WO2011070499A1 - Biomarqueurs de la voie de la phosphatidylinotisol-3-kinase - Google Patents
Biomarqueurs de la voie de la phosphatidylinotisol-3-kinase Download PDFInfo
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- WO2011070499A1 WO2011070499A1 PCT/IB2010/055604 IB2010055604W WO2011070499A1 WO 2011070499 A1 WO2011070499 A1 WO 2011070499A1 IB 2010055604 W IB2010055604 W IB 2010055604W WO 2011070499 A1 WO2011070499 A1 WO 2011070499A1
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Definitions
- the present disclosure relates to methods for treating breast cancer.
- the cancer may be resistant to treatment with one or more known breast cancer treatment drugs.
- the present disclosure also provides a patient selection strategy (i.e., identify patients with "PI3K activated" tumors) for predicting patient response to drug therapy.
- the disclosure is also related to methods of treating breast cancer patients with a pan-ErbB tyrosine kinase inhibitor.
- Constitutive PI3K activation in human cancer is thought to contribute to drug resistance to targeted agents and standard cytotoxic therapy.
- the combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contribute to the difficulty in measuring PI3K activation as a biomarker.
- Neratinib is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity.
- Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP- binding pocket of the receptor.
- Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation.
- Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells.
- EGFR epidermal growth factor receptor
- Trastuzumab (Herceptin) is a monoclonal antibody that interferes with the HER2/Neu HER2/neu receptor.
- the HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off.
- the HER proteins regulate cell growth, survival, adhesion, migration, and differentiation— functions that are amplified or weakened in cancer cells.
- the HER2 receptor is defective and stuck in the "on" position, and causes breast cells to reproduce uncontrollably, causing breast cancer.
- the invention provides methods for treating breast cancer in a subject which comprise obtaining a sample from the subject; detecting the presence or absence of one or more of PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression; and treating a patient that is positive for the presence of one or more of PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression by administering a pan-ErbB tyrosine kinase inhibitor.
- the pan-ErbB inhibitor is irreversible and prevents binding of PIK3CA to the intracellular portion of the ErbB receptor and in some embodiments the intracellular inhibitor of ErbB receptor tyrosine kinases is neratinib.
- the invention provides methods of treatment as described herein where the mutation in the PIK3CA gene comprises one or more of the following point mutations: in exon 9 E is substituted with K at position 542 of the mature protein sequence; E with K or D at amino acid 545; and in exon 20 H is substituted with R at amino acid 1047 of the mature protein sequence.
- detection of the mutation in the PIK3CA gene comprises a Polymerase Chain Reaction (PCR) assay, or direct nucleic acid sequencing or hybridization with a nucleic acid probe specific for the PIK3CA gene.
- the detection of PTEN expression comprises one or more of: reverse phase protein array, western blotting, semi-quantitative or quantitative IHC.
- the invention provides methods for treating breast cancer in a subject which comprise obtaining a sample from the subject; detecting the presence or absence of one or more of PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression; and treating a patient that is positive for the presence of one or more of PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression by administering an pan-ErbB inhibitor and which further comprise administering one or more compositions or therapies to the subject if the subject is positive for PIK3CA gene amplification wherein the compositions or therapies are useful for treating breast cancer.
- the additional treatment can comprise one or more of surgery, radiation or additional chemotherapy agents selected from one or more of the following: aromatase inhibitors, including letrozole (Femara), anastrazole (Arimidex), fulvestrant (Faslodex) and exemestane (Aromasin); goserelin (Zoladex); anthracyclines, including doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil); taxanes, including docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane), Cyclophosphamide (Cytoxan); Capecitabine (Xeloda) and 5 fluorouracil (5 FU); Vinorelbine (Navelbine); Gemcitabine (Gemzar);Trastuzumab (Herceptin), lapatin
- the invention provides methods for treating breast cancer in a subject which comprise obtaining a sample from the subject; detecting the presence or absence of one or more of PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression; and treating a patient that is negative for all three of these biomarkers with Trastuzumab.
- the invention provides methods of treating a breast cancer subject which comprise detecting the presence or absence of one or more of PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression; wherein if a subject is negative for PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression the subject is administered Trastuzumab.
- the invention provides methods for determining if a subject with breast cancer is a candidate for treatment with a pan-ErbB tyrosine kinase inhibitor which comprises: obtaining a sample from the subject; detecting the presence or absence of PIK3CA gene amplification; wherein if the subject is positive for the presence of one or more of the following: PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression, then the subject is a identified as a candidate for treatment with a pan-ErbB tyrosine kinase inhibitor.
- the pan-ErbB inhibitor is irreversible and prevents binding of PIK3CA to the intracellular portion of the ErbB receptor and in some embodiments the intracellular inhibitor of ErbB receptor tyrosine kinases is neratinib.
- the methods for determining if a subject is a candidate for treatment with a pan-ErbB tyrosine kinase inhibitor or e.g., neratinib comprise detecting a mutation in the PIK3CA gene is selected from the following point mutations: in exon 9 E is substituted with K at position 542 of the protein sequence; in exon 9 is substituted with E with K or D at amino acid 545; and in exon 20 H is substituted with R at amino acid 1047.
- methods for determining if a subject is a candidate for treatment with a pan-ErbB tyrosine kinase inhibitor or e.g., neratinib comprise the detection of the mutation in the PIK3CA gene comprises a Polymerase Chain Reaction (PCR) assay, direct sequencing of the PIK3CA gene; sequencing of a cDNA generating from a sample in the patient.
- PCR Polymerase Chain Reaction
- methods for determining if a subject is a candidate for treatment with a pan-ErbB tyrosine kinase inhibitor or e.g., neratinib comprise the detection of PTEN expression by one or more of: reverse phase protein array, western blotting, semi-quantitative or quantitative IHC.
- the disclosure provides assays to determine pathway activation using combined approaches genetic, genomic, and protein biomarkers to accurately characterize "PI3K activated" tumors.
- Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into “pathway on” and “pathway off' subsets to compare the treatment effect in each arm.
- determining the pathway on versus pathway off status can help select a treatment protocol for a patient suffering from breast cancer.
- the treatment protocol selected comprises administering neratinib to a breast cancer patient.
- this strategy discloses the use of a collection of biomarkers to identify a specific "pathway on" patient population that will have clinical benefit from administration of a particular therapeutic pathway inhibitor.
- a more recent development in patient selection is the identification of drug resistance mechanisms in an effort to distinguish those patients who will achieve clinical benefit from a specific agent from those who will not (e.g., V-Ki-ras2 Kirsten rat sarcoma [KRAS] mutation status identifies those patients who will not benefit from the addition of antibody-based epidermal growth factor receptor (EGFR) inhibitors in colon cancer (1 )
- EGFR epidermal growth factor receptor
- PI3K is one of several signaling cascades engaged by the oncogenic RTK complexes at the membrane and may represent a key therapeutic target (recently reviewed in (5).
- the critical role of this signaling node in cancer is highlighted by the proportion of human malignancies with genetic lesions in genes encoding the components of the cascade, namely PIK3CA, PTEN, PDK1, and AKT.
- ErbB pathway inhibitors e.g., trastuzumab, lapatinib, neratinib, BIBW2992J, PI3K inhibitors (e.g., XL147, PX-866), mTOR inhibitors (e.g., temsirolimus, everolimus), and dual PI3K-mTOR inhibitors (e.g., BEZ235).
- the activation of the PI3K pathway has been associated with resistance to ErbB2-targeted therapy in breast cancer, as well as resistance to cytotoxics.
- Akt phosphorylation is not an entirely specific marker for this signaling node at PI3K and may not completely capture PI3K activation in all tumor samples (6, 7) and (2) tumor- specific levels of PI P3, the most proximal pathway marker, may pose a challenge in the setting of preserved tissues, where accurate measurement of phosphorylated lipids may be more difficult than that of phosphorylated proteins (8).
- Novel biomarkers aimed at capturing the underlying biology of pathway activation represent promising approaches to measuring pathway activation.
- Clinical strategies are being developed to answer questions related to biopsy timing and the feasibility of genomic approaches in clinical development paradigms and will help to answer some of these key question in the near future. Nonetheless, such approaches currently remain challenging to implement in the setting of global phase 3 trials. In this setting, it will be imperative to develop panels of assays that are applicable in preserved tumor specimens and performed globally in a homogeneous manner and under standardized conditions (i.e., good laboratory practice).
- Biomarker discovery for targeted pathway inhibitors in the preclinical setting can employ several distinct approaches, including (1 ) modeling of drug resistance using panels of xenograft models or cell lines exposed to the drug or (2) modeling of pathway activation after perturbing the pathway in preclinical model systems at the molecular level (e.g., siRNA). Biomarkers derived from such models can be further assessed by measuring pathway markers in human tumor tissues.
- Class IA phosphatidylinositol-3-kinase is a heterodimeric lipid kinase complex with two subunits, the p1 10a catalytic domain and the p85 regulatory domain.
- PI3K Upon ligand binding and receptor tyrosine kinase (RTK) autophosphorylation, PI3K is recruited to the cell membrane, binds to the intracellular arm of the RTK, and catalyzes the conversion of phosphatidylinositol (4,5)-diphosphate (PI P2) to phosphatidylinositol (3,4,5)-triphosphate (PIP 3 ).
- PI3K plays a key role in the regulation of cellular processes, such as proliferation, migration, and apoptosis.
- Akt/PKB and phosphoinositide-dependent kinase-1 are recruited to the membrane and activated by direct binding to the accumulated pool of PI P3.
- Active PDK1 propagates signaling via phosphorylation of substrates (Akt/PKB, SGK3).
- Akt/PKB is phosphorylated by both PDK1 (at site T308) and PDK2/mammalian target of rapamycin (mTOR) C2 (at site S473), leading to full activation of Akt/PKB downstream signaling, which leaves Akt/PKB both upstream and downstream of mTOR (6, 9-1 1 ).
- the kinase activity of the PI3K complex is opposed by the dual phosphatase known as phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which converts PI P3 to PI P2 and essentially functions as a "check" on the activity of PI3K.
- PTEN tensin homologue deleted on chromosome 10
- Neratinib (also called HKI-272) inhibits phosphorylation of the ErbB receptors and downstream substrates; due to this activity in preclinical models, neratinib has been shown to inhibit phosphorylation and activation of the PI3K complex. (See, e.g., WO09/052264 at pages 6-7; US2007/0104721 at paragraphs 7 and 21 ; and U.S. Patent No. 7,399,865).
- PI3K pathway aberrations are present at diagnosis in a significant percentage of breast cancer patients and data suggest that these represent de novo resistance mechanisms to standard therapy.
- a novel targeted therapy such as a pan-ErbB inhibitor
- the concept behind this type of biomarker strategy is to identify a biologic subset of patients that are predicted to be resistant to the standard of care therapy, where the addition or substitution of the novel pathway inhibitor would be expected to have greater therapeutic efficacy by overcoming that resistance mechanism.
- PI3K pathway activation predicts resistance to trastuzumab (12-15).
- Biomarkers of PI3K pathway activation that differentiate two patient subsets is used to identify patients predicted to have a response to standard trastuzumab therapy (“PI3K OFF") and those who might require treatment with novel pathway inhibitors (e.g., pan-ErbB inhibitors, in the setting of "PI3K ON") to achieve a clinical response.
- novel pathway inhibitors e.g., pan-ErbB inhibitors, in the setting of "PI3K ON
- PI P3 levels at the cell membrane that leads to enhanced downstream signaling.
- the goal of a biomarker strategy incorporating PI3K activation is to develop a series of assays that will be able to differentiate patients and group them into distinct subsets based on the presence of tumors that are (1 ) driven by or dependent on downstream signaling via PI3K or (2) not dependent on this signaling pathway.
- the combined assessment of PIK3CA mutations and PTEN loss has demonstrated that PI3K pathway activation is a resistance mechanism to trastuzumab therapy in patients with metastatic ErbB2+ breast cancer (12).
- the known genetic events observed in primary breast cancer samples in the PIK3CA gene leading to pathway activation are composed of hotspot mutations in exons 9 or 20, gene amplification, or the combination of both.
- Loss of PTEN has been routinely studied in the clinic using standard IHC approaches, typically with an antibody that recognizes a C-terminal protein epitope caused by mutations that can produce truncated forms of the protein.
- IHC approaches typically with an antibody that recognizes a C-terminal protein epitope caused by mutations that can produce truncated forms of the protein.
- Various examples of concordance versus discordance between known genetic loss events and the expression of PTEN via IHC exist in the literature; this can lead to some challenges in the interpretation of the underlying biology (16-17).
- IHC methods can be qualitative or semiquantitative and differences in interpretation can lead to different results.
- IHC methods detect all species of the full-length protein (functional or dysfunctional) and "reduced" protein levels may derive from either destabilizing mutations, miRNA expression, or co-expressed stabilizing proteins, whereas a full complement of the PTEN protein can be observed with a point mutation in the phosphatase domain (18-19).
- neratinib is administered to a subject at a dose between 100 and 500 mg per day, between 200 and 400 mg per day, and at a dose of about 250 mg per day.
- the invention provides a method of treating breast cancer with neratinib in conjunction with another treatment for breast cancer.
- Additional treatment or treatments can include surgery, radiation or additional chemotherapy agents selected from one or more of the following: aromatase inhibitors, including letrozole (Femara), anastrazole (Arimidex), fulvestrant (Faslodex) and exemestane (Aromasin); goserelin (Zoladex); anthracyclines, including doxorubicin (Adriamycin), epirubicin (Ellence), and liposomal doxorubicin (Doxil); taxanes, including docetaxel (Taxotere), paclitaxel (Taxol), and protein-bound paclitaxel (Abraxane), Cyclophosphamide (Cytoxan); Capecitabine (Xeloda) and 5 fluorouracil (5 FU); Vinorelbine (Nave
- “Inhibition” of PI3K activity can be direct, as in via preventing the complex from binding to substrate and or sequestering of the enzyme, or indirect, as in preventing transcription or translation of the PIK3CA gene.
- inhibition of PI3K activity comprises administering a pan-ErbB tyrosine kinase inhibitor, e.g., neratinib.
- pan-ErbB tyrosine kinase inhibitor e.g., neratinib.
- intracellular inhibition of PI3K indicates that the PI3K complex is prevented from activity by direct interference with the PI3K pathway inside the cell, as opposed to an inhibition that occurs via blocking binding or inactivation of a transmembrane cell receptor, e.g., as in inhibition with trastuzumab.
- treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
- treatment refers to the act of treating as “treating” is defined immediately above.
- subject and “patient” are used interchangeably.
- Quantitative assessment of PTEN protein expression Standard IHC methods are used to stain tumors for PTEN protein expression. Digital images are obtained and OD scores for both normal tissue (e.g. stromal or endothelial cell) PTEN, as well as tumor PTEN compartments are obtained. The sample's PTEN score is calculated as tumor PTEN OD/normal tissue PTEN OD. A range of tumor PTEN scores are presented with slight differences in normal tissue (e.g. stromal) PTEN expression. Normalization allows for correction in staining differences as an internal control. PTEN, phosphatase and tensin homolog deleted on chromosome 10; OD, optical density.
- PIK3CA gene which encodes the p1 10a subunit of the class PI3K complex
- PIK3CA gene which encodes the p1 10a subunit of the class PI3K complex
- mutations in PIK3CA have been observed in approximately one quarter of patients in different cohorts tested (range, 8%-40%). Most mutations in breast cancer have been found to cluster in either the kinase or helical domains in exons 9 and 20 of the PIK3CA gene. These gain-of-function mutations disrupt folding interactions in the p1 10a unit and the interface between the p1 10a and p85 subunits, leading to structural changes in the kinase domain that result in increased enzymatic activity.
- PI3K signaling activity Both helical and kinase domain mutations in exons 9 and 20 lead to a gain of PI3K signaling activity.
- Studies in breast cancer patients have shown that PIK3CA mutations in total, or specific groups with exon 9 or 20 mutations, have a negative prognostic value.
- Helical and kinase domain mutations may have different predictive value as well; exon 9 mutations alone predict enhanced sensitivity to the combination of everolimus and letrozole (vs. letrozole alone) in the neoadjuvant setting.
- Activating mutations in exons 9 and 20 are measured by allele-specific polymerase chain reaction (PCR).
- PIK3CA amplification is one of the key mechanisms of PI3K pathway activation in ovarian and endometrial cancers; in these patients, amplification leads to increased gene dosage and increased pathway activity and correlates with resistance to standard therapy and poor prognosis (21 , 22, 25, 26). PIK3CA amplifications are observed with less frequency in breast cancer.
- FISH fluorescence in situ hybridization
- the tumor suppressor PTEN is a dual-specificity phosphatase (lipid and protein) that functions as a check (or the "brakes") on the PI3K signaling complex. PTEN mediates the dephosphorylation of PIP3 to PIP2, eliminating the membrane binding site for PDK1 and Akt/PKB and thus antagonizing the activity of PI3K.
- the PTEN gene (at locus 10q23) is inactivated in a number of human malignancies, including breast, brain, endometrial, kidney, and prostate cancers (29-32) The inactivation of PTEN correlates with disease progression and poor prognosis, suggesting a key role in oncogenesis (16, 33-34).
- PTEN protein expression As used herein, "positive for the presence of a decrease in PTEN protein expression” means a decrease in PTEN expression levels as compared to non tumorigenic tissue (e.g., non-tumorigenic stromal or endothelial tissue).
- a sample is obtained from a patient with breast cancer.
- the sample is analyzed for the presence or absence of one or more of PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression.
- the presence of one or more of these results in the patient being designated as having a tumor that is "PI3K ON.” If a patient is designated as "PI3K ON", then the patient is treated with neratinib.
- any clinical benefit associated with the neratinib or therapeutic combination can be compared with that seen in the standard of care treatment group.
- PI3K activation is a marker of resistance to trastuzumab (12, 14, 48)
- alternative treatments available such as the tyrosine kinase inhibitor class of agents (e.g., the irreversible pan-ErbB inhibitor, neratinib, or the reversible Her1/Her2 inhibitor, lapatinib).
- Two groups of patients are created within a randomized trial— one group of patients in which PI3K pathway activation is apparent in the tumor sample (i.e., "PI3K ON” or patients with the presence of one or more of these: PIK3CA gene amplification; a mutation in PIK3CA; and a decrease in PTEN protein expression) and another group with no evidence of PI3K activation (i.e., "PI3K OFF” or patients with the absence of all three of these: PIK3CA gene amplification; a mutation in PI K3CA; and a decrease in PTEN protein expression).
- PI3K ON can be defined as "PIK3CA mutation +" and/or "PIK3CA gene amplification” and/or "PTEN loss” and/or "PTEN low.” Based on preliminary biomarker data obtained prior to the clinical trial (to support its predictability of response), such biomarkers can be considered as exploratory endpoints or as secondary endpoints with stratification. Such a grouping of the patients in a randomized trial could be treated as a separate level of stratification in the trial, with a different null hypothesis than standard geographic or prior treatment group stratifications (where the null hypothesis is that differences exist in the strata). For such a pathway grouping stratification, the null hypothesis would be that no difference exists in the treated group.
- PI3K ON is “PIK3CA mutant” or “PIK3CA amplified” or "PTEN null” or “PTEN reduced.”
- PI3K OFF is defined as "PIK3CA wild-type and non-amplified,” and "PTEN normal.”
- PI3K ON patients are treated with neratinib. The clinical benefit can then be compared between these two populations using linear regression methods.
- the null hypothesis is that the differential treatment effect in the "PI3K ON” group is the same as the differential treatment effect in the "PI3K OFF” group.
- pan-ErbB inhibitors may be somewhat effective in patients with tumors defined as "PTEN loss” or “PTEN low,” whereas PI3K inhibitors may have less activity against "PTEN loss” tumors and increased efficacy in tumors harboring PIK3CA mutations or amplifications.
- Li DM, Sun H (1997) TEP1 encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124-2129.
- Li DM Sun H (1998) PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA 95:15406-1541 1.
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Abstract
L'invention concerne des méthodes de traitement du cancer du sein, spécifiquement de cancers résistant à un traitement utilisant un ou plusieurs médicaments connus pour traiter le cancer du sein, et des stratégies de sélection de patient correspondantes qui permettent de prédire une réponse de patient à une thérapie médicamenteuse, lesdites stratégies incluant la détection de la présence ou de l'absence, chez un patient, d'un ou de plusieurs des événements comprenant une amplification du gène PIK3CA, une mutation de PIK3CA et une diminution de l'expression de la protéine PTEN ; et traiter le patient présentant un ou plusieurs desdits événements par l'administration, à celui-ci, d'un inhibiteur de la tyrosine kinase pan-ErbB.
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US13/514,556 US20130189274A1 (en) | 2009-12-11 | 2010-12-06 | Phosphatidylinositol-3-kinase pathway biomarkers |
CA2783743A CA2783743C (fr) | 2009-12-11 | 2010-12-06 | Biomarqueurs de la voie de la phosphatidylinotisol-3-kinase |
EP19170821.3A EP3575413A1 (fr) | 2009-12-11 | 2010-12-06 | Biomarqueurs de la voie phosphatidylinositol-3-kinase |
EP10805335A EP2510121A1 (fr) | 2009-12-11 | 2010-12-06 | Biomarqueurs de la voie de la phosphatidylinotisol-3-kinase |
US15/099,429 US20160222467A1 (en) | 2009-12-11 | 2016-04-14 | Phosphatidylinositol-3-kinase pathway biomarkers |
US16/416,083 US20190271047A1 (en) | 2009-12-11 | 2019-05-17 | Phosphatidylinositol-3-kinase pathway biomarkers |
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WO2013083810A1 (fr) * | 2011-12-09 | 2013-06-13 | F. Hoffmann-La Roche Ag | Identification de non-répondeurs aux inhibiteurs de her2 |
US9139558B2 (en) | 2007-10-17 | 2015-09-22 | Wyeth Llc | Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof |
US9211264B2 (en) | 2009-11-09 | 2015-12-15 | Wyeth Llc | Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea |
US9211291B2 (en) | 2009-04-06 | 2015-12-15 | Wyeth Llc | Treatment regimen utilizing neratinib for breast cancer |
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US9265784B2 (en) | 2008-08-04 | 2016-02-23 | Wyeth Llc | Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine |
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US10729672B2 (en) | 2005-11-04 | 2020-08-04 | Wyeth Llc | Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272 |
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JP2022519317A (ja) | 2019-02-06 | 2022-03-22 | ベンセラ,インコーポレイティド | 局所ホスホイノシチド3-キナーゼ阻害剤 |
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- 2010-12-06 CA CA2783743A patent/CA2783743C/fr active Active
- 2010-12-06 US US13/514,556 patent/US20130189274A1/en not_active Abandoned
- 2010-12-06 WO PCT/IB2010/055604 patent/WO2011070499A1/fr active Application Filing
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CA2783743A1 (fr) | 2011-06-16 |
JP2016169229A (ja) | 2016-09-23 |
JP2022022296A (ja) | 2022-02-03 |
JP2017101072A (ja) | 2017-06-08 |
CA2783743C (fr) | 2022-10-04 |
JP2019052187A (ja) | 2019-04-04 |
US20190271047A1 (en) | 2019-09-05 |
JP2020169212A (ja) | 2020-10-15 |
US20130189274A1 (en) | 2013-07-25 |
JP2015110669A (ja) | 2015-06-18 |
US20220170107A1 (en) | 2022-06-02 |
EP3575413A1 (fr) | 2019-12-04 |
US20160222467A1 (en) | 2016-08-04 |
EP2510121A1 (fr) | 2012-10-17 |
JP2011121944A (ja) | 2011-06-23 |
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