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Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
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study of radiotherapy and concurrent bevacizumab temozolamide followed by bevacizumab. Irinotecan temozolamide in newly diagnosed patients
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Five-year overall survival in children with high-grade glioma (HGG) and diffuse, intrinsic brainstem glioma (DIPG) are  approximately 25% and 10%, respectively 1-3.  Achieving cure for all children with HGG and DIPG  remains a major goal of pediatric neuro-oncology. DIPGs are infiltrative gliomas, and have typically been found to be  high-grade in histology 1,3 when tissue confirmation has been available.  HGGs are highly vascularized and infiltrative tumors. They are dependent on endothelial cell proliferation regulated by proangiogenic cytokines, especially vascular endothelial growth factor [VEGF]. In fact, VEGF expression has been shown to correlate with worse prognosis in patients with HGG 4,5. Furthermore, in a xenograft model, antibodies to VEGF have inhibited the growth of GBM6. Recently, the targeting of VEGF signaling, with bevacizumab  in patients with recurrent HGG has led to unprecedented rates of durable responses both clinically and radiographically, with a tolerable toxicity profile among recurrent malignant glioma patients7. We propose targeting of VEGF signaling as a potential therapeutic target for pediatric HGG and DIPG.  Pre-clinical and clinical studies with VEGF  targeting agents  have demonstrated in vitro and in vivo activity of these agents in HGG. 8-11 The most effective and well-studied  drug targeting VEGF signaling is bevacizumab, a VEGFspecific recombinant, humanized monoclonal antibody. Bevacizumab + irinotecan has led to response rates of 60% and 6 month progression-free survival rates of 46% in adults with recurrent HGG.   In this application, we propose a pilot study, designed to assess feasibility, tolerability, molecular activity and therapeutic potential of bevacizumab and irinotecan±temozolomide (TEM) in children with newly diagnosed HGG and DIPG.  Data from this pilot study will be used in the rational design of future studies to stratify patients for targeted therapy and improve the clinical and functional outcome in children with these poor prognosis tumors. Hypothesis 1: The treatment regimens proposed (bevacizumab± temozolomide and concurrent radiotherapy followed by bevacizumab and irinotecan ± temozolomide) are feasible, well-tolerated  and efficacious in children with newly diagnosed HGG and DIPG tumors  1.1 To determine the proposed regimen’s feasibility and toxicities  in patients with HGG and DIPG. 1.2 To determine the one year EFS, median PFS and median OS  in newly diagnosed patients with HGG treated with radiotherapy and concurrent temozolomide, bevacizumab  followed by bevacizumab, irinotecan and temozolomide for 12 courses. 1.3 To determine the 1-yr EFS, median PFS and OS  in newly diagnosed patients with DIPG undergoing radiotherapy and concurrent bevacizumab  followed by bevacizumab,  irinotecan for 12 courses.  Hypothesis 2: Children with HGG and DIPG  have characteristic molecular and radiographic features that correlate with  response and PFS. 2.1 To estimate the incidence of VEGF expression and pathway activation in tumor  as well as  blood of patients with HGG and DIPG (blood only) and at different time points 2.2 To document changes in MR perfusion and diffusion within 24-48 hours after the 2rd dose of bevacizumab during radiotherapy and correlate functional changes in tumor with responses to treatment  2.3 To conduct gene expression profiling, CGH  and SNP arrays in tumor and blood of patients  2.4 To assess telomerase activity, hTert expression, and telomere length in patients’ blood and tumor   2.5 To correlate the results of the biology studies in serum or tumor with PFS Hypothesis 3: The proposed treatment in children with HGG and DIPG  will lead to better quality of life and functional outcomes   3.1  To assess the health related quality of life of patients by   parent report, and when possible, patient report at key points in therapy 3.2 To assess functional abilities and level of independence of patients during and  following treatment. 
 
Statistical Considerations: The primary objective of the study is to assess the safety and feasibility of the study regimen. Stopping rules have been defined. We will estimate event-free-survival and overall survival for patients by each stratum using Kaplan-Meier curves. Descriptive statistics will be used to investigate the secondary objectives. We will estimate the frequency of the laboratory marker/indicator and perform exploratory analysis to correlate them with the survival outcomes.

Executive Summary

Five-year overall survival in children with high-grade glioma (HGG) and diffuse, intrinsic brainstem glioma (DIPG) are  approximately 25% and 10%, respectively1-3.  Achieving cure for all children with HGG and DIPG  remains a major goal of pediatric neuro-oncology. DIPGs are infiltrative gliomas, and have typically been found to be  high-grade in histology 1,3when tissue confirmation has been available.  HGGs are highly vascularized and infiltrative tumors. They are dependent on endothelial cell proliferation regulated by proangiogenic cytokines, especially vascular endothelial growth factor [VEGF]. In fact, VEGF expression has been shown to correlate with worse prognosis in patients with HGG 4,5. Furthermore, in a xenograft model, antibodies to VEGF have inhibited the growth of GBM6. Recently, the targeting of VEGF signaling, with bevacizumab  in patients with recurrent HGG has led to unprecedented rates of durable responses both clinically and radiographically, with a tolerable toxicity profile among recurrent malignant glioma patients7. We propose targeting of VEGF signaling as a potential therapeutic target for pediatric HGG and DIPG.  Pre-clinical and clinical studies with VEGF  targeting agents  have demonstrated in vitro and in vivo activity of these agents in HGG. 8-11 The most effective and well-studied  drug targeting VEGF signaling is bevacizumab, a VEGFspecific recombinant, humanized monoclonal antibody. Bevacizumab + irinotecan has led to response rates of 60% and 6 month progression-free survival rates of 46% in adults with recurrent HGG.   In this application, we propose a pilot study, designed to assess feasibility, tolerability, molecular activity and therapeutic potential of bevacizumab and irinotecan±temozolomide (TEM) in children with newly diagnosed HGG and DIPG.  Data from this pilot study will be used in the rational design of future studies to stratify patients for targeted therapy and improve the clinical and functional outcome in children with these poor prognosis tumors. Hypothesis 1: The treatment regimens proposed (bevacizumab± temozolomide and concurrent radiotherapy followed by bevacizumab and irinotecan ± temozolomide) are feasible, well-tolerated  and efficacious in children with newly diagnosed HGG and DIPG tumors  1.1 To determine the proposed regimen’s feasibility and toxicities  in patients with HGG and DIPG. 1.2 To determine the one year EFS, median PFS and median OS  in newly diagnosed patients with HGG treated with radiotherapy and concurrent temozolomide, bevacizumab  followed by bevacizumab, irinotecan and temozolomide for 12 courses. 1.3 To determine the 1-yr EFS, median PFS and OS  in newly diagnosed patients with DIPG undergoing radiotherapy and concurrent bevacizumab  followed by bevacizumab,  irinotecan for 12 courses.  Hypothesis 2: Children with HGG and DIPG  have characteristic molecular and radiographic features that correlate with  response and PFS.  2.1 To estimate the incidence of VEGF expression and pathway activation in tumor  as well as  blood of patients with HGG and DIPG (blood only) and at different time points 2.2 To document changes in MR perfusion and diffusion within 24-48 hours after the 2rd dose of bevacizumab during radiotherapy and correlate functional changes in tumor with responses to treatment  2.3 To conduct gene expression profiling, CGH  and SNP arrays in tumor and blood of patients  2.4 To assess telomerase activity, hTert expression, and telomere length in patients’ blood and tumor   2.5 To correlate the results of the biology studies in serum or tumor with PFS Hypothesis 3:  The proposed treatment in children with HGG and DIPG  will lead to better quality of life and functional outcomes   3.1        To assess the health related quality of life of patients by   parent report, and when possible, patient report at key points in therapy 3.2        To assess functional abilities and level of independence of patients during and  following treatment. 
 
Statistical Considerations: The primary objective of the study is to assess the safety and feasibility of the study regimen. Stopping rules have been defined. We will estimate event-free-survival and overall survival for patients by each stratum using Kaplan-Meier curves. Descriptive statistics will be used to investigate the secondary objectives. We will estimate the frequency of the laboratory marker/indicator and perform exploratory analysis to correlate them with the survival outcomes 

Description of Research Proposal

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Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Integer fermentum vestibulum lacinia. Duis id aliquam nibh, ut mattis leo. Nulla ac dui at sapien posuere facilisis ut quis ex. Aliquam vestibulum blandit tristique. Integer pretium dui ac nulla accumsan, et finibus velit euismod. Proin placerat, nunc eu sodales facilisis, tellus justo efficitur risus, non blandit diam nulla ac ligula. Aliquam ullamcorper quam leo, porttitor dictum ex tempor ac. Ut efficitur, justo et auctor volutpat, ex ex pulvinar est, sed consequat turpis leo nec ipsum. Nunc tempor, turpis ut ullamcorper tempor, dolor dui varius dui, et congue quam nisi vel nunc.

Class aptent taciti sociosqu ad litora torquent per conubia nostra, per inceptos himenaeos. Donec faucibus, turpis sit amet maximus dapibus, sapien nisl bibendum turpis, pharetra commodo tellus libero vel nulla. Sed nec velit viverra, congue sapien et, gravida libero. Proin eget ante eget turpis egestas accumsan. Aliquam arcu nibh, aliquam rhoncus vulputate in, pellentesque at sem. Maecenas cursus tempus nibh id tempus. Mauris dolor sapien, lacinia sit amet condimentum at, dapibus eget lectus. Phasellus vel pellentesque ex. Nunc aliquam in ligula at tristique. In mollis suscipit felis eu finibus. Nullam non dignissim nibh, nec suscipit ex. Suspendisse tincidunt et mauris id finibus. Aliquam vehicula a sem quis venenatis.

Suspendisse leo odio, rutrum et viverra ut, consequat finibus enim. Vivamus dolor nisl, viverra eu egestas vel, blandit in nulla. Curabitur auctor purus non est volutpat bibendum. Proin fringilla magna sed metus maximus, in dictum neque suscipit. Sed ornare ut mi ut sodales. Nulla efficitur urna nunc, non molestie nunc egestas ut. Nunc arcu lorem, semper ut tincidunt ac, eleifend quis elit.

Sed at tortor et tortor tincidunt feugiat id in dui. Vivamus eget justo nisl. Aenean congue laoreet nisl a elementum. Nunc consectetur velit non ligula sollicitudin, quis eleifend urna sollicitudin. Sed tincidunt, nisl quis varius venenatis, dui massa condimentum tellus, sed sollicitudin diam magna mollis augue. Sed venenatis commodo purus id malesuada. Aenean volutpat elit vel gravida consectetur. Vestibulum diam quam, lacinia ac tortor eget, tincidunt dapibus dui. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Proin nisl leo, pretium sed arcu imperdiet, hendrerit sollicitudin sem. Duis non magna at nunc sagittis ullamcorper a id est. Maecenas cursus nisl in faucibus hendrerit.

Sed hendrerit vitae purus et tempor. Aenean vitae varius velit. Nullam aliquet ipsum elit. Mauris vestibulum purus et metus imperdiet, quis gravida eros pretium. Curabitur rutrum nunc vitae tincidunt condimentum. Aenean sit amet augue velit. Nunc tristique quis lorem id pharetra. Pellentesque sollicitudin, eros sed egestas rutrum, nulla nisl sodales elit, ut imperdiet nunc lectus sit amet nulla. Ut malesuada finibus libero. Curabitur mi dolor, sollicitudin quis bibendum quis, dictum sed enim.

Pellentesque nibh erat, egestas sit amet sagittis malesuada, rhoncus at neque. Mauris maximus commodo tortor, non egestas magna finibus vitae. Sed hendrerit nulla vel venenatis tempor. Suspendisse tristique tincidunt libero et placerat. Nam tincidunt condimentum lorem, vel pharetra est iaculis sed. Nullam ac tincidunt orci. Quisque pharetra ut sem sit amet aliquam. Phasellus risus libero, varius in condimentum vel, commodo id ipsum. Aliquam in metus cursus, mattis diam ut, aliquam magna. Suspendisse facilisis dui et orci varius, suscipit facilisis augue dapibus. In eget nibh ipsum. Suspendisse eget pharetra est, quis condimentum felis. Fusce scelerisque congue libero, sed aliquam mi elementum a. Etiam scelerisque ante non auctor porta. Nam eu nunc id ex finibus dictum. Praesent dui ex, dictum ac massa eget, rutrum gravida nisi.

Sed egestas arcu in dui euismod, eget faucibus massa iaculis. Etiam efficitur lectus et purus lobortis, ac blandit eros rutrum. Proin bibendum consectetur leo vel gravida. Etiam et ultricies sapien. Nam lacinia tellus erat, id facilisis est consequat et. Morbi quis risus in neque iaculis pharetra ut consectetur libero. Aenean feugiat tempor mi eu posuere.

Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.