25.9) | 36.8 | 36.9 (26.2-52.0) | 44.8 | 27.6 (18.9-40.3) | NOS not otherwise specified. Conclusion: Major HCC risk factor profile is differ across race/ethnical groups. While diabetes is most common risk factor overall, it is most prevalent in Hispanics. HCC related to HCV is more common in blacks and Asians, and to HBV in Asians. Citation Format: Oxana V. Makarova-Rusher, Sean F. Altekruse, Timothy S. McNeel, Barry I. Graubard, Austin G. Duffy, Susanna V. Ulahannan, Tim F. Greten, Katherine A. McGlynn. Risk factors for hepatocellular carcinoma (HCC) by race/ ethnicity in the United States. [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 875. doi:10.1158/1538-7445.AM2015-875

e17591 Background: Background: Curative treatments are less frequently used in racial/ethnic minorities with hepatocellular carcinoma (HCC) leading to worse survival. It is unknown if any progress was made in reducing these disparities in the past decade. Methods: Patients with HCC (histology 8170-8175, topography C22.0) were identified in SEER 18 database 2000-2011, analyzed by ethnicity/race (Hispanics and non-Hispanic (NH) whites, Asians, blacks and American Indians/Alaska Natives (AI/AN) and divided into 3 time intervals (2000-2003, 2004-2007, and 2008-2011). Treatment variables included curative (transplantation, resection, and ablation) and palliative. Statistical analysis was performed using Chi-Square and Kaplan-Meier tests. Relative survival (RS) was calculated to adjust for differences in background mortalities. Results: We identified 40148 patients with race/ethnicity as follows: NH whites (N 19584), NH Asians (N 7444), NH blacks (N 5228), NH AI/AN (N 443) and Hispanics (N 7449). The analysis s...

639 Background: ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of eukaryotic translation initiation factor 4E (eIF4E), a potent oncogene. In preclinical models, ISIS demonstrated enhanced activity in combination with irinotecan (Iri). The purpose of this study was to determine maximum tolerated dose (MTD) and explore efficacy in an irinotecan-refractory colorectal cancer (CRC) population. Methods: Phase (Ph) I: Patients (pts) with advanced carcinoma (ECOG 0-2) received ISIS 183750 at 800 or 1,000 mg IV q-weekly in combination with Iri 180 mg/m2 q-2weekly. Ph II: Pts with irinotecan-refractory colorectal cancer were treated with ISIS 183750 1,000mg IV q-weekly in combination with Iri 160 mg/m2. Peripheral blood was analyzed for eIF4E mRNA. Tumor biopsies were obtained at baseline and C1D15 for ISIS 183750 IHC and eIF4E mRNA quantification. Response was assessed q8weeks by RESIST criteria. Results: 24 pts (14M/10F, median age 63 (range 43-79), ECOG PS 0/1/2: 5/18/1, prior chemotherapy regiments 3 (1-7)) were treated with ISIS 183750 + Iri. Ph 1: N=14 (colorectal (9), pancreas (3), endometrial (1), small bowel (1)). Ph 2: N=10 (colorectal). Median time on treatment was 56 days (2-232). The most common grade 3-4 adverse events were neutropenia 8/24 pts (33%) and hypoalbuminemia 6/24(25%). No dose limiting toxicities were seen. Efficacy data were evaluated in 15 irinotecan-refractory CRC pts. There were no objective responses. Stable disease was seen in 7/15 (47%) patients, median time of disease control was 22.1 wks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, intracellular presence of ISIS 183750 was detected by IHC in all biopsied patients. Conclusions: ISIS 183750 at the maximum dose tested of 1,000 mg in combination with irinotecan was feasible and relatively well tolerated. Even though intracellular penetration of ISIS was observed, it did not result in objective tumor response. Consequently, further exploration of resistance mechanisms is needed. Clinical trial information: NCT01675128.

TPS788 Background: AMP-224, a B7-DC Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not to PD-1LOcells which represent the normal activated T cell population. Several preclinical studies have documented an increase in peripheral antitumor immunity following radiation, a phenomenon known as the “abscopal effect”. Tumor PD-L1 expression has also been shown to be induced by radiation, which can suppress the anti-tumor immune response. Inhibition of PD-1/PDL-1 axis has been shown to improve anti-tumor immunity by blocking the tumor-mediated suppression of cytotoxic T cells. The aim of the study is to evaluate whether the anti-tumor immunity of anti-PD1 therapy (with AMP-224) can be enhanced by radiation therapy. Methods: Patients with histologically confirmed metastatic colorectal cancer to liver are being enrolled to this pilot study. The objectives are to determine the safety, tolerability and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) to metastatic hepatic metastasis in patients with advanced colorectal cancer. Select eligibility are as follows: at least 1 measurable metastatic hepatic lesion by RECIST 1.1 criteria and amenable to SBRT. Patient must have progressed on or been intolerant of at least one prior oxaliplatin- and/or irinotecan-containing regimen and have metastatic lesions that are not amenable to curative resection; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: awaited.

291 Background: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and causes ADCC and apoptosis of proliferating endothelium. Sorafenib is the only FDA-approved drug in HCC. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) + sorafenib (10 mg/kg daily p.o.) or sorafenib alone with assessment for CD105 expression, tumor size. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid. Correlative biomarkers included DCE-MRI, color Doppler ultrasonography, circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors, soluble CD105 and tumor IHC for CD105. Samples were also collected for immunogenicity and pharmacokinetics. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors by sorafenib. Anti-CD105 antibody + sorafenib reduced tumor volume compared to sorafenib alone. Clinical trial: 19 pts were enrolled; Hep B/C/NA: 2/10/7; M:F 13:6; Mean age of 60 (range 18-76); 1 DLT (increased AST) occurred at 10mg/kg. Three of 14 (21%) evaluable pts achieved PR by RECIST. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median time on study was 4 months (range 2 to 22 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity was observed and the study is proceeding to the phase 2 stage. Full correlative and clinical data will be presented. Clinical trial information: NCT01306058.

355 Background: Transplant, resection, and ablation are potentially curative treatments for hepatocellular carcinoma (HCC) with limited outcome data in young-old (65-74) and older (≥75) patients. Methods: We evaluated curative treatment and relative survival (RS) outcomes in patients with HCC in 3 age groups (