Abstract:
The present invention relates to a method of treatment of patients suffering from cancer and harbouring mutations of EGFR in the tumour, for instance an activating mutation of the EGFR or a mutation responsible for resistance or the emergence of acquired resistance to treatment with reversible EGFR and/or HER2 inhibitors or irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357, comprising administering an effective amount of the irreversible EGFR inhibitor BIBW2992 (1) 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, to a person in need of such treatment, optionally in combination with the administration of a further chemotherapeutic agent, in combination with radiotherapy, radio-immunotherapy and/or tumour resection by surgery, and to the use of a BIBW 2992 (1) for preparing a pharmaceutical composition for the treatment of patients suffering from cancer and harbouring mutations of EGFR in the tumour.

Description:
[0001]    The present invention relates to a method of treating patients suffering from cancer and harbouring mutations of EGFR in the tumour. The said method comprises administration of an effective amount of the irreversible EGFR inhibitor BIBW2992 (1) to a person in need of such treatment, optionally in combination with the administration of a further chemotherapeutic agent (2), in combination with radiotherapy, radio-immunotherapy and/or tumour resection by surgery. The mutation of the EGFR encompasses at least all amplifications or activating gene mutations that are relevant to enhanced expression (e.g. reduced CA-repeats (CA: cytosine-adenosine) in the first intron or other specific polymorphisms), increased sensitivity to activation or genuinely activating mutations (e.g. L858R or G719S point mutations or specific exon 19 deletions). It also includes those mutations associated with resistance (e.g. D761Y, insertions D770_N771insNPG) or emergence of acquired resistance (e.g. T790M) to treatment with reversible EGFR and/or HER2 inhibitors such as gefitinib, erlotinib, vandetanib (ZD-6474), AEE-788, PKI-166, lapatinib, cetuximab, nimotuzumab, matuzumab, panitumumab, trastuzumab and pertuzumab or other irreversible inhibitors such asCI-1033, EKB-569, HKI-272 or HKI-357. 
       BACKGROUND OF THE INVENTION 
       [0002]    Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers have generated enormous interest, providing an approach to predict for sensitivity to TK inhibitors (TKIs). While mutational status is of great importance in determining response to TKIs, it is not the sole factor, and evidence is accumulating that EGFR gene amplification, other members of the EGFR family (HER2, HER3) and genes downstream of EGFR signaling (KRAS, BRAF), may be involved in cancer pathogenesis and the response of TKIs. 
         [0003]    WO 2006/084058 discloses a method for the treatment of gefitinib and/or erlotinib resistant cancer comprising administered a pharmaceutical composition comprising an irreversible epidermal growth factor receptor (EGFR) inhibitor to a person in need of such treatment, specifying the irreversible EGFR inhibitors EKB-569, HKI-272 and HKI-357. 
         [0004]    Epithelial cell cancers, for example, prostate cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, ovarian cancer, cancer of the spleen, testicular cancer, cancer of the thymus, etc., are diseases characterized by abnormal, accelerated growth of epithelial cells. This accelerated growth initially causes a tumor to form. Eventually, metastasis to different organ sites can also occur. Although progress has been made in the diagnosis and treatment of various cancers, these diseases still result in significant mortality. 
         [0005]    Lung cancer remains the leading cause of cancer death in industrialized countries. Cancers that begin in the lungs are divided into two major types, non-small cell lung cancer and small cell lung cancer, depending on how the cells appear under a microscope. Non-small cell lung cancer (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) generally spreads to other organs more slowly than does small cell lung cancer. About 75 percent of lung cancer cases are categorized as non-small cell lung cancer (e.g., adenocarcinomas), and the other 25 percent are small cell lung cancer. Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States, Japan and Western Europe. For patients with advanced disease, chemotherapy provides a modest benefit in survival, but at the cost of significant toxicity, underscoring the need for therapeutic agents that are specifically targeted to the critical genetic lesions that direct tumor growth (Schiller J H et al., N Engl J Med, 346: 92-98, 2002). 
         [0006]    Two of the more advanced compounds in clinical development include Gefitinib (compound ZD 1839 developed by AstraZeneca UK Ltd.; available under the tradename IRESSA; hereinafter “IRESSA”) and Erlotinib (compound OSI-774 developed by Genentech, Inc. and OSI Pharmaceuticals, Inc.; available under the tradename TARCEVA; hereinafter “TARCEVA”); both have generated encouraging clinical results. Conventional cancer treatment with both IRESSA and TARCEVA involves the daily, oral administration of no more than 500 mg of the respective compounds. In May, 2003, IRESSA became the first of these products to reach the United States market, when it was approved for the treatment of advanced non-small cell lung cancer patients. IRESSA is an orally active quinazoline that functions by directly inhibiting tyrosine kinase phosphorylation on the EGFR molecule. It competes for the adenosine triphosphate (ATP) binding site, leading to suppression of the HER-kinase axis. The exact mechanism of the IRESSA response is not completely understood, however, studies suggest that the presence of EGFR is a necessary prerequisite for its action. 
         [0007]    A significant limitation in using these compounds is that recipients thereof may develop a resistance to their therapeutic effects after they initially respond to therapy, or they may not respond to EGFR-tyrosine kinase inhibitots (TKIs) to any measurable degree at all. The response rate to EGFR-TKIs varies between different ethnic groups. At the low end of EGFR-TKI responders, in some populations, only 10-15 percent of advanced non-small cell lung cancer patients respond to EGFR kinase inhibitors. Thus, a better understanding of the molecular mechanisms underlying sensitivity to IRESSA and TARCEVA would be extremely beneficial in targeting therapy to those individuals whom are most likely to benefit from such therapy. 
         [0008]    There is a significant need in the art for a satisfactory treatment of cancer, and specifically epithelial cell cancers such as lung, ovarian, breast, brain, colon and prostate cancers, which incorporates the benefits of TKI therapy and overcoming the non-responsiveness exhibited by patients. Such a treatment could have a dramatic impact on the health of individuals, and especially older individuals, among whom cancer is especially common. 
         [0009]    BIBW2992 (1) is known as the compound 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0010]    BIBW 2992 (1) is a potent and selective dual inhibitor of erbb1 receptor (EGFR) and erbB2 (Her2/neu) receptor tyrosine kinases. Furthermore, BIBW 2992 (1) was designed to covalently bind to EGFR and HER2 thereby irreversibly inactivating the receptor molecule it has bound to. This compound, salts thereof such as the dimaleate salt, their preparation as well as pharmaceutical formulations comprising BIBW2992 (1) or a salt thereof are disclosed in WO 02/50043 and WO 2005/037824. These documents are incorporated by reference regarding these aspects. 
       SUMMARY OF THE INVENTION 
       [0011]    Surprisingly, the irreversible dual EGFR/HER2 inhibitor BIBW2992 (1) is advantageously effective in the treatment of cancer in patients harbouring a mutation of the EGFR in the tumour, such as an activating mutation of the EGFR, especially where the activating mutation is associated with another mutation responsible for resistance or the emergence of acquired resistance to treatment with reversible EGFR inhibitors such as e.g. gefitinib and/or erlotinib or other irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357. Therefore. patients who show a reduced response or are not or no longer responding to gefitinib and/or erlotinib therapies may benefit from a BIBW 2992 treatment. 
         [0012]    Thus, as a first aspect and in the broadest embodiment the present invention relates to a method of treating patients suffering from cancer and harbouring a mutation of the EGFR gene in the tumour, compared to the native sequence of the EGFR. The said method comprises administering an effective amount of the irreversible EGFR inhibitor BIBW2992 (1) to a person in need of such treatment, optionally in combination with the administration of a further chemotherapeutic agent (2), and/or optionally in combination with radiotherapy, radio-immunotherapy and/or tumour resection by surgery. 
         [0013]    A second aspect of the present invention is the use of BIBW 2992 (1) for preparing a pharmaceutical composition for the treatment of a patient suffering from cancer and harbouring a mutation of the EGFR gene in the tumour, compared to the native receptor, optionally in combination with a further chemotherapeutic agent (2). 
         [0014]    In a first preferred embodiment of the present invention the mutation of the EGFR gene is an activating mutation. 
         [0015]    In a second preferred embodiment of the present invention the mutation of the EGFR is an activating mutation associated with a resistance or acquired resistance mutation to treatment with reversible EGFR and HER2 inhibitors such as gefitinib, erlotinib, vandetanib (ZD-6474), AEE-788, PKI-166, lapatinib, cetuximab, nimotuzumab, matuzumab, panitumumab, trastuzumab and pertuzumab or other irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357. 
         [0016]    Thus, in one embodiment, the present invention provides a method for the treatment of cancer resistant to treatment with reversible EGFR inhibitors, such as gefitinib and/or erlotinib resistant cancer. In this embodiment, progression of cancer in a subject is monitored at a time point after the subject has initiated gefitinib and/or erlotinib treatment or treatment with another reversible EGFR inhibitor. Progression of the cancer is indicative of cancer that is resistant to treatment with the reversible EGFR inhibitor. 
         [0017]    The progression of cancer may be monitored by methods well known to those of skill in the art. For example, the progression may be monitored by way of visual inspection of the cancer, such as, by means of X-ray, CT scan or MRI. Alternatively, the progression may be monitored by way of tumor biomarker detection. 
         [0018]    In one embodiment, the patient is monitored at various time points throughout the treatment of the cancer. For example, the progression of a cancer may be monitored by analyzing the progression of cancer at a second time point and comparing this analysis to an analysis at a first time point. The first time point may be before or after initiation of gefittinib and/or erlotinib treatment and the second time point is after the first. An increased growth of the cancer indicates progression of the cancer. 
         [0019]    In one embodiment, the cancer is epithelial cell cancer. In one embodiment, the cancer is gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, esophageal cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer. 
         [0020]    In one embodiment, the size of the cancer is monitored at additional time points, and the additional time points are after the second time point. 
         [0021]    In one embodiment, the later time point is at least 2 months after the preceding time point. In one embodiment, the later time point is at least 6 months after preceding time point. In one embodiment, the later time point is at least 10 months after preceding time point. In one embodiment, the later time point is at least one year after preceding time point. 
         [0022]    In another embodiment, the present invention provides a method of treating cancer, comprising administering to a subject having a mutation in EGFR, namely, a substitution of a methionine for a threonine at position 790, known as the T790M in the art, a pharmaceutical composition comprising an effective amount of BIBW 2992 (1). The T790M mutation confers resistance to gefitinib and/or erlotinib treatment. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0023]    The broadest embodiments of the present invention are not restricted with regard to the mutation of the EGFR, that is any difference in the sequence of the EGFR gene compared to the native sequence is to be understood as a mutation within the embodiments of the invention defined hereinbefore, e.g. the EGFR mutations selected from the group consisting of mutations listed in table 1. All EGFR mutations mentioned in table 1 are described in the state of the art. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 EGFR mutations 
               
             
          
           
               
                   
                 No. 
                 Position 
                 Amino Acid 
                 Type 
               
               
                   
                   
               
             
          
           
               
                   
                  1 
                 1 
                 M1_A566del 
                 activating 
               
               
                   
                  2 
                 30 
                 V30_K209del 
                 activating 
               
               
                   
                  3 
                 30 
                 V30_R297 &gt; G 
                 activating 
               
               
                   
                  4 
                 297 
                 R297 &gt; [aa30-297] 
                 activating 
               
               
                   
                  5 
                 545 
                 E545-G627del 
                 activating 
               
               
                   
                  6 
                 660 
                 V660L 
                 activating 
               
               
                   
                  7 
                 660 
                 V660L 
                 activating 
               
               
                   
                  8 
                 689 
                 p.Val689Met 
                 activating 
               
               
                   
                  9 
                 690 
                 E690-end 
                 activating 
               
               
                   
                  10 
                 700 
                 N700D 
                 activating 
               
               
                   
                  11 
                 709 
                 E709K 
                 activating 
               
               
                   
                  12 
                 709 
                 E709Q 
                 activating 
               
               
                   
                  13 
                 709 
                 E709A + L858R 
                 activating 
               
               
                   
                  14 
                 709 
                 E709G + L858R 
                 activating 
               
               
                   
                  15 
                 709 
                 E709K + L858R 
                 activating 
               
               
                   
                  16 
                 718 
                 L718P 
                 activating 
               
               
                   
                  17 
                 719 
                 G719A 
                 activating 
               
               
                   
                  18 
                 719 
                 G719C 
                 activating 
               
               
                   
                  19 
                 719 
                 G719S 
                 activating 
               
               
                   
                  20 
                 719 
                 G719D 
                 activating 
               
               
                   
                  21 
                 720 
                 S720F 
                 activating 
               
               
                   
                  22 
                 720 
                 S720P 
                 activating 
               
               
                   
                  23 
                 735 
                 G735S 
                 activating 
               
               
                   
                  24 
                 746 
                 E746_A750 &gt; QP 
                 activating 
               
               
                   
                  25 
                 746 
                 E746_A750del 
                 activating 
               
               
                   
                  26 
                 746 
                 E746_S752 &gt; A 
                 activating 
               
               
                   
                  27 
                 746 
                 E746_S752 &gt; V 
                 activating 
               
               
                   
                  28 
                 746 
                 E746_S752del 
                 activating 
               
               
                   
                  29 
                 746 
                 E746_T751 &gt; A 
                 activating 
               
               
                   
                  30 
                 746 
                 E746_A750 &gt; DP 
                 activating 
               
               
                   
                  31 
                 746 
                 E746_A750 &gt; IP 
                 activating 
               
               
                   
                  32 
                 746 
                 E746_A750 &gt; RP 
                 activating 
               
               
                   
                  33 
                 746 
                 E746_P753 &gt; LS 
                 activating 
               
               
                   
                  34 
                 746 
                 E746_P753 &gt; VS 
                 activating 
               
               
                   
                  35 
                 746 
                 E746_S752 &gt; A 
                 activating 
               
               
                   
                  36 
                 746 
                 E746_S752 &gt; D 
                 activating 
               
               
                   
                  37 
                 746 
                 E746_S752 &gt; I 
                 activating 
               
               
                   
                  38 
                 746 
                 E746_S752 &gt; T 
                 activating 
               
               
                   
                  39 
                 746 
                 E746_S752 &gt; V 
                 activating 
               
               
                   
                  40 
                 746 
                 E746_T751 &gt; A 
                 activating 
               
               
                   
                  41 
                 746 
                 E746_T751 &gt; I 
                 activating 
               
               
                   
                  42 
                 746 
                 E746_T751 &gt; IP 
                 activating 
               
               
                   
                  43 
                 746 
                 E746_T751 &gt; V 
                 activating 
               
               
                   
                  44 
                 746 
                 E746_T751 &gt; VA 
                 activating 
               
               
                   
                  45 
                 746 
                 E746_T751 &gt; VP 
                 activating 
               
               
                   
                  46 
                 746 
                 E746_P753 &gt; LS 
                 activating 
               
               
                   
                  47 
                 746 
                 E746_P753 &gt; VS 
                 activating 
               
               
                   
                  48 
                 746 
                 E746_S752 &gt; D 
                 activating 
               
               
                   
                  49 
                 746 
                 E746_S752 &gt; I 
                 activating 
               
               
                   
                  50 
                 746 
                 E746_S752 &gt; T 
                 activating 
               
               
                   
                  51 
                 746 
                 E746_T751 &gt; I 
                 activating 
               
               
                   
                  52 
                 746 
                 E746_T751 &gt; IP 
                 activating 
               
               
                   
                  53 
                 746 
                 E746_T751 &gt; V 
                 activating 
               
               
                   
                  54 
                 746 
                 E746_T751 &gt; VA 
                 activating 
               
               
                   
                  55 
                 746 
                 E746_T751 &gt; VP 
                 activating 
               
               
                   
                  56 
                 746 
                 E746_T751del 
                 activating 
               
               
                   
                  57 
                 747 
                 L747-K754 &gt; SR 
                 activating 
               
               
                   
                  58 
                 747 
                 L747_E749del 
                 activating 
               
               
                   
                  59 
                 747 
                 p.Leu747_Glu749del; 
                 activating 
               
               
                   
                   
                   
                 p.Ala750Pro 
               
               
                   
                  60 
                 747 
                 L747_P753 &gt; S 
                 activating 
               
               
                   
                  61 
                 747 
                 L747_S752 &gt; Q 
                 activating 
               
               
                   
                  62 
                 747 
                 L747_S752del 
                 activating 
               
               
                   
                  63 
                 747 
                 L747_T751 &gt; P 
                 activating 
               
               
                   
                  64 
                 747 
                 L747_T751 &gt; S 
                 activating 
               
               
                   
                  65 
                 747 
                 L747_T751del 
                 activating 
               
               
                   
                  66 
                 747 
                 L747-K754 &gt; ST 
                 activating 
               
               
                   
                  67 
                 747 
                 K745_L747del 
                 activating 
               
               
                   
                  68 
                 747 
                 L747_A750 &gt; P 
                 activating 
               
               
                   
                  69 
                 747 
                 L747_P753 &gt; Q 
                 activating 
               
               
                   
                  70 
                 747 
                 L747_R748 &gt; FP 
                 activating 
               
               
                   
                  71 
                 747 
                 L747_S752 &gt; QH 
                 activating 
               
               
                   
                  72 
                 747 
                 L747_T751 &gt; Q 
                 activating 
               
               
                   
                  73 
                 750 
                 A750P 
                 activating 
               
               
                   
                  74 
                 752 
                 S752_I759del 
                 activating 
               
               
                   
                  75 
                 765 
                 p.Val765Ala 
                 activating 
               
               
                   
                  76 
                 766 
                 M766_A767insAI 
                 activating 
               
               
                   
                  77 
                 767 
                 A767_S768insSVA 
                 activating 
               
               
                   
                  78 
                 767 
                 A767_S768insTLA 
                 activating 
               
               
                   
                  79 
                 768 
                 S768I 
                 activating 
               
               
                   
                  80 
                 773 
                 H773R 
                 activating 
               
               
                   
                  81 
                 776 
                 R776C 
                 activating 
               
               
                   
                  82 
                 783 
                 T783A 
                 activating 
               
               
                   
                  83 
                 796 
                 G796S 
                 activating 
               
               
                   
                  84 
                 804 
                 E804G 
                 activating 
               
               
                   
                  85 
                 826 
                 N826S 
                 activating 
               
               
                   
                  86 
                 835 
                 H835L 
                 activating 
               
               
                   
                  87 
                 838 
                 L838V 
                 activating 
               
               
                   
                  88 
                 839 
                 A839T 
                 activating 
               
               
                   
                  89 
                 858 
                 L858R 
                 activating 
               
               
                   
                  90 
                 861 
                 L861Q 
                 activating 
               
               
                   
                  91 
                 863 
                 G863D 
                 activating 
               
               
                   
                  92 
                 761 
                 D761N 
                 resistance 
               
               
                   
                  93 
                 770 
                 D770_N771insNPG 
                 resistance 
               
               
                   
                  94 
                 770 
                 D770_N771insSVD 
                 resistance 
               
               
                   
                  95 
                 770 
                 D770_P772 &gt; ASVDNR 
                 resistance 
               
               
                   
                  96 
                 790 
                 T790M 
                 resistance 
               
               
                   
                  96-a 
                 870 
                 H870R 
                 resistance 
               
               
                   
                  97 
                 884 
                 E884K 
                 resistance 
               
               
                   
                  98 
                 46 
                 D46N; G63R 
               
               
                   
                  99 
                 108 
                 R108K 
               
               
                   
                 100 
                 263 
                 T263P 
               
               
                   
                 101 
                 289 
                 A289D 
               
               
                   
                 102 
                 289 
                 A289T 
               
               
                   
                 103 
                 289 
                 A289V 
               
               
                   
                 104 
                 324 
                 R324L 
               
               
                   
                 105 
                 330 
                 E330K 
               
               
                   
                 106 
                 596 
                 P596L 
               
               
                   
                 107 
                 598 
                 G598V 
               
               
                   
                 108 
                 624 
                 C624F 
               
               
                   
                 109 
                 624 
                 C624F 
               
               
                   
                 110 
                 688 
                 L688P 
               
               
                   
                 111 
                 694 
                 P694L 
               
               
                   
                 112 
                 694 
                 P694S 
               
               
                   
                 113 
                 703 
                 L703V 
               
               
                   
                 114 
                 707 
                 L707L 
               
               
                   
                 115 
                 715 
                 I715S 
               
               
                   
                 116 
                 718 
                 L718L 
               
               
                   
                 117 
                 719 
                 G719C + S768I 
               
               
                   
                 118 
                 719 
                 G719S + S768I 
               
               
                   
                 119 
                 724 
                 G724S 
               
               
                   
                 120 
                 725 
                 T725M 
               
               
                   
                 121 
                 727 
                 Y727C 
               
               
                   
                 122 
                 729 
                 G729E 
               
               
                   
                 123 
                 730 
                 L730F 
               
               
                   
                 124 
                 731 
                 W731* 
               
               
                   
                 125 
                 733 
                 P733L 
               
               
                   
                 126 
                 734 
                 E734K 
               
               
                   
                 127 
                 735 
                 G735S 
               
               
                   
                 128 
                 742 
                 V742A 
               
               
                   
                 129 
                 743 
                 A743S 
               
               
                   
                 130 
                 743 
                 A743P 
               
               
                   
                 131 
                 744 
                 I744_K745insKIPVAI 
               
               
                   
                 132 
                 745 
                 K745_L747del 
               
               
                   
                 133 
                 745 
                 K745R 
               
               
                   
                 134 
                 746 
                 E746del 
               
               
                   
                 135 
                 746 
                 E746K 
               
               
                   
                 136 
                 746 
                 E746V 
               
               
                   
                 137 
                 751 
                 T751_I759 &gt; S 
               
               
                   
                 138 
                 751 
                 T751I 
               
               
                   
                 139 
                 752 
                 S752_I759del 
               
               
                   
                 140 
                 752 
                 S752Y 
               
               
                   
                 141 
                 753 
                 P753P 
               
               
                   
                 142 
                 753 
                 P753S 
               
               
                   
                 143 
                 754 
                 K754R 
               
               
                   
                 144 
                 755 
                 A755A 
               
               
                   
                 145 
                 761 
                 D761_E762insEAFQ 
               
               
                   
                 146 
                 764 
                 Y764Y 
               
               
                   
                 147 
                 768 
                 S768-D770insIVD 
               
               
                   
                 148 
                 768 
                 S768I + V769L 
               
               
                   
                 149 
                 768 
                 S768I + V774M 
               
               
                   
                 150 
                 769 
                 D769_D770 &gt; GY 
               
               
                   
                 151 
                 769 
                 V769_D770insASV 
               
               
                   
                 152 
                 769 
                 V769_D770insCV 
               
               
                   
                 153 
                 769 
                 V769_D770insGSV 
               
               
                   
                 154 
                 769 
                 V769_D770insGVV 
               
               
                   
                 155 
                 769 
                 V769L 
               
               
                   
                 156 
                 769 
                 V769M 
               
               
                   
                 157 
                 769 
                 V769_D770insASV 
               
               
                   
                 158 
                 769 
                 V769_D770insCV 
               
               
                   
                 159 
                 769 
                 V769_D770insDNV 
               
               
                   
                 160 
                 769 
                 V769_D770insGSV 
               
               
                   
                 161 
                 769 
                 V769_D770insGVV 
               
               
                   
                 162 
                 769 
                 V769-771 &gt; VAS 
               
               
                   
                 163 
                 770 
                 D770_N771insAPW 
               
               
                   
                 164 
                 770 
                 D770_N771insG 
               
               
                   
                 165 
                 770 
                 D770_N771insN 
               
               
                   
                 166 
                 770 
                 D770_N771insSVD 
               
               
                   
                 167 
                 770 
                 D770_N771insSVQ 
               
               
                   
                 168 
                 770 
                 D770-P772 &gt; DNV 
               
               
                   
                 169 
                 770 
                 D770_N771 &gt; AGG 
               
               
                   
                 170 
                 770 
                 D770_N771insG 
               
               
                   
                 171 
                 770 
                 D770_N771insN 
               
               
                   
                 172 
                 770 
                 D770N 
               
               
                   
                 173 
                 771 
                 N771-H773 &gt; APW 
               
               
                   
                 174 
                 771 
                 N771-H773insNPH 
               
               
                   
                 175 
                 771 
                 N771_P772 &gt; SVDNR 
               
               
                   
                 176 
                 771 
                 N771 &gt; GF 
               
               
                   
                 177 
                 772 
                 P772_H773insX 
               
               
                   
                 178 
                 772 
                 P772-H773insN 
               
               
                   
                 179 
                 773 
                 H773_V774insH 
               
               
                   
                 180 
                 773 
                 H773_V774insNPH 
               
               
                   
                 181 
                 773 
                 H773_V774insPH 
               
               
                   
                 182 
                 773 
                 H773_V774insH 
               
               
                   
                 183 
                 773 
                 H773_V774insNPH 
               
               
                   
                 184 
                 773 
                 H773_V774insPH 
               
               
                   
                 185 
                 773 
                 H773 &gt; NPY 
               
               
                   
                 186 
                 773 
                 H773L 
               
               
                   
                 187 
                 774 
                 V774_C775insHV 
               
               
                   
                 188 
                 774 
                 V774M 
               
               
                   
                 189 
                 774 
                 V774-776 &gt; NPH 
               
               
                   
                 190 
                 779 
                 G779F 
               
               
                   
                 191 
                 783 
                 T783I 
               
               
                   
                 192 
                 784 
                 S784F 
               
               
                   
                 193 
                 787 
                 Q787R 
               
               
                   
                 194 
                 792 
                 L792P 
               
               
                   
                 195 
                 798 
                 L798F 
               
               
                   
                 196 
                 803 
                 R803L 
               
               
                   
                 197 
                 810 
                 G810S 
               
               
                   
                 198 
                 810 
                 G810S 
               
               
                   
                 199 
                 819 
                 V819V 
               
               
                   
                 200 
                 833 
                 L833V 
               
               
                   
                 201 
                 834 
                 V834L 
               
               
                   
                 202 
                 841 
                 R841K 
               
               
                   
                 203 
                 846 
                 K846R 
               
               
                   
                 204 
                 847 
                 T847I 
               
               
                   
                 205 
                 850 
                 H850N 
               
               
                   
                 206 
                 851 
                 V851A 
               
               
                   
                 207 
                 851 
                 V851I 
               
               
                   
                 208 
                 853 
                 I853T 
               
               
                   
                 209 
                 856 
                 F856L 
               
               
                   
                 210 
                 864 
                 A864T 
               
               
                   
                 211 
                 866 
                 E866K 
               
               
                   
                 212 
                 872 
                 E872* 
               
               
                   
                 213 
                 873 
                 G873E 
               
               
                   
                 214 
                 897 
                 V897I 
               
               
                   
                 215 
                 983 
                 G983_end 
               
               
                   
                 216 
                 1036 
                 L1036_end 
               
               
                   
                 217 
                 1038 
                 L1038 &gt; [aa688-1038] 
               
               
                   
                 218 
                 1048 
                 A1048V 
               
               
                   
                 219 
                 1054 
                 G1054 &gt; [aa688-1054] 
               
               
                   
                 220 
                 1070 
                 S1070A 
               
               
                   
                 221 
                 1071 
                 S1071A 
               
               
                   
                   
               
             
          
         
       
     
         [0024]    In the table above mutations have been described as single events. It should be noted that in terms of frequency 90% of the sensitizing mutations are covered by exon 19 deletions (e.g positions 746 and 747, 61%) and exon 21 point mutations (L858R, 24 %; L861Q, 4%). It should also be noted that complex mutation combination patterns are often observed (e.g. G719S+S768I). In acquired resistance where the resistance mutation (e.g. T790M) is acquired in an activating background, a complex combination pattern is a common rule. 
         [0025]    In the first preferred embodiment of the present invention the mutation of the EGFR is an activating mutation, e.g selected from the group consisting of mutations identified in table 1 under No. 1 to 91, or, even more preferred, identified in table 1 under No. 1 to 29, 57 to 65, 73, 75, 76, 77, 79 and 80-91. 
         [0026]    In the second preferred embodiment of the present invention the mutation of the EGFR is an activating mutation associated with a resistance or acquired resistance mutation to treatment with reversible EGFR and HER2 inhibitors such as gefitinib, erlotinib, vandetanib (ZD-6474), AEE-788, PKI-166, lapatinib, cetuximab, nimotuzumab, matuzumab, panitumumab, trastuzumab and pertuzumab or other irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357, e.g selected from the group consisting of mutations identified in table 1 under No. 92 to 97, or, even more preferred, identified in table 1 under No. 92, 93, 96, 96-a and 97. 
         [0027]    According to a third subgroup of preferred embodiments of the present invention the mutation of the EGFR is predictive for Gefitinib and/or Erlotinib sensitivity and includes deletion of residues 747 (lysine) to 749 (glutamic acid) combined with a mutation in 750 (alanine), deletion of residues 747 (lysine) to 750 (alanine), substitution of arginine for leucine at residue 858, or substitution of glutamine for leucine at residue 861. 
         [0028]    In a fourth preferred embodiment of the present invention the mutation of the EGFR is selected from the group consisting of T790M, E746_A750del, E746_S752&gt;V, L747_P753&gt;S, L858R, L747_A750&gt;P, S752_I759del. 
         [0029]    Examples of carcinomas showing resistance or acquired resistance to treatment with reversible EGFR and HER2 inhibitors such as gefitinib or erlotinib or to other irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357 within the scope of the invention include but are not limited to adenocarcinoma (AC), squamous cell carcinoma (SCC) and mixed or undifferentiated carcinomas. Carcinomas within the scope of the invention include but are not limited to the following histologies:
       Head and neck tumours: SCC, AC, transitional cell cancers, mucoepidermoid cancers, undifferentiated carcinomas;   Central nervous system tumours: Astrocytoma, glioblastoma, meningeoma, neurinoma, schwannoma, ependymoma, hypophysoma, oligodendroglioma, medulloblastoma;   Bronchial and mediastinal tumours:
           Bronchial tumours:
               Small cell lung cancers (SCLC): oat-cell lung cancer, intermediate cell cancer, combined oat-cell lung cancer;   Non-small cell lung cancers (NSCLC): SCC, spindle cell carcinoma, AC, bronchioalveolar carcinoma, large cell NSCLC, clear cell NSCLC;   
               Mesothelioma;   Thymoma;   Thyroid carcinomas: papillary, follicular, anaplastic, medullary;   
           Tumours of the gastrointestinal tract:
           Oesophageal cancers: SCC, AC, anaplastic, carcinoid, sarcoma;   Gastric cancers: AC, adenosquamous, anaplastic;   Colorectal cancers: AC, including hereditary forms of AC, carcinoid, sarcoma;   Anal cancers: SCC, transitional epithelial cancer, AC, basal cell carcinoma;   Pancreatic cancers: AC, including ductal and acinary cancers, papillary, adenosquamous, undifferentiated, tumours of the endocrine pancreas;   Hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, hepatoblastoma;   Biliary carcinomas: AC, SCC, small cell, undifferentiated;   Gastrointestinal stroma tumours (GIST);   
           Gynaecological cancers:
           Breast cancers: AC, including invasive ductal, lobular and medullary cancers, tubular, mucinous cancers, Paget-carcinoma, inflammatory carcinoma, ductal and lobular carcinoma in situ;   Ovarian cancers: Epithelial tumours, stroma tumours, germ cell tumours, undifferentiated tumours;   Cervical cancers: SCC, AC, mixed and undifferentiated tumours;   Endometrial cancers: AC, SCC, mixed, undifferentiated tumours;   Vulvar cancers: SCC, AC;   Vaginal cancers: SCC, AC;   
           Urinary tract and testicular cancers:
           Testicular cancers: seminoma;   Non-seminomatous germ cell tumours: teratoma, embryonal cell carcinoma, choriocarcinoma, yolk sac tumour, mixed, Sertoli and Leydig-cell tumours;   Extragonadal germ cell tumours;   Prostate cancers: AC, small cell, SCC;   Renal cell cancers: AC, including clear cell, papillary and chromophobous carcinomas, hereditary forms (e.g. von-Hippel-Lindau syndrome), nephroblastoma;   Urinary bladder cancers: transitional cell (urothelial) cancers, SCC, AC;   Urethral cancers: SCC, transitional cell cancers, AC;   Penile cancers: SCC;   
           Tumours of endocrine tissue:
           Thyroid cancers: papillary, follicular, anaplastic, medullary carcinomas, including MEN syndrome;   Tumours of the endocrine pancreas;   Carcinoids;   Pheochromocytoma.
 
Preferably, the resistant cancer indication is selected from the group consisting of
   Head and neck tumours: SCC, AC, transitional cell cancers, mucoepidermoid cancers, undifferentiated carcinomas;   Colorectal cancers, metastatic or non-metastatic: AC, including hereditary forms of AC, carcinoid, sarcoma;   Pancreatic cancers: AC, including ductal and acinary cancers, papillary, adenosquamous, undifferentiated, tumours of the endocrine pancreas;   Breast cancers, metastatic or non-metastatic: AC, including invasive ductal, lobular and medullary cancers, tubular, mucinous cancers, Paget-carcinoma, inflammatory carcinoma, ductal and lobular carcinoma in situ;   Prostate cancers: AC, small cell, SCC;   Non-small cell lung cancers (NSCLC): SCC, spindle cell carcinoma, AC, bronchioalveolar carcinoma, large cell NSCLC, clear cell NSCLC.   
               
 
         [0075]    Within the meaning of the present invention, the following classes of chemotherapeutic agents (2) are especially of interest, although not representing a limitation:
       Synthetic small molecule VEGF receptor antagonists   Small molecule growth factor (GF) receptor antagonists   Inhibitors of the EGF receptor and/or HER2 receptors and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are not classified under the synthetic small-molecules   Small molecule Polo-like kinase-1 (PLK-1) inhibitors   Small molecule inhibitors of the Ras/Raf/MAPK or PI3K/AKT pathways or any other serine/threonine kinases.   Inhibitors of the Ras/Raf/MAPK or PI3K/AKT pathways or any other serine/threonine kinases, which are not classified under the synthetic small-molecules   Inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are synthetically manufactured antibodies, antibody fragments or fusion proteins   Inhibitors directed to circulating VEGF, which are synthetically manufactured antibodies, antibody fragments or fusion proteins   Inhibitors directed to the IGF1 receptor and/or IGF1 or IGF2 growth factor, which are synthetically manufactured chemical entities or antibodies, antibody fragments or fusion proteins   Compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds   Compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents   Anti-metabolites   Naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics (BLM-group antibiotics)   Inhibitors of DNA transcribing enzymes, especially topoisomerase I or topoisomerase II inhibitors   Chromatin modifying agents   Mitosis inhibitors, anti-mitotic agents, or cell-cycle inhibitors   Compounds interacting with or binding tubulin   Compounds inhibiting mitotic kinesins or other motor proteins including but not limited to Eg5, CENP-E, MCAK, Kid, MKLP-1   Proteasome inhibitors   Heat shock protein inhibitors   Compounds targeting the anti-apoptotic function of Bcl-2, Bcl-x 1  and like molecules   Enzymes Hormones, hormone antagonists or hormone inhibitors, or inhibitors of steroid biosynthesis   Steroids   Cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines or oral and parenteral tolerance induction strategies   Supportive agents   Antiinflammatory compounds such as but not limited to COX-2 inhibitors   Chemical radiation sensitizers and protectors   Photochemically activated drugs   Synthetic poly- or oligonucleotides   Other chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agents, such as cytotoxic antibiotics, antibodies targeting surface molecules of cancer cells, antibodies targeting growth factors or their receptors, inhibitors of metalloproteinases, inhibitors of oncogenes, inhibitors of gene transcription or of RNA translation or protein expression, or complexes of rare earth elements.       
 
         [0106]    In another preferred embodiment of the invention the chemotherapeutic agent (2) is selected from the group consisting of a small molecule VEGF receptor antagonist such as vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, a dual EGFR/HER2 antagonist such as gefitinib, erlotinib, HKI-272, CI-1033 or GW-2016, an EGFR antagonist such as iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569 or herceptin, an antagonist of the mitogen-activated protein kinase such as BAY-43-9006 or BAY-57-9006, a protein kinase receptor antagonist which is not classified under the synthetic small molecules such as atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), bivatuzumab mertansine, IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, a protein tyrosine kinase inhibitor which is a fusion protein such as VEGFtrap, an alkylating agent or a platinum compound such as melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, a nitrogen mustard such as mechlorethamine, an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide such as propamidine or stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, a pyrimidine or purine analogue or antagonist or an inhibitor of the nucleoside diphosphate reductase such as cytarabine, 5-fluorouracile (5-FU), pemetrexed, tegafur/uracil, uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, or folic acid, a phleomycin, a bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, a camptothecin such as irinotecan (camptosar) or topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, an histonedeacetylase inhibitor such as SAHA, MD-275, trichostatin A, CBHA, LAQ824, or valproic acid, an anti-cancer drug from plants such as paclitaxel (taxol), docetaxel or taxotere, a vinca alkaloid such as navelbine, vinblastin, vincristin, vindesine or vinorelbine, a tropolone alkaloid such as colchicine or a derivative thereof, a macrolide such as maytansine, an ansamitocin or rhizoxin, an antimitotic peptide such as phomopsin or dolastatin, an epipodophyllotoxin or a derivative of podophyllotoxin such as etoposide or teniposide, a steganacin, an antimitotic carbamate derivative such as combretastatin or amphetinile, procarbazine, a proteasome inhibitor such as bortezomib, an enzyme such as asparaginase, pegylated asparaginase (pegaspargase) or a thymidine-phosphorylase inhibitor, a gestagen or an estrogen such as estramustine (T-66) or megestrol, an anti-androgen such as flutamide, casodex, anandron or cyproterone acetate, an aromatase inhibitor such as aminogluthetimide, anastrozole, formestan or letrozole, a GNrH analogue such as leuprorelin, buserelin, goserelin or triptorelin, an anti-estrogen such as tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene or zindoxifene, a derivative of 17β-estradiol such as ICI 164,384 or ICI 182,780, aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, a LH-RH antagonist such as leuprolide, a steroid such as prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone or triamcinolone, an interferon such as interferon β, an interleukin such as IL-10 or IL-12, an anti-TNFα antibody such as etanercept, TNF-α (tasonermin), an immunomodulatory drug such as thalidomide, its R- and S-enantiomers and its derivatives, or revimid (CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone such as BMY-42355, AZQ or EO-9, a 2-nitroimidazole such as misonidazole, NLP-1 or NLA-1, a nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a “dual-function” nitro aromatic such as RSU-1069 or RB-6145, CB-1954, a N-oxide of nitrogen mustard such as nitromin, a metal complex of a nitrogen mustard, an anti-CD3 or anti-CD25 antibody, a tolerance induction agent, a biphosphonate or derivative thereof such as minodronic acid or its derivatives (YM-529, Ono-5920, YH-529), zoledronic acid monohydrate, ibandronate sodium hydrate or clodronate disodium, a nitroimidazole such as metronidazole, misonidazole, benznidazole or nimorazole, a nitroaryl compound such as RSU-1069, a nitroxyl or N-oxide such as SR-4233, an halogenated pyrimidine analogue such as bromodeoxyuridine, iododeoxyuridine, a thiophosphate such as WR-2721, a photo-chemically activated drug such as porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide derivative, merocyanin 540 (MC-540) or tin etioporpurin, an ant-template or an anti-sense RNA or DNA such as oblimersen, a non-steroidal inflammatory drug such as acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib, rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal inflammatory drug, a cytotoxic antibiotic, an antibody targeting the surface molecules of cancer cells such as apolizumab or 1D09C3, an inhibitor of metalloproteinases such as TIMP-1 or TIMP-2, Zinc, an inhibitor of oncogenes such as P53 and Rb, a complex of rare earth elements such as the heterocyclic complexes of lanthanides, a photo-chemotherapeutic agent such as PUVA, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of HER-2 expression, such as the heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin or 17-AAG, or a therapeutic agent selected from IM-842, tetrathiomolybdate, squalamine, combrestatin A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukin diftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane, pipobroman, plicamycin, tamoxifen and testolactone. 
         [0107]    For instance, cancers may initially be diagnosed as gefitinib/erlotinib sensitive or predicted to be gefitinib/erlotinib sensitive by means ofthe methods described in Lynch et al., 2004; 350:2129-2139. Gefitinib/erlotinib sensitivity may be predicted by the presence in the tumor of EGFR mutations including, for example, deletion of residues 747 (lysine) to 749 (glutamic acid) combined with a mutation in 750 (alanine), deletion of residues 747 (lysine) to 750 (alanine), substitution of arginine for leucine at residue 858, of substitution of glutamine for leucine at residue 861. 
         [0108]    Cancers may be diagnosed as resistant to treatment with reversible EGFR and HER2 inhibitors such as gefitinib or erlotinib or to treatment with other irreversible inhibitors such as CI-1033, EKB-569, HKI-272 or HKI-357 after treatment with the respective actives has commenced. Alternatively, cancers may be diagnosed as resistant to the actives mentioned hereinbefore prior to initiation of treatment with such compounds. For instance, Gefitinib and/or erlotinib resistance in the tumor may occur after, e.g., 6 months or longer of gefitinib and/or erlotinib treatment. Alternatively, gefitinib and/or erlotinib resistance ofthe tumor may be diagnosed less than 6 months after gefitinib and/or erlotinib treatment has commenced. Diagnosis of gefitinib and/or erlotinib resistance may be accomplished by way of monitoring tumor progression during gefitinib and/or erlotinib treatment. Tumor progression may be determined by comparison of tumor status between time points after treatment has commenced or by comparison of tumor status between a time point after treatment has commenced to a time point prior to initiation of gefitinib and/or erlotinib treatment. Tumor progression may be monitored during gefitinib and/or erlotinib treatment visually, for example, by means of radiography, for example, X-ray, CT scan, or other monitoring methods known to the skilled artisan, including palpitation of the cancer or methods to monitor tumor biomarker levels. Progression of the cancer during treatment with gefitinib and/or erlotinib indicates gefitinib and/or erlotinib resistance. A rise in level of tumor biomarkers indicates tumor progression. Thus, a rise in tumor biomarker levels during treatment with gefitinib and/or erlotinib indicates gefitinib and/or erlotinib resistance. Detection of new tumors or detection of metastasis indicates tumor progression. Cessation of tumor shrinkage indicates tumor progression. Growth of the cancer is indicated by, for example, increase in tumor size, metastasis or detection of new cancer, and/or a rise in tumor biomarker levels. The same applies analogously in the case of resistance to other actives mentioned hereinbefore. 
         [0109]    The development of resistance to the actives mentioned hereinbefore may be monitored by means of testing for presence of a mutation associated with resistance to the respective active in circulating tumor cells obtained from the circulation, or other bodily fluid, of the subject. For instance, presence of gefitinib and/or erlotinib resistance associated mutations in tumor cells from the subject is indicative of a gefitinib and/or erlotinib resistant tumor. 
         [0110]    In one embodiment, the subject&#39;s tumor harbors mutations indicative of gefitinib and/or erlotinib sensitivity, yet it is resistant to gefitinib and/or erlotinib treatment. In one embodiment, the subject&#39;s tumor harbors mutations indicative gefitinib and/or erlotinib sensitivity and harbors mutations indicative of gefitinib and/or erlotinib resistance, e.g., the T790M mutation, that is, where a methione residue is substituted for the native threonine residue, in EGFR, e.g. increased EGFR internalization. In one embodiment, the subject&#39;s tumor does not harbor mutations indicative of gefitinib and/or erlotinib sensitivity and does harbor mutations indicative of gefitinib and/or erlotinib resistance, e.g., the T790M mutation in EGFR, e.g., increased EGFR internalization. 
         [0111]    In connection with the administration of the drug, an “effective amount” indicates an amount that results in a beneficial effect for at least a statistically significant fraction of patients, such as a improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition. 
         [0112]    Method of Treatment: 
         [0113]    The method of treatment according to the invention comprises administration of therapeutically effective amount of BIBW 2992 (1) or a pharmaceutically acceptable salt thereof, preferably the dimaleate salt, optionally in combination with the administration of a further chemotherapeutic agent (2), to a patient in need thereof, [s.u.] optionally in combination with radiotherapy, radio-immunotherapy and/or tumour resection by surgery. 
         [0114]    The term “therapeutically effective amount” shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician, resulting in a beneficial effect for at least a statistically significant fraction of patients, such as a improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, improvement in quality of life. 
         [0115]    In accordance with the present invention BIBW 2992 (1) and the optional chemotherapeutic (2) may be administered by oral (including buccal or sublingual), enterical, parenteral (e.g., intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection, or implant), nasal, vaginal, rectal, or topical (e.g. inhalative) routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. 
         [0116]    In a preferred embodiment BIBW 2992 (1) is administered orally, enterically, transdermally, intravenously, peritoneally or by injection, preferably orally. 
         [0117]    Dosages/BIBW 2992: 
         [0118]    In one embodiment the invention relates to the method of treatment described above, characterised in that BIBW 2992 (1), or its polymorph, metabolite, hydrate, solvate, or a pharmaceutically acceptable salt thereof, is administered intermittent or in a daily dosage such that the plasma level of the active substance preferably lies between 10 and 5000 nM for at least 12 hours of the dosing interval. 
         [0119]    BIBW 2992 (1) may be administered to the human patient in a daily dose of 0.01-4 mg/kg of body weight (bw), preferably 0.1-2 mg/kg, particularly preferred in a dose of 0.2-1.3 mg/kg bw. For oral treatment the compounds of formula (I) may be administered daily in a total dose of 10, 20, 30, 40, 50, 60, 70, 100, 200, or 300 mg, optionally divided into multiple doses, e.g. 1 to 3 doses to be administered through the day. Preferably the oral daily dose is administered only once a time. Especially for higher doses periods of treatment should alternate with periods of recovery, without administering the active of formula (I). For instance, treatment could follow a “7 day on—7 day off”, a “14 day on—14 day off”, a “21 day on 7 day off” or a continuous dosing schedule. “On-off” time periods can be chosen shorter, especially if higher doses are administered, or individually adapted to the needs of the patient. 
         [0120]    The dosage for intravenous use of BIBW2992MA 2  may be 1-1000 mg, preferably 5-300 mg, particularly preferred 10-100 mg (dosages refer to the base form BIBW2992 (1)), either given as a bolus or, especially if higher doses are applied, as a slow intravenous infusion over several hours, e.g. over about 1, 2, 4, 6, 10, 12 or 24 hours. 
         [0121]    However, it may optionally be necessary to deviate from the amounts specified, depending on the body weight or method of administration, the individual response to the medication, the nature of the formulation used and the time or interval over which it is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified above, while in other cases the upper limit specified will have to be exceeded. When large amounts are administered it may be advisable to spread them over the day in a number of single doses. 
         [0122]    Dosages/Chemotherapeutic Agents (2): 
         [0123]    Dosages and treatment schedules for the individual chemotherapeutic agents (2) are known in the art and may be applied analogously within the invention. Depending on the individual activity of the specific combination dosage of the chemotherapeutic agents (2) may be reduced, e.g. may vary in the range of 1/1 to 1/20 of the dosages described in the prior art. 
         [0124]    For patients with metastatic breast cancer the combination with docetaxel may be given at a dose between 55 mg/m 2  and 100 mg/m 2  and most specifically at a dose of 60 to 75 mg/m 2  in administration schedule of once every 21 days. In a weekly administration schedule the dose of docetaxel may be lowered. 
         [0125]    A similar dose range of docetaxel will be used in the treatment of hormone-refractory prostate cancer. In this case docetaxel is administered together with daily prednisone and/or with the administration of estramustine. The dose of estramustine is 14 mg per kg of body weight given in 3 or 4 divided doses daily. Most patients are treated at a dose range between 10 and 16 mg/kg body weight. 
         [0126]    Docetaxel is also used in the treatment of non-small cell lung cancer at similar doses and schedules. 
         [0127]    In patients with metastatic breast cancer, the administration of paclitaxel is at a dose of up to 175 mg/m 2  over 3 hours every 3 weeks. In a weekly administration schedule paclitaxel dose may be lower. In an adjuvant setting, paclitaxel will be administered at doses up to 175 mg/m 2  over 3 hours every 3 weeks sequentially to a combination with a doxorubicin-containing chemotherapy (four courses of doxorubicin and cyclophosphamide were used). 
         [0128]    For patients with non-small cell lung cancer the recommended dose of paclitaxel is 135 mg/m 2  IV over 24 hours every 3 weeks. The administration of paclitaxel is followed by cisplatin at 75 mg/m 2 . Another option is the combination of paclitaxel with carboplatin. 
         [0129]    In patients with ovarian carcinoma, paclitaxel is used at a dose of 175 mg/m 2  IV over 3 hours followed by cisplatin at 75 mg/m 2  or at a dose of 135 mg/m 2  over 24 hours followed by cisplatin at a dose of 75 mg/m 2 . Paclitaxel can also be combined with carboplatin. This cycle will be repeated every 3 weeks. Another treatment schedule in the more advanced disease setting is the administration of paclitaxel at either 135 or 175 mg/m 2  IV over 3 hours every 3 weeks. 
         [0130]    Carboplatin is administered as a single agent in recurrent ovarian carcinoma at a dose of 360 mg/m 2  IV on day 1 every 4 weeks. In advanced ovarian carcinoma it is used at a dose of 300 mg/m 2  on day 1 every 4 weeks for six cycles together with cyclophosphomide 600 mg/m 2  on day 1 every four weeks for 6 cycles. Carboplatin is also used in combination with paclitaxel for the treatment of advanced ovarian cancer and advanced non-small cell lung cancer. 
         [0131]    In patients with breast cancer and colorectal cancer, the administration of capecitabine is used at a dose of up to 1250 mg/m 2  twice daily for 2 weeks followed by a 1-week rest before repating this 3-week regimen. Such a dose will also be used in the adjuvant treatment of colorectal cancer for a total of eight 3-week cycles. When combining with drugs like docetaxel dose reductions according to actually experienced side effects may become necessary. 
         [0132]    In patients with metastatic breast cancer, gemcitabine at a dose of 1250 mg/m 2  over 30 minutes on days 1 and 8 of each 21-day treatment cycle will be used in combination with paclitaxel. Paclitaxel should be administered at 175 mg/m 2  as a 3-hour infusion before the administration of gemcitabine on day 1. 
         [0133]    Gemcitabine is also used for the treatment of pancreatic cancer at a dose of up to 1000 mg/m 2  over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding the dose) followed by a week of rest. Subsequent cycles will be administration for 3 consecutive weeks every 4 weeks. 
         [0134]    In non-small cell lung cancer, gemcitabine is used in two schedules. In the first schedule, gemcitabine is administered at 1000 mg/m 2  over 30 minutes on days 1, 8, and 15 every 4 weeks. Cisplatin is administerd at 100 mg/m 2  IV on day 1 after the infusion of gemcitabine. In another schedule gemcitabine is administered at 1250 mg/m 2  IV over 30 minutes on days 1 and 8 every 3 weeks. Cisplatin should be administered at 100 mg/m 2  IV on day 1. 
         [0135]    Trastuzumab is used either single agent or in combination with paclitaxel for the treatment of HER2-positive breast cancer. Trastuzumab is recommended at an initial loading dose of of 4 mg/kg as a 90-minute infusion. The weekly recommended maintenance dose is 2 mg/kg as a 30 minute infusion. Additional dose schedules are under consideration. 
         [0136]    In combination with a dosing schedule (FOLFOX4) for the treatment of colorectal cancer, oxaliplatin may be administerd on day 1 in a dose of up to 85 mg/m 2  (in infusions of up to 2 hours or more). Leucovorin in this schedule may be up to 200 mg/m 2  (in infusions of up to 2 hours or more) while fluorouracil may used in doses up to 400 mg/m 2  (bolus) followed by infusion of 600 mg/m 2  over 22 hours. On day 2, the administration will be leucovorin may be up to 200 mg/m 2  (in infusions of up to 2 hours or more) while fluorouracil may used in doses up to 400 mg/m 2  (bolus) followed by infusion of 600 mg/m 2  over 22 hours. Such an regimen may be repeated every 2 weeks. Other treatment schedules based on variations of administration lengths of oxaliplatin, leucovorin and fluorouracil may also apply. 
         [0137]    Also in the treatment of colorectal cancer other schedules may be used. These include irinotecan 125 mg/m 2  as a 90 minute infusion, leucovorin as a 20 mg/m 2  (15 minute bolus or IV push) followed by fluorouracil 500 mg/m 2  (bolus every week×4). This schedule will be repeated every 6 weeks. Another treatment schedule is the administration of irinotecan 180 mg/m 2  as a 90 minute infusion (day 1, 15, 29), leucovorin at 200 mg/m 2  over 2 hours (days 1, 2, 15, 16, 29, 30), and fluorouracil as 400 mg/m 2  bolus followed by an infusion of 600 mg/m 2  over 22 hours (both on days 1, 2, 15, 16, 29, 30). This schedule will be repeated on day 43. Other treatment schedules based on variations of administration lengths of irinotecan, leucovorin and fluorouracil may also apply. 
         [0138]    Irinotecan may also applied for colorectal cancer in a dosing schedule of 125 mg/m 2  over 90 minutes on days 1, 8, 15, 22 followed by 2 week rest before repeating the schedule. Another option would be dosing of irinotecan at 350 mg/m 2  over 90 minutes every 3 weeks. 
         [0139]    Another treatment schedule for colorectal cancer may be administered by combination with leucovorin at 200 mg/m 2  (2-hour infusion) followed by fluorouracil 400 mg/m 2  (bolus) and 600 mg/m 2  (22 hour infusion) at day 1. On day 2 this schedule is repeated. Such a schedule is repeated every 2 weeks. Other treatment schedules based on variations of administration lengths of leucovorin and fluorouracil may also apply. 
         [0140]    However, it may optionally be necessary to deviate from the amounts specified, depending on the body weight or method of administration, the individual response to the medication, the nature of the formulation used and the time or interval over which it is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified above, while in other cases the upper limit specified will have to be exceeded. When large amounts are administered it may be advisable to spread them over the day in a number of single doses. 
         [0141]    Dosages/Radiotherapy or Radio-Immunotherapy: 
         [0142]    Dosages and treatment schedules for radiotherapy and radio-immunotherapy are known in the art and may be applied analogously within the invention. Depending on the individual activity of the specific combination with BIBW 2992 (1) and, optionally, chemotherapeutic agent (2), dosage of the radiotherapy and radio-immunotherapy component may be reduced, e.g. may vary in the range of 1/1 to 1/20 of the dosages described in the prior art. 
         [0143]    Pharmaceutical Compositions: 
         [0144]    As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts. The amount of pharmaceutically active compound in each case should be in the range from 0.1-90 wt. %, preferably 0.5-50 wt. % of the total composition, i.e. in amounts which are sufficient to achieve the dosage ranges given hereinbefore. The doses specified may, if necessary, be given several times a day. 
         [0145]    As already mentioned before, within the meaning of the present invention, the components BIBW 2992 (1) and optional component (2) may be administered separately (which implies that they are formulated separately) or together (which implies that they are formulated together). Hence, the administration of one element of the combination of the present invention may be prior to, concurrent to, or subsequent to the administration of the other element of the combination. 
         [0146]    The pharmaceutical compositions for the administration of the components BIBW 2992 (1) and (2) of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which is constituted of one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredients into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired dosage form. In the pharmaceutical compositions the active compounds are included in an amount sufficient to produce the desired pharmacologic effect. 
         [0147]    Suitable excipients may be, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolin, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silica and silicates), sugar (e.g. glucose, lactose and dextrose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate). 
         [0148]    The preparations are administered in the usual way, preferably by oral or transdermal route, particularly preferably by oral route. When administered orally the tablets may, of course, contain additives, such as e.g. sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatine and the like, in addition to the abovementioned carriers. Lubricants such as magnesium stearate, sodium laurylsulphate and talc may also be used to form tablets. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the abovementioned excipients. 
         [0149]    For parenteral use, solutions of the active substances may be prepared using suitable liquid carrier materials. 
         [0150]    The pharmaceutical compositions containing the active ingredients BIBW 2992 (1) and (2), separately or together, that are suitable for oral administration may be in the form of discrete units such as hard or soft capsules, tablets, troches or lozenges, each containing a predetermined amount of the active ingredients, or in the form of a dispersible powder or granules, or in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, or in the form of syrups or elixirs, or in the form of an oil-in-water emulsion or a water-in-oil emulsion. 
         [0151]    Dosage forms intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical formulations and such compositions. The excipients used may be, for example: (a) inert diluents such as mannitol, sorbitol, calcium carbonate, pregelatinized starch, lactose, calcium phosphate or sodium phosphate; (b) granulating and disintegrating agents, such as povidone, copovidone, hydroxypropylmethylcellulose, corn starch, alginic acid, crospovidone, sodiumstarchglycolate, croscarmellose, or polacrilin potassium; (c) binding agents such as microcrystalline cellulose or acacia; and (d) lubricating agents such as magnesium stearate, stearic acid, fumaric acid or talc. 
         [0152]    Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets. 
         [0153]    Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. In some cases, formulations for oral use may be in the form of hard gelatin or HPMC (hydroxypropylmethylcellulose) capsules wherein the active ingredients BIBW 2992 (1) or (2), separately or together, is mixed with an inert solid diluent, for example pregelatinized starch, calcium carbonate, calcium phosphate or kaolin, or dispensed via a pellet formulation. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, medium chain triglycerides or olive oil. 
         [0154]    The tablets, capsules or pellets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed action or sustained action over a longer period. For example, a time delay material such as celluloseacetate phtalate or hydroxypropylcellulose acetate succinate or sustained release material such as ethylcellulose or ammoniomethacrylate copolymer (type B) may be employed. 
         [0155]    Liquid dosage forms for oral administration in accordance with the present invention include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, perfuming and preserving agents. 
         [0156]    Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates. 
         [0157]    Definitions: 
         [0158]    The terms “ErbB 1”, “epidermal growth factor receptor” and “EGFR” are used interchangeably herein and refer to native sequence EGFR as disclosed, for example, in Carpenter et al. Ann. Rev. Biochem. 56:881-914 (1987), including variants thereof (e.g. a deletion mutant EGFR as in Humphrey et al. PNAS (USA) 87:4207-4211 (1990)). erbBl refers to the gene encoding the EGFR protein product. As used herein, the EGFR protein is disclosed as GenBank accession no. NP — 005219 which is encoded by the erbBl gene, GenBank accession no. NM — 005228. The sequences are disclosed as SEQ ID NO: 1, and SEQ ID NO: 2, respectively, in FIG. 5 of WO 2006/084058. 
         [0159]    The term “activating mutation of the EGFR” as used herein refers to a variance (i.e. mutation) in the nucleotide sequence of erbBl, the gene gene encoding the EGFR, that results in an increased kinase activity. The increased kinase activity is a direct result of the variance in the nucleic acid and is associated with the protein for which the gene encodes. 
         [0160]    The following Examples serve to illustrate the invention without restricting it: 
       Example 1 
     Coated Tablets Containing 75 mg of Active Substance 
       [0161]      
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 1 tablet core contains: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 75.0 mg 
               
               
                   
                 calcium phosphate 
                 93.0 mg 
               
               
                   
                 corn starch 
                 35.5 mg 
               
               
                   
                 polyvinylpyrrolidone 
                 10.0 mg 
               
               
                   
                 hydroxypropylmethylcellulose 
                 15.0 mg 
               
               
                   
                 magnesium stearate 
                  1.5 mg 
               
               
                   
                   
                 230.0 mg  
               
               
                   
                   
               
             
          
         
       
     
         [0162]    Preparation: 
         [0163]    The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Weight of core: 
                 230 mg 
               
               
                   
                 die: 
                  9 mm, convex 
               
               
                   
                   
               
             
          
         
       
     
         [0164]    The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Weight of coated tablet: 
                 245 mg. 
               
               
                   
                   
               
             
          
         
       
     
       Example 2 
     Tablets Containing 100 mg of Active Substance 
       [0165]      
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 1 tablet contains: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 100.0 mg  
               
               
                   
                 lactose 
                 80.0 mg 
               
               
                   
                 corn starch 
                 34.0 mg 
               
               
                   
                 polyvinylpyrrolidone 
                  4.0 mg 
               
               
                   
                 magnesium stearate 
                  2.0 mg 
               
               
                   
                   
                 220.0 mg  
               
               
                   
                   
               
             
          
         
       
     
         [0166]    Preparation: 
         [0167]    The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50° C. it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Weight of tablet: 
                 220 mg 
               
               
                   
                 Diameter: 
                  10 mm, biplanar, facetted on both sides and 
               
               
                   
                   
                 notched on one side. 
               
               
                   
                   
               
             
          
         
       
     
       Example 3 
     Tablets Containing 150 mg of Active Substance 
       [0168]    1 Tablet Contains: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 active substance 
                 150.0 mg  
               
               
                   
                 powdered lactose 
                 89.0 mg 
               
               
                   
                 corn starch 
                 40.0 mg 
               
               
                   
                 colloidal silica 
                 10.0 mg 
               
               
                   
                 polyvinylpyrrolidone 
                 10.0 mg 
               
               
                   
                 magnesium stearate 
                  1.0 mg 
               
               
                   
                   
                 300.0 mg  
               
               
                   
                   
               
             
          
         
       
     
         [0169]    Preparation: 
         [0170]    The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Weight of tablet: 
                 300 mg 
               
               
                   
                 die: 
                  10 mm, flat 
               
               
                   
                   
               
             
          
         
       
     
       Example 4 
     Hard Gelatine Capsules Containing 150 mg of Active Substance 
       [0171]      
         [0000]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 1 capsule contains: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 50.0 
                 mg 
               
               
                   
                 corn starch (dried) 
                 approx. 80.0 
                 mg 
               
               
                   
                 lactose (powdered) 
                 approx. 87.0 
                 mg 
               
               
                   
                 magnesium stearate 
                 10.0 
                 mg 
               
               
                   
                   
                 approx. 420.0 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
         [0172]    Preparation: 
         [0173]    The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 Capsule filling: 
                 approx. 320 mg 
               
               
                   
                 Capsule shell: 
                 size 1 hard gelatine capsule. 
               
               
                   
                   
               
             
          
         
       
     
       Example 5 
     Suppositories Containing 150 mg of Active Substance 
       [0174]    1 Suppository Contains: 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 active substance 
                 150.0 
                 mg 
               
               
                   
                 polyethyleneglycol 1500 
                 550.0 
                 mg 
               
               
                   
                 polyethyleneglycol 6000 
                 460.0 
                 mg 
               
               
                   
                 polyoxyethylene sorbitan 
                 840.0 
                 mg 
               
               
                   
                 monostearate 
                   
               
               
                   
                   
                 2,000.0 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
         [0175]    Preparation: 
         [0176]    After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds. 
       Example 6 
     Suspension Containing 50 mg of Active Substance 
       [0177]      
         [0000]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 100 ml of suspension contain: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 1.00 
                 g 
               
               
                   
                 carboxymethylcellulose-Na-salt 
                 0.10 
                 g 
               
               
                   
                 methyl p-hydroxybenzoate 
                 0.05 
                 g 
               
               
                   
                 propyl p-hydroxybenzoate 
                 0.01 
                 g 
               
               
                   
                 glucose 
                 10.00 
                 g 
               
               
                   
                 glycerol 
                 5.00 
                 g 
               
               
                   
                 70% sorbitol solution 
                 20.00 
                 g 
               
               
                   
                 flavouring 
                 0.30 
                 g 
               
               
                   
                 dist. water ad 
                 100.0 
                 ml 
               
               
                   
                   
               
             
          
         
       
     
         [0178]    Preparation: 
         [0179]    The distilled water is heated to 70° C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air. 
         [0180]    5 ml of suspension contain 50 mg of active substance. 
       Example 7 
     Ampoules Containing 10 mg Active Substance 
       [0181]      
         [0000]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Composition: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 10.0 
                 mg 
               
               
                   
                 0.01 N hydrochloric acid q.s. 
               
               
                   
                 double-distilled water ad 
                 2.0 
                 ml 
               
               
                   
                   
               
             
          
         
       
     
         [0182]    Preparation: 
         [0183]    The active substance is dissolved in the requisite amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules. 
       Example 8 
     Ampoules Containing 50 mg of Active Substance 
       [0184]      
         [0000]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Composition: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 50.0 
                 mg 
               
               
                   
                 0.01 N hydrochloric acid q.s. 
               
               
                   
                 double-distilled water ad 
                 10.0 
                 ml 
               
               
                   
                   
               
             
          
         
       
     
         [0185]    Preparation: 
         [0186]    The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules. 
       Example 9 
     Capsules for Powder Inhalation Containing 5 mg of Active Substance 
       [0187]      
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 1 capsule contains: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                  5.0 mg 
               
               
                   
                 lactose for inhalation 
                 15.0 mg 
               
               
                   
                   
                 20.0 mg 
               
               
                   
                   
               
             
          
         
       
     
         [0188]    Preparation: 
         [0189]    The active substance is mixed with lactose for inhalation. The mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg). 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 weight of capsule: 
                 70.0 mg 
               
               
                   
                 size of capsule 
                 3 
               
               
                   
                   
               
             
          
         
       
     
       Example 10 
     Solution for Inhalation for Hand-Held Nebulisers Containing 2.5 mg Active Substance 
       [0190]      
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 1 spray contains: 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 active substance 
                 2.500 mg 
               
               
                   
                 benzalkonium chloride 
                 0.001 mg 
               
               
                   
                 1N hydrochloric acid q.s. 
                 2.500 mg 
               
               
                   
                 ethanol/water (50/50) ad 
                 15.000 mg  
               
               
                   
                   
               
             
          
         
       
     
         [0191]    Preparation: 
         [0192]    The active substance and benzalkonium chloride are dissolved in ethanol/water (50/50). The pH of the solution is adjusted with 1N hydrochloric acid. The resulting solution is filtered and transferred into suitable containers for use in hand-held nebulisers (cartridges). 
         [0193]    Contents of the container: 4.5 g