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Patent
Betta Pharmaceuticals Co. | Date: 2014-06-09

The present invention relates to the polymorphic forms of the compound of Formula I, preparation thereof and pharmaceutical compositions, and use of a polymorph above in the treatment of a disease, a disorder or a condition, or in the manufacturing of a medicament for the treatment of a disease, a disorder or a condition.


The present invention relates to the technical field of medicine, and specifically provides methods for preparing Icotinib, Icotinib hydrochloride, and intermediates thereof. These methods avoid the use of phosphorus oxychloride, thereby greatly reducing the emission of pollutants, which is of major benefits to the economy and environment.


Hu X.,Chinese Academy of Sciences | Han B.,Shanghai JiaoTong University | Gu A.,Shanghai JiaoTong University | Zhang Y.,Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology | And 16 more authors.
Lung Cancer | Year: 2014

Background: The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. Methods: This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125. mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. Results: Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21-95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively. Conclusions: The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting. © 2014 Elsevier Ireland Ltd. Source


Zhou L.,University of Sichuan | He J.,University of Sichuan | Xiong W.,University of Sichuan | Liu Y.,University of Sichuan | And 13 more authors.
Lung Cancer | Year: 2016

Objectives: Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. Materials and methods: EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3 + 3 design. The patients received icotinib with escalating doses (125-625 mg, tid), and the concurrent WBRT (37.5 Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. Results: Fifteen patients were included in this study, 3 at each dose level from 125 mg-375 mg and 6 at 500 mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375 mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R2 = 0.599, P < 0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375 mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P = 0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. Conclusions: WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375 mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment. © 2016 Elsevier Ireland Ltd. Source


Hu X.,Peking Union Medical College | Zhang L.,Sun Yat Sen University | Zhang L.,Peking Union Medical College | Shi Y.,Peking Union Medical College | And 17 more authors.
PLoS ONE | Year: 2015

Background Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum- based chemotherapy. Methods Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125mg tablet, three times per day). The primary endpoint was progression- free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety. Results From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9-6.6 m) and 5.4 months (95%CI 3.1-7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7%respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow- up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127). Conclusions In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy. © 2015 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

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