Showing papers by "Albiruni Ryan Abdul Razak published in 2013"
TL;DR: HP(+) LNs involute more quickly than HPV(-) LNs but undergo a more prolonged process to eventual CR beyond the time of initial assessment at 8 to 12 weeks after treatment, which may be avoided for selected non-CR N2 HPV(+) cases with a significant LN involution.
Abstract: Purpose To compare the temporal lymph node (LN) regression and regional control (RC) after primary chemoradiation therapy/radiation therapy in human papillomavirus-related [HPV(+)] versus human papillomavirus-unrelated [HPV(−)] head-and-neck cancer (HNC). Methods and Materials All cases of N2-N3 HNC treated with radiation therapy/chemoradiation therapy between 2003 and 2009 were reviewed. Human papillomavirus status was ascertained by p16 staining on all available oropharyngeal cancers. Larynx/hypopharynx cancers were considered HPV(−). Initial radiologic complete nodal response (CR) (≤1.0 cm 8-12 weeks after treatment), ultimate LN resolution, and RC were compared between HPV(+) and HPV(−) HNC. Multivariate analysis identified outcome predictors. Results A total of 257 HPV(+) and 236 HPV(−) HNCs were identified. The initial LN size was larger (mean, 2.9 cm vs 2.5 cm; P P P =.18). The mean post treatment largest LN was 36% of the original size in the HPV(+) group and 41% in the HPV(−) group ( P P P P =.14). On multivariate analysis, HPV(+) status predicted ultimate LN resolution (odds ratio, 1.4 [95% confidence interval, 1.1-1.7]; P P Conclusions HPV(+) LNs involute more quickly than HPV(−) LNs but undergo a more prolonged process to eventual CR beyond the time of initial assessment at 8 to 12 weeks after treatment. Post radiation neck dissection is advisable for all non-CR HPV(−)/non-CR N3 HPV(+) cases, but it may be avoided for selected non-CR N2 HPV(+) cases with a significant LN involution if they can undergo continued imaging surveillance. The role of positron emission tomography for response assessment should be investigated.
96 citations
TL;DR: Dacomitinib demonstrated clinical activity in RM-SCCHN and the primary end point of this study was met, and the toxicity profile of this agent was generally manageable with dose interruptions and adjustments.
91 citations
TL;DR: The utilization of expansion cohorts has increased with time and may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.
Abstract: Purpose To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use. Methods We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression. Results We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation. Conclusion The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.
75 citations
TL;DR: RO4929097 in combination with cediranib is generally well tolerated and preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation.
Abstract: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.
67 citations
TL;DR: In cancers, the majority of tumor suppressor proteins (TSP) are transported out of the nucleus exclusively by Exportin 1 (XPO1/CRM1), rendering these TSPs non-functional.
Abstract: 2505 Background: In cancers, the majority of tumor suppressor proteins (TSP) are transported out of the nucleus exclusively by Exportin 1 (XPO1/CRM1), rendering these TSPs non-functional. KPT-330 i...
14 citations
TL;DR: This first-in-human phase I study explored the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of REGN910 as a single agent.
Abstract: 2517 Background: REGN910 is a selective, fully human Ang2 MAb that potently blocks signaling through the Tie2 receptor regulating tumor angiogenesis and growth. In multiple mouse xenograft models o...
7 citations
TL;DR: The primary objective of this Phase l first-in-man study was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients with advanced solid malignancies (preselected CYP2C9 genotypes only).
Abstract: 2561^ Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultane...
4 citations
Medical College of Wisconsin1, University of Chicago2, University of North Carolina at Chapel Hill3, University of Texas MD Anderson Cancer Center4, University of Maryland Marlene and Stewart Greenebaum Cancer Center5, University of Texas Health Science Center at San Antonio6, City of Hope National Medical Center7, Emory University8, University of Michigan9, Vanderbilt University10, University of Southern California11
TL;DR: Dasatinib is a potent and selective inhibitor of ckit proto-oncogene that acts as a ‘spatially aggregating force’ to knock down the activity of this gene in patients with ACC.
Abstract: 6022 Background: ACC is a rare disease, accounting for 1/3rd of MSGT, in which 90% of cases express the protein product of the ckit proto-oncogene. Dasatinib is a potent and selective inhibitor of ...
4 citations
TL;DR: ENMD-2076 is an oral Aurora A and angiogenic kinase inhibitor that hasdemonstrated the ability to abrogate tumor growth in STS.
Abstract: 10528 Background: The use of angiogenic and Aurora kinase inhibitors has been shown to abrogate tumor growth in STS. ENMD-2076 is an oral Aurora A and angiogenic kinase inhibitor that has demonstra...
2 citations
TL;DR: In several mouse xenograft models, combination of the 2 anti-angiogenic compounds, REGN910 and ZAFL, demonstrated significantly enhanced tumor growth inhibition relative to either agent alone, suggesting that dual angiogenic blockade is worth exploring in cancer patients.
Abstract: TPS2618 Background: REGN910 is a selective, fully human Angiopoietin-2 (ANG-2) MAb, which potently blocks signaling through the Tie2 receptor. Ziv-aflibercept (ZAFL) is a recombinant human fusion p...
1 citations
TL;DR: An association between an initial reduction in TP and tumor shrinkage in pts receiving AMG386+T is revealed and Measurement of Tie2 and TP in circulating M is feasible, with no discrete Tie2+/- populations identified.
Abstract: Background: The Ang/Tie2 pathway plays a critical role in tumor angiogenesis, and several agents targeting this axis are in development. Tie2 is expressed by monocytes (M), and TEMs may be angiogenic mediators. Thymidine phosphorylase (TP), an angiogenic enzyme, is increased in TEMs upon Tie2 stimulation. We used flow cytometry to evaluate TEMs in a phase I study of AMG386 (Ang1/2 peptibody) + T in patients (pts) with solid tumors. Methods: Peripheral blood was collected from healthy volunteers and pts with advanced cancer (n=10 each) for assay development. For phase I study pts (n=5 to date), blood was collected on Cycle 1 Day 1 (D1), D3 and D8. Extracellular Tie2 staining was performed after hypotonic red blood cell lysis. TP staining followed formaldehyde fixation and Triton X-100 permeabilization. M and lymphocytes (L) were gated with CD45 and CD33. Median fluorescence intensities (MFI) were measured and normalized by calculating a M/L ratio. Tumor response was assessed every 2 cycles. Results: Tie2 staining was present on all M (absent in other leukocytes) in healthy controls and cancer pts, with no discrete Tie2+/- populations. Tie2 and TP M/L were similar between these 2 groups. Tie2, TP and response data from the first 5 pts receiving AMG386 + T are presented. Preliminary results reveal an association between change in TP D1 to D3 and tumor response. TP M/L decreased in all pts with tumor shrinkage (mean -18%), but increased (+6%) in the pt with tumor growth. No consistent association between Tie2 M/L and response was observed. Conclusions: Measurement of Tie2 and TP in circulating M is feasible. No discrete Tie2+ M population is identifiable. Tie2 and TP staining are similar in cancer pts and healthy volunteers. Preliminary analyses reveal an association between an initial reduction in TP and tumor shrinkage in pts receiving AMG386+T. Enrolment continues and additional data will be presented. Citation Format: David W. Cescon, Philippe L. Bedard, Sue Chow, Helen Chen, Albiruni Razak, Monika Wizemann, Lillian L. Siu, David Hedley. Tie2-expressing monocytes (TEMs) as potential biomarkers of angiopoietin-Tie2 (Ang/Tie2) directed therapies: correlative analysis of a phase I study of AMG386 + temsirolimus (T). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4647. doi:10.1158/1538-7445.AM2013-4647