Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial.

BACKGROUND: We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS: Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION: Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING: Amgen.

A phase 2 randomized trial of radiotherapy (RT) plus panitumumab compared to chemoradiotherapy in patients with unresected, locally advanced squamous cell carcinoma of the head and neck (SCCHN): interim pooled safety analysis

Background: Panitumumab (pmab), a fully human monoclonal antibody against the epidermal growth factor receptor (EGFR), is indicated as monotherapy for treatment of metastatic colorectal cancer. This ongoing study is designed to assess the efficacy and safety of pmab in combination with radiotherapy (PRT) compared to chemoradiotherapy (CRT) as initial treatment of unresected, locally advanced SCCHN (ClinicalTrials.gov Identifier: NCT00547157). Methods: This is a phase 2, open-label, randomized, multicenter study. Eligible patients (pts) were randomized 2:3 to receive cisplatin 100 mg/m2 on days 1 and 22 of RT or pmab 9.0 mg/kg on days 1, 22, and 43. Accelerated RT (70 to 72 Gy − delivered over 6 to 6.5 weeks) was planned for all pts and was delivered either by intensity-modulated radiation therapy (IMRT) modality or by three-dimensional conformal (3D-CRT) modality. The primary endpoint is local-regional control (LRC) rate at 2 years. Key secondary endpoints include PFS, OS, and safety. An external, independent data monitoring committee conducts planned safety and efficacy reviews during the course of the trial. Results: Pooled data from this planned interim safety analysis includes the first 52 of the 150 planned pts; 44 (84.6%) are male; median (range) age is 57 (33−77) years; ECOG PS 0: 65%, PS 1: 35%; 20 (39%) pts received IMRT, and 32 (61%) pts received 3D-CRT. Fifty (96%) pts completed RT, and 50 pts received RT per protocol without a major deviation. The median (range) total RT dose administered was 72 (64−74) Gy. The most common grade _ 3 adverse events graded using the CTCAE version 3.0 are shown (Table). Conclusions: After the interim safety analysis, CONCERT-2 continues per protocol. Study enrollment is estimated to be completed by October 2009.

Diffusionless first-order phase transitions in systems with frozen configurational degrees of freedom

We consider systems that can be described in terms of two kinds of degree of freedom. The corresponding ordering modes may, under certain conditions, be coupled to each other. We may thus assume that the primary ordering mode gives rise to a diffusionless first-order phase transition. The change of its thermodynamic properties as a function of the secondary-ordering-mode state is then analyzed. Two specific examples are discussed. First, we study a three-state Potts model in a binary system. Using mean-field techniques, we obtain the phase diagram and different properties of the system as a function of the distribution of atoms on the different lattice sites. In the second case, the properties of a displacive structural phase transition of martensitic type in a binary alloy are studied as a function of atomic order. Because of the directional character of the martensitic-transition mechanism, we find only a very weak dependence of the entropy on atomic order. Experimental results are found to be in quite good agreement with theoretical predictions.

p21 as a transcriptional co-repressor of S-phase and mitotic control genes.

It has been previously described that p21 functions not only as a CDK inhibitor but also as a transcriptional co-repressor in some systems. To investigate the roles of p21 in transcriptional control, we studied the gene expression changes in two human cell systems. Using a human leukemia cell line (K562) with inducible p21 expression and human primary keratinocytes with adenoviral-mediated p21 expression, we carried out microarray-based gene expression profiling. We found that p21 rapidly and strongly repressed the mRNA levels of a number of genes involved in cell cycle and mitosis. One of the most strongly down-regulated genes was CCNE2 (cyclin E2 gene). Mutational analysis in K562 cells showed that the N-terminal region of p21 is required for repression of gene expression of CCNE2 and other genes. Chromatin immunoprecipitation assays indicated that p21 was bound to human CCNE2 and other p21-repressed genes gene in the vicinity of the transcription start site. Moreover, p21 repressed human CCNE2 promoter-luciferase constructs in K562 cells. Bioinformatic analysis revealed that the CDE motif is present in most of the promoters of the p21-regulated genes. Altogether, the results suggest that p21 exerts a repressive effect on a relevant number of genes controlling S phase and mitosis. Thus, p21 activity as inhibitor of cell cycle progression would be mediated not only by the inhibition of CDKs but also by the transcriptional down-regulation of key genes.

Exact lower bounds to the ground-state energy of spin systems: The two-dimensional S=1/2 antiferromagnetic Heisenberg model

We present a very simple but fairly unknown method to obtain exact lower bounds to the ground-state energy of any Hamiltonian that can be partitioned into a sum of sub-Hamiltonians. The technique is applied, in particular, to the two-dimensional spin-1/2 antiferromagnetic Heisenberg model. Reasonably good results are easily obtained and the extension of the method to other systems is straightforward.

Sex of College Students Moderates Associations among Bedtime, Time in Bed, and Circadian Phase Angle.

Sex differences in circadian rhythms have been reported with some conflicting results. The timing of sleep and length of time in bed have not been considered, however, in previous such studies. The current study has 3 major aims: (1) replicate previous studies in a large sample of young adults for sex differences in sleep patterns and dim light melatonin onset (DLMO) phase; (2) in a subsample constrained by matching across sex for bedtime and time in bed, confirm sex differences in DLMO and phase angle of DLMO to bedtime; (3) explore sex differences in the influence of sleep timing and length of time in bed on phase angle. A total of 356 first-year Brown University students (207 women) aged 17.7 to 21.4 years (mean = 18.8 years, SD = 0.4 years) were included in these analyses. Wake time was the only sleep variable that showed a sex difference. DLMO phase was earlier in women than men and phase angle wider in women than men. Shorter time in bed was associated with wider phase angle in women and men. In men, however, a 3-way interaction indicated that phase angles were influenced by both bedtime and time in bed; a complex interaction was not found for women. These analyses in a large sample of young adults on self-selected schedules confirm a sex difference in wake time, circadian phase, and the association between circadian phase and reported bedtime. A complex interaction with length of time in bed occurred for men but not women. We propose that these sex differences likely indicate fundamental differences in the biology of the sleep and circadian timing systems as well as in behavioral choices.

Deicer Scaling Resistance of Concrete Mixtures Containing Slag Cement Phase 2: Evaluation of Different Laboratory Scaling Test Methods, TPF-5(100), 2012

With the use of supplementary cementing materials (SCMs) in concrete mixtures, salt scaling tests such as ASTM C672 have been found to be overly aggressive and do correlate well with field scaling performance. The reasons for this are thought to be because at high replacement levels, SCM mixtures can take longer to set and to develop their properties: neither of these factors is taken into account in the standard laboratory finishing and curing procedures. As a result, these variables were studied as well as a modified scaling test, based on the Quebec BNQ scaling test that had shown promise in other research. The experimental research focused on the evaluation of three scaling resistance tests, including the ASTM C672 test with normal curing as well as an accelerated curing regime used by VDOT for ASTM C1202 rapid chloride permeability tests and now included as an option in ASTM C1202. As well, several variations on the proposed draft ASTM WK9367 deicer scaling resistance test, based on the Quebec Ministry of Transportation BNQ test method, were evaluated for concretes containing varying amounts of slag cement. A total of 16 concrete mixtures were studied using both high alkali cement and low alkali cement, Grade 100 slag and Grade 120 slag with 0, 20, 35 and 50 percent slag replacement by mass of total cementing materials. Vinsol resin was used as the primary air entrainer and Micro Air® was used in two replicate mixes for comparison. Based on the results of this study, a draft alternative test method to ASTM C762 is proposed.

Non-Destructive Evaluation of Iowa Pavements Phase 2: Development of a Fully Automated Software System for Rapid Analysis/Processing of the Falling Weight Deflectometer Data, 2009

The Office of Special Investigations at Iowa Department of Transportation (DOT) collects FWD data on regular basis to evaluate pavement structural conditions. The primary objective of this study was to develop a fully-automated software system for rapid processing of the FWD data along with a user manual. The software system automatically reads the FWD raw data collected by the JILS-20 type FWD machine that Iowa DOT owns, processes and analyzes the collected data with the rapid prediction algorithms developed during the phase I study. This system smoothly integrates the FWD data analysis algorithms and the computer program being used to collect the pavement deflection data. This system can be used to assess pavement condition, estimate remaining pavement life, and eventually help assess pavement rehabilitation strategies by the Iowa DOT pavement management team. This report describes the developed software in detail and can also be used as a user-manual for conducting simulation studies and detailed analyses. *********************** Large File ***********************

Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial.

BACKGROUND: Over 50% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced disease. Those at intermediate-to-high risk of recurrence after definitive therapy exhibit advanced disease based on tumour size or lymph node involvement, non-oropharynx primary sites, human papillomavirus (HPV)-negative oropharyngeal cancer, or HPV-positive oropharynx cancer with smoking history (>10-pack-years). Non-surgical approaches include concurrent chemoradiotherapy, induction chemotherapy followed by definitive radiotherapy or chemoradiotherapy, or radiotherapy alone. Following locoregional therapies (including surgical salvage of residual cervical nodes), no standard intervention exists. Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC. EGFR-targeted cetuximab is the only targeted therapy that impacts overall survival and is approved for HNSCC in the USA or Europe. However, resistance often occurs, and new approaches, such as targeting multiple ErbB family members, may be required. Afatinib, an irreversible ErbB family blocker, demonstrated antiproliferative activity in preclinical models and comparable clinical efficacy with cetuximab in a randomized phase II trial in recurrent or metastatic HNSCC. LUX-Head & Neck 2, a phase III study, will assess adjuvant afatinib versus placebo following chemoradiotherapy in primary unresected locoregionally advanced intermediate-to-high-risk HNSCC. METHODS/DESIGN: Patients with primary unresected locoregionally advanced HNSCC, in good clinical condition with unfavourable risk of recurrence, and no evidence of disease after chemoradiotherapy will be randomized 2:1 to oral once-daily afatinib (40 mg starting dose) or placebo. As HPV status will not be determined for eligibility, unfavourable risk is defined as non-oropharynx primary site or oropharynx cancer in patients with a smoking history (>10 pack-years). Treatment will continue for 18 months or until recurrence or unacceptable adverse events occur. The primary endpoint measure is duration of disease-free survival; secondary endpoint measures are disease-free survival rate at 2 years, overall survival, health-related quality of life and safety. DISCUSSION: Given the unmet need in the adjuvant treatment of intermediate-to-high-risk HNSCC patients, it is expected that LUX-Head & Neck 2 will provide new insights into treatment in this setting and might demonstrate the ability of afatinib to significantly improve disease-free survival, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT01345669.

A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

PURPOSE: As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n = 8, and cholangiocarcinoma of the liver, n = 1). EXPERIMENTAL DESIGN: Gemcitabine at 500, 750 and 1,125 mg/m(2) was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20 min of stop-flow perfusion, and in peripheral plasma for 420 min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH </= 7.2, pO(2) nadir ratio </=0.70 or pCO(2) peak ratio >/=1.35. The tolerability of this procedure was also assessed. RESULTS: Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20 min of stop-flow perfusion, with C (max) levels in the abdominal circuit of 246 (+/-37%), 2,039 (+/-77%) and 4,780 (+/-7.3%) mug/ml for the three dose levels 500, 750 and 1,125 mg/m(2), respectively. These C (max) were between 13 (+/-51%) and 290 (+/-12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUC(t0-20), was between 5.5 (+/-43%) and 200 (+/-66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P < 0.01 for C (max) and AUC(t0-20), both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P < 0.05) was found between systemic C (max) of gemcitabine and the nadir of both leucocytes and neutrophils. CONCLUSIONS: Regional exposure to gemcitabine-the current standard drug for advanced adenocarcinoma of the pancreas-can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125 mg/m(2). However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherapy.

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.

BACKGROUND: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. METHODS: Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789. FINDINGS: 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23 100 copies per mL Vacc-4x vs 71 800 copies per mL placebo; p=0·025) and week 52 (median 19 550 copies per mL vs 51 000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. INTERPRETATION: The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. FUNDING: Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.

Field Evaluation of Compaction Monitoring Technology: Phase II Volumes 1 and 2, TR-495, 2006

This report documents an extensive field program carried out to identify the relationships between soil engineering properties, as measured by various in situ devices, and the results of machine compaction monitoring using prototype compaction monitoring technology developed by Caterpillar Inc. Primary research tasks for this study include the following: (1) experimental testing and statistical analyses to evaluate machine power in terms of the engineering properties of the compacted soil (e.g., density, strength, stiffness) and (2) recommendations for using the compaction monitoring technology in practice. The compaction monitoring technology includes sensors that monitor the power consumption used to move the compaction machine, an on-board computer and display screen, and a GPS system to map the spatial location of the machine. In situ soil density, strength, and stiffness data characterized the soil at various stages of compaction. For each test strip or test area, in situ soil properties were compared directly to machine power values to establish statistical relationships. Statistical models were developed to predict soil density, strength, and stiffness from the machine power values. Field data for multiple test strips were evaluated. The R2 correlation coefficient was generally used to assess the quality of the regressions. Strong correlations were observed between averaged machine power and field measurement data. The relationships are based on the compaction model derived from laboratory data. Correlation coefficients (R2) were consistently higher for thicker lifts than for thin lifts, indicating that the depth influencing machine power response exceeds the representative lift thickness encountered under field conditions. Caterpillar Inc. compaction monitoring technology also identified localized areas of an earthwork project with weak or poorly compacted soil. The soil properties at these locations were verified using in situ test devices. This report also documents the steps required to implement the compaction monitoring technology evaluated.

Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06).

BACKGROUND: Pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients. METHODS: Bevacizumab (10 mg/kg) and PLD (20 mg/m(2)) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination. RESULTS: Thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%. CONCLUSIONS: In this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this setting.

Freeze-Thaw Durability of Concretes with Infilling of Ettringite in Voids, Phase 2, MLR-94-9, 1997

Examination of field portland cement concrete cores, from Iowa pavements with premature deterioration, reveals extensive infilling of calcium sulfate aluminum (CSA) compound in their air voids. A previous study (Phase I) has shown some evidence of the correlation between freeze-thaw durability of concretes and ettringite infilling. To further verify the previous observation, a more extensive experimental program was conducted in this Phase 2 study. A total of 101 concrete mixes were examined. Seven cements, six fly ashes, two water reducers and three coarse aggregates were used in the concrete mixes. Specimens were under moist curing for up to 223 days before being subjected to the freeze-thaw cycling. An environmental treatment consisting of three consecutive wet [70 deg F (21 deg C) in distilled water]/dry [120 deg F (49 deg C) in oven] cycles was applied to some specimens. Immediately prior to the freeze-thaw cycling, most specimens were examined by a low-vacuum scanning electron microscope (SEM) for their microstructure. The results obtained further demonstrate the correlation between concrete freeze-thaw response and CSA compound infilling in the air voids. The extent of the infilling depends on the period of moist curing as well as the wet/dry treatment. The extent of the infilling also relates to materials used. Concrete mixes with extensive infilling are more vulnerable to the freeze-thaw attack. Based on the obtained results, material criteria on cements and fly ashes for mainline paving were proposed for minimizing potential infilling of CSA compound in concrete.