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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. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1α (HIF-1α), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1α. Hypoxic conditions up-regulated HIF-1α expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1α activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1α and HIF-1β were examined using clinical gastric cancer samples. A strong inverse correlation (r = −0.68) was observed between CD133 and HIF-1α, but not between CD133 and HIF-1β. In conclusion, these results indicate that HIF-1α down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1α in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells. [Cancer Res 2009;69(18):7160–4]

Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non-Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25-72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose-limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100-500 mg dose range, vorinostat area under the concentration-time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached.

Purpose Motesanib (AMG 706) is a multitargeted anticancer agent with an inhibitory action on the human vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and the cellular stem-cell factor receptor (KIT). The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate. Methods All patients had experienced progression or relapse while undergoing with imatinib as 400 mg/day or higher. The patients were administered 125 mg of motesanib once daily. The primary endpoint was overall response. Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumor, and safety was assessed according to the Common Terminology Criteria for Adverse Events (version 3). Results Of 35 enrolled and treated patients, no patient showed a complete response, and one patient showed a partial response (PR). Seven had stable disease (SD) for at least 24 months, two of whom continued to have SD for more than 2 years. The median progression-free survival time was 16.1 weeks. Motesanib was well tolerated; commonly reported treatment-related adverse events were hypertension, diarrhea, and fatigue. Anemia was the only hematological toxicity that was reported. Conclusions One patient showed PR, and seven patients showed SD more than 24 weeks. Motesanib was found to be safe and well tolerated. The observed toxicities were consistent with Phase I study findings.

Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to "UGT1A1*28 or *6" on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated.Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time-concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan-cisplatin-combination therapy (62 patients).Higher SN-38 AUC values were observed in ABCB1 2677GT (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421CA (Q141K) and IVS12 + 49GT ((#) IIB) and SLCO1B1 521TC (V174A) (*15 x 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 (#) IIB, SLCO1B1*15 x 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory.Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.

Objective: rhuMAb 2C4 (pertuzumab, RO4368451), a human epidermal growth factor receptor-2 (HER2) targeted antibody that binds to an epitope distinct from trastuzumab, blocks ligand-associated heterodimerization of HER2 with other HER receptor family members. This study evaluated the toxicity, pharmacokinetics and anti-tumor activities of pertuzumab in Japanese patients with solid tumors. Methods: Patients with solid tumors refractory to standard therapy were administered pertuzumab 5, 10, 15, 20 and 25 mg/kg intravenously once every 3 weeks. Grade 3 toxicities were considered as dose limiting. The maximum tolerated dose (MTD) was a dose at which two out of six patients had Grade 3 toxicities. Results: Eighteen patients, aged 38–66 (median 57) years, with solid tumors were enrolled and a total of 32 cycles of pertuzumab were administered. Toxicities were generally acceptable. Grade 3 elevation of gamma-glutamyl transpeptidase was observed in one patient at 25 mg/kg and was considered to be dose limiting. MTD was not reached up to a dose level of 25 mg/kg. The serum concentration of pertuzumab declined slowly (terminal half-life is approximately 3 weeks). The AUC proportionally increased over the dose range tested. There was limited evidence of activity (stable disease 2; progressive disease 13; and not evaluable 3); however, tumor shrinkage and tumor marker decrease were observed in an ovarian cancer and a non-small-cell lung cancer patient, respectively. Conclusions: Pertuzumab is well tolerated up to 25 mg/kg. Although objective tumor response was not observed, it is worth evaluating as a flat dose and in combination with other cytotoxics and molecular-targeted agents.

SRPX2 (Sushi repeat containing protein, X-linked 2) was first identified as a downstream molecule of the E2A-HLF fusion gene in t(17;19)-positive leukemia cells and the biological function of this gene remains unknown. We found that SRPX2 is overexpressed in gastric cancer and the expression and clinical features showed that high mRNA expression levels were observed in patients with unfavorable outcomes using real-time RT-PCR. The cellular distribution of SRPX2 protein showed the secretion of SRPX2 into extracellular regions and its localization in the cytoplasm. The introduction of the SRPX2 gene into HEK293 cells did not modulate the cellular proliferative activity but did enhance the cellular migration activity, as shown using migration and scratch assays. The conditioned-medium obtained from SRPX2-overexpressing cells increased the cellular migration activity of a gastric cancer cell line, SNU-16. In addition, SRPX2 protein remarkably enhanced the cellular adhesion of SNU-16 and HSC-39 and increased the phosphorylation levels of focal adhesion kinase (FAK), as shown using western blotting, suggesting that SRPX2 enhances cellular migration and adhesion through FAK signaling. In conclusion, the overexpression of SRPX2 enhances cellular migration and adhesion in gastric cancer cells. Here, we report that the biological functions of SRPX2 include cellular migration and adhesion to cancer cells. © 2008 Wiley-Liss, Inc.

7-Ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan hydrochloride (CPT-11), has potent antitumor activity. Moreover, we have reported the strong antitumor activity of NK012 (i.e., SN-38–releasing polymeric micelles) against human cancer xenografts compared with CPT-11. Here, we investigated the advantages of NK012 over CPT-11 treatment in mouse models of gastric cancer with peritoneal dissemination. NK012 or CPT-11 was i.v. administered thrice every 4 days at their respective maximum tolerable doses (NK012, 30 mg/kg/day; CPT-11, 67 mg/kg/day) to mice receiving orthotopic transplants of gastric cancer cell lines (44As3Luc and 58As1mLuc) transfected with the luciferase gene (n = 5). Antitumor effect was evaluated using the photon counting technique. SN-38 concentration in gastric tumors and peritoneal nodules was examined by high-performance liquid chromatography (HPLC) 1, 24, and 72 hours after each drug injection. NK012 or CPT-11 distribution in these tumors was evaluated using a fluorescence microscope on the same schedule. In both models, the antitumor activity of NK012 was superior to that of CPT-11. High concentrations of SN-38 released from NK012 were detected in gastric tumors and peritoneal nodules up to 72 hours by HPLC. Only a slight conversion from CPT-11 to SN-38 was observed from 1 to 24 hours. Fluorescence originating from NK012 was detected up to 72 hours, whereas that from CPT-11 disappeared until 24 hours. NK012 also showed antitumor activity against peritoneal nodules. Thus, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. [Cancer Res 2008;68(22):9318–22]

To evaluate safety and tolerability of cediranib, a highly potent and selective vascular endothelial growth factor signaling inhibitor, in Japanese patients with advanced solid tumors refractory to standard therapies.In part A (n = 16), patients received once-daily oral cediranib (10-45 mg) to identify the maximum tolerated dose (MTD). In part B (n = 24), patients with non-small-cell lung cancer or colorectal cancer received multiple daily doses at the MTD.Cediranib 30 mg/day was considered the MTD since 50% of evaluable patients receiving 45 mg/day experienced dose-limiting toxicities in part A (proteinuria and diarrhea n = 1, proteinuria n = 1, thrombocytopenia n = 1). The most common adverse events were diarrhea (n = 34) and hypertension (n = 32). Pharmacokinetic analysis confirmed cediranib as suitable for once-daily oral dosing. Of 32 evaluable patients, two had partial RECIST responses and 24 had stable diseaseor =8 weeks.Cediranib was generally well tolerated ator =30 mg/day in these Japanese patients and showed encouraging antitumor activity.

Panitumumab is a fully human, monoclonal antibody against the epidermal growth factor receptor. Previous studies in non-Japanese patients with solid tumors showed that panitumumab exhibited nonlinear pharmacokinetics, was well tolerated (skin toxicities were the most common treatment-related adverse events), and had antitumor activity in some patients. This open-label, phase 1 study investigated panitumumab safety and pharmacokinetics in Japanese patients. Japanese patients with advanced solid tumors were enrolled into one of three sequential panitumumab dose cohorts (cohort 1, 2.5 mg/kg weekly; cohort 2, 6.0 mg/kg every 2 weeks; and cohort 3, 9.0 mg/kg every 3 weeks) and received panitumumab until disease progression or drug intolerability. Safety endpoints included the incidence of adverse events, changes in laboratory values, and the appearance of anti-panitumumab antibodies. Serial pharmacokinetic samples were collected after the first and third doses of panitumumab. Tumors were assessed at week 8 and every 8 weeks thereafter. Eighteen patients (6 per cohort) were enrolled. No dose-limiting toxicities, investigator-reported infusion reactions, or deaths occurred. Seven patients had grade-3/4 adverse events; fatigue and anorexia were most common. The most common skin toxicities were rash and acneiform dermatitis. No neutralizing anti-panitumumab antibodies were detected. Panitumumab exhibited nonlinear pharmacokinetics, and antitumor activity was observed in 31% (4/13) of the patients with colorectal cancer. In Japanese patients with solid tumors, panitumumab was well tolerated, demonstrated pharmacokinetic and safety profiles similar to those observed previously in non-Japanese patients, and exhibited encouraging antitumor activity in patients with colorectal cancer.

Background. Small-bowel adenocarcinoma (SBA) is a rare tumor that has a poor response to chemotherapy and a poor prognosis. Treatment strategies for SBA have not been clearly established. Methods. All patients with SBA treated using a combination of cisplatin and irinotecan (IP) as fichemotherapy at the National Cancer Center Hospital in Japan between January 1999 and February 2007 were studied retrospectively. Results. Eight patients received IP as fi rst-line chemotherapy. The median follow-up was 9.5 months (range, 4.2‐37.5 months). The median number of cycles of IP was three (range, 1‐5). The overall response rate (complete or partial response) was 12.5% (complete response, n = 0; partial response, n = 1). The disease control rate (complete or partial response or stable disease) was 75%. The median time to treatment failure was 4.5 months (95% confi dence interval, 0.9‐5.8 months), and overall survival was 17.3 months (range, 1.9‐21.3 months). The most common adverse events were neutropenia and anorexia. Conclusion. IP combination chemotherapy may be an acceptable option for patients with SBA. Further studies are warranted to determine the optimal chemotherapeutic regimen for SBA.

The multidrug resistance-associated protein 2 (MRP2) encoded by the ABCC2 gene is expressed in the liver, intestine and kidneys and preferentially exports organic anions or conjugates with glucuronide or glutathione. In this study, all 32 exons and the 5'-flanking region of ABCC2 in 236 Japanese were resequenced, and 61 genetic variations including 5 novel nonsynonymous ones were detected. A total of 64 haplotypes were determined/inferred and classified into five *1 haplotype groups (*1A, *1B, *1C, *1G, and *1H) without nonsynonymous substitutions and *2 to *9 groups with nonsynonymous variations. Frequencies of the major 4 haplotype groups *1A (-1774delG), *1B (no common SNP), *1C (-24C>T and 3972C>T), and *2 [1249G>A (Val417Ile)] were 0.331, 0.292, 0.172, and 0.093, respectively. This study revealed that haplotype *1A, which has lowered activity, is quite common in Japanese, and that the frequency of *1C, another functional haplotype, was comparable to frequencies in Asians and Caucasians. In contrast, the haplotypes harboring 3972C>T but not -24C>T (*1G group), which are reportedly common in Caucasians, were minor in Japanese. Moreover, the allele 1446C>T (Thr482Thr), which has increased activity, was not detected in our Japanese population. These findings imply possible differences in MRP2-mediated drug responses between Asians and Caucasians.

Treatment policies for metastatic colorectal cancer (CRC; mCRC) are similar in Japan and in Western countries. An important goal is the global development of new molecular-targeted drugs. To achieve this goal, controlled clinical trials should be performed to determine whether S-1, an oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, can replace 5-fluorouracil for the treatment of CRC. On the other hand, the use of adjuvant chemotherapy differs slightly between Japan and Western countries. An underlying reason is the difference in surgical results. In Japan, the use of adjuvant chemotherapy with oral fluoropyrimidines evolved independently from developments in Western countries. However, clinical studies of adjuvant chemotherapy require more patients and longer follow-up periods than clinical studies of mCRC. The use of international collaborative clinical trials is essential to ensure that more effective drugs will be promptly provided to patients in every country. Improved quality control of surgery in patients participating in clinical trials or a better collective understanding of the quality of centers performing such studies will most likely facilitate the design of international collaborative clinical trials. International meetings, including the participation of oncologists and surgeons, should be held in the near future to promote collective understanding and the design of high-quality clinical studies.

Objective: To better understand the clinical implications of insulin-like growth factor type 1 receptor (IGF-1R), epidermal growth factor receptor (EGFR) and HER2 expressions in gastric cancer (GC). Methods: The study group comprised 86 patients who received first-line chemotherapy for advanced GC at the National Cancer Center Hospital. Using laser-captured microdissection and a real-time RT-PCR assay, we quantitatively evaluated mRNA levels of IGF-1R, EGFR and HER2 in paraffin-embedded cancer specimens of surgically removed primary tumors. Results: In univariate analysis of the study group as a whole, patients with low expression of both IGF-1R and EGFR (n = 13) had a significantly longer overall survival than the other patients (n = 51; median, 24.6 vs. 12.8 months; log-rank p = 0.013). Multivariate survival analysis demonstrated that high EGFR expression [hazard ratio, HR: 2.94 (95% confidence interval, CI: 1.40–6.17), p = 0.004] and poor performance status [HR: 1.96 (95% CI: 1.12–3.42), p = 0.018] were significant predictors of poor survival. In patients given first-line S-1 monotherapy (n = 29), low IGF-1R (p = 0.002) and low EGFR (p = 0.035) gene expression correlated with a better response, without a significant prolongation of survival. Conclusion: Our data warrant further investigations on the strategy of co-targeting IGF-1R and EGFR in GC.

Some approaches such as adjuvant chemotherapy, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy have been tried to improve the efficacy of treatment for resectable esophageal cancer patients. The usefullness of neoadjuvant chemotherapy, has remained a matter of controversy. However, there is a report from JCOG9907 in Japan that two courses of neoadjuvant 5-FU/CDDP improved the survival of esophageal squamous cell cancer patients. Neoadjuvant chemoradiotherapy has not had a consistent evaluation because of the varying results of each trial. But from the results of meta-analysis and CALGB9781, the neoadjuvant chemoradiotherapy called "trimodality therapy" has been a standard treatment in the United States. We should evaluate whether there would be similar effectiveness in Japan, where the histology and operative approach are different. Some approaches such as DNA microarray and proteomics, which can predict the treatment effect, are being tried.

We investigated the correlation between the response to fluoropyrimidines as first-line therapy and the expressions of genes in patients with primary colorectal cancer (CRC). The study group comprised 92 patients with metastatic CRC. Total RNA was isolated from laser-captured tumour cells in surgically resected primary lesions, and gene expression was quantitatively evaluated by real-time RT-PCR assay. Low thymidylate synthase (TS), low gamma-glutamyl hydrolase, high reduced folate carrier 1, high O6-methylguanine-DNA methyltransferase (MGMT) and low cyclin E expressions were associated with a good response (P=0.0030, 0.0250, 0.0120, 0.0030 and 0.0020, respectively) on univariate analysis. On multivariate logistic regression analysis, TS and MGMT remained independent predictors of the response. The clinical response rates were 63.2% in the low TS or high MGMT group and 14.3% in high TS and low MGMT group (P

This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg m(-2), and the dose was escalated according to the accelerated titration method. Nineteen patients were recruited. The tumour types treated included pancreatic (n=11), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common haematological toxicity. A grade 3 fever developed in one patient given 180 mg m(-2). No other grades 3 or 4 nonhaematological toxicities, including neuropathy, was observed during the entire study period. DLTs occurred in two patients given 180 mg m(-2) (grade 4 neutropenia lasting for more than 5 days). Thus, this dose was designated as the MTD. Grade 2 hypersensitivity reactions developed in only one patient given 180 mg m(-2). A partial response was observed in one patient with pancreatic cancer. The maximum concentration (C(max)) and area under the concentration (AUC) of NK105 were dose dependent. The plasma AUC of NK105 at 150 mg m(-2) was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the RD for the phase II study was determined to be 150 mg m(-2) every 3 weeks. The results of this phase I study warrant further clinical evaluation.

SN-38, an active metabolite of irinotecan, is detoxified by glucuronidation with UGT1A isoforms, 1A1, 1A7, 1A9, and 1A10. The pharmacogenetic information on UGT1A haplotypes covering all these isoforms is important for the individualized therapy of irinotecan. Associations between UGT1A haplotypes and pharmacokinetics/pharmacodynamics of irinotecan were investigated to identify pharmacogenetic markers.Associations between UGT1A haplotypes and the area under concentration curve ratio (SN-38 glucuronide/SN-38) or toxicities were analyzed in 177 Japanese cancer patients treated with irinotecan as a single agent or in combination chemotherapy. For association analysis, diplotypes of UGT1A gene segments [(1A1, 1A7, 1A9, 1A10), and Block C (common exons 2-5)] and combinatorial haplotypes (1A9-1A7-1A1) were used. The relationship between diplotypes and toxicities was investigated in 55 patients treated with irinotecan as a single agent.Among diplotypes of UGT1A genes, patients with the haplotypes harboring UGT1A1*6 or *28 had significantly reduced area under concentration curve ratios, with the effects of UGT1A1*6 or *28 being of a similar scale. A gene dose effect on the area under concentration curve ratio was observed for the number of haplotypes containing *28 or *6 (5.55, 3.62, and 2.07 for 0, 1, and 2 haplotypes, respectively, P0.0001). In multivariate analysis, the homozygotes and double heterozygotes of *6 and *28 (*6/*6, *28/*28 and *6/*28) were significantly associated with severe neutropenia in 53 patients who received irinotecan monotherapy.The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients.

Purpose: AZD2171 is an oral, highly potent, and selective vascular endothelial growth factor signaling inhibitor that inhibits all vascular endothelial growth factor receptor tyrosine kinases. The purpose of this study was to investigate the activity of AZD2171 in gastric cancer.Experimental Design: We examined the antitumor effect of AZD2171 on the eight gastric cancer cell lines in vitro and in vivo.Results: AZD2171 directly inhibited the growth of two gastric cancer cell lines (KATO-III and OCUM2M), with an IC50 of 0.15 and 0.37 μmol/L, respectively, more potently than the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Reverse transcription-PCR experiments and immunoblotting revealed that sensitive cell lines dominantly expressed COOH terminus–truncated fibroblast growth factor receptor 2 (FGFR2) splicing variants that were constitutively phosphorylated and spontaneously dimerized. AZD2171 completely inhibited the phosphorylation of FGFR2 and downstream signaling proteins (FRS2, AKT, and mitogen-activated protein kinase) in sensitive cell lines at a 10-fold lower concentration (0.1 μmol/L) than in the other cell lines. An in vitro kinase assay showed that AZD2171 inhibited kinase activity of immunoprecipitated FGFR2 with submicromolar Ki values (∼0.05 μmol/L). Finally, we assessed the antitumor activity of AZD2171 in human gastric tumor xenograft models in mice. Oral administration of AZD2171 (1.5 or 6 mg/kg/d) significantly and dose-dependently inhibited tumor growth in mice bearing KATO-III and OCUM2M tumor xenografts.Conclusions: AZD2171 exerted potent antitumor activity against gastric cancer xenografts overexpressing FGFR2. The results of these preclinical studies indicate that AZD2171 may provide clinical benefit in patients with certain types of gastric cancer.

Purpose: The anticancer agent indisulam is metabolized by the cytochrome P450 of enzymes CYP2C9 and CYP2C19. Polymorphisms of these enzymes may affect the elimination rate of indisulam. Consequently, variant genotypes may be clinically relevant predictors for the risk of developing severe hematologic toxicity. The purposes of this study were to evaluate the effect of genetic variants of CYP2C9 and CYP2C19 on the pharmacokinetics of indisulam and on clinical outcome and to assess the need for pharmacogenetically guided dose adaptation.Experimental Design: Pharmacogenetic screening of CYP2C polymorphisms was done in 67 patients treated with indisulam. Pharmacokinetic data were analyzed with a population pharmacokinetic model, in which drug elimination was described by a linear and a Michaelis-Menten pathway. The relationships between allelic variants and the elimination pharmacokinetic parameters (CL, Vmax, Km) were tested using nonlinear mixed-effects modeling. Polymorphisms causing a high risk of dose-limiting neutropenia were identified in a simulation study.Results: The Michaelis-Menten elimination rate (Vmax) was decreased by 27% (P < 0.0001) for heterozygous CYP2C9*3 mutants. Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38% (P < 0.0001). The risk of severe neutropenia was significantly increased by these mutations and dose reductions of 50 to 100 mg/m2 per mutated allele may be required to normalize this risk.Conclusions: CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms resulted in a reduced elimination rate of indisulam. Screening for these CYP2C polymorphisms and subsequent pharmacogenetically guided dose adaptation may assist in the selection of an optimized initial indisulam dosage.

Introduction ZD6474 (vandetanib) is an orally available inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and RET receptor tyrosine kinase activity. This study assessed the safety and tolerability of escalating doses of ZD6474 in Japanese patients with solid, malignant tumors. Methods Adult patients with solid tumors refractory to standard therapy received a once-daily oral dose of ZD6474 (100–400 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. Results Eighteen patients were treated at doses of 100 mg ( n = 3), 200 mg ( n = 6), 300 mg ( n = 6), and 400 mg ( n = 3). Dose-limiting toxicities at the completion of cycle 2 were hypertension ( n = 3), diarrhea ( n = 1), headache ( n = 1), toxic skin eruption ( n = 1), and alanine aminotransferase increase ( n = 1). A dose of 400 mg/day was considered to exceed the maximum tolerated dose (MTD). Toxicities were manageable with dose interruption and/or reduction. Objective tumor response was observed in four of nine patients with non-small cell lung cancer (NSCLC) at doses of either 200 or 300 mg. Terminal half-life was about 90–115 hours. Plasma trough concentrations achieved steady-state conditions after approximately 1 month of daily dosing. Conclusions It was concluded that a dose of 400 mg/day was considered to exceed the MTD, and doses for phase II study were thought to be not more than 300 mg/day. The objective response observed in some NSCLC patients is encouraging for further studies in this tumor type.

Ixabepilone (BMS-247550) is the first in a new class of anti-neoplastic agents, the epothilone analogs, and is a highly active non-taxane anti-microtubule agent. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety profile, pharmacokinetics, and antitumor activity of ixabepilone in Japanese patients.Patients with solid tumors previously treated with up to four chemotherapy regimens received a 3-h intravenous infusion of ixabepilone every 3 weeks.Fourteen patients received 43 cycles (median 3, range 1-8). The most common adverse events were neutropenia, mild-to-moderate fatigue, anemia, and peripheral neuropathy. DLTs occurred in one patient receiving 40 mg/m2 (grade 4 neutropenia for 9 days) and in two patients receiving 50 mg/m2 (grade 3 mucositis, ileus and febrile neutropenia; grade 4 neutropenia for 10 days). One paclitaxel- and docetaxel-pretreated patient with non-small cell lung cancer achieved a partial response lasting for 3 months; six additional patients (43%) achieved disease stabilization with tumor shrinkage of 3-35%. The plasma concentration-time profiles of ixabepilone during cycle 1 were similar across all doses evaluated.The MTD of ixabepilone is 50 mg/m2 given over 3 h every 3 weeks. The recommended phase II dose is 40 mg/m2, which is well tolerated and active. Data from Japanese patients are consistent with published phase I data from non-Japanese patients.

Background: Although BRAF V600-mutated (BRAFm) colorectal carcinoma (CRC) does not generally respond to BRAF inhibitors, results of preclinical studies suggest strong synergistic activity between a BRAF inhibitor and an EGFR inhibitor or a PI3K inhibitor. The aims of this study were to establish safety and preliminary activity of combination therapy with encorafenib (ENC), a highly selective BRAF V600 inhibitor, the EGFR monoclonal antibody cetuximab (CTX), ± the α-specific PI3K inhibitor alpelisib (ALP) in patients (pts) with BRAFm CRC; and assess the potential clinical significance of biomarkers and microsatellite instability (MSI) status by genomic analysis of tumor samples. Methods: In this phase I study, the maximum tolerated dose/recommended phase II dose (RP2D) was determined and safety, tolerability, and anti-tumor activity of ENC + CTX ± ALP were evaluated, in pts with advanced BRAFm/KRAS wild-type CRC. Archival or fresh screening tumor samples were analyzed for somatic mutations and copy number aberrations to evaluate potential correlation with response. Results: Fifty-four pts were enrolled in the dose-escalation phase; 26 in the dual arm (ENC + CTX) and 28 in the triple arm (ENC + ALP + CTX). RP2D for each treatment arm was established as 200 mg ENC QD + CTX weekly (dual arm) + 300 mg ALP once daily (triple arm). The most common grade 3/4 treatment-related adverse events were fatigue and hypophosphatemia in the dual arm (8% each), and nausea and hypophosphatemia in the triple arm (4% each). Hyperglycemia was observed in one patient (3.8%) in the dual arm and 8 patients (29%) in the triple arm. Overall response rates (≥ partial response [PR]) for the dual and triple arms were 23% (1 CR, 4 PR, and 1 unconfirmed (u) PR) and 32% (4 PR and 5 uPR), respectively. Median progression-free survival was 3.7 and 4.3 months, respectively. Biomarker analysis was performed on 21 tumor samples. Several genetic alterations occurred with similar frequency between patient samples and the FoundationOne database (PIK3CA, TP53, APC). Specifically, the PIK3CA mutation and PTEN alterations were found in 24% and 38% of patient samples, respectively; however, these alterations did not appear to be correlated with response. Non-MSI-high status was associated with a lower PFS for the dual arm (2.8 vs 3.7 months), but not the triple arm (4.4 vs 4.3 months). Updated biomarker analyses, including MSI status, will be presented. Conclusions: These results indicate that both ENC + CTX and ENC + CTX + ALP are well tolerated with promising antitumor activity in pts with advanced BRAFm CRC who failed at least one prior therapy. Additional biomarker analyses will help to clarify the clinical significance of genetic alterations, particularly with MSI status and the PI3K pathway. Enrollment in the phase II portion of the study is ongoing. Citation Format: Jan H. M. Schellens, Robin van Geel, Johanna C. Bendell, Anna Spreafico, Martin Schuler, Takayuki Yoshino, Jean-Pierre Delord, Yasuhide Yamada, Martijn P. Lolkema, Jason E. Faris, Ferry A. L. M. Eskens, Sunil Sharma, Rona Yaeger, Heinz-Josef Lenz, Zev A. Wainberg, Emin Avsar, Arkendu Chatterjee, Savina Jaeger, Tim Demuth, Josep Tabernero. Final biomarker analysis of the phase I study of the selective BRAF V600 inhibitor encorafenib (LGX818) combined with cetuximab with or without the α-specific PI3K inhibitor alpelisib (BYL719) in patients with advanced BRAF-mutant colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT136. doi:10.1158/1538-7445.AM2015-CT136

3023 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718...

e14574 Background: For metastatic colorectal cancer (mCRC) treatment, anti-epidermal growth factor receptor (EGFR) treatment is one of the major options. However, there are few reliable biomarkers ...

4047 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718...

11013 Background: Peritoneal metastasis (PM) is the most frequent form of metastasis in gastric cancer (GC), especially in diffuse type adenocarcinoma (DTAC). Microscopic PM can be identified accur...

10533 Background: Although three-year imatinib adjuvant therapy is recommended by GIST guidelines, there is a lack of clinical data regarding use of adjuvant therapy, adherence, and indications. A ...

4045 Background: Definitive chemoradiotherapy (dCRT) has been recognized as one of treatment options for esophageal squamous cell carcinoma (ESCC) patients who are not fit for surgery. Recent studies revealed that surveillance after dCRT was important in an adenocarcinoma dominant population. However, clinical utility of surveillance for ESCC is not clear. Methods: The subjects of this retrospective study were patients who underwent dCRT for stage II/III (excluding T4 disease) ESCC from 2000 to 2011 at National Cancer Center Hospital in Tokyo, Japan. We reviewed the patterns of relapse after clinical complete response (cCR). Each patient was generally surveyed with computed tomography (CT) and esophagogastroduodenoscopy (EGD) every 3-6 months. We also recorded new cancers (NC) diagnosed by EGD during surveillance after cCR. Local-regional relapse (LRR) without distant metastasis was classified into luminal-only relapse (LR) and other type of regional relapse (RR) with or without luminal relapse. Overall s...

100 Background: Serum α-1-acid glycoprotein (AAG) level was an independent predictor of response and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel chemotherapy. However, it has not been determined whether AAG is associated with the outcomes of esophageal cancer patients who have been treated with a combination of docetaxel, cisplatin and 5-fluorouracil (DCF) as neoadjuvant therapy. Methods: This retrospective study included a cohort of 39 patients with clinical stage II/III esophageal cancer, based on the International Union Against Cancer TNM classification system 7th edition, who were treated with neoadjuvant DCF followed by surgery. DCF consisted of docetaxel (70mg/m2) and cisplatin (70mg/m2) on day 1, and continuous infusion of 5-fluorouracil (750mg/m2/day) on days 1-5, with this regimen repeated every 3 weeks up to three cycles. Patients were divided into groups by median value of baseline AAG levels. Patient characteristics, preoperative clinical stage, chemotherapy effect, and survival were compared between the high and low AAG groups. Results: The clinical stage IIA, IIB, IIIA, IIIB and IIIC were 4, 4, 14, 17 and 0, respectively. The completion rate of three cycles of chemotherapy was 76.9% (30/39). All patients underwent surgery and the R0 resection rate was 97.4% (38/39). The best overall response rate of DCF was 48.7% with a pathological complete response of 5.1%. The 2-year progression-free survival and overall survival (OS) rates were 60.5% and 76.9%, respectively. The median serum AAG was 95 g/L, ranging from 57 to 228 g/L. A trend of lower response rate (35.0% vs. 57.9%; P = 0.20) and shorter OS (median not reached; hazard ratio [HR] 2.08; P = 0.24) was observed in patients with a high AAG level (AAG > 95 g/L) compared with a low AAG level (AAG ≦ 95 g/L). Multivariate analysis showed an AAG level hazard ratio of 1.60 (P = 0.59) for OS. Conclusions: There was a trend toward improved response and survival with low serum AAG level, for patients with esophageal cancer who received neoadjuvant DCF chemotherapy.

179 Background: Recurrence after definitive chemoradiotherapy (dCRT) for locally advanced esophageal cancer is associated with poor outcome. We examined patterns of recurrence and clinical outcomes in patients with recurrence after complete response (CR) to dCRT. Methods: We retrospectively investigated 238 patients who had achieved initial CR after dCRT for locally advanced esophageal cancer between January 2000 and December 2010. From among these patients we selected 95 who had developed disease recurrence after CR. Overall survival was defined as survival time from recurrence to death and was calculated by using the Kaplan-Meier method. Univariate and multivariate analyses were performed with the Cox regression model to determine prognostic factors for survival. Results: The characteristics of the 95 patients were as follows: male: female = 84:11; median age = 64 years (range 46 to 80); clinical stage at diagnosis (UICC 6th edition) IIA/IIB/III = 20/31/44; and performance status at recurrence (0/1) = (51/44). Primary CRT consisted of 5-FU+cisplatin (n = 87), 5-FU+nedaplatin (n = 3), S-1+cisplatin (n = 3), 5-FU+cisplatin+ nimotuzumab (n = 1), or docetaxel (n = 1). The pattern of recurrence was locoregional failure (n = 53) or any distant failure (n = 42). Median time from the start of dCRT to recurrence was 13.0 months, and median survival time from recurrence to death was 19.6 months. Median survival time according to the pattern of failure was 34.7 months (locoregional failure) or 17.0 months (any distant failure). Application of the Cox regression model, including the additional prognostic variables of age, ECOG performance status, number of organs in which metastases were present, and LDH, revealed that any distant failure (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.2 to 4.1; P = 0.01) and recurrence before 13.0 months (HR 2.1; 95% CI 1.2 to 3.6; P = 0.01) were predictors of poor overall survival. Conclusions: Early recurrence and any distant failure were associated with poor prognosis after CR to dCRT for locally advanced esophageal cancer.

180 Background: In advanced gastric cancer (AGC), there are many reports about prognostic factors for overall survival (OS), and we have proposed a prognostic index using four prognostic factors (PS, number of metastatic sites, prior gastrectomy and ALP; Oncologist 2014) based on a phase III trial JCOG 9912 for the first-line treatment (Lancet Oncol. 2009). However, there is no report about prognostic factors for progression free survival (PFS). In this ancillary study, we explored whether prognostic factors are similar or not between OS and PFS. Methods: The subjects of this study were selected from the JCOG9912 which intended to confirm the superiority of irinotecan plus cisplatin (IP) and the non-inferiority of S-1 to5-FU for patients with AGC. Of all enrolled patients in JCOG9912, those who had target lesions and whose complete data were available were analyzed with multivariate analysis using Cox proportional hazard model. Results: 492 out of the 703 pts of JCOG9912 were analyzed, who received either 5-FU (n=163), IP (n=164) or S-1(n=165). The median PFS was 3.7 months for all the subjects, and 2.2 months for 5-FU, 4.9 months for IP and 3.8 months for S-1. Multivariate analysis in all 492 analyzed patients demonstrated seven independent prognostic factors for PFS (Table). Prognostic factors in each treatment were; sex (HR 1.66, 95%CI 1.11-2.49), PS (1.51, 1.04-2.18), Ca (0.39, 0.17-0.86), GPT (2.46, 1.30-4.66) and LDH (1.67, 1.16-2.48) in 5-FU, sex (1.77, 1.10-2.86) in IP, and Na (2.00, 1.01-3.99) and creatinine clearance (0.37, 0.15-0.93) in S-1. Conclusions: There were no common prognostic factors among the three treatment regimens. Prognostic factors for PFS may be different by treatment regimen, although further investigations with larger sample size are needed. [Table: see text]

204 Background: Patients with metastatic or recurrent esophageal squamous cell carcinoma (ESCC) have a poor prognosis. For decades, 5-fluorouracil /Cisplatin (FP) have been mostly used for these patients as first line chemotherapy. But there were few reports which reveal the reality containing the efficacy of FP regimen for ESCC. We conduct this retrospective study to reveal the efficacy and prognostic factors of the patients treated with FP as first line chemotherapy for ESCC. Methods: Patients with metastatic or recurrent ESCC after esophagectomy were enrolled. FP comprised of CDDP at a dose of 80mg/m2 on day1, and 5-FU at a dose of 800mg/m2given by continuous on days 1-5 every 4 weeks. Cox-proportional hazard model was used for multivariate analysis to evaluate prognostic factors. Results: Between April 2001 and March 2012 in the National Cancer Center Hospital, data of 187 patients were collected by medical records. Characteristics of 187 patients were as follows; the median age (range) 62 (34-84); (male/female) 163/24; (performance status: 0/1/2) 69/110/8; (metastatic/recurrent) 116/71; median number of metastasis 1(range1-4); median cycles of FP 2(range1-10). Overall response rate was 31.6% (95%CI: 25.0-38.7%). Median progression free and overall survival time was 4.9 month and 10.5 month, respectively. In multivariate analysis, serum CRP (≥2 vs 3.5 mg/dl) (HR=1.85, p=0.001) at the time of diagnosis and number of metastatic site (≥2 vs

43 Background: Although adding docetaxel to cisplatin plus 5-fluorouracil (i.e. the DCF regimen) for esophageal cancer treatment may improve outcomes, this regimen has increased toxicity. However, the risk factors for severe non-hematological toxicities remain unknown. Methods: We analyzed data on esophageal cancer patients given at least one cycle of DCF between July 2009 and April 2014 at the National Cancer Center Hospital, Japan. DCF consisted of docetaxel 70 mg/m2/day (day 1), cisplatin 70 mg/m2/day (day 1), and continuous infusion of 5-fluorouracil 750 mg/m2/day (days 1–5), repeated every 3 weeks. Data on adverse events developing within three cycles were collected from medical records. Risk factors for severe adverse events were analyzed. Results: One hundred patients were enrolled, with a median age of 63 (range, 37 to 76); 81 male and 19 female; 96 squamous cell carcinomas and 4 adenocarcinomas; clinical situation neoadjuvant/induction/palliative: 69/23/8/1; clinical stage I/II/III/IV: 1/12/64/23; and performance status (PS) 0/1/2: 44/55/1. Forty patients (40%) developed grade 3 or more non-hematological adverse events, including anorexia (12%), mucositis (6%), and esophagitis (2%); 45 developed grade 4 hematological adverse events. Seventeen experienced febrile neutropenia (FN). There was one case of treatment-related death from serious infection. In multivariate analysis, age≥63 was at significantly increased risk of FN (P=0.013). Conclusions: DCF chemotherapy was safe in most patients and its toxicity was controllable. However, elderly patients may suffer from intense toxicity during DCF therapy.

The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg/m2/day for 5 days. After a washout period of 9 days, the 10 patients received two divided doses daily for 28 days. S-1 was administered orally at about 9 a.m. and 7 p.m. Plasma concentrations of 5-FU and F-beta-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition in the same 10 patients on days 1-5 of PVI of 5-FU and on days 1-5 of oral S-1. The area under the curve (AUC0-10h) of 5-FU on day 5 was 728 +/- 113 ng x hr/ml for PVI of 5-FU and 1,364 +/- 374 ng x hr/ml for S-1. The median 5-FU PVI: S-1 ratio of the AUC0-10h of 5-FU was 1.9. The AUC0-10h of FBAL on day 5 of PVI of 5-FU was 9,465 +/- 3,225 ng x hr/ml, AUC0-10h, as compared with 1,725 +/- 605 ng x hr/ml on day 5 of S-1 treatment. The AUC0-10h of uracil on day 5 was 252 +/- 60 ng x hr/ml with PVI of 5-FU and 12,582 +/- 3,060 ng x hr/ml with S-1. The AUC0-10h of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.

S-1 is an attractive oral fluorouracil antitumor drug, which is being called "a self-rescuing drug". This novel oral fluoropyrimidine is combined with three pharmacological agents: tegafur (FT) which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) activity, and potassium oxonate (Oxo) which reduces gastrointestinal toxicity. Phase I and an early phase II clinical trials were performed about ten years ago, and these results had already been introduced to the Journal "Clinical Cancer Research Vol. 5, pages 2000-2005, 1999". The data of this article in this journal was referred from the results of the figures and tables based on the above trial. Most of the authors in this article have contributed on that pharmacokinetics study and published the above manuscripts. In that study, the pharmacokinetics of 5-FU, intact FT, CDHP and Oxo after administration of the standard dose of S-1 had been performed. These studies were carried out at two hospitals, Department of Surgery (Section 1) Sapporo Medical University and Chemotherapy Cancer Center, Cancer Institute Hospital and Japanese Foundation for Cancer Research (Ohtsuka). The number of patients accepted for this trial is twelve, 5 patients with gastric cancer, 4 with colorectal cancer and 3 with breast cancer. Single administration trial was referred to all patients, but consecutive administration trial was limited to ten patients. The results of plasma concentration, Cmax, Tmax, AUC0-14, and T1/2 of 5-FU, FT, CDHP, and Oxo were ascertained in details. It was a surprise that the indicated data was very similar to that of the intravenous 5-FU continuous infusion. Therefore, the low dose administration of 5-FU (FT) as S-1 may result in good antitumor effects with minimum adverse effects to the patients.

Irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and Leucovorin (LV) became the standard first-line chemotherapy for colorectal cancer in the U.S. and Europe in 2000, largely owing to the results of controlled randomized phase III trials of 5-FU/LV with or without CPT-11. One of the regimens for CPT-11 plus infusional 5-FU/LV therapy is the FOLFIRI regimen. This regimen consists of CPT-11 180 mg/m(2) as a 90-min infusion on day 1 and l-LV 200 mg/m(2) as a 2-h infusion during CPT-11, immediately followed by a bolus dose of 5-FU 400 mg/m(2) and a 46-h continuous infusion of 2,400 mg/m(2) every 2 weeks. FOLFIRI, as well as oxaliplatin/5-FU/LV therapy (FOLFOX), is an internationally accepted standard chemotherapy for metastatic colorectal cancer. Safe use of this effective regimen requires adequate supportive therapy in Japan, as well as in Western countries.

Oxaliplatin, a platinum compound, has been commonly used around the world for treating advanced colorectal cancer. The generally recommended dose and schedule of oxaliplatin monotherapy is 130 mg/m(2) every 3 weeks. This trial was conducted to evaluate the safety and pharmacokinetics of oxaliplatin monotherapy in Japanese patients with solid tumors.Oxaliplatin was administered as a 2-h intravenous infusion every 3 weeks at a dose of 90 and 130 mg/m(2). Blood was collected to determine the total platinum and the ultrafiltrate platinum concentrations in plasma in all cycles.Nine patients were enrolled; three were given oxaliplatin monotherapy at 90 mg/m(2) and six received 130 mg/m(2). All tumors were colorectal cancer. The major adverse reactions included myelosuppressive, neurological and gastrointestinal toxicities, although most were grades 1 and 2 at both dose levels. Peripheral sensory neuropathy of without movement disturbance (grade 1 or 2) was observed in all patients at both dose levels. The 130 mg/m(2) dose level was not found to be the maximum tolerated dose, but was judged to be the recommended dose. No objective responses were seen and five cases of no change were observed. A bi-exponential open model best described the disappearance of platinum in the plasma, and a tri-exponential open model best described the disappearance of ultrafilterable platinum in the plasma at both dose levels. No racial difference was suggested in the pharmacokinetics of oxaliplatin.The oxaliplatin monotherapy dose schedule of 130 mg/m(2) every 3 weeks, recommended worldwide, is acceptable for Japanese patients.

The aims of this study are to retrospectively analyze data on the epidemiology, clinical characteristics, and treatment outcomes of 14 cases of small cell carcinoma of the esophagus.Patient records were reviewed for data on demographics, presenting symptoms, diagnosis, disease stage, type of treatment and outcome.Between January 1990 and December 2001, 14 patients with small cell carcinoma of the esophagus were treated at the National Cancer Center Hospital, representing 0.8% of all esophageal carcinomas diagnosed during this period. Eleven patients presented with extensive disease at the time of diagnosis, while three patients were noted to have limited disease. Nine patients received combination chemotherapy with or without radiotherapy. Three of these patients achieved a complete response to first-line treatment and two of them have survived more than two years. Five patients underwent esophagectomy as an initial treatment with curative intent. All of these patients developed early relapse after esophagectomy, and only one patient has survived more than two years. The overall median survival was 7.7 months (range: 0.6-89.1 months) for all 14 patients.Although curative esophagectomy may be effective as a primary treatment in some patients, systemic chemotherapy with or without concurrent radiotherapy should be considered as an important treatment option for small cell carcinoma of the esophagus.

A highly specific antibody against recombinant human dihydropyrimidine dehydrogenase (DPD) has been developed to immunohistochemically assess DPD expression in tumors. A new oral DPD inhibitory fluoropyrimidine (DIF), S-1, is reportedly effective against gastric scirrhous carcinoma.In this study, the relationship between immunoreactivity to DPD in biopsy specimens and the effects of chemotherapy were investigated in 61 patients treated with first-line fluoropyrimidine-based chemotherapy (S-1:DIF, 5-FU:non-DIF) for gastric scirrhous carcinoma.The response rate was significantly higher in patients with DPD-positive tumors than in those with DPD-negative tumors in the S-1 group (45.5%, 10.0%: p0.05), as compared to the 5-FU group (0%, 5.6%: p = 0.398). According to the median survival time, there was no significant difference between patients with DPD-positive tumors (364 days) and those with DPD-negative tumors (406 days; p = 0.626) in either the S-1 group or the 5-FU group (181 days and 256 days, respectively; p = 0.543).This study indicates that S-1 may be effective even in gastric scirrhous carcinoma with a high level of DPD activity.

Purpose: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. Experimental design: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m2. Pharmacokinetic assessments were performed during and after the first administration. Results: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m2 dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3–4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C max values of 103±17 ng/ml at the 13 mg/m2 dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1–2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4–3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression ≥50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. Conclusions: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m2. The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m2. The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

We describe the long-term survival of a patient following the diagnosis of primary gastric small cell carcinoma. In January 2000, a 73-year-old male was found to have advanced gastric small cell carcinoma directly invading his liver. He received combination chemotherapy with cisplatin and irinotecan as first-line chemotherapy, then cisplatin and etoposide as second-line chemotherapy. He had a complete response after four cycles of second-line chemotherapy. In March 2001, the tumor recurred in the stomach and the patient underwent a total gastrectomy. He has survived free of disease for more than 2 years after the first diagnosis.

MCC-465 is an immunoliposome-encapsulated doxorubicin. The liposome is tagged with polyethylene glycol and the F(ab')2 of a monoclonal antibody named GAH, a human antibody obtained by the hybridoma technique. The epitope recognized by GAH is not well characterized, but human gastric, colorectal, and mammary cancer cells were GAH-positive, while the normal counterparts were GAH-negative. Pegylated liposome doxorubicin (PLD) and MCC-465 did not show significant antitumor activity against GAH-negative Caco-2 xenografts. On the other hand, MCC-465 exhibited significantly superior antitumor effects against GAH-positive WiDr-Tc and SW837 xenografts, compared with PLD. Immunohistochemistry with GAH revealed that 94% (100 of 106) of surgical specimens of colorectal cancer were GAH-positive. These results warrant a phase I clinical trial of MCC-465 for patients with metastatic colorectal cancer.

Despite the fact that there are only a few reports of phase II studies, S-1 is widely used in single-agent or combination therapies for patients with advanced gastric cancer in Japan. We retrospectively analyzed the effectiveness of S-1 as single-agent chemotherapy for patients with advanced gastric cancer.A total of 119 patients with advanced or recurrent gastric cancer were treated with S-1 as first-line monochemotherapy from September 1999 to March 2003 at the National Cancer Center Hospital. S-1 was administered orally twice daily, at a standard dose of 80 mg/m2 per day for 28 days, followed by a 14-day rest.One hundred and eleven patients were analyzed retrospectively. The overall response rate was 26.1% (29/111; 95% confidence interval [CI], 17.8% to 34.1%). Median time to progression and median overall survival were 141 days (95% CI, 108 to 175 days) and 378 days (95% CI, 310 to 447 days), respectively. The response rate of ascites, according to the Japanese classification of gastric carcinoma, was 36.8% (14/38; 95% CI, 25.4% to 56.6%). Among all of the pretreatment variables examined, hemoglobin level and the presence of lymph node metastasis were related to the response.Single-agent chemotherapy of S-1 for chemo-naive patients with advanced gastric cancer was modestly effective and well-tolerated in the outpatient setting.

ZD0473 is new platinum agent that was rationally designed to circumvent platinum resistance and reduce the potential for nephro-and neurotoxicity. This Phase I dose-escalating study investigated the pharmacokinetics, tolerability and efficacy of ZD0473 in Japanese patients with solid, refractory tumours. ZD0473 was administered as a 1-h intravenous infusion every 3 weeks. Nine patients received a total of 16 cycles of ZD0473 (median 1 cycle/patient), with 3 patients treated at each of 3 doses (60, 90, 120 mg/m2). The maximum plasma concentration (C(max)) and the area under the concentration-time curve to infinity (AUC(0-infinity)) increased with dose in a linear fashion for both total platinum and ZD0473 in plasma ultrafiltrate, suggesting that the pharmacokinetics of ZD0473 are linear. Haematological and non-haematological toxicities such as nausea and vomiting were mild (grade 1 or 2) and transient. No clinically significant nephro-, oto- or neurotoxicity was observed. Dose-limiting toxicity (DLT) was not observed and the maximum tolerated dose (MTD) was not identified. ZD0473 treatment showed evidence of disease stabilisation in 3 patients (33%). In conclusion, ZD0473 appears to have linear pharmacokinetics, and an acceptable tolerability profile at doses up to 120 mg/m2 in Japanese patients with refractory solid malignancies. Following evaluation of the data from all the Western trials, the ZD0473 development programme changed and this Japanese trial was stopped.