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100 Background: AVAGAST study showed regional differences in efficacy, including notable differences in progression free survival (PFS) and overall survival in the PL arm. In Japan, there is a certain number of pts with minimal peritoneal metastasis (PM) diagnosed only by laparoscopy or open surgery, which seems unusual in Western as well as in other Asian countries, and it might have led the differences. Therefore, an exploratory analysis was conducted among the PL arm to examine pt characteristics including PM associated with differences in outcome between JPN and ROW. Methods: We compared PFS of PL arm between pts enrolled from JPN and those from ROW. Hazard ratio (HR) and its 95% confidence interval (95%CI) between JPN and ROW were calculated using Cox’s proportional hazard model for each major covariates (disease status, performance status, prior gastrectomy, prior (neo)adjuvant chemotherapy, age, sex, primary site, liver metastasis (mets), number of metastatic sites, disease measurability, histologic type, maximum of tumor size, sum of tumor size, bone mets, PM and only PM) Results: 188 pts from 14 sites were enrolled from JPN, of which 94 pts were randomized to PL arm. Compared with 293 pts from ROW in PL arm, PFS tend to be favorable in JPN. Subgroups of JPN without liver mets, with diffuse or mixed type gastric cancer (GC), with PM and with only PM were clearly favorable than that of ROW. The difference in subgroup with PM was especially large with lower confidence limit of 1.21. When the pts with only PM were excluded, the difference of PFS in PL arm between JPN and ROW became smaller ( Table ). Conclusions: In this exploratory analysis, pts with PM in JPN had a better prognosis than ROW pts. Understanding this unique pt population may provide insight to the regional differences in outcome noted on this study. [Table: see text]

527 Background: The treatment benefits of epidermal growth factor receptor (EGFR) monoclonal antibodies for patients with KRAS mutations have not been demonstrated. However, some studies have suggested that all KRAS mutations are not equivalent, and that KRAS G13D mutations might have some survival benefit. Methods: We retrospectively analyzed the efficacy and toxicity of treatment with EGFR monoclonal antibody in 8 patients with KRAS G13D mutations and 5-FU/oxaliplatin/irinotecan (CPT) refractory metastatic colorectal cancer compared with 94 KRAS wild type patients at the National Cancer Center Hospital. Results: Eight patients with KRAS G13D mutations were treated with anti-EGFR monoclonal antibodies between July, 2009 and July, 2011. The median age was 66 (42-70); male/female 6/2; PS was 0/1/2, 2/5/1; treatment regimen was cetuximab/ cetuximab+CPT/ panitumumab+CPT, 2/5/1. Response rate (RR) was 12.5% and disease control rate (DCR) was 50.0% with 1 PR, 3 SD, and 4 PD. The PR case treated with cetuximab+CPT showed marked regression of tumor and long duration of treatment (9 months). The progression free survival (PFS) of 2 SD cases was 4.2 and 3.9 months. The other SD case is now on treatment. The median PFS of the 8 patients was 2.1 months (95% confidence interval [CI]: 0.0-5.2). The median overall survival (OS) has not been reached. Grade 3/4 toxicities included 1 hypomagnesemia G4 and 1 rash acneiform G3. Meanwhile, 94 KRAS wild type patients treated with anti EGFR monoclonal antibodies had an RR of 22.3% and DCR was 66.0% with 21 PR, 41 SD, 30 PD, and 2 NE. PFS was 5.6 months (95% CI: 4.9-6.3) and OS was 8.6 months (95% CI: 6.5-10.7). Conclusions: In this analysis, we identified one PR to anti-EGFR monoclonal antibody in a patient with KRAS G13D mutation and chemo-refractory metastatic colorectal cancer. However, we were unable to demonstrate equivalent efficacy in patients with KRAS G13D mutations and KRAS wild type patients. Further studies are needed to evaluate the efficacy and prognosis for this treatment.

Fluoropyrimidines have shown efficacy against a variety of cancers and have evolved into a range of different uses and formulations. These drugs have been tested extensively as monotherapies and as part of numerous different chemotherapy combinations. The efficacy and safety profile of bolus intravenous (IV) 5-fluorouracil (5-FU) has been improved by continuous IV administration. The availability of the first 5-FU oral form in Europe, capecitabine, has added a clear value in terms of convenience for patients, while forcing physicians and nurses to learn how to manage the toxicity profile of this compound. S-1 is a new oral formulation combining a 5-FU prodrug (tegafur) and two targeted modulators of its metabolism (gimeracil and oteracil) preserving the efficacy and improving the safety of the prodrug. S-1 has become the backbone treatment for advanced gastric cancer in Japan since its introduction in 1999. Extensive experience from clinical trials, post-marketing studies and patient registries of over 4,000 patients in Japan show that S-1 has improved measures of survival in advanced gastric cancer and has an acceptable safety profile. S-1 has recently been approved for advanced gastric cancer treatment in Europe. Since 5-FU metabolism differs between Asian and Caucasian populations, the introduction of S-1 in Caucasians has necessitated an entirely new clinical trial programme. Phase I trials indicated different dose levels were necessary in Westerners versus Asians (25 versus 40 mg/m2). In the FLAGS study of over 1,000 patients with advanced gastric cancer (the largest study ever conducted in this indication), S-1 plus cisplatin was demonstrated to be non-inferior in efficacy but superior in safety to 5-FU + cisplatin. Based on these results, S-1 was approved in Europe in March 2011 under the trade name Teysuno®. Further clinical trials are in progress to evaluate S-1 in advanced gastric cancer (AGC) and its use as part of triplet therapies is currently being investigated. This will further define the role of S-1 as a key part of advanced gastric cancer management in Western countries.

Background: Cabozantinib is a potent orally available small molecule inhibitor of multiple receptor tyrosine kinases with growth promoting and angiogenic properties. The primary targets of cabozantinib are MET and VEGFR2. In preclinical models, cabozantinib demonstrated significant tumor growth inhibition in multiple tumor models including human medullary thyroid cancer (MTC), human breast cancer, human lung carcinoma and rat glioblastoma. Anti-tumor activity in patients has been observed across a broad range of tumor types including MTC, prostate, ovarian and breast cancer, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma and glioblastoma. The primary objectives of this open-label phase 1 study are determination of the maximum tolerated dose (MTD) and recommended phase 2 dose in Japanese patients. Methods: Patients with advanced solid malignancies are enrolled in successive cohorts to receive escalating doses of cabozantinib in a 3+3 trial design. Patients are treated with continuous 4-week cycles of cabozantinib administered orally (PO) once daily (QD). Dose limiting toxicities (DLTs) are determined using Cycle 1 data. Response is assessed on Day 29 and every 8 weeks thereafter by modified RECIST v1.0 criteria and patients with stable disease (SD) or objective response receive continued therapy. Pharmacokinetic (PK) parameters of cabozantinib and relevant plasma markers including VEGF-A, sVEGFR2 and PlGF are being evaluated. Results: As of 1 September 2011, 6 patients with advanced malignancies have been enrolled: NSCLC (n=3), colorectal cancer, gastrointestinal stromal tumor (GIST), leiomyosarcoma (n=1 each). Patients were pretreated with a median of 3 prior regimens (range, 2 − 7). Patients have been treated at 2 dose levels of 40mg and 60mg free base equivalents (salt strengths of 50mg and 75mg, respectively) PO QD. There have been no DLTs or serious adverse events reported to date. The MTD has not yet been defined. Observed adverse events were generally mild to moderate and include hypertension, palmer-plantar erythrodysesthesia, diarrhea, mucositis, rash, edema and headache. Laboratory abnormalities include elevated AST/ALT, neutropenia, thrombocytopenia and increases in alkaline phosphatase, LDH, lipase and TSH. Results of preliminary PK analysis at the 40mg QD dose level showed that cabozantinib appeared to reach steady-state plasma concentrations by Day 15 and there was evidence of 6- to 7-fold accumulation on Day 19. One patient with NSCLC has had a confirmed partial response with 38% reduction in the sum of target lesions. Three pretreated patients including 2 with NSCLC and 1 with GIST have had SD with reductions in the sum of target lesions of 20, 13 and 16% respectively, and continue treatment with cabozantinib. Conclusions: Cabozantinib appears well tolerated at doses tested to date. Early signs of antitumor activity including prolonged stable disease and response have been observed in the initial dosing cohorts. Determination of the MTD is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C26.

The underlying mechanism regulating the expression of the cancer stem cell / tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. We recently have reported that the expression of CD133 in cancer cells could be regulated though the inhibition of signal transduction by molecular-targeted drugs (Matsumoto K. et al. Cancer Res. 2009). Here, we screened the expression changes of CD133 using wide variety of molecular-targeted drugs in FGFR2-amplified and CD133-overexpressing gastric cancer cell lines. CD133 expression was remarkably upregulated by FGFR inhibitor PD173074 exposure in these cells. Further analysis revealed that PD173074 upregulated the CD133 expression both mRNA and protein levels in dose- and time-dependent manners. In addition, the expression change was correlated with the mRNA expression levels of stem cell factors including OCT3/4, SOX2 and NANOG. As expected, PD173074 exhibited a potent growth inhibitory effect on FGFR2-amplified gastric cancer cells in vitro. These results suggest that the mechanism regulating the expression of CD133 is involved in FGFR2 signaling and also in addicted signaling pathway for cancer cells in FGFR2-amplified gastric cancer cells. 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 5207. doi:10.1158/1538-7445.AM2011-5207

Forkhead Box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (28-fold / colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using siRNA resulted in a decrease in p21CIP1/WAF1 expression, and a reporter assay and ChIP assay showed that p21CIP1/WAF1 was one of target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21CIP1/WAF1 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity (EGFP: 2/15, FOXQ1: 7/15) and enhanced tumor growth (437 ± 301 vs. 1735 ± 769 mm3, p In conclusion, FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth presumably through its angiogenic and anti-apoptotic effects. Our findings demonstrate that FOXQ1 is a new member of the cancer-related FOX family. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3893.

BACKGROUND: Increasing evidence suggests that there is a small subset of cells, called cancer stem cells (CSC), that are responsible for cancer initiation, development, metastasis and treatment resistance. Although CD133 and CD44 are thought to be the putative markers to characterize CSC of various solid tumors such as brain cancer, colorectal cancer, breast cancer and prostate cancer, the link between expression status of CD133/44 and the clnical future of resected gastric cancer tissues after neo-adjuvant chemotherapy has not yet studied. We evaluated CD133/44 expression status in resected gastric cancer issue after neoadjuvant chemotherapy. PATIENTS AND METHODS: 32 cases were selected from advanced gastric cancer specimens of patients who underwent neo-adjuvant chemotherapy (S-1 and cisplatin or irinotecan and cisplatin or S-1 monotherapy) and surgical resection between 2001 and 2007 at the National Cancer Center Hospital. Immunohistochemical staining with anti-CD133 and anti-CD44 antibody were performed with these specimens. Immunopositive cells were counted from 10 fields in the representative section and expressed as a percentage. The specimen with necrosis or disappearance of the tumor cells in more than 1/3 of the whole lesion was defined as positive histological response specimen. Correlation of immunoreactivity with clinicopathological variables was evaluated and survival curves were compared between CD133/CD44 positive and negative cases. RESULTS: Patient characteristics: median age 57 years (range 31-74); male/female 22/10; histological type diffuse-type/intestinal-type 25/7. CD133 and CD44 expression (positive cells: 0% CONCLUSION: CD133 and CD44 were frequently expressed in gastric cancer tissues after neoadjuvant chemotherapy. This study had limited numbers of patient sample and we were unable to study the CD133/44 status before treatment. Further study to identify the usefulness of CD133 and CD44 to predict the prognosis in gastric cancer patients is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3364.

Alternative splicing is a major source of protein diversity and cancer is driven by mutations in genes that control the proliferation of cells. The specific exon abnormality may contribute to the etiology of cancer and may provide selective drug targets. However, most studies of alternative splicing in human disease have used a targeted approach and focused on individual genes among whole genome. In this study, we evaluated an integrated approach of whole genome scale exon array and SNP array to detect cancer-associated alternative splicing, especially focusing on the protein kinase family. We investigated exon-level expression profiling against 22 gastric and colorectal cancer cell lines using Affymetrix Human Exon 1.0 ST Array. Array-based comparative genomic hybridization (CGH) analysis using high-density SNP Array (Affymetrix 250K Nsp /SNP6.0 Array) was also performed to explore genomic amplification/deletion. Several candidate alternative splicing or abnormalities of specific exon expression were detected in cancer-associated genes which detected genomic amplification/deletion frequently; exampling FGFR2, CDKN2A, and CDH13. We found the gene amplification of FGFR2 with C-terminus truncation. We also detected the existence of short CDH13 transcript resulted from small genomic deletion including consecutive 3 exons. In addition, exon-level expression pattern was compared between gastric and colorectal cancer cell lines. In conclusion, integration of whole genome exon array analysis and array CGH analysis may be a promising approach to explore the alternative exon abnormalities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2156.

PURPOSE: Both CD133 and CD44 have been reported as putative markers for cancer-initiating cell in various malignancies such as colon, prostate and pancreatic cancers. No immunohistochemical analysis correlated with clinicopathological outcome have been reported in squamous cell carcinoma of the esophagus. We evaluated the values of CD133/44 as markers for prognosis and chemoresistance in the patients with esophageal cancer. MATERIALS AND METHODS: The expression of CD133/44 was assessed by immunohistochemistry in a series of 58 surgical specimens of squamous cell carcinoma of the esophagus after neoadjuvant chemotherapy: 2 courses of 5-fluorouracil and cisplatin. Immunopositive cells were counted from 10 fields in the representative section and expressed as a percentage. The specimen with necrosis or disappearance of the tumor cells in more than 1/3 of the whole lesion was determined as positive histological response specimen. RESULTS: CD133 expression (positive cells: 0% CONCLUSION: CD133 expression can be a prognostic marker and also a marker for chemoresistance of 5-fluorouracil and cisplatin in patients with squamous cell carcinoma of the esophagus. CD44 expression is not a marker for any clinicopathological outcome in patients with squamous cell carcinoma of the esophagus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3361.

Background: Survivin is a protein known to regulate apoptosis and cell division and highly expressed in various types of cancers. The inhibition of survivin is expected to normalize the cell cycle and selectively eradicate tumor cells. LY2181308 is a second generation antisense oligonucleotide (ASO) designed to complementarily bind to human survivin mRNA and to inhibit the gene/protein expression, which in turn should restore the normal apoptotic pathway in cancer cells. To evaluate the tolerability, pharmacokinetics (PK), and anti-tumor effect of LY2181308 in Japanese patients (pts) with solid tumors, a phase 1 dose-escalation study was conducted. Methods: The primary objective of this study was to evaluate the tolerability of LY2181308 up to 750 mg. The secondary objectives included evaluation of PK and anti-tumor response. Dose-escalation cohorts include 3–6 pts starting at 400 mg with sequential escalations to 600 and 750 mg. The treatment schedule consisted in a loading dose of 3 consecutive daily intravenous infusions over 3 hours, followed by a maintenance weekly intravenous infusion over 3 hours. Results: A total of 14 pts (11 male /3 female) were enrolled into 3 cohorts (4 at 400 mg; 4 at 600 mg; 6 at 750 mg): median age = 60 (44–73). The median treatment period was 2.0 cycle (1–4). Of the 14 pts, 12 pts were evaluable for dose limiting toxicities (DLTs, 3 at 400 mg; 3 at 600 mg; 6 at 750 mg); 2 pts each at 400 mg and 600 mg were excluded due to early disease progression. Only 1 pt at 750 mg reported DLTs; Grade 3 elevations in ALT/AST/ -GTP. All 14 pts were evaluable for safety and PK. The most frequent adverse events (AEs) were hyperhidrosis, prothrombin time ratio increased, and pyrexia. Most AEs were CTCAE Grade 1 or 2. No deaths or study discontinuations due to any adverse events were reported. One serious AE (Grade 3 blood bilirubin increased) was observed in 1 pt with pancreatic cancer (600 mg); this toxicity was not judged to be causally related to the study drug due to disease progression. Abnormalities of blood coagulation values, commonly observed with second generation ASOs, were reported in most pts; they were all Grade 1. The plasma PK profile primarily illustrated tissue distribution, and only a small percentage of the plasma exposure (∼7%) was eliminated under the terminal elimination t½. The terminal elimination t½ was ∼21 days. The geometric mean AUC0-∞ and Cmax following 750-mg dose on Day3 were 324000 ng*h/mL and 66700 ng/mL, which were comparable with those of non-Japanese pts. The terminal t½ was derived from a 4-compartment model which was found to fit adequately the data. Consistent with the long terminal t½, the PK analyses showed that the clearance to tissue and elimination clearance were low to moderate (i.e ∼2 L/h and ∼30 L/h, respectively) and that the volume of distribution was high (>10000 L). Of the 14 pts, 12 pts who had target lesions were evaluable for anti-tumor response. Eleven pts were Progressive Disease, and 1 pt was Stable Disease. Conclusions: LY2181308 monotherapy in doses of up to 750 mg was confirmed to be tolerable for Japanese pts with solid tumors. LY2181308 showed very long half-life and was considered to be extensively distributed into tissues based on the rapid decrease of plasma LY2181308 concentration after the administration. Further investigations in combination with other anti-tumor drugs are ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B48.

Background: Sorafenib (BAY 43-9006) is a multi-kinase inhibitor, targeting Raf kinase and the receptor tyrosine kinases VEGFR-2 and PDGFR-. S-1, an oral fluoropyrimidine, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase 1 study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP in patients (pts) with AGC. Methods: Pts with histologically confirmed previously untreated AGC were enrolled in the study. Treatment of pts in 3 cohorts was planned. Cohort 1: sorafenib (400 mg bid, day 1–35), S-1 (40 mg/m2 bid, day 1–21) and CDDP (60 mg/m2, day 8); cohort 2: sorafenib (400 mg bid, day 1–28), S-1 (25 mg/m2 bid, day 1–21), and CDDP (75 mg/m2, day 1); cohort 3: sorafenib (400 mg bid, day 1–28), S-1 (40 mg/m2 bid, day 1–21), and CDDP (75 mg/m2, day 1). Treatment schedule and dosages for cohort 1 were set based on the SPIRITS study (Koizumi, et al. Lancet Oncol. 9, 2008), and for cohorts 2 and 3 on the FLAGS study (Ajani, et al. ASCO, 2009). Treatment was continued until disease progression or unacceptable toxicity occurred. Results: Between May/2008 and Jan/2009, 13 Japanese pts were enrolled in cohort 1 and received at least one dose of the study treatment. Cohorts 2 and 3 were canceled because of negative results of the FLAGS study reported during our study of cohort 1. Pt characteristics were: 10 male and 3 female, median age 61 years (range 41–72), ECOG PS 0 in 9 pts and 1 in 4 pts. At the data cut off (30/Jun/2009), 12 of 13 pts had discontinued the study treatment (7 due to adverse events (AEs) and 5 due to disease progression) and 1 remained under treatment. The most common AEs occurring in ≥10 pts were neutropenia (92%), thrombocytopenia (92%), rash/desquamation (100%), anorexia (100%), hand-foot skin reaction (85%), nausea (85%), fatigue (77%), and lipase increase (77%). The grade 3/4 AEs occurring in ≥3 pts were neutropenia (54%), anemia (23%), lipase increase (62%), hand-foot skin reaction (23%), fatigue (23%), and amylase increase (23%). AEs resulted in treatment discontinuation included neutropenia (Gr 3) and anemia (Gr 2) that persisted for more than 4 weeks, AST/ALT increase (Gr 4), diarrhea (Gr 3), gastric perforation (Gr 3), hand-foot skin reaction (Gr 3), and auditory disturbance (Gr 1) attributed to CDDP. A total of ≥5 cycles of the study treatment was delivered in 6 pts. Two pts did not complete the 1st cycle due to Gr 1 auditory disturbance and Gr 4 AST/ALT increase, respectively. No treatment-related death was observed. Five pts had partial response and 7 had stable disease as the best response. Conclusions: Hematological, skin-related, and gastrointestinal events were the main toxicities of sorafenib plus S-1 and CDDP combination. The regimen demonstrated antitumor activity in untreated AGC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A260.

14015 Background: Vorinostat (Zolinza™), a potent inhibitor of histone deacetylase (HDAC), induces tumor growth inhibition, differentiation, and apoptosis in vitro. Increasing evidence has revealed clinical activity of vorinostat in patients (pts) with various types of cancer including cutaneous T-cell lymphoma. Methods: Japanese pts with solid tumor who failed standard therapy were enrolled in a single institution, National Cancer Center hospital, Phase I study. Pts were dosed with vorinostat BID for 14 consecutive days followed by 7 day-rest starting at 100 mg and escalated by 100 mg BID until MTD was established. Subsequently single daily dosing was tested at 400 and 500 mg. PK was measured at total of 41 timepoints. Response was also evaluated according to the international workshop criteria. Results: MTD was established as 200 mg BID and 500 mg QD for 14 consecutive days followed by a 7 day-rest. All 18 enrolled pts were assessed for safety and PK. Median age was 58 yrs [25–72]. Ten of 18 pts had lung cancer. Two of 6 pts receiving 200 mg BID experienced DLTs: Grade 4 thrombocytopenia, and Grade 4 thrombocytopenia and Grade 3 anorexia. None of 3 pts receiving 400 mg QD experienced DLT. One of 6 pts receiving 500 mg QD experienced Grade 3 anorexia and fatigue. AUC of vorinostat increased generally proportional to dose in the range of 100–500 mg. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine ( No significant financial relationships to disclose.

14602 Background: Endothelin (ET)-1 and its primary receptor, the ETA receptor, contribute to tumor cell growth, survival, angiogenesis and invasion. Atrasentan is a highly potent, selective ETA receptor antagonist. This study assessed safety and pharmacokinetics (PK) in Japanese patients with hormone refractory prostate cancer. Methods: This open-label, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5, 10 or 20 mg) given daily on day 1 and day 4 through 27 (except day 2 and 3). Dose-limiting toxicity (DLT) was defined as Grade 3 or greater adverse events related to study drug. Results: Eighteen patients, aged 54–74 (median; 66) were treated in cohorts of 6 patients each. The compliance of all patients was 100%. The most common toxicities were rhinitis, peripheral edema, headache, hypotension and anemia, all of which were well tolerated. These events were consistent with the anticipated vasodilatory effects or with a hemodilution effect of the study drug. DLTs were not observed. Atrasentan was rapidly absorbed following oral administration of 2.5 to 20 mg, maximum plasma concentrations averaged from 0.4 to 0.8 hours. After peaking, plasma concentrations declined bi-exponentially with a terminal half-life of approximately 25 hours. In the 10 mg dosing group, the steady-state maximum plasma concentration (Cmax) and the area under the curve (AUC0–24h) averaged 135.5 ng/mL and 533 ng h/mL, respectively. The Cmax and AUC values generally increased linearly with increasing dose after single- and multiple-dose administration. Compared to baseline, PSA decreased 50% or more in 1 patient (20 mg) and increased 25% or more in 10 patients (2.5 mg;2, 10 mg;5, 20 mg;3). The PSA of the remaining 7 patients (2.5 mg;4, 10 mg;1, 20 mg;2) ranged from < 25% increase to < 50% decrease. Fourteen patients continued on study drug in an extension study. Conclusions: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 20 mg in Japanese patients. The main adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing. No significant financial relationships to disclose.

2050 Background: The epothilones are a new class of non-taxane tubulin- polymerizing agents obtained by fermentation of the myxobacterium Sorangium cellulosum. ixabepilone, a semi-synthetic analog ...

2030 Background: E7070 is a sulphonamide derivative being developed as an anticancer agent. In vitro studies indicate that the drug disrupts the G1/S phase of the cell cycle, thereby inducing cell cycle arrest and apoptosis. The objectives of this phase I study of E7070 in Japanese patients were to estimate the maximal tolerated dose (MTD), determine the recommended dose for phase II, establish the pharmacokinetic profile of E7070 and examine its relation to polymorphisms of CYP2C9 (*2, *3) and CYP2C19 (*2, *3), and seek preliminary evidence of efficacy. Methods: Patients received 1–2 hr iv infusions of E7070 (400, 600, 700, 800 or 900 mg/m2) on Day 1 of a 21-day cycle. Dose-limiting toxicity (DLT) was defined as G4 leukopenia, G4 neutropenia lasting 5 days or with fever ≥ 38.5°C, thrombocytopenia (less than 25,000/μL), and G3 non-hematologic toxicity (except nausea/vomiting or alopecia). Results: Twenty-one patients (age 35–70 years, M/F 15/6, 15 colorectal, 2 SCLC, 4 others) received between 1 and 8 cyc...

Background Capecitabine plus cisplatin (XP) is recognized as one of the global standard first-line chemotherapy regimens for patients with metastatic gastric cancer (mGC). Recent multinational phase III trials in mGC have been conducted with XP as the control arm, although no data on XP in Japanese patients with mGC have been published to date. The AVAGAST (XP ± bevacizumab in mGC) and ToGA (XP ± trastuzumab in human epidermal growth factor receptor 2 [HER2]-positive mGC) studies were the first two global studies including Japanese mGC patients. The aim of this analysis was to investigate the efficacy and safety of XP in Japanese mGC patients, using AVAGAST and ToGA subgroup data. Methods Efficacy and safety analyses were carried out in Japanese patients with mGC receiving XP alone, based on results from the AVAGAST and ToGA studies. There were differences in the target populations between the two studies; for example, the ToGA study limited patients to those with HER2-positive tumors; therefore, efficacy was evaluated separately. Results Ninety-four Japanese patients in the AVAGAST study and 50 in the ToGA study received XP alone. Median overall and progression-free survivals were 14.2 and 5.7 months, respectively, in the AVAGAST study, and 17.7 and 5.6 months, respectively, in the ToGA study. Overall response rates were 49.2 % in the AVAGAST and 58.5 % in the ToGA study. Adverse events were generally mild; the most common grade 3/4 events were neutropenia, anemia, anorexia, and nausea. Conclusions XP is effective and well tolerated in Japanese patients with mGC, and could be one of the standard regimens for the first-line treatment in this cohort.

Purpose BMS-690514 is a novel oral tyrosine kinase inhibitor of ErbB and vascular endothelial growth factor receptor. This open-label phase I dose-escalation study (ClinicalTrials.gov Identifier: NCT00516451) aimed to assess the safety, preliminary efficacy, pharmacokinetics, and pharmacodynamics of BMS-690514 in Japanese patients with advanced or metastatic solid tumors. Methods Patients with advanced or metastatic solid tumors received oral BMS-690514 once daily continuously until disease progression or intolerable toxicity occurred. Dose-limiting toxicity (DLT) was evaluated from the first dose to Day 29. Dose levels at 100 and 200 mg were investigated. Assessments included adverse events, tumor response, pharmacokinetics, pharmacodynamics, 2 [18F] fluoro-2-deoxyglucose positron-emitting tomography, and epidermal growth factor receptor and K-ras mutations. Results BMS-690514 at the dose of 100 mg (n = 3) or 200 mg (n = 3) was administered once daily to totally nine patients and was well tolerated up to 200 mg. No treatment-related serious adverse events or DLTs were reported. Frequently observed treatment-related AEs were acne, diarrhea, dry skin, hypertension, stomatitis, blood fibrinogen increased, hemoglobin decreased, pruritus, and hypoalbuminemia. These were generally reported as Grade 1 and 2. Five of 9 patients (56 %) had stable disease. Plasma concentrations of BMS-690514 reached Cmax within 3 h and declined with an effective half-life of approximately 10 and 12 h at 100 and 200 mg, respectively. Conclusions Oral BMS-690514 was well tolerated in Japanese patients with advanced or metastatic solid tumors up to 200 mg.

Purpose This phase 1 study aimed to assess the tolerability, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of lenvatinib capsules in Japanese patients with solid tumors when administered orally up to 24 mg on a once-daily (QD) continuous schedule. Methods Patients were enrolled in one of the two sequential cohorts (20 or 24 mg) of lenvatinib on a 28-day cycle based on the conventional 3 + 3 dose escalation design. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Tolerability was judged based on dose-limiting toxicities (DLTs) during Cycle 1. The drug was defined as tolerable when the incidence of DLTs was less than 33 %. Results Nine patients received lenvatinib [20 mg (n = 3); 24 mg (n = 6)]. No DLTs were observed. The most common AEs were thrombocytopenia, blood thyroid stimulating hormone increased, and hypertension (89 %), followed by leukopenia, headache, and proteinuria (78 %). The area under the concentration–time curve and maximum observed concentration increased dose proportionally. The PK profiles were similar to those in non-Japanese phase 1 studies. One patient with leiomyosarcoma showed a partial response, and three patients have maintained stable disease for more than 6 months. Conclusions The 24-mg QD continuous dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in Japanese patients with solid tumors.