Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment : the M77001 study group

Purpose: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: Patients were randomly assigned to six cycles of docetaxel 100 mg/m 2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. Conclusion: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity. © 2005 by American Society of Clinical Oncology.

Prognostic factors in patients with advanced non-small cell lung cancer : data from the phase III FLEX study

The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs ≥65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs ≥40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs ≥65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. © 2012 Elsevier Ireland Ltd.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m, followed by 250 mg/m2 weekly thereafter). Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone. © 2007 European Society for Medical Oncology.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

A natural oil-based emulsion containing allantoin versus aqueous cream for managing radiation-induced skin reactions in patients with cancer : a phase III double-blind randomised controlled trial

Purpose To investigate the effects of a natural oil-based emulsion containing allantoin versus aqueous cream for preventing and managing radiation induced skin reactions (RISR). Methods and Materials A total of 174 patients were randomised and participated in the study. Patients either received Cream 1 (the natural oil-based emulsion containing allantoin) or Cream 2 (aqueous cream). Skin toxicity, pain, itching and skin-related quality of life scores were collected for up to four weeks after radiation treatment. Results Patients who received Cream 1 had a significantly lower average level of Common Toxicity Criteria at week 3 (p<0.05), but had statistically higher average levels of skin toxicity at weeks 7, 8 and 9 (all p<0.001). Similar results were observed when skin toxicity was analysed by grades. With regards to pain, patients in the Cream 2 group had a significantly higher average level of worst pain (p<0.05) and itching (p=0.046) compared to the Cream 1 group at week 3, however these differences were not observed at other weeks. In addition, there was a strong trend for Cream 2 to reduce the incidence of grade 2 or more skin toxicity in comparison to Cream 1 (p=0.056). Overall, more participants in the Cream 1 group were required to use another topical treatment at weeks 8 (p=0.049) and 9 (p=0.01). Conclusion The natural oil-based emulsion containing allantoin appears to have similar effects for managing skin toxicity compared to aqueous cream up to week 5, however, it becomes significantly less effective at later weeks into the radiation treatment and beyond treatment completion (week 6 and beyond). There were no major differences in pain, itching and skin-related quality of life. In light of these results, clinicians and patients can base their decision on costs and preferences. Overall, aqueous cream appears to be a more preferred option.

Risk assessment and preventive strategies for herbicide resistance in NR (phase III)

The threat and management of glyphosate# resistant weeds are major issues facing northern region growers. At present five weeds are confirmed glyphosate-resistant: barnyard grass, liverseed grass, windmill grass, annual ryegrass and flaxleaf fleabane. This project used 25 experiments to investigate the ecology of the grass weeds, plus new or improved chemical and non-chemical control tactics for them. The refined glyphosate resistance model developed in this project used the experiments' findings to predict the long-term impacts on evolution of resistance and on seed bank numbers of resistant weeds. These data led to revised management and resistance avoidance strategies, which were published in the Reporter newsletter, and via an on-line risk assessment tool. - See more at: http://finalreports.grdc.com.au/UQ00054#sthash.oTkCN4Sk.dpuf

Herbicide tolerance of barley and wheat cultivars in NR (phase III)

During the past 10 years, this project tested 23 barley and 51 wheat varieties with 19 and 34 registered herbicides, respectively. It concentrated on new varieties and herbicides. The research highlighted that Northern Region (NR) wheat and barley varieties differed considerably in their sensitivity to these herbicides. Overall, 9 per cent of wheat variety x herbicide combinations and 6 per cent of barley variety x herbicide combinations had significant yield losses (3 to 38%) from herbicides at recommended rates and crop stages. In addition, 21 to 23 per cent had significant yield losses from herbicides at double rates, indicating a narrow margin of crop safety.

Targeting the dopamine receptor in schizophrenia: investigational drugs in Phase III trials

Introduction: Antipsychotic drugs date back to the 1950s and chlorpromazine. Soon after, it was established that blockade of dopamine and, in particular, the D-2 receptor was central to this effect. Dopamine continues to represent a critical line of investigation, although much of the work now focuses on its potential in other symptom domains. Areas covered: A search was carried out for investigational drugs using the key words `dopamine', `schizophrenia' and `Phase III' in an American clinical trial registry (clinicaltrials.gov), published articles using the National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. Drugs were excluded that were already FDA approved. Expert opinion: There remains interest, albeit diminished, in developing better antipsychotic compounds. The greatest enthusiasm currently centres on dopamine's role in negative and cognitive symptom domains. With theories conceptualising hypodopaminergic activity as underlying these deficits, considerable effort is focused on drug strategies that will enhance dopamine activity. Finally, a small body of research is investigating dopaminergic compounds vis-a-vis side-effect treatments. In domains beyond psychosis, however, dopamine arguably is not seen as so central, reflected in considerable research following other lines of investigation.

The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, 'Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients'.

BACKGROUND: The impact of aromatase inhibitors (AIs) on non-cancer-related outcomes, which are known to be affected by oestrogens, has become increasingly important in postmenopausal women with hormone-dependent breast cancer. So far, data related to the effect of AIs on lipid profile in postmenopausal women is scarce. This study, as a companion substudy of an EORTC phase II trial (10951), evaluated the impact of exemestane, a steroidal aromatase inactivator, on the lipid profile of postmenopausal metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: The EORTC trial 10951 randomised 122 postmenopausal breast cancer patients to exemestane (E) 25 mg (n = 62) or tamoxifen (T) 20 mg (n = 60) once daily as a first-line treatment in the metastatic setting. Exemestane showed promising results in all the primary efficacy end points of the trial (response rate, clinical benefit rate and response duration), and it was well tolerated with low incidence of serious toxicity. As a secondary end point of this phase II trial, serum triglycerides (TRG), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), lipoprotein a (Lip a), and apolipoproteins (Apo) B and A1 were measured at baseline and while on therapy (at 8, 24 and 48 weeks) to assess the impact of exemestane and tamoxifen on serum lipid profiles. Of the 122 randomised patients, those who had baseline and at least one other lipid assessment are included in the present analysis. The patients who received concomitant drugs that could affect lipid profile are included only if these drugs were administered throughout the study treatment. Increase or decrease in lipid parameters within 20% of baseline were considered as non-significant and thus unchanged. RESULTS: Seventy-two patients (36 in both arms) were included in the statistical analysis. The majority of patients had abnormal TC and normal TRG, HDL, Apo A1, Apo B and Lip a levels at baseline. Neither exemestane nor tamoxifen had adverse effects on TC, HDL, Apo A1, Apo B or Lip a levels at 8, 24 and 48 weeks of treatment. Exemestane and tamoxifen had opposite effects on TRG levels: exemestane lowered while tamoxifen increased TRG levels over time. There were too few patients with normal baseline TC and abnormal TRG, HDL, Apo A1, Apo B and Lip a levels to allow for assessment of E's impact on these subsets. The atherogenic risk determined by Apo A1:Apo B and TC:HDL ratios remained unchanged throughout the treatment period in both the E and T arms. CONCLUSIONS: Overall, exemestane has no detrimental effect on cholesterol levels and the atherogenic indices, which are well-known risk factors for coronary artery disease. In addition, it has a beneficial effect on TRG levels. These data, coupled with E's excellent efficacy and tolerability, support further exploration of its potential in the metastatic, adjuvant and chemopreventive setting.

Final Report of the Phase III Archaeological Investigations at the Dr. Upton Scott House (18AP18), Annapolis, Anne Arundel County, Maryland, 1998-1999

In the summers of 1998 and 1999, the Archaeology in Annapolis project carried out archaeological investigation at the eighteenth century Dr. Upton Scott House site (18AP18)located at 4 Shipwright Street in the historic district of Annapolis, Anne Arundel County, Maryland. The Upton Scott House is significant as one of only a few Georgian houses with remnants of its original plantation-inspired landscape still visible (Graham 1998:147). Investigation was completed in agreement with the owners of the historic property, Mr. and Mrs. Paul Christian, who were interested in determining the condition and arrangement of Dr. Upton Scott’s well-documented pleasure gardens. Betty Cosans’ 1972 Archaeological Feasibility Report, the first real archaeological study of the Upton Scott House site, guided the research design and recovery efforts. Cosans determined that testing and survey in the back and side yards of the Scott property would yield important information on the use and history of the property, including that of Scott’s famous gardens. Excavation units and trenches were placed within three separate areas of backyard activity on the site which included Area One: extant brick stables in the southwest of the property; Area Two: the brick foundations of a small outbuilding located in the northwest area of the site; and Area Three: the area of Scott’s formal gardens. The research design included an interest in recovering evidence of African-American spiritual practice and domestic life at the site. Also of significant importance was an analysis of Scott’s garden beds, concerning the order and layout. Also sought was an understanding of the change in perception and use of the backyard by the various owners of the property.

Three Hundred Years in Annapolis: Phase III Archaeological Investigations of the Anne Arundel County Courthouse Site (18AP63), Annapolis, Maryland

During the summer of 1994, Archaeology in Annapolis conducted archaeological investigations of the city block bounded by Franklin, South and Cathedral Streets in the city of Annapolis. This Phase III excavation was conducted as a means to identify subsurface cultural resources in the impact area associated with the proposed construction of the Anne Arundel County Courthouse addition. This impact area included both the upper and lower parking lots used by Courthouse employees. Investigations were conducted in the form of mechanical trenching and hand excavated units. Excavations in the upper lot area yielded significant information concerning the interior area of the block. Known as Bellis Court, this series of rowhouses was constructed in the late nineteenth century and was used as rental properties by African-Americans. The dwellings remained until the middle of the twentieth century when they were demolished in preparation for the construction of a Courthouse addition. Portions of the foundation of a house owned by William H. Bellis in the 1870s were also exposed in this area. Construction of this house was begun by William Nicholson around 1730 and completed by Daniel Dulany in 1732/33. It was demolished in 1896 by James Munroe, a Trustee for Bellis. Excavations in the upper lot also revealed the remains of a late seventeenth/early eighteenth century wood-lined cellar, believed to be part of the earliest known structure on Lot 58. After an initially rapid deposition of fill around 1828, this cellar was gradually covered with soil throughout the remainder of the nineteenth century. The fill deposit in the cellar feature yielded a mixed assemblage of artifacts that included sherds of early materials such as North Devon gravel-tempered earthenware, North Devon sgraffito and Northem Italian slipware, along with creamware, pearlware and whiteware. In the lower parking lot, numerous artifacts were recovered from yard scatter associated with the houses that at one time fronted along Cathedral Street and were occupied by African- Americans. An assemblage of late seventeenth century/early eighteenth century materials and several slag deposits from an early forge were recovered from this second area of study. The materials associated with the forge, including portions of a crucible, provided evidence of some of the earliest industry in Annapolis. Investigations in both the upper and lower parking lots added to the knowledge of the changing landscape within the project area, including a prevalence of open space in early periods, a surprising survival of impermanent structures, and a gradual regrading and filling of the block with houses and interior courts. Excavations at the Anne Arundel County Courthouse proved this to be a multi-component site, rich in cultural resources from Annapolis' Early Settlement Period through its Modern Period (as specified by Maryland's Comprehensive Historic Preservation Plan (Weissman 1986)). This report provides detailed interpretations of the archaeological findings of these Phase III investigations.

Site Report for Phase III Archaeological Investigations at Reynolds Tavern (18AP23), 4 Church Circle, Annapolis, Maryland. 1982-1984

This report details the archaeology completed at Reynolds Tavern in the years 1982,1983, and 1984. It was completed in 2013, nearly 30 years after the excavation took place, using archival materials such as the draft interim reports, unit summary forms, original notes and photographs which are currently stored in the University Archives at Hornbake Library, at the University of Maryland, College Park. This report has been a collaboration across time and space, drawing from preliminary reports written by Anne Yenstch and Susan Mira in 1982 and Joe Dent and Beth Ford in 1983, as well as original notes from students of the field schools held there during those years, various analyses by scholars from many universities (including the University of Maryland, University of Georgia, and the College of William and Mary), and historical research by Nancy Baker. Thomas Cuddy began the writing of this report in 2002, completing the first three chapters in addition to the artifact analysis that led to the postexcavation identification of the African bundles in the Reynolds Tavern basement. This remarkable discovery was made along with Mark Leone of the University of Maryland, founder and director of Archaeology in Annapolis, who also served as the Principle Investigator during all three years of the Reynolds Tavern excavations. Dr. Leone contributed the fifth and final chapter to this report, the Conclusions and Recommendations, during its final compilation in 2013. The final report, including the fourth chapter on the archaeology itself, was written in part and compiled by Patricia Markert of the University of Maryland in the spring of 2013. Reynolds Tavern has been part of the landscape of Annapolis for two-hundred and fifty five years (at the time of the publication of this report). It sits on Church Circle facing St. Anne’s Church, and is a beautiful example of 18th century Georgian architecture as well one of the defining features of Historic Annapolis today. It currently operates as a popular restaurant and pub, but has served variously as a hat shop, a tavern, an inn, a library and a bank over time, among other things. Its long history contributes to its significance as an archaeological site, and also as a historic marker in present day Annapolis. The archaeology conducted at Reynolds Tavern shed light on life in 18th and 19th century Annapolis, illuminating details of the occupants’ lives through the material traces they left behind. These include an 18th century cobblestone road that ran diagonally through the Tavern’s yard, telling of the movement through early Annapolis; a large and intact well, which was found ii to contain a 19 foot wooden pipe; a large, ovular privy containing many of the objects used on a day to day basis at the Tavern or the structures around it; a subterranean brick storage feature in the basement of the Tavern, which may have been used by Reynolds during his days operating a hat shop; and also in the basement, two African caches of objects, providing a glimpse into West African spiritual practices alive in historic Annapolis and the presence of African American individuals at the Tavern in the 18th and 19th centuries. The purpose of this report is to detail these archaeological investigations and their findings, so that a public record will be available and the archaeology completed at Reynolds Tavern can continue to contribute to the history of Annapolis.