Fuchs C.S.,Dana-Farber Cancer Institute |
Tomasek J.,Masaryk Memorial Cancer Institute |
Yong C.J.,Yonsei University |
Dumitru F.,Emergency County Hospital Dr Constantin Opris |
And 21 more authors.
The Lancet | Year: 2014
Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.
Lessene G.,Walter and Eliza Hall Institute of Medical Research |
Lessene G.,University of Melbourne |
Czabotar P.E.,University of Melbourne |
Czabotar P.E.,Walter and Eliza Hall Institute of Medical Research |
And 39 more authors.
Nature Chemical Biology | Year: 2013
The prosurvival BCL-2 family protein BCL-XL is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X L will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X L -selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-XL and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X L and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-XL from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-XL for their sustained growth. © 2013 Nature America, Inc. All rights reserved.
Kenner D.J.,Eastern Health |
Kenner D.J.,Monash University |
Bhagat S.,Eastern Health |
Fullerton S.L.,Peter llum Cancer Center
Journal of Palliative Medicine | Year: 2015
Background: Nonsteroidal anti-inflammatory analgesics (NSAIDs) are useful in cancer pain but the specific use of subcutaneous parecoxib has not been previously reported. Objective: This pilot study aimed to establish the efficacy and side effect profile of short-term sequential single daily dose subcutaneous parecoxib sodium in patients with severe cancer bone pain. Methods: Nineteen hospitalized patients with advanced cancer and uncontrolled malignant bone pain (9 males, 10 females) received 24 courses of one, two, or three days sequential therapy with 'off-label' daily subcutaneous parecoxib. All patients were receiving opioid therapy; the median baseline daily oral equivalent dose (OED) of morphine was 180?mg. Pain was assessed at baseline, 24 hours, 48 hours, and 72 hours. Pain scores as assessed on an 11-point numeric pain rating scale (NPRS), any side effects including subcutaneous site reactions, as well as patient satisfaction rating with analgesia were recorded. A clinically significant decrease in pain scores was defined as a reduction of two or more points on the NPRS. Results: Median pain score of all patient treatments decreased from 7 to 4.5 at 24 hours (p<0.001) and 4.0 at 48 hours. A response was seen in 17 (71%) of the 24 treatments at 24 hours. There was no difference between median negative change in pain scores in 19 (79%) treatments where pain was either strongly movement related, or in 22 (94%) treatments where local bone tenderness was more pronounced. No major side effects were observed during treatment. One patient died from pulmonary embolism after cessation of concurrent prophylactic low molecular weight heparin prior to staging liver biopsy. Subcutaneous site reactions occurred in 2 (8%) treatments and were mild and self limiting. Conclusions: Short-term daily subcutaneous parecoxib injection was effective for malignant bone pain when added to existing analgesic therapy and was well tolerated. Further research is warranted into the short-term use of parecoxib in hospitalized patients with intractable malignant bone pain. © 2015, Mary Ann Liebert, Inc.
PubMed | Royal Adelaide Hospital, SBIO Pte Ltd., Dana-Farber Cancer Institute, Peter llum Cancer Center and 5 more.
Type: Clinical Trial, Phase II | Journal: Blood | Year: 2015
Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100000 10(9)/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a 35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a 50% reduction in spleen size by physical examination. Median MF symptom improvement was 50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT00745550.
Komrokji R.S.,H. Lee Moffitt Cancer Center and Research Institute |
Seymour J.F.,Peter llum Cancer Center |
Seymour J.F.,University of Melbourne |
Roberts A.W.,University of Melbourne |
And 11 more authors.
Blood | Year: 2015
Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100 000× 109/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a ±35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a ±50% reduction in spleen size by physical examination. Median MF symptom improvement was ±50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. © 2015 by The American Society of Hematology.
Zilliacus E.,Prince of Wales Hospital |
Zilliacus E.,University of New South Wales |
Meiser B.,Prince of Wales Hospital |
Meiser B.,University of New South Wales |
And 6 more authors.
Supportive Care in Cancer | Year: 2012
Purpose Women with breast cancer, who are found to be BRCA1/2 mutation carriers, have a high risk of ovarian cancer and metachronous breast cancer. Treatment-focused genetic testing (TFGT), offered around the time of diagnosis, allows genetic test results to inform surgical treatment decisions. However, concern has been raised that offering TFGT at this time may overly increase psychological burden. This study aimed to qualitatively explore women's attitudes and experiences of TFGT. Methods Women who had been diagnosed with breast cancer at age 50 years or less undertook a semi-structured telephone interview (n=26). The sample included women who had been offered TFGT, based on family history and/or other risk criteria (n=14), and women who had been diagnosed within the past 6-12 months and had not been offered TFGT (n=12). Interviews explored women's attitudes towards TFGT, perceived benefits and disadvantages, implications of TFGT and impact on surgical decision making. Interviews were transcribed verbatim and thematically analysed. Results Women expressed positive attitudes towards TFGT and felt it was highly relevant to their surgical decision making. They did not feel that an offer of TFGT shortly after, or at the time of diagnosis, added undue psychological burden. The majority of women interviewed felt that TFGT should be incorporated into standard clinical care. Conclusions TFGT is viewed favourably by women newly diagnosed with breast cancer. Future randomized controlled trials are needed to examine the long-term impact of TFGT. We conclude that an offer of TFGT is not perceived as 'too much, too soon' by relevant patients. © Springer-Verlag 2012.
Read E.D.,RMIT University |
Eu P.,Peter llum Cancer Center |
Little P.J.,RMIT University |
Piva T.J.,RMIT University
Targeted Oncology | Year: 2015
Rituximab, the CD20-directed antibody, has become a standard component of treatment regimens for patients with B cell non-Hodgkin’s lymphoma (NHL). The use of rituximab has resulted in greatly improved response and survival rates with less toxicity relative to standard chemotherapeutic regimes. However, relapse and recurrence is common, particularly in indolent varieties which remain incurable, requiring alternate therapeutic options. The subsequent coupling of β-emitting isotopes such as 131I and 90Y to anti-CD20 monoclonal antibodies (mAbs), including rituximab, has been steadily growing over the last decade and demonstrates even greater therapeutic efficacy with more durable responses. 177Lutetium-labelled rituximab offers a number of convenient advantages over 131I and 90Y anti-CD20 mAbs for treatment of NHL, and a number of alpha-emitting isotopes lie at the frontier of consolidation therapy for residual, micrometastatic disease. © 2014, Springer International Publishing Switzerland.
Alejandro Fernandez-Rojo M.,University of Queensland |
Alejandro Fernandez-Rojo M.,Center for Microscopy and Microanalysis |
Restall C.,Peter llum Cancer Center |
Ferguson C.,University of Queensland |
And 20 more authors.
Hepatology | Year: 2012
Caveolin-1 (CAV1) is a structural protein of caveolae involved in lipid homeostasis and endocytosis. Using newly generated pure Balb/C CAV1 null (Balb/CCAV1-/-) mice, CAV1-/- mice from Jackson Laboratories (JAXCAV1-/-), and CAV1-/- mice developed in the Kurzchalia Laboratory (KCAV1-/-), we show that under physiological conditions CAV1 expression in mouse tissues is necessary to guarantee an efficient progression of liver regeneration and mouse survival after partial hepatectomy. Absence of CAV1 in mouse tissues is compensated by the development of a carbohydrate-dependent anabolic adaptation. These results were supported by extracellular flux analysis of cellular glycolytic metabolism in CAV1-knockdown AML12 hepatocytes, suggesting cell autonomous effects of CAV1 loss in hepatic glycolysis. Unlike in KCAV1-/- livers, in JAXCAV1-/- livers CAV1 deficiency is compensated by activation of anabolic metabolism (pentose phosphate pathway and lipogenesis) allowing liver regeneration. Administration of 2-deoxy-glucose in JAXCAV1-/- mice indicated that liver regeneration in JAXCAV1-/- mice is strictly dependent on hepatic carbohydrate metabolism. Moreover, with the exception of regenerating JAXCAV1-/- livers, expression of CAV1 in mice is required for efficient hepatic lipid storage during fasting, liver regeneration, and diet-induced steatosis in the three CAV1-/- mouse strains. Furthermore, under these conditions CAV1 accumulates in the lipid droplet fraction in wildtype mouse hepatocytes. Conclusion: Our data demonstrate that lack of CAV1 alters hepatocyte energy metabolism homeostasis under physiological and pathological conditions. © 2011 American Association for the Study of Liver Diseases.
Meiser B.,Prince of Wales Hospital |
Meiser B.,University of New South Wales |
Gleeson M.,Prince of Wales Hospital |
Kasparian N.,University of New South Wales |
And 7 more authors.
Gynecologic Oncology | Year: 2012
Objective: There is growing evidence that the BRCA mutation status of women newly diagnosed with ovarian cancer may be used to make treatment recommendations in the future. This qualitative study aimed to assess women's attitudes and experiences toward treatment-focused genetic testing (TFGT). Methods: Women (N = 22) with ovarian cancer who had either (i) advanced disease and had previously had TFGT (n = 12) or (ii) had a recent ovarian cancer diagnosis and were asked about their hypothetical views of TFGT (n = 10), were interviewed in-depth. Results: This study demonstrates that patients diagnosed with ovarian cancer found the concept of TFGT acceptable with the primary motivation for genetic testing being to increase their treatment options. Women reported that there was no decision to make about TFGT, and the advantages of TFGT were perceived to outweigh the disadvantages. Many women described elements of resilience and active coping, in the context of hypothetical and actual TFGT. Conclusions: Resilience and active coping strategies are important factors that warrant investigation as potential moderators of psychological distress in future prospective studies exploring the optimal way of offering BRCA genetic testing to women newly diagnosed with ovarian cancer, and to assess the impact of TFGT upon patients' survival, psychological distress, and quality of life. © 2011 Elsevier Inc. All rights reserved.
Ebert M.A.,Sir Charles Gairdner Hospital |
Ebert M.A.,University of Western Australia |
Haworth A.,Peter llum Cancer Center |
Haworth A.,RMIT University |
And 9 more authors.
Physics in Medicine and Biology | Year: 2010
This study examined the variation of dose-volume histogram (DVH) data sourced from multiple radiotherapy treatment planning systems (TPSs). Treatment plan exports were obtained from 33 Australian and New Zealand centres during a dosimetry study. Plan information, including DVH data, was exported from the TPS at each centre and reviewed in a digital review system (SWAN). The review system was then used to produce an independent calculation of DVH information for each delineated structure. The relationships between DVHs extracted from each TPS and independently calculated were examined, particularly in terms of the influence of CT scan slice and pixel widths, the resolution of dose calculation grids and the TPS manufacturer. Calculation of total volume and DVH data was consistent between SWAN and each TPS, with the small discrepancies found tending to increase with decreasing structure size. This was significantly influenced by the TPS model used to derive the data. For target structures covered with relatively uniform dose distributions, there was a significant difference between the minimum dose in each TPS-exported DVH and that calculated independently. © 2010 Institute of Physics and Engineering in Medicine.