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A pilot, pharmacokinetic (PK), and pharmacodynamic (PD) study to determine the feasibility of intrapatient dose escalation to tolerable rash and the activity of maximal doses of erlotinib (E) in previously treated patients with advanced non-small cell lung cancer (NSCLC)
... Tasidotin (ILX-651), an orally active synthetic microtubule-targeted derivative of the marine depsipeptide dolastatin-15, is currently undergoing clinical evaluation for cancer treatment. Phase-I trials with ILX651, in patients with advanced solid tumors, indicated that the compound is well tolerated and no cardiotoxicities were observed, as observed with the compound LU-103793 (Mita et al., 2006). Tasidotin has completed three rounds of clinical tests II in patients with hormone refractory prostate cancer and advanced or metastatic non-small-lung carcinoma (Tan, 2010). ...
Abstract The cyanobacteria (blue-green algae) are photosynthetic prokaryotes having applications in human health with numerous biological activities and as a dietary supplement. It is used as a food supplement because of its richness in nutrients and digestibility. Many cyanobacteria (Microcystis sp, Anabaena sp, Nostoc sp, Oscillatoria sp., etc.) produce a great variety of secondary metabolites with potent biological activities. Cyanobacteria produce biologically active and chemically diverse compounds belonging to cyclic peptides, lipopeptides, fatty acid amides, alkaloids and saccharides. More than 50% of the marine cyanobacteria are potentially exploitable for extracting bioactive substances which are effective in killing cancer cells by inducing apoptotic death. Their role as anti-viral, anti-tumor, antimicrobial, anti-HIV and a food additive have also been well established. However, such products are at different stages of clinical trials and only a few compounds have reached to the market.
... The MTD needs to be further defined in smokers, as this population of patients may require a higher erlotinib dose than that currently used to achieve the same level of drug exposure in nonsmokers. Preliminary results of a study of the feasibility of dose escalation with erlotinib in patients with NSCLC were presented at this year's Annual Meeting of the American Society of Clinical Oncology [10]. Comis 469 8.9%, versus 0.9% for the placebo-treated group, and the median duration of response was better for the drug-treated patients, 34.3 weeks versus 15.9 weeks, respectively. ...
... 18 Furthermore, a study is ongoing to investigate if the dose of erlotinib can be escalated above the current MTD in individual patients using the onset of rash as the stopping rule. 19 To allow dosing flexibility in the clinic, erlotinib is formulated as oral tablets available in 3 dose strengths: 25 mg, 100 mg, and 150 mg. Although the active and inactive ingredients are the same for each dose strength, the erlotinib-to-excipient ratio is different in the 25-mg tablets compared with the 100-mg and 150-mg tablets. ...
A randomized, open-label, 2-period crossover study was conducted to evaluate the bioequivalence of 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg (arm A, n = 42) and the oral bioavailability of the 150-mg tablet versus a 25-mg intravenous infusion (arm B, n = 20) in healthy subjects. The washout period was 2 weeks between treatments. Plasma concentrations of erlotinib and its active metabolite, OSI-420, were measured after each dose. The ratios of geometric means for AUC(0-infinity) and Cmax of erlotinib following 6 tablets of erlotinib 25 mg and 1 tablet of erlotinib 150 mg were (1 and 0.95) within the predefined bioequivalence range of 0.80 to 1.25. The mean absolute oral bioavailability, using compartmental analysis, was estimated as 59% (95% confidence interval, 55%-63%). Overall, 6 tablets of erlotinib 25 mg are bioequivalent to a single 150-mg tablet. Both intravenous and oral erlotinib were generally well tolerated with an estimated bioavailability of 59% following oral administration.
... However, titration of erlotinib to skin rash in an attempt to optimize efficacy is likely to be difficult given that diarrhea has been demonstrated as the main dose-limiting toxicity. A dose-torash study is currently ongoing with erlotinib in lung cancer to explore this issue further (Mita et al 2005). ...
Pancreatic cancer is a largely chemo-resistant disease with a poor prognosis. Despite the adoption of gemcitabine monotherapy as a standard of care, outcomes remain poor. Until recently randomized phase III studies have not demonstrated superiority of various cytotoxic combinations or a number of the newer biologic targeted drugs. The situation has changed with capecitabine and erlotinib, either of which in combination with gemcitabine produces a small increase in survival. Erlotinib is a small molecule tyrosine kinase inhibitor against epidermal growth factor receptor which has an important role in the molecular pathogenesis of pancreatic cancer. In both pre-clinical and early clinical evaluation it has shown anti-tumor activity against pancreatic cancer in combination with gemcitabine. A randomized phase III study in locally advanced and metastatic pancreatic cancer has shown a survival advantage for the combination of gemcitabine plus erlotinib over gemcitabine alone. The rationale for the clinical development of erlotinib in combination with gemcitabine in pancreatic cancer culminating in this randomized trial, together with pharmacologic, toxicity and patient selection considerations form the focus of this review.
Within the past 2 years, epidermal growth factor receptor (EGFR) inhibitors have moved from experimental agents to approved drugs for the management of advanced non-small cell lung cancer (NSCLC). This evolution has been accompanied by dramatic improvements in the understanding of how these drugs work and the clinical populations that may benefit. The identification of mutations in the ATP-binding domain of the EGFR that predict for dramatic responses introduces the possibility of truly individualized therapy in a subset of advanced NSCLC patients. The fact that these mutations may be more prevalent in certain patient populations, including patients of Asian ethnicity, female gender, and never-smoker status, raises intriguing questions regarding the pathogenesis of lung cancer. Another emerging area in the understanding of these agents revolves around the clinical observation that acneform rash may predict for superior outcome and the question of how this rash may relate to polymorphisms in the EGFR gene. EGFR polymorphisms, both germline and somatic, may be a relevant factor in unraveling the mechanism of the benefit of erlotinib in patients who do not harbor an EGFR ATP-binding site mutation. Numerous questions have arisen regarding how to best incorporate EGFR-targeted agents into patient management, as well as the role of the clinical laboratory in these decisions and the design of future trials.
Epidermal growth factor receptor (EGFR) inhibitors are associated with unique and dramatic dermatologic side effects. Cetuximab, erlotinib, and gefitinib have been approved for patients with colorectal and non-small cell lung cancer refractory or intolerant to chemotherapy. Our aim was to describe key clinical features of common dermatologic adverse reactions among EGFR inhibitors, focusing mainly on skin toxicity, as well as to discuss the pathology, possible causes, and suggested treatments for these reactions. The most commonly encountered adverse effect was a mild skin toxicity characterized by a sterile follicular and pustular rash that may be treated empirically and usually does not require treatment modification. Although the precise mechanism for development of rash is not well defined, it is related to inhibition of EGFR-signaling pathways in the skin, and may serve as visible markers of anti-tumor activity and therapeutic efficacy. Secondary adverse reactions seen with anti-EGFR therapy include xerosis, pruritus, paronychia, hair abnormality, and mucositis.
Biologic agents targeting the epidermal growth factor receptor (EGFR) have emerged as a robust treatment option for various solid tumors. Despite lower systemic side effects than conventional chemotherapy, the majority of patients treated with these agents experience cutaneous toxicities, including papulopustular rashes, hair and nail changes, xerosis and pruritus, which have a significant impact on health and quality of life. Currently no consensus or management guidelines exist for these untoward events. Therefore, a retrospective survey was carried out across 110 oncology practioners in the US that were administering EGFR inhibitors. Providers were queried on the impact and management of these untoward events in their practices. Responses suggest that combination therapies (topical and oral) were more effective than either therapy alone, and also lead to a more rapid resolution of the papulopustular rash. Providers also reported that patients frequently complained of physical symptoms associated with the rash (itching and pain), and that they had a positive perception when being treated for their cutaneous side effects. The survey results support that attentive cutaneous care is important in patients treated with EGFR inhibitors, and that proactive/combined interventions may enhance quality of life and optimize consistent drug administration.
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