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Aim: Vascular endothelial growth factor (VEGF) and VEGF-receptor 2-mediated signaling and angiogenesis likely contribute to HCC pathogenesis. RAM is a fully human IgG1 monoclonal antibody and a VEGF-receptor 2 antagonist. Methods: Eligible pts had advanced HCC, stage BCLC C or B refractory or not amenable to locoregional therapy; Child-Pugh A; ECOG PS 0 or 1; intolerance to sorafenib despite dose reduction, or disease progression during or following sorafenib; and adequate hematologic and biochemical parameters. Pts were randomized 1:1 to receive RAM (8 mg/kg IV) plus best supportive care (BSC) or placebo (PBO) plus BSC every 2 weeks until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The sample size of 544 pts was calculated to enable 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.75. Results: Between Nov 2010 and April 2013, 565 eligible pts were randomized (RAM 283; PBO 282). Baseline pt characteristics were balanced between arms. The OS HR was 0.866 (95% CI 0.717, 1.046; p = 0.1391); median OS was 9.2m for RAM vs 7.6m for PBO. Median PFS with RAM and PBO was 2.8m and 2.1m, respectively (HR 0.63, 95% CI 0.52–0.75; p 5% of treated RAM pts included: hypertension (12.3% RAM arm vs 3.6% PBO arm), asthenia (5.1% vs 1.8%), aspartate aminotransferase increased (5.4% vs 8.3%), and malignant neoplasm progression (6.5% vs 4.0%). In 250 pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (pre-specified), OS HR was 0.67 (95% CI 0.51–0.90; p=0.0059) median OS was 7.8m for RAM vs 4.2m for PBO. Conclusions: No new safety signals were observed. The primary end point was not met. In a selected pt population with an elevated baseline AFP, a meaningful OS improvement in the RAM arm was observed. The relationship between AFP and RAM benefit warrants further investigation. Disclosure: J.F. Blanc: reports personal fees from Imclone systems / Lilly, during the conduct of the study; T.E. Pfiffer: reports Lilly, the sponsor of REACH trial, gave financial support to "Instituto do Cancer do Estado de Sao Paulo" ICESP to run part of the trial, during the conduct of the study; personal fees from Lilly, outside the submitted work; T. Okusaka: received grant money and personal fees from Eli Lilly. Relevant financial activities outside the submitted work include grant money and personal fees from several companies; J. Trojan: reports participation as a speaker and on the advisory board for Eli Lilly; J. Sastre: reports receiving personal fees for lectures from Eli Lilly, Roche, Merck, Bayer, Sanofi, and MSD; I. Chau: received research support from Eli Lilly & Co, honorarium from ImClone LLC and Eli Lilly & Co., has also been a consultant, received payment for lectures, educational presentations, and travel and meeting expenses from several other companies; S. Chang and P.B. Abada: is an employee of and has stock ownership in Eli Lilly & Co.; L. Yang: is an employee of ImClone Systems, a wholly owned subsidiary of Eli Lilly and Co., and has stock ownership in Eli Lilly and Co.; J. Schwartz: was an employee of Imclone Systems and has stock ownership in Eli Lilly. All other authors have declared no conflicts of interest.

Disclosure K. Mansouri: K. Mansouri is an employees of Eli Lilly and Co. L. Cirri: L. Cirri is an employees of Eli Lilly and Co. P. Shi: P. Shi is an employees of Eli Lilly and Co. O. Hamid: O. Hamid is an mployees of Eli Lilly and Co. All other authors have declared no conflicts of interest. AIs are used as first-line treatment for postmenopausal women with hormone-receptor-positive MBC. Overexpression of PKC α has been linked to AI resistance in several studies. We examined whether Enza, a serine/threonine kinase inhibitor that targets PKC, could improve the effect of Ful in pts who progressed following first-line AI treatment for MBC. Postmenopausal pts with hormone-receptor-positive, HER2-negative, locally advanced or MBC who progressed on prior AI received a loading dose of Ful 500 mg IM on Day (D) 1 and 250 mg on D 15 of Cycle (C) 1 and D 1 of each cycle thereafter. Enza 500 mg or PBO was administered orally once daily (QD) or 250 mg twice daily (BID). Primary endpoint was the clinical benefit rate (CBR). Secondary endpoints were response rate (RR), duration of CB, progression-free survival (PFS) and safety. A total of 156 pts was randomly assigned to therapy; 152 received at least 1 dose of study drug (39 BID; 55 QD; 58 PBO). Baseline disease characteristics were balanced across arms. There was no statistically significant difference in CBR between pts in Ful + Enza vs Ful + PBO. There was no statistically significant difference in CBRs, RRs and PFS between pts on QD and BID dosing schedules. Pts on BID dosing had numerically more TEAEs vs those on QD and PBO (61.5%, 43.6%, and 46.6%, respectively) and numerically more Grade 3/4 TEAEs vs QD and PBO (17.9%, 9.1%, and 5.2%, respectively). Most frequent Grade 3/4 TEAEs in the BID arm were fatigue (n [%]) (4 [10.3%]), dyspnea (2 [5.1%]) and nausea (2 [5.1%]). 8 pts died; 5 due to disease, 3 due to AEs: 1 drug-related hepatic dysfunction (Enza QD arm), 1 non-drug-related myocardial infarction and 1 non-drug-related respiratory failure (both in the Enza BID arm). Ful + Enza [QD + BID] N = 94 Ful + PBO N = 58 P-value vs PBO CBR Number of responders, n (%), (95% CI) 41 (43.6) (33.4, 54.2) 24 (44.8) (31.7, 58.5) 0.62 RR, % (95% CI) 5.3 (1.7, 12.0) 5.2 (1.1, 14.4) 0.64 PFS, months (95% CI) 5.2 (3.5, 7.4) 5.5 (3.8, 7.4) 0.59 Median duration of CB, months 9.6 9.7 0.86 CBR = complete response + partial response + stable disease Addition of Enza to Ful does not improve disease outcome in pts with locally advanced or MBC after progression on AI.

Summary Purpose; To determine the safety and activity of LY231514 (ALIMTA®, MTA, pemetrexed disodium, Eli Lilly and Co., Indianapolis, IN) in chemotherapy-naive patients with advanced pancreatic cancer. Patients and methods; Patients with unresectable or metastatic pancreatic cancer received LY231514 600 mg/m 2 as a 10-minute infusion every three weeks. Results: Forty-two patients were enrolled in this phase II trial. The median age was 60.3 (range 37-77) years; 79% had metastatic disease. Neutropenia was common (40% of patients ^ grade 3) but infectious complications were rare. Significant anemia or thrombocytopenia occurred in < 20% of patients. Non-hematologic toxicities included grade 2 or 3 skin reaction which was ameliorated by dexamethasone. Elevations of bilirubin or transaminases were infrequent (