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Purpose We generated methods for evaluating clinical outcomes including treatment response in oncology using the unstructured data from electronic health records (EHR) in Japanese language. Methods This retrospective analysis used medical record database and administrative data of University of Miyazaki Hospital in Japan of patients with lung/breast cancer. Treatment response (objective response [OR], stable disease [SD] or progressive disease [PD]) was adjudicated by two evaluators using clinicians’ progress notes, radiology reports and pathological reports of 15 patients with lung cancer (training data set). For assessing key terms to describe treatment response, natural language processing (NLP) rules were created from the texts identified by the evaluators and broken down by morphological analysis. The NLP rules were applied for assessing data of other 70 lung cancer and 30 breast cancer patients, who were not adjudicated, to examine if any difference in using key terms exist between these patients. Results A total of 2,039 records in progress notes, 131 in radiology reports and 60 in pathological reports of 15 patients, were adjudicated. Progress notes were the most common primary source data for treatment assessment (60.7%), wherein, the most common key terms with high sensitivity and specificity to describe OR were “reduction/shrink”, for SD were “(no) remarkable change/(no) aggravation)” and for PD were “(limited) effect” and “enlargement/grow”. These key terms were also found in other larger cohorts of 70 patients with lung cancer and 30 patients with breast cancer. Conclusion This study demonstrated that assessing response to anticancer therapy using Japanese EHRs is feasible by interpreting progress notes, radiology reports and Japanese key terms using NLP.

A framework that extracts oncological outcomes from large-scale databases using artificial intelligence (AI) is not well established. Thus, we aimed to develop AI models to extract outcomes in patients with lung cancer using unstructured text data from electronic health records of multiple hospitals.We constructed AI models (Bidirectional Encoder Representations from Transformers [BERT], Naïve Bayes, and Longformer) for tumor evaluation using the University of Miyazaki Hospital (UMH) database. This data included both structured and unstructured data from progress notes, radiology reports, and discharge summaries. The BERT model was applied to the Life Data Initiative (LDI) data set of six hospitals. Study outcomes included the performance of AI models and time to progression of disease (TTP) for each line of treatment based on the treatment response extracted by AI models.For the UMH data set, the BERT model exhibited higher precision accuracy compared to the Naïve Bayes or the Longformer models, respectively (precision [0.42 vs. 0.47 or 0.22], recall [0.63 vs. 0.46 or 0.33] and F1 scores [0.50 vs. 0.46 or 0.27]). When this BERT model was applied to LDI data, prediction accuracy remained quite similar. The Kaplan-Meier plots of TTP (months) showed similar trends for the first (median 14.9 [95% confidence interval 11.5, 21.1] and 16.8 [12.6, 21.8]), the second (7.8 [6.7, 10.7] and 7.8 [6.7, 10.7]), and the later lines of treatment for the predicted data by the BERT model and the manually curated data.We developed AI models to extract treatment responses in patients with lung cancer using a large EHR database; however, the model requires further improvement.The use of artificial intelligence (AI) to derive health outcomes from large electronic health records is not well established. Thus, we built three different AI models: Bidirectional Encoder Representations from Transformers (BERT), Naïve Bayes, and Longformer to serve this purpose. Initially, we developed these models based on data from the University of Miyazaki Hospital (UMH) and later improved them using the Life Data Initiative (LDI) data set of six hospitals. The performance of the BERT model was better than the other two, and it showed similar results when it was applied to the LDI data set. The Kaplan–Meier plots of time to progression of disease for the predicted data by the BERT model showed similar trends to those for the manually curated data. In summary, we developed an AI model to extract health outcomes using a large electronic health database in this study; however, the performance of the AI model could be improved using more training data.

This open-label Phase II trial supports the efficacy and safety of sunitinib in Japanese patients with panNETs. Dose reductions and interruptions are critical to maximize the efficacy of sunitinib., Background In an interim analysis of a Phase II trial in Japanese patients with pancreatic neuroendocrine tumors (panNETs), sunitinib demonstrated antitumor activity with an objective response rate (ORR) of 50% (95% confidence interval [CI], 21–79) and a median progression-free survival (PFS) of 16.8 months (95% CI, 9.3–26.2). Here, we report the final analyses of efficacy and safety, as well as additional analyses, from this Phase II study. Methods This was a multicenter, open-label, Phase II trial (NCT01121562) of sunitinib in Japanese patients with panNETs. Patients received oral sunitinib 37.5 mg/day on a continuous daily dosing schedule. Dose modifications were permitted. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included ORR, PFS, overall survival (OS), safety and pharmacokinetics. Results Of 12 patients enrolled and treated, all discontinued treatment—the majority (n = 8) owing to disease progression. Most patients were male (n = 8)

Purpose Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials. Materials and methods This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and "as-treated" populations for efficacy and safety endpoints, respectively. Results In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p l 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p l 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p l 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. Conclusion These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.

ObjectivePost-marketing surveillance (PMS) was performed in Japan to obtain information on the safety and efficacy of crizotinib.MethodsTarget patients included almost all patients with anaplastic lymphoma kinase-positive non-small cell lung cancer who were administered crizotinib. The observation period was 52 weeks. In the present study, we focused on the treatment status and safety of crizotinib therapy and analyzed the real-world data obtained by this PMS (ClinicalTrials.gov: NCT01597258).ResultsThe safety analysis set included 2028 Japanese patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of adverse drug reactions (ADRs) was 91.6%, and common ADRs (incidence ≥15%) were nausea (32.2%), diarrhea (24.3%), photopsia (18.9%), vomiting (17.5%) and dysgeusia (16.8%). Many patients (623 patients) discontinued treatment of crizotinib because of adverse events within 12 weeks after therapy initiation, which tended to frequently occur in the following cases: (1) elderly, (2) body weight ConclusionsNo new safety concerns were observed in this PMS study. Our results provide useful information regarding the status of crizotinib therapy in the clinical setting.

Background Sunitinib is approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced or metastatic disease. Safety and efficacy data in Japanese patients are limited. We report outcomes from a post-marketing surveillance study of sunitinib treatment in Japanese patients. Methods Sunitinib 37.5 mg once daily was orally administered in Japanese patients aged ≥ 15 years with pNETs. The primary endpoints included adverse events (AEs) occurring during the observation period of 168 days and objective response rate (ORR). Results Sunitinib was administered in 62 patients with pNETs. The median duration of treatment was 165 days. At 168 days from the start of treatment, 31 patients were still receiving sunitinib treatment and treatment continuation rate was 50.0%. Of the 31 patients who discontinued treatment, 18 (58.1%) discontinued because of AEs and 16 (51.6%) patients discontinued due to insufficient clinical effect. Of the 18 patients who discontinued due to AEs, 10 did so within 42 days of treatment initiation. The most common all-grade AEs were platelet count decreased (33.9%), diarrhea (29.0%), neutrophil count decreased (27.4%), hypertension (24.2%), and palmar-plantar erythrodysesthesia syndrome (24.2%). In the 51 patients eligible for the efficacy analysis, ORR was 13.7% (95% confidence interval, 5.7–26.3) and clinical benefit rate was 70.6%. Conclusions There were no new safety concerns in real-world use of sunitinib in Japanese patients with pNETs. The short treatment duration likely led to low tumor response. Appropriate AEs management through dose interruption/reduction is essential for sunitinib treatment success in this patient population.

Introduction The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting. Methods Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists. Results The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema-like shadows with or without diffuse alveolar damage pattern were observed in crizotinib-associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2-4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD. Conclusions Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.

Objective: This study was conducted to expand the sunitinib safety database in Japanese imatinibresistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. Methods: Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. Results: No unexpected safety issues occurred. Grade ≥ 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16–24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7–24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88–94). Higher relative dose intensity (≥70 vs.

The efficacy of fluoroquinolones (FQs) correlates with the pharmacokinetic/pharmacodynamic (PK-PD) parameter, AUC/MIC. To our knowledge, however, no prospective studies have reported the relationship between FQ efficacy and PK-PD parameters in intraabdominal infection; therefore, we prospectively investigated the relationship between the efficacy of intravenous ciprofloxacin (CPFX IV) and PK-PD parameters. The study included 16 patients diagnosed with peritonitis between 2006 and 2008: 14 patients infected with a single organism and 2 patients infected with more than one organism. Each patient was treated with CPFX IV (300 mg twice daily). The response rate was 56% (9 responders and 7 non-responders). Non-responders were infected with Escherichia coli, Pseudomonas aeruginosa, and Bacteroides fragilis (6 patients were infected with a single organism and 1 with more than one organism). Plasma drug concentrations were measured 1 h and 2 or 4 h after administration of CPFX IV. AUC for 24 h (AUC(0-24))/MIC values was calculated. The range of AUC(0-24)/MIC values in responders [95.3-3628.4 (geometric mean, 521.6)] was significantly different from that in non-responders [7.0-45.2 (geometric mean, 16.5)] (p = 0.001). The target AUC/MIC value of CPFX IV would be considered to be 45-95 in patients with peritonitis.

Summary Background Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. Methods This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Results Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional ‘3 + 3’ design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Conclusions Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.

Mycoplasma genitalium has been shown to be one of the pathogens responsible for uterine cervicitis by many studies. However, there are no clinical recommendations for treating M. genitalium-positive uterine cervicitis. Our study retrospectively investigated the antimicrobial efficacies of several antibiotics against uterine cervicitis caused by M. genitalium. We studied a total of 257 women with M. genitalium-positive uterine cervicitis, except for those with chlamydial and gonococcal infections, who were treated with one of the following antibacterial therapies: azithromycin extended release formulation (AZM-SR) 2 g single dose, azithromycin (AZM) 1 g single dose, clarithromycin (CAM) 400 mg/day for 7 days, CAM 400 mg/day for 14 days, moxifloxacin (MFLX) 400 mg/day for 7 days, MFLX 400 mg/day for 14 days, levofloxacin (LVFX) 500 mg/day for 7 days, LVFX 500 mg/day for 14 days, sitafloxacin (STFX) 200 mg/day for 7 days, and STFX 200 mg/day for 14 days. A PCR-based assay was performed to evaluate the microbiological efficacy of eradication in these patients. M. genitalium was eradicated from the uterine cervix in 19 of the 21 (90.5%) patients treated with AZM-SR 2 g single dose, in 38 of the 42 (90.5%) patients treated with MFLX 400 mg/day for 7 days, in 42 of the 42 (100%) patients treated with MFLX 400 mg/day for 14 days, and in 12 of the 13 (92.3%) patients treated with STFX 200 mg/day for 14 days. In conclusion, AZM-SR 2 g single dose, MFLX 400 mg/day for 14 days, and STFX 200 mg/day for 14 days would each be an effective treatment for M. genitalium infection.

Fungal peritonitis associated with Curvularia geniculata and Pithomyces species in a patient with vulvar cancer who was successfully treated with oral voriconazole

The prevalence of female sexually transmitted infection (STI) in Japan is in the decreasing tendency after 2002, however it still actualizes as a social problem. Azithromycin, which is 15-member macrolide antimicrobial agent, has indication to treat the chlamydia STI in a single dose of 1 g. In April 2009, a single dose of 2 g of azithromycin extended release (ER) formulation, which is improved formulation by the viewpoint of pharmacokinetics-pharmacodynamics, was approved and has indications to treat not only chlamydial STI but also gonococcal STI. We considered the clinical application of azithromycin ER to treat female STI, including our new our own experiences because the clinical studies of azithromycin ER for STI had not been conducted. In conclusion, azithromycin ER was suggested theoretically becoming one of the choices of new treatment STI caused by not only chlamydia but also gonococcus, more clinical consideration to treat STI will be necessary in the future.

We investigated antifungal susceptibility of 96 Candida species strains (37 strains of Candida albicans, 30 of Candida glabrata, 16 of Candida tropicalis and 13 of Candida parapsilosis) isolated from patients with invasive fungal peritonitis. Antifungal activity showed micafungin (MCFG), voriconazole (VRCZ)itraconazole (ITCZ)fluconazole (FLCZ). Judged by clinical breakpoints of Clinical and Laboratory Standards Institute (CLSI), FLCZ-resistant C. albicans, ITCZ-resistant C. albicans and VRCZ-resistant C. albicans were detected in the frequency of 5.4% (2/37), 21.6% (8/37) and 5.4% (2/37), respectively. We also retrospectively investigated the association of both antifungal susceptibility judged by CLSI breakpoints and clinical efficacy in 16 patients with invasive fungal peritonitis treated by injectable ITCZ. Clinical success and failure were obtained in cases of ITCZ MICor = 1 microg/mL andor = 4 microg/ml, respectively. We conclude that we should re-consider CLSI breakpoints on ITCZ.

This phase I, open-label study investigated the Toll-like receptor 9 agonist, PF-3512676, in combination with carboplatin and paclitaxel in Japanese patients with advanced, non-small-cell lung cancer (NSCLC). Patients (n = 12) with treatment-naive stage IIIB or IV NSCLC received single-agent PF-3512676 subcutaneously once during the first 7 days (monotherapy phase) in three escalating dose levels (0.1, 0.2, and 0.4 mg/kg) followed by a combination phase during which patients received 0.1 or 0.2 mg/kg PF-3512676 subcutaneously on days 8 and 15 of each 3-week cycle of carboplatin (area under the curve, 6 mg x min/mL) and paclitaxel (200 mg/m(2)). Safety and pharmacokinetics of PF-3512676 were assessed during monotherapy and combination therapy phases. PF-3512676 was tolerable as monotherapy or in combination with chemotherapy in patients with NSCLC. Most common treatment-related, non-hematologic adverse events (AEs) throughout the study were injection-site reactions (n = 12, 100%) and flu-like symptoms (n = 11, 91.7%) that were each grade 1 or 2 in all but one patient. All patients experienced neutropenia and leukopenia (>or=grade 3 in 11 [91.7%] and seven [58.3%] patients, respectively). One patient in dose level 2 had a dose-limiting toxicity: grade 3 rash and grade 3 increase in gamma-glutamyltransferase during combination therapy. Mean PF-3512676 half-life ranged from 4.8 to 21.6 h (longer with higher doses). Four (33%) patients had objective responses (one complete response, three partial responses), and seven (58%) patients achieved stable disease. PF-3512676 as monotherapy and in combination with chemotherapy had an acceptable safety profile in Japanese patients with treatment-naive NSCLC.

The idea of the European Court of Justice operating as an ‘independent authority’, albeit on behalf of (and in concert with, to use Charles de Gaulle’s phrase — see Nelsen and Stubb, 1994, Chapter 5) the supranational EC/EU system as a whole, brings us back to the notion of ‘sovereignty’ which KlausDieter Borchardt (1994; 1995) and Josephine Shaw (1993; 1996) seem to have in mind. Their notion is similar to that to be gleaned from various other, less legally focused but still highly pertinent, writings, including those by Clive Archer and Fiona Butler (1992); Jamie Shea (1993); Neill Nugent (1991); and Monica den Boer (1994). Archer and Butler argue: To understand the European Community, one must comprehend the position of the sovereign state in Europe. The sovereign state is […] a European invention and its genesis can be dated back to the fourteenth century [Strayer, 1970, p. 57] with the touchstone of ‘constitutional self-containment’ [Manning, 1962, p. 166] having been well established by a number of states in Europe by the Peace of Westphalia in 1648. If it is true that ‘sovereignty […] consists of being constitutionally apart, of not being contained, however loosely, within a wider constitutional scheme’ [James, 1986, p. 24], then [the] Peace of Westphalia, which ended the Thirty Years War, established […] that there existed sovereign states in Europe that could not be contained within the Holy Roman Empire […]. It ‘paved the way for a system of states to replace a hierarchical system under the leadership of the Pope and the Hapsburg family complex […]’ [Holsti, 1991, p. 26]. (Archer and Butler, 1992, pp. 1–2)

During the run-up to the UK’s spring 1997 parliamentary General Election, the contesting political parties variously set out their stalls on a range of issues while, without exception, prominently displaying their views on the UK’s part in the process of European integration by way of the progress of the European Union. For instance, John Major, prime minister and leader of the Conservative Party, attempted to ‘push the threat to British jobs posed by the EU’s social chapter into the forefront of the […] election campaign with an attack on [the] Labour [Party] for wanting to import a ‘‘Trojan Horse’’ that would supposedly bring industry to its knees’ (White, 4 February 1997; see also Palmer and White, 5 February 1997; and Kampfner, 1997). At the same stage in the election campaign, Robin Cook, the Labour Party’s shadow Foreign Secretary, fuelled the debate about the UK’s participation in the programme of European economic and monetary union (EMU) entailing the introduction of a European single currency, planned for January 1999,1 by letting it be known that a ‘Labour government would take sterling into a European single currency by 2002 if it proved to be ‘‘stable’’ ‘ by then (Parker and Peston, 3 February 1997): ‘Echoing comments made by [Hiroshi Okuda, the president of Toyota], the shadow foreign secretary warned that Britain would lose out on inward investment if it stayed outside the single currency in the longer term’.2.

Methodological questions aside, these survey results can be interpreted as a sign of the times, as a small part of a huge swathe of evidence of the new times which had been suddenly, surprisingly and even shockingly (Ambrose, 1993, p.352) sprung upon the world towards the close of the twentieth century. These findings are symptomatic of how the world had become a remarkably different place from what it had been before, and in particular from what it had been during the previous four or five decades: of how the world system2 or global system3 had undergone a swift, sweeping and fundamental transformation initiated by a set of events in 1989.

This extract from Shelley and Winck’s contribution to a quartet of books on What is Europe? draws attention to some of the main practical (everyday), political (policy) and sociological (theoretical) issues concerning the patterns, ramifications and implications of late-twentieth-century European cultures.1

The European Union’s one directly, democratically elected and accountable political institution is relatively under-developed. The European Parliament has not accumulated anything like the degree of decision-making responsibility or competence which balances out that degree which has been relinquished by the equivalent institutions (the parliaments) at the nation-state level, leaving aside the degree relinquished by the full range of political institutions (including the governments and the courts) at the nation-state level. The decision-making powers which have been transferred from the nation-state level, including from the parliaments, to the Union level have been largely re-distributed to supranational institutions which are not directly (electorally) accountable at nation-state level. It would seem that the Union, by virtue of the particular way in which it has re-distributed its acquired and accumulated supranational decision-making powers among its institutions, currently participates in the process of governance (geo-political management) in a far more top-down (see Elliott, 3 March 1997; and our Chapter 3) manner than has traditionally been the case among its current Member States. The more the Union progresses as a supranational organisation without altering its managerial style so as to far more closely resemble the approach to governance which has traditionally characterised and distinguished western liberal democracies (see Dunleavy and O’Leary, 1987; Hancock, 1993; Laffan, 1996a; Richardson, 1996), the more the Union’s democratic deficit will grow; and the more the Union will be a supranational regime that leaves itself open to the accusation of being a dictatorship: John Major yesterday made Brussels’ ‘dictatorship’ over Westminster a central battleground for the next election, after the European Court threw out Britain’s objection to the 48-hour Working Time Directive.

For us, European integration by way of the evolution of the European Union — that is, by way of both the institutional deepening and the geopolitical expansion of the Union — entails, and so can only be understood in terms of, four interdependent developments: (i) the progressive consolidation of the EU’s supranational institutions and decision-making powers, authority and sovereignty; (ii) the Union’s increasing engagement in pan-European governance; or, that is, in pan-European geo-political management; (iii) the EU’s construction and re-construction of zones of pan-European, and even more extensive, governance which are centred on itself as the inner (core, or umbral) zone, and are managed and manipulated very largely in the Union’s own (economic, political, security) interests; (iv) the EU’s increasing engagement in extra-EU geo-political management in a manner which is consistent with a (suitably modified) realist approach to the study and analysis of ‘international relations’, or global-system relationships, structures, processes and change.

SummaryBackground. Pancreatic neuroendocrine tumors (NETs) are rare but are frequently diagnosed at advanced stages and require systemic therapy. Patients and methods. This multicenter, open-label, phase II study evaluated sunitinib in Japanese patients with well-differentiated pancreatic NET. Patients received sunitinib 37.5 mg/day on a continuous daily dosing (CDD) schedule. The primary endpoint was clinical benefit rate (CBR; percentage of complete responses [CRs] plus partial responses [PRs] plus stable disease [SD] ≥24 weeks). Secondary endpoints included objective response rate (ORR), tumor shrinkage, progression-free survival (PFS) probability, safety, pharmacokinetics, and biomarkers. Results. Twelve patients received treatment. The CBR was 75 % (95 % confidence interval [CI], 43–94) and included 6 patients with a PR and 3 with SD. The ORR was 50 % (95 % CI, 21–79). PFS probability was 91 % (95 % CI, 54–99) at 6 months and 71 % (95 % CI, 34–90) at 12 months. Commonly reported treatment-emergent (all-causality), any-grade adverse events included diarrhea (n = 10), hand–foot syndrome and hypertension (both n = 8), fatigue and headache (both n = 7), and neutropenia (n = 6). No deaths on study were reported; one death due to disease progression occurred >28 days after end of treatment. Sunitinib on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles. Tumor responses in all 12 patients did not appear to correlate with decreases in chromogranin A levels. Conclusions. Sunitinib 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese patients with unresectable, well-differentiated pancreatic NET. Commonly reported adverse events were consistent with the known safety profile of sunitinib.

Summary Background Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors. Methods Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m2 on day 1 of repeated 21-day cycles. Results Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug–drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease. Conclusions Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m2) was well tolerated in previously treated patients with advanced solid tumors.