Search

Background. Primary central nervous system lymphoma (PCNSL) is a rare and biologically distinct subset of non-Hodgkin lymphoma. Due to its low incidence, optimal treatment strategies remain uncertain and are currently based upon outcomes from retrospective series and small phase-II studies. In addition to improving survival outcomes in systemic B cell lymphomas, rituximab penetrates the CSF after intravenous administration and also reduces CNS relapse in high-risk systemic DLBCL. However its role in PCNSL remains uncertain. We report the results of a retrospective study examining the impact of rituximab, methotrexate, cytarabine and radiotherapy in patients managed with curative intent at four university teaching hospitals between 1996-2011. Methods. A retrospective study of consecutive cases of PCNSL treated at the participating institutions was performed in accordance with institutional ethical guidelines. Patients were included if they were HIV negative and had a first presentation of biopsy-proven primary CNS lymphoma or intravascular large B cell lymphoma according to WHO 2008 criteria. Patients were excluded if they were HIV positive or not treated with curative intent. Survival correlates were assessed by Cox regression using SPSS. Results. Of 164 patients, 30 were treated with palliative intent; 134 patients met the criteria for the study. The median age was 65 years (range 21-81), 49% male. At diagnosis, 31% had an ECOG performance status (PS) >1 and 43% an elevated serum lactate dehydrogenase (LD). Deep lesions, multiple lesions and cytology positive CSF involvement were found in 63%, 52% and 14% respectively. There was no difference in base-line characteristics between rituximab recipients and non-recipients. Histological diagnosis was DLBCL (122), T cell lymphoma (4), low-grade B cell lymphoma (1), indeterminate (3) and intravascular large B cell lymphoma (4).Chemotherapy regimens included single agent high-dose methotrexate (HD-MTX, >=2g/m2; n=83), comb

Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assign

Background. The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. Methods. This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). Results. One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P =. 66). ORR was 14% (combination) versus 6% (monotherapy) (P =. 18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P =. 38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. Conclusions. Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.Copyright © 2015 The Author(s) 2015.

Background: Effective treatment options are needed for patients with genotype 1 or 3 hepatitis C virus (HCV) infection in whom previous therapy has failed. Objective(s): To assess the efficacy and safety of sofosbuvir plus velpatasvir, with and without ribavirin, in treatment-experienced patients. Design(s): Randomized, phase 2, open-label study. (ClinicalTrials .gov: NCT01909804) Setting: 58 sites in Australia, New Zealand, and the United States. Patient(s): Treatment-experienced adults with genotype 3 HCV infection without cirrhosis (cohort 1) and with compensated cirrhosis (cohort 2) and patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor with peginterferon and ribavirin (50% could have compensated cirrhosis) (cohort 3). Intervention(s): All patients received 12 weeks of treatment that included 400 mg of sofosbuvir once daily. Patients in each cohort were randomly assigned to 25 mg of velpatasvir once daily with or without ribavirin or 100 mg of velpatasvir once daily with or without ribavirin. Measurements: Proportion of patients with sustained virologic response at week 12 after treatment (SVR12). Result(s): In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea. Limitation(s): Treatment assignments were not blinded, and no inferential statistics were planned. Conclusion(s): Treatment with 400 mg of sofosbuvir plus 100 mg of velpatasvir for 12

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. Design In this Phase 2b double-blind, placebocontrolled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferonalfa: 2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCVRNA< lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa: 2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1

Introduction: GS-5816 is a pangenotypic HCV NS5A inhibitor. In Phase 2 studies, the combination of sofosbuvir (SOF) and GS-5816 for 12 weeks demonstrated high efficacy in patients with genotype 3 HCV. This Phase 3 study compared treatment with a fixed dose combination (FDC) of SOF/GS-5816 for 12 weeks to standard of care, SOF+RBV for 24 weeks, in patients with genotype 3 HCV. Method(s): Patients at 75 sites in North America, Europe, Australia and New Zealand were randomized 1:1 to received SOF/GS-5816 (400 mg /100 mg daily) FDC for 12 weeks or SOF (400mg daily) with RBV (1000-1200mg daily) for 24 weeks. HCV RNA was measured with the CAP/CTM HCV 2.0 assay with LLOQ =15 IU/mL The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12) with a pre-specified non-inferiority margin of 10%. Result(s): Of 552 patients randomized and treated, 62% were male, 89% were white, 39% had IL28B CC genotype, 26% had prior treatment failure, and 30% had cirrhosis. Eight patients discontinued treatment due to adverse events, all of which were in the SOF +RBV treatment group. The most common AEs (>10% in either treatment group) are presented below. Five patients in the SOF/GS-5816 treatment group and 8 patients in the SOF+RBV treatment group experienced SAEs. One SAE, acute generalized exanthematous pustulosis, in a SOF+RBV treated patient was assessed as related to study drugs by the investigator. Hemoglobin decline and total bilirubin increases were more commonly observed in the group treated with SOF +RBV consistent with RBV-induced hemolysis. No other significant lab abnormalities were observed. HCV RNA declined rapidly in both treatment groups with 92% and 88% of patients achieving HCV RNA < LLOQ after 4 weeks of treatment in the SOF/GS-5816 and SOF+RBV treatment groups, respectively. SVR12 data for all patients will be presented. Conclusion(s): The once daily, all-oral, single tablet regimen of SOF/GS-5816 was well tolerated in treatment-naive and treatm

The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 x 109/l and <=50 x 109/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 x 109/l) or partial response (PR; platelet count >50 x 109/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 x 109/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m2 four-dose schedule in relapsed/chronic ITP.Copyright © 2014 John Wiley & Sons Ltd.

Background: Recent pancreatic cancer (PC) series show 41% (95%CI 40-43%) of patients (pts) achieve an R0 resection (margin clearance 1mm). In neoadjuvant chemotherapy trials for resectable PC, only 5489% undergo pancreatic resection with R0 rates of 7480%. Nabpaclitaxel( nabpacli) and gemcitabine(GEM) chemotherapy(CX) is an active regimen in metastatic disease. We aimed to determine feasibility and R0 resection rate of 85% with perioperative nabpacli and GEM for resectable PC. Method(s): Pts with operable PC received 2 cycles of neoadjuvant nabpacli 125mg/m2 followed by GEM 1000mg/m2CX on days(D) 1, 8 and 15(28D cycle) followed by resection and then postoperative CX(4 cycles). Result(s): Fortyone pts were enrolled (201214). Median age = 65 (range 4379), 41% male. Thirtysix (88%) pts underwent surgery, while five (12%) did not (2 disease progression, 2 refused surgery, 1 cholangitis). Only 4/36 (10%) had grade septic events, no grade pancreatic leak, and no treatment related deaths. Thirty pts had pancreatic resection (73%; 29 had evaluable cancer and 15/29 (52%) had grade 02 tumour regression; one did not have cancer on central pathology review). Six (15%) pts had unresectable disease at surgery. Preoperative nabpacli and GEM produced an R0 rate of 52% (15/29; 95%CI 34-69%) with a minimum 1mm margin and an R0 rate of 86% (25/29; 95%CI 68-96%) with a 0mm margin. 39/41 (95%) completed planned induction CX (although dose modifications/omission were required mostly omission of D15). Postoperatively, eighteen pts (18/30, 60%) commenced CX, with 14/18 (78%) completing all 4 cycles of planned CX; whilst four pts commenced chemoradiation, but 2 withdrew due to disease progression. Conclusion(s): Preoperative nabpacli and GEM was delivered safely and achieved an R0 resection rate clinically significantly higher than the mean of surgical series using similar pathology criteria. Our preoperative regimen was delivered to 95% of patients, but in contrast postoperative CX was les

INTRODUCTION: High levels of oxidative stress can have considerable impact on the outcomes of in vitro fertilisation (IVF). Recent studies have reported that melatonin, a neurohormone secreted from the pineal gland in response to darkness, has significant antioxidative capabilities which may protect against the oxidative stress of infertility treatment on gametes and embryos. Early studies of oral melatonin (3-4 mg/day) in IVF have suggested favourable outcomes. However, most trials were poorly designed and none have addressed the optimum dose of melatonin. We present a proposal for a pilot double-blind randomised placebo-controlled dose-response trial aimed to determine whether oral melatonin supplementation during ovarian stimulation can improve the outcomes of assisted reproductive technology. METHODS AND ANALYSES: We will recruit 160 infertile women into one of four groups: placebo (n=40); melatonin 2 mg twice per day (n=40); melatonin 4 mg twice per day (n=40) and melatonin 8 mg twice per day (n=40). The primary outcome will be clinical pregnancy rate. Secondary clinical outcomes include oocyte number/quality, embryo number/quality and fertilisation rate. We will also measure serum melatonin and the oxidative stress marker, 8-hydroxy-2'-deoxyguanosine at baseline and after treatment and levels of these in follicular fluid at egg pick-up. We will investigate follicular blood flow with Doppler ultrasound, patient sleepiness scores and pregnancy complications, comparing outcomes between groups. This protocol has been designed in accordance with the SPIRIT 2013 Guidelines. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Monash Health HREC (Ref: 13402B), Monash University HREC (Ref: CF14/523-2014000181) and Monash Surgical Private Hospital HREC (Ref: 14107). Data analysis, interpretation and conclusions will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12613001317785

Background: Recent pancreatic cancer (PC) series show 41% (95%CI 40-43%) of patients (pts) achieve an R0 resection (margin clearance 1mm). In neoadjuvant chemotherapy trials for resectable PC, only 54-89% undergo pancreatic resection with R0 rates of 74- 80%. Nab-paclitaxel(nab-pacli) and gemcitabine(GEM) chemotherapy(CX) is an active regimen in metastatic disease. We aimed to determine feasibility and R0 resection rate of 85% with peri-operative nab-pacli and GEM for resectable PC. Method(s): Pts with operable PC received 2 cycles of neo-adjuvant nab-pacli 125mg/m2 followed by GEM 1000mg/m2CX on days(D) 1, 8 and 15(28D cycle) followed by resection and then post- operative CX(4 cycles). Result(s): Forty-one pts were enrolled (2012-14). Median age = 65 (range 43-79), 41% male. Thirty-six (88%) pts underwent surgery, while five (12%) did not (2 disease progression, 2 refused surgery, 1 cholangitis). Only 4/36 (10%) had grade septic events, no grade pancreatic leak, and no treatment related deaths. Thirty pts had pancreatic resection (73%; 29 had evaluable cancer and 15/29 (52%) had grade 0-2 tumour regression; one did not have cancer on central pathology review). Six (15%) pts had unresectable disease at surgery. Pre-operative nab-pacli and GEM produced an R0 rate of 52% (15/29; 95%CI 34-69%) with a minimum 1mm margin and an R0 rate of 86% (25/29; 95%CI 68-96%) with a 0mm margin. 39/41 (95%) completed planned induction CX (although dose modifications/omission were required - mostly omission of D15). Post- operatively, eighteen pts (18/30, 60%) commenced CX, with 14/18 (78%) completing all 4 cycles of planned CX; whilst four pts commenced chemoradiation, but 2 withdrew due to disease progression. Conclusion(s): Pre-operative nab-pacli and GEM was delivered safely and achieved an R0 resection rate clinically significantly higher than the mean of surgical series using similar pathology criteria. Our pre-operative regimen was delivered to 95% of patients, but in contrast

Background: The all-oral combination of daclatasvir (DCV; pangenotypic NS5A inhibitor), asunaprevir (ASV; NS3 protease inhibitor), and beclabuvir (BCV; non-nucleoside NS5B inhibitor) achieved high rates of SVR12 in a phase 2 clinical trial. This regimen, in a twice-daily fixed-dose combination tablet-DCV-TRIO regimen-was evaluated without ribavirin in HCV genotype (GT) 1-infected treatment-naive and -experienced patients without cirrhosis in a phase 3, open-label, international clinical trial. Method(s): All patients received 12 weeks of treatment with the fixed-dose combination of DCV 30 mg, ASV 200 mg, and BCV 75 mg twice daily. Key efficacy outcomes were SVR12 rates in the treatment-naive and -experienced cohorts, assessed separately. Result(s): Baseline characteristics in the treatment-naive (N=312) and treatment-experienced (N=103) cohorts were comparable. Overall, patients were 58% male and 26% IL28B (rs1297860) CC genotype; 73% were infected with GT 1a and 27% with GT 1b. SVR12 was achieved by 92% and 89% of treatment-naive and -experienced patients, respectively. 17 patients with GT1b infection had NS5A resistance-associated variants (RAVs) at baseline; all 17 achieved SVR12. 25 of the 34 GT1a-infected patients with baseline NS5A RAVs achieved SVR12. Overall, 34 (8%) patients experienced virologic failure, including 21 with posttreatment relapse and 13 with on-treatment virologic failure. Among patients with GT1a infection who experienced failure, RAVs at positions NS5A-Q30, NS3-R155 and/or NS5B-P495 were the most frequently observed variants. One death occurred posttreatment and was considered not related to study treatment. There were 7 serious adverse events, all unrelated, and 3 (<1%) adverse events leading to treatment discontinuation. Adverse events (any grade) that were observed in >10% of patients included headache, fatigue, diarrhea, and nausea. Conclusion(s): Twelve weeks of all-oral treatment with the fixed-dose combination of DCV, ASV, and BCV ac

Background: Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. Method(s): This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (>=36 weeks gestation) babies, who weighed at least 2500 g, and were 0-5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. Finding(s): 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0.78, 95% CI 0.55-0.88; p<0.0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0.68, 0.44-0.81; p<0.0001). A serum IgA re

Bendamustine is a bifunctional alkylating agent with proven activity in myeloma. In this study 60 newly diagnosed myeloma patients were given bendamustine plus bortezomib and prednisone in a regimen consisting of one cycle of bortezomib twice weekly for 6 weeks (1.3 mg/m(2) on days 1, 4, 8, 11, 22, 25, 29, and 32), plus bendamustine (90 mg/m(2) on days 1 and 4) and prednisone. The following cycles included bortezomib once weekly. Patients who were transplant candidates proceeded to stem cell collection after four cycles and the transplant was performed after six cycles. Patients who were not candidates for transplantation received up to nine cycles. Forty-two patients were transplant candidates and after six cycles, 50% achieved at least a very good partial response, with 24% having complete responses; 35 proceeded to a transplant, and the complete response rate was 54%. Seventeen patients continued up to nine cycles, and 57% achieved at least a very good partial response, including 26% with complete responses. The 2-year progression-free survival and overall survival rates were 62% and 86%, respectively. The safety profile was manageable, but stem cell mobilization was compromised in 35% of patients. In summary, this combination is effective in untreated patients, with an acceptable toxicity profile, but given the introduction of second-generation novel agents and monoclonal antibodies, the combination will probably be better reserved for relapsing patients, in whom stem cell collection is not needed, while cost-effective combinations with non-cross-resistant drugs continue to represent a medical need. This trial was registered with ClinicalTrials.gov, number NCT01376401. Copyright© Ferrata Storti Foundation.

Summary: Lumiliximab is a chimeric monoclonal antibody that targets CD23 on the surface of chronic lymphocytic leukaemia (CLL) B-cells. Early phase clinical studies with lumiliximab alone and in combination with fludarabine, cyclophosphamide and rituximab (FCR) established its potential efficacy and tolerability. The 152CL201 trial [Lumiliximab with fludarabine, cyclophosphamide and rituximab (FCR) versus FCR alone in subjects with relapsed CLL; LUCID] was a phase 2/3, randomized (1:1), open-label, multicentre study of lumiliximab in combination with FCR versus FCR alone in patients with relapsed CLL. Six hundred and twenty-seven patients were randomized to either arm. Overall the combination of lumiliximab with FCR was not significantly better than FCR alone (overall response rate 71% vs. 72%, complete response rate 16% vs. 15%, median progression-free survival 24.6 vs. 23.9 months respectively, for FCR with and without lumiliximab). There was a slightly increased incidence of adverse events with lumiliximab but these increases did not appear to lead to differences in eventual outcomes. An interim analysis failed to show sufficient efficacy of the combination of lumiliximab with FCR. The study was therefore stopped early for lack of efficacy. Despite the eventual outcome, the LUCID trial is one of the largest studies that provides valuable insight into the efficacy and tolerability of FCR as a therapeutic option for patients with relapsed CLL.Copyright © 2014 John Wiley & Sons Ltd.

It is essential to identify intermediate marker endpoints of carcinogenesis for the evaluation of the effectiveness of cancer-chemopreventive agents. We have observed that levels of proteolytic activities (as detected by 4 different substrates) are increased 2-3-fold (P < 0.003) in oral buccal mucosa cells of smokers and patients with oral leukoplakia or erythroplakia as compared to a nonsmoking comparison group. In addition, proteolytic activity levels in the buccal cells were increased nearly 3-fold in patients with oral trauma (P < 0.01) or diabetes (P < 0.02), as well as pregnant women (P < 0.04). Excluding these subgroups of patients in epidemiological studies increase the differences in levels of proteolytic activities between both the nonsmoking comparison group and smokers and between the comparison group and patients with oral leukoplakia or erythroplakia. Evaluation of prerandomization levels of proteolytic activities of patients in cancer chemoprevention trials will increase the statistical power by allowing stratified randomization based on levels of proteolytic activities. The observed increases in levels of proteolytic activities in tissues at higher than normal risk of cancer development suggest that levels of proteolytic activities should be used as immediate marker endpoints in human cancer prevention trials using protease inhibitors as potential anticarcinogenic agents.

Background and Hypothesis: Thrombolysis with tissue plasminogen activator is proven to reduce disability when given within 4.5h of ischemic stroke onset. However, tissue plasminogen activator only succeeds in recanalizing large vessel arterial occlusion in a minority of patients. We hypothesized that anterior circulation ischemic stroke patients, selected with 'dual target' vessel occlusion and evidence of salvageable brain using computed tomography or magnetic resonance imaging 'mismatch' within 4.5h of onset, would have improved reperfusion and early neurological improvement when treated with intra-arterial clot retrieval after intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone. Study Design: EXTEND-IA is an investigator-initiated, phase II, multicenter prospective, randomized, open-label, blinded-endpoint study. Ischemic stroke patients receiving standard 0.9mg/kg intravenous tissue plasminogen activator within 4.5h of stroke onset who have good prestroke functional status (modified Rankin Scale <2, no upper age limit) will undergo multimodal computed tomography or magnetic resonance imaging. Patients who also meet dual target imaging criteria: vessel occlusion (internal carotid or middle cerebral artery) and mismatch (perfusion lesion:ischemic core mismatch ratio >1.2, absolute mismatch >10ml, ischemic core volume <70ml) will be randomized to either clot retrieval with the Solitaire FR device after full dose intravenous tissue plasminogen activator, or tissue plasminogen activator alone. Study Outcomes: The coprimary outcome measure will be reperfusion at 24h and favorable clinical response (reduction in National Institutes of Health Stroke Scale by >=8 points or reaching 0-1) at day 3. Secondary outcomes include modified Rankin Scale at day 90, death, and symptomatic intracranial hemorrhage. © 2013 World Stroke Organization.

Background: Gynaecological cancers of several pathological subtypes express estrogen and/or progesterone hormone receptors (ER/PR). Previous studies, [all or mostly] retrospective, have reported variable rates of tumour response and clinical benefit. Prospective studies are needed to determine the activity of aromatase inhibitors in women with potentially hormone responsive recurrent gynaecological cancers, and to determine possible predictors of response. Method(s): PARAGON is a Gynecologic Cancer InterGroup phase 2 trial lead by the Australia New Zealand Gynaecological Oncology Group and NHMRC Clinical Trials Centre, in collaboration with Cancer Research UK and the Belgian Gynaecological Oncology Group. The study is designed to facilitate research in rare tumours. The protocol enrols postmenopausal women with recurrent gynaecological cancers of 7 different subtypes: epithelial ovarian cancer (EOC) with only rising CA125 after first line chemotherapy; platinum resistant/refractory EOC; low grade EOC; endometrial carcinomas; endometrial stromal sarcomas; miscellaneous sarcomas; and, granulosa cell and other sex cord stromal tumours. ER/PR positivity must be demonstrated by immunohistochemistry. Each subgroup will enrol 25-50 patients with defined stopping rules based on response and reviewed by an independent data monitoring committee (IDMC). Study treatment is anastrozole 1 mg daily until disease progression or unacceptable toxicity. The primary endpoint is clinical benefit (complete response, partial response, or stable disease at x months). Secondary endpoints include progression free survival, response duration, aspects of QoL, toxicity. Blood and tumour samples are being collected for translational studies and confirmation of ER/PR positivity. Recruitment commenced in 2011 in Australia, New Zealand and the United Kingdom. 236 of 350 planned patients have been enrolled to February 2014. Accrual to the platinum resistant/refractory subgroup closed on 9 December 2

Purpose/Objective(s): The 5-fluorouracil (5-FU) chemotherapy dose used during chemoradiation for locally advanced rectal cancer is adequate for radiosensitization but suboptimal for possible micrometastatic disease. The aim of this study was to determine the tolerability rate, dose intensity, complete pathologic response rate, and toxicity rates of a novel preoperative regimen of split-course chemoradiation with interdigitating chemotherapy in the setting of a multi-center study. This trial was performed under the auspices of the Trans-Tasman Radiation Oncology Group. Materials/Methods: Eligible patients for this study were those with MRIstaged T3-4 Nany M0 adenocarcinoma of the rectum. The preoperative treatment regimen consisted of FOLFOX chemotherapy (oxaliplatin 100 mg/m2 day 1, 5-FU 400 mg/m2 bolus day 1, leucovorin 200 mg/m2 day 1, then continuous infusion 2.4 g/m2 over 46 hours) given in week 1, 6, and 11 with split-course pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fx with concurrent oxaliplatin 85 mg/m2 day 1, and 5-FU continuous infusion 200 mg/m2/day) given in week 3-5, and week 8-10. Surgery was to be performed 4 to 6 weeks later. In total, patients received, in 11 weeks, 3 courses of FOLFOX and pelvic radiation 50.4 Gy with concurrent oxaliplatin and 5-FU. Result(s): Forty-one patients were recruited with 40 analyzable patients. The median age was 61.5 (range 29-77) years. Seventy-two percent were men. MRI-stage of the rectal primary was T3 88% and T4 12%. N-stage was N0 20%, N1 52%, N2 28%. Thirty-eight patients (95%) reached week eleven of the treatment (80% CI = [87% - 99%]). All patients received the planned radiation dose of 50.4 Gy. Relative dose intensity of >= 75% was achieved by 92% and 98% of patients for oxaliplatin and 5-FU respectively. During the preoperative protocol therapy period, grade 3 toxicity included neutropenia 25%, diarrhea 10%, ALT 10%, fatigue 5%, proctitis 5%, and urinary frequency 5%. All grade 4 toxicities were neutro

Introduction: The combination of sofosbuvir (SOF) and GS-5816 for 12 weeks has demonstrated high efficacy in treatment naive patients without cirrhosis with chronic genotype 1-6 HCV infection. This Phase 2 study evaluated SOF + GS-5816 +/- RBV for 12 weeks in treatment experienced patients with genotype 1 or 3 HCV infection with or without cirrhosis. Method(s): Three cohorts of treatment experienced patients were evaluated: patients with genotype 3 HCV infection without cirrhosis, patients with genotype 3 HCV infection with cirrhosis, and patients with genotype 1 HCV infection with and without cirrhosis who had failed treatment with a protease-inhibitor containing regimen. Within each cohort, patients were randomized 1:1:1:1 to SOF+GS-5816 25mg, SOF+GS-5816 25mg+RBV, SOF+GS-5816 100mg or SOF+GS-5816 100 mg+RBV. The SOF dose was 400 mg. Ribavirin was administered 1000-1200mg in a divided daily dose. Result(s): 321 patients were randomized and treated; 65% had genotype 3 HCV infection, 69% were male, 89% were white, 27% had IL28B CC genotype and 43% had cirrhosis. The SVR12 rates in treatment experienced genotype 3 infected patients with and without cirrhosis administered SOF +GS-5816 100mg were 88% and 100%, respectively. The SVR12 rate was 100% in genotype 1 HCV infected patients administered SOF +GS-5816 100mg. Relapse accounted for all virologic failures. The most frequently reported adverse events (> 10%) in patients were fatigue, headache, nausea and insomnia. Patients administered RBV containing regimens also commonly reported pruritus and rash. One patient discontinued treatment with SOF +GS-5816 25mg +RBV after 81 days of treatment due to elevated ALT and GGT. Nine patients reported 10 SAEs; none were considered related to study treatment. Anemia was only observed in patients receiving RBV. Conclusion(s): High SVR12 rates were achieved in treatment experienced patients with genotype 1 or genotype 3 HCV infection administered SOF +GS-5816 100 mg for 12 weeks.

No large prospective trial of bortezomib (Btz)/dexamethasone (Dex) from cycle (C) 1 in relapsed (r) multiple myeloma (MM) has been published, despite common use and data showing that adding Dex to Btz in patients (pts) with SD or PD improves overall response (OR). While Btz maintenance (mnt) improves time to progression (TTP) in untreated pts, there is limited data in rMM. 20 sites enrolled 100 rMM pts (Karnofsky>=60, platelets>=50?109/L and eGFR>=20mL/min) requiring 2nd line therapy (or 3rd line if prior thalidomide (Thal) and/or Dex monotherapy) in a Phase 2 study of IV Btz (1.3mg/m2; Day (D)1,4,8+11) plus PO Dex (20mg; D1,2,4,5,8,9,11+12) for stable disease received Btz (1.3mg/m2;D1) and Dex (20mg;D1,2) q14d until progression. 35/100 pts completed at least 1 C of mnt. A prospectively defined matched analysis of the 1o endpoint OR and 2o endpoints (Complete Response (CR) and TTP) with the Btz-only arm of APEX was performed. The algorithm matched 90 BoMeR and APEX pts for prior (P) Dex, P Thal, time since last therapy, P transplant, and # of P regimens. Toxicity during induction was similar to APEX (Harrison, ASCO 2010). OR by EBMT criteria (CR, PR, MR) was 62% BoMeR vs 42% APEX (odds ratio (OdR) 0.44 (0.244-0.806)), >PR 56% BoMeR vs 36% APEX (OdR 0.44 (0.242- 0.804)), with >50% (100%) reduction in M-protein in 76% (30%) of BoMeR vs 51% (18%) APEX pts (n=67). The median TTP was signifi- cantly longer in BoMeR (300 days) vs. APEX (154 days) (p<0.001). The BoMeR protocol significantly improved OR, M-protein reduction and TTP for rMM pts vs APEX.

Background: AMG 386, an investigational peptide-Fc fusion protein, inhibits angiogenesis by preventing the interaction of angiopoietin-1 and -2 with their receptor, Tie2. This study estimated the efficacy and assessed the safety of AMG 386 plus FOLFIRI in patients with mCRC. Method(s): Eligible patients (>=18 years) had adenocarcinoma of the colon or rectum with progression within 6 months of having received 1 prior 5-FU- and oxaliplatin-based chemotherapy regimen for metastatic disease, ECOG status 0-1, and >=1 measurable lesion per RECIST. Patients were randomized 2:1 to receive FOLFIRI IV Q2W plus either (Arm A) AMG 386 10 mg/kg IV QW or (Arm B) placebo IV QW. Randomization was stratified by ECOG performance status (0 vs 1). The study was designed to estimate the treatment effect as measured by investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) per RECIST, adverse events (AEs), and pharmacokinetics (PK). Result(s): 144 patients were randomized (Arms A/B, N=95/49). The median PFS (80% CI) in Arms A and B was 3.5 (2.9-4.2) and 5.2 (3.8-5.5) months, respectively. Based on a Cox regression model stratified by ECOG status, the hazard ratio (HR) (80% CI) for Arm A vs B was 1.23 (0.94-1.61; P=0.33). In Arms A/B (n=84/45; 16 patients were too early to evaluate for response), the ORR (80% CI) was 14% (10-20) in Arm A and 0% (0-5) in Arm B. Median Cmax and Cmin values of AMG 386 at steady state following coadministration with FOLFIRI were generally similar to those reported for AMG 386 monotherapy. Coadministration of FOLFIRI with AMG 386 did not affect the PK of AMG 386. Based on sparse PK sampling the SN-38 and 5-FU exposures were approximately 50% lower with AMG 386 coadministration. The incidence of AEs was similar between treatment arms. Most frequent AEs included diarrhea (Arm A/B, 47/ 41%; grade >=3, 4/0%), nausea (44/37%; grade >=3, 0/2%), neutropenia (41/57%; grade >=3, 31/41%), asthenia (31/33%; grade

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention.

Background: This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer. Method(s): Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2: 1 to also receive intravenous trebananib 10 mg kg-1 once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS). Result(s): One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade >=3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%). Conclusion(s): Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib. © 2013 Cancer Research UK. All rights reserved.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNalpha-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNalpha-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 mug q4wk or Peg-IFNalpha-2a 180 mug qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (<=yen;15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNalpha-2a and albIFN 1500 mug; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNalpha-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNalpha/ribavirin therapy and commonly persisted for <=yen;6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research. © 2013 Blackwell Publishing Ltd.

Background and Purpose-: Two phase 2 studies of alteplase in acute ischemic stroke 3 to 6 hours after onset, Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET; a randomized, controlled, double-blinded trial), and Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study (DEFUSE; open-label, treatment only) using MR imaging-based outcomes have been conducted. We have pooled individual patient data from these to assess the response to alteplase. The primary hypothesis was that alteplase would significantly attenuate infarct growth compared with placebo in mismatch-selected patients using coregistration techniques. Methods-: The EPITHET-DEFUSE study datasets were pooled while retaining the original inclusion and exclusion criteria. Significant hypoperfusion was defined as a Tmax delay >6 seconds), and coregistration techniques were used to define MR diffusion-weighted imaging/perfusion-weighted imaging mismatch. Neuroimaging, parameters including reperfusion, recanalization, symptomatic intracerebral hemorrhage, and clinical outcomes were assessed. Alteplase and placebo groups were compared for the primary outcome of infarct growth as well for secondary outcome measures. Results-: From 165 patients with adequate MR scans in the EPITHET-DEFUSE pooled data, 121 patients (73.3%) were found to have mismatch. For the primary outcome analysis, 60 patients received alteplase and 41 placebo. Mismatch patients receiving alteplase had significantly attenuated infarct growth compared with placebo (P=0.025). The reperfusion rate was also increased (62.7% vs 31.7%; P=0.003). Mortality and clinical outcomes were not different between groups. Conclusions-: The data provide further evidence that alteplase significantly attenuates infarct growth and increases reperfusion compared with placebo in the 3-to 6-hour time window in patients selected based on MR penumbral imaging. Clinical Trial Registration-: URL: http://www.clinicaltrials. gov. Unique ident

Background:Cetuximab can reverse chemotherapy resistance in colorectal cancer. This study evaluated the efficacy and safety of the combination of docetaxel and cetuximab as a second-line treatment in docetaxel-refractory oesophagogastric cancer. Method(s):Patients received docetaxel 30 mg m-2 on days 1 and 8, every 3 weeks and cetuximab 400 mg m-2 on day 1, then 250 mg m-2 weekly. Biomarker mutation analysis was performed. Result(s):A total of 38 patients were enrolled. Response rates were PR 6% (95% CI 2-19%), s.d. 43% (95% CI 28-59%). Main grade 3/4 toxicities were febrile neutropenia, anorexia, nausea, diarrhoea, stomatitis, and acneiform rash. Median progression-free and overall survival were 2.1 and 5.4 months, respectively. A landmark analysis showed a trend to improved survival times with increased grade of acneiform rash. No KRAS, BRAF or PIK3CA mutations were observed. Conclusion(s):Cetuximab and docetaxel achieve modest responses rates, but maintain comparable survival times to other salvage regimens with low rates of toxicity. © 2013 Cancer Research UK.

Background Dysregulation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway signaling has been implicated in the pathogenesis of lymphoma. SAR245409 is a potent inhibitor of class I PI3K isoforms (alpha, beta, gamma and delta) and also inhibits mTORC1 and TORC2. In the phase 1 dose-expansion cohort of study TED11440 (NCT00485719), SAR245409 showed promise in several lymphoma subtypes: 1 complete response (CR) in a transformed lymphoma and 2 partial response (PR) [1 diffuse large B cell lymphoma (DLBCL) and 1 mantle cell lymphoma (MCL) and 3 patients with stable disease (SD) longer than 3 months [1 follicular lymphoma (FL), 1 MCL and 1 Hodgkin Lymphoma (Papadopoulos et al. ASH 2011). The Sanofi sponsored study ARD12130 (NCT01403636) is an ongoing multicenter, multinational, open-label, phase 2 study of SAR245409 in patients with lymphoproliferative malignancies enrolling on 4-arms: FL, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), MCL and DLBCL. Preliminary Stage 1 results from FL patients (pts) are reported. Methods Eligible pts for the FL arm had relapsed or refractory FL (Grade 1, 2, or 3a) with no clinical suspicion of transformation to an aggressive subtype and who had received >=2 but <= 6 prior chemotherapy regimens. Pts were treated with SAR245409 at 50 mg twice daily orally until disease progression or withdrawal for other reasons including toxicity. Tumor response was based on modified International Working Group response criteria. A Simon 2-stage design was used to evaluate the primary efficacy endpoint of objective response rate (ORR) in the FL arm; if at least 6 of the first 24 evaluable patients in Stage 1 achieved an objective response (OR), the study would continue to Stage 2 with a total of 45 evaluable patients. If 14 or greater total patients among the 45 total evaluable achieved OR, the null hypothesis would be rejected. Results Twenty-eight FL patients were enrolled to stage 1. Median age was

Background: This randomized phase II study evaluated the efficacy and safety of P, a fully human mAb against the epidermal growth factor receptor combined with T-based chemotherapy in advanced OG cancer. Method(s): Eligible pts had histologically confirmed metastatic OG cancer (adeno-carcinoma and squamous cell carcinoma) were 18 years of age, PS 0-2, with adequate renal, haematologic and liver function with measurable disease. All pts provided informed consent. Selection was not based on kras determination. Pts received T 30mg/m2 d1,8, C 60mg/m2 d1 and F; investigator choice of 5FU infusion 160mg/m2/d or capecitabine 500mg/m2bd continuous +/-P 9 mg/kg d1 q3w. Treatment was administered for 8 cycles or until PD. The primary endpoint was response rate according to RECIST (1.1) assessed q6w. Planned enrolment target was 100 pts. Stratification variables included histology, PS and choice of F. Result(s): From April 2010 to November 2011, 77 pts were enrolled from 15 institutions. A safety alert from the REAL3 study (also involving P in OG cancer) prompted an unplanned review of data from ATTAX3 by the IDMC. The IDMC found no evidence of adverse outcomes associated with P, but as it did not appear that P would significantly improve efficacy, they recommended cessation of the study to new enrolment. Previously enrolled pts were treated and followed according to protocol. Median follow up is 24m. Treatment arms were well balanced; median age 59, 64y, male 77%, 87%, PS0-1 95%,90%, adenocarcinoma 90%,90%, capecitabine 67%, 66% for TCF/TCF-P, respectively. Common grade 3/4 toxicities include infection 18%,24%, febrile neutropenia 10%, 5%, anorexia 10%, 24%, nausea 18%,30%, stomatitis 3%,5%, diarrhoea 15%,24% , acneiform rash 0%, 8%, fatigue 18%, 30%, hypomagnesemia 10%, 16% for TCF/TCF-P. Efficacy outcomes are summarized in Table. Conclusion(s): The addition of P to T-based chemotherapy in advanced OG cancer did not improve efficacy and was associated with an increase in som