JP7438496B2 - Use of RXR agonists in the treatment of HER2+ cancer - Google Patents

Description

Article 30, Paragraph 2 of the Patent Act applies Meeting name: 4th International FASEB Conference on Retinoids, Date: June 12, 2018

Compounds with retinoid-like biological activity are well known in the art and include, but are not limited to, U.S. Pat. and numerous US patent specifications, all of which are incorporated by reference into this disclosure. Preclinical studies using rexinoids have shown that selective activation of retinoid This suggests that it is useful for treating various related diseases.

For example, TARGRETIN® (bexarotene), a retinoid It is approved by the U.S. Food and Drug Administration as an oral and topical treatment for the skin manifestations of cellular lymphoma. TARGRETIN® has shown promising results in multiple Phase II trials in NSCLC. However, a pivotal phase III clinical trial showed no improvement in survival. One possible reason for the limited success of bexarotene is that RAR activation reduces its effectiveness as an anticancer agent. Therefore, more selective RXR agonists are considered more promising.

Drugs that target human epidermal growth factor receptor 2 (Her2), both anti-Her2 antibodies and Her2 tyrosine kinase activity inhibitors, have great but not panacea potential in the treatment of Her2 ⁺ cancers, especially Her2 ⁺ breast cancers. It has brought success.

Cancer treatments are constantly evolving, becoming more specialized and sophisticated. Early nonsurgical cancer treatments generally targeted rapidly dividing cells, which are more sensitive to radiation and chemical attack. Gradually, more specific and generally less toxic treatments have been developed. Some treatments, such as immune checkpoint inhibitors or rexinoids, are broadly applicable. Others target cancers that express specific antigens or other biomarkers involved in controlling proliferation or differentiation, and include many monoclonal antibodies and kinase inhibitors. However, as the number of cancer treatments increases, it has become difficult to determine which treatments to use for which indications and which combinations of treatments are effective.

US Patent No. 5,466,861 US Patent No. 5,675,033 US Patent No. 5,917,082

This disclosure discloses improved methods of treating Her2 ⁺ cancers that include treating patients with Her2 ⁺ tumors with a combination of Her2-targeted therapeutics and RXR agonists that can inhibit cancer growth. be done. In some embodiments, the therapeutic combination further includes thyroid hormone.

In some embodiments, the RXR agonist is capable of activating the RXR/Nurr1 heterodimeric receptor. In some embodiments, the RXR agonist is a compound of Formula I disclosed below, or a pharmaceutically acceptable salt thereof. In some embodiments, the RXR agonist is a compound of Formula II disclosed below, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of Formula I and Formula II and pharmaceutically acceptable salts thereof are referred to as a method of activating the RXR/Nurr1 heterodimeric receptor or a rexinoid method of inhibiting tumor growth. be done.

In some embodiments, Her2-targeted therapeutics are inhibitors of Her2 kinase activity or Her2-mediated signaling. In some embodiments, the Her2-targeted therapeutic is a therapeutic anti-Her2 antibody. Therapeutic antibodies may mediate antibody-dependent cellular cytotoxicity (ADCC) instead of, or in addition to, inhibition of signal transduction (kinase activity). As disclosed below, trastuzumab and pertuzumab are examples of therapeutic anti-Her2 antibodies. In some embodiments, such antibodies are referred to as immunoglobulin methods that inhibit the proliferation of Her2 ⁺ tumor cells, ADCC-mediated therapy of Her2 ⁺ tumor cells, or immunoglobulin methods that inhibit Her2 signaling.

In some embodiments, the Her2-targeted therapeutic is an antibody-drug conjugate comprising an anti-Her2 antibody. In some embodiments, the anti-Her2 antibody alone has therapeutic activity, while in other embodiments the anti-Her2 antibody alone has no therapeutic activity and merely serves to deliver a cytotoxic agent to Her2 ⁺ cells. be. As disclosed below, ado-trastuzumab emtansine is an example of a Her2-targeted antibody-drug conjugate. In some embodiments, such antibody-drug conjugates are referred to as a method of delivering cytotoxic agents to Her2 ⁺ cells.

In some embodiments, the inhibitor of Her2 kinase activity or Her2-mediated signaling is a small organic molecule (small molecule drug) inhibitor of Her2 kinase activity. As disclosed below, lapatinib and neratinib are examples of Her2 kinase inhibitors. In some embodiments, such small molecule drug inhibitors of Her2 kinase activity are referred to as small molecule therapies that inhibit Her2 kinase activity.

In some embodiments, the Her2 ⁺ cancer is a Her2 ⁺ breast cancer. In some embodiments, the Her2 ⁺ cancer is Her2 ⁺ ovarian cancer, gastric cancer, lung adenocarcinoma, uterine cancer (such as serous endometrial cancer), gastric cancer, or salivary duct cancer.

In some embodiments, treatments in the present disclosure are performed concurrently with other medical therapies or radiation therapy. In other embodiments, the treatments in this disclosure are exclusive treatments while they are being administered. In some embodiments, the treatments in this disclosure serve as debulking therapy in preparation for subsequent surgical removal of the tumor. In some embodiments, the treatments in this disclosure are applied as adjunctive therapy following surgical removal of the tumor to address any residual or potential recurrent disease.

Other embodiments include combination pharmaceutical compositions or formulations that include at least one Her2-targeted therapeutic agent and at least one RXR agonist capable of inhibiting cancer growth. In other embodiments, the combination (used in therapy) may include two or more agents of one or the other class (Her2 targeting agents and/or RXR agonists). In yet other embodiments, the combination may further include thyroid hormone. In some embodiments, the thyroid hormone is thyroxine.

FIG. 1A is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and trastuzumab, alone and in combination, on a breast cancer cell line (MCF7 cells (FIG. 1A)). FIG. 1B is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and trastuzumab, alone and in combination, on a breast cancer cell line (SkBr3 cells (FIG. 1B)). FIG. 2A is a three-dimensional plot showing the growth inhibitory effects of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line (MCF7 cells (FIG. 2A)). FIG. 2B is a three-dimensional plot showing the growth inhibitory effects of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line (SkBr3 cells (FIG. 2B)). FIG. 2C is a three-dimensional plot showing the growth inhibitory effects of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line (BT474 cells (FIG. 2C)). FIG. 2D is a three-dimensional plot showing the growth inhibitory effects of IRX4204 and lapatinib, alone and in combination, on a breast cancer cell line (MDA-MB-361 cells (FIG. 2D)). FIG. 3A is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line (MCF7 cells (FIG. 3A)). FIG. 3B is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line (SkBr3 cells (FIG. 3B)). FIG. 3C is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line (BT474 cells (FIG. 3C)). FIG. 3D is a three-dimensional plot depicting the growth inhibitory effects of IRX4204 and neratinib, alone and in combination, on a breast cancer cell line (MDA-MB-361 cells (FIG. 3D)).

Embodiments in the present disclosure include methods of treating Her2 ⁺ cancers, such as Her2 ⁺ breast cancer, by combining retinoid X (rexinoid) receptor (RXR) agonists and Her2-targeted anticancer drugs. Some embodiments further include administering thyroid hormone in combination with an RXR agonist. Embodiments include RXR agonists for use in combination with Her2-targeted anti-cancer drugs or thyroid hormone and Her2-targeted anti-cancer drugs in the treatment of Her2 ⁺ cancers. In some embodiments, the Her2 ⁺ cancer is a Her2 ⁺ breast cancer.

Treatment methods include the administration of two, three or more therapeutic agents in combination. Additionally, administration of one of these drugs may be described as being performed in concert or in combination with the other of these drugs. Such a combination or coordinated or concomitant administration means that the method of administration of each of these drugs is such that the physiological effects of the drugs overlap in time. Although this does not require that the drugs be included in the same composition or formulation or be administered simultaneously, by the same route of administration, or on the same schedule as separate compositions, in some embodiments, It may be either. Indeed, while RXR agonists, thyroid hormones and Her2 kinase inhibitors can be administered on a daily basis, antibodies are more typically administered at intervals of several weeks.

Some previous successful targeted cancer treatments target human epidermal growth factor receptor 2 (Her2). Her2-targeted therapies include monoclonal antibodies (mAbs) such as trastuzumab and pertuzumab and inhibitors of Her2 kinase activity such as lapatinib, neratinib and afatinib, all of which also inhibit epidermal growth factor receptor (EGFR). It will be done. Rexinoid IRX4204 is a model system (e.g., U.S. Pat. , particularly when used in combination with thyroid hormones (e.g., U.S. Patent Application Publication No. 2008-0300312, which is incorporated by reference into this disclosure for all its teachings on the use of RXR agonists for the treatment of cancer). It has shown activity against various cancers. In this disclosure, the combination of IRX4204 and Her2 targeted therapeutics is shown to be particularly effective against Her2 ⁺ cancers, such as Her2 ⁺ breast cancer. Accordingly, various embodiments are combinations of IRX4204 and Her2 targeted therapeutics as well as treatments that include administration of both IRX4204 and Her2 targeted therapeutics. Some embodiments further include administration of thyroid hormone or thyroid hormone. Other embodiments do not include administration of thyroid hormone or thyroid hormone.

The Her2-targeted therapeutic agent used in the present disclosure is a therapeutic agent that inhibits cancer cell proliferation by inhibiting Her2 function. Such agents include mAbs that bind Her2, antibody drug conjugates comprising such mAbs, and inhibitors of Her2 tyrosine kinase activity. Such drugs may be collectively referred to as Her2-targeted therapies. Some embodiments specifically include or contain one or more of these classes of drugs, or one or more species within one or more of these classes of drugs. limited to. Some embodiments specifically do not include one or more of these classes of drugs, or one or more species within one or more of these classes of drugs. Accordingly, Her2-targeted therapies are mAbs that bind Her2, antibody drug conjugates comprising mAbs that bind Her2, and inhibitors of Her2 tyrosine kinase activity. In some embodiments, the mAb in the antibody-drug conjugate itself has therapeutic activity; in other embodiments, it has no therapeutic activity.

Although many embodiments include administration of a single anti-Her2 mAb, some embodiments include administration of multiple anti-Her2 mAbs, eg, trastuzumab and pertuzumab. Although most disclosed embodiments are described as using anti-Her2 mAbs, in further embodiments anti-Her2 polyclonal antisera can be used in place of anti-Her2 mAbs. Some embodiments may include administration of additional mAbs targeting other antigens, and some embodiments specifically do not include administration of other antibodies.

(Anti-Her2 antibody)
Her2 is a growth factor receptor found in and associated with various cancers, especially breast cancer, including gastroesophageal cancer, ovarian cancer, gastric cancer, lung adenocarcinoma, uterine cancer (serous It is also found and associated with cancers such as endometrial cancer) and salivary duct cancer. Anti-Her2 antibodies exhibit anticancer effects through a combination of mechanisms of action, including inhibition of Her2-mediated signaling, antibody-dependent cytotoxicity (ADCC), and mediating the presentation of tumor antigens by antigen-presenting cells (APCs) such as macrophages. Although it is thought to act as an agent, additional mechanisms of action may also exist. The best understood and most clinically advanced anti-Her2 antibodies are trastuzumab, pertuzumab and margetuximab.

In some embodiments, these antibodies are administered by intravenous infusion. In typical embodiments, infusions are given over a period of 30-90 minutes and may be given at 1-3 week intervals over a period of one year. In some such embodiments, the antibody is administered at high doses initially and at lower doses thereafter. In some such embodiments, the initial high dose is twice the subsequent low dose. In some such embodiments, the initial administration is a single dose. In other such embodiments, the initial dose is administered multiple times before switching to a subsequent lower dose. Specific examples of dosages and dosing regimens can be found in the HERCEPTIN® and PERJETA® prescribing information, which are incorporated by reference into this disclosure in their entirety.

Trastuzumab (sold as HERCEPTIN®) binds to domain IV of the extracellular segment of Her2. Trastuzumab inhibits proliferation of cells overexpressing Her2 and mediates ADCC. Biosimilar antibodies for trastuzumab have been developed and are commercially available in some countries and regions.

Pertuzumab (sold as PERJETA®) recognizes the extracellular dimerization domain (domain II) of Her2, a different epitope than trastuzumab. Preventing ligand-dependent dimerization causes inhibition of Her2-mediated signaling, cell growth arrest and apoptosis. Pertuzumab also mediates ADCC. Pertuzumab enhanced trastuzumab activity in a tumor xenograft model overexpressing Her2.

Margetuximab (currently in clinical development) recognizes the same epitope as trastuzumab, but has an Fc region designed to enhance Fc-dependent immune attack mechanisms such as ADCC. This engineered Fc region increases binding to the activating Fc-γ receptor (CD16A) on immune effector cells, including monocytes, macrophages, dendritic cells, and natural killer (NK) cells, and inhibits the inhibitory Fc-γ receptor (CD16A). -Decreases binding to γ receptor (CD16B).

Additionally, anti-Her2 mAbs include TrasGEX®, HM2, Hertuzumab and HT-19. TrasGEX® and HM2 are being developed as "biobetters" of trastuzumab, while the other two are independently derived. In HM2, a metal binding motif is incorporated into trastuzumab to facilitate conjugation. TrasGEX® is a glycosylation-optimized version of trastuzumab. Hertuzumab has a higher affinity for Her2 than trastuzumab by ELISA. HT-19 is an IgG1 antibody that is non-competitive with trastuzumab and pertuzumab for HER2 binding. That is, HT-19 binds to a different epitope than these two mAbs.

Although many embodiments include the administration of a single anti-Her2 mAb, some embodiments include the administration of multiple anti-Her2 mAbs, eg, trastuzumab and pertuzumab. Although most disclosed embodiments are referred to as using anti-Her2 mAb, additional embodiments can use anti-Her2 polyclonal antisera in place of anti-Her2 mAb.

(Antibody-drug conjugate)
In addition to using anti-Her2 mABs themselves as therapeutic agents, anti-Her2 mABs have also been incorporated into antibody-drug conjugates. One example is ado-trastuzumab emtansine (sold as KADCYLA®). Additionally, A166, ALT-P7 (trastuzumab biobetter HM2 site-specifically conjugated with monomethyl auristatin E), ARX788 (site-specific monomethyl HER2-targeted monoclonal antibody conjugated with auristatin F), DHES0815A (HER-2-targeted monoclonal antibody conjugated with pyrrolo[2,1-c][1,4]benzodiazepine monoamide), DS-8201a (trastuzumab derx Tecan; trastuzumab, enzymatically cleavable maleimidoglycine glycine-phenylalanine-glycine (GGFG) peptide linker and topoisomerase I inhibitor), RC48 (humanized conjugated to monomethyl auristatin E (MMAE) via a cleavable linker) anti-HER2 antibody hertuzumab), SYD985 (([vic-]trastuzumab duocarmazine; trastuzumab conjugated to the synthetic duocarmycin analog secoduocarmycin hydroxybenzamide azaindole via a cleavable valine-citrulline peptide) , MEDI4276 (AZ13599185, a HER2 bispecific antibody targeting two different epitopes on HER2, a potent tubulysin-based microtubule inhibitor, site-specifically via a maleimidocaproyl linker) Examples include HER2 bispecific antibody (conjugated with HER2 bispecific antibody) and XMT-1522 (TAK-522; HT-19 conjugated with auristatin F-hydroxypropylamide on the DOLAFLEXIN® platform).

In some embodiments, the Her2 targeting moiety comprises an antibody drug conjugate that includes an anti-Her2 antibody or is an antibody drug conjugate that includes an anti-Her2 antibody.

(Her2 kinase inhibitor)
Her2 and EGFR are closely related protein tyrosine kinases, and many drugs developed as inhibitors of one are also inhibitors of the other. At least four drugs that are irreversible inhibitors of these kinases, lapatinib, neratinib, afatinib, and dacomitinib, are currently marketed as cancer treatments, albeit for different indications. It should be noted that not all EGFR inhibitors are irreversible inhibitors nor are they known to reciprocally inhibit Her2. EGFR inhibitors that do not inhibit Her2 or are not known to inhibit Her2 do not fall under the term "Her2 inhibitor" as used in this disclosure. In some embodiments, the Her2 inhibitor is an irreversible inhibitor. In some embodiments, the Her2 inhibitor is not a reversible inhibitor.

Lapatinib (sold as TYKERB®) can be administered in 21-day treatment cycles according to the prescription instructions, which are incorporated by reference in their entirety into this disclosure. Lapatinib and capecitabine will be administered from days 1 to 14. Lapatinib will be administered alone from day 15 to day 21. At the end of the 21 days, the treatment cycle is repeated unless disease progression or unacceptable toxicity occurs. Capecitabine is administered orally in two divided doses approximately 12 hours apart at a dose of 2000 mg/m ² /day.

Neratinib (sold as NERLYNX®) is administered with food at an initial dose of 240 mg/day and can be administered daily for one year according to the prescription instructions, which are incorporated by reference in their entirety into this disclosure. If toxicity is greater than Grade 1, the dose may be reduced stepwise by 40 mg/day until toxicity is Grade 1 or less. If the dose is reduced to 120 mg/day and toxicity remains above grade 1, treatment with neratinib should be discontinued.

Afatinib (sold as GILOTRIF®) is administered at 40 mg/day per day unless disease progression occurs or is no longer tolerated by the patient, according to the prescribing instructions, which are incorporated by reference in their entirety into this disclosure. It can be administered orally once without meals.

Dacomitinib (sold as VIZIMPRO®) is administered at 45 mg/day once daily with meals unless disease progression or unacceptable toxicity occurs, according to the Prescribing Instructions, which are incorporated by reference into this disclosure. Or it can be administered orally without food. If unacceptable toxicity occurs, the dosage can be reduced stepwise to 30 or 15 mg/day.

The above administration information, in addition to disclosing specific embodiments in which these Her2 kinase inhibitors may be used in combination with RXR agonists, provides general instructions regarding the practice of administering such agents. The disclosed embodiments are not necessarily limited to these particular dosing regimens, and it is within the skill of the physician to modify these regimens for the individual patient. Improved and synergistic effects of these drugs when used in combination with RXR agonists to achieve beneficial therapeutic effects while avoiding unacceptable toxicity through the use of low doses of kinase inhibitors. I can do it.

(RXR agonist)
Preclinical studies using rexinoids have shown that selective activation of retinoid It has been suggested that it may be useful in treating various diseases related to function.

Retinoic acid receptors (RARs) and RXRs and their cognate ligands function by different mechanisms of action. The term "RAR" as used in this disclosure means one or more of RARα, RARβ or RARγ. The term "RXR" as used in this disclosure means one or more of RXRα, RXRβ or RXRγ. RAR biomarkers are characteristic biological, biochemical, or biologically derived indicators of RAR activity in a patient. RAR biomarkers include, but are not limited to, CYP26 levels, CRBPI levels, etc., and combinations thereof.

In some embodiments, RAR activation threshold refers to one or more of a CYP26 level increased by 25% above baseline and a CRBPI level increased by 25% above baseline. RAR forms heterodimers with RXR, and these RAR/RXR heterodimers bind to specific response elements in the promoter region of target genes. Binding of the RAR agonist to the heterodimeric RAR receptor activates transcription of target genes and induces retinoid action. On the other hand, the RXR agonists of the present disclosure do not activate RAR/RXR heterodimers. RXR heterodimeric complexes, such as RAR/RXR, can be used to generate transcriptional activation by ligand binding only in non-RXR proteins (e.g., RAR) and not in RXR. Can be referred to as a permissive RXR heterodimer.

RXR also interacts with nuclear receptors other than RAR, and RXR agonists may elicit some of their biological effects by binding to such RXR/receptor complexes. These RXR/receptor complexes can be referred to as permissive RXR heterodimers, since activation of transcription upon ligand binding can occur at RXR, other receptors, or both receptors. Examples of permissive RXR heterodimers include, but are not limited to, peroxisome proliferator-activated receptor/RXR (PPAR/RXR), farnesyl X receptor/RXR (FXR/RXR), nuclear receptor-related 1 protein (Nurr1/RXR). ) and liver X receptor/RXR (LXR/RXR). RXR also forms RXR/RXR homodimers, which can be activated by RXR agonists and induce rexinoid effects. RXR also interacts with proteins other than nuclear receptors, and rexinoid effects can also be induced by binding of a ligand to RXR within such protein complexes. Because of these differences in their mechanisms of action, RXR agonists and RAR agonists induce different biological effects, and even when they mediate similar biological effects, they do so by different mechanisms of action. Furthermore, undesirable side effects of retinoids, such as pro-inflammatory responses or mucocutaneous toxicity, are mediated by activation of one or more RAR receptor subtypes. Stated differently, the biological effects mediated through the RXR pathway do not induce pro-inflammatory responses and therefore do not result in undesirable side effects.

Accordingly, aspects of the disclosure, in part, provide RXR agonists. As used in this disclosure, the term "RXR agonist" is synonymous with "selective RXR agonist" and is intended to induce gene transcription through one or more RXRα, RXRβ or RXRγ It refers to a compound that selectively binds to RXR receptors such as. As used in this disclosure with respect to RXR agonists, the term "selectively binds" refers to RXR agonists that do not substantially bind to non-target receptors such as RARα, RARβ or RARγ, means that the RXR agonist differentially binds to the intended target receptor. In some embodiments, the term "RXR agonist" includes esters of RXR agonists.

ＲはＨまたは炭素数１から６の低級アルキルまたは、アゴニストは、薬学的に許容される化合物の塩である。 For each disclosed embodiment, the RXR agonist can be a compound having the structure of Formula I;

R is H or lower alkyl having 1 to 6 carbon atoms, or the agonist is a salt of a pharmaceutically acceptable compound.

This disclosure also discloses esters of RXR agonists. The ester may be derived from the carboxylic acid at C1, or the ester may be derived from the carboxylic acid functionality elsewhere on the molecule, such as the phenyl ring. Although not intended to be limiting, the ester may be an alkyl ester, an aryl ester, or a heteroaryl ester. The term "alkyl" has the meaning commonly understood by those skilled in the art and refers to a straight, branched or cyclic alkyl moiety. Particularly useful are C _1-6 alkyl esters, where the alkyl portion of the ester has 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, Includes, but is not limited to, t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and combinations thereof having 1 to 6 carbon atoms. In some embodiments, the RXR agonist is an ethyl ester of Formula I.

In some embodiments, the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1, also known as IRX4204. 2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, which has the following chemical structure.

Pharmaceutically acceptable salts of RXR agonists can also be used in the disclosed embodiments. Compounds are disclosed that have functional groups that are sufficiently acidic, sufficiently basic, or both, such that they can react with any of a number of organic or inorganic bases and inorganic and organic acids to form salts. has been done.

Acids commonly used to form acid addition salts from RXR agonists with basic groups include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and p-toluenesulfone. organic acids such as methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. Examples of such salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides. Bromide, Iodide, Acetate, Propionate, Decanoate, Caprylate, Acrylate, Formate, Isobutyrate, Caproate, Heptanoate, Propiolate, Oxalate, Malone Acid salt, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate Acid salts, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates , γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

Bases commonly used to form base addition salts from RXR agonists with acidic groups include, for example, alkali metal hydroxides such as sodium, potassium and lithium; alkaline earth metals such as calcium and magnesium; hydroxides of metals; hydroxides of other metals such as, for example, aluminum and zinc; ammonia and, for example, unsubstituted or hydroxy-substituted mono-, di- or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl , N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine or tris-(hydroxymethyl)methylamine - or tris-(2-hydroxy lower alkyl amines), N,N-di-lower alkyl-N-(hydroxy lower alkyl) amines such as N,N-dimethyl-N-(2-hydroxyethyl) amines or Examples include, but are not limited to, tri-(2-hydroxyethyl)amine; organic amines such as N-methyl-D-glucamine; and amino acids such as arginine and lysine.

IRX4204, like some other RXR ligands, does not activate nonpermissive heterodimers such as RAR/RXR. However, IRX4204 is unique in that it specifically activates Nurr1/RXR heterodimers and does not activate other permissive RXR heterodimers such as PPAR/RXR, FXR/RXR and LXR/RXR. Other RXR ligands generally activate these permissive RXR heterodimers. Therefore, all RXR ligands cannot be classified as belonging to one class. IRX4204 belongs to a unique class of RXR ligands that specifically activates only the Nurr1/RXR heterodimer, one of the RXR homodimers and permissive RXR heterodimers.

In one embodiment, the selective RXR agonist does not appreciably activate the permissive heterodimers PPAR/RXR, FXR/RXR and LXR/RXR. In other embodiments, the selective RXR agonist activates the permissive heterodimer Nurr1/RXR. As an example of such a selective RXR agonist, 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2, 3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid (IRX4204), the structure of which is shown in Formula II. In other aspects of this embodiment, activation of a permissive heterodimer, PPAR/RXR, FXR/RXR or LXR/RXR, by an RXR agonist activates a similar permissive heterodimer. 1% or less, 2% or less, 3% or less, 4% or less, 5% or less, 6% or less, 7% or less, 8% or less, 9% or less, or 10% or less. Examples of RXR agonists that activate one or more of PPAR/RXR, FXR/RXR or LXR/RXR include LGD1069 (bexarotene) and LGD268.

Binding specificity refers to the ability of an RXR agonist to discriminate between RXR receptors and receptors that do not contain a binding site for the RXR agonist, such as RAR receptors.

Certain embodiments provide a method of treating cancer comprising administering an RXR agonist to a patient in need of treatment at a level below an RAR activation threshold and above an RXR activation threshold.

For IRX4204, the RAR EC ₁₀ (concentration effective to induce 10% of RAR maximal activity) is 300 nM for the α isoform and 200 nM for the β and γ isoforms. Therefore, in some embodiments, concentrations not exceeding 200 nM are considered to be below RAR activating concentrations. For IRX4204, the RXR EC ₉₀ (concentration effective to induce 90% of maximal activity of RXR) is 0.1 nM for the α and γ isoforms and 1 nM for the β isoform. Thus, in some embodiments, a concentration of at least 0.1 nM is considered to exceed the RXR activation threshold. Based on studies in humans, an oral dose of IRX4204 of 20 mg/m ² /day results in systemic concentrations that remain below 200 nM. Similarly, oral doses in the range of 0.01-0.02 mg/m ² /day are estimated to result in systemic concentrations of 0.1 nM or greater. Accordingly, in various embodiments, the dosage of IRX4204 is at least 0.01, 0.02, 0.03, 0.05, 0.1, 0.3, 0.5, 1, 3 or 5 mg/ m ² /day and does not exceed the range delimited by 150, 200 or 300 mg/m ² /day, or a combination of these values.

In other embodiments, the dosage for adult humans of the RXR agonist, e.g., IRX4204, is 0.2 to 300 mg/day, in each embodiment 0.5, 1, 2, 3, 4, 5, , 7, 8, 9 or 10 mg/day, but not exceeding the range delimited by 10, 15, 20, 50 or 100 mg/day, or any combination of these values.

RXR agonists can be administered to mammals using standard administration techniques including parenteral, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual or suppository administration. It can be administered to The term "parenteral" as used in this disclosure includes intravenous, intramuscular, subcutaneous, rectal, vaginal and intraperitoneal administration. The RXR agonist is preferably suitable for oral administration, eg as a pill, tablet or capsule. Administration may be continuous or intermittent. In certain embodiments, the total number of daily doses of the RXR agonist can be a single dose or two doses administered 8 to 16 hours or 10 to 14 hours apart during a 24 hour period.

(thyroid hormone)
Both biologically derived and synthetic thyroid hormones have been used in medicine. The major forms of thyroid hormone are T3 (triiodothyronine) and T4 (thyroxine). Thyroxine has a low activity but a long half-life and is sometimes considered a prohormone of triiodothyronine. As used in this disclosure, the term "thyroid hormone" refers to thyroxine and triiodothyronine. Thyroxine (thyroid hormone T4, levothyroxine sodium) is a tyrosine-based hormone produced by the thyroid gland and is primarily involved in regulating metabolism. Both are widely commercially available and suitable for use in embodiments of the present disclosure. However, levothyroxine, a synthetic form of T4, is much more commonly available (except for patients who cannot convert T4 to T3) because its long half-life in the body facilitates once-daily administration. be done. In some embodiments, the thyroid hormone administered is specifically thyroxine. In some embodiments, the thyroid hormone administered is triiodothyronine.

Administration of RXR agonists or their esters can lead to suppression of serum thyroid hormones, possibly leading to clinical hypothyroidism and related diseases. However, in some embodiments, thyroid hormones are not co-administered (or not initially co-administered) to improve suppression of serum thyroid hormone levels. Coadministration of thyroid hormones and RXR agonists improves the anticancer effects of RXR agonists compared to the effects of RXR agonists alone, likely through multiple mechanisms of action. Also, co-administered thyroid hormones can reduce the hypothyroidism-inducing effects of RXR agonists, thereby improving the clinical safety and tolerability of the treatment. Accordingly, in a preferred embodiment, thyroid hormone is administered in conjunction with an RXR agonist to enhance the efficacy of treatment, regardless of whether administration of the RXR agonist has caused or is expected to cause clinical hypothyroidism. Administered simultaneously. Administering thyroid hormone in concert or in combination with an RXR agonist means that the method of administering each of these two drugs is such that the physiological effects of the two drugs overlap in time. Although this does not require that the RXR agonist and thyroid hormone be included in the same composition or formulation or that they be administered as separate compositions at the same time, by the same route of administration, or on the same schedule, some implementations The form may be any of those described above.

Suitable thyroxine dosages generally range from about 5 μg/day to about 250 μg/day orally initially, with dosage increases every 2 to 4 weeks as necessary. In other embodiments, suitable thyroxine dosages are about 5 μg/day to about 225 μg/day, about 7.5 μg/day to about 200 μg/day, about 10 μg/day to about 175 μg/day, about 12.5 μg/day day to about 150 μg/day, about 15 μg/day to 125 μg/day, about 17.5 μg/day to about 100 μg/day, about 20 μg/day to about 100 μg/day, about 22.5 to about 100 μg/day, 25 μg/day day to about 100 μg/day, about 5 μg/day to about 200 μg/day, about 5 μg/day to about 100 μg/day, about 7.5 μg/day to about 90 μg/day, about 10 μg/day to about 80 μg/day, about 12.5 μg/day to about 60 μg/day, about 15 μg/day to about 50 μg/day. Dose increases are generally about 5 μg/day, about 7.5 μg/day, about 10 μg/day, about 12.5 μg/day, about 15 μg/day, about 20 μg/day or about 25 μg/day. In certain embodiments, a suitable thyroid hormone dose is one that produces serum levels of T4 in the top 50%, top 60%, top 70%, top 80%, or top 90% of the normal range within the laboratory. be. The normal range for T4 levels may vary from laboratory to laboratory, and the target T4 level is based on the normal range determined for a particular laboratory.

For each embodiment that includes a combination of an RXR agonist and a Her2 targeted therapeutic, there are similar embodiments where such combination further includes a thyroid hormone.

(Pharmaceutical compositions and formulations)
The various active pharmaceutical ingredients used in the treatments described in this disclosure typically exist as pharmaceutical compositions or formulations. Such compositions or formulations may be liquid, semi-solid or solid formulations. The formulations of the present disclosure can be manufactured in a manner that forms one phase, eg, an oil or a solid. Alternatively, the formulations of the present disclosure can be manufactured in a two-phase manner, eg, as an emulsion. Pharmaceutical compositions of the present disclosure intended for such administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

Liquid preparations suitable for parenteral injection or nasal spray include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile injectable solutions or dispersions. It may also include a sterile powder for reconstitution. Formulations suitable for nasal administration may include sterile physiologically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols such as propylene glycol, polyethylene glycol (PEG), glycerol, suitable mixtures thereof, vegetable oils such as olive oil, and Includes injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the necessary particle size in the case of dispersions and by the use of surfactants.

Pharmaceutical compositions of the present disclosure can optionally include a pharmaceutically acceptable carrier that facilitates processing of the active compound into a pharmaceutically acceptable composition. As used in this disclosure, the term "pharmaceutically acceptable" means that, within the scope of sound medical judgment, the complication of undue toxicity, irritation, allergic reactions, or other issues is commensurate with a reasonable benefit/risk ratio. (This definition also applies to the phrase "pharmaceutically acceptable salts thereof") ). As used in this disclosure, the term "pharmaceutically acceptable carrier" is synonymous with "pharmaceutical carrier" and includes any carrier that does not produce substantial long-term or permanent adverse effects when administered. Refers to carrier and includes terms such as pharmaceutically acceptable vehicle, stabilizer, diluent, additive, adjuvant or excipient. Such carriers are generally capable of being mixed with, diluting or encapsulating the active compound and can be solid, semi-solid or liquid medicaments. It is understood that the active compound may be soluble or delivered as a suspension in the desired carrier or diluent. Various pharmaceutically acceptable optional carriers include, but are not limited to, aqueous media such as water, saline, glycine, hyaluronic acid; for example, starch, magnesium stearate, mannitol, sodium saccharin, talc. , solid carriers such as cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other non-active ingredients. can be used. The choice of pharmaceutically acceptable carrier will depend on the mode of administration. Their use in pharmaceutically acceptable compositions is contemplated except where the pharmaceutically acceptable carrier is incompatible with the active compound. Non-limiting examples of specific uses of such pharmaceutical carriers include Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al. eds, Lippincott Williams & Wis. lkins Publishers, ^7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, ^20th ed. 2000); Goodman &Gilman' s The Pharmaceutical Basis of Therapeutics (Joel G. Hardman et al. eds, McGraw-Hill Professional , ^10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, ^4th edition 2003) can be found. These protocols are defined and any modifications are within the scope of those skilled in the art and are well possible from the teachings of this disclosure.

The pharmaceutical compositions of the present disclosure optionally include other pharmaceutically acceptable ingredients (or pharmaceutical ingredients), including, but not limited to, buffers, preservatives, tonicity agents, salts, antioxidants. , osmotic pressure regulators, physiologically active substances, pharmacologically active substances, fillers, emulsifiers, wetting agents, sweeteners or flavoring agents, and the like, but are not limited to these. Various buffering agents and pH adjustment methods can be used in preparing the pharmaceutical compositions of the present disclosure, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline and phosphate buffered saline. It is understood that acids or bases can be used to adjust the pH of the composition, if desired. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium disulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stabilized oxychloro compositions such as, for example, sodium chlorite, and, for example, DTPA or DTPA-bisamides. , calcium DTPA and CaNaDTPA-bisamide. Tonicity agents useful in pharmaceutical compositions include, but are not limited to, salts such as, for example, sodium chloride, potassium chloride, mannitol or glycerin, and other pharmaceutically acceptable tonicity agents. Pharmaceutical compositions may be provided as salts and can be formed with a number of acids including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. It is understood that these and other substances known in the pharmaceutical art may be included in the pharmaceutical compositions useful in the present invention.

Pharmaceutical formulations suitable for administration by inhalation include particulate dusts or mists, which can be produced by various types of metered dose pressurized aerosols, nebulizers or inhalers.

Semisolid formulations suitable for topical administration include, but are not limited to, ointments, creams, salves and gels. In such solid formulations, the active compound may be mixed with at least one inert customary excipient (or carrier), such as lipids and/or polyethylene glycols.

Solid formulations suitable for oral administration include capsules, tablets, pills, powders and granules. In such solid formulations, the active compound is present in at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or filler, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants such as glycerol, (d) disintegrants such as agar, calcium carbonate, potato. or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retardants, such as paraffin; (f) absorption enhancers, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol. and glycerol monostearate, (h) adsorbents such as kaolin and bentonite and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. . In the case of capsules, tablets and pills, the dosage form may also include a buffering agent.

The small molecule components of various embodiments, namely RXR agonists, thyroid hormones and Her2 kinase inhibitors, can be formulated into solid oral dosage forms. Antibody components are generally formulated for intravenous infusion, typically as a liquid. In other embodiments, the antibody component may be supplied in lyophilized form for reconstitution as a liquid locally at the treatment site, typically injected intravenously into the patient. Although intravenous infusion is typical, in other embodiments the antibody may be administered by another route of administration, such as subcutaneous injection or infusion.

(treatment)
As used in this disclosure, the terms "treatment", "treating" and the like mean obtaining a desired pharmacological and/or physiological effect. This may be directly observed as slowing of tumor growth, stabilization of the disease state or partial or complete response (ie, tumor shrinkage or tumor removal) or prolongation of overall survival or disease-free survival. Treatment may also be observed as improvement or alleviation of symptoms associated with the underlying cancer. However, as a cancer therapy, the purpose and mechanism of action of the disclosed embodiments is to inhibit, stabilize or reduce tumor growth (including tumor metastasis) or to partially or completely eliminate a tumor. The aim is to increase overall survival or disease-free survival, with effects on other cancer symptoms being secondary. Direct treatment of such other symptoms (eg, pain, nausea, loss of appetite, etc.) is not within the scope of cancer treatment as used in this disclosure. That is, treating a cancer patient's symptoms, such as cachexia, is not treating cancer. However, drugs that treat cancer (e.g., affect cancer growth and/or metastasis) may also be used to treat cancer, either indirectly through effects on cancer or directly through pleiotropic effects, such as cachexia. May improve symptoms. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, weight, and the ability of the Her2-targeted therapeutic agent, RXR agonist, and thyroid hormone, if used, to elicit the desired response in the individual. be.

However, the dose administered to a mammal, particularly a human, in the context of this method should be sufficient to effect a therapeutic response in the mammal within a reasonable time frame. Those skilled in the art will also be aware of the precise dosage and composition and the selection of the most appropriate delivery regimen, especially based on the pharmacological properties of the formulation, the nature and severity of the disease being treated and the physical condition and mental acuity of the patient. and recognize that the efficacy of a particular compound is influenced by the age, disease, weight, sex and response of the patient being treated and the stage/severity of the disease.

Therapeutic activities, whether by a medical professional, the patient himself or herself, or any other person, include, among other things, the administration to a patient of the medicaments, dosage forms and pharmaceutical compositions described in this disclosure in accordance with the various treatment methods in this disclosure. including. Therapeutic activities include orders, instructions, and advice of health care professionals, such as physicians, physician assistants, nurses, etc., which are then carried out by other health care professionals or any other person, including the patient himself. In some embodiments, the treatment action may be performed by an insurance company or pharmacy benefit manager, etc., such as approving coverage of a drug, denying coverage of a substitute drug, including the drug in an adopted formulary, or requesting a substitute drug. Recommending, inducing, or mandating that a particular drug or combination of drugs be selected for the treatment of a disease, such as by excluding a drug or providing a financial incentive for its use, and that the drug is actually used. may also be included. In some embodiments, therapeutic activities also include the selection of a particular drug for the treatment of a disease by policy or practice standards, such as those that may be established by a hospital, clinic, health maintenance organization, medical practice, or physician group. and may include recommending, inducing or requiring that the drug be used in practice.

To benefit from the combined effects of an RXR agonist of Formula I (or a pharmaceutically acceptable salt thereof) and a Her2 ^- targeted therapeutic agent, embodiments provide an RXR agonist of Formula I (or (a pharmaceutically acceptable salt thereof) and a Her2-targeted therapeutic agent. Some embodiments further include administering thyroid hormone in conjunction with administering the RXR agonist. In some embodiments, the Her2 ⁺ cancer is a Her2 ⁺ breast cancer. In some embodiments, the Her2 ⁺ cancer is a Her2 ⁺ gastroesophageal cancer, ovarian cancer, gastric cancer, lung adenocarcinoma, uterine cancer (such as serous endometrial cancer), or salivary duct cancer . Some embodiments specifically include one or more of these cancers. Other embodiments specifically exclude one or more of these cancers.

In various embodiments, the treatments of the present disclosure may be used as a primary treatment, as debulking therapy prior to surgical removal of a tumor, or in any form to address residual disease and/or reduce the risk of cancer recurrence. It can be applied as an adjunctive therapy following the primary treatment (especially surgery).

In some embodiments, the patient with Her2 ⁺ cancer has not been previously treated with either a Formula I RXR agonist (or a pharmaceutically acceptable salt thereof) or a Her2-targeted therapeutic agent. In some embodiments, the patient has been previously treated with an RXR agonist of Formula I (or a pharmaceutically acceptable salt thereof) and has achieved stable disease or partial response (in some embodiments, RECIST or iRECIST criteria), i.e., the cancer is sensitive to the RXR agonist of Formula I (or a pharmaceutically acceptable salt thereof), and a Her2-targeted therapy is added to the treatment regimen. has been done. In some embodiments, the patient has been previously treated with a Her2-targeted therapeutic and has achieved stable disease or a partial response (as defined by RECIST or iRECIST criteria in some embodiments), i.e. Cancers are sensitive to Her2-targeted therapeutics, and an RXR agonist of Formula I (or a pharmaceutically acceptable salt thereof) is added to the treatment regimen.

Accordingly, some embodiments limit administration of an RXR agonist to patients who have had Her2 ⁺ tumors who have received, are receiving, or will receive a Her2 targeted therapy. Some embodiments limit the administration of the RXR agonist to patients for whom the Her2-targeted therapy had some therapeutic effect (less than a complete response), i.e., include the administration of the RXR agonist in the treatment regimen of the Her2-targeted therapy. to add. Some embodiments limit administration of Her2-targeted therapy to patients for whom the RXR agonist (or RXR agonist in combination with thyroid hormone) had some therapeutic effect (less than a complete response), i.e., Her2-targeted therapy Add the drug to the RXR agonist treatment regimen.

Periodic evaluation of treated patients allows the effectiveness of treatment to be monitored. For repeated administration over a period of several days or longer, treatment can be repeated until the desired suppression of the disease or condition occurs. However, other dosing regimens may be useful and are within the scope of this disclosure. Antibodies typically have a much longer half-life in the body than other active agents used in these methods, and therefore the dosing intervals are typically much longer (weeks). ).

The effectiveness of cancer treatments is usually evaluated in terms of "response." Techniques to monitor response may be similar to tests used to diagnose cancer, including, but not limited to:
・Lumps and tumors, including lymph nodes, can be observed and evaluated externally during physical examinations. ・Some internal cancer tumors can be seen with X-rays or CT scans and measured with a ruler. ・Measuring organ function・For certain cancers, tumor marker tests may be performed.

Regardless of the test used, such as a blood test, cell count or tumor marker test, it is repeated at specific intervals so that results can be compared with previous tests of the same type.

Response to cancer treatment is defined in several ways.
・Complete response: All of the cancer or tumor has disappeared and the patient is disease-free and alive. Tumor marker expression levels (if applicable) may fall within normal limits.
・Partial response: The cancer has shrunk by a certain percentage, but the disease remains. Levels of tumor markers (if applicable) may be decreasing (or increasing, based on tumor markers, as a sign of decreasing tumor burden), but evidence of disease remains.
・Stable condition: The cancer does not grow or shrink, and there is no change in the disease. There are also no significant changes in tumor markers (if applicable).
・Deterioration of the condition: The cancer is growing and the disease is worse than before treatment. Tumor marker testing (if applicable) shows elevated tumor markers.

Other measures of effectiveness of cancer treatment include overall survival (i.e., time from diagnosis or initiation of treatment being evaluated to death from any cause), cancer-free survival (i.e., cancer-free survival (i.e., the period after a complete response in which no tumor growth is detectable) and progression-free survival (i.e., the period after stable disease or partial response in which no recurrence of tumor growth is detectable).

There are two standard methods for evaluating the therapeutic effects of solid cancers regarding tumor size (tumor burden): the WHO criteria and the RECIST criteria. These methods measure solid tumors and modify treatment regimens to compare current tumors to past measurements or to compare changes to future measurements. In the WHO method, the long axis and short axis of a solid tumor are measured and the product thereof is calculated. If there are multiple solid tumors, calculate the sum of all products. In the RECIST method, only the long axis is measured. If there are multiple solid tumors, calculate the sum of all long axis measurements. However, for lymph nodes, the short axis is measured instead of the long axis. There is also the RECIST method for immunotherapy (iRECIST), which takes into account the unique behaviors associated with this class of therapeutics, such as delayed response after pseudo-progression. Both the RECIST 1.1 guidelines and the iRecist guidelines are incorporated by reference into this disclosure in their entirety.

In some embodiments of the disclosed methods, the treated patient has a tumor burden of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%. %, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100% or Reduce within the range bounded by these values.

In other embodiments, the one-year survival rate for treated subjects is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100% or bounded by these values increase to the extent possible.

In other embodiments, the five-year survival rate for treated subjects is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100% or bounded by these values increase to the extent possible.

In other embodiments, the 10-year survival rate for treated subjects is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, about 100% or bounded by these values increase to the extent possible.

In still other embodiments, the subject is at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, Sustained remission for at least 20 months, at least 22 months, at least 24 months, at least 27 months, at least 30 months, at least 33 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months or at least 60 months or more have.

In other embodiments, the method can additionally assist in treating or alleviating a disease, condition, or disorder associated with cancer. In some embodiments, these diseases or conditions include anemia, asthenia, cachexia, Cushing's syndrome, fatigue, gout, periodontal disease, hematuria, hypercalcemia, hypothyroidism, internal bleeding, Hair loss, mesothelioma, nausea, night sweats, neutropenia, paraneoplastic syndrome, pleurisy, polymyalgia rheumatica, rhabdomyolysis, stress, lymphadenopathy, thrombocytopenia, vitamin D deficiency or weight This includes, but is not limited to, a decrease. Cancer treatment can reduce or treat the associated medical condition, but it is not expected that the tumor will shrink or disappear or that the growth or spread of the tumor will be inhibited. What you do is not cancer treatment.

Toxicity and adverse events are often evaluated on a five-point scale. Grade 1 or mild toxicity induces no symptoms or only mild symptoms; can be characterized by clinical or diagnostic observations only; and no therapeutic intervention is indicated. Grade 2 or moderate toxicity may impair activities of daily living (e.g., preparing meals, shopping, managing finances, using the telephone), but requires only minimal, topical, or non-invasive therapeutic intervention. is instructed. Grade 3 toxicities are medically significant but not immediately life-threatening; hospitalization or extended hospitalization may be indicated, and self-care activities of daily living (bathing, dressing, dressing, eating, toileting, taking medications, and bed rest) may be indicated. (e.g., not being damaged) may be impaired. Grade 4 toxicity is life-threatening and emergency medical intervention is indicated. Grade 5 toxicity results in death related to adverse events. Accordingly, in various embodiments, the use of an RXR agonist or an RXR agonist and a thyroid hormone is related to the use of Her2-targeted therapy by allowing lower doses to be used without substantially sacrificing efficacy. reduce the toxicity grade. In some embodiments, the use of an RXR agonist or an RXR agonist and a thyroid hormone in combination with a Her2-targeted therapy results in the use of an RXR agonist or an RXR agonist and a thyroid hormone without a substantial decrease in efficacy as would be expected from a Her2-targeted therapy alone. Reduce toxicity to below grade 1 or produce no toxic findings. In some embodiments, the combination of a Her2-targeted therapeutic agent and an RXR agonist or an RXR agonist and a thyroid hormone in cases where treatment with a Her2-targeted therapeutic agent would have had to be discontinued due to unacceptable toxicity; This allows continued use of Her2-targeted therapeutics at low doses that are therapeutically effective. In some of these embodiments, the Her2-targeted therapeutic comprises a Her2 kinase inhibitor.

The combination of RXR agonists and Her2-targeted therapeutics of the present disclosure provides a synergistic effect. That is, they interact in a positive manner resulting in greater inhibition of tumor cell proliferation than would be expected from their independent (non-reciprocal) effects. Accordingly, some embodiments provide improved efficacy. Other embodiments allow for lower dosages to reduce toxicity while still achieving at least similar efficacy as provided by the individual therapeutic agent. In some embodiments, both reduced toxicity and improved efficacy (as compared to more toxic single agents) are achieved.

For each therapy, the use of an RXR agonist in combination with a Her2 ^- targeted therapeutic or a Her2-targeted therapeutic and thyroid hormone to treat Her2 ⁺ cancer; Further similar embodiments exist for the aforementioned methods of directing the use of RXR agonists in the manufacture of therapeutic agents or agents for use in combination with Her2-targeted therapeutic agents and thyroid hormones.

Further embodiments include combinations comprising an RXR agonist and a Her2-targeted therapeutic as detailed in this disclosure. Some embodiments further include thyroid hormone. In some embodiments, the Her2-targeted therapeutic is an anti-Her2 antibody. In some embodiments, the Her2-targeted therapeutic is a Her2 kinase inhibitor.

Further embodiments include kits containing the combinations described above. Kits may further include solvents, diluents, syringes, etc. that may facilitate administration of one or more therapeutic agents. The kit may further include instructions for the coordinated use of therapeutic agents utilized in the disclosed methods, whether or not any particular agent is provided within the kit.

(List of specific embodiments)
The following list of embodiments is illustrative of the various embodiments described in this disclosure with respect to scope, combinations and subcombinations, classifications of inventions, etc., but is not exhaustive of all embodiments supported by this disclosure. It is not intended to be an enumeration.

ＲはＨまたは炭素数１～６の低級アルキルであり、
患者は、Ｈｅｒ２標的治療薬を投与されたことがある、投与されている、または投与される予定である、
方法。 Embodiment 1. A method of treating a patient with Her2 ⁺ cancer comprising administering to the patient an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, the method comprising:

R is H or lower alkyl having 1 to 6 carbon atoms,
The patient has received, is receiving, or will receive a Her2-targeted therapeutic agent;
Method.

式中、ＲはＨまたは炭素数１～６の低級アルキルである。 Embodiment 2. A method of treating a patient with Her2 ⁺ cancer comprising administering an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof and a Her2 targeted therapeutic agent.

In the formula, R is H or lower alkyl having 1 to 6 carbon atoms.

ＲはＨまたは炭素数１～６の低級アルキルであり、
完全奏効未満である治療効果の証拠がある、
方法。 Embodiment 3. of a patient with Her2+ cancer undergoing treatment with an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, including continuing treatment with an RXR agonist and initiating treatment with a Her2-targeted therapeutic agent. A treatment method,

R is H or lower alkyl having 1 to 6 carbon atoms,
There is evidence of treatment efficacy that is less than a complete response;
Method.

ＲはＨまたは炭素数１～６の低級アルキルであり、
完全奏効未満である治療効果の証拠がある、
方法。 Embodiment 4. Her2 ⁺ cancers undergoing treatment with a Her2-targeted therapeutic agent, comprising continuing treatment with a Her2-targeting therapeutic agent and starting treatment with an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof. A method for treating patients with

R is H or lower alkyl having 1 to 6 carbon atoms,
There is evidence of treatment efficacy that is less than a complete response;
Method.

ＲはＨまたは炭素数１～６の低級アルキルであり、
患者は、Ｈｅｒ２標的治療法を受けたことがある、受けている、または受ける予定である、
方法。 Embodiment 5. A method of treating a patient with Her2 ⁺ cancer comprising administering to the patient an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, the method comprising:

R is H or lower alkyl having 1 to 6 carbon atoms,
The patient has received, is receiving, or will receive a Her2-targeted therapy;
Method.

Embodiment 6. Her2 targeted therapy is
A method for inhibiting the proliferation of Her2 ⁺ tumor cells,
A method for mediating ADCC of Her2 ⁺ tumor cells;
immunoglobulin methods that inhibit Her2 signaling;
A method for delivering a cytotoxic agent to Her2 ⁺ cells, or
small molecule methods to inhibit Her2 kinase activity;
The method according to embodiment 5.

Embodiment 7. A method of treating a Her2 ⁺ cancer patient comprising undergoing a method of activating the RXR/Nurr1 heterodimeric receptor or a rexinoid method of inhibiting tumor growth, the patient being administered a Her2-targeted therapeutic agent. The method that has been, is being administered, or will be administered.

Embodiment 8. 8. The method of any one of embodiments 1-7, further comprising administering thyroid hormone in combination with an RXR agonist.

Embodiment 9. 9. The method of embodiment 8, wherein the thyroid hormone is thyroxine.

Embodiment 10. A method according to any one of embodiments 1 to 9, wherein the RXR agonist, the method of activating the RXR/Nurr1 heterodimeric receptor or the rexinoid method of inhibiting tumor growth is a compound of Formula I.

Embodiment 11. Any of embodiments 1-9, wherein the RXR agonist, the method of activating the RXR/Nurr1 heterodimeric receptor or the rexinoid method of inhibiting tumor growth is a pharmaceutically acceptable salt of a compound of Formula I The method described in one.

Embodiment 12. The method according to any one of embodiments 1-9, wherein the RXR agonist, the method of activating the RXR/Nurr1 heterodimeric receptor or the rexinoid method of inhibiting tumor growth is a compound of Formula II.

Embodiment 13. The method according to any one of embodiments 1-12, comprising:
Her2 targeted therapeutic drug,
A method for inhibiting the proliferation of Her2 ⁺ tumor cells,
Methods for mediating ADCC of Her2 ⁺ tumor cells;
immunoglobulin methods that inhibit Her2 signaling, or
A method for delivering a cytotoxic agent to Her2 ⁺ cells, comprising:
comprising an anti-Her2 therapeutic antibody;
Method.

Embodiment 14. 14. The method of embodiment 13, wherein the therapeutic antibody is trastuzumab or pertuzumab.

Embodiment 15. The method of embodiment 13, wherein the therapeutic antibody is margetuximab, TrasGEX, HM2, hertuzumab or HT-19.

Embodiment 16. Any one of embodiments 1-13, wherein the Her2-targeted therapeutic agent, method of inhibiting Her2 ⁺ tumor cell proliferation or immunoglobulin method of inhibiting Her2 signaling comprises an antibody-drug conjugate, and the antibody is an anti-Her2 antibody. The method described in.

Embodiment 17. 17. The method of embodiment 16, wherein the antibody drug conjugate or the method of delivering a cytotoxic agent to Her2 ⁺ cells is ado-trastuzumab emtansine.

Embodiment 18. Described in embodiment 16, wherein the method of delivering an antibody drug conjugate or a cytotoxic agent to Her2 ⁺ cells is A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 or XMT-1522. the method of.

Embodiment 19. 13. The method of any one of embodiments 1-12, wherein the Her2-targeted therapeutic or small molecule method of inhibiting Her2 kinase activity comprises a Her2 kinase inhibitor.

Embodiment 20. 20. The method of embodiment 19, wherein the Her2 kinase inhibitor is lapatinib or neratinib.

Embodiment 21. 20. The method of embodiment 19, wherein the Her2 kinase inhibitor is afatinib or dacomitinib.

Embodiment 22. 22. The method according to any one of embodiments 1-21, wherein the treatment is by weight loss therapy.

Embodiment 23. 22. The method according to any one of embodiments 1-21, wherein the treatment is by adjuvant therapy.

Embodiment 24. 24. The method according to any one of embodiments 1-23, wherein the Her2 ⁺ cancer is a Her2 ⁺ breast cancer.

Embodiment 25. The Her2 ⁺ cancer is Her2 ⁺ gastroesophageal cancer, ovarian cancer, stomach cancer, lung adenocarcinoma, uterine cancer (such as serous endometrial cancer), or salivary duct cancer, according to embodiments 1 to 23. Any one of the methods.

Embodiment 26. 26. The method of any one of embodiments 1-25, wherein the therapeutic response to the RXR agonist and Her2-targeted therapeutic agent is greater than the response to either agent alone.

Embodiment 27. 27. The method of embodiment 26, wherein the greater therapeutic response is slowing tumor growth, stabilizing disease, partial response, complete response, prolonging overall survival or disease-free survival.

Embodiment 28. 28. The method of embodiment 26 or 27, wherein response is assessed according to RECIST criteria or iRECIST criteria.

Embodiment 29. 29. The method of any one of embodiments 26-28, comprising reducing or ameliorating secondary symptoms.

式中、ＲはＨまたは炭素数１～６の低級アルキルである。 Embodiment 30. A combination comprising a Her2-targeted therapeutic agent or method and an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof.

In the formula, R is H or lower alkyl having 1 to 6 carbon atoms.

Embodiment 31. The combination according to embodiment 30,
The Her2-targeted therapeutic agent or Her2-targeted therapy is
A method for inhibiting the proliferation of Her2 ⁺ tumor cells,
Methods for mediating ADCC of Her2 ⁺ tumor cells;
immunoglobulin methods that inhibit Her2 signaling;
A method for delivering a cytotoxic agent to Her2 ⁺ cells, or
small molecule methods to inhibit Her2 kinase activity;
including,
combination.

Embodiment 32. The combination according to embodiment 30 or 31, further comprising thyroid hormone.

Embodiment 33. A combination according to any one of embodiments 30-32, wherein the RXR agonist is a compound of formula II.

Embodiment 34. The combination according to any one of embodiments 30 to 33,
Her2 targeted therapeutic drug,
A method for inhibiting the proliferation of Her2 ⁺ tumor cells,
Methods for mediating ADCC of Her2 ⁺ tumor cells;
immunoglobulin methods that inhibit Her2 signaling, or
A method for delivering cytotoxic drugs to Her2 ⁺ cells is
comprising an anti-Her2 therapeutic antibody;
combination.

Embodiment 35. A combination according to embodiment 34, wherein the therapeutic antibody is trastuzumab or pertuzumab.

Embodiment 36. Any one of embodiments 30-34, wherein the Her2-targeted therapeutic agent, method of inhibiting Her2 ⁺ tumor cell proliferation or immunoglobulin method of inhibiting Her2 signaling comprises an antibody-drug conjugate, and the antibody is an anti-Her2 antibody. combinations listed in.

Embodiment 37. A combination according to embodiment 36, wherein the antibody drug conjugate is adotrastuzumab emtansine.

Embodiment 38. A combination according to any one of embodiments 30-33, wherein the Her2-targeted therapeutic or small molecule method of inhibiting Her2 kinase activity comprises a Her2 kinase inhibitor.

Embodiment 39. A combination according to embodiment 38, wherein the Her2 kinase inhibitor is lapatinib or neratinib.

Embodiment 40. A kit comprising a combination according to any one of embodiments 30-39.

ＲはＨまたは炭素数１から６の低級アルキルであり、
患者は、Ｈｅｒ２標的治療薬を投与されたことがある、投与されている、または投与される予定である、
ＲＸＲアゴニスト。 Embodiment 41. An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of patients with Her2 ⁺ cancer, comprising:

R is H or lower alkyl having 1 to 6 carbon atoms,
The patient has received, is receiving, or will receive a Her2-targeted therapeutic agent;
RXR agonist.

ＲはＨまたは炭素数１から６の低級アルキルである、
ＲＸＲアゴニストまたは薬学的に許容されるその塩、およびＨｅｒ２標的治療薬。 Embodiment 42. An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof and a Her2-targeted therapeutic agent for use in combination in the treatment of Her2 ⁺ cancer patients, comprising:

R is H or lower alkyl having 1 to 6 carbon atoms,
RXR agonists or pharmaceutically acceptable salts thereof, and Her2-targeted therapeutics.

ＲはＨまたは炭素数１から６の低級アルキルである、式ＩのＲＸＲアゴニストまたは薬学的に許容されるその塩およびＨｅｒ２^＋がん患者の治療に使用するＨｅｒ２標的治療薬の組み合わせ。 Embodiment 43.

A combination of an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof and a Her2-targeted therapeutic agent for use in the treatment of Her2 ⁺ cancer patients, wherein R is H or lower alkyl having 1 to 6 carbon atoms.

式中、ＲはＨまたは炭素数１～６の低級アルキルである。 Embodiment 44. A pharmaceutical combination for treating Her2 ⁺ cancer comprising an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof and a Her2 targeted therapeutic agent.

In the formula, R is H or lower alkyl having 1 to 6 carbon atoms.

ＲはＨまたは炭素数１～６の低級アルキルであり、
Ｈｅｒ２標的治療薬を投与されたことがある、投与されている、または投与される予定である患者における、Ｈｅｒ２^＋がんを治療する医薬品の製造に使用する、
ＲＸＲアゴニスト。 Embodiment 45. An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, comprising:

R is H or lower alkyl having 1 to 6 carbon atoms,
for use in the manufacture of a medicament for treating Her2 ⁺ cancer in patients who have received, are receiving, or will receive a Her2-targeted therapeutic agent;
RXR agonist.

式中、ＲはＨまたは炭素数１から６の低級アルキルである。 Embodiment 46. An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, and a Her2-targeted therapeutic agent for use in the manufacture of a medicament for use in combination to treat Her2 ⁺ cancer.

In the formula, R is H or lower alkyl having 1 to 6 carbon atoms.

ＲはＨまたは炭素数１～６の低級アルキルであり、
ＲＸＲアゴニストと組み合わされる、
Ｈｅｒ２標的治療薬。 Embodiment 47. A Her2-targeted therapeutic agent for the treatment of Her2 ⁺ cancer in patients with Her2 ⁺ cancer who exhibit less than a complete response to treatment with an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof. hand,

R is H or lower alkyl having 1 to 6 carbon atoms,
combined with an RXR agonist,
Her2 targeted therapy.

ＲはＨまたは炭素数１～６の低級アルキルであり、
Ｈｅｒ２標的治療薬と組み合わされる、
ＲＸＲアゴニスト。 Embodiment 48. An RXR agonist of formula I or a pharmaceutically acceptable salt thereof for the treatment of Her2 ⁺ cancer in patients with Her2 ⁺ cancer who exhibit less than a complete response to treatment with a Her2-targeted therapeutic agent. There it is,

R is H or lower alkyl having 1 to 6 carbon atoms,
combined with a Her2-targeted therapeutic agent,
RXR agonist.

It is clear that each embodiment or embodiments 41-48 can be modified in a manner similar to the modification of embodiments 1-5 and 7 by embodiments 5 and 8-29.

(Example)
The following non-limiting examples are provided for illustrative purposes only, to facilitate a more complete understanding of presently contemplated representative embodiments. These examples should not be construed as limiting any embodiments described in this disclosure.

(Example 1)
Inhibitory effect of breast cancer cell proliferation by combination of IRX4204 and trastuzumab Two breast cancer cell lines, MCF7 and SkBr3, were cultured in the presence of 0, 10, 100 or 1000 nM IRX4204 and 0, 0.1, 1 or 10 μg/ml trastuzumab. . MCF7 is an ER ⁺ PR ⁺ Her2 ⁻ cell line. SkBr3 is an ER ^- PR ^- Her2 ⁺ cell line. Cells were plated in 96-well optical plates and IRX-4204 and trastuzumab were added 24 hours after cell plating. After an additional 6 days, cells were fixed with 4% paraformaldehyde phosphate buffered saline (PBS). Nuclei were stained with DAPI and imaged with a MetaXpress® microscope (Molecular Devices, San Jose, CA). Cell nuclei were segmented and counted by defining pixel intensities of background and object size using the MetaXpress® image analysis software algorithm. Experimental data points were performed a minimum of four times and results were reported as mean cell number±standard deviation (SD). As shown in Figure 1A, neither drug individually showed more than a modest effect on the Her2 ^- MCF7 cell line. As shown in Figure 1B, both drugs individually have a mild growth inhibitory effect on the Her2 ⁺ SkBr3 cell line, and when used in combination, even at the lowest concentration tested, a very large , had an antiproliferative effect.

To assess whether this improved growth inhibitory effect is synergistic, we compared the inhibition rate observed at the highest concentration of the combined therapeutics to those when the therapeutics act independently, i.e. without interaction. , compared to the expected inhibition rate for the combination, based on the observed inhibition of the treatments used alone (see Table 1). That is, PAE = (FE1 + ((1 - FE1) x FE2)) x 100, where PAE is the expected additive effect, FE1 is the small effect observed at the first treatment, and FE2 is the observed at the second treatment. This is a fractional effect.

The combined inhibitory effect of IRX4204 and trastuzumab would be expected to be 68.5% if there was no interaction between the effects of the two drugs, but the actual degree of inhibition observed was 88.7%, indicating that IRX4204 and trastuzumab are synergistic. It was clearly shown that the effect was effective.

(Example 2)
Breast Cancer Cell Growth Inhibitory Effect of Combination of IRX4204 and Lapatinib or Neratinib The experiment of Example 1 was repeated using the Her2 kinase inhibitors lapatinib or neratinib at 0, 0.1, 1 or 10 nM instead of trastuzumab. Additionally, the panel of breast cancer cell lines was expanded to also include the ER ⁺ PR ⁺ Her2 ⁺ cell line BT474 and the ER ⁺ PR ^- Her2 ⁺ cell line MDA-MB-361. The general pattern seen above, with Her2 ⁻ MCF7 cell lines generally showing a modest response to treatment, and Her ⁺ cell lines showing a greater degree of inhibition to the combination than either drug alone. was again observed (see Figures 2 and 3).

To assess whether this improved growth inhibitory effect is synergistic, we compared the inhibition rate observed at the highest concentration of the combined therapeutics to those when the therapeutics act independently, i.e. without interaction. , compared to the expected inhibition rates for the combination based on the observed inhibition of the therapeutic agents used alone (see Tables 2-4).

In both cases, the degree of inhibition observed indicates that there is no interaction between the effects of the two drugs, even though each individual therapeutic agent is highly effective alone, leaving little room for synergistic effects to be observed. The degree of inhibition exceeded that expected in this case. These data also clearly demonstrate that IRX4204 and small molecule Her2 kinase inhibitors interact synergistically.

Finally, although aspects of the present disclosure have been emphasized by reference to particular embodiments, those skilled in the art will readily appreciate that these disclosed embodiments are merely illustrative of the principles of the presently disclosed subject matter. to understand. Therefore, it is to be understood that the disclosed subject matter is in no way limited to the particular methodologies, protocols and/or reagents, etc. described in this disclosure. Thus, various modifications or configuration changes or substitutions of the disclosed subject matter may be made in accordance with the teachings of the present disclosure without departing from the spirit of the disclosure. Finally, the terminology used in this disclosure is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the claims. Therefore, the invention is not limited to what has been precisely shown and described.

Certain embodiments of this invention are described in this disclosure, including the best mode known to the inventors for carrying out the invention. Of course, modifications to these described embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to adopt such variations as appropriate, and the inventors do not intend that the invention may be practiced otherwise than as specifically described in this disclosure. Intended. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended to this disclosure as permitted by applicable law. Furthermore, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention, unless otherwise indicated in this disclosure or clearly contradicted by context.

Alternative embodiments, groupings of elements or steps of the invention are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other group members disclosed in this disclosure. It is anticipated that one or more members of a group may be included in or removed from a group for reasons of convenience and/or patentability. If such inclusion or deletion is made, the present disclosure will be deemed to include the modified group and will therefore satisfy all Markush group descriptions as used in the appended claims.

Unless otherwise indicated, all numerical values expressing properties, items, quantities, parameters, properties, terms, etc., used in this disclosure and the claims are modified in all cases by the term "about." shall be understood as. As used in this disclosure, the term "about" means that the property, item, amount, parameter, property or term so modified is greater or less than the value of the property, item, amount, parameter, property or term described. means to include a range of plus or minus 10 percent. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this disclosure and the appended claims are approximations that may vary. At the very least, without any attempt to limit the application of the doctrine of equivalents to the claims, each numerical representation shall be construed, at a minimum, in light of the reported number of significant digits and by applying normal rounding techniques. It is something that should be done. Notwithstanding that the numerical ranges and numerical values indicating the broad scope of the invention are approximations, the numerical ranges and numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently includes a certain amount of error that necessarily results from the standard deviation found in each test measurement. The recitation of numerical ranges in this disclosure is merely intended to serve as shorthand for individually referring to each individual value within the range. Unless otherwise indicated in this disclosure, each individual value of a numerical range is incorporated into this disclosure as if individually set forth herein.

The terms "a", "an", "the" and similar reference words used in the context of describing the present invention (particularly in the context of the following claims), unless otherwise indicated in this disclosure or depending on the context, Unless clearly contradictory, terms shall be construed to include both the singular and the plural. All methods described in this disclosure may be performed in any suitable order, unless otherwise indicated in this disclosure or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided in this disclosure is merely intended to better illuminate the invention, and the use of any and all examples or exemplary language (e.g., "such as") provided in this disclosure is merely intended to better illuminate the invention, does not impose any limitations on the scope of No language in the disclosure should be construed as indicating any non-claimed element essential to the practice of the invention.

Certain embodiments disclosed in this disclosure may be further limited using the phrases "consisting of" or "consisting essentially of" in the claims. When used in a claim, whether as filed or added by amendment, the transitional phrase "consisting of" refers to any element, step or component not specified in the claim. This excludes. The transitional phrase "consisting essentially of" limits the scope of the claim to those that do not materially affect the specified materials or steps and the fundamental novel property(s). Embodiments of the invention as claimed are described and brought into being, either inherently or expressly, in this disclosure.

All patents, patent publications, and other publications referenced and identified in this disclosure are included, for example, for the purpose of describing and disclosing the compositions and methodologies described in such publications that may be used in connection with the present invention. The disclosure herein is individually and expressly incorporated by reference in its entirety. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements regarding the dates or contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents.

ＲはＨまたは炭素数１から６の低級アルキルであり、前記患者は、Ｈｅｒ２標的治療薬を投与されたことがある、投与されている、または投与される予定である、
ＲＸＲアゴニスト。 (Additional note)
(Additional note 1)
An RXR agonist of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of Her2 ⁺ cancer patients, comprising:

R is H or lower alkyl having 1 to 6 carbon atoms, and the patient has received, is being administered, or will be administered a Her2-targeted therapeutic agent.
RXR agonist.

ＲはＨまたは炭素数１から６の低級アルキルである、
ＲＸＲアゴニストまたは薬学的に許容されるその塩、およびＨｅｒ２標的治療薬。 (Additional note 2)
An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof and a Her2-targeted therapeutic agent for use in combination in the treatment of Her2 ⁺ cancer patients, comprising:

R is H or lower alkyl having 1 to 6 carbon atoms,
RXR agonists or pharmaceutically acceptable salts thereof, and Her2-targeted therapeutics.

ＲはＨまたは炭素数１～６の低級アルキルであり、
前記ＲＸＲアゴニストと組み合わされる、Ｈｅｒ２標的治療薬。 (Additional note 3)
A Her2-targeted therapeutic agent for the treatment of Her2 ⁺ cancer in patients with Her2 ⁺ cancer who exhibit less than a complete response to treatment with an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof. hand,

R is H or lower alkyl having 1 to 6 carbon atoms,
A Her2-targeted therapeutic agent in combination with said RXR agonist.

ＲはＨまたは炭素数１～６の低級アルキルであり、
前記Ｈｅｒ２標的治療薬と組み合わされる、
ＲＸＲアゴニスト。 (Additional note 4)
An RXR agonist of formula I or a pharmaceutically acceptable salt thereof for the treatment of Her2 ⁺ cancer in patients with Her2 ⁺ cancer who exhibit less than a complete response to treatment with a Her2-targeted therapeutic agent. There it is,

R is H or lower alkyl having 1 to 6 carbon atoms,
combined with said Her2 targeted therapeutic agent;
RXR agonist.

(Appendix 5)
RXR agonist according to any one of appendices 1 to 4, wherein thyroid hormone is administered in combination with said RXR agonist.

(Appendix 6)
RXR agonist according to appendix 5, wherein the thyroid hormone is thyroxine.

(Appendix 7)
RXR agonist according to any one of appendices 1 to 6, wherein said RXR agonist is a compound of formula I.

(Appendix 8)
RXR agonist according to any one of clauses 1 to 6, wherein said RXR agonist is a pharmaceutically acceptable salt of a compound of formula I.

(Appendix 9)
RXR agonist according to any one of appendices 1 to 6, wherein said RXR agonist is a compound of formula II.

(Appendix 10)
The Her2-targeted therapeutic agent according to any one of Supplementary Notes 1 to 9, comprising an anti-Her2 therapeutic antibody.

(Appendix 11)
The Her2-targeted therapeutic agent according to appendix 10, wherein the therapeutic antibody is trastuzumab or pertuzumab.

(Appendix 12)
The Her2-targeted therapeutic agent according to any one of appendices 1 to 9, comprising an antibody-drug conjugate, wherein the antibody is an anti-Her2 antibody.

(Appendix 13)
The Her2-targeted therapeutic agent according to appendix 12, wherein the antibody-drug conjugate is ado-trastuzumab emtansine.

(Appendix 14)
The Her2-targeted therapeutic agent according to any one of appendices 1 to 9, comprising a Her2 kinase inhibitor.

(Appendix 15)
The Her2-targeted therapeutic agent according to appendix 14, wherein the Her2 kinase inhibitor is lapatinib or neratinib.

(Appendix 16)
The RXR agonist and/or Her2 ^- targeted therapeutic agent according to any one of Supplementary Notes 1 to 15, wherein the Her2 ⁺ cancer is Her2 + breast cancer.

(Appendix 17)
Any one of Supplementary Notes 1 to 15, wherein the Her2 ⁺ cancer is Her2 ⁺ gastroesophageal cancer, ovarian cancer, stomach cancer, lung adenocarcinoma, uterine cancer, serous endometrial cancer, or salivary gland cancer. RXR agonist and/or Her2-targeted therapeutic agent according to.

(Appendix 18)
A combination comprising a Her2-targeted therapeutic agent and an RXR agonist of Formula I or a pharmaceutically acceptable salt thereof.

(Appendix 19)
In the formula, R is H or lower alkyl having 1 to 6 carbon atoms.

(Additional note 20)
The combination according to appendix 18, further comprising thyroid hormone.

(Additional note 21)
19. A combination according to clause 18, wherein said RXR agonist is a compound of formula II.

(Additional note 22)
19. The combination according to appendix 18, wherein the Her2-targeted therapeutic agent comprises an anti-Her2 therapeutic antibody.

(Additional note 23)
23. The combination according to appendix 22, wherein the therapeutic antibody is trastuzumab or pertuzumab.

(Additional note 24)
19. The combination according to clause 18, wherein the Her2-targeted therapeutic agent comprises an antibody-drug conjugate, and the antibody is an anti-Her2 antibody.

(Additional note 25)
The combination according to appendix 24, wherein the antibody-drug conjugate is ado-trastuzumab emtansine.

(Additional note 26)
19. The combination according to clause 18, wherein the Her2-targeted therapeutic agent comprises a Her2 kinase inhibitor.

(Additional note 27)
27. The combination according to clause 26, wherein the Her2 kinase inhibitor is lapatinib or neratinib.

Claims (17)

A pharmaceutical composition for use in the treatment of Her2 ⁺ cancer , said pharmaceutical composition comprising:
An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, comprising:

R is H or lower alkyl having 1 to 6 carbon atoms, including an RXR agonist or a pharmaceutically acceptable salt thereof;
A pharmaceutical composition for use in the treatment of Her2+ cancer for use in a patient who has received, is being administered, or will be administered a Her2 ^- targeted therapeutic agent. A pharmaceutical composition for use in the treatment of Her2 ⁺ cancer , said pharmaceutical composition comprising:
An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, comprising:

R is H or lower alkyl having 1 to 6 carbon atoms; an RXR agonist or a pharmaceutically acceptable salt thereof;
Her2-targeted therapeutic drug,
A pharmaceutical composition for use in the treatment of Her2 ⁺ cancer , comprising : 3. A pharmaceutical composition according to claim 1 or 2, wherein thyroid hormone is administered in combination with the RXR agonist. 4. The pharmaceutical composition according to claim 3, wherein the thyroid hormone is thyroxine. A pharmaceutical composition according to any one of claims 1 to 4, wherein the RXR agonist is a compound of formula II.

A pharmaceutical composition according to any one of claims 1 to 5, comprising an anti-Her2 therapeutic antibody. 7. The pharmaceutical composition of claim 6, wherein the therapeutic antibody is trastuzumab or pertuzumab. The pharmaceutical composition according to any one of claims 1 to 5, further comprising an antibody-drug conjugate, wherein the antibody is an anti-Her2 antibody. 9. The pharmaceutical composition of claim 8, wherein the antibody drug conjugate is adotrastuzumab emtansine. The pharmaceutical composition according to any one of claims 1 to 5, further comprising a Her2 kinase inhibitor. 11. The pharmaceutical composition of claim 10, wherein the Her2 kinase inhibitor is lapatinib or neratinib. A pharmaceutical composition for use in the treatment of Her2 ⁺ cancer, said pharmaceutical composition comprising:
Her2-targeted therapeutic drug ,
An RXR agonist of Formula I or a pharmaceutically acceptable salt thereof, comprising :

R is H or lower alkyl having 1 to 6 carbon atoms; an RXR agonist or a pharmaceutically acceptable salt thereof;
A pharmaceutical composition for use in the treatment of Her2 ⁺ cancer , comprising a combination of . 13. The pharmaceutical composition according to claim 12, further comprising thyroid hormone. 13. The pharmaceutical composition of claim 12, wherein the RXR agonist is a compound of Formula II.

13. The pharmaceutical composition of claim 12, wherein the Her2-targeted therapeutic agent comprises an anti-Her2 therapeutic antibody selected from trastuzumab or pertuzumab. 13. The pharmaceutical composition of claim 12, wherein the Her2 targeted therapeutic comprises an antibody drug conjugate, and wherein the antibody is an anti-Her2 antibody comprising adotrastuzumab emtansine. 13. The pharmaceutical composition of claim 12, wherein the Her2-targeted therapeutic agent comprises a Her2 kinase inhibitor selected from lapatinib or neratinib.

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