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14535 Background: ABT-869, an orally administered, potent small molecule inhibitor of VEGF receptors 1–3 and platelet derived growth factor, is active in solid malignancies. Consistent with similar...

14109 Background: Transfer constant (Ktrans) and IAUC60 normalized with arterial input function are commonly used dynamic contrast enhanced magnetic resonance imaging (DCE MRI) parameters. The distributed parameters model (DP) is a DCE MRI model that enables derivation of blood flow and capillary permeability-surface area product (PS). We aim to study the distributed parameters model as an alternative method of angiogenesis assessment and correlate the above parameters to drug exposure and patient outcome in a Phase I anti- angiogenic trial. Methods: Fifteen evaluable patients from an on-going Phase I trial (ABT 869) with 3 dose escalations formed the study population. Pharmacokinetic study was performed on Day 1 and the area under the concentration time curve extrapolated to infinity (AUCinfinity) was used as an indicator of drug exposure. All patients underwent DCE MRI at baseline, Day 3 and Day 15 with temporal resolution of 4 seconds. Gadolinium concentrations were estimated using a dual flip angle method. Patients demonstrating progressive disease in first 2 evaluation scans (cycle 2 or 4) based on RECIST criteria were considered progressors and all other patients non-progressors. Receiver operating curve (ROC) analysis was performed. Correlation with AUCinfinity was analyzed. Results: There is good correlation (Spearman’s coefficient -0.67, p = 0.008) between AUCinfinity and DP derived PS and less strong correlation with normalized IAUC60 (Spearman’s coefficient -0.57, p = 0.03). There is no correlation for Ktrans (Spearman’s coefficient 0.04). ROC analysis for predicting progressors versus non-progressors showed a higher ROC area for PS compared to Ktrans (0.83 versus 0.47, p = 0.037). Normalized IAUC60 showed a slightly lower area compared to PS (0.77 versus 0.83) but the difference is not significant (p = 0.58). Conclusions: PS derived from DP model shows better correlation with drug exposure and may predict patient outcome better than Ktrans. [Table: see text]

18104 Background: Asian NSCLC patients are known to have higher response rates to the EGFR TKI gefitinib (G) and erlotinib (E). Anecdotal reports suggest some activity for a second EGFR TKI after failure of the first. Methods: A retrospective review of the electronic pharmacy records, clinical and radiographic records of patients with advanced NSCLC at the National University Hospital who received both G and E in the previous 2 years was conducted. Objectives were to assess the disease control (response/stable disease) of the second TKI after failure of the first and characterize the clinical, pathological and molecular features of patients benefiting from a 2nd TKI. Results: 14 patients with advanced NSCLC who received a 2nd EGFR TKI after progression on the 1st TKI were identified. Patient characteristics: Chinese 12, female 10, and non-smokers 13. Histologic subtype: adenocarcinoma 7, bronchioloalveolar carcinoma (BAC) 3, squamous-cell carcinoma 1, NSCLC unspecified 3. 12 patients received cytotoxic chemotherapy with a median of 2 lines, (range 1–5). G and E was used as 1st/2nd/3rd/=4th line treatment in 8/2/2/2 and 0/4/2/8 patients respectively. G was used before E in 13 cases and disease control was seen in 8/14 (57%) patients. With a 2nd TKI after disease progression, disease control was seen 4/14 (28%) patients. Patient characteristics were: adenocarcinoma 3, BAC 1, all were never smokers and all received and responded to prior G. Median duration of control in these 4 patients for G was 8 (range 7–12) months, and subsequently to E was 2.5 (range 2–8) months. Disease control was associated with symptomatic improvement. Conclusion: This study documents disease control in 28% of Asian NSCLC patients treated with a second EGFR TKI after failure of a first. The molecular basis for these observations is currently being investigated. No significant financial relationships to disclose.

2008 Background: Genotypic variation for drug metabolising enzymes, targets and transporters is associated with inter-patient and inter-ethnic variability in toxicity and efficacy. Gemcitabine is a nucleoside anti-metabolite used in a range of solid tumors. Aims: 1) to determine genotype distribution of genes involved in gemcitabine pharmacology pathway in ethnic groups; 2) to evaluate the association between genotypes and treatment related outcomes in patients with chemo-naive, advanced NSCLC receiving gemcitabine based chemotherapy on a prospective study. Methods: Candidate genes involved in gemcitabine pharmacology were identified from a comprehensive search of public databases (NCBI, PharmGKB), and publications. 25 variants of 9 candidate genes (RRM-1, SLC28A1, SLC28A2, SLC28A3, SLC29A2, POLA2, DCTD, CDA, TS) were genotyped from blood in 94 healthy donors and 76 cancer patients (breast 22, NSCLC 54) with pyrosequencing. Chi-squared, Kruskall-Wallis, and Kaplan-Meier analysis were used to evaluate associations between genotypes and ethnic groups and clinical end points. Results: Significant differences in genotype distribution between Chinese, Malay and Indian were seen in 5/25 loci (see table ). In NSCLC patients, POLA2 2089 (G > A) was associated with neutropenia (p = 0.022), SLC28A1-1576 (C > T) with neutropenia nadir (p = 0.030) and thrombocytopenia nadir (p = 0.037), RRM-1 -524 (T > C) with neutropenia (p = 0.024) and SLC28A2–283 (CA 18.3 vs CC 8.5 months, p = 0.004), and SLC28A2–22 (CC 8.0 vs CT 18.3 months, p = 0.002) with survival. Conclusions: Our results suggest there is significant genotypic variability among ethnic groups. Variants in gemcitabine transporters and targets may be useful indicators of gemcitabine related toxicity and survival. Further studies should be performed to confirm these preliminary findings. [Table: see text] No significant financial relationships to disclose.

3145 Cyclin dependent kinase (CDK) inhibition mimics tumor suppressor protein function and induces cell cycle arrest and apoptosis in cancer cell lines. Seliciclib, an orally administered inhibitor...

Objectives To examine the association between cyclooxygenase-2 (COX-2) expression with epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and latent membrane protein 1 (LMP-1) expression and with COX-2 promoter methylation status in primary nasopharyngeal cancer (NPC) tumors and to determine COX-2 promoter methylation status in NPC cell lines. Design Retrospective study. Setting Patients with NPC were referred to the Department of Otolaryngology–Head and Neck Surgery for treatment. Patients Formalin-fixed, paraffin-embedded NPC specimens from 42 patients were obtained. Interventions Immunohistochemical expression of COX-2, EGFR, VEGF, iNOS, and LMP-1 was performed in 42 NPC samples. COX-2 promoter methylation status was studied in 20 separate specimens and in 4 NPC cell lines. Main Outcome Measures (1) COX-2, EGFR, VEGF, iNOS, and LMP-1 expression; and (2) COX-2 promotor methylation status. Results COX-2 was overexpressed in 79% of NPC specimens and was associated with EGFR status ( P = .03) but not with LMP-1 or iNOS. In primary NPC tissue, methylation of the COX-2 promoter was seen in 4 of 7 COX-2–negative and 1 of 13 COX-2–positive immunohistochemical cases. COX-2 promoter methylation was found in the CNE-1 cell line. Conclusions Nasopharyngeal cancer may be a useful target for selective COX-2 inhibition. The absence of promoter methylation may be a necessary component of COX-2 overexpression, and promoter methylation may be one of the mechanisms that regulate COX-2 expression.

Introduction The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are gaining an increasing role in the management of advanced non-small cell lung cancer (NSCLC). There is mounting interest in the benefit of administering a second TKI after failure of the first TKI, especially in Asian patients, in whom they are expected to be more efficacious. Methods We did a retrospective analysis of patients receiving both gefitinib and erlotinib in our institution during a 2-year period. Patients were to have received the second TKI after progressive disease on the first TKI. EGFR gene mutation analysis was done on patient tumor samples. Results Fourteen patients were included in the analysis, all of whom received erlotinib after progression on gefitinib. Chinese race, females, never-smokers, and adenocarcinoma subtype were predominant in their respective categories. Disease control rate was 64.3% (9 of 14) for gefitinib. Disease control rate for erlotinib administered after progression on gefitinib was 35.7% (5 of 14). All patients who achieved disease control with erlotinib after progression on gefitinib were never-smokers with adenocarcinoma subtype, who had prior disease control on gefitinib. Presence of EGFR mutations predicted for disease control with gefitinib, and for disease control with erlotinib after gefitinib failure. Conclusion A significant proportion of typical gefitinib-sensitive Asian NSCLC patients can have disease control with erlotinib after gefitinib failure. The role of subsequent administration of a second EGFR TKI after failure of the first TKI in advanced NSCLC should be further pursued.

Purpose Linifanib, a potent, selective inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, has single-agent activity in non–small-cell lung cancer (NSCLC). We evaluated linifanib with carboplatin and paclitaxel as first-line therapy of advanced nonsquamous NSCLC. Patients and Methods Patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned to 3-week cycles of carboplatin (area under the curve 6) and paclitaxel (200 mg/m2) with daily placebo (arm A), linifanib 7.5 mg (arm B), or linifanib 12.5 mg (arm C). The primary end point was progression-free survival (PFS); secondary efficacy end points included overall survival (OS) and objective response rate. Results One hundred thirty-eight patients were randomly assigned (median age, 61 years; 57% men; 84% smokers). Median PFS times were 5.4 months (95% CI, 4.2 to 5.7 months) in arm A (n = 47), 8.3 months (95% CI, 4.2 to 10.8 months) in arm B (n = 44), and 7.3 months (95% CI, 4.6 to 10.8 months) in arm C (n = 47). Hazard ratios (HRs) for PFS were 0.51 for arm B versus A (P = .022) and 0.64 for arm C versus A (P = .118). Median OS times were 11.3, 11.4, and 13.0 months in arms A, B, and C, respectively. HRs for OS were 1.08 for arm B versus A (P = .779) and 0.88 for arm C versus A (P = .650). Both linifanib doses were associated with increased toxicity, including a higher incidence of adverse events known to be associated with VEGF/PDGF inhibition. Baseline plasma carcinoembryonic antigen/cytokeratin 19 fragments biomarker signature was associated with PFS improvement and a trend toward OS improvement with linifanib 12.5 mg. Conclusion Addition of linifanib to chemotherapy significantly improved PFS (arm B), with a modest trend for survival benefit (arm C) and increased toxicity reflective of known VEGF/PDGF inhibitory effects.

e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/m2 and SAHA 100 mg b.i.d (dose level 3). Median number of previous treatment regimens was 3 (R:1-6). Dose limiting toxicities (DLT) were seen in 2/2 pts at dose level 1: grade 4 thrombocytopenia (1 pt), grade 3 nausea, vomiting and fatigue (2 pts), and grade 5 hepatic failure (1 pt). Two of six patients at dose level 2 experienced DLT: grade 3 fatigue (1 pt) and worsening of pre-existing Sweet’s Syndrome (1 pt). Common AEs (G1/2) included fatigue (73%), cough (64%), anorexia (55%), and injection site reaction (45%). One minor response was seen and 5 pt had prolonged stable disease (>16 weeks), including one patient for 88 weeks. Analysis of post-treatment tumor biopsies showed demethylation of EBV lytic cycle gene promoters after treatment. SAHA PK, IHC results for EBV gene expression in tumor tissue, EBV viral load and characterization of circulating EBV will be presented. Conclusions: 5AC/SAHA appears to be tolerable at dose level 3 with suggestion of clinical benefit. Analysis of post-treatment tumor and blood samples suggests that modulation of EBV gene expression may play a role in the mechanism underlying clinical benefit. Continued accrual at dose level 3 is ongoing. Clinical trial information: NCT00336063.

SummaryIdentification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.

Background Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide due to poor patient prognosis and clinical outcome. Here, we studied the genetic variations underlying NSCLC pathogenesis based on their association to patient outcome after gemcitabine therapy. Results Bioinformatics analysis was used to investigate possible effects of POLA2 G583R (POLA2+1747 GG/GA, dbSNP ID: rs487989) in terms of protein function. Using biostatistics, POLA2+1747 GG/GA (rs487989, POLA2 G583R) was identified as strongly associated with mortality rate and survival time among NSCLC patients. It was also shown that POLA2+1747 GG/GA is functionally significant for protein localization via green fluorescent protein (GFP)-tagging and confocal laser scanning microscopy analysis. The single nucleotide polymorphism (SNP) causes DNA polymerase alpha subunit B to localize in the cytoplasm instead of the nucleus. This inhibits DNA replication in cancer cells and confers a protective effect in individuals with this SNP. Conclusions The results suggest that POLA2+1747 GG/GA may be used as a prognostic biomarker of patient outcome in NSCLC pathogenesis.