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LBA5 Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.

110 Background: VEGF-mediated angiogenesis contributes to breast cancer (BC) pathogenesis. RAM (IMC-1121B), a fully human IgG1 monoclonal antibody (MAb), targets VEGFR-2, blocking the interaction of VEGF ligands and VEGFR‑2. DC101 (murine anti-VEGFR-2 MAb) impairs vascular function and increases tumor hypoxia in xenograft BC models and inhibits tumor growth in cytotoxic-resistant models. E is a novel non-taxane microtubule inhibitor indicated in MBC pts who have received ≥2 prior chemotherapy regimens, including an anthracycline and a taxane. It is hypothesized that addition of RAM to E as 3rd-5th line therapy in MBC will result in an improvement of median PFS in this ongoing, multicenter, US study. A planned safety analysis of an initial cohort is reported. Methods: Pts with locally recurrent or MBC (HER2+ or HER2-) and 2-4 prior chemotherapy regimens are randomized 1:1 to receive RAM+E or E (E 1.4 mg/m2 Days 1, 8; RAM 10 mg/kg Day 1; q21 days). Pts are stratified by TNBC and prior antiangiogenic therapy status and must have ECOG PS 0-1 and normal LVEF. Planned accrual: 134 pts. Results: Evaluable pts (n=13, 8 RAM+E) received ≥1 dose of RAM+E or E and completed 2 cycles of therapy (or discontinued prior to completing the initial 2 cycles). Median age is 55 yrs. Assessment of adverse events (all cause) revealed nausea, fatigue, headache, and neutropenia were more frequent for RAM+E; anemia was more frequent for E. G1 sensory neuropathy was reported for 1 pt in each arm. One RAM+E pt experienced G3 febrile neutropenia and odynophagia, recovered within a week, and subsequently received reduced dosage (E = 1.1 mg/m2; RAM = 8 mg/kg). No deaths are reported. The safety assessment committee recommended to continue the trial unmodified. Conclusions: Based on preliminary data, the combination of RAM+E demonstrates an acceptable toxicity profile. Accrual continues, with planned updated safety and dose intensity data to be presented at the meeting. [Table: see text]

Background: Nilotinib is a novel, oral ATP-competitive inhibitor of BCR-ABL; it is significantly more potent (>30-fold) and selective than imatinib. ENACT is an ongoing multicenter, open-label, expanded-access study for pts with imatinib-resistant/intolerant CML in all phases. The primary objective is to evaluate the safety of nilotinib in these pts. Methods: Pts with imatinib-resistant or -intolerant CML-CP, -AP, or -BC, who received prior therapies including imatinib and dasatinib were eligible to receive nilotinib 400mg twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction due to toxicity were allowed to have a dose re-escalation to 400mg BID after resolution of the adverse events (AE) to ≤Grade 1, lack of response, or persistent disease at the investigator’s discretion. Results: To date, 1152 pts have been enrolled. Results for the first 587 pts enrolled between January 2006 and January 2007 are presented, 582 received nilotinib and are included for safety analysis (BC n=73, AP n=62, CP n=447): median time since CML diagnosis 52.8 (2.5–468.6) mos; 68.4% were imatinib-resistant and 31.4% were imatinib-intolerant; median duration of nilotinib exposure was 77 days (overall), 84 days for CP, 71 days for AP, and 48 days for BC. At data cutoff (January 31, 2007), 425(73%) pts were continuing on nilotinib, 10% for ≥6 mos. The main reason for discontinuation was unsatisfactory therapeutic effect (11% overall), which as expected was most frequent in BC pts (n=23, 32%). Discontinuations due to AEs occurred in 7% of pts but did not differ significantly among the CML phases: BC 9 (12%); AP 5 (8%); CP 29 (7%). Of the safety population (N=582), 536 (92%) had AEs reported in the database. The incidence and severity of hematologic AEs were higher in BC or AP. Nonhematologic AEs were overall mostly mild to moderate and included headache, rash, nausea, pyrexia, elevated lipase, vomiting, hyperbilirubinemia and myalgia. Among the 536 pts with AEs reported, 15 (2.8%) deaths occurred, most frequently in pts with BC (n=9, 12.5%), rather than AP (n=3, 5.1%) or CP (n=3, 0.7%). The most frequent causes of death in BC were intracranial hemorrhage (n=4), infectious complications (n=2), CML (n=2), or respiratory failure (n=1). Among pts in AP or CP, deaths were attributed to disease progression (n=2), infectious complications (n=2), CML (n=1), or respiratory failure (n=1). Conclusion: Preliminary analysis of this large expanded-access study further demonstrates that nilotinib is safe and well-tolerated in heavily pretreated pts with CML. Importantly, the occurrence of nonhematological AEs for CP, AP and BC pts enrolled in the study appear similar. Overall, both hematologic and nonhematologic AEs have been mild to moderate, and preliminary results from this safety study are consistent with previous published clinical experience with nilotinib phase I/II pivotal studies.

4003Background: Patients (pts) with advanced HCC and elevated AFP have a poorer prognosis compared to the general HCC population, and need effective, well tolerated treatment options. Increased VEG...