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Posted by Felixon 28.11.2016 16:46:29: iressa after tarceva

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ТЕМА: Posted by Felixon 28.11.2016 16:46:29: iressa after tarceva

Posted by Felixon 28.11.2016 16:46:29: iressa after tarceva 8 года 4 мес. назад #893

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Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521-9.
Figure 1 Comparison of erlotinib binding to active and inactive EGFR-TKD models
Erlotinib is also known by its brand name, Tarceva (pronounced tar-see-vah). It is a treatment for
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20. Lilenbaum R, Axelrod R, Thomas S, et al: Randomized phase II trial of erlotinib or standard chemotherapy in patients with advanced non-small-cell lung cancer and a performance status of 2. J Clin Oncol 26:863–869, 2008.
Cost of Tarceva (erlotinib) 150mg Tablets in Hongkong
C]-erlotinib as a radiotracer,
Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer: molecular and clinical predictors of outcome. N Engl J Med 2005;353: 133-44
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Erlotinib has been tested for genotoxicity in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration, and mammalian cell mutation) and an in vivo mouse bone marrow micronucleus test and did not cause genetic damage.
Ebenfalls mit den Literaturdaten in Übereinstimmung zu bringen sind die Ergebnisse zum Gesamtüberleben nach Beginn der Erlotinib-Einnahme und dem Raucherstatus der Patienten ([Abb. 2 ]). Das längste mediane OS mit 8,3 Monaten haben Patienten, die nie geraucht haben. In unserem Patientengut weisen die ehemaligen Raucher das schlechteste mediane Überleben auf (4,5 Monate), während die aktiven Raucher ein geringfügig besseres medianes Überleben (6,4 Monate) zeigen. Bei fehlender Differenzierung bezüglich der Länge der „Ex-Raucher-Phase“ sind jedoch beide letztgenannten Gruppen in unserer Analyse eher als Einheit zu betrachten.
These findings have prompted some clinicians to consider the feasibility of increasing the dose of erlotinib until a tolerable rash occurs, as a rational management strategy [2. 23 ]. There is thus a need to develop U.K. guidelines for optimal management, to limit the impact of rash on patients and on the overall therapeutic effectiveness of erlotinib.
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TG101348 sensitizes NSCLC cells to the cytotoxicity of erlotinib
Patients received erlotinib initially at a dose of 150 mg/day. Dose reduction to 100, 75 or 50 mg/day and dose interruption were performed when intolerable toxicities were observed. Therapy was continued until disease progression, intolerable toxicity or patient withdrawal.
This phase II clinical trial included 41 patients with advanced papillary renal cell carcinoma (20 with advanced hereditary leiomyomatosis and renal cell cancer and 21 with advanced sporadic papillary renal cell carcinoma). Nineteen of the patients had received at least one previous systemic therapy, such as sunitinib (Sutent), that had not been successful in preventing their disease progressing. Patients received bevacizumab 10 mg/kg given intravenously once every 2 weeks, combined with erlotinib 150 mg taken orally every day. Treatment was continued until disease progression or unacceptable toxic side effects.
Next, we examined the effects of erlotinib and gefitinib on lymphocytic cell migration using a Transwell chemotaxis assay system (Fig. 3

. The addition of both erlotinib and gefitinib to the media led to an increase in the number of cells attracted by chemokines; however, erlotinib activated cell migration more potently than gefitinib. In this assay, cells were incubated for 2 h, and EC 50 values were determined. The EC 50 values for lymphocytic cell migration were 470 nM for erlotinib and 1400 nM for gefitinib. The relative E max values were 1.9 for erlotinib and 1.7 for gefitinib.
Early investigations of EGFR-TKIs indicated several clinicopathological factors that predict a better outcome, including gender (female), smoking status (never), ethnicity (east Asian including Japan) and histology (adenocarcinoma) (13 ,14 ). In the IDEAL 1 trial, Japanese patients appeared to have higher sensitivity to gefitinib than western patients (13 ). On the other hand, interstitial lung disease (ILD), known as a fatal adverse effect, was frequently observed in Japanese patients (13 ). Although a clinical benefit of EGFR-TKI therapy for Japanese patients can be expected, the occurrence of ILD should be carefully monitored. Most SCC patients are commonly male and current smokers, factors which significantly predict high incidence of ILD in gefitinib treatment (15 ). However, there is little data on the efficacy and safety of erlotinib for Japanese patients with pretreated SCC.
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The erlotinib mean relative dose intensity was 92% with a range from 29% to 101%. Thirty-five per cent of erlotinib patients were on drug for >16 weeks and 6% for >52 weeks.
Ahora leo que tarceva se receta cuando al menos un tratamiento de quimio a fallado, a nosotros en ningun momento nos dijeron que habia fallado y ahora tengo la sensacion que los medicos no nos lo cuentan todo.
Kabbinavar F. Miller V. Johnson B. O’Connor P. Soh C. (2010) Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (

therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 28. 15s (suppl; abstr 7526).
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Common BP Drug May Prevent Resistance to Tarceva in NSCLC Patients
Given the dichotomy of response profiles related to EGFR dependence, we next set out to examine the presence of a possible correlation between the EGFR dependence of clones and their EGFR kinase domain sequence alterations. We sequenced EGFR kinase domain exons 18 to 21 to examine the primary sequences of the EGFR -TK domain in the resistant clones. The EGFR-independent clones (Fig. 2B. e.g. #10) showed no genetic alterations in their EGFR kinase domain. In stark contrast, we found that all of the EGFR-dependent resistant clones invariably shared a common EGFR exon 20 T790M mutation with the signature chromatographic peak robustly detectable through classical Sanger sequencing (Fig. 2B. e.g. #6; Supplementary Fig. S1A and S1B). To check whether a subset of these resistant clones developed resistance by cmet gene amplification, we carried out real-time quantification of cmet gene copy number and found no statistically significant evidence of such a genetic change (Supplementary Fig. S2A). In addition to cmet amplification, PTEN deletion was reported to be involved in resistance to erlotinib (28 ). PTEN protein expression of afatinib-resistant clones, however, was found to be comparable with that of parental PC9 cells (Supplementary Fig. S2B). No morphologic alteration, indicative of epithelial-mesenchymal transition, was notable among resistant cells.
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Understanding genetic alterations of tumors is essential for the successful development of novel strategies to circumvent resistance to TKIs. Currently, it is known that irreversible EGFR TKIs, such as HKI-272 and HKI-357, may overcome gefitinib resistance in T790M cells by irreversibly binding to the ATP-binding cleft, even in the presence of the T790M mutation. Although irreversible binding capacity of those TKIs appears to be the main reason for overcoming gefitinib resistance, it should also be noted that these TKIs target not only EGFR but also HER2. Down-regulation of HER2 causes a loss of viability in T790M cells, suggesting the importance of HER2 inhibition in overcoming resistance to EGFR TKI (14 ). Similar to these results, our study showed that lapatinib dissociated heterodimerization of EGFR and HER2 in T790M cells, whereas gefitinib-resistant T790M cells maintained EGFR/HER2 heterodimerization in spite of gefitinib treatment. Lapatinib is a reversible dual TKI for both EGFR and HER2 that binds to an inactive conformation of EGFR that is quite different from the active structure bound by the selective EGFR inhibitor, erlotinib, which suggests that this TKI has a different mechanism of actions (32 ). Therefore, besides irreversibility of TKIs, our data also suggest that inhibition of HER2 may play a role in reversing the resistance in terms of receptor dedimerization. Moreover, lapatinib has a very slow off-rate from purified intracellular domains of EGFR and HER2 compared with erlotinib or gefitinib. Lapatinib is currently under active clinical investigation and has shown promising activity against HER2-overexpressing breast cancer cells. However, the efficacy of lapatinib has not been investigated in NSCLC, and its role in EGFR TKI-resistant NSCLC is unknown. In this study, we showed that lapatinib revealed moderately enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo . Based on its dedimerization effect on EGFR and HER2, lapatinib may partially attenuate the resistance to EGFR TKI in T790M lung cancer cells.
A Study Evaluating ABT-263 With Erlotinib, ABT-263 With Irinotecan, and ABT-263 Monotherapy in Cancer Subjects
- Los pacientes que recibían Tarceva poseían estabilidad o el control de sus síntomas relacionados con el cáncer de pulmón, como tos, dificultades respiratorias y dolor, durante mucho más tiempo.
The remaining 78 patients were assigned to receive the same chemotherapy dosing followed by placebo on Days 15 to 28, followed by placebo until disease progression occurred. Then they were placed on erlotinib therapy.
Tarceva (erlotinib) for Non-Small Cell Lung Cancer: "My 63 year old mom was diagnosed with the EGFR gene mutation, stage iv lung cancer 4 months ago. The cancer was also in her brain. lung and bone. Since Tarceva started she has done extremely well. Her recent scan showed a 70% decrease of tumor size on the lung, the spot on the liver is gone and the ones on her brain are slowly getting smaller, even with a direct hit of full brain radiation. She has had some side effects such as rash, which she was very annoyed with but went away, diarrhea which she still has and recently stomach pain. Hoping it subsides."
Erlotinib inhibits chordoma xenograft growth in vivo
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Previous studies of this combination in non-small cell lung cancer, renal cell carcinoma and metastatic breast cancer have indicated a potential synergistic effect for these two agents. Preliminary data for the use of bevacizumab in advanced ovarian cancer indicates that this agent has single-agent activity. As a result, the researchers are interested in exploring the role of the combination of erlotinib and bevacizumab in advanced ovarian cancer.
The analyses presented here suggest physicians and patients should view the development of rash as a desirable outcome, perhaps as a sign of erlotinib-induced biological effect. The patient who does not develop a characteristic rash within 2 to 4 weeks is less likely to benefit from erlotinib. There is a need to develop methods for managing the rash without interfering with improvement in outcomes associated with the rash. Further studies are needed to identify which patients are more likely to develop rash and whether increasing the dose of erlotinib can induce rash in patients without rash at the standard dose and improve outcome.
Section 3(d) of Indian patent Act has been a source of rising debate especially when pharmaceutical companies are considered. Thus this paper thrashes out two important cases pertaining to the interpretation of section 3(d) 1,2 with respect to products Glivec and Erlotinib. While the inclusion of section 3(d) by the way of an amendment in 2005 of the Indian Patent Act supports humanitarian aspect like affordable drug prices but is not very encouraging from business perspective. Further on, the article also deals with the benefits that section 3 (d) offers by preventing “ever greening”.
The MTD for Part 1 was 50 mg daily of erlotinib combined with standard cetuximab. Bevacizumab at 10 mg/kg biweekly can be safely administered with the MTD for erlotinib and cetuximab combination.
toxicity of ipilimumab and erlotinib in EGFR mutated patients [ Time Frame: 36 months ] [ Designated as safety issue: Yes ]
BAS 100 was obtained from Bioavailabilty Systems (Cocoa Beach, FL, USA), and erlotinib and OSI-420 were obtained from Toronto Research Chemicals (North York, ON, Canada). All other chemicals and reagents were purchased from Sigma-Aldrich (St Louis, MO, USA). Female BALB/c mice (6–8 weeks old) were kept in a controlled environment, with food and water available ad libitum . All procedures were carried out with NCI Animal Care and Use Committee approval. In the first study, BAS 100 and erlotinib were formulated in 10% DMSO and 5% polysorbate 80 in saline. Mice were randomised to receive erlotinib (10 mg kg −1. p.o.) alone or 30 min after BAS 100 (10 mg kg −1. p.o.). Blood was collected by cardiac puncture from three mice per time point at 0.083, 0.25, 0.5, 1, 2, 4, 6 and 24 h following erlotinib administration, and centrifuged to obtain plasma. In the second study, erlotinib was formulated in 0.3% carboxymethylcellulose and 0.1% polysorbate 80 in saline. Female CYP3A4 transgenic mice (Granvil et al . 2003 ) and wild-type FVB/NCr mice (14 weeks old) received erlotinib (10 mg kg −1. p.o.) alone or 30 min after BAS 100 (25 mg kg −1. p.o.). Blood was collected 2 h after erlotinib administration. All samples were stored at −80°C until analysis. Plasma concentrations of erlotinib and OSI-420 were measured as described previously (Zhao et al . 2003 ). Plasma concentrations of BAS 100 were measured by a novel liquid chromatography-tandem mass spectrometry method. Briefly, plasma samples were prepared by protein precipitation with acetonitrile. BAS 100 and the internal standard (temazepam) were resolved isocratically on a Waters XTerra MS C18 column (50 × 2.1 mm internal diameter; 3.5 μ m particle size). The mass spectrometer was equipped with an electrospray ionisation source and operated in positive mode. Detection was performed by multiple reaction monitoring. The lower limit of quantitation was 10 ng ml −1. Pharmacokinetic parameters were determined by noncompartmental analysis using WinNonlin Professional Version 5.2 (Pharsight Corporation, Mountain View, CA, USA). Bailer's method (Bailer, 1988 ) was used to estimate the variance of the area under the curve (AUC). A Z -test was used for the pairwise comparison of AUCs (Yuan, 1993 ).