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To determine the risk and risk factors for mental illness among colorectal cancer (CRC) survivors across short-term and long-term follow-up periods.We used the Utah Cancer Registry to identify CRC survivors diagnosed between 1997 and 2013. Mental health diagnoses were available in electronic medical records and statewide facilities data that were linked by the Utah Population Database. CRC survivors were matched to individuals from a general population cohort. The risk of developing a mental illness was compared between cohorts. The association between mental illness and mortality was also analyzed.In total, 8961 CRC survivors and 35,897 individuals in a general population cohort were identified. CRC survivors were at increased risk for any mental health diagnosis at 0 to 2 years (hazard ratio [HR], 3.70; 95% confidence interval [CI], 3.47-3.95),2 to 5 years (HR, 1.23; 95% CI, 1.09-1.38), and5 years (HR, 1.20; 95% CI, 1.07-1.36) after cancer diagnosis. CRC survivors were also at increased risk of depressive disorders specifically during the same time periods. At5 years, CRC survivors still had an increased risk of developing many mental health diagnoses. Factors associated with increased risk of any mental health disorder among CRC survivors included colostomy and Charlson Comorbidity Index of 1+. There was an increased risk of death for CRC survivors diagnosed with any mental health disorder (HR, 2.18; 95% CI, 2.02-2.35) and depression (HR, 2.10; 95% CI, 1.92-2.28).CRC survivors are at increased risk for mental health disorders in the short-term and long-term. Survivors who develop mental health disorders also experience decreased survival.

Rivoceranib is a highly potent and selective inhibitor of VEGFR-2 and subsequent angiogenesis through this receptor signaling pathway. This phase I study was the first global study with rivoceranib outside of China in Korean and Caucasian patients and was designed to determine the safety profile (including maximum tolerated dose), pharmacokinetics, and efficacy in patients with advanced solid tumors. Thirty-one adult patients with advanced malignant solid tumors were enrolled to investigate 6 dose levels of rivoceranib. Twenty-five patients were initially enrolled to 5 dose levels of rivoceranib from 81 to 685 mg and an additional 6 patients were later enrolled in a supplemental study to evaluate the 805 mg dose level. Rivoceranib was very well tolerated. At the 805 mg dose level, 2 dose-limiting toxicities were observed but the 685 mg dose was well tolerated over multiple cycles of therapy. The maximum tolerated dose for rivoceranib was 685 mg (equivalent to 850 mg rivoceranib mesylate) and recommended for further study in patients with advanced solid tumors. The most common adverse events were hypertension (all grades %/≥G3%: 58/29), nausea (42/0), diarrhea (39/0), anorexia (32/3), and fatigue (29/6). Rivoceranib pharmacokinetics were proportional across all dose levels but interpatient variability was high. Of the 31 patients enrolled, 21 were evaluable for efficacy. In this evaluable group, partial response was recorded in 5 patients, stable disease in 10, and disease progression in 6. Results indicate the potential clinical benefit of daily rivoceranib in patients with advanced malignant solid tumors with a tolerable safety profile.Trial registration: NCT01497704 (ClinicalTrials.gov) registered on December 22, 2011 and NCT02711969 (ClinicalTrials.gov) registered on March 17, 2016.

BackgroundDisulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement.MethodsDisulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. ProteinS-glutathionylation was evaluated as a pharmacodynamic marker.ResultsTwenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28–124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. IncreasedS-glutathionylation of serum proteins was observed with treatment.ConclusionDisulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase inS-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function.Trial registrationNCT00742911, first posted 28/08/2008.

Adult head and neck (HN) sarcomas are a rare malignancy with limited data delineating the role of postoperative radiotherapy (PORT), particularly for a positive surgical margin. There are no randomized trials supporting the use of PORT, therefore treatment trends vary between institutions. A positive margin predicts recurrence and poor survival outcomes. This study uses the National Cancer Database (NCDB) to investigate whether PORT improves overall survival (OS) in adult HN sarcomas with a positive margin and how utilization has changed.Patients (n = 1142) in the NCDB from 2004-2013 with adult HN sarcomas who underwent resection and had a positive margin.Factors significantly associated with increased utilization of PORT were: having insurance, salivary gland primary site, high-risk histology, poor differentiation, and a macroscopic positive margin. Treatment with PORT was associated with improved 5-year OS for all patients with a positive margin (57% vs 48%; P = .002), both microscopic (57% vs 49%; P = .010) and macroscopic (57% vs 41%; P = .036). Improved OS was significant after controlling for other known covariates on multivariate analysis (HR: 0.76; [0.64-0.90]; P = .002). Treatment at a community-based facility was an independent predictor for reduced OS (HR: 1.37; [1.15-1.64]; P .001). The percentage utilization (53%) of PORT for these patients did not change significantly over time.PORT provides a significant survival benefit for adult HN sarcoma patients with either a microscopic or macroscopic positive margin; however, PORT is underutilized. Treatment at academic/research cancer programs was associated with increased utilization of PORT and improved survival outcomes.

Background This phase I/II trial evaluated toxicity and antitumor activity of everolimus plus mFOLFOX6 + bevacizumab for first-line treatment of metastatic colorectal cancer (mCRC). Methods A phase I, modified 3 + 3 Fibonacci schema determined the maximum tolerated dose (MTD) of everolimus, followed by phase II dose expansion. The phase II primary objective was progression-free survival at 6 months (PFS-6 m). Results The everolimus MTD was 10 mg daily with mFOLFOX6 + bevacizumab based on safety from phase I (n = 22). Twenty-five patients were treated in the phase II at 10 mg everolimus daily. Frequent grade 3-4 adverse events were neutropenia (64%), leukopenia (28%) and hypokalemia (26%). Grade 2 stomatitis was observed in 62% of patients. Two dose-limiting toxicities were observed with one attributed to everolimus 10 mg daily (grade 3 diarrhea, hypokalemia, and anorexia) and grade 3 coronary vasospasm attributed to fluorouracil. The objective response rate was 53% and was higher (86%) in those with PTEN deficiency. PFS-6 m was 96% (95% CI 89-99.9%) at the MTD (n = 35). The everolimus recommended phase II dose of this regimen is 7.5 mg daily due to frequent stomatitis and dose reductions. Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC. Further studies are warranted in PTEN deficiency.

Background: Tumors with deficient mismatch repair (dMMR) have a favorable immunological phenotype permitting exploitation by immunotherapies. We aimed to assess our institutional experience of dMMR advanced gastrointestinal (GI) cancers treated with the PD-1 inhibitor pembrolizumab. Materials and Methods: We conducted an observational cohort study of a clinical series of patients with dMMR metastatic GI cancers treated with pembrolizumab from 2015 to 2017. Patients were assessed for best response, time to and reason for discontinuation, and adverse events. Results: A total of 13 patients received at least one dose of pembrolizumab. Median age was 62 years (range 33–74 years). Diagnoses included colorectal (colorectal cancer [CRC], n = 7); extrahepatic and intrahepatic cholangiocarcinoma (EHCC,n = 2;n = 1); pancreatic (pancreatic ductal adenocarcinoma [PDAC], n = 2); and adenocarcinoma of the appendix (n = 1). Five patients received concurrent chemotherapy (FOLFOX or capecitabine) with pembrolizumab (200 mg intravenous [IV] q 2 weeks with FOLFOX or 2 mg/kg IV q 3 weeks with capecitabine). Pembrolizumab was administered 2 mg/kg IV q 3 weeks to all patients who received single-agent treatment. Eleven patients were evaluable for response assessment. Three patients had a complete response (CRC and two EHCC) and one of these patients received concomitant pembrolizumab and FOLFOX. Two patients had a partial response, one with PDAC (−88% per RECIST, continues on treatment after 15.7 months) and the other with CRC (−45% per RECIST, continues after 14.6 months), both patients received concomitant pembrolizumab and FOLFOX and are now maintained on single-agent pembrolizumab. The objective response rate was 42%. Three patients experienced immune-related adverse events requiring discontinuation. Conclusions: This single-institution case series confirms the activity of pembrolizumab in various GI cancers harboring dMMR. Future studies are warranted to determine the role of combinatorial treatment with chemotherapy and/or novel immunotherapies in this population.

Objectives To investigate clinicopathologic and treatment factors associated with survival in adult head and neck sarcomas in the National Cancer Database (NCDB). To analyze whether treatment settings and therapies received influence survival outcomes and to compare trends in utilization via an aggregated national data set. Study Design Prospectively gathered data. Setting NCDB. Subjects and Methods The study comprised a total of 6944 adult patients treated for a head and neck sarcoma from January 2004 to December 2013. Overall survival (OS) was the primary outcome. Results Increased age and tumor size, nodal involvement, and poorly differentiated histology had significantly reduced OS ( P < .001). Angiosarcoma, malignant nerve sheath tumor, malignant fibrous histiocytoma, osteosarcoma, and rhabdomyosarcoma histologic subtypes had significantly reduced OS, while liposarcoma, chondrosarcoma, and chordoma had improved OS ( P < .001). Utilization of surgical therapy was associated with improved OS, while positive surgical margins were associated with treatment at a community-based cancer program and had reduced OS ( P < .001). On multivariate analysis, treatment with radiation and/or chemotherapy was not significantly associated with OS; however, primary treatment with definitive chemoradiotherapy had significantly reduced OS. Patients treated at academic/research cancer programs (n = 3874) had significantly improved 5- and 10-year OS (65% and 54%, respectively) when compared with patients treated at community-based cancer programs (n = 3027; 49% and 29%; P < .001). The percentage utilization of these programs (56% vs 44%) did not change over the study period. Conclusion For adult head and neck sarcomas, treatment at an academic/research cancer program was associated with improved survival; however, despite increasing medical specialization, the percentage utilization of these programs for this rare tumor remains constant.

Background The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. Subjects, Materials, and Methods Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. Results E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3–4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. Conclusion At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. Implications for Practice At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known. We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET−/− thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcγRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET−/− thymocytes. Indeed, genetic depletion of FcγRIIB in ESET−/− thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET−/− mice. Therefore, impaired T cell development in ESET−/− mice is partly due to the aberrant expression of FcγRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development.

Evaluate current practice patterns in the use of adjuvant radiation for T1-2N1 OCSCC patients and investigate its efficacy in the population-based setting.This study extracted patients who were treated surgically for T1N1 and T2N1 OCSCC without adverse nodal features from the SEER database from 2004 to 2013. Patients with distant metastatic disease, unknown surgery or radiation status, or prior malignancies were excluded. Patients were divided into those who underwent surgical resection with and without adjuvant radiation. Disease-specific survival (DSS) and overall survival (OS) were the primary outcomes measured.746 patients met inclusion criteria and 70% received adjuvant radiation therapy. Treatment with adjuvant radiation therapy was significantly associated with improved 5-year DSS (65% versus 51%; p 0.001) and OS (54% versus 44%; p = 0.007) for T1N1 tumors. Likewise, improved 5-year DSS (58% versus 38%; p = 0.009) and OS (48% versus 28%; p = 0.004) was shown in T2N1 tumors. Patients with T2N1 tumors wer significantly more likely to receive adjuvant radiation (75% versus 63%; p 0.001). Those with insurance and high risk primary subsites: buccal, retromolar trigone, and hard palate were more likely to receive adjuvant radiation. The percent utilization of adjuvant radiation remained constant through the study period for T2N1 tumors (72-74%) but significantly decreased for T1N1 (71-55%) (p = 0.047).Adjuvant radiation therapy is independently associated with a significant survival benefit for patients with both T1N1 and T2N1 OCSCC. However, this study demonstrates that patients with T1N1 cancer are less likely to receive adjuvant radiation and utilization is decreasing.

Purpose KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients. Experimental design 20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m2 IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs). Results The most common adverse events were grade 1–2 (rash and hypomagnesemia); 3 (16 %) patients had grade III–IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs. Conclusions The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.

The aims of this study is to determine the maximum tolerated dose of capecitabine and oxaliplatin (CAPOX) delivered concurrent with radiation therapy (RT) in the treatment of locally advanced pancreatic adenocarcinoma and to retrospectively compare outcomes with this regimen to concurrent 5-fluorouracil or capecitabine with RT (5FU-RT) or concurrent gemcitabine-based chemotherapy with RT (GEM-RT).Twelve patients were enrolled in a phase I study using 50.4 Gy RT concurrent with capecitabine chemotherapy (twice daily, 7 days per week) and oxaliplatin (once weekly during weeks 1, 2, 4, and 5). Capecitabine and oxaliplatin doses were 400 mg/m(2) and 50 mg/m(2), respectively, at dose level 1; 600 mg/m(2) and 50 mg/m(2) at level 2; and 600 mg/m(2) and 60 mg/m(2) at level 3. A standard dose of gemcitabine was recommended following RT or following surgery (if done). The outcomes of patients treated with this regimen were retrospectively compared to 20 patients treated with 5FU-RT and 30 patients treated with GEM-RT.Dose level 3 was tolerated with acceptable toxicity. Survival in patients receiving CAPOX-RT did not differ from GEM-RT or 5FU-RT. Response of the primary tumor was observed in 38% of patients treated with CAPOX-RT, 31% of patients treated with 5FU-RT, and 66% of patients treated with GEM-RT (p = 0.03 GEM-RT versus 5FU-RT).CAPOX-RT has acceptable toxicity. A retrospective comparison shows higher response rate with GEM-RT versus 5FU-RT, but this difference did not translate into improvement in overall survival.

792 Background: Defective DNA mismatch repair is associated with increased mutation load and expression of neoantigens. Increased activity of PD-1 inhibitor is reported in patients with GI cancers with dMMR. Here, we describe our experience at Huntsman Cancer Institute with PD-1 inhibition in subjects with GI malignancies with dMMR. Methods: Retrospective chart review of patients with metastatic GI malignancies with dMMR, treated with pembrolizumab at Huntsman Cancer Institute between July 15, 2015 and September 26, 2016. Results: A total of 9 patients were identified that received at least 1 dose of pembrolizumab (colorectal n=5; cholangiocarcinoma n=2; pancreatic n=2). Of the 9 patients, 5 received concurrent cytoxic chemotherapy. Median number of doses given was 3 (range 1 to 17). Three patients received pembrolizumab on clinical trial with concomitant mFOLFOX6. Five patients have restaging scans at the time of abstract submission. The first patient has cholangiocarcinoma and experienced a -73% response per RECIST criteria from baseline (time to progression +8 months). The second patient has pancreatic adenocarcinoma and showed a total -56.7% response per RECIST criteria from baseline (time to progression +5 months). The third patient has colorectal carcinoma and had stable disease by RECIST at restaging after 2 months (biochemical response with a 50% decrease in CEA). The fourth patient has cholangiocarcinoma and had a biochemical response with a 50% decrease in CA 19-9 and a mixed response on first restaging scan (time to progression +3.5 months). All 4 of these patients continue to have response to therapy at the time of abstract submission. The fifth patient who had colorectal cancer and died from upper GI bleeding. Restaging CT scans showed response to therapy after 6 weeks of treatment. Four additional patients initiated treatment recently and have yet to undergo restaging scans. Conclusions: Single-institution data seem to confirm activity of PD-1 inhibitor in GI malignancies that harbor dMMR. All 5 restaged patients demonstrated response to PD-1 inhibition by RECIST criteria or decreased tumor marker. Updated responses for all patients will be presented during the meeting.

Increasing evidence suggests that the formation of oxidized low-density lipoprotein (Ox-LDL) in vivo is associated with the development of atherosclerotic vascular disease. We investigated the effects of Ox-LDL on two vascular endothelial cell coagulant properties, tissue factor expression, and protein C activation. The Ox-LDL increased human arterial and venous endothelial cell tissue factor activity, with 100 micrograms/ml of Ox-LDL increasing factor activity fourfold. Native LDL modified by incubation with cultured human arterial and venous endothelial cells also induced endothelial cell tissue factor activity. This modification was blocked by coincubation with the antioxidants, probucol or ascorbic acid. It was determined, based on inhibition by known scavenger receptor antagonists (fucoidin, dextran sulfate), that binding of Ox-LDL via the acetyl LDL (scavenger) receptor was partially responsible for the increase in tissue factor expression. Whereas endothelial cell tissue factor expression was increased by incubation with Ox-LDL, protein C activation was reduced approximately 80% by incubating cultured endothelial cells with Ox-LDL. The effect of Ox-LDL on protein C activation was not inhibited by antagonists to the scavenger receptor. These data indicating that an atherogenic lipoprotein can regulate key vascular coagulant activities provide an additional link between vascular disease and thrombosis.

2525 Background: VEGF-mediated signaling pathways are critical to tumor growth. Apatinib mesylate is a novel, oral angiogenesis inhibitor that potently and selectively inhibits vascular endothelial...

Post-transplant lymphoproliferative disorder (PTLD) is a condition affecting immunosuppressed transplant patients and has a variety of clinical presentations. It is rarely found in the skin, and cases of PTLD in the skin are usually linked with lymph node or other organ involvement.We report a case of plasmacytoid PTLD that is limited to the skin. A 63-year-old man with a history of cardiac transplant presented with exophytic tumors involving the lower extremity. The diagnosis and classification of the various forms of PTLD are discussed.Histology, immunohistochemical stains, and in situ hybridization revealed an aggressive plasmacytoid tumor that was Epstein-Barr virus positive. The patient's tumors resolved with decreased immunosuppression and localized radiation.This case is unusual for several reasons including involvement limited to the skin, presentation 15 years following transplant, and plasmacytoid phenotype of the tumor. This disorder will likely be seen by dermatologists and dermatopathologists with the increasing use of immunosuppressive medications in the dermatologist's patient population.

Aim: Metastatic PC is associated with one of the worst prognoses among all the types of solid tumors. The presence of LMs and multiple sites of metastasis are factors associated with poorer prognosis. In the MPACT trial, nab-P + Gem demonstrated superior overall survival (OS, primary endpoint) vs Gem alone as first-line treatment for metastatic PC (Table). We report the efficacy and safety of nab-P + Gem vs Gem alone based on the presence of LMs and the number of metastatic sites. Methods: Previously untreated pts (N = 861) with metastatic PC were randomized 1:1 (stratified by performance status, region, and the presence of LMs) to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle or Gem alone 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: Treatment arms were well balanced with respect to LMs and the number of metastatic sites: 84% of pts had LMs and 79% had 2 or 3 metastatic sites. In pts with LMs, median OS was significantly longer with nab-P + Gem vs Gem alone (Table). Similar trends were seen for PFS (5.4 vs 3.6 mo; HR 0.65; P Patient Population n Median OS, mo nab-P + Gem Gem nab-P + Gem Gem HR P Value ITT 431 430 8.5 6.7 0.72 Subgroups With LMs 365 360 8.3 5.9 0.69 No. of metastatic sites 1 33 21 13.5 9.0 0.41 0.021 2 202 206 8.3 7.1 0.75 0.015 3 136 140 8.0 5.9 0.79 0.093 > 3 60 63 8.6 5.0 0.50 0.001 Conclusions: In the MPACT trial, nab-P + Gem demonstrated longer OS vs Gem alone in the ITT population. The results for pts with LMs and in subgroups defined by the number of metastatic sites were consistent with the ITT findings. No new safety signals were observed. Disclosure: C. Weekes: has received honoraria for advisory board participation in the past 3 years from Celgene F. Parnis: servied on the advisory board for Specialised Therapeutics; A. Santoro: is a consultant/advisor to Celgene; A. Romano, D. McGovern and D. Penenberg: is an employee of Celgene and owns stock; D.D. Von Hoff: is a consultant/advisory for Celgene and receives honoraria from them. He also receives research funding from TGen Clinical Research Service. All other authors have declared no conflicts of interest.

e14177 Background: Mutational Analyses are being increasingly performed on colorectal cancer patients. More efforts are needed to correlate this data to clinical outcomes such as disease prognosis, metastasis, and tumor responsiveness to chemotherapy or targeted therapy. We assessed the mutational status of patients diagnosed with colorectal cancer in the GI oncology clinics of Huntsman Cancer Institute. Methods: We examined 46 patients diagnosed with colorectal cancer that had molecular profiling performed. To determine effectiveness of mutation analysis we compared the time to progression (TTP) of patients in correlation to KRAS or BRAF, PIK3CA and PTEN status. KRAS, BRAF and PIK3CA testing was performed by direct sequence analysis on genomic DNA isolated from a formalin-fixed paraffin-embedded tumor sample. Testing utilized custom primers designed to flank, amplify and sequence codons 12 and 13 in exon 2 and codon 61 in exon 3 of the KRAS gene, codons 464-469 of exon 11 and codon 600 of exon 15 in the BRAF gene located at 7q34, and codons 539-546 of exon 9 and codons 1043-1049 of exon 20 in the PIK3CA gene located at 3q26.3. PTEN expression was determined by immunohistochemistry. H-score of ≤10 was considered PTEN Low. Results: Of the patients reviewed there were 26 male, 20 female with a median age of 59 (23-81). 43 patients had metastatic disease and 3 patients had localized disease. Mutations found were 48% KRAS, 6% BRAF, 13% PIK3CA, 46% PTEN Low, 13% KRAS + PIK3CA, and 28% KRAS/BRAF + PTEN Low. In patients with KRAS/BRAF wild type (n=14), median TTP from diagnosis to starting first chemotherapy for metastatic disease was 365 days as compared to KRAS/BRAF mutant (n=21) of 182 days (p=0.008). This study could not detect any correlation between dual alterations in RAS with PI3 kinase pathway and TTP probably as a function of lower sample sizes. Conclusions: Our data supports association of KRAS and BRAF mutational status to TTP rates in colorectal cancer patients. Substantial numbers of patients have alterations in the PI3-Kinase pathway in combination with the RAS pathway. Continued testing of molecular mutational status is needed in order to improve these predictive models.

3057 Background: Panitumumab, a monoclonal antibody against EGFR, led to improved progression-free survival (PFS) in patients with (wt)KRAS mCRC. However, the benefit of panitumumab is limited to a not yet identified small subset of (wt)KRAS patients. The CpG island methylator phenotype (CIMP-high) is present in 15-20% of CRC patients. Epigenetic silencing through methylation of PTEN and/or genes in the EGFR pathway might play a role in resistance to therapy. We assessed whether decitabine (a hypomethylating agent) reverted resistance to anti-EGFR therapies. Methods: Patients (n=19) with (wt)KRAS mCRC previously treated with anti-EGFR therapies were enrolled. Patients were treated with decitabine 45mg/kg IV on day (d)1 and d15 and panitumumab 6mg/kg IV on d8 and d22 q28days. Peripheral blood, skin biopsies and buccal smear samples were collected on d1, d8, d15 and d22 to assess methylation changes in PTEN, RASSF1A and SOCS-1 in response to therapy. Tumors were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exon 9 and 20 by PCR as well as for PTEN by immunohistochemistry. Results: Median age was 53 (range 31-72). Eleven (58%) patients were female; 15 (79%) had ECOG PS 1; 3 (16%) had ECOG PS 2; and 1 had ECOG PS 0. Median number of previous therapies was 4. The most common toxicities were rash (68%), hypomagnesemia (26%) and neutropenia (10%) (all grade 1-2). The most common grade 3-4 toxicities were neutropenic fever (5%) and hypomagnesemia (5%). Of 19 (wt)KRAS mCRC patients previously treated with anti-EGFR therapies, 2 (11%) had a partial response (PR) (-50% and -30%, respectively) and 3 (16%) had stable disease (SD) >4 months (7.8, 5.9 and 4.2 months). Both responders were (wt)PIK3CA and (wt)PTEN. Clinical benefit rate (PR+SD) was 27%. Median PFS was 60 days (95% CI 45.4-74.5), similar to median PFS after last anti-EGFR therapy, 61d (95% CI 50.6-71.3). Conclusions: Panitumumab + decitabine is an active combination in a subset of patients with mCRC previously treated with anti-EGFR therapies (2 PRs in this population). Efficacy assessment in an anti-EGFR therapy naïve population is warranted. Methylation studies are ongoing.

600 Background: This study was designed to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and efficacy of the mTOR inhibitor RAD001 in combination with mFOLFOX-6 and bevacizumab in metastatic colorectal cancer. Methods: Twenty patients with previously untreated metastatic colorectal cancer received mFOLFOX-6, bevacizumab and RAD001 using a standard three patient cohort dose escalation schema. Seventeen of the twenty patients were evaluable with a median age of 52 (ten females and seven males). RAD001 was administered orally at escalating doses of 2.5 mg, 5 mg and 10 mg daily. mFOLFOX-6 and bevacizumab were administered in standard fashion. Results: The most common grade 3/4 hematological adverse events (AEs) were neutropenia (59%), leucopenia (29%) and thrombocytopenia (12%). The most common grade 3 non-hematological AEs were diarrhea (24%) and hypokalemia (18%). One dose-limiting toxicity was noted at 10 mg/day due to grade 3 anorexia, grade 3 diarrhea, and grade 3 hypokalemia. Grade 1 mucositis was noted in 12% of patients and grade 2 mucositis was noted in 47% of patients. There was no grade 3/4 mucositis. Fourteen patients are evaluable for efficacy. The RR is 86% including 2 CRs, 7 PRs, and 3 SDs. Conclusions: RAD001 in combination with mFOLFOX6 and bevacizumab is well-tolerated at a dose of 10 mg/day. The regimen appears to be effective. Evidence of anti-tumor activity correlated with mutation status (k-ras, BRAF, PIK3CA) and PTEN deletion status will be presented.

Background: Disulfiram inhibits hepatic aldehyde dehydrogenase causing accumulation of acetaldehyde when alcohol is ingested and is used to treat alcohol addiction. When metal ions such as copper are combined with disulfiram, key oncoproteins are bound, and inactivated. Disulfiram and copper can inhibit tumor cell growth in cell culture, and xenograft models, and induce cell killing via apoptosis. Here we determined the safety and tolerability of disulfiram when administered together with copper gluconate in patients with advanced treatment-refractory solid tumors involving the liver. Methods: Four preselected oral doses of copper gluconate were tested (2, 4, 6, and 8 mg tid) in a standard “3+3” design. Disulfiram 250 mg was administered once daily. Patients were observed for DLTs, and pharmacodynamic studies were performed. Patients were required to refrain from alcohol consumption during the study. Results: As of November 15, 2010, 15 patients with treatment refractory solid tumors metastatic to the liver have been enrolled. The average number of prior treatments was 7 (range 1-16). Malignancies represented included pancreatic (2), breast (4), colon (1), prostate (1), lung (1), cutaneous melanoma (2), and ocular melanoma (2). Grade 3 toxicities included dehydration (1), hyperglycemia (1), constipation (1), LFT elevations (2) and troponin elevation (1) but these were felt to be more likely related to advanced malignancy or to causes other than the study drugs. Although hepatic toxicity is a potential side effect of disulfiram, the only Grade 3 LFT elevations that occurred on treatment were in patients with disease progression in the liver suggesting that these events were not drug related. There was one reported Grade 2 disulfiram reaction due to exposure to alcohol. Other Grade 1 and 2 toxicities included changes in mental status (6), headaches (2), and dizziness (3) though many of these events corresponded to progression of the underlying malignancy. No radiographic responses to treatment have been observed. Six patients progressed within 28 days of starting treatment. One patient with advanced colon cancer achieved disease stability for 125 days. The average duration on treatment was 37 days (range 1 – 125 days). Reasons for discontinuing treatment included functional decline (4), disease progression (10), and death (1). Two remaining slots are open on the 8 mg dose cohort. Analysis of S-glutathionylation of proteins in response to treatment is ongoing. Conclusions: Disulfiram dosed at 250 mg daily together with copper gluconate at doses of 6 mg three times daily is well tolerated in patients with advanced solid tumors involving the liver. No DLT has yet been observed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1308. doi:10.1158/1538-7445.AM2011-1308