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Antineoplastic combinations containing hki-272 and vinorelbine

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Antineoplastic combinations containing hki-272 and vinorelbine


A combination of HKI-272 compound and a vinorelbine compound in the treatment of a neoplasm is provided. Regimens, kits, and methods for treatment of neoplasm, including breast cancer including metastatic breast cancer, and lung cancer, using this combination, optionally in combination with other anti-neoplastic agents, or immune modulators are also described.
Related Terms: Neoplasm Vinorelbine

Browse recent Wyeth LLC patents - Madison, NJ, US
Inventor: Charles Michael Zacharchuk
USPTO Applicaton #: #20120270896 - Class: 514283 (USPTO) - 10/25/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms >Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos >Pentacyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos >Ring Nitrogen In The Pentacyclo Ring System Is Shared By Five-membered Cyclo And Six-membered Cyclo (e.g., Vincamine, Etc.)



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The Patent Description & Claims data below is from USPTO Patent Application 20120270896, Antineoplastic combinations containing hki-272 and vinorelbine.

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BACKGROUND OF THE INVENTION

Breast cancer is the most frequently diagnosed malignancy in women and one of the top two causes of cancer-related deaths in women worldwide. The incidence of breast cancer in the world is increasing, and it is estimated that the disease will affect 5 million women in the next decade. Treatments permit control of symptoms, prolongation of survival, and maintenance of quality of life. However, in about 40% to 50% of all patients treated with curative intent, incurable metastatic disease will develop. Since there is no cure for metastatic breast cancer, current therapeutic goals are palliative.

In several cancer types, deregulation of growth factor signaling is observed, associated with a hyperactivation of the ErbB receptors. The ErbB receptor family includes ErbB-1 (also known as HER-1, epidermal growth factor receptor (EGFR)), ErbB-2 (a.k.a. neu or HER-2), HER-3 (a.k.a. ErbB-3), and HER-4 (a.k.a. ErbB-4). Overexpression of ErbB-1 is observed in non-small cell lung cancer (NSCLC) (40%-80%), breast cancer (14%-91%), and pancreatic cancer (30%-89%). In NSCLC, activation by mutation of amplification of ErbB-1 also occurs in 10% to 30% of patients.

Overexpression of ErbB-2, usually resulting from erbB-2 gene amplification, is observed in tumor tissue in 25% to 30% of patients of patients with metastatic breast cancer (MBC) and is associated with malignant transformation. ErbB-2 overexpression is usually associated with a more aggressive tumor phenotype, worse overall prognosis, and faster relapse times at all stages of cancer development. In women with MBC, this overexpression confers a relative resistance to treatment with either anthracycline/alkylator- or taxane-based chemotherapy. ErbB-2 overexpression in tumorigenesis has been mainly studied in breast cancers but is also observed in other cancers.

Among current therapeutics for cancers, specifically those characterized by overexpression of ErbB-2, are vinorelbine, trastuzumab and HKI-272. Vinorelbine, a semisynthetic vinca alkaloid having broad antitumor activity, acts through microtubule disruption. Vinorelbine presents a lower neurotoxicity profile than vincristine or vinblastine. Vinorelbine has been shown to be less toxic to axonal microtubules than vincristine or vinblastine at therapeutic concentrations. In studies conducted on subjects with advanced breast cancer, treatment with vinorelbine as a single agent is at least as efficient as other chemotherapies but with a lower risk of toxicity. However, the risk of toxicity increases in parallel with the number of previous anticancer treatments.

Trastuzumab (HERCEPTIN® drug) is a humanized monoclonal antibody specific for the extracellular domain of ErbB-2. It presents significant clinical benefit and significant antitumor activity when used alone or in combination with taxanes in metastatic breast cancer in first-line treatment or in patients who have tumor progression after chemotherapy. Because of the improvement in survival, trastuzumab-based therapies have become standard of care for women with ErbB-2-positive MBC. For women with advanced or metastatic disease, breast cancer eventually recurs despite trastuzumab treatment. Trastuzumab-based therapy is also associated with potential cardiac toxicity. Certain breast cancer cells are resistant to trastuzumab due to the occurrence of secondary ErbB-2 mutations, such as truncation of extracellular domain ErbB-2 receptor. Such mutations can result in cancer cells which are not recognized by the antibody.

In recent studies, trastuzumab in combination with either vinorelbine or taxane (paclitaxel with or without carboplatin, or docetaxel) was utilized to treat subjects with ErbB-2-overexpressing MBC. As expected, the most frequent grade toxicity observed with the combination of trastuzumab and vinorelbine was neutropenia.

HKI-272 is a small molecule, irreversible pan-ErbB receptor inhibitor specific for epidermal growth factor receptor (ErbB-1 or EGFR), ErbB-2 (HER-2), and ErbB-4 (HER-4). HKI-272 blocks kinase activity of the receptor through binding to the intracellular adenosine triphosphate (ATP) binding site of the receptor. HKI-272 blocks ErbB receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation. In vitro, HKI-272 alone inhibits kinase activity of ErbB-1, ErbB-2, and HER-4, inhibits tumor cell growth with breast and lung tumor cell lines, and presents a potent growth inhibition of lung cancer cells resistant to gefitinib or erlotinib. In vivo, HKI-272 blocks tumor growth in xenograft animal models. Overall, HKI-272 is less potent against ErbB-1-dependent tumors than ErbB-2-dependent tumors in vivo, even though it has equivalent activity against the 2 kinases in vitro.

There remains a need in the art for therapeutic methods, regimens, compositions, and kits which are useful in treating metastatic breast cancer and solid tumors.

SUMMARY

OF THE INVENTION

This invention addresses the need in the art by providing regimens, compositions and methods using a HKI-272 compound and a vinorelbine compound for the treatment of cancers, such as solid tumors and metastatic breast cancer.

In one aspect, regimens for treating a neoplasm in a subject are provided and include administering a vinorelbine compound and administering a HKI-272 compound. Desirably, the vinorelbine compound is vinorelbine and the HKI-272 compound is HKI-272. In one embodiment, the neoplasm is breast cancer.

In another aspect, a regimen for treating a solid tumor associated with overexpression or amplification of HER-2 in a subject is provided, wherein one cycle of the regimen includes 21 days. The regimen includes orally administering at least one unit dose of HKI-272 starting on day 1 of the cycle and intravenously administering at least one unit dose of vinorelbine on days 1 and 8 of the cycle.

In a further aspect, a regimen for treating a metastatic cancer associated with overexpression or amplification of HER-2 in a subject is provided. One cycle of the regimen includes 21 days and the regimen includes orally administering at least one unit dose of HKI-272 starting on day 2 of the cycle and intravenously administering at least one unit dose of vinorelbine on days 1 and 8 of the cycle.

In still another aspect, a product comprising a vinorelbine compound and HKI-272 compound is provided as a combined preparation for simultaneous, separate or sequential use in treating a neoplasm in a mammal.

In yet a further aspect, a pharmaceutical pack for treating a neoplasm in one individual mammal is provided and includes (a) at least one unit dose of vinorelbine; and (b) at least one unit dose of HKI-272.

In another aspect, a pharmaceutical composition is described and contains vinorelbine, HKI-272, and at least one pharmaceutically acceptable carrier.

In still another aspect, a method of treating a neoplasm associated with overexpression or amplification of HER-2 in a mammal in need thereof is provided and includes administering a unit dose of a vinorelbine compound and administering a unit dose of a HKI-272 compound.

Other aspects and advantages of the invention will be readily apparent from the following detailed description of the invention.

DESCRIPTION OF THE INVENTION

This invention provides compositions, methods, and regimens using a combination of a HKI-272 compound and a vinorelbine compound for the treatment of cancers. This invention provides in one embodiment compositions comprising HKI-272 and vinorelbine for the treatment of neoplasms. Also provided are products containing HKI-272 and vinorelbine formulated for simultaneous, separate or sequential use in treating neoplasms in a mammal. The invention is also useful as an adjuvant and/or neoadjuvant therapy of earlier stages of breast cancer. The invention provides, in another embodiment, methods for the combined use or administration of a HKI-272 compound and vinorelbine compound.

The Therapeutic Regimen and its Components

Without wishing to be bound by theory, the inventors hypothesize that the combination of HKI-272 and vinorelbine for treating a neoplasm is desirable because HKI-272 targets the intracellular ErbB-2 kinase rather than the extracellular domain. Thus, this combination has different mechanisms of sensitivity and resistance, and then presents an advantage over the therapeutic combination of trastuzumab and vinorelbine. Further, the combination of HKI-272 and vinorelbine is anticipated to be more effective than combinations of vinorelbine with other pan-ErbB inhibitors due to the tyrosine kinase inhibition activity of HKI-272 through an irreversible binding at a targeted cysteine residue in the ATP binding pocket of the receptor.

These methods, combinations and products are useful in the treatment of a variety of neoplasms, particularly those associated with overexpression or amplification of HER-2. In one embodiment, the neoplasm is a solid tumor or an advanced solid tumor. In a further embodiment, the neoplasm is metastatic. In another embodiment, neoplasms that may be treated as described herein include, e.g., lung cancers (such as bronchioalveolar carcinoma and non small cell lung cancer), breast cancers (such as metastatic breast cancer and HER-2-positive breast cancer), prostate cancers, myeloma, head and neck cancer, transitional cell carcinoma, small cell and large cell neuroendocrine carcinoma of the uterine cervix. In still another embodiment, the neoplasm is resistant to trastuzumab.

The regimens, methods, and compositions described herein include the concurrent, simultaneous, sequential or separate administration of the components, i.e., a HKI-272 compound and a vinorelbine compound. The term “composition” as used herein is intended to cover both pharmaceutical compositions in which 2 or more components are mixed, compositions of matter such as pharmaceutical kits and packs in which the components are individually packaged for concurrent, simultaneous, sequential, or separate administration. In one aspect of the invention, “a combination” includes simultaneous administration of the HKI-272 and vinorelbine compounds. In a further aspect of the invention, “a combination” includes sequential administration of the HKI-272 and vinorelbine compounds. In one embodiment the HKI-272 is administered before the vinorelbine compound. In another embodiment the vinorelbine compound is administered before the HKI-272 compound. In another aspect, “a combination” includes separate administration of the HKI-272 and vinorelbine compounds in a particular therapeutic regimen in which the two components of the combination are administered at specific times and amounts with respect to each other. In one embodiment, the combination of the HKI-272 and vinorelbine compounds produces a more beneficial therapeutic effect than that achievable by the administration of either a HKI-272 compound alone or a vinorelbine compound alone. Where the administration of those agents is sequential or separate, the delay in administering the second component should not be such as to lose the benefits provided the combination therapy.

In one embodiment, the combination of the HKI-272 and vinorelbine compounds is particularly well suited for treatment of metastatic breast cancer. In another embodiment, the combination of the HKI-272 and vinorelbine compounds are well suited for treatment of breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, and lung), and polycystic kidney disease.

As used herein and except where noted, the terms “individual”, “subject” and “patient” are used interchangeably, and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, non-human primates, and humans. Desirably, the term “individual”, “subject” or “patient” refers to a human. In certain circumstances, these terms refer to experimental animals such as rabbits, rats, and mice, and other animals. In most embodiments, the subjects or patients are in need of the therapeutic treatment. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the HKI-272 and vinorelbine compounds can be administered. In one embodiment, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, e.g., conventional work-ups to determine risk factors that are associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and formulations of the present invention. In one embodiment, the “individual”, “subject” or “patient” may have had no previously chemotherapeutic treatment. In another embodiment, the “individual”, “subject” or “patient” may have previously undergone chemotherapeutic treatment. In another embodiment, the “individual”, “subject” or “patient” may have previously been administered an aniloquinazoline class inhibitor. In a further embodiment, the “individual”, “subject” or “patient” may have previously been administered lapatinib or geftinib as the aniloquinazoline class inhibitor. Desirably, the blood count of the patient prior to treatment with the described combinations is stable enough to permit administration of the combinations described herein. In one embodiment, the neutrophil count of the patient prior to administration of the vinorelbine and HKI-272 compounds is at least 1500. In another embodiment, the platelet count of the patient prior to administration of the vinorelbine and HKI-272 compounds is at least 100,000/L.

As used herein, “a HKI-272 compound” refers, in one embodiment, to a compound having the following core structure:

or a derivative or pharmaceutically acceptable salt thereof. Suitable derivatives may include, e.g., an ester, ether, or carbamate. The core structure represented above is a particularly HKI-272 compound, called HKI-272, which has the chemical name (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide. In one embodiment, the HKI-272 compound useful in the compositions and methods described herein is HKI-272.

In another embodiment, an HKI-272 compound has the structure:

wherein:

R1 is halogen;

R2 is pyridinyl, thiophenyl, pyrimidinyl, thiazolyl, or phenyl, wherein R2 is optionally substituted with up to three substituents;

R3 is O or S;

R4 is CH3 or CH2CH2OCH3;

R5 is CH3 or CH2CH3; and

n is 0 or 1.

The term “halogen” as used herein refers to Cl, Br, I, and F.

These HKI-272 compounds, of which HKI-272 is a species, are characterized by the ability to act as potent HER-2 inhibitors. See, e.g., U.S. Pat. Nos. 6,288,082 and 6,297,258 and US Patent Application Publication No. 2007/0104721, which are hereby incorporated by reference. These compounds and their preparation are described in detail in US Patent Application Publication No. 2005/0059678, which is hereby incorporated by reference. For convenience, “a HKI-272 compound” is used throughout this specification. However, any compound of the structure(s) provided above can be substituted for HKI-272 in the combinations described in detail below.

HKI-272, other HKI-272 compounds, and methods of making and formulating same have been described. See, e.g., US Patent Application Publication No. 2005/0059678 and U.S. Pat. No. 6,002,008, which are hereby incorporated by reference. The methods described in these documents can also be used to prepare the substituted 3-quinoline compounds used herein and are hereby incorporated by reference. In addition to the methods described in these documents, International Patent Publication Nos. WO-96/33978 and WO-96/33980, which are hereby incorporated by reference, describe methods that are useful for the preparation of these HKI-272 compounds. Although these methods describe the preparation of certain quinazolines, they are also applicable to the preparation of correspondingly substituted 3-cyanoquinolines and are hereby incorporated by reference.

As used herein, the term “a vinorelbine compound” means vinorelbine or a pharmaceutically acceptable salt thereof, which has broad antitumor activity and that acts through microtubule disruption. See, Widakowich et al., Anticancer Agents Med. Chem., 8(5):488-496 (June 2008) and Wissner et al., Arch. Pharm. (Weinheim), (May 20, 2008 e-publication). The term includes the neutral vinorelbine compound, i.e., 4-(acetyloxy)-6,7-didehydro-15-((2R,6R,8S)-4-ethyl-1,3,6,7,8,9-hexohydro-8-(methoxycarbonyl)-2,6-methano-2H-azecino(4,3-b)indol-8-yl)-3-hydroxy-16-methoxy-l-methyl, methyl ester, (2β, 3β, 4β, 5α, 12R, 19α)-aspidospermidine-3-carboxylic acid (vinorelbine; tradename: Navelbine). Vinorelbine and its pharmaceutically acceptable salts are available from commercial vendors including Adventrx/SD Pharmaceuticals (SDP-012® drug), Hana (ALOCREST® drug), and Inex Pharmaceuticals Corp. (INX0125™ drug), and other vinorelbine compounds, including those discussed in U.S. Pat. No. 7,235,564, which is hereby incorporated by reference. In one embodiment, a vinorelbine compound includes a compound with a structural similarity to the vinorelbine compound structure below, e.g., compounds with a similar alkaloid structure that have been modified to enhance therapeutic benefit.

The preparation of vinorelbine compounds are described by Langlois et al., in J. Am. Chem. Soc. 98:7017-7024 (1976); and by Mangeney et al., in Tetrahedron, 35:2175-2179 (1979).

The HKI-272 and vinorelbine compounds and corresponding pharmaceutically acceptable salts or esters thereof include isomers either individually or as a mixture, such as enantiomers, diastereomers, and positional isomers.

“Pharmaceutically acceptable salts and esters” refers to salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include, e.g., salts that can be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include, e.g., those formed with the alkali metals or alkaline earth metals, e.g. sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include, e.g., those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts can also include acid addition salts formed from the reaction of basic moieties, such as amines, in the parent compound with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane-and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid).



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stats Patent Info
Application #
US 20120270896 A1
Publish Date
10/25/2012
Document #
13404390
File Date
02/24/2012
USPTO Class
514283
Other USPTO Classes
600/1
International Class
/
Drawings
0


Neoplasm
Vinorelbine


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