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PURPOSE: Young-onset colorectal cancer is an emerging cause of significant morbidity and mortality globally. Despite this, limited data exist regarding clinical characteristics and outcomes, particularly in safety-net populations where access to care is limited. We aimed to study disparities in clinical characteristics and outcomes in patients with young-onset colorectal cancer in the safety-net setting. METHODS: We performed a retrospective review of patients < 50 years old diagnosed and/or treated for colorectal cancer between 2001 and 2017 at a safety-net hospital. Kaplan-Meier and Cox regression models were constructed to compare overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS) by race and ethnicity, stratifying for relevant clinical and pathologic factors. RESULTS: A total of 395 young-onset patients diagnosed at a safety-net hospital were identified and 270 were included in the analysis (49.6% Hispanic, 25.9% non-Hispanic Black, 20.0% non-Hispanic White, and 4.4% other). Non-Hispanic White race was independently associated with worse OS (hazzard ratio [HR], 0.53; 95% CI, 0.29 to 0.97), as were lack of insurance, higher clinical stage, and mismatch repair proficiency. There was no significant difference seen in PFS or RFS between racial and ethnic groups. CONCLUSION: Non-Hispanic White race or ethnicity was found to be independently associated with worse OS in a safety-net population of patients with young-onset colorectal cancer. Other independent predictors of worse OS include higher stage, lack of insurance, and mismatch repair proficiency.

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

Background: We studied the effect of race and ethnicity on disease characteristics and survival in gastrointestinal neuroendocrine tumors. Methods: The Surveillance, Epidemiology, and End Results database was used to select patients with non-pancreatic gastrointestinal neuroendocrine tumors diagnosed between 2004 and 2015. Trends in survival were evaluated among three groups: Hispanic, non-Hispanic White, and non-Hispanic Black. Kaplan&ndash, Meier and Cox regression methods were performed to calculate overall survival and cause-specific survival after adjusting for patient and tumor characteristics. Results: A total of 26,399 patients were included in the study: 65.1% were non-Hispanic White, 19.9% were non-Hispanic Black, and 15% were Hispanic. Non-Hispanic White patients were more likely to be male (50.0%, p &lt, 0.001), older than 60 years (48.0%, p &lt, 0.001), and present with metastatic disease (17.7%, p &lt, 0.001). Non-Hispanic White patients had small intestine neuroendocrine tumors, while Hispanic and non-Hispanic Black patients had rectum neuroendocrine tumors as the most common primary site. Hispanic patients had better overall survival, while non-Hispanic Black patients had better cause-specific survival versus non-Hispanic White patients. This finding was confirmed on multivariable analysis where Hispanic patients had improved overall survival compared to non-Hispanic White patients (Hazard ratio (HR): 0.89 (0.81&ndash, 0.97)), whereas non-Hispanic Black patients had better cause-specific survival compared to non-Hispanic White patients (HR: 0.89 (0.80&ndash, 0.98)). Conclusions: Race/ethnicity is an independent prognostic factor in patients with gastrointestinal neuroendocrine tumors.

Background & AimsPancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression. The progression of PDA is a highly complex and dynamic process featuring changes in cancer cells and stromal cells; however, a comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression.MethodsWe employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models.ResultsOur data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression. We also found distinct populations of macrophages with increasing inflammatory features during PDA progression. In addition, we noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts are dynamically regulated by epigenetic mechanisms.ConclusionThis study systematically outlines the landscape of cellular heterogeneity during the progression of PDA. It strongly improves our understanding of the PDA biology and has the potential to aid in the development of therapeutic strategies against specific cell populations of the disease.

[Background] In the phase III CORRECT trial, regorafenib significantly improved survival in treatment‐refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization., [Methods] This prospective, single‐arm study enrolled patients in 25 countries at 186 sites. Patients with treatment‐refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4‐week cycle. The primary endpoint was safety. Progression‐free survival (PFS) per investigator assessment was the only efficacy evaluation., [Results] In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment‐emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib‐related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib‐related TEAEs occurred in, [Conclusion] In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. [Implications for Practice] Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment‐refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events., This study was sponsored by Bayer. Editorial assistance in the preparation of this manuscript was provided by Ann Contijoch (Bayer) and Jennifer Tobin (SuccinctChoice Medical Communications, London, UK, with financial support from Bayer).

e15516 Background: The biology of microsatellite instability-high (MSI-H) in elderly colorectal cancer (CRC) patients is attributed to hypermethylation of promoter region of genes coding for mismatch repair proteins. It is unknown if such patients are predisposed to other malignancies. It is also unknown if the presence or absence of multiple primary malignancies affects elderly MSI-H CRC patients' survival. We aimed to evaluate the clinicopathologic features and outcomes in elderly CRC patients with MSI-H and multiple primary malignancies. Methods: We analyzed the National Cancer Database and included elderly (≥ 65 years) patients with CRC diagnosed between 2010-2016. MSI status was determined using genetic and immunohistochemical testing and categorized as microsatellite stable (MSS) and MSI-H. We further categorized the population into single primary malignancy versus multiple primary malignancies. We compared the baseline characteristics using the Chi-square test. Kaplan-Meier and log-rank tests were performed to calculate the overall survival (OS). Results: Among 52,494 elderly CRC patients, 78.0% were MSS, and 22.0% were MSI-H. The probability of MSI-H disease increased with increasing age, female gender, and non-Hispanic White ethnicity (all p < .001). MSI-H patients were associated with elevated CEA, wild-type KRAS, multiple neoplasms, right-sided tumors, stage II disease, and grade III/IV histology. The proportion of patients with multiple primary malignancies was higher in the MSI-H population versus MSS (36% vs. 31%, p < 0.001). The rate of multiple primary malignancies increased with age in both groups. Among MSI-H CRC patients, the factors associated with multiple primary malignancies included female gender (61.6%), non-Hispanic White ethnicity (86.3%), comorbidity index ≥ 2 (14.8%), and right-sided tumors (77.2%). Multiple primary malignancies were more frequently associated with stage I-III CRC as compared to metastatic CRC. For stage III-IV elderly MSI-H patients, the utilization of chemotherapy was 57.8% overall, but it was not significantly different between single primary malignancy versus multiple primary malignancies groups. MSI-H patients with single primary malignancy had the highest OS, followed by MSS patients with single primary malignancy, MSI-H patients with multiple primary malignancies, and MSS patients with multiple primary malignancies (74.7, 66.7, 58.1, 54.8 mos, respectively) (log-rank p < 0.001). Conclusions: Elderly CRC patients with MSI-H had a higher rate of multiple primary malignancies than MSS. This was associated with female gender, non-Hispanic White ethnicity, and right-sided tumor. MSI-H patients with single primary malignancy had the highest survival while the presence of multiple primary malignancies adversely affected survival in both MSI-H and MSS populations.

40 Background: Colorectal cancer patients with brain metastases experience poor outcomes; however treatment strategies are understudied. In this study, we investigated the impact of different treatments for colorectal cancer patients with brain metastases. Methods: We identified stage 4 colorectal adenocarcinoma patients with brain metastasis using the National Cancer Database diagnosed between 2010 and 2015. Patients with unknown survival data, other histologies, and multiple primary sites were excluded. Patients with and without brain metastasis were compared using the Chi-square test. Kaplan-Meier method was performed to calculate univariable overall survival (OS). We used the Cox regression model for multivariable analysis after adjusting by age, race/ethnicity, comorbidity score, surgery, chemotherapy, and radiotherapy. Results: Among 75,901 patients with stage 4 colorectal adenocarcinoma, 1.6% had brain metastasis. Patients with brain metastasis were more likely to have bone (23% vs. 5%, p < 0.001) and lung metastasis (52% vs. 21%, p < 0.001), but less likely to have liver metastasis (56% vs. 72%, p < 0.001) compared to patients without brain metastasis. Patients with brain metastasis had higher KRAS mutation rate (54% vs. 43%, p < 0.001). Patients with brain metastasis were more likely to be age ≥ 50 years (85% vs. 83%, p = 0.01), white race (76% vs. 71%, p = 0.001), and receive radiotherapy (63% vs. 12%, p < 0.001). Total 26.4% of patients with brain metastasis underwent metastasectomy, and those patients had better OS compared to patients with non-metastasectomy (median OS 12 vs. 4 months, p < 0.001). Median OS in all patients with brain metastasis was 5.5 months. Patients with brain metastasis who received multiagent chemotherapy had improved OS compared with patients who received single-agent chemotherapy (mOS 13 vs. 6 months, p < 0.001). Patients with brain metastasis who received brain radiotherapy had better OS (mOS 6.3 vs. 3.7 months, p = 0.005) than those who did not. On multivariable analysis, metastasectomy (HR 0.65 95% CI [0.57-0.75]) and receipt of multiagent chemotherapy (HR 0.68 95% CI [0.54-0.86]) were associated with favorable prognosis, but brain radiotherapy was not (HR 1.04 95% CI [0.91-1.19]). Conclusions: Brain metastases are rare in colorectal cancer but portend poor survival. Lung and bone metastases are found more frequently in these patients. Treatment with metastasectomy or multiagent chemotherapy is associated with improved overall survival.

e16710 Background: Pancreatic neuroendocrine tumor (PNET) is a rare disease. There is a lack of data on the association of age and sociodemographic characteristics on survival in patients with NET. Our study aimed to evaluate clinical, molecular differences, and survival outcomes in young-onset PNET (YOPNET) and late-onset PNET (LOPNET). Methods: We used the National Cancer Database to identify patients with YOPNET ( < 50 years) and LOPNET (≥50 years) who underwent definitive surgery diagnosed between 2004 and 2015. We calculated the survival outcomes using Kaplan Meier and Cox regression methods before and after 1:1 nearest neighbor propensity score matching. We used the AACR Genie cohort to compare mutation frequency with the Benjamini-Hochberg method between YOPNET and LOPNET. Results: A total of 6,259 patients with PNET were selected, of which 27% were YOPNET. Patients with YOPNET were more likely to be female, black, and Hispanic, have private insurance versus LOPNET (all p < .001). Patients with YOPNET had less comorbidity score, but greater tumor size ( > 4 cm) and higher stage (all p < .001). Patients with LOPNET were more likely to be treated in an academic/research facility ( p < .001). Patients with YOPNET were more likely to be located in the head of the pancreas ( p = .004). Patients with YOPNET had better overall survival (OS) as compared to patients with LOPNET which persisted after propensity score matching ( p < .001). This difference continued after adjusting for clinically significant variables (unmatched p = .008; matched p = .01) (Table). For genomic analysis, we identified 177 patients; 27% was YOPNET, and patients with YOPNET had a significantly lower rate of MEN1 mutation than patients with LOPNET (26% vs. 56%, p < .001). Rate of other mutations was not different. Conclusions: Patients with YOPNET who underwent surgery had better OS than LOPNET and were more likely to have higher stage and greater tumor size. YOPNET represents a disease with distinct clinical and molecular features. [Table: see text]

e16088 Background: Neoadjuvant short-course (SC) radiation (RT) followed by fluoropyrimidine based chemotherapy prior to surgery (Polish II approach) is a less utilized treatment in the United States for rectal cancer. Based on data suggesting equivalent or improved outcomes at lower cost compared to the long course neoadjuvant chemoradiation, our team started utilizing this approach for rectal cancer management at Simmons Comprehensive Cancer Center. We aim to document our experience with Polish II approach at NCI-designated comprehensive cancer center program. Methods: A retrospective review of stage I-IV rectal cancer patients, seen at an academic center or the Dallas County safety net hospital and treated at Simmons Comprehensive Cancer Center from Nov 2017 to Dec 2019. Patients were treated with neoadjuvant SC-RT followed by 3 cycles of FOLFOX prior to surgery and followed by adjuvant FOLFOX. Descriptive data for demographic, radiation, chemotherapy and surgery, hospitalizations, 30 day post-surgery admission, time to relapse, and laboratory parameters was collected. Results: Thirty-nine patients met the inclusion criteria (average age 58 years; 74% men/26% women). Forty-six percent of patients were Hispanic, 28.2% White, 15.4% African American and 7.7% Asian. The majority of patients had stage IIIB (46.2%), followed by IIIC (17.9%), IIA (12.8%), IIIA (7.7%), while rest were stage I, IVA or unknown (5.1%). All patients received 5 x 5 SC-RT, 100% completed 3 cycles of planned neoadjuvant FOLFOX (12.8% received 4-8 cycles) and 36/39 (92%) of patients underwent planned surgery. Median duration from SC-RT to chemotherapy was 12 days, and from chemotherapy to surgery was 37 days. Hospitalization occurred in 3 patients (7.7%) during neoadjuvant therapy, and in 8 patients (20.5%) within 30 days post-surgery. Complete pathological response was seen in 6 patients (16.6%) and near-complete pathological response in 3 patients (8.3%). Relapse occurred in 10.3% patients at time of data acquisition. Grade 3 and 4 neutropenia, anemia, and thrombocytopenia in neoadjuvant phase was observed in 8.6%, 25.7%, and 2.8% patients, respectively. Conclusions: In rectal cancer patients treated at a comprehensive cancer center, neoadjuvant Polish-II approach was feasible and well tolerated. Pathological response rates were comparable to historical data. SC-RT based neo-adjuvant therapy approach should be favored due to lower pelvic radiation dose, tolerance and convenience to patients.

4103 Background: Prior studies have observed under-utilization of adjuvant chemotherapy (ACT) in stage III colon cancer. Our aims were to observe the rate of utilization of ACT in very healthy or “ideal candidates”, identify reasons for omission and socioeconomic factors associated with ACT use, and observe patient outcomes. Methods: We queried patients from the National Cancer Database (NCDB) with stage III colon cancer, age

607 Background: There is paucity of data about racial/ethnic disparities in gastrointestinal tract neuroendocrine tumors (GiNET). We aimed to study the race/ethnic differences in disease characteristics and survival in GiNET. Methods: We analyzed the SEER database to identify cases with non-pancreatic GiNET between 2004 and 2015. We evaluated trends in incidence and outcomes between Hispanic, non-Hispanic/non-Black (NH/NB) and non-Hispanic Black (NHB). Kaplan-Meier method and cox regression model were performed for overall survival (OS) after adjusting for stage, grade, gender, race/ethnicity, and surgery. Results: 25,826 cases were included, 12.7% were Hispanic, 18.5% NHB and 68.8% NH/NB; males comprised 46.8%, 50.5%, 41.9%, respectively (p < 0.001). The overall incidence of GiNET increased two-folds in the ten years. The highest increase in incidence was observed in appendiceal NET followed by small intestine NET, and this increase was observed mostly among Hispanic population. NH/NB cases were older ( > 65 years) (31.3% vs. 23.3% vs. 23.5%; p < 0.001) and presented with metastatic disease (17.8% vs. 12.7%, 12.0%; p < 0.001). On multivariate analysis Hispanic population had significantly better OS than NH/NB and NHB (HR: 1.25 95% CI: 1.14-1.37 and HR: 1.15 95% CI: 1.033-1.28, respectively). For stage-4 low- and intermediate-grade GiNET, OS was better if surgery was performed (p < 0.001), and this trend was most pronounced among Hispanic as compared to NH/NB (HR 1.35, 95% CI 1.07-7.71). Conclusions: The incidence of GiNET had increased two-fold in the last ten years with the highest increase in Hispanic. However, Hispanic had significantly better overall survival than NH/NB and NHB population.[Table: see text]

674 Background: Young-onset pancreatic adenocarcinoma (YOPC) is uncommon but there are limited studies for these patients. We used a population based registry to compare the characteristics and outcomes of young-onset vs. older patients with pancreatic adenocarcinoma. Methods: We selected the patients with pancreatic adenocarcinoma from the SEER registry diagnosed between 2004 and 2015. Cases with age of diagnosis less than 50 were termed young-onset pancreatic cancer. Stage 4 patients were excluded. We compared baseline characteristics of YOPC vs. older using Chi-square. Kaplan Meier and Cox regression were used for survival analysis of these patients. Results: Of 28,904 patients, 1,415 (4.9%) had YOPC while 27,489 (95.1%) were older. YOPC were more likely to have stage 3 compared to older patients with PC (31.6% vs. 25.3%). YOPC had a higher rate of surgery than older patients (40% vs. 29.1%, p < 0.001), were more likely to be male, black and of Hispanic ethnicity. The primary tumor location was not different between the two groups. Overall survival (OS) was higher in YOPC versus older patients (12 vs. 9 months, p < 0.001). The analysis of multivariable Cox regression confirmed that there is a significant association between survival and YOPC group after adjusting for stage, grade, gender, ethnicity, surgery and race (HR 1.23, 95% CI: 1.13-1.33, p < 0.001). Conclusions: Patients with non-metastatic YOPC represent a group of patients with distinct clinical characteristics. YOPC have a higher rate of surgery and better overall survival compared to older patients. [Table: see text]

Purpose: Blocking the function of myeloid-derived suppressor cells (MDSC) is an attractive approach for cancer immunotherapy. Having shown DC-HIL/GPNMB to be the T-cell-inhibitory receptor mediating the suppressor function of MDSCs, we evaluated the potential of anti-DC-HIL mAb as an MDSC-targeting cancer treatment. Experimental Design: Patients with metastatic cancer (n = 198) were analyzed by flow cytometry for DC-HIL or PDL1 expression on blood CD14+HLA-DRno/lo MDSCs. Their suppressor function was assessed by in vitro coculture with autologous T cells, and the ability of anti-DC-HIL or anti-PDL1 mAb to reverse such function was determined. Tumor expression of these receptors was examined histologically, and the antitumor activity of the mAb was evaluated by attenuated growth of colon cancers in mice. Results: Patients with metastatic cancer had high blood levels of DC-HIL+ MDSCs compared with healthy controls. Anti-DC-HIL mAb reversed the in vitro function in ∼80% of cancer patients tested, particularly for colon cancer. Despite very low expression on blood MDSCs, anti-PDL1 mAb was as effective as anti-DC-HIL mAb in reversing MDSC function, a paradoxical phenomenon we found to be due to upregulated expression of PDL1 by T-cell-derived IFNγ in cocultures. DC-HIL is not expressed by colorectal cancer cells but by CD14+ cells infiltrating the tumor. Finally, anti-DC-HIL mAb attenuated growth of preestablished colon tumors by reducing MDSCs and increasing IFNγ-secreting T cells in the tumor microenvironment, with similar outcomes to anti-PDL1 mAb. Conclusions: Blocking DC-HIL function is a potentially useful treatment for at least colorectal cancer with high blood levels of DC-HIL+ MDSCs. See related commentary by Colombo, p. 453

Background The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naive patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. Patients and methods Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0–1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. Results Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1–20; 5-FU/cisplatin: 1–30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. Conclusions These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. ClinicalTrial.gov registration number NCT01285557.

There is interest in improving the tumoricidal effects of preoperative radiotherapy for rectal carcinoma by studying new radiosensitizers. The safety and toxicity profile of these combination regimens needs rigorous clinical evaluation. The primary objective of this study was to evaluate the toxicity of combining bavituximab, an antibody that targets exposed phosphatidylserine, with capecitabine and radiation therapy.Patients with stage II or III rectal adenocarcinoma were enrolled on a phase I study combining radiation therapy, capecitabine, and bavituximab. A standard 3+3 trial designed was used.In general, bavituximab was safe and well tolerated in combination with radiation therapy and capecitabine in the treatment of rectal adenocarcinoma. One patient at the highest dose level experienced a grade III infusion reaction related to the bavituximab. One tumor demonstrated a complete pathologic response to the combination treatment.Bavituximab is safe in combination with capecitabine and radiation therapy at the doses selected for the study. Further clinical investigation would be necessary to better define the efficacy of this combination.

Background ARQ761 (β-lapachone) is a hydroquinone analog that exploits the unique elevation of NQO1 found in 90% of pancreatic cancer cells and causes tumor-specific cell death by eliciting a futile redox cycle generating high levels of reactive oxygen species and ultimately PARP1 hyperactivation-dependent cell death. ARQ761 induces cell death which is: (i) not dependent on p53 status; (ii) not dependent on cell cycle status; (iii) not affected by known oncogenic driver or carrier mutations; and (iv) not affected by loss of caspases. We demonstrated that ARQ761 has synergistic antitumor activity with chemotherapy in pancreatic cancer preclinical models. Methods This was a single arm phase-1b clinical trial of ARQ-761 plus gemcitabine and nab-paclitaxel for patients with pancreatic cancer. The primary objective was to determine the maximum tolerated dose of ARQ 761 in combination with chemotherapy. Secondary objectives were to assess clinical activity, safety, tolerability and pharmacodynamic effects. Patients with metastatic pancreatic adenocarcinoma not treated with prior gemcitabine with adequate hematologic, renal and liver function and good performance status were enrolled. Dose levels are described in the table. Immunohistochemistry was used to assess for NQO1 expression. Results Fifteen patients were evaluable for safety, 67% were male, 53% had received prior chemotherapy and 96% tested positive for NQO1 expression. The most common treatment related toxicities were anemia and fatigue. The following dose limiting toxicities were observed (dose level 1: neutropenia, anemia, dose level -1 fatigue). The maximum tolerated dose of ARQ761/gemcitabine/nab-paclitaxel is 156/800/100mg/m2. Tumour response was stable disease in 53% Pharmacodynamic analysis was performed on post treatment biopsies. Conclusions We report results of a phase 1b clinical trial of the novel NQO1 bioactivatable compound, ARQ761, in combination with gemcitabine/nab-paclitaxel. Treatment related toxicities were observed which were noted in preclinical models and managed with routine dose adjustment. Clinical trial identification NCT02514031. Legal entity responsible for the study UT Southwestern Medical Center. Funding Pancreatic Cancer Action Network, Rising Tide, Gateway, Arqule Pharmaceuticals. Disclosure M.S. Beg: Research grant / Funding (institution): Arqule; Advisory / Consultancy: Array; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: Guardant; Advisory / Consultancy: Genentech. D. Boothman: Research grant / Funding (institution): Arqule; Advisory / Consultancy: Toray global; Speaker Bureau / Expert testimony: systems oncology. Y. Arriaga: Full / Part-time employment: IBM. A. Sanjeeviaiah: Advisory / Consultancy, 1500$: Guardant health. B. Schwartz: Full / Part-time employment: Arqule. All other authors have declared no conflicts of interest.

3605 Background: Ethnic disparities can impact clinical outcomes of young-onset colorectal cancer (CRC) patients. We aimed to determine if differences in outcomes based on ethnicity exist in young–onset CRC treated at an NCI-designated comprehensive cancer center program. Methods: A retrospective chart review for stage II – IV young-onset CRC patients ≤45 years old diagnosed between 04/2011 and 11/2015. Patients had to undergo treatment at safety-net Parkland Hospital (PH) or at the Simmons Comprehensive Cancer Center (SCCC) in Dallas, TX. Demographic data, dates of surgery, adjuvant chemotherapy, recurrence or death were obtained. Results: Of 123 patients that met inclusion criteria, 15 were excluded due to incomplete information. Of the remaining 108 patients, 36 (33%) and 72 patients (67%) were treated at SCCC and PH, respectively. Sixty (55%) were non-Hispanic vs 48 (44.4%) Hispanic. There were more Stage IV patients at SCCC vs Parkland (58.3% vs 30.6%, p < 0.01) but there was no difference regarding ethnicity. Also, no significant difference was seen between non-Hispanic White (NHW), Hispanic, and Black patients in median days to colectomy (1 vs 13 vs 0; p = .402) or adjuvant chemotherapy (55.5 vs 53.0 vs 64.0 days, p = .820). Hispanic patients had significantly better overall survival (OS) than Black or NHW patients (p = 0.025). The OS benefit was driven by improved 5-year OS in stage II/III Hispanic vs NHW vs Black patients (95% vs 62% vs 60%; p = 0.06). Multivariate Cox Regression analysis showed stage II/III (p < 0.001) and Hispanic ethnicity (p < 0.001) were independently associated with improved outcomes. Conclusions: In young-onset CRC treated at an NCI-designated comprehensive cancer center, Hispanic ethnicity had better OS than other ethnicities and this was largely due to better outcomes in stage II and III CRC. The causes for these ethnic differences in young-onset CRC patients needs further exploration. [Table: see text]

BACKGROUND A previous study has shown that shorter bevacizumab infusions (0.5 mg/kg/min) can be safely administered without increasing the risk of infusion-related hypersensitivity reactions (HSRs). However, the risk of proteinuria and hypertension in patients receiving shorter infusions of bevacizumab is undetermined. PATIENTS AND METHODS This was a multicenter, prospective, observational study in patients receiving

BACKGROUND: Recent studies have demonstrated the feasibility of combining oxaliplatin with 5-fluorouracil (5-FU) or capecitibine and radiation therapy. The addition of bevacizumab to chemotherapy improves overall survival for metastatic disease. We initiated a phase 2 trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX) and bevacizumab for locally advanced rectal cancer. METHODS: Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled. Preoperative treatment was capecitabine (825 mg/m2 twice daily from Monday to Friday), oxaliplatin (50 mg/m2 weekly), bevacizumab (5 mg/kg on days 1, 15, 29), and radiation therapy (50.4 Gy). Surgery was performed by 6 weeks after neoadjuvant therapy. Beginning 8 to 12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles. RESULTS: Fifty-four of 57 enrolled patients were eligible. Forty-nine (91%) patients completed preoperative therapy and underwent surgery. Nine patients (17%; 90% confidence interval, 9%-27%) achieved pathologic complete response. Thirty-two patients (59%) experienced pathologic tumor downstaging, and 53% and 15% of patients experienced worst grade 3 and grade 4 acute toxicity, respectively. Forty-seven percent of patients who underwent surgery experienced a surgical complication. CONCLUSIONS: The primary endpoint of a 30% pathologic complete response rate was not reached; however, the majority of patients experienced pathologic downstaging with this regimen. Increased wound-healing delays and complications may have been related to the addition of bevacizumab, oxaliplatin, or both. Continued observation of these patients will establish the long-term morbidity and efficacy of this combined modality approach. Cancer 2013. © 2012 American Cancer Society.

3504Background: While both anti-VEGF(R) and EGFR antibodies have activity in metastatic RAS wild type CRC, the combination of the two appeared to be detrimental when combined with chemotherapy in u...

10027Background: Previous studies have suggested that racial disparities exist for DNR orders in cancer patients. We examined racial differences in DNR orders for pancreatic cancer patients in an u...

489 Background: There has been an increase in Palliative care utilization in cancer patients. We examined trends of palliative care and intensive care utilization in pancreatic cancer patients in an urban setting safety net hospital. Methods: This is a retrospective analysis of pancreatic cancer patients seen at the Parkland Health and Hospital System between January 1999 and September 2016. Cancer cases and receipt of palliative care were identified from prospectively maintained registries. Health care utilization including intensive care unit (ICU) was reviewed. All statistical analysis was done using IBM SPSS version 24. Results: We identified 455 new diagnoses of pancreatic cancer, mean age 61 years, 227 (50%) female and 228 (50%) white. Of these, 277 (61%) received palliative care ever. Patient who received palliative care were more likely to be younger (mean age, 59.3+-12 vs 62.8 +- 12 years) and have stage 4 disease vs stage 1-3 disease (p 0.006, and p 0.003 respectively). There was no statistically significant difference in palliative care utilization between gender and ethnicity groups. 140 patients had a DNR order and 29 required ICU admission at any point. A first contact with palliative care consult was obtained < = 7 days before death for 29 (10%) patients, < = 30 days before death for 86 (31%) patients, 30-60 days before death for 50 (18%) and more than 60 days before death for 141 (51%) patients. Patients receiving palliative care were more likely to have a DNR status (p < 0.001) but had no difference in ICU use within the last 30 days of life (p 0.285). Conclusions: The rate of palliative care in patients with pancreatic cancer in this cohort from a safety net hospital is higher than nationally reported studies. Most patients received palliative care > 30 days before death. While patients received early palliative care, it did not result in reduced ICU care. Factors influencing ICU care utilization near the end of life need further study.

463 Background: FOLFIRINOX therapy is associated with improved outcome in patients with gastrointestinal cancers. The regimen can be associated with significant toxicity and empiric dose modifications are often used. We analyzed 1) real-world prescribing patterns of FOLFIRINOX and 2) toxicity of therapy. Methods: Patients undergoing FOLFIRINOX chemotherapy at an academic, NCI-Designated Comprehensive Cancer Center were identified and electronic medical records reviewed. Patients who received at least one dose of FOLFIRINOX were included. Chemotherapy dose, growth factor use and toxicity data was abstracted for the first 8 weeks. ‘Standard FOLFIRNOX’ was defined as the regimen utilized by Conroy et al (NEJM 2011). Any empiric reduction/withholding of drug dose for cycle 1 was classified as ‘modified FOLFIRINOX’. Bivariate analysis was performed on the data. Results: There were 111 patients seen between 5/2011-3/2017 and 94% had pancreatic cancer. Age range was 29-87 years and 52% were female. 59% received ‘modified FOLFIRINOX’ and 20% received empiric growth factors. Line of therapy for standard vs modified respectively was 71.1% vs 45.5% for 1st, 17.8% vs 36.4% for 2nd, and 11.1% vs 18.2% for beyond 2nd (p = 0.03). Patients with ‘modified FOLFIRINOX’ were more likely to have metastatic disease (p = 0.01), have received second line or beyond, and higher ECOG score (p = 0.03). Patients with ‘modified FOLFIRINOX’ had a trend toward fewer treatment-related ED visits or hospitalization vs ‘standard FOLFIRINOX’ (27.2% vs 42.2% p = 0.10) and fewer treatment delays (25.8% vs 42.2% p = 0.07). Conclusions: In the real world setting, a majority of patients on FOLFIRINOX receive empiric dose modifications. Although modified dose did not translate to a significant difference in ED visits, hospitalizations or treatment delays, there was a trend toward fewer events.

861 Background: Previous studies have demonstrated that KRAS mutations were associated with higher rates of depression in patients with metastatic colorectal cancer (CRC). The objective of this study was to evaluate the feasibility of extracting EMR data to examine the association between KRAS mutations and positive screening test for depression in CRC patients. Methods: Retrospective review of stage I to IV CRC patients seen between 2011 and 2015 at an academic, NCI-Designated Comprehensive Cancer Center was performed. At each clinic visit, depression was assessed using the Patient Health Questionnaire-2 (PHQ-2), which is part of the institution’s universal Distress Screening tool. PHQ-2 score of 2 and above was considered positive screening test for depression. PHQ-2 and KRAS mutation data were extracted from the EMR via the Clinical Data Exchange Network bioinformatics tool and confirmed by retrospective chart review. Chi-square test was used to assess the association between KRAS mutation and depression. Multiple imputation was used to impute the missing values. Results: Of the 484 CRC patients, KRAS status was known in 45 cases: 22 (49%) were KRAS mutated and 23 (51%) were KRAS wild type. PHQ-2 score was 0 in 42 cases (93.3%), 1 in 2 cases (4.4%), and ≥2 in 1 case (2.3%). The rate of positive PHQ-2 for KRAS mutated vs wild type was 4% vs 0% (p = 0.36). The result based on 50 imputed datasets suggests a trend towards an association between KRAS mutation and depression (p = 0.09). Conclusions: This study did not demonstrate an association between KRAS mutation and depression in patients with colorectal cancer, probably due to a high proportion of missing data. Bioinformatics studies that extract and analyze EMR data are a feasible and effective platform to assess the association of genomic data with clinical outcomes. Additional validated algorithms and data are needed to further optimize such studies.

Lessons Learned The 5-year oncologic outcomes from the trial regimen were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy. Due to the lack of an improvement in the pathologic complete response rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study. Background. The addition of bevacizumab to chemotherapy improves overall survival for metastatic colorectal cancer. We initiated a phase II trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy (RT) followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab for locally advanced rectal cancer. The purpose of this report is to describe the 5-year oncologic outcomes of this regimen. Methods. In a phase II Simon two-stage design study, we evaluated preoperative treatment with capecitabine (825 mg/m2 b.i.d. Monday–Friday), oxaliplatin (50 mg/m2 weekly), bevacizumab (5 mg/kg on days 1, 15, and 29), and RT (50.4 Gy). Surgery was performed by 8 weeks after RT. Beginning 8–12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles (oxaliplatin stopped after 9 cycles). The primary endpoint was a pathologic complete response (path-CR) rate of 30%. Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled between 2006 and 2010. Results. Of 57 enrolled patients, 53 were eligible and included in the analysis. Forty-eight (91%) patients completed preoperative therapy, all of whom underwent curative surgical resection. Nine patients (17%) achieved path-CR. There were 29 worst grade 3 events, 8 worst grade 4 events, and 2 patient deaths, 1 of which was attributed to study therapy. Twenty-six patients (54%) began adjuvant chemotherapy. After a median follow-up period of 41 months, the 5-year overall survival (OS) rate for all patients was 80%. Only 2 patients experienced cancer recurrence: 1 distant (liver) and 1 loco-regional (pelvic lymph nodes), respectively. Both of these patients are still alive. The 5-year relapse-free survival rate was 81%. Conclusion. Despite the path-CR primary endpoint of this trial not being reached, the 5-year OS and recurrence-free survival rates were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy. Because of the lack of an improvement in the path-CR rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study.

Myeloid-derived suppressor cells (MDSC) are the most potent suppressors of T-cell function, and their exponential proliferation in cancer states counteracts the benefits of immunotherapy given to these patients. Having discovered the T cell-inhibitory DC-HIL receptor, we showed that DC-HIL is responsible for MDSC’s T-cell suppressive function. We found that melanoma patients (but not healthy controls) harbor in the blood an expanded population of DC-HIL+ MDSC, whose suppressor effects in vitro can be blocked by our 3D5 anti-DC-HIL mAb. To determine whether similar outcomes apply to non-melanoma cancers, we recruited patients with metastases from bladder (BL, n=4), breast (BR, n=11), colon (CO, n=44), kidney (KI, n=6), lung (LU, n=20), pancreatic (PA, n=17), and prostate (PR, n=9) cancer. FACS analysis of blood samples showed all cancer types (except LU) were associated with elevated blood HLA-DRno/low CD14+ MDSC vs. age-matched controls (n=21, median of 0.5%). % DC-HIL+ MDSC in PBMC was also significantly high in all cancer types; median of 2.5% for BL; 1.7% for BR; 3.5% for CO; 3.6% for KI; 0.3% for LU; 1.8% for PA; and 4.8% for PR, vs. 0.04% for healthy controls. MDSC in all cancer types showed high DC-HIL-positivity (20-90% vs. 8% for controls). We assayed T-cell suppressor activity by purifying MDSC and T-cells from the same patient and co-culturing them at varying cell ratios, with co-stimulators. Activity was determined by % suppression in IFN-γ secretion, which was correlated with % DC-HIL-positivity of MDSC. MDSC from KI (n=3) were more suppressive than those from CO and PA, with suppressor activity correlating with DC-HIL-positivity: Pearson’s r for 0.5 for CO (n=13) and 0.73 for PA (n=8). We evaluated effects of anti-DC-HIL mAb on co-cultures of MDSC/ T-cells from cancer patients (n=25). The mAb restored IFN-γ secretion by >30% in 8/15 cases of CO; 4/8 of PA, and 2/2 of KI. To determine whether DC-HIL+ MDSC migrate into cancer sites, lesional specimens from CO patients (n=5) with high blood counts of DC-HIL+ MDSC were immunohistochemically stained for CD14 and DC-HIL expression: DC-HIL was absent from all cancer cells, but present strongly in many CD14+ cells surrounding the cancers. This outcome contrasts starkly with melanoma, in which DC-HIL was expressed highly by the cancer cells surrounded by only a few DC-HIL+ CD14+ cells. Finally we evaluated in vivo effects of blocking DC-HIL using a mouse model of MC38 colon cancer, which is DC-HILneg. MC38 tumor challenge induced DC-HIL+ Gr1lowLy6Chigh MDSC in the tumor site. Intravenous infusion of anti-DC-HIL mAb into mice with pre-established MC38 tumor significantly inhibited tumor growth by 50-70%, reduced blood levels of MDSC, and enhanced cytotoxic T-lymphocyte response. Our findings support DC-HIL blockade as a potential treatment for metastatic cancers, with high blood levels of DC-HIL+ MDSC as a prognostic marker for the best responders. Citation Format: Masato Kobayashi, Jin-Sung Chung, Muhammad Beg, Yull Arriaga, Udit Verma, Kevin Courtney, John Mansour, Barbara Haley, Saad Khan, Yutaka Horiuchi, David Harker, Purva Gopal, Ponciano D. Cruz, Kiyoshi Ariizumi. Blocking the DC-HIL receptor reverses the T-cell suppression induced by proliferating myeloid-derived suppressor cells in common cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3660. doi:10.1158/1538-7445.AM2017-3660

e15752 Background: Insulin resistance (IR) in pancreatic cancer (PC) patients is associated with cachexia and poor outcome. Pioglitazone (PIO) improves insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR gamma). Effects of PIO on insulin sensitivity, glucose homeostasis, and circulating adipokine levels in PC have not been examined. Methods: Patients with metastatic PC were administered PIO 45mg/day orally for 8 weeks concurrent with chemotherapy. Patients with known DM at enrollment were identified Fasting plasma was collected at baseline, weeks 2, 4, 6, 8 of pioglitazone treatment and at 2 weeks-post treatment. The primary objective was to describe changes in indicators of IR, including glucoregulatory hormone levels, glucose tolerance, and inflammatory cytokines. Results: Fourteen patients (age 64y), with a mean BMI of 28 were enrolled. Mean adiponectin increased from baseline to week 8 of treatment (14.2± 3.3 and 46.9±11.4µg/ml, respectively, P ≤ 0.01), and returned to baseline levels at 2 weeks post-treatment (15.1±1.9 µg/ml). Markers of IR (serum glucose, insulin, glucagon, and response to an oral glucose bolus) did not correlate with tumor size, inflammatory cytokine levels, GM-CSF, or CA19-9. A dichotomous response to PIO treatment was observed between non-diabetic and T2DM patients. Fasting insulin increased 70.6±31.3% from baseline to treatment week 8 in patients with T2DM. In contrast, treatment of non-diabetic patients decreased fasting insulin by 40.2±6.3%, demonstrating a significant, P ≤ 0.01, difference in treatment response between PC patients with or without T2DM. Conclusions: We have demonstrated that PC patients respond to 8 weeks of PIO treatment with a significant rise in the insulin sensitizing adipokine, Adiponectin, with a complete wash-out after 2 weeks of cessation. PIO results in opposing fasting insulin responses in non-diabetic and DM patients suggests that diabetes status plays a significant role in the glucoregulatory effects of PIO treatment in PC patients. Clinical trial information Clinical trial information: NCT01838317.

Lessons Learned The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group. The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma. Background Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro. Methods Patients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed. Results In total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients. Conclusion The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC.

651 Background: Regorafenib is an oral multi kinase inhibitor with clinical activity in colorectal cancer, gastrointestinal stromal tumors and hepatocellular cancer. Drug- drug interactions are commonly encountered in clinical practice and warfarin continues to be the most commonly prescribed anticoagulant among cancer patients in the clinic. The interaction of regorafenib with warfarin has not been studied. Methods: Patients at a single institution being prescribed regorafenib were identified and charts reviewed for concurrent warfarin therapy. Baseline characteristics, indications for regorafenib and warfarin therapy was determined. Patients were followed up to the first 8 weeks of combination therapy. Results: We identified 6 patients on concurrent regorafenib and warfarin. All patients had refractory colon cancer. Median age was 74, 4 were male and 5 white. Indication for warfarin was venous thromboembolism in 5 and atrial fibrillation in 1. Baseline INR ranged from 1.1 to 2.4. An increase in INR was seen in all six patients (peak INR range 4.5 to > 12) which improved with dose modification. Time to peak INR was less than 6 weeks (INR trends in all patients shown in figure 1). There were no bleeding complications noted in any patient. Conclusions: We report a clinically significant interaction between warfarin and regorafenib with patients demonstrating an increase in INR. Patients who are anticoagulated with warfarin and start regorafenib should be closely monitored and upfront warfarin dose reduction should be considered. Further drug-drug interaction studies are needed to determine the exact mechanism of drug-drug interaction between these medications.

In the last decade, immunomodulation has emerged as a mode of therapy capable of mediating the regression of cancer in some patients. This article reviews our experience with immunomodulation following transplant and non-transplant chemotherapy. We used interferon and cyclosporine A following conventional chemotherapy in a non-transplant setting for a B 16 melanoma in a murine model. This combination generated cells with MHC-unrestricted cytotoxicity. We have also used immunotherapy in the transplant setting with IL-2 activated PBSC in patients with breast cancer. Of the 28 patients treated, 20 developed GVHD and the average time to reconstitution was 12 days (comparable to a control group). This article also raises the possibility of extending immunomodulation to breast cancer patients in the nontransplant setting to induce an antitumor immune response following cytoreductive chemotherapy.

3524Background: In the phase 3 CORRECT trial, regorafenib improved survival vs placebo in treatment-refractory mCRC. The large, single-arm, phase 3b CONSIGN trial (NCT01538680) was designed to prov...

e15623Background: Unresectable and metastatic BTC portend very poor overall survival (OS), with historical OS less than 1.5 years. Gemcitabine (G) and cisplatin (C) combination has become the stand...

735 Background: In the phase III CORRECT study, regorafenib significantly improved overall survival and progression-free survival (PFS) vs placebo in patients with treatment-refractory mCRC. CONSIGN (NCT01538680) was a large phase IIIb study that included 2872 patients from 25 countries; it was designed to provide continued access to regorafenib for patients with mCRC who failed standard therapy and to further characterize the safety of regorafenib. In CONSIGN, adverse events (AEs) and PFS were consistent with those reported in phase III studies. We present a retrospective subgroup analysis of patients enrolled in CONSIGN in the USA. Methods: Patients with mCRC who progressed on standard therapies and had an ECOG PS 0─1 received regorafenib 160 mg QD for the first 3 weeks of each 4-week cycle. Treatment was continued until disease progression, death, or unacceptable toxicity. The primary endpoint was safety. PFS (per investigator) was the only efficacy variable assessed. Results: A total of 364 patients in the USA were assigned to treatment (all evaluable for safety). The median age was 60 years; 38% and 62% had ECOG PS 0 and 1, respectively. KRAS mutation was present in 59%, KRAS wt in 38%; 74% had ≥ 3 prior regimens for metastatic disease. Median duration of treatment was 2.3 months (range: 0–30). Median PFS (95% CI) was 2.3 (2.0–2.6) months (2.1 months KRAS wt; 2.3 months KRAS mutant). NCI-CTCAE v4.0 grade ≥ 3 AEs occurred in 81% of patients and were considered drug-related in 53% (Table). Grade ≥ 3 hepatobiliary disorders occurred in 2%. Grade ≥ 3 treatment-emergent laboratory toxicities included bilirubin (9%), AST (6%), and ALT (3%). Conclusions: In patients from the USA enrolled in CONSIGN, the safety profile of regorafenib was consistent with that of the overall population and the known safety profile of regorafenib in mCRC. Median PFS was in the range of that reported in phase III trials. Clinical trial information: NCT01538680. [Table: see text]

The catalytic subunits of IκB kinase (IKK) complex, IKKα and IKKβ, are involved in activation of NF-κB and in mediating a variety of other biological functions. Though these proteins have a high-sequence homology, IKKα exhibits different functional characteristics as compared with IKKβ. Earlier, we have shown that cyclin D1 is overexpressed and predominantly localized in the nucleus of IKKα−/− cells, indicating that IKKα regulates turnover and subcellular distribution of cyclin D1, which is mediated by IKKα-induced phosphorylation of cyclin D1. Because cyclin D nuclear localization is implicated in tumor development, we examined whether the absence of IKKα leads to tumor development as well. In the current study, we show that IKKα plays a critical role in tumorigenesis. Though IKKα−/− MEF cells show a slower anchorage-dependent growth, they are clonogenic in soft agar. These cells are tumorigenic in nude mice. Microarray analysis of IKKα−/− cells indicates a differential expression of genes involved in proliferation and apoptosis. Furthermore, analysis of microarray data of human lung cancer cell lines revealed decreased IKKα RNA expression level as compared with cell lines derived from normal bronchial epithelium. These results suggest that IKKα may function as a tumor suppressor gene. Absence of IKKα may induce tumorigenicity by nuclear localization of cyclin D1 and modulating the expression of genes involved in neoplastic transformation. Mol Cancer Res; 9(3); 341–9. ©2011 AACR.

Purpose This study evaluated safety, pharmacokinetics, and efficacy of 2 dose schedules and 2 infusion times of panitumumab in patients with advanced solid malignancies. Patients and Methods This phase I multicenter, openlabel study sequentially enrolled patients with advanced solid tumors refractory to standard therapy, or for which no standard therapy exists, to receive panitumumab 6 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. Patients receiving panitumumab every 2 weeks received either all infusions over 60 minutes or a 60-minute infusion for the first dose followed by 30-minute infusions if the first infusion was well tolerated. Patients in the every-3-week cohort received 60-minute infusions. Safety outcomes included the incidence of adverse events and antipanitumumab antibody formation. Pharmacokinetic properties were determined. Efficacy endpoints included response rate and duration of response. Results Eighty-six patients were enrolled; 84 (98%) received panitumumab. Treatment-related adverse events occurred in 90% of patients. Safety profiles were similar between patients receiving 30-minute (n = 20) and 60-minute (n = 43) infusions every 2 weeks and patients receiving panitumumab every 3 weeks (n = 21). Panitumumab exposure at steady state increased dose proportionally, and peak serum concentrations were similar in patients receiving either 30- or 60-minute infusions every 2 weeks. Objective responses were seen in 4 patients (5%) with colon, rectal, esophageal, and bladder cancers. Conclusion Similar drug exposures and safety profiles were observed in patients receiving panitumumab 6 mg/kg every 2 weeks with either 30- or 60-minute infusions and antitumor activity was seen in some patients. Exposure increased approximately dose proportionally at steady state.

Objectives: Preclinical studies using sequences of topoisomerase I and II inhibitors suggested synergism; preliminary clinical studies, resulting in enhanced antitumor responses, confirm this in selected malignancies. This study determined the maximum-tolerated dose (MTD), toxicity, and pharmacokinetics of irinotecan (CPT-11), capecitabine, and epirubicin in patients with metastatic adenocarcinoma of lung, breast, or gastrointestinal tract. Correlation of topoisomerase IIβ was also done. Methods: Eligibility criteria included the following: documented adenocarcinoma of the lung, breast, or gastrointestinal tract

3537 Background: Simtuzumab (SIM) is a humanized antibody that inhibits lysyl oxidase-like molecule 2 (LOXL2), a matrix enzyme that catalyzes the cross-linking of collagen and is widely expressed a...

4015 Background: The prognosis for metastatic DGAC is poor but the first line therapy for patients (pts) with DGAC is the same as that of without DGAC. Analyses of the FLAGS study suggested that S-...

345 Background: Bavituximab a first-in-class immunomodulator targeting phosphatidylserine (PS), a lipid externalized on tumor and endothelial cells. Preclinical and phase I studies demonstrated that sorafenib upregulates PS externalization and can be given safely with bavituximab. We evaluated the safety and clinical activity of bavituximab plus sorafenib in HCC. Methods: Patients with advanced HCC deemed ineligible for curative therapy with no previous systemic treament, ECOG score ≤ 2, Child Pugh score A or B7 received bavituximab, 3 mg/kg IV weekly, and sorafenib, 400 mg PO BID until disease progression or intolerable toxicity. 38 patients were accrued providing a power of 80% and two-sided significance level of 10% to show an 8.2 month time to progression compared to historical control, 5.5 months. Secondary endpoints included safety and tolerability, 4-month progression free survival, overall survival, and response rates. Correlative studies using pre- and post-treatment tumor biopsies included IHC analysis of regulatory, cytotoxic, and helper T cells in addition to macrophage infiltrates. Results: 38 patients were accrued, 7 still on treatment. Patient characteristics: median age: 60.5 years, male 74%, HCV: 79%, Black: 47%/Hispanic: 29%/White: 21%, previous treatment 37%, and metastases: 24%. Median follow-up is currently 6.1 months with current median TTP of 6.8 months (95% CI 3,10). Four month PFS is 76% and there are no partial or complete responses. Treatment related adverse events were observed in 53% of patients, one grade 3 (GI bleed), four grade 2 (DVT, anorexia, diarrhea, and infusion reaction). Most common grade 1 events were diarrhea (18%), fatigue (16%), and anorexia (16%). Six patients had tissue analyzed pre- and post-treatment, 2 of 6 demonstrated increase tumor infiltration of CD4+, CD8+, and macrophages with a corresponding decrease in Tregs. Conclusions: Bavituximab and sorafenib were well tolerated in patients with advanced HCC. When compared with historical controls, combination therapy demonstrated an improvement in TTP and PFS at four months. Combination therapy increases immune tumor infiltrates. Clinical trial information: NCT01264705.

In preclinical tumor models, inhibition of nuclear factor-κB (NF-κB) has been associated with increased sensitivity to chemotherapeutic agents such as irinotecan (CPT-11). This is based on the fact that a variety of chemotherapy agents such as CPT-11 activate NF-κB to result in the expression of genes such as c-IAP1 and c-IAP2 that might be responsible for the inhibition of chemotherapy-induced apoptosis. In this study, RNA interference [small interfering RNA (siRNA)] was used to down-regulate the NF-κB p65 subunit in the HCT116 colon cancer cell line, and its role, in the presence and absence of CPT-11, was assessed on cell growth and apoptosis. Reduction of endogenous p65 by siRNA treatment significantly impaired CPT-11-mediated NF-κB activation, enhanced apoptosis, and reduced colony formation in soft agar. Furthermore, the in vivo administration of p65 siRNA reduced HCT116 tumor formation in xenograft models in the presence but not the absence of CPT-11 administration. These data indicate that the administration of siRNA directed against the p65 subunit of NF-κB can effectively enhance in vitro and in vivo sensitivity to chemotherapeutic agents.

e15200 Background: CT is the main treatment option for patients (pts) with advanced BTC. There is limited randomized data to guide treatment selection. Based on phase 3 data, gemcitabine (G)/cisplatin (C) is an acceptable 1st line CT, but 5-FU based regimens are also used. We reviewed data from our institution to elucidate treatment preferences and responses. Methods: This is a retrospective analysis of pts treated at UTSW and PH from Jan 2008 to Dec 2011. Patient lists were obtained from the tumor registry at each hospital from Jan 2008 to Dec 2011. Results: 60 pts had inoperable or metastatic disease. 26/60 pts did not receive CT due to poor functional status. 34/60 pts received 1st-line CT- 26 cholangiocarcinoma, 7 gall bladder cancer, 1 ampullary cancer. 10/34 pts were not evaluated for treatment response due to lack of follow-up. Of the remaining 24 pts, 12 received 2nd line CT. In combined analysis of 1st and 2nd line CT in pts with adequate clinic follow-up, G alone (n=10) or in combination (with C n=9, C+ Cetuximab (CX) n=1, Oxaliplatin n=5, Capecitabine (CAP) n=1, Docetaxel n=1) was the most frequently used CT. 2 pts received CAP with radiation. 6 pts received 5-FU based regimen (FOLFOX n=1, FOLFOX/CX n=1, FOLFIRI n=1, FOLFIRI/CX n=1, FOLFIRI/panitumumab n=2). In 1st line, best response (BR)—partial response (PR) 4 pts, stable disease (SD) 14 pts, progressive disease (PD) 6 pts. Response duration range (RDR) in 1st line was 2-22 months (m). In 2nd line, BR—PR 1 pt, SD 7 pts, PD 2 pts. RDR in 2nd line was 2-10 m. Of the 4 pts who received CT combined with an EGFR inhibitor (EGFRI), 2 had SD, 2 had PR; RDR 3-10 m. Disease control (DC) rate (PR+SD) from 1st line CT 53%, 2nd line CT 67%. All 4 pts who received EGFRI in combination with CT showed evidence of DC. Conclusions: CT is effective in BTC with benefit seen in the majority of treated pts. 43% of pts were unable to receive CT which underscores the poor outlook in this malignancy. Interestingly we noted that even in our small subgroup who received EGFRI based combination CT, there was clinical benefit even in 2nd line CT. There is some published data to support this finding. EGFRI based CT should be further studied in this population.

3605 Background: Oxaliplatin and bevacizumab potentiate the antitumor activity of fluoroyprimidines and radiotherapy in preclinical and clinical studies of colorectal cancer. This phase II trial evaluated the efficacy of the preoperative combination of capecitabine, oxaliplatin, and bevacizumab with radiotherapy in rectal cancer. Methods: Eligibility: resectable T3/T4 adenocarcinoma of the rectum ≤ 12 cm. from anal verge. Preoperative treatment was capecitabine (825 mg/m² bid M-F), oxaliplatin (50 mg/m² weekly), bevacizumab (5 mg/kg D1,15,29), and pelvic external beam radiotherapy (50.4 Gy/28 fractions). Surgery was performed within 6-8 weeks. Within 12 weeks of surgery, patients received 12 cycles of FOLFOX + bevacizumab (5 mg/kg) Q2 weeks. Pathologic complete response (path CR) was the primary endpoint. Secondary endpoints included resection rate and toxicity. Results: Fifty-seven patients (pts) enrolled from 7/06 to 5/10 and 54 were eligible. Clinical staging: T3/4 (50/4), NX0/1/2 (2/16/31/5). Most common grade 3/4 non-hematologic toxicities during treatment were rectal pain (9), fatigue (8), and diarrhea (7). Two patients died of aspiration. Nine pts had early postsurgical complications (9 wound infections, 6 dehiscence, 1 abscess) and 23 had late surgical complications (23 non-healing wounds, 12 dehiscence, 5 bowel obstruction/ileus, 2 abscess). Pathologic staging: T0/1/2/3 (11/3/15/19), N0/1/2 (32/10/7). Nine pts had path CRs (17%, 90% CI:[9%-27%]. Surgery was LAR (38) and APR (11). Twenty-two pts did not receive postoperative chemotherapy (39%), 16 due to adverse events. Five local recurrences have been reported. RFS and OS data are immature. Conclusions: The addition of oxaliplatin and bevacizumab to capecitabine and radiotherapy for locally advanced rectal cancer resulted in downstaging for the majority of pts but did not improve the pathologic complete response rate compared to historical controls. The combination resulted in significant early and late postsurgical complications.