Introduction Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in-vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1, and that Notch1 activation correlates with a decrease in tumor markers for NET. Thus, this study aimed to evaluate the role of valproic acid in treating NETs and if VPA induced the Notch signaling pathway signaling in-vivo‥ Patients & Methods Eight patients with low grade NETs (carcinoid and pancreatic) were treated with valproic acid 500 mg orally twice a day with dosing adjusted to maintain a goal VPA level between 50–100 mcg/mL. All patients were followed for 12 months or until disease progression. Results Notch1 signaling was absent in all tumors prior to treatment, and was upregulated with VPA. One patient had an unconfirmed PR and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5/7 patients. Overall, treatment with VPA was well tolerated. Conclusion Valproic acid activates Notch1 signaling in-vivo and may have a role in treating low grade NET.

Background A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. Methods In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1–3 along with cisplatin on day 1 and etoposide on days 1–3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. Results Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1–3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. Conclusions AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

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338 Background: Retrospective data suggest that neoadjuvant therapy in patients with resectable pancreatic cancer may improve the R0 resection rate and potentially survival. We examined the impact of neoadjuvant therapy on survival rates at a population level for patients with resected pancreatic adenocarcinoma. Methods: Treatment and outcome data were obtained from the Surveillance, Epidemiology and End Results (SEER) Medicare database for patients with pancreatic adenocarcinoma, who underwent a curative intent pancreatectomy from 2001-2007. Patients were stratified by treatment (neoadjuvant vs no neoadjuvant therapy). Kaplan Meier curves were constructed to analyze survival. Cox proportional hazards regression models with and without propensity score weighting were performed to determine the effect of neoadjuvant therapy and race on mortality while adjusting for age, gender, race, marital status, SEER site, urban/rural location, income, education, year of diagnosis, and Charlson Comorbidity Score. Results: 2608 patients were included. 58.4% (n=1523) were between age 66-75 and 41.6% (n=1085) were age 76 or older. 94% (n=2459) did not receive neoadjuvant therapy and 6% (n=162) received neoadjuvant therapy. Patients undergoing neoadjuvant therapy were 28% less likely to experience death at one year (HR 0.72; 95% CI, 0.53-0.97; p=0.03). There was also a trend towards a lower risk of death in this group at 2 years (HR 0.82; 95% CI, 0.66-1.01; p=0.07). Conclusions: Patients with pancreatic adenocarcinoma who underwent neoadjuvant therapy followed by resection had an improved one-year survival relative to patients who did not receive neoadjuvant therapy in this cohort. This effect may partially reflect the role of neoadjuvant chemotherapy in allowing for better selection of patients likely to benefit from surgery. To our knowledge this is the first population-based study that suggests an improved survival in patients with pancreas cancer undergoing neoadjuvant therapy prior to resection. [Table: see text]