WO2011069962A1 - Bibw 2992 pour utilisation dans le traitement du cancer du sein triple négatif - Google Patents

Bibw 2992 pour utilisation dans le traitement du cancer du sein triple négatif Download PDF

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Publication number
WO2011069962A1
WO2011069962A1 PCT/EP2010/068968 EP2010068968W WO2011069962A1 WO 2011069962 A1 WO2011069962 A1 WO 2011069962A1 EP 2010068968 W EP2010068968 W EP 2010068968W WO 2011069962 A1 WO2011069962 A1 WO 2011069962A1
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inhibitors
treatment
compounds
receptor
breast cancer
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PCT/EP2010/068968
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English (en)
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Christian Haslinger
Flavio Solca
Martina Uttenreuther-Fischer
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Boehringer Ingelheim International Gmbh
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Priority to JP2012541532A priority Critical patent/JP2013512882A/ja
Priority to EP10787754A priority patent/EP2509592A1/fr
Priority to US13/511,172 priority patent/US20130012465A1/en
Publication of WO2011069962A1 publication Critical patent/WO2011069962A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method of treating patients suffering from triple negative breast cancer comprising administration of an effective amount of the irreversible EGFR/HER1 and HER2 inhibitor BIBW 2992 ( ⁇ ) 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.
  • BIBW 2992 is known as the compound 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N- dimethylamino)-l-oxo-2 -quinazoline,
  • BIBW 2992 is a potent and selective dual inhibitor of erbbl receptor (EGFR) and erbB2 (Her2/neu) receptor tyrosine kinases. Furthermore, BIBW 2992 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 BIBW 2992 or a salt thereof, indications to be treated with BIBW 2992 and combinations including BIBW 2992 are disclosed in WO 02/50043, WO 2005/037824, WO 2007/054550 and WO 2007/054551.
  • TNBC triple-negative breast cancer
  • This subtype of breast cancer is clinically characterised as more aggressive and less responsive to standard (receptor-mediated) treatment, including Herceptin and Tamoxifen, and associated with poorer overall patient prognosis.
  • triple negative breast cancer can be extremely aggressive, and more likely to metastasize than other subtypes of breast cancer. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). It is diagnosed more frequently in younger (premenopausal) women, women with BRCA1 mutations, and in African-American and Hispanic ethnic groups.
  • Triple-negative breast cancer accounts for approximately 15% of all breast cancer cases.
  • TNBC is typically responsive to chemotherapy - a combination of three medications called ACT, which stands for Adriamycin, cyclophosphamide (Cytoxan), and taxanes (e.g. paclitaxel, docetaxel).
  • ACT a combination of three medications called ACT, which stands for Adriamycin, cyclophosphamide (Cytoxan), and taxanes (e.g. paclitaxel, docetaxel).
  • the irreversible EGFR/HER1 and HER2 inhibitor BIBW2992 (1) is advantageously effective in the treatment of patients suffering from triple negative breast cancer.
  • the present invention relates to a method of treating patients suffering from triple negative breast cancer comprising administering an effective amount of the irreversible EGFR/HERl and HER2 inhibitor BIBW 2992 ( ⁇ ) 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.
  • a second aspect of the present invention is BIBW 2992 ( ⁇ ), or a salt thereof, for the treatment of a patient suffering from triple negative breast cancer, e.g. a pharmaceutical composition comprising BIBW 2992 ( ⁇ ) for the treatment of a patient suffering from triple negative breast cancer.
  • a third aspect of the present invention is the use of BIBW 2992 ( ⁇ ) for preparing a pharmaceutical composition for the treatment of a patient suffering from triple negative breast cancer.
  • the method of treatment according to the invention is neoadjuvant/adjuvant treatment of triple negative breast cancer.
  • the indication to be treated is triple negative metastatic breast cancer.
  • the method of treatment according to the invention is a 1 st line treatment after failure of neoadjuvant or adjuvant chemotherapy or without prior exposure to neoadjuvant/adjuvant chemotherapy in case of primary metastatic disease.
  • the method of treatment according to the invention is a 2nd line treatment after failure of one prior chemotherapy.
  • the method of treatment according to the invention is a 3rd line treatment after failure of two different prior chemotherapies.
  • the method of treatment according to the invention is a combination treatment comprising administering an effective amount of BIBW 2992 ( ⁇ ), in combination with the administration of an effective amount of one, two or three of the chemotherapeutics selected from Adriamycin, cyclophosphamide (Cytoxan), taxanes (e.g. paclitaxel, docetaxel) and platinum compounds (e.g. cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin or iproplatin), preferably after surgery and radiation treatments, to a person in need of such treatment.
  • chemotherapeutics selected from Adriamycin, cyclophosphamide (Cytoxan), taxanes (e.g. paclitaxel, docetaxel) and platinum compounds (e.g. cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin or iproplatin
  • the method of treatment according to the invention is a single agent treatment with BIBW 2992 (1), or a combination treatment comprising administering an effective amount of BIBW 2992 £1 ⁇ in combination with an effective amount of an established or experimental chemotherapeutic agent such as a further chemotherapeutic agent (2) or one, two or three of the chemotherapeutics selected from adriamycin, cyclophosphamide (cytoxan), taxanes (e.g. paclitaxel, docetaxel) and platinum compounds (e.g.
  • cisplatin carboplatin, oxaliplatin, satraplatin, tetraplatin or iproplatin
  • HER1, HER3 and/or HER4 erbB receptor
  • cognate ligand EGF TGFa, AREG, Hb-EGF, BTC, Epigen, EREG, NRG1, NRG2, NRG3, NRG4, Tomoregulin and neurglycan
  • overexpression or mutation that can be detected at the protein, mRNA or DNA level using methods familiar to people skilled to the art.
  • tumoral erbB receptor dysfunction can be be detected by hallmarks of erbB receptor activation (e.g phosphorylated EGFR, phosphorylated HER2, phosphorylated HER3, phosphorylated HER4, homo-or heterodimerized EGFR, homo-or heterodimerized HER2, heterodimerized HER3, homo-or heterodimerized HER4) using methods familiar to people skilled to the art.
  • erbB receptor activation e.g phosphorylated EGFR, phosphorylated HER2, phosphorylated HER3, phosphorylated HER4, homo-or heterodimerized EGFR, homo-or heterodimerized HER2, heterodimerized HER3, homo-or heterodimerized HER4
  • tumour shrinkage stable disease or progression of the tumour diesease
  • objective response or tumour shrinkage, stable disease or progression of the tumour diesease may be monitored by way of visual inspection of the cancer, such as, by means of clinical assessment.
  • X-ray, CT scan or MRI may be monitored by way of tumor biomarker detection.
  • the patient is monitored at various time points throughout the treatment of the cancer.
  • 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 BIBW 2992 ( ⁇ ) treatment and the second time point is after the first.
  • An increased growth of the cancer indicates progression of the cancer.
  • the method of treatment according to the invention comprises administration of a therapeutically effective amount of BIBW 2992 (1) or a pharmaceutically acceptable salt thereof, optionally in combination with the administration of a further chemotherapeutic agent (2), to a patient in need thereof, optionally in combination with radiotherapy, radio-immunotherapy and/or tumour resection by surgery.
  • Dosages or amounts of actives provided in the context of this invention refer in any case to the free base equivalent, that is BIBW 2992 (1) in the free base form.
  • (1) is optionally applied in the form of the tautomers and pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts are preferably selected from the group consisting of the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrolactate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydromaleate, hydrofumarate and hydromethanesulphonate.
  • chemotherapeutic agents are especially of interest, although not representing a limitation:
  • GF growth factor
  • 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
  • Cytokines Chitokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines or oral and parenteral tolerance induction strategies
  • Antiinflammatory compounds such as but not limited to COX-2 inhibitors
  • chemother apeutic 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.
  • the chemotherapeutic agent (2) is selected from the group consisting of a small molecule VEGF receptor antagonist such as vatalanib (PTK- 787/ZK222584), 3-Z-[l -(4-(N-((4-methyl-piperazin-l -yl)-methylcarbonyl)-N-methyl-amino)-anilino)- 1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone (BIBF 1120) or a salt thereof, preferably BIBF 1120 monoethanesulphonate, SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP- 547632, CEP-7055, AG-013736, IM-842 or GW-786034, small molecule EGFR and HER2 antagonist such as PF-299,804, AZD-8931, AC-480, BMS
  • 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.
  • BIBW 2992 (1) is administered orally, enterically, transdermally, intravenously, peritoneally or by injection, preferably orally.
  • Dosage forms and formulations suitable within the present invention are known in the art. For instance, such dosage forms and formulations include those disclosed for BIBW 2992 Qj in WO 02/50043, WO 2007/054550 and WO 2007/054551 or in the Examples of the subject application.
  • 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 tiM for at least 12 hours of the dosing interval.
  • 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.
  • BIBW 2992 (1) may be administered orally in a total daily dose of 10 to 150 mg, preferably 20 to 70 mg, most preferred 40 to 60 mg.
  • the daily oral dosis administered may be 10, 20, 30, 40, 50, 60, 70, 100 or 150 mg, most preferred is a total daily dose of 50 mg.
  • the daily dosage may optionally be divided into multiple doses, e.g. 1, 2 or 3 doses to be administered through the day.
  • the oral daily dose is administered only once a time.
  • the dosage for intravenous use of BIBW 2992 (1) may be 1 - 500 mg, preferably 5 - 300 mg, particularly preferred 10 - 100 mg, 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.
  • Dosages / chemotherapeutic agents (2) Pharmaceutical compositions, 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.
  • 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.
  • doxorubicin For patients with metastatic breast cancer the combination with adriamycin (doxorubicin) may be given at a dose between 50 mg/m 2 and 80 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 doxorubicin may be lowered.
  • cytoxan cyclophosphamide
  • cytoxan may be given intravenously as 40 to 50 milligrams (mg) per 2.2 pounds of body weight in divided doses over a period of 2 to 5 days. It may also be given as 10 to 15 mg per 2.2 pounds of body weight every 7 to 10 days or 3 to 5 mg per 2.2 pounds of body weight twice weekly
  • paclitaxel In patients with metastatic breast cancer, the administration of paclitaxel (taxol) 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, e.g 80 mg/m 2 . 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).
  • vinorelbine may be used at a dose of up to 25 mg/m 2 in a weekly administration schedule.
  • 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.
  • Dosages and treatment schedules for radiotherapy and radio-immunotherapy are known in the art and may be applied analogously within the invention.
  • 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 art.
  • ErbB 1 refers 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.
  • 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.
  • terapéuticaally 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, stable disease, extension of life, or improvement in quality of life.
  • o Cohort B Patients with HER2 -negative, HR-positive mBC.
  • a total of 80 patients was planned to be enrolled into the trial: 80, i.e. 40 patients per cohort.
  • An early stopping rule was implemented after 20 patients in each cohort.
  • BIBW 2992 plasma concentrations 5 ml of venous blood were collected on Day 1 of Course 1 and Day 15 of Course 2 at the following time points: predose and 1, 2 and 3 hours after drug administration. In addition, a voluntary PK sample could be requested within 4 to 24 hours after BIBW 2992 administration. Additional predose plasma samples were taken on Day 15 of Course 1, on Day 1 of Course 2 and on Day 1 of all subsequent courses (Course 3 onwards).
  • BIBW 2992 drug concentrations were determined by a validated high performance liquid chromatography-mass spectroscopy (HPLC-MS/MS) assay. The distribution of BIBW 2992 plasma concentrations was summarised by timepoint by descriptive statistics, and if feasible, was graphically inspected.
  • tumour samples fresh or paraffin material
  • ER-status and PgR-status must be assessed by IHC and Allred (Harvey JM et al., J Clin Oncol 1999, 17(5), 1474-1481).
  • BIBW 2992 has a safety profile similar to other EGFR TKIs.
  • the most frequently observed drug-related side-effects are gastrointestinal and skin related AEs, which were mostly manageable.
  • Table 1 Breast cancer: triple negative breast cell panel 1 BIBW 2992 lapatinib
  • HCC 1937 >4000 >4000 >4000 >4000
  • MDA-MB-231 >10000 2154 > 10000 >4000
  • SUM 149 express large amounts of EGFR, AREG, EREG and TGFa
  • Example 3 Pharmaceutical compositions of solid BIBW 2992 MA tablets
  • Formulations A, B and C, D and E are tablets which can be coated with a film-coat according to Table 2.
  • composition of filmcoatings for formulation A-E Exemplary composition of filmcoatings for formulation A-E
  • Figure 3 Tumour volume [mm'] of breast cancer / triple negative, EGFR positive SUM 149 Xenografts in mice upon treatment with 20 mg/kg BIBW 2992 BS (dosage provided for the free base), in comparison to 2 x 200 mg/kg lapatinib, against control (vehicle)

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Abstract

La présente invention concerne un procédé de traitement de patients souffrant d'un cancer du sein triple négatif comprenant l'administration d'une quantité efficace de l'inhibiteur irréversible de EGFR/HER1 et HER2 BIBW 2992 (1) à une personne nécessitant un tel traitement, facultativement en combinaison avec l'administration d'un autre agent chimiothérapeutique (2), en combinaison avec une radiothérapie, une radio-immunothérapie et/ou la résection de tumeur par chirurgie.
PCT/EP2010/068968 2009-12-07 2010-12-06 Bibw 2992 pour utilisation dans le traitement du cancer du sein triple négatif WO2011069962A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2012541532A JP2013512882A (ja) 2009-12-07 2010-12-06 トリプルネガティブ乳癌の治療に使用するｂｉｂｗ２９９２
EP10787754A EP2509592A1 (fr) 2009-12-07 2010-12-06 Bibw 2992 pour utilisation dans le traitement du cancer du sein triple négatif
US13/511,172 US20130012465A1 (en) 2009-12-07 2010-12-06 Bibw 2992 for use in the treatment of triple negative breast cancer

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EP09178179 2009-12-07
EP09178179.9 2009-12-07

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US8545884B2 (en) 2008-06-06 2013-10-01 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising BIBW 2992
US8586608B2 (en) 2000-12-20 2013-11-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US8722694B2 (en) 1999-06-21 2014-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
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WO2015152409A1 (fr) * 2014-04-04 2015-10-08 大鵬薬品工業株式会社 Médicament anti-tumoral contenant un composé taxane, et renforçateur d'effet anti-tumoral
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US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9545381B2 (en) 2009-07-06 2017-01-17 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
WO2017184597A1 (fr) * 2016-04-19 2017-10-26 Exelixis, Inc. Procédé de traitement du cancer du sein négatif triple
WO2017203532A1 (fr) * 2016-05-25 2017-11-30 Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science Agents à utiliser pour le traitement de tumeurs résistantes aux médicaments et du cancer du sein triple négatif
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272

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