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Traditionally, dose-finding process for oncology compound is carried out in phase I dose escalation study and is driven by safety in order to find maximum tolerated dose (MTD). However, with the recent paradigm shift from cytotoxic drugs to new generation of targeted therapies and immuno-oncology therapies, it may be difficult or unnecessary to identify the MTD because of the possible non-monotonic dose–response curves, and efficacy data should be incorporated into the dose-finding process. In this article, we have proposed efficacy-driven dose-finding designs with a safety-driven warm-up phase. Both local investigation and adaptive randomization using the framework of double-sided isotonic regression are investigated. Simulation studies are used to compare the proposed design to the original double-sided isotonic design. The results show that a safety-driven warm-up phase at the beginning can significantly improve the performance of double-sided isotonic regression, and both local investigation and adaptive randomization have good operating characteristics for finding the best dose/dose range under different tested scenarios.

Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population. © 2012 Cancer Research UK All rights reserved.

A reliable determination of progression is of key importance in determining progression-free survival in oncology trials. An independent review of tumour assessments made by investigators is often implemented with the aim of reducing a possible bias. Often, the independent review is performed in a prespecified but retrospective fashion by reviewing a patient after all assessments have been performed. It has been discussed that this mechanism can lead to informative censoring with respect to independent review. This is caused by the fact that often no further assessments are available after the investigator has declared the patient to be progressive, possibly leading to a considerable amount of patients being judged progressive by the investigator and being censored by independent review. We introduce and investigate a model for the error in assessment with the aim of quantifying the bias in independent review. The model is based on single error probabilities at each assessment time-point that are independent from each other but dependent on the time to the true progression time-point. The bias introduced for the independent review is described and quantified. We show that the investigator assessments of progression can lead to less bias for progression-free survival than the results for independent review. Results show that a within-arm discordance rate is not necessarily correlated with the bias in independent review. Finally, we propose an approach for a sensitivity analysis that is a useful tool to sandwich the true underlying distribution by the results for independent review itself and the described sensitivity analysis.

We consider stationary Poisson–Voronoi tessellations (PVT) in the Euclidean plane and study the properties of Voronoi tessellations induced by linear Poisson processes on the edges of the PVT. We are especially interested in simulation algorithms for the typical cell. Two different simulation algorithms are introduced. The first algorithm directly simulates the typical cell, whereas the second algorithm simulates cells from which distributional properties of the typical cell can be obtained. This second algorithm can also be used for simulating the typical cell of other Cox–Voronoi tessellations. The implementation of both algorithms is tested for their correctness using random software tests. Then different cell characteristics are studied by simulation and compared with the typical cell of PVT and Cox–Voronoi tessellations based on linear Poisson processes on the lines of Poisson line processes. Our results can be applied, for example, in the analysis of telecommunication networks and vesicle paths on c...

The relative purchasing power—i.e., the purchasing power per inhabitant—is one of the key characteristics for businesses deciding on site selection. Apart from that it also plays a major role in regional planning, pricing policy and market research. In this study we investigate the spatial correlations for relative purchasing power of the townships in Baden–Wurttemberg. In particular, changes in relative purchasing power are analysed for three different time intervals, 1987–1993, 1993–1998 and 1998–2004, by means of distance-dependent characteristics like the mark–correlation function, the Simpson indices α(r) and β(r) and by tests on random labelling. It is shown that there are positive correlations for small distances between different townships but that these positive correlations become weaker over the years until they are almost nonexistent (in the sense that hypotheses of random labelling are no longer rejected). A conclusion from this loss of spatial correlations with time is that the relative purchasing power might become more and more purely random. This means that the relative purchasing power in a township is less and less influenced by the relative purchasing power of townships nearby. We further analysed these changes in the Bodensee–Oberschwaben and Stuttgart regions to compare the development of the relative purchasing power in both urban and rural environments.

We consider random geometric models for telecommunication access networks and analyse their serving zones which can be given, for example, by a class of so-called Cox–Voronoi tessellations (CVTs). Such CVTs are constructed with respect to locations of network components, the nucleii of their induced cells, which are scattered randomly along lines induced by a Poisson line process. In particular, we consider two levels of network components and investigate these hierarchical models with respect to mean shortest path length and mean subscriber line length, respectively. We explain point-process techniques which allow for these characteristics to be computed without simulating the locations of lower-level components. We sustain our results by numerical examples which were obtained through Monte Carlo simulations, where we used simulation algorithms for typical Cox–Voronoi cells derived in a previous paper. Also, briefly, we discuss tests of correctness of the implemented algorithms. Finally, we present a short outlook to possible extensions concerning multi-level models and iterated random tessellations.

We explore real telecommunication data describing the spatial geometrical structure of an urban region and we propose a model fitting procedure, where a given choice of different non-iterated and iterated tessellation models is considered and fitted to real data. This model fitting procedure is based on a comparison of distances between characteristics of sample data sets and characteristics of different tessellation models by utilizing a chosen metric. Examples of such characteristics are the mean length of the edge-set or the mean number of vertices per unit area. In particular, after a short review of a stochastic-geometric telecommunication model and a detailed description of the model fitting algorithm, we verify the algorithm by using simulated test data and subsequently apply the procedure to infrastructure data of Paris.

Polo-like kinases (Plks) play an important role in cell cycle checkpoint controls and are over-expressed in acute myeloid leukaemia (AML). BI 2536, a novel Plk inhibitor, induces mitotic arrest and apoptosis. In this phase I/II trial of BI 2536 in 68 elderly patients with relapsed/refractory AML, three schedules were investigated (day 1, days 1-3, and days 1 + 8). Maximum tolerated dose was 350 and 200 mg in the day 1 and days 1 + 8 schedules, respectively. The day 1-3 schedule appeared equivalent to the day 1 schedule and was discontinued early. BI 2536 exhibited multi-compartmental pharmacokinetic behaviour. The majority of patients showed an increase of bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe. The overall response rate in the day 1 and day 1 + 8 schedules was 9% (5/54) with 2 complete and 3 partial responses. The majority of drug-related adverse events grade ≥3 were haematological. Taken together, Plk inhibition induced cell cycle arrest in AML blasts in vivo and BI 2536 monotherapy showed modest clinical activity in this poor prognosis patient group.

Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract., Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: BIBW 2992 (Tovok™*) is a novel, oral, irreversible inhibitor of the epidermal growth factor receptor (EGFR)/ human epidermal growth factor receptor (HER)1 and HER2 inhibitor. It has promising preclinical activity in HER2-negative MDA-MB-453 and triple-negative SUM 149-PT cell lines, and showed clinical Phase I activity. First results of a Phase II study of BIBW 2992 in patients with HER2-negative, hormone receptor (HR)-positive or triple-negative breast cancer who have progressed following no more than two prior lines of chemotherapy are presented. The trial was conducted as a multi-institutional, open-label study in Germany and Belgium.Methods: Eligible patients had stage IIIB or IV HER2-negative metastatic breast cancer (MBC), with progression following no more than two prior lines of chemotherapy. No prior EGFR-targeted therapy was allowed and measurable disease, Eastern Cooperative Oncology Group performance status of 0–2 and an adequate organ function were required. Patients received 50 mg BIBW 2992 once-daily until disease progression. Tumor assessment was performed every other treatment course (one course is 28 days). The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors criteria in patients with HR-positive and triple-negative MBC. The latter was changed to clinical benefit, i.e. objective response (OR) or stable disease (SD) on treatment for at least four cycles for patients with triple-negative disease. Safety data were collected and analyses are still ongoing.Results: A total of 56 patients were enrolled with 50 actually starting treatment on the trial, including 29 patients with triple-negative and 21 patients with HER2-negative and HR-positive MBC. No ORs were observed in either cohort. Three patients in the triple-negative cohort had SD for at least 4 treatment cycles, one of them for 12 cycles. The most frequently observed side-effects at snapshot date (on 49 patients) are diarrhea (Common Terminology Criteria for Adverse Events Grade 3 in 18 patients [36.7%]) and Grade 3 skin rash in two patients [4.1%]). These were managed by symptomatic treatments and dose reductions.Conclusion: Long-term oral administration of BIBW 2992 was safe in HER2-negative MBC patients. Side effects mainly affected the skin and gastrointestinal tract, and were manageable. Clinical benefit was achieved in a fraction of triple-negative MBC patients.*Trade name not FDA approved. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5062.

Cell migration is an essential element in the immune response on the one hand and in cancer metastasis on the other hand. The architecture of the actin network in lamellipodia determines the elasticity of the leading edge and contributes to the regulation of migration. We have implemented a new method for the analysis of actin network morphology in the lamellipodia of B16F1 mouse melanoma cells. This method is based on fitting multi-layer geometrical models to electron microscopy images of lamellipodial actin networks. The chosen model and F-actin concentrations are thereby deterministic parameters. Using this approach, we identified distinct structural features of actin networks in lamellipodia. The mesh size which defines the elasticity of the lamellipodium was determined as 34 and 78?nm for a two-layer network at a total actin concentration of 9.6?mg?ml?1. These data lead to estimates of the low frequency elastic shear moduli which differ by more than a magnitude between the two layers. These findings indicate an anisotropic shear modulus of the lamellipodium with the stiffer layer being the dominant structure against deformations in the lamellipodial plane and the softer layer contributing significantly at lower indentations perpendicular to the lamellipodial plane. This combination creates a material that is optimal for pushing forward as well as squeezing through narrow spaces.

Abstract 3316 Background: Patients with refractory or relapsed AML have a poor prognosis and new treatments are needed for this patient population. While younger AML patients might benefit from intensive salvage treatments, a substantial number of elderly patients are considered ineligible for intensive treatment approaches. For these patients, repeated cycles of low-dose cytarabine (LD-Ara-C) are an accepted therapeutic option for palliative treatment. The serine/threonine kinase Polo-like kinase 1 (Plk1) controls several key steps in mitosis. BI 6727 is a first in class, highly selective and potent cell cycle kinase inhibitor targeting Plk1, and has demonstrated antiproliferative activity in multiple cell lines and animal models. Targeting Plk1 with BI 6727 results in cell cycle arrest in prometaphase (referred to as polo arrest) leading to eventual apoptosis. In a phase I dose escalation trial in patients with advanced solid tumors a favorable safety profile and encouraging antitumor activity was reported. BI 6727 has demonstrated a long terminal half life of 111 hours and a high volume of distribution suggesting excellent tissue distribution in patients. Here, we present preliminary results from the Phase I part of an ongoing Phase I/II study of BI 6727 in combination with LD-Ara-C in patients with relapsed or refractory AML considered ineligible for intensive treatment. Methods: This study follows a two stage design: the maximum tolerated dose (MTD) of BI 6727 in combination with fixed dose LD-Ara-C was evaluated in the Phase I dose escalation part of the trial following a 3+3 design with de-escalation. In a second ongoing treatment schedule the MTD of single agent BI 6727 is investigated, the MTD of single agent BI 6727 has not been reached yet. In the planned randomized Phase II part of the study, efficacy of BI 6727 plus LD-Ara-C will be compared to LD-Ara-C alone. BI 6727 was administered as a one hour intravenous infusion on days 1+15 every 28 days in combination with fixed dose LD-Ara-C (20 mg bid s.c). The BI 6727 starting dose was based on the MTD previously determined in solid tumor patients. Patients with no progression after the first cycle were allowed to continue treatment. Results: Patient characteristics were as follows: median age was 71 years (range 40 – 81); ECOG performance score 0: 9 pts; 1: 17 pts; 2: 5 pts. Increasing BI 6727 doses in combination with LD-Ara-C were evaluated in 31 patients (21 males, 10 females). Safety: Drug related adverse events (AEs) were reported in 17 of the 31 patients. The most frequent AEs reported (>5%) were: anemia and febrile neutropenia (each 9.7%), infections (pneumonia), decreased appetite and headache (each 6.5%). Dose-limiting toxicities (DLTs) were reported in 4 patients treated with BI 6727 + LD-Ara-C. DLTs as rated per protocol were: pneumonia, mucositis, hypersensitivity/allergic reaction and myocardial infarction. Based on the preliminary reports on DLTs the MTD for BI 6727 in combination with LD-Ara-C was determined. Preliminary response data of 28 patients with relapsed/refractory AML treated at different BI 6727 doses in combination with LD-Ara-C are available: 5 patients achieved a CRi or CR, 2 patients achieved a PR. Six patients had temporarily stable blood values (“no change” as best response). 10 patients suffered from progression during or at the end of the 1st treatment cycle, and 5 patients were ineligible for response assessment. An update of the phase I part of this trial with further details on patient/disease characteristics, safety and efficacy of BI 6727 in combination with LD-Ara-C will be reported at the meeting. Conclusion: Preliminary results indicate that BI 6727 in combination with LD-Ara-C is well tolerated in patients with relapsed/refractory AML ineligible for intensive treatment. The MTD of BI 6727 in combination with LD-Ara-C was determined. BI 6727 in combination with LD-Ara-C showed first signs of clinical activity in AML patients. Safety and efficacy of BI 6727 + LD-Ara-C will be further explored in the phase II part of the trial. Disclosures: Off Label Use: LD-Ara-C in combination with BI 6727 for treatment of patients with relapsed refractory AML ineligible for intensive treatment. Fleischer:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. Taube:Boehringer Ingelheim Pharma GmbH & Co KG: Employment.

We propose a mathematical model to describe the microstructure of the gas diffusion layer (GDL) in proton exchange membrane fuel cells (PEMFCs) based on tools from stochastic geometry. The GDL is considered as a stack of thin sections. This assumption is motivated by the production process and the visual appearance of relevant microscopic images. The thin sections are modeled as planar [two-dimensional (2D)] random line tessellations which are dilated with respect to three dimensions. Our 3D model for the GDL consists of several layers of these dilated line tessellations. We also describe a method to fit the proposed model to given GDL data provided by scanning electron microscopy images which can be seen as 2D projections of the 3D morphology. In connection with this, we develop an algorithm for the segmentation of such images which is necessary to obtain the required structural information from the given grayscale images.

Background A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. Methods Patients with advanced solid malignancies received docetaxel 75 mg/m(2) intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. Results Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m(2) docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m(2). The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. Conclusion Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published