WO2024023766A1 - P13k inhibitor combination therapy - Google Patents

P13k inhibitor combination therapy Download PDF

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Publication number
WO2024023766A1
WO2024023766A1 PCT/IB2023/057651 IB2023057651W WO2024023766A1 WO 2024023766 A1 WO2024023766 A1 WO 2024023766A1 IB 2023057651 W IB2023057651 W IB 2023057651W WO 2024023766 A1 WO2024023766 A1 WO 2024023766A1
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inhibitor
class
pi3k
serd
pharmaceutical composition
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PCT/IB2023/057651
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French (fr)
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Monica Binaschi
Alessio FIASCARELLI
Dirk LAURENT
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Berlin-Chemie Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • CDKs cycline-dependent kinases
  • ESR1 estrogen receptor 1
  • Cyclins and CDKs are essential in regulating the progression through the distinct phases of the cell cycle, G1, S, G2 and M phases.
  • CDKs are serine/threonine kinases which are regulated by their interactions with cyclins and CDK inhibitors.
  • CDK activity is often dysregulated in cancer cells and hence they are an attractive target for anti-cancer therapy.
  • CDKs and 29 cyclins (8).
  • CDK1, CDK2, CDK3, CDK4, CDK6, and CDK7 directly regulate cell-cycle transitions and cell division, whereas CDK 7–11 mediate cell-cycle associated gene transcription.
  • Targeted therapies such as Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors have improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by combating the resistance seen with traditional endocrine therapy.
  • Phosphoinositide 3-kinase inhibitors are a class of medical drugs used to treat various cancers, but they can also have very severe side effects.
  • PI3K phosphoinositide 3-kinase
  • Class I PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) and p110 delta (PIK3CD). Inhibiting different p110 isoforms can have different effects.
  • PI3K inhibitors are also under investigation as treatments for inflammatory respiratory disease.
  • a selective estrogen receptor degrader or downregulator (SERD) is a type of drug that binds to the estrogen receptor (ER) and causes the ER to be degraded.
  • the present disclosure is based on the surprising discovery that a pharmaceutical combination of a Phosphoinositide 3-kinase (PI3K) class I inhibitor and a selective estrogen receptor degrader (SERD) yields synergistic effects in treating hormone receptor–positive (HR-positive)/human epidermal growth factor receptor 2–negative (HER-2-negative) breast cancer resistant to or that progressed over a first line of therapy.
  • PI3K Phosphoinositide 3-kinase
  • SETD selective estrogen receptor degrader
  • the present disclosure relates to a combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use.
  • the SERD is suitable for oral administration.
  • the PI3K class I inhibitor is suitable for oral administration.
  • the pharmaceutical combination comprises component (a) and/or (b) each formulated as pharmaceutical composition adapted for oral administration.
  • the SERD is nonsteroidal.
  • the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof.
  • the Elacestrant is in the form of a dihydrochloride salt.
  • the PI3K class I inhibitor is a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2- morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
  • PI3K class I inhibitor is a PI3K class Ia selective inhibitor.
  • the PI3K class I inhibitor is selective for PI3K class Ia over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id.
  • the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia over PI3K class Id (“PI3K class Ia selective inhibitor”), wherein the PI3K class Ia selective inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2- morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
  • PI3K class Ia selective inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2- morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
  • the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia over PI3K class Id (“PI3K class Ia selective inhibitor”), wherein the PI3K class Ia selective inhibitor comprises 5-(7- methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin- 2-amine or the pharmaceutically acceptable salt thereof.
  • PI3K class Ia selective inhibitor comprises 5-(7- methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin- 2-amine or the pharmaceutically acceptable salt thereof.
  • the P,,I3K class I inhibitor comprises 5-(7-methanesulfonyl-2- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or the pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination is adapted for oral administration.
  • the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering a pharmaceutical combination comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor.
  • SESD selective degrader and modulator of the estrogen receptor
  • the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor.
  • the first and second pharmaceutical composition are administered simultaneously.
  • the first pharmaceutical composition is administered prior to, during, or after the second pharmaceutical composition.
  • the patient is suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer.
  • the cancer is a breast cancer.
  • the breast cancer is Hormone receptor-positive and HER2- negative (HR+/HER2-) breast cancer.
  • the breast cancer is Estrogen Receptor-positive and HER2- negative (ER+/HER2-) breast cancer.
  • the breast cancer comprises PI3KCA mutations.
  • the breast cancer is resistant to or progressed over a previous treatment with: endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or CDK4/6 inhibitors.
  • the breast cancer is advanced or metastatic.
  • SERD is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
  • the PI3K class I inhibitor is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
  • a therapeutically effective amount of the SERD is administered to the patient.
  • both the first and the second pharmaceutical compositions are adapted for oral administration.
  • the second pharmaceutical composition comprising a PI3K class I inhibitor is adapted for oral administration, and comprises hypromellose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.
  • the therapeutically effective amount of the SERD is determined based on monitoring binding of estradioal to the estrogen-receptor-alpha (ER ⁇ ).
  • the method comprises administering a PI3K class I inhibitor comprising a PI3K class Ia inhibitor.
  • the PI3K class I inhibitor comprises 5-(7-methanesulfonyl-2- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the PI3K class I inhibitor is determined based on monitoring PI3K activity.
  • the first pharmaceutical composition provides a delayed release of the SERD.
  • the first and/or the second pharmaceutical composition are adapted for oral administration.
  • the second pharmaceutical composition provides a delayed release of the PI3K class I inhibitor.
  • the first and/or the second pharmaceutical composition is administered once daily.
  • the patient is a mammal.
  • the patient is human.
  • the present disclosure relates to a pharmaceutical combination for use in a method of treating a patient suffering from a cancer, comprising administering a pharmaceutical combination comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor.
  • SESD selective degrader and modulator of the estrogen receptor
  • the present disclosure relates to a pharmaceutical combination for use in a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor.
  • a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor in the preparation of a medicament for treating a cancer in a subject, wherein the use comprises administering to the subject a therapeutically effective amount of the SERD and the PI3K class I inhibitor.
  • kits comprising a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor.
  • the kit further comprises instructions for treating a cancer in a subject in need thereof.
  • An oral pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the oral pharmaceutical combination are formulated separately or are each formulated into an oral pharmaceutical composition to allow simultaneous, separate or sequential use.
  • a pharmaceutical composition comprising (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor.
  • the pharmaceutical composition is adapted for oral administration.
  • the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof, preferably wherein the Elacestrant is in the form of a dihydrochloride salt.
  • the PI3K class Ia inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
  • the PI3K class Ia inhibitor comprises 5-(7-methanesulfonyl-2-morpholin-4-yl- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or the pharmaceutically acceptable salt thereof.
  • the PI3K class I inhibitor is selective for PI3K class Ia over PI3K class Id, optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for PI3K class Ia, class Ib, and class Ig over PI3K class Id.
  • CI Combination Index
  • a CI ⁇ 1 represents a synergistic effect of the combination of the two drugs at the indicated dose shown in Table 1.
  • Each symbol series represents a different group of Elacestrant concentration combined with different concentrations of MEN1611. Circles: Elacestrant 1 ⁇ M, squares: Elacestrant 0.1 ⁇ M, up-pointing triangles: Elacestrant 0.01 ⁇ M, down-pointing triangles: Elacestrant 0.001 ⁇ M, diamond: Elacestrant 0.0001 ⁇ M.
  • the Figure reference number indicates specific combinations as described in Table 1 in the “ Figure Ref” column. Fig.
  • FIG. 2 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer ER+/HER2- PDX model HBCx-3, harboring a mutation in PTEN gene.
  • Fig. 2A depicts the measured tumor volume as a function of days post beginning of treatment. Arrows represent Elacestrant and MEN1611 dosing as indicated. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (diamond), and the combination of Elacestrant and MEN1611 (triangle).
  • Fig. 1 vehicle (circle), MEN1611 alone (hexagon), Elacestrant (diamond), and the combination of Elacestrant and MEN1611 (triangle).
  • FIG. 2B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the HBCx-3 model at day 29 post beginning of treatment.
  • Fig. 3 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer ER+/HER2- PDX model CTG-2308, harboring a mutation in PIK3CA gene.
  • Fig. 3A depicts the measured tumor volume as a function of days post beginning of treatment. Bracket under the graph represents beginning and end of Elacestrant and MEN1611 dosing.
  • Fig. 3B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the CTG-2308 model at day 59 post beginning of treatment.
  • Fig. 4 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer ER+/HER2- PDX model CTG-1260, harboring a mutation in PIK3CA and ESR1 genes.
  • Fig.4A depicts the measured tumor volume as a function of days post beginning of treatment. Bracket under the graph represents beginning and end of Elacestrant and MEN1611 dosing. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (diamond), and the combination of Elacestrant and MEN1611 (triangle).
  • Fig. 4B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the CTG-1260 model at day 55 post beginning of treatment. Fig.
  • FIG. 5 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer cell-derived xenograft model MCF7 Red F-luc, harboring a mutation in PIK3CA gene.
  • Fig. 5A depicts the measured tumor volume as a function of days post beginning of treatment. Bracket under the graph represents beginning and end of Elacestrant and MEN1611 dosing. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (triangle), and the combination of Elacestrant and MEN1611 (diamond).
  • Fig. 5A depicts the measured tumor volume as a function of days post beginning of treatment. Bracket under the graph represents beginning and end of Elacestrant and MEN1611 dosing. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (triangle), and the combination of Elacestrant and MEN1611 (d
  • 5B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the xenograft model MCF7 Red F-luc at day 39 post beginning of treatment.
  • PI3K Phosphoinositide 3-kinase
  • SESD selective estrogen receptor degrader
  • the working examples presented herein showed that combining a PI3K class I inhibitor and a SERD resulted in a synergistic reduction in tumor volume in HR+/HER2- breast cancer models that are resistant or progresses over to the first line of therapy compared to using the PI3K class I inhibitor or the SERD individually.
  • the presently disclosed compositions and methods achieved synergistic inhibitory effects on tumor growth in several different breast cancer models that are resistant or progressed over a first line of therapy.
  • a pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use.
  • the SERD is suitable for oral administration.
  • the PI3K class I inhibitor is suitable for oral administration.
  • the SERD and PI3K class I inhibitor are suitable for oral administration.
  • the term “pharmaceutical combination” refers to a combination of separate components so that the components can be administered separately or sequentially.
  • the components of the pharmaceutical combination may also be administered simultaneously.
  • the components in the pharmaceutical combination described herein may most preferably be formulated separately or may each be formulated into a suitable pharmaceutical composition.
  • a pharmaceutical combination may comprise two or more pharmaceutical compositions, wherein a first pharmaceutical composition comprises a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprises a phosphatidylinositol 3-kinase (PI3K) class I inhibitor.
  • a pharmaceutical composition may comprise two or more pharmaceutical compositions, wherein a first pharmaceutical composition comprises a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprises a phosphatidylinositol 3-kinase (PI3K) class I inhibitor.
  • SESD selective degrader and modulator of the estrogen receptor
  • PI3K phosphatidylinositol 3-kinase
  • some or all of the components may be co-formulated into a pharmaceutical composition comprising the SERD and
  • Each component of the pharmaceutical combination described herein can optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components can each independently comprise, or some or all of the components together comprise, a pharmaceutically acceptable carrier and/or an excipient.
  • the pharmaceutically acceptable carrier and/or an excipient are selected based on desired administration route as described in greater detail below.
  • the components in the pharmaceutical combination disclosed herein can be administered independently, or some or all of the components are co-administered in proper routes including most preferably, but not limited to, oral administration.
  • the present disclosure provides an oral pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the oral pharmaceutical combination are formulated separately or are each formulated into an oral pharmaceutical composition to allow simultaneous, separate or sequential use.
  • a selective degrader and modulator of the estrogen receptor SELD
  • PI3K phosphatidylinositol 3-kinase
  • Phosphoinositide 3-kinase The enzyme phosphatidylinositol-3 -kinase (PI3K) is known as type of phosphorylase that phosphorylates in position 3 of an inositol ring of the phosphatidylinositol. PI3K is classified into three groups, precisely Class I, Class II and Class III based upon the primary structure, the type of phosphatidylinositols which act as substrate.
  • Class I PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) and p110 delta (PIK3CD).
  • PI3K inhibitors function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes.
  • Numerous PI3K inhibitors have been developed with varying selectivity towards PI3K enzymes, efficacy and safety profiles. Although PI3K inhibitors may be effective in preventing or inhibiting cancer growth, they may also have side effects.
  • PI3K inhibitors may be specific or selective to the different subtypes or isoforms of the catalytic subunits of the PI3K inhibitors. Accordingly, PI3K inhibitors can be Class I, Class II, and Class III PI3K inhibitors. PI3K inhibitor selective for Class I p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) or p110 delta (PIK3CD) isoforms may be referred to herein as selective for class Ia, Ib, Ig, or Id, respectively.
  • a PI3K inhibitor is selective for one of the subtypes or isoforms Ia, Ib, Ig, or Id, if it inhibits one of the subtypes more effectively than the others.
  • a PI3K inhibitor may be selective for one, two, or three class I isoforms, or if it inhibits all four isoforms, the inhibitor may be referred to as non-selective or pan-inhibitor.
  • a PI3K inhibitor of the present invention may selectively inhibit the class Ia isoform over the PI3K class Id.
  • PI3K inhibitor may be selective for both PI3K class Ia and PI3K class Ig over PI3K class Id.
  • PI3K inhibitor may be selective for PI3K class Ia, PI3K class Ib, and PI3K class Ig over PI3K class Id.
  • a PI3K class I inhibitor of the present invention may selectively inhibit the class Ia isoform over the PI3K class Id and/or the PI3K class Ib.
  • the PI3K inhibitor may be selective for both PI3K class Ia and PI3K class Ig over PI3K class Id and/or PI3K class Ib.
  • the PI3K inhibitors may also be selective to varying degrees. The degree of selectivity can be measure by calculating a “selectivity ratio”.
  • the selectivity ratio can be expressed as [Ix]/[Iy], where [Ix] is a measurement of inhibition of the isoform the inhibitor is not selective for, and [Iy] is a measurement of inhibition of the isoform the inhibitor is selective for.
  • the PI3K Ia inhibitor that selectively inhibits PI3K class Ia over PI3K class Id has a [Id]/[Ia] selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000, when the measurement of inhibition is the inhibitor’s IC 50 .
  • the PI3K class Ia selective inhibitor has a [Id]/[ Ia] selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850, when the measurement of inhibition is the inhibitor’s IC 50 .
  • the [Id]/[Ia] selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K Id isoform by the inhibitor's IC50 against PI3K I isoform.
  • the PI3K inhibitor is selective for both PI3K class Ia and PI3K class Ig over the PI3K class Id.
  • the PI3K inhibitor selective for both classes Ia and Ig over class Id has a [Id]/[Ia] selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000, when the measurement of inhibition is the inhibitor’s IC 50, and a [Id]/[Ig] selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000, when the measurement of inhibition is the inhibitor’s IC50.
  • the PI3K inhibitor selective for both class Ia and Ig over class Id has a [Id]/[Ia] selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850, when the measurement of inhibition is the inhibitor’s IC50, and a [Id]/[Ig] selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850, when the measurement of inhibition is the inhibitor’s IC50.
  • the [Id]/[Ia] selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K Id isoform by the inhibitor's IC 50 against PI3K Ia isoform and the [Id]/[Ig] selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K Id isoform by the inhibitor's IC50 against PI3K Ig isoform.
  • non-selective or pan-PI3K inhibitors may include buparlisib, CH5132799, pilaralisib, ZSTK474, sonolisib, pictilisib, copanlisib, B591, TG100115, RIDR- PI-103.
  • the PI3K inhibitors may have selectivity to one or more isoforms over others such as alpelisib, serabelisib, GSK2636771, idelalisib, zandelisib, amg319, linperlisib, parsaclisib, umbralisib, leniolisib, eganelisib, tenalisib, taselisib, AZD8186, AZD8825, or duvelisib.
  • PI3K inhibitors may also inhibit both the PI3K enzyme and the downstream targets of the PI3K enzyme such as dactolisib, apitolisib, gedatolisib, SF1126, omnipalisib, samotolisib, bimiralisib, paxalisib, or voxtalisib.
  • Other PI3K inhibitors are for examples fimepinostat or rigosertib.
  • the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia over PI3K class Id (“PI3K class Ia selective inhibitor”), wherein the PI3K class I selective inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H- pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3- d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
  • PI3K class Ia selective inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H- pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3- d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
  • the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia, Ib, and Ig over PI3K class Id comprising 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine (sometimes referred to as MEN1611 or CH5132799) or the pharmaceutically acceptable salt thereof.
  • a PI3K class I inhibitor selective for PI3K class Ia, Ib, and Ig over PI3K class Id comprising 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine (sometimes referred to as MEN1611 or CH5132799) or the pharmaceutically acceptable salt thereof.
  • MEN1611 is a PI3K inhibitor active on p110alpha (both mutants and wt), beta and gamma (8.6- and 2.2- fold less potent compared to the alpha, respectively), while sparing the delta isoform (36-fold less potent compared to the alpha).
  • the PI3K inhibitor is a 2-morpholin-4-yl-6,7-dihydro- 5H- pyrrolo[2,3-d]pyrimidine derivative, or 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3- d]pyrimidine derivative as described in detail in EP2050749, incorporated in its entirety herein.
  • the compound 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H- pynOlo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or pharmaceutically acceptable salts thereof, also known in literature as MEN1611 (or CH5132799) is a PI3K class I inhibitor, having the following Formula I: Formula I
  • the compound according to Formula I and method of its preparation were described in EP2050749 or WO 2008/018426, incorporated in their entirety herein. The pharmacological features of the compound were described in scientific literature by Jun Ohwada et al. on Bioorganic & Medicinal Chemistry Letter , 21 (2001) pages 1767-1772.
  • the terms “MEN1611” and “CH5132799” refer to the same chemical compound.
  • the PI3K class I inhibitor comprises 5-(7- methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin- 2-amine or the pharmaceutically acceptable salt thereof.
  • the PI3K inhibitor is a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or 2- morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative as described in detail in EP2050749 or WO 2008/018426, incorporated in their entirety herein.
  • MEN1611 Pharmaceutically acceptable salts of MEN1611 include hydrochlorides, dihydrochlorides, hydrobromides, hydroiodides, nitrates, sulphates, bisulphates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, bitartrates, succinates, oxalates, malates, fumarates, gluconates, malonates, saccharates, benzoates, mandelates, salicylates, trifluoroacetates, propionates, glutarates, methane-sulphonates, ethane- sulphonates, benzensulphonates, p-toluensulphonate and l,r-methylene-bis-2-hydroxy-3- naphtates.
  • salts include a hydrohalide salt (for instance, hydrochloride, hydrobromide, hydroiodide and the like), an inorganic acid salt (for instance, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), an organic carboxylate salt (for instance, acetate salt, maleate salt, tartrate salt, fumarate salt, citrate salt and the like), an organic sulfonate salt (for instance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), a quaternary ammonium salt, an alkaline metal salt (for instance, sodium salt, potassium salt and the like), an alkaline earth metal salt (magnesium salt, calcium salt and the like) and the like.
  • hydrochloride salt, sulfate salt, methanesulfonate salt, acetate salt and the like are preferred as “pharmacologically acceptable salt” of the compounds according to the present invention.
  • basic salts include salts of alkali metals such as sodium salts and potassium salts, salts of alkaline-earth metals such as calcium salts and magnesium salts, ammonium salts, addition salts with water-soluble amines such as salts of N- methylglucamine, inferior alkanol ammonium salts and salts derived from other pharmaceutically acceptable bases of organic amines.
  • SESD selective estrogen receptor degrader
  • ER estrogen receptor
  • Elacestrant also referred to as RAD1901
  • RAD1901 and ER-306323 refer to the same chemical compound including salts, solvates (e.g.
  • Elacestrant or RAD1901 has the structure according to the following Formula II including salts, solvates (e.g. hydrate), and prodrugs thereof:
  • Formula II Elacestrant/ RAD1901 is a nonsteroidal combined selective estrogen receptor modulator and selective estrogen receptor degrader (referred to herein as a “SERD”). Unlike the SERD fulvestrant, Elacestrant is able to readily cross the blood-brain-barrier into the central nervous system, where it can target breast cancer metastases in the brain, and is orally bioavailable and does not require intramuscular injection.
  • Elacestrant is further described in Wardell et al., Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr Relat Cancer, 2015 Oct;22(5):713-24; Garner et al., RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs, 2015 Oct;26(9):948- 56; Bihani et al., Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models. Clin Cancer Res.
  • Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. Breast Cancer Res. 2019 Dec 18;21(1):146.
  • the SERD is suitable for oral administration.
  • the SERD is nonsteroidal.
  • the SERD is Elacestrant/ RAD1901, or a pharmaceutically acceptable salt thereof.
  • the Elacestrant is in the form of a dihydrochloride salt.
  • salt used herein is not limited as long as the salt is formed with RAD1901 or solvates (e.g., hydrate) or salts thereof and is pharmacologically acceptable; preferred examples of salts include a hydrohalide salt (for instance, hydrochloride, dihydrochloride, hydrobromide, hydroiodide and the like), an inorganic acid salt (for instance, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), an organic carboxylate salt (for instance, acetate salt, maleate salt, tartrate salt, fumarate salt, citrate salt and the like), an organic sulfonate salt (for instance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), an inorgan
  • hydrochloride salt, sulfate salt, methanesulfonate salt, acetate salt and the like are preferred as “pharmacologically acceptable salt” of the compounds according to the present invention.
  • the Elacestrant is in the form of a dihydrochloride salt.
  • Isomers of RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611 can be purified using general separation means, including for example recrystallization, optical resolution such as diastereomeric salt method, enzyme fractionation method, various chromatographies (for instance, thin layer chromatography, column chromatography, glass chromatography and the like) into a single isomer.
  • a single isomer herein includes not only an isomer having a purity of 100%, but also an isomer containing an isomer other than the target, which exists even through the conventional purification operation.
  • a crystal polymorph sometimes exists for RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611, and all crystal polymorphs thereof are included in the present invention.
  • the crystal polymorph is sometimes single and sometimes a mixture, and both are included herein.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611 may be in a prodrug form, meaning that it must undergo some alteration (e.g., oxidation or hydrolysis) to achieve its active form.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611 may be a compound generated by alteration of a parental prodrug to its active form.
  • compositions comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3- kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use.
  • SESD selective degrader and modulator of the estrogen receptor
  • PI3K phosphatidylinositol 3- kinase
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the PI3K class I inhibitor such as MEN1611 or solvates (e.g., hydrate) or salts thereof may be administered as part of a single formulation.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the PI3K class I inhibitor such as MEN1611 or solvates (e.g., hydrate) or salts thereof are formulated in a pharmaceutical composition.
  • the pharmaceutical combination and each component thereof are adapted for oral administration.
  • compositions of the present invention can be formulated and administered by oral or parenteral route (such as by intravenous, intramuscular, subcutaneous, rectal, nasal, intracisternal, vaginal, abdominal, intracystic route or locally).
  • oral or parenteral route such as by intravenous, intramuscular, subcutaneous, rectal, nasal, intracisternal, vaginal, abdominal, intracystic route or locally.
  • pharmaceutical compositions for oral administration include tablets, capsules, granules, powders, pills, solutions and aqueous and non-aqueous oral suspensions.
  • pharmaceutical compositions for the parental administration include aqueous or oily solution for intravenous, intramuscular, subcutaneous injections.
  • formulations such as ointments, gels, creams, suppositories, sprays by oral or nasal route, emulsions, oily agents and suspending agents, can be equally used if suitable to the contingent situation.
  • the solutions for parental use usually are distributed in containers suitable for the administration in small individual doses.
  • the formulation of the various active principles such as the PI3K class I inhibitor and the SERD should be so as to allow the administration of customized quantities of the medicament and not the administration of standard quantities.
  • the administration form can be adapted to the various administration methods for controlled or delayed release formulation.
  • the first and/or the second pharmaceutical composition are adapted for oral administration.
  • the first pharmaceutical composition provides a delayed release of the SERD.
  • the second pharmaceutical composition provides a delayed release of the PI3K class I inhibitor.
  • both the PI3K class I inhibitor and the particular SERD RAD1901 are usually administered by oral route and therefore it will be formulated in any form suitable for such administration route.
  • other administration routes are not excluded.
  • the pharmaceutical composition comprising the SERD and the pharmaceutical composition comprising the PI3K may be of the same type.
  • both pharmaceutical compositions may be adapted for oral administration (e.g., via two separate pills) or for injection (e.g., via two separate injectable formulations).
  • the pharmaceutical compositions may be adapted for different routes of administration.
  • one compound may be in a pharmaceutical composition adapted for oral administration, while the other is in a pharmaceutical composition adapted for injection.
  • dosage forms include a tablet, a powder, a subtle granule, a granule, a coated tablet, a capsule, a syrup, a troche, an inhalant, a suppository, an injectable, an ointment, an ophthalmic ointment, an eye drop, a nasal drop, an ear drop, a cataplasm, a lotion and the like.
  • additives such as a diluent, a binder, an disintegrant, a lubricant, a colorant, a flavoring agent, and if necessary, a stabilizer, an emulsifier, an absorption enhancer, a surfactant, a pH adjuster, an antiseptic, an antioxidant and the like can be used.
  • the oral pharmaceutical compositions as disclosed herein can be formulated readily by combining the components (SERD or PI3K class I inhibitor) with pharmaceutically acceptable carriers for oral administration that are well known in the art.
  • Such carriers enable the compounds of embodiments herein to be formulated as nanoparticles, nanoparticle suspension, tablets, troches, pills, dragees, capsules, powders, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Oral compositions can also be prepared using a fluid carrier, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutical combinations and compositions for oral administration can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), and polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as, but not limited to, the cross- linked PVP, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores can be provided with suitable coatings.
  • concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, PVP, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical compositions which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredient in an admixture with one or more fillers (e.g., lactose), one or more binders (e.g., starches), and/or one or more lubricants (e.g., talc or magnesium stearate) and, optionally, one or more stabilizers.
  • the active compound can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid PEG.
  • suitable liquids such as fatty oils, liquid paraffin, or liquid PEG.
  • stabilizers can be added. All compositions for oral administration should be in dosages (e.g., about 5 mg to about 500 mg) suitable for such administration.
  • the oral compositions may take the form of, e.g., lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, PVP or HPMC); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., pregelatinized maize starch, PVP or HPMC
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or sodium starch glycolate
  • wetting agents e.g., sodium
  • compositions containing one of the components as disclosed herein can be in any form suitable for oral use, including, e.g., troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • the oral pharmaceutical composition as disclosed herein is a tablet.
  • Tablets may contain one of the components of the pharmaceutical combination in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents (e.g., corn starch, or alginic acid); binding agents (for example starch, gelatin or acacia); and lubricating agents (for example magnesium stearate, stearic acid or talc).
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • the tablet is formulated for immediate release.
  • the tablet is formulated for controlled release.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
  • the pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions.
  • the oral pharmaceutical composition may comprise one of the components of the pharmaceutical combination and a buffer.
  • the buffer may be selected from the group consisting of citric acid monohydrate, sodium phosphate, water, and a combination thereof.
  • the oral composition comprises one of the components of the pharmaceutical combination and a stabilizer.
  • the stabilizer is selected from a group consisting of povidone, sodium benzoate, water, sodium lauryl sulfate, and a combination thereof.
  • the oral composition further includes a buffer, an acid, sodium benzoate, sodium phosphate, citric acid, or a combination thereof.
  • the oral composition comprises one of the components of the pharmaceutical combination and a stabilizer and a buffer.
  • the oral composition further comprises a lubricant, a pH modifier, a binder, a diluent, a granulating agent, a glidant, a disintegrant, a filler, a sorbent, an anti-adherent, a coloring agent, a compression aid, a coating material, a sweetener, a preservative, an antioxidant, or a combination thereof.
  • a lubricant e.g., about 5 mg to about 500 mg.
  • the oral composition is a suspension, tablet, capsule, nanoparticle powder, nanoparticle suspension, cachet, pellet, pill, powder, granules, or a combination thereof.
  • the lubricant may be selected from the group consisting of stearic acid or its salts (e.g., magnesium stearate, calcium stearate), sodium lauryl sulfate, PEG, mineral oil, sodium benzoate, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, and a combination thereof.
  • the pH modifier may be an acid (e.g., hydrochloric acid, acetic acid, citric acid, phosphoric acid, sulfuric acid, or a combination thereof).
  • the binder may be selected from the group consisting of a natural or synthetic polymer (e.g., starches, sugars, sugar alcohols, or cellulose derivatives) such as gelatin, glucose, lactose, sorbitol, xylitol, maltitol, methyl cellulose, microcrystalline cellulose (MCC), ethyl cellulose, HPMC, hydroxypropyl cellulose (HPC), starch, PVP, PEG, sodium alginate, CMC, and a combination thereof.
  • a natural or synthetic polymer e.g., starches, sugars, sugar alcohols, or cellulose derivatives
  • the compression aid may be selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, a physical mixture of MCC-colloidal silicon dioxide, and a combination thereof.
  • the disintegrant may be selected from the group consisting of starch, cellulose derivatives and alginates, PVP, croscarmellose sodium, sodium starch glycolate, and a combination thereof.
  • the filler may be selected from the group consisting of lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate, plant cellulose, dibasic calcium phosphate, dibasic sodium phosphate, vegetable fats and oils, and a combination thereof.
  • the diluent may be selected from the group consisting of sugar compounds (e.g., sucrose, lactose, dextrin, glucose, sorbitol, or the like), inorganic compounds (e.g., silicates, calcium salts, or magnesium salts), sodium chloride, potassium chloride, and a combination thereof.
  • sugar compounds e.g., sucrose, lactose, dextrin, glucose, sorbitol, or the like
  • inorganic compounds e.g., silicates, calcium salts, or magnesium salts
  • sodium chloride potassium chloride
  • the preservative may be selected from the group consisting of an antioxidant (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), an amino acid (e.g., cysteine, or methionine), citric acid, sodium citrate, a synthetic preservative (e.g., a paraben such as methyl paraben or propyl paraben), and a combination thereof.
  • the glidant may be selected from the group consisting of colloidal anhydrous silicon and other silica compounds, such as fumed silica, magnesium carbonate, colloidal silicon dioxide (AEROSILTM), cornstarch, talc, and a combination thereof.
  • the oral pharmaceutical composition comprising one of the components of the pharmaceutical combination is a tablet.
  • the tablet contains one of the components of the pharmaceutical combination in the form of nanoparticles.
  • the tablet may be coated.
  • the tablet may be coated with an enteric coating.
  • the tablet may be coated with a coating selected from a sugar coating, film coating, organic film coating, aqueous film coating, pan coating, dip coating, electrostatic coating, compression coating, plasticizer dry coating, heat dry coating, electrostatic dry coating, or the like.
  • ingredients used for coating may include aqueous acrylic enteric system such as that sold under the trade name ACRYL-EZETM, film coating system sold under the trade name OPADRYTM, HPMC, methyl hydroxyethyl cellulose, ethylcellulose, povidone, cellulose acetate phthalate, acrylate polymers (such as those sold under the trade name EUDRAGITTM & EUDRAGITTM), HPMC phthalate, or a combination thereof.
  • a tablet may be manufactured by spraying the nanosuspension (above) onto sucrose to form a spray granulate intermediate, granulating the spray granulate intermediate with excipients to form a final granulation, and compressing the final granulation to form a tablet.
  • the sucrose could be any sugar, including, e.g., glucose, fructose, maltose, galactose, lactose, or the like.
  • the excipients for the tablet formulation may include lactose monohydrate, PVP, silicified microcrystalline cellulose (e.g., sold under the trade name PROSOLV.RTM. SMCC HD 90), magnesium stearate, or a combination thereof.
  • the tablet comprises about 5 mg to about 300 mg of Compound I.
  • excipients included in the pharmaceutical compositions disclosed herein may contain, for example, (1) an oil such as a soybean oil, a beef tallow and synthetic glyceride; (2) hydrocarbon such as liquid paraffin, squalane and solid paraffin; (3) ester oil such as octyldodecyl myristic acid and isopropyl myristic acid; (4) higher alcohol such as cetostearyl alcohol and behenyl alcohol; (5) a silicon resin; (6) a silicon oil; (7) a surfactant such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, a solid polyoxyethylene castor oil and polyoxyethylene polyoxypropylene block co-polymer; (8) water soluble macromolecule such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethyleneglycol, polyvinylpyrrolidone and methylcellulose
  • Additives for use in the above formulations may include, for example, 1) lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide as the diluent; 2) polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polypropylene glycol-poly oxyethylene-block co-polymer, meglumine, calcium citrate, dextrin, pectin and the like as the binder; 3) starch, agar, gelatine powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectic, carboxymethylcellulose/calcium and the like as the disintegrant; 4) magnesium stearate, talc, polyethyleneglycol, silica,
  • compositions adapted for oral administration are most preferable, other pharmaceutical compositions adapted for other routes of administration are not excluded.
  • the SERD such as Elacestrant or solvates (e.g., hydrate) or salts thereof and the PI3K class I inhibitor such as MEN1161 or solvates (e.g., hydrate) or salts thereof for use in the presently disclosed methods can be formulated into a pharmaceutical composition comprising a physiologically acceptable carrier (also referred to as a pharmaceutically acceptable carrier or solution or diluent) adapted for any administrative route.
  • a physiologically acceptable carrier also referred to as a pharmaceutically acceptable carrier or solution or diluent
  • Such compositions are prepared in accordance with acceptable pharmaceutical procedures such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R.
  • pharmaceutically acceptable carrier refers to a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered and are compatible with the other ingredients in the formulation.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.
  • Dosages and dosage forms of the components of the pharmaceutical combination can be formulated into unitary dosage forms, meaning physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times q.d.). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • the compounds may be formulated for controlled or delayed release.
  • the typical dosage of PI3K inhibitor of formula I effective for a patient in case of oral preparation preferably is from 0.1 to 1000 mg and more preferably from 1 to 100 mg, per kg of body weight daily. Preferred dosages are from 1 to 10 mg/Kg for example 3, 4, 5, 6, 7, 8 or 9 mg/Kg body weight.
  • the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from 1 to 10 mg/Kg body weight.
  • the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from 5 to 7 mg/Kg body weight.
  • the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor of 3, 4, 5, 6, 7, 8 or 9 mg/Kg body weight.
  • the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD from about 10 to about 100 mg/Kg body weight.
  • the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD from about 10 to about 40 mg/Kg body weight.
  • the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD from about 50 to about 100 mg/Kg body weight.
  • the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD of about 30 mg/Kg body weight, or about 60 mg/Kg body weight.
  • the dosages of the PI3K inhibitor as well as of the SERD can be suitably modified based upon symptoms, age, body weight, relative health state, presence of other drugs, administration route and the like.
  • the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering to the patient a pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use.
  • the SERD is suitable for oral administration.
  • the SERD is suitable for oral administration.
  • the PI3K and PI3K class I inhibitor class I inhibitor are suitable for oral administration.
  • the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor.
  • the present disclosure relates to a pharmaceutical composition for use in a method of treating a patient suffering from a cancer, comprising administering a pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor.
  • the present disclosure relates to a pharmaceutical composition for use in a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor.
  • a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor in the preparation of a medicament for treating a cancer in a subject, wherein the use comprises administering to the subject a therapeutically effective amount of the SERD and the PI3K class I inhibitor.
  • the first and second pharmaceutical composition are administered simultaneously.
  • the first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD) is administered prior to, during, or after the second pharmaceutical composition a PI3K class I inhibitor.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the subject or cell being treated, and may be performed for prophylactic purposes or during clinical pathology. Desirable therapeutic effects include prevention of onset or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or slowing of the disease state, and remission or improved prognosis.
  • the development of a disease or disorder is delayed using a pharmaceutical composition of the invention.
  • “Inhibiting growth” of a tumor or cancer cells as used herein may refer to slowing the rate of tumor or cancer cell growth, or halting tumor or cancer cell growth entirely.
  • the terms "individual (individual)", “subject”, or “patient” are used interchangeably herein.
  • the patient or subject is a vertabrate.
  • the vertebrate is a mammal.
  • the term "mammal” for therapeutic purposes refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc.
  • the mammal is a human.
  • the subject or patient may include, but is not limited to, farm animals (such as cattle), sport animals, pets (such as cats, dogs, and horses), primates, mice, and rats.
  • the subject or patient is human.
  • tumor refers to the growth and proliferation of all neoplastic cells (malignant or benign), and all precancerous and cancerous cells and tissues.
  • cancer cancer, “cancerous”, “cell proliferative disorder”, “proliferative disorder” and “tumor” are not mutually exclusive.
  • the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation.
  • cancer examples include, but are not limited to, carcinoma, lymphoma (such as Hodgkin's lymphoma and non-Hodgkin's lymphoma), blastoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, leukemia, and other lymphoproliferative disorders, as well as various types of head and neck cancer.
  • lymphoma such as Hodgkin's lymphom
  • the patient is suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer, and even more preferable, the cancer is breast cancer.
  • the breast cancer is Hormone receptor-positive and HER2- negative (HR+/HER2-) breast cancer.
  • the breast cancer is estrogen receport prositive (ER+) and HER2 negative (ER+/HER2-).
  • the breast cancer comprises PI3KCA mutations.
  • the breast cancer is resistant to endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or resistant to CDK4/6 inhibitors.
  • the breast cancer is advanced or metastatic. “Tumor regression” or “regression” of an tumor (e.g.
  • HR-/HER2+ tumor as used herein may refer to reducing the size or maximum size of a tumor. Tumor size can be determined by bioluminescence as shown in the working examples herein. Other methods of monitor tumor regression includes gene profiling.
  • the methods of tumor growth inhibition or tumor regression provided herein further comprise gene profiling the subject, wherein the gene to be profiled is one or more genes selected from the group consisting of ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EW
  • this invention provides a method of treating a subpopulation of breast cancer patients wherein said sub-population has increased expression of one or more of the genes disclosed supra, and treating said sub-population with an effective dose of a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof according to the dosing embodiments as described in this disclosure.
  • administration of a combination as described herein, or solvates (e.g., hydrate) or salts thereof may result in a decrease in tumor size versus baseline (i.e., size prior to initiation of treatment), or even eradication or partial eradication of a tumor.
  • the methods of tumor regression provided herein may be alternatively characterized as methods of reducing tumor size versus baseline
  • both the SERD Elacestrant and the PI3K class I inhibitor MEN1611 can individual inhibit tumor growth
  • the combination, compositions and methods disclosed herein were surprisingly effective in inhibiting tumor growth of: ⁇ the breast cancer ER+/HER2- PDX model HBCx-3 that is resistant to or progressed over a prior treatment with Palbociclib and Fulvestrant and harbors the mutation P246 fs8aa in the PTEN gene (see Fig. 2); ⁇ the breast cancer ER+/HER2- PDX model CTG-2308 that is resistant to or progressed over a prior treatment with Palbociclib, and Fulvestrant (Fig.
  • ⁇ the breast cancer ER+/HER2- PDX model CTG-1260 is resistant to or progressed over a prior treatment with Palbociclib and Fulvestrant, and it harbors the double mutations D350H and H1047R in the PIK3CA gene, and the D538G mutation in ESR1 gene (Fig. 4); and ⁇ the breast cancer ER+/HER2-cell-derived xenograft model MCF7 red F-luc harbors the E545K mutation in the PIK3CA gene (Fig. 5).
  • the methods and compositions disclosed herein are particularly useful for treating hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer, preferably Estrogen receport positive and HER2-negative (ER+/HER2-) breast cancer, but are not limited to treating this type of cancer.
  • the methods and compositions disclosed herein can treat a patient suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer.
  • Examples of cancer treated with the combinations of the present invention include solid tumors, whereas examples of solid tumors include breast cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer and non-small cell lung cancer.
  • the cancer is a breast cancer.
  • the breast cancer is Hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer, preferably Estrogen receport positive and HER2-negative (ER+/HER2-) breast cancer.
  • the breast cancer comprises PI3KCA mutations.
  • the breast cancer is resistant to or progressed over a previous treatment with: endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or resistant to CDK4/6 inhibitors.
  • the breast cancer is advanced or metastatic.
  • the tumor may be associated with luminal breast cancer that may or may not be positive for HER2, and for HER2+ tumors, the tumors may express high or low HER2.
  • the patient has a tumor located in another tissue or organ (e.g., bone, muscle, brain), but is nonetheless associated with breast, uterine, ovarian, or pituitary cancer (e.g., tumors derived from migration or metastasis of breast, uterine, ovarian, or pituitary cancer).
  • the tumor being targeted is a metastatic tumor and/or the tumor has an overexpression of ER in other organs (e.g., bones and/or muscles).
  • the tumor being targeted is a brain tumor and/or cancer.
  • the tumor being targeted is more sensitive to a treatment of RAD1901 and a PI3K class I inhibitor than treatment with another SERD (e.g., fulvestrant, TAS-108 (SR16234), ZK191703, RU58668, GDC-0810 (ARN-810), GW5638/DPC974, SRN-927, ICI182782 and AZD9496), Her2 inhibitors (e.g., trastuzumab, lapatinib, ado- trastuzumab emtansine, and/or pertuzumab), chemo therapy (e.g., abraxane, adriamycin, carboplatin, cytoxan, daunorubicin, doxil, ellence, fluorouracil, gemzar, helaven, lxempra, methotrexate, mitomycin, micoxantrone, navelbine, taxol, taxotere
  • the methods further comprise a step of determining whether a patient has a tumor expressing ER ⁇ , HR, and/or HER2 prior to administering a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • the methods further comprise a step of determining whether the patient has a tumor expressing mutant ER ⁇ prior to administering a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • the methods further comprise a step of determining whether a patient has a tumor expressing ER ⁇ , HR, or HER2 that is responsive or non-responsive to fulvestrant treatment prior to administering a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof may be made using any method of expression detection known in the art, and may be performed in vitro using a tumor or tissue sample removed from the subject.
  • methods are provided herein for inhibiting growth or producing regression of a tumor that is positive for ER ⁇ having one or more mutants within the ligand-binding domain (LBD), selected from the group consisting of Y537X1 wherein X1 is S, N, or C, D538G, L536X2 wherein X2 is R or Q, P535H, V534E, S463P, V3921, E380Q, especially Y537S ER ⁇ , in a subject with cancer by administering to the subject a therapeutically effective amount of a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • LBD ligand-binding domain
  • “Mutant ER ⁇ ” as used herein refers to ER ⁇ comprising one or more substitutions or deletions, and variants thereof comprising, consisting of, or consisting essentially of an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 99.5% identity to the amino acid sequence of wild type ER ⁇ .
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 or solvates (e.g., hydrate) or salts thereof are administered in combination to a subject in need.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof may be administered before, during, simultaneously, or after the administration of MEN1611.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 can be administered in about one week apart, about 6 days apart, about 5 days apart, about 4 days apart, about 3 days apart, about 2 days apart, about 24 hours apart, about 23 hours apart, about 22 hours apart, about 21 hours apart, about 20 hours apart, about 19 hours apart, about 18 hours apart, about 17 hours apart, about 16 hours apart, about 15 hours apart, about 14 hours apart, about 13 hours apart, about 12 hours apart, about 11 hours apart, about 10 hours apart, about 9 hours apart, about 8 hours apart, about 7 hours apart, about 6 hours apart, about 5 hours apart, about 4 hours apart, about 3 hours apart, about 2 hours apart, about 1 hour apart, about 55 minutes apart, about 50 minutes apart, about 45 minutes apart, about 40 minutes apart, about 35 minutes apart, about
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 or solvates (e.g., hydrate) or salts thereof are administered to the subject simultaneously or substantially simultaneously.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 or solvates (e.g., hydrate) or salts thereof may be administered as part of a single formulation.
  • a therapeutically effective amount of a combination of MEN1611 or solvates (e.g., hydrate) or salts thereof and RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein is an amount that, when administered over a particular time interval, results in achievement of one or more therapeutic benchmarks (e.g., slowing or halting of tumor growth, resulting in tumor regression, cessation of symptoms, etc.).
  • the combination for use in the presently disclosed methods may be administered to a subject one time or multiple times. In those embodiments wherein the compounds are administered multiple times, they may be administered at a set interval, e.g., daily, every other day, weekly, or monthly.
  • a therapeutically effective amount of the combination may be administered for one day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 50 days, at least 55 days, at least 60 days, at least 65 days, at least 70 days, at least 75 days, at least 80 days, at least 85 days, or at least 90 days.
  • a therapeutically effective amount of the combination may be administered for from one day to 90 days, from one day to 7, from 7 days to 14 days, from 14 days to 21 days, from 7 days to 28 days, from 14 days to 36 days, from 21 days to 36 days, from 36 days to 48 days, from 32 days to 58 days, from 48 days to 60 days, from 36 days to 80 days, from 7 days to 90 days, from 14 days to 90 days, from 21 days to 90 days, from 42 days to 90 days, or from one day to 28 days, from one day to 21 days.
  • a therapeutically effective amount of the combination may be administered for from one month to three month, from two months to four months, from one month to six months, from one month to twelve months, or for more than a year.
  • the therapeutically effective amount of the combination may be administered for one week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 10 weeks, or at least 15 weeks. In other embodiments, the therapeutically effective amount of the combination may be administered for one to five weeks, one to six weeks, one to seven weeks, two to five weeks, two to six weeks, three to six weeks, or four to eight weeks.
  • the status of the cancer or the regression of the tumor is monitored during or after the treatment, for example, by a FES- PET scan of the subject.
  • the dosage of the combination administered to the subject can be increased or decreased depending on the status of the cancer or the regression of the tumor detected.
  • the pharmaceutical combinations disclosed herein are administered once daily.
  • the PI3K class I inhibitor can be administered once a day for 7, 10, 12, 15 or 20 days (qldx7, 10, 12, 15 o 20), and the SERD can be administered according to an identical or different regime, but on alternate days with respect to the PI3K class I inhibitor.
  • the first section will include a number of unitary doses (tablets, capsules, etc) sufficient for the daily administration for a period ranging from 7 to 40 days or from 10 to 30 days or from 12 to 20 days (qldx7-40 or qldx 10- 30 or qldx 12-20).
  • the second section will include unitary doses sufficient for one administration or daily or weekly or bi-weekly or monthly administration for a period, according to prescription, overlapped to the period of treatment with the first medicament. For example by starting the two overlapped treatments on the same day 1, the second medicament could be subsequently administered every 4, 5, 7, 10 or 12 days.
  • the second medicament is an antibody usually a limited number (2-4) of administrations are sufficient for a complete cycle.
  • SERD is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
  • the PI3K class I inhibitor is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
  • the first time period may be for one day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 55 days, at least about 56 days, at least about 57 days, at least about 58 days, at least about 59 days, at least about 60 days, or at least about 65 days.
  • the first time period may be for about 1 to about 7 days, about 1- about 14 days, about 1- about 90 days, about 7- about 14 days, about 14- about 21 days, about 14- about 28 days, about 21- about 36 days, about 21- about 42 days, about 7- about 90 days or about 14- about 90 days or about 21- about 90 days, or about 42- about 90 days.
  • the second time period may be for about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 55 days, at least about 56 days, at least about 57 days, at least about 58 days, at least about 59 days, at least about 60 days, or at least about 65 days.
  • the second time period may be for about 1 to about 7 days, about 1- about 14 days, about 1- about 90 days, about 7- about 14 days, about 14- about 21 days, about 14- about 28 days, about 21- about 36 days, about 21- about 42 days, about 7- about 90 days or about 14- about 90 days or about 21- about 90 days, or about 42- about 90 days.
  • the "therapeutically effective amount” or “effective amount” of a substance/molecule such as RAD1901 or MEN1611 of the invention may vary depending on factors such as: the disease state, age, sex and weight of the individual, and the ability of the substance/molecule to induce a desired response in the individual.
  • a therapeutically effective amount is also an amount that has a therapeutically beneficial effect over any toxic or detrimental effect of the substance/molecule.
  • prophylactically effective amount refers to an amount of dosage and time necessary to effectively achieve the desired prophylactic result. Since prophylactic doses are used in individuals prior to or early in the disease, the prophylactically effective amount is typically (but not necessarily) less than the therapeutically effective amount. In a preferred embodiment, the therapeutically effective amount does not exceed the maximum tolerated dosage at which 50% or more of treated subjects experience nausea or other toxicity reactions that prevent further drug administrations.
  • a therapeutically effective amount may vary for a subject depending on a variety of factors, including variety and extent of the symptoms, sex, age, body weight, or general health of the subject, administration mode and salt or solvate type, variation in susceptibility to the drug, the specific type of the disease, and the like.
  • treatment can be paused due to illness, adverse event, etc., and is resumed upon resolution, reduction or amelioration of such illness, adverse event, etc.
  • a therapeutically effective amount of the SERD is administered to the patient.
  • the therapeutically effective amount comprises from about 1 to about 10 mg/Kg body weight.
  • the therapeutically effective amount comprises from about 5 to about 15mg/Kg body weight.
  • the therapeutically effective amount comprises from about 10 to about 100 mg/Kg body weight.
  • the therapeutically effective amount comprises from about 10 to about 40 mg/Kg body weight.
  • the therapeutically effective amount comprises from about 0.1 to about 1, from about 10 to about 15, about 5 to about 10, about 10 to about 25, or about 30 to 50 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 50 to about 150 mg, about 100 to about 200 mg, about 250 to about 500 mg, or about 300 to about 600 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 50 to about 100 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises about 30 mg/Kg body weight, or about 60 mg/Kg body weight.
  • the dosage of RAD1901 or solvates (e.g., hydrate) or salts thereof in a combination with MEN1611 or solvates (e.g., hydrate) or salts thereof for use in the presently disclosed methods general for an adult subject may be approximately 30 mg to 2,000 mg, 100 mg to 1,500 mg, or 150 mg to 1,500 mg p.o., q.d.
  • This daily dosage may be achieved via a single administration or multiple administrations
  • Further examples of therapeutically effective amounts of a RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein include, without limitation, about 150 to about 1,500 mg, about 200 to about 1,500 mg, about 250 to about 1,500 mg, or about 300 to about 1,500 mg dosage q.d.
  • the therapeutically effective amounts of a RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein include, without limitation, from about 50 to about 150 mg, from about 300 to about 500 mg, about 300 to about 550 mg, about 300 to about 600 mg, about 250 to about 500 mg, about 250 to about 550 mg, about 250 to about 600 mg, about 200 to about 500 mg, about 200 to about 550 mg, about 200 to about 600 mg, about 150 to about 500 mg, about 150 to about 550 mg, or about 150 to about 600 mg q.d. dosage.
  • the dosage of a compound of Formula II (e.g., RAD1901) or a salt or solvate thereof for use in the presently disclosed methods general for an adult subject may be about 10 mg, about 50 mg, about 100 mg, about 150 mg, 200 mg, about 400 mg, about 30 mg to about 2,000 mg, about 100 mg to about 1,500 mg, or about 150 mg to about 1,500 mg p.o., q.d.
  • This daily dosage may be achieved via a single administration or multiple administrations.
  • RAD1901 (Elacestrant) is used at a dosage of 800 mg/day, 700 mg/day, 600 mg/day, 500 mg/day, 400 mg/day, 300 mg/day, 200 mg/day, 100 mg/day, or 50 mg/day. In some preferable embodiments, RAD1901 (Elacestrant) is used at a dosage of 50 to 800 mg/day. In some preferable embodiments, RAD1901 (Elacestrant) is used at a dosage of 100 to 500 mg/day. Most preferably, RAD1901 (Elacestrant) is used at a dosage of 400 mg/day.
  • the typical dosage of PI3K inhibitor of formula I effective for a patient in case of oral preparation preferably is from about 0.1 to about 1, from about 0.1 to 1000 mg and more, or from 1 to 100 mg, per kg of body weight daily.
  • Preferred dosages are from 1 to 10 mg/Kg for example 3, 4, 5, 6, 7, 8 or 9 mg/Kg body weight.
  • daily dosages from about 40 mg/day to about 100 mg/day are administered.
  • two 48-mg capsules daily (total 96 mg daily) are administered.
  • the typical effective quantity preferably is from about 0.1 to about 1000 mg and more preferably from about 1 to about 100 mg per kg of body weight daily.
  • a therapeutically effective amount of the PI3K class I inhibitor is administered to the patient.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises from about 1 to about 10 mg/Kg body weight.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg/Kg body weight.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises from about 5 to about 7 mg/Kg body weight, or preferably about 6.5 mg/Kg body weight.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises from about 0.1 to about 0.5, from about 1 to about 5, about 2 to about 7, about 6 to about 12, about 7 to about 12, about 8 to about 12, about 9 to about 15, about 10 to about 15, or about 11 to about 15 mg/Kg body weight.
  • the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from 10 to 100 mg.
  • the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor of about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, or about 22 mg.
  • the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor of about 16 mg.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises from about 50 to about 150 mg/day, or preferably about 96 mg/day.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises from about 60, about 64, about 68, about 72, about 76, about 80, about 84, about 88, about 92, about 96, about 100, about 104, about 108, or about 112 mg/day.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises about 96 mg/day.
  • the dose can be adjusted by monitoring tumor growth as described elsewhere herein. In some embodiments, the dose can be adjusted by measuring effects of the SERD on estradiol-ER binding. In some embodiments, the therapeutically effective amount of the SERD is determined based on monitoring binding of estradioal to the estrogen-receptor-alpha (ER ⁇ ). In these methods, estradiol-ER binding can serve as a proxy for tumor growth inhibition, or a supplemental means of evaluating growth inhibition. If estradiol-ER binding is not affected or exhibits a decrease below a predetermined threshold (e.g., a decrease in binding versus baseline of less than 5%, less than 10%, less than 20%, less than 30%, or less than 50%), the first dosage is deemed to be too low.
  • a predetermined threshold e.g., a decrease in binding versus baseline of less than 5%, less than 10%, less than 20%, less than 30%, or less than 50%
  • the dosage can be adjusted by measuring PI3K activity or downstream effects of the PI3K signaling pathway.
  • PI3K activity can serve as a proxy for tumor growth inhibition, or a supplemental means of evaluating growth inhibition.
  • these methods comprise an additional step of administering an increased second dosage of the compounds (e.g. the SERD or the PI3K class I inhibitor).
  • the methods herein includes a method comprising a) administering a first dosage of the SERD, measuring estradiol-ER binding, and if estradiol-ER binding is detectable or above a threshold, then increase the first dosage to a second dosage; b) administering a first dosage of the PI3K class I inhibitor, measuring PI3K activity, and if PI3K activity is detectable or above a threshold, then increase the first dosage to a second dosage; optionally repeat steps a and b to optimize the dosage of the SERD and the PI3K class I inhibitor, thereby determine the optimal dosage of the SERD and the PI3K class I inhibitor.
  • kits An additional embodiment of the invention consists in a kit of parts, that is a package ready for use containing in a first section the first medicament that is the PI3K class I inhibitor of formula I, in a second section the second medicament that is the SERD, and a package leaflet with instructions for the combined, contemporary, consecutive or alternated administration of the two medicaments.
  • the kit comprises a number of mono-doses of the first and the second medicament required and sufficient for a complete treatment cycle.
  • the first section will include a blister of mono-doses of the first medicament for oral administration, for example tablets, stiff or soft capsules or phials of lyophilised medicament or powder sachets or granulate sufficient for a complete cycle
  • the second section will equally include blisters or phials or sachets, as in the first section, including the second medicament for oral use or phials including the solution or phials including the lyophilizate of the second medicament for parental use.
  • the respective sections will include the required disposable amounts of the solvent suitable to bring the lyophilizate back to solution.
  • the present disclosure relates to a kit comprising a pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor as described elsewhere herein.
  • the present disclosure relates to a kit comprising a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor.
  • the kits disclosed herein may further comprise the following embodiments:
  • the first and second pharmaceutical composition are administered simultaneously.
  • the first pharmaceutical composition is administered prior to, during, or after the second pharmaceutical composition.
  • the patient is suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer.
  • the cancer is a breast cancer.
  • the breast cancer is Hormone receptor-positive and HER2- negative (HR+/HER2-) breast cancer, preferably Estrogen receport positive and HER2- negative (ER+/HER2-) breast cancer.
  • the breast cancer comprises PI3KCA mutations.
  • the breast cancer is resistant to or progressed over a previous treatment with: endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or CDK4/6 inhibitors.
  • the breast cancer is advanced or metastatic.
  • SERD is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
  • the PI3K class I inhibitor is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
  • a therapeutically effective amount of the SERD is administered to the patient.
  • both the first and the second pharmaceutical compositions are adapted for oral administration.
  • the second pharmaceutical composition comprising a PI3K class I inhibitor is adapted for oral administration, and comprises hypromellose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.
  • the therapeutically effective amount of the SERD comprises from about 10 to about 100 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD comprises from about 10 to about 40 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD comprises from about 50 to about 100 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD comprises about 30 mg/Kg body weight, or about 60 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD is determined based on monitoring binding of estradioal to the estrogen-receptor-alpha (ER ⁇ ).
  • ER ⁇ estradioal to the estrogen-receptor-alpha
  • the PI3K class I inhibitor comprises 5-(7-methanesulfonyl-2- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or a pharmaceutically acceptable salt thereof.
  • the PI3K class I inhibitor comprises a 2-morpholin-4-yl-6,7- dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro- pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
  • PI3K class I inhibitor is a PI3K class Ia inhibitor.
  • a therapeutically effective amount of the PI3K class I inhibitor is administered to the patient.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises from about 1 to about 10 mg/Kg body weight.
  • the therapeutically effective amount of the PI3K class I inhibitor comprises from about 5 to about 7 mg/Kg body weight, or preferably about 6.5 mg/Kg body weight.
  • the therapeutically effective amount of the PI3K class I inhibitor is determined based on monitoring PI3K activity.
  • the first and/or the second pharmaceutical composition are adapted for oral administration.
  • the first pharmaceutical composition provides a delayed release of the SERD.
  • the first pharmaceutical composition provides a delayed release of the SERD.
  • the second pharmaceutical composition provides a delayed release of the PI3K class I inhibitor.
  • the first and/or the second pharmaceutical composition is administered once daily.
  • the patient is a mammal. In some embodiments, the patient is human. Definitions As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used.
  • the word “or” when used without a preceding “either” shall be interpreted to be inclusive (e.g., “x or y” means one or both x or y).
  • the term “and/or” shall also be interpreted to be inclusive (e.g., “x and/or y” means one or both x or y). In situations where “and/or” or “or” are used as a conjunction for a group of three or more items, the group should be interpreted to include one item alone, all the items together, or any combination or number of the items.
  • X and/or Y may refer, in one embodiment, to X only (optionally including elements other than Y); in some embodiments, to Y only (optionally including elements other than X); in yet some embodiments, to both X and Y (optionally including other elements).
  • a stated range of 1 to 10 should be considered to include and provide support for claims that recite any and all subranges or individual values that are between and/or inclusive of the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more and ending with a maximum value of 10 or less (e.g., 5.5 to 10, 2.34 to 3.56, and so forth) or any values from 1 to 10 (e.g., 3, 5.8, 9.9994, and so forth).
  • Any listed range may be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc.
  • each range discussed herein may be readily broken down into a lower third, middle third and upper third, etc.
  • all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which may be subsequently broken down into subranges as discussed herein.
  • a range includes each individual member.
  • a group having 1-3 layers refers to groups having 1, 2, or 3 layers.
  • a group having 1-5 layers refers to groups having 1, 2, 3, 4, or 5 layers, and so forth.
  • inhibitor or its grammatical equivalent, such as “inhibiting,” is not intended to require complete reduction in biological activity of a target (e.g., PI3K or SERD). Such reduction is preferably by at least about 50%, at least about 75%, at least about 90%, and more preferably by at least about 95% of the activity of the molecule in the absence of the inhibitory effect, e.g., in the absence of an inhibitor, such as a SERD or PI3K inhibitor disclosed in the invention. More preferably, the term refers to an observable or measurable reduction in activity. In treatment scenarios, preferably the inhibition is required to produce a therapeutic benefit in the condition being treated (e.g., cancer).
  • a target e.g., PI3K or SERD
  • Such reduction is preferably by at least about 50%, at least about 75%, at least about 90%, and more preferably by at least about 95% of the activity of the molecule in the absence of the inhibitory effect, e.g., in the absence of an inhibitor
  • MEN1611 was synthesized by MENARINI RICERCHE SPA Pisa. For in vitro studies, the powder was dissolved in DMSO. For in vivo studies, the powder was dissolved in a DMSO/Cremophor EL solution (50%/50% v/v), divided into aliquots and stored at 4°C until use. MEN1611 stock solution at 6.5 mg/ml was prepared by dissolving hydroxypropyl-beta cyclodextrin (HPCD) and polyethylene Glycol 400 in distilled water as 10% (w/v) and 10% (v/v) respectively (formulation media).
  • HPCD hydroxypropyl-beta cyclodextrin
  • HPCD hydroxypropyl-beta cyclodextrin
  • polyethylene Glycol 400 polyethylene Glycol 400
  • MEN1611 stock solution was diluted 10-fold in formulation media to obtain the dosing solution at 0,65 mg/ml.
  • Elacestrant (RAD1901) was obtained by MENARINI RICERCHE SPA Pisa.
  • the powder was dissolved in a DMSO.
  • the powder was dissolved in a 0.5% solution of carboxymethylcellulose Animal studies In vivo study on the breast cancer PDX model was performed at XenTech.
  • the authorization to use animals in the CERFE facility was obtained by The Direction Départementale de la Protection des Populations, Mini incident de l'Agriculture et de l'Alimentation,France "Direction of the Veterinar ⁇ an Services, Ministry of Agriculture and Food, France” (agreement No. D-91-228-107).
  • In vivo study on the breast cancer PDX model was performed by transplanting tumor fragments from the patient subcutaneously into immunocompromised mice.
  • the breast tumor-bearing mice received estrogen diluted in drinking water (3-oestradiol, 8.5 mg/l) from the date of tumor implant to the end of the study.
  • the tumor growth was evaluated by measuring tumor diameters with a caliper by using the following formula: [length (mm) ⁇ width2 (mm) ⁇ d]/2.
  • the weight of the mice was monitored during the study.
  • the treatment was started when the tumor masses achieved an average volume of 150-200 mm 3 .
  • Treatment effectiveness was assessed as TVI% in treated versus control mice.
  • TVI is short for tumor volume inhibition percentage.
  • In vivo study on breast cancer PDX model CTG-2308 and CTG-1260 were performed at Georgia Oncology.
  • the breast cancer PDX models CTG-2308 and CTG-1260 were obtained by transplanting the tumor fragments from the patient subcutaneously into immunocompromised mice.
  • the tumor growth was evaluated by measuring tumor diameters with a caliper, using the following formula: [length (mm) ⁇ width2 (mm) ⁇ d]/2 (two times a week). The weight of the mice was monitored during the study. The treatment was started when the tumor masses achieved an average volume of 150-200 mm 3 . Treatment effectiveness was assessed as TVI% in treated versus control mice. In vivo study on breast cancer cell-derived xenograft MCF7 red F-luc model was performed at Menarini Ricerche.
  • MCF7 red F-luc cells were re-suspended in 0.2 ml of BME type III (Trevigen) at 5.6 mg/ml, and then injected subcutaneously into the right flank of 6-8 weeks old female CD-1 mice.
  • the MCF7 red F-luc cells are genetically modified to express the luciferase protein, which in presence of its substrate luciferin can generate a bioluminescence signal detected by the in vivo imaging tool IVIS®-CT Spectrum.
  • the tumor growth can be followed in vivo by measuring bioluminescence signal from the MCF7 red F-luc in the whole animal.
  • the breast tumor-bearing mice were implanted subcutaneously with 17- ⁇ estradiol pellet (0.72 mg/pellet), from the date of tumor implant to the end of the study.
  • the tumor growth was followed by measuring the bioluminescence produced by the tumor cells expressed in Total Flux photons per second (p/s). Also the weight of the mice was monitored during the study.
  • the treatment was started when the tumor masses achieved an average bioluminescence signal of 1.96 x10 7 and 8.1 x 10 8 p/s. Each group was composed of 5 mice. Treatment effectiveness was assessed as TVI% in treated versus control mice. Determination of Synergy using the Chou-Talalay combination index (Cl- Chou-Talalay combination index Cl).
  • Synergism may be quantified using the Chou-Talalay combination index (CI) (see “Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses”, Zhao L, et al. Clin Cancer Res. (2004) Dec. 1; 10(23):7994-8004; and “Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design”, Chou T C, Motzer R J, Tong Y, Bosl G J., J. Natl. Cancer Inst. (1994) Oct.
  • CI Chou-Talalay combination index
  • the Chou-Talalay combination index (CI) method is based on the multiple drug effect equation derived from the median-effect principle of the mass-action law. Such index provides a quantitative definition of the synergy and in particular: Cl ⁇ 0.3 designates a strong synergy, 0.3 ⁇ Cl ⁇ 0.9 designates synergy, 0.9 ⁇ CI ⁇ 1.1 designates an additive effect, and CI> 1.1 designates antagonism.
  • the Chou-Talalay combination index may be estimated using the Synergy R package (see “Preclinical versus Clinical Drugs Combination Studies”, Chou T C. Leuk. Lymphoma. (2008); 49(11):2059-2080, and references therein, all of which are specifically incorporated herein by reference).
  • the CI of the combination may be tested in a suitable cell-line, e.g. in MCF7 cells, e.g. under the conditions used in Example 9. according to what designated in Preclinical versus Clinical Drugs Combination Studies.
  • Working Example 1 showed synergistic effect of Elacestrant and MEN1611 in vitro
  • the in vitro antitumor activity of Elacestrant in combination with MEN1611 was investigated in ER+/HER2- breast cancer cell lines.
  • the in vitro cytotoxic activity of the combination Elacestrant and MEN1611 was evaluated in terms of Combination Index (CI) in breast cancer cell line MCF7.
  • the MCF7 cells were treated with Elacestrant and MEN1611 at different concentration as shown in Table 1 below.
  • Table 1 Combination Index
  • Table 1 Effects of different combinations of Elacestrant and MEN1611 (ELA is short for Elacestrant and 1611 is short for MEN1611)
  • Table 2 Effects of single agent treatments The CI value for each of the combinations of Elacestrant and MEN1611 shown in Table 1 was determined based on the inhibitory effects on MCF7 cells of the combinations, and the effects of the single agents as shown in Table 2.
  • the CI values shown in Table 1 were plotted in Fig. 1, and the different combinations of Elacestrant and MEN1611 are indicated with a Figure Ref number as shown in Table 1. As shown in Fig.
  • Treatment effectiveness was assessed as tumor volume inhibition (TVI%) in treated versus control mice.
  • the breast cancer ER+/HER2- PDX model HBCx-3 is resistant to Palbociclib and Fulvestrant and harbors the mutation P246 fs8aa in the PTEN gene.
  • This breast cancer model was treated with the combination of MEN1611 and Elacestrant as shown in Table 3 above. As shown in Fig. 2, the treatment with both MEN1611 with Elacestrant showed a synergistic effect at the end of the treatment.
  • the breast cancer ER+/HER2- PDX model CTG-2308 is resistant to endocrine therapy, Palbociclib, and Fulvestrant. This model harbors the mutation E545K in the PIK3CA gene. As shown in Fig.
  • the combination of MEN1611 and Elacestrant showed a synergistic effect at the end of the study.
  • the breast cancer ER+/HER2- PDX model CTG-1260 is resistant to Palbociclib and Fulvestrant, and it harbors the double mutations D350H and H1047R in the PIK3CA gene, and the D538G mutation in ESR1 gene. As shown in Fig. 4, treating the CTG-1260 model with the combination of MEN1611 and Elacestrant showed a synergistic effect at the end of the treatment.

Abstract

The present invention relates to combinations of the P13K class I inhibitor and a selective estrogen receptor degrader (SERB) that provide synergistic effects in treating cancer. The present invention provides in particular that a combination of a P13K class la selective inhibitor such as 5-(7-methanesulfonyl-2-morpholin-4-yl- 6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-il-amine or pharmaceutically acceptable salts thereof, and the selective estrogen receptor degrader Elacestrant acts synergistically to treat breast cancer resistant to traditional treatment.

Description

PI3K inhibitor combination therapy CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/393,061, filed on July 28, 2022, the contents of which are incorporated herein by reference in its entirety. BACKGROUND Hormone receptor-positive and HER2-negative breast cancer (HR + BC) is the most prevalent breast cancer. Endocrine therapy, with or without cycline-dependent kinases CDK inhibitors, is the standard therapy for this patient group. However, acquired resistance to standard therapy remains a major therapeutic challenge for treating breast cancer. Mutations resulting in deregulation of the cycline-dependent kinases (CDKs), the PI3K pathway, and the estrogen receptor 1 (ESR1) are commonly found in breast cancer. More than 70% of breast cancer patients are HR positive/HER2 negative, and about 40% of these patients harbor activating PI3K mutations. Numerous compounds that inhibit the activity of CDKs, PI3K, and ESR1 have been disclosed in the art, including Sci Transl Med. 2015 April 15; 7(283): 283ra51; Annals of Oncology 30 (Supplement 10): x3–x11, 2019; Curr Oncol. 2021 Jun; 28(3): 1803–1822; Int J Mol Sci. 2021 Aug; 22(15): 7812, Baselga J., Everolimus in postmenopausal hormone- receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9; André F., Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med.2019 May 16;380(20):1929-1940). Cyclins and CDKs are essential in regulating the progression through the distinct phases of the cell cycle, G1, S, G2 and M phases. CDKs are serine/threonine kinases which are regulated by their interactions with cyclins and CDK inhibitors. CDK activity is often dysregulated in cancer cells and hence they are an attractive target for anti-cancer therapy. In human cells, there are 20 CDKs and 29 cyclins (8). CDK1, CDK2, CDK3, CDK4, CDK6, and CDK7 directly regulate cell-cycle transitions and cell division, whereas CDK 7–11 mediate cell-cycle associated gene transcription. Targeted therapies such as Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors have improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by combating the resistance seen with traditional endocrine therapy. Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are a class of medical drugs used to treat various cancers, but they can also have very severe side effects. Nunnery et al., Annals of Oncology, 30, Suppl. 10, pages 21-26 (2019). They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates normal cellular functions such as growth and survival, and may be hyperactive in many cancer cells, allowing the cancer cells to better survive and multiply. There are different classes and isoforms of PI3Ks. In particular, Class I PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) and p110 delta (PIK3CD). Inhibiting different p110 isoforms can have different effects. PI3K inhibitors are also under investigation as treatments for inflammatory respiratory disease. A selective estrogen receptor degrader or downregulator (SERD) is a type of drug that binds to the estrogen receptor (ER) and causes the ER to be degraded. They are used to treat estrogen receptor-sensitive or progesterone receptor-sensitive breast cancer, along with older classes of drugs like selective estrogen receptor modulators (SERMs) and aromatase inhibitors. In view of the number of pathological responses that may result from treatment with such compounds, there remain a need for compounds or combination of compounds that can provide efficient treatment of cancer, and in particular breast cancer that is resistant to traditional endocrine therapy. The present disclosure addresses this need. SUMMARY OF THE INVENTION The present disclosure is based on the surprising discovery that a pharmaceutical combination of a Phosphoinositide 3-kinase (PI3K) class I inhibitor and a selective estrogen receptor degrader (SERD) yields synergistic effects in treating hormone receptor–positive (HR-positive)/human epidermal growth factor receptor 2–negative (HER-2-negative) breast cancer resistant to or that progressed over a first line of therapy. In one aspect, the present disclosure relates to a combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use. In some embodiments, the SERD is suitable for oral administration. In some embodiments, the PI3K class I inhibitor is suitable for oral administration. In some embodiments, the pharmaceutical combination comprises component (a) and/or (b) each formulated as pharmaceutical composition adapted for oral administration. In some embodiments, the SERD is nonsteroidal. In some embodiments, the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof. In some embodiments, the Elacestrant is in the form of a dihydrochloride salt. In some embodiments, the PI3K class I inhibitor is a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2- morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof. In some embodiments, PI3K class I inhibitor is a PI3K class Ia selective inhibitor. In some embodiments, the PI3K class I inhibitor is selective for PI3K class Ia over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id. In some embodiments, the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia over PI3K class Id (“PI3K class Ia selective inhibitor”), wherein the PI3K class Ia selective inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2- morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof. In some embodiments, the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia over PI3K class Id (“PI3K class Ia selective inhibitor”), wherein the PI3K class Ia selective inhibitor comprises 5-(7- methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin- 2-amine or the pharmaceutically acceptable salt thereof. In some embodiments, the P,,I3K class I inhibitor comprises 5-(7-methanesulfonyl-2- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination is adapted for oral administration. In another aspect, the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering a pharmaceutical combination comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor. In another aspect, the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor. In some embodiments, the first and second pharmaceutical composition are administered simultaneously. In some embodiments, wherein the first pharmaceutical composition is administered prior to, during, or after the second pharmaceutical composition. In some embodiments, the patient is suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the breast cancer is Hormone receptor-positive and HER2- negative (HR+/HER2-) breast cancer. In some embodiments, the breast cancer is Estrogen Receptor-positive and HER2- negative (ER+/HER2-) breast cancer. In some embodiments, the breast cancer comprises PI3KCA mutations. In some embodiments, the breast cancer is resistant to or progressed over a previous treatment with: endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or CDK4/6 inhibitors. In some embodiments, the breast cancer is advanced or metastatic. In some embodiments, SERD is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period. In some embodiments, the PI3K class I inhibitor is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period. In some embodiments, a therapeutically effective amount of the SERD is administered to the patient. In some embodiments, both the first and the second pharmaceutical compositions are adapted for oral administration. In some embodiments, the second pharmaceutical composition comprising a PI3K class I inhibitor is adapted for oral administration, and comprises hypromellose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. In some embodiments, the therapeutically effective amount of the SERD is determined based on monitoring binding of estradioal to the estrogen-receptor-alpha (ERα). In some embodiments, the method comprises administering a PI3K class I inhibitor comprising a PI3K class Ia inhibitor. In some embodiments, the PI3K class I inhibitor comprises 5-(7-methanesulfonyl-2- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor is determined based on monitoring PI3K activity. In some embodiments, the first pharmaceutical composition provides a delayed release of the SERD. In some embodiments, the first and/or the second pharmaceutical composition are adapted for oral administration. In some embodiments, the second pharmaceutical composition provides a delayed release of the PI3K class I inhibitor. In some embodiments, the first and/or the second pharmaceutical composition is administered once daily. In some embodiments, the patient is a mammal. In some embodiments, the patient is human. In another aspect, the present disclosure relates to a pharmaceutical combination for use in a method of treating a patient suffering from a cancer, comprising administering a pharmaceutical combination comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor. In another aspect, the present disclosure relates to a pharmaceutical combination for use in a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor. In another aspect, the present disclosure relates to use of a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor in the preparation of a medicament for treating a cancer in a subject, wherein the use comprises administering to the subject a therapeutically effective amount of the SERD and the PI3K class I inhibitor. In another aspect, the present disclosure relates to a kit comprising a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor. In some embodiments, the kit further comprises instructions for treating a cancer in a subject in need thereof. An oral pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the oral pharmaceutical combination are formulated separately or are each formulated into an oral pharmaceutical composition to allow simultaneous, separate or sequential use. A pharmaceutical composition comprising (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor. In some embodiments, the pharmaceutical composition is adapted for oral administration. In some embodiments of the pharmaceutical composition, the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof, preferably wherein the Elacestrant is in the form of a dihydrochloride salt. In some embodiments of the pharmaceutical composition, the PI3K class Ia inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof. In some embodiments of the pharmaceutical composition, the PI3K class Ia inhibitor comprises 5-(7-methanesulfonyl-2-morpholin-4-yl- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or the pharmaceutically acceptable salt thereof. In some embodiments of the pharmaceutical composition, the PI3K class I inhibitor is selective for PI3K class Ia over PI3K class Id, optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for PI3K class Ia, class Ib, and class Ig over PI3K class Id. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graphical representation of the Combination Index (CI) determined for the in vitro combination of Elacestrant and MEN1611. The graph depicts CI as a function of the fraction affected (Fa). A CI < 1 represents a synergistic effect of the combination of the two drugs at the indicated dose shown in Table 1. Each symbol series represents a different group of Elacestrant concentration combined with different concentrations of MEN1611. Circles: Elacestrant 1μM, squares: Elacestrant 0.1μM, up-pointing triangles: Elacestrant 0.01μM, down-pointing triangles: Elacestrant 0.001μM, diamond: Elacestrant 0.0001μM. The Figure reference number indicates specific combinations as described in Table 1 in the “Figure Ref” column. Fig. 2 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer ER+/HER2- PDX model HBCx-3, harboring a mutation in PTEN gene. Fig. 2A depicts the measured tumor volume as a function of days post beginning of treatment. Arrows represent Elacestrant and MEN1611 dosing as indicated. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (diamond), and the combination of Elacestrant and MEN1611 (triangle). Fig. 2B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the HBCx-3 model at day 29 post beginning of treatment. Fig. 3 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer ER+/HER2- PDX model CTG-2308, harboring a mutation in PIK3CA gene. Fig. 3A depicts the measured tumor volume as a function of days post beginning of treatment. Bracket under the graph represents beginning and end of Elacestrant and MEN1611 dosing. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (diamond), and the combination of Elacestrant and MEN1611 (triangle). Fig. 3B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the CTG-2308 model at day 59 post beginning of treatment. Fig. 4 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer ER+/HER2- PDX model CTG-1260, harboring a mutation in PIK3CA and ESR1 genes. Fig.4A depicts the measured tumor volume as a function of days post beginning of treatment. Bracket under the graph represents beginning and end of Elacestrant and MEN1611 dosing. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (diamond), and the combination of Elacestrant and MEN1611 (triangle). Fig. 4B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the CTG-1260 model at day 55 post beginning of treatment. Fig. 5 is a graphical representation of the antitumor activity of MEN1611 in combination with Elacestrant in breast cancer cell-derived xenograft model MCF7 Red F-luc, harboring a mutation in PIK3CA gene. Fig. 5A depicts the measured tumor volume as a function of days post beginning of treatment. Bracket under the graph represents beginning and end of Elacestrant and MEN1611 dosing. The legend symbols in the graph indicate vehicle (circle), MEN1611 alone (hexagon), Elacestrant (triangle), and the combination of Elacestrant and MEN1611 (diamond). Fig. 5B depicts a graph comparing the difference in tumor volume between vehicle control, MEN1611, Elacestrant, and the combination of Elacestrant and MEN1611 treatment groups of the xenograft model MCF7 Red F-luc at day 39 post beginning of treatment. DETAILED DESCRIPTION The present disclosure is based on the surprising discovery that a combination of a Phosphoinositide 3-kinase (PI3K) class I inhibitor and a selective estrogen receptor degrader (SERD) yields synergistic effects in treating hormone receptor–positive (HR-positive)/human epidermal growth factor receptor 2–negative (HER-2-negative) breast cancer resistant to or that progressed over a first line of therapy. In particular, the working examples presented herein showed that combining a PI3K class I inhibitor and a SERD resulted in a synergistic reduction in tumor volume in HR+/HER2- breast cancer models that are resistant or progresses over to the first line of therapy compared to using the PI3K class I inhibitor or the SERD individually. As shown in the working examples and Figs. 1-5 herein, the presently disclosed compositions and methods achieved synergistic inhibitory effects on tumor growth in several different breast cancer models that are resistant or progressed over a first line of therapy. Moreover, no toxicity, in terms of body weight changes or death events, was observed in any group treated with the combination of Elacestrant and MEN1611 as shown for example in working example 2. Hence the present disclosure provides a pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use. In some embodiments, the SERD is suitable for oral administration. In some embodiments, the PI3K class I inhibitor is suitable for oral administration. In some embodiments, the SERD and PI3K class I inhibitor are suitable for oral administration. As used herein, the term “pharmaceutical combination” refers to a combination of separate components so that the components can be administered separately or sequentially. In some embodiments, the components of the pharmaceutical combination may also be administered simultaneously. The components in the pharmaceutical combination described herein may most preferably be formulated separately or may each be formulated into a suitable pharmaceutical composition. Hence, in some embodiments a pharmaceutical combination may comprise two or more pharmaceutical compositions, wherein a first pharmaceutical composition comprises a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprises a phosphatidylinositol 3-kinase (PI3K) class I inhibitor. In some embodiments, some or all of the components may be co-formulated into a pharmaceutical composition comprising the SERD and the PI3K class I inhibitor. Each component of the pharmaceutical combination described herein can optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components can each independently comprise, or some or all of the components together comprise, a pharmaceutically acceptable carrier and/or an excipient. The pharmaceutically acceptable carrier and/or an excipient are selected based on desired administration route as described in greater detail below. The components in the pharmaceutical combination disclosed herein can be administered independently, or some or all of the components are co-administered in proper routes including most preferably, but not limited to, oral administration. Hence, most preferably, the present disclosure provides an oral pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the oral pharmaceutical combination are formulated separately or are each formulated into an oral pharmaceutical composition to allow simultaneous, separate or sequential use. Further exemplary, non-limiting description of the components of the pharmaceutical combination, suitable pharmaceutical composition for administering the components, and dosages, administration and use of the pharmaceutical combination is provided below. Inhibitors of Phosphoinositide 3-kinase (PI3K) The enzyme phosphatidylinositol-3 -kinase (PI3K) is known as type of phosphorylase that phosphorylates in position 3 of an inositol ring of the phosphatidylinositol. PI3K is classified into three groups, precisely Class I, Class II and Class III based upon the primary structure, the type of phosphatidylinositols which act as substrate. In particular, Class I PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) and p110 delta (PIK3CD). PI3K inhibitors function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes. Numerous PI3K inhibitors have been developed with varying selectivity towards PI3K enzymes, efficacy and safety profiles. Although PI3K inhibitors may be effective in preventing or inhibiting cancer growth, they may also have side effects. PI3K inhibitors may be specific or selective to the different subtypes or isoforms of the catalytic subunits of the PI3K inhibitors. Accordingly, PI3K inhibitors can be Class I, Class II, and Class III PI3K inhibitors. PI3K inhibitor selective for Class I p110 alpha (PIK3CA), p110 beta (PIK3CB), p110 gamma (PIK3CG) or p110 delta (PIK3CD) isoforms may be referred to herein as selective for class Ia, Ib, Ig, or Id, respectively. A PI3K inhibitor is selective for one of the subtypes or isoforms Ia, Ib, Ig, or Id, if it inhibits one of the subtypes more effectively than the others. A PI3K inhibitor may be selective for one, two, or three class I isoforms, or if it inhibits all four isoforms, the inhibitor may be referred to as non-selective or pan-inhibitor. For example, a PI3K inhibitor of the present invention may selectively inhibit the class Ia isoform over the PI3K class Id. In some embodiments, PI3K inhibitor may be selective for both PI3K class Ia and PI3K class Ig over PI3K class Id. In some embodiments, PI3K inhibitor may be selective for PI3K class Ia, PI3K class Ib, and PI3K class Ig over PI3K class Id. In some embodiments, a PI3K class I inhibitor of the present invention may selectively inhibit the class Ia isoform over the PI3K class Id and/or the PI3K class Ib. In some preferred embodiments, the PI3K inhibitor may be selective for both PI3K class Ia and PI3K class Ig over PI3K class Id and/or PI3K class Ib. The PI3K inhibitors may also be selective to varying degrees. The degree of selectivity can be measure by calculating a “selectivity ratio”. The selectivity ratio can be expressed as [Ix]/[Iy], where [Ix] is a measurement of inhibition of the isoform the inhibitor is not selective for, and [Iy] is a measurement of inhibition of the isoform the inhibitor is selective for. For example, the PI3K Ia inhibitor that selectively inhibits PI3K class Ia over PI3K class Id has a [Id]/[Ia] selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000, when the measurement of inhibition is the inhibitor’s IC50. In some embodiments, the PI3K class Ia selective inhibitor has a [Id]/[ Ia] selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850, when the measurement of inhibition is the inhibitor’s IC50. In some embodiments, the [Id]/[Ia] selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K Id isoform by the inhibitor's IC50 against PI3K I isoform. In some embodiments, the PI3K inhibitor is selective for both PI3K class Ia and PI3K class Ig over the PI3K class Id. In some embodiments, the PI3K inhibitor selective for both classes Ia and Ig over class Id has a [Id]/[Ia] selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000, when the measurement of inhibition is the inhibitor’s IC50, and a [Id]/[Ig] selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000, when the measurement of inhibition is the inhibitor’s IC50. In some embodiments, the PI3K inhibitor selective for both class Ia and Ig over class Id has a [Id]/[Ia] selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850, when the measurement of inhibition is the inhibitor’s IC50, and a [Id]/[Ig] selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850, when the measurement of inhibition is the inhibitor’s IC50. In some embodiments, the [Id]/[Ia] selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K Id isoform by the inhibitor's IC50 against PI3K Ia isoform and the [Id]/[Ig] selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K Id isoform by the inhibitor's IC50 against PI3K Ig isoform. For example, non-selective or pan-PI3K inhibitors may include buparlisib, CH5132799, pilaralisib, ZSTK474, sonolisib, pictilisib, copanlisib, B591, TG100115, RIDR- PI-103. In some embodiments, the PI3K inhibitors may have selectivity to one or more isoforms over others such as alpelisib, serabelisib, GSK2636771, idelalisib, zandelisib, amg319, linperlisib, parsaclisib, umbralisib, leniolisib, eganelisib, tenalisib, taselisib, AZD8186, AZD8825, or duvelisib. PI3K inhibitors may also inhibit both the PI3K enzyme and the downstream targets of the PI3K enzyme such as dactolisib, apitolisib, gedatolisib, SF1126, omnipalisib, samotolisib, bimiralisib, paxalisib, or voxtalisib. Other PI3K inhibitors are for examples fimepinostat or rigosertib. In some embodiments, the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia over PI3K class Id (“PI3K class Ia selective inhibitor”), wherein the PI3K class I selective inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H- pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3- d]pyrimidine derivative or the pharmaceutically acceptable salt thereof. Most preferably, the PI3K class I inhibitor comprises a PI3K class I inhibitor selective for PI3K class Ia, Ib, and Ig over PI3K class Id comprising 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine (sometimes referred to as MEN1611 or CH5132799) or the pharmaceutically acceptable salt thereof. In particular, MEN1611 is a PI3K inhibitor active on p110alpha (both mutants and wt), beta and gamma (8.6- and 2.2- fold less potent compared to the alpha, respectively), while sparing the delta isoform (36-fold less potent compared to the alpha). In some embodiments, the PI3K inhibitor is a 2-morpholin-4-yl-6,7-dihydro- 5H- pyrrolo[2,3-d]pyrimidine derivative, or 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3- d]pyrimidine derivative as described in detail in EP2050749, incorporated in its entirety herein. In particular, the compound 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H- pynOlo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or pharmaceutically acceptable salts thereof, also known in literature as MEN1611 (or CH5132799) is a PI3K class I inhibitor, having the following Formula I:
Figure imgf000015_0001
Formula I The compound according to Formula I and method of its preparation were described in EP2050749 or WO 2008/018426, incorporated in their entirety herein. The pharmacological features of the compound were described in scientific literature by Jun Ohwada et al. on Bioorganic & Medicinal Chemistry Letter , 21 (2001) pages 1767-1772. As used herein, the terms “MEN1611” and “CH5132799” refer to the same chemical compound. In some embodiments, the PI3K class I inhibitor comprises 5-(7- methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin- 2-amine or the pharmaceutically acceptable salt thereof. In some embodiments, the PI3K inhibitor is a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or 2- morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative as described in detail in EP2050749 or WO 2008/018426, incorporated in their entirety herein. Pharmaceutically acceptable salts of MEN1611 include hydrochlorides, dihydrochlorides, hydrobromides, hydroiodides, nitrates, sulphates, bisulphates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, bitartrates, succinates, oxalates, malates, fumarates, gluconates, malonates, saccharates, benzoates, mandelates, salicylates, trifluoroacetates, propionates, glutarates, methane-sulphonates, ethane- sulphonates, benzensulphonates, p-toluensulphonate and l,r-methylene-bis-2-hydroxy-3- naphtates. preferred examples of salts include a hydrohalide salt (for instance, hydrochloride, hydrobromide, hydroiodide and the like), an inorganic acid salt (for instance, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), an organic carboxylate salt (for instance, acetate salt, maleate salt, tartrate salt, fumarate salt, citrate salt and the like), an organic sulfonate salt (for instance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), a quaternary ammonium salt, an alkaline metal salt (for instance, sodium salt, potassium salt and the like), an alkaline earth metal salt (magnesium salt, calcium salt and the like) and the like. In addition, hydrochloride salt, sulfate salt, methanesulfonate salt, acetate salt and the like are preferred as “pharmacologically acceptable salt” of the compounds according to the present invention. Examples of basic salts include salts of alkali metals such as sodium salts and potassium salts, salts of alkaline-earth metals such as calcium salts and magnesium salts, ammonium salts, addition salts with water-soluble amines such as salts of N- methylglucamine, inferior alkanol ammonium salts and salts derived from other pharmaceutically acceptable bases of organic amines. Selective estrogen receptor degrader (SERD) A selective estrogen receptor degrader or downregulator (SERD) is a type of drug which binds to the estrogen receptor (ER) and causes the ER to be degraded. They are used to treat estrogen receptor-sensitive or progesterone receptor-sensitive breast cancer. Examples of SERDs include fulvestrant (brand name Faslodex™), brilanestrant and Elacestrant. The preferred SERD used in the presently disclosed compositions, methods and kits is Elacestrant (also referred to as RAD1901). As used herein, the terms “RAD1901” and “Elacestrant” and “ER-306323” refer to the same chemical compound including salts, solvates (e.g. hydrate), and prodrugs thereof, and are used interchangeably. As used herein, Elacestrant or RAD1901 has the structure according to the following Formula II including salts, solvates (e.g. hydrate), and prodrugs thereof:
Figure imgf000017_0001
Formula II Elacestrant/ RAD1901 is a nonsteroidal combined selective estrogen receptor modulator and selective estrogen receptor degrader ( referred to herein as a “SERD”). Unlike the SERD fulvestrant, Elacestrant is able to readily cross the blood-brain-barrier into the central nervous system, where it can target breast cancer metastases in the brain, and is orally bioavailable and does not require intramuscular injection. Elacestrant is further described in Wardell et al., Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr Relat Cancer, 2015 Oct;22(5):713-24; Garner et al., RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs, 2015 Oct;26(9):948- 56; Bihani et al., Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models. Clin Cancer Res. 2017 Aug 15;23(16):4793-4804; Patel et al., Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. Breast Cancer Res. 2019 Dec 18;21(1):146. In certain embodiments, the SERD is suitable for oral administration. In some embodiments, the SERD is nonsteroidal. In some embodiments, the SERD is Elacestrant/ RAD1901, or a pharmaceutically acceptable salt thereof. In some embodiments, the Elacestrant is in the form of a dihydrochloride salt. The term “salt” used herein is not limited as long as the salt is formed with RAD1901 or solvates (e.g., hydrate) or salts thereof and is pharmacologically acceptable; preferred examples of salts include a hydrohalide salt (for instance, hydrochloride, dihydrochloride, hydrobromide, hydroiodide and the like), an inorganic acid salt (for instance, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), an organic carboxylate salt (for instance, acetate salt, maleate salt, tartrate salt, fumarate salt, citrate salt and the like), an organic sulfonate salt (for instance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), a quaternary ammonium salt, an alkaline metal salt (for instance, sodium salt, potassium salt and the like), an alkaline earth metal salt (magnesium salt, calcium salt and the like) and the like. In addition, hydrochloride salt, sulfate salt, methanesulfonate salt, acetate salt and the like are preferred as “pharmacologically acceptable salt” of the compounds according to the present invention. In preferred embodiments, the Elacestrant is in the form of a dihydrochloride salt. Isomers of RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611 (e.g., geometric isomers, optical isomers, rotamers, tautomers, and the like) can be purified using general separation means, including for example recrystallization, optical resolution such as diastereomeric salt method, enzyme fractionation method, various chromatographies (for instance, thin layer chromatography, column chromatography, glass chromatography and the like) into a single isomer. The term “a single isomer” herein includes not only an isomer having a purity of 100%, but also an isomer containing an isomer other than the target, which exists even through the conventional purification operation. A crystal polymorph sometimes exists for RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611, and all crystal polymorphs thereof are included in the present invention. The crystal polymorph is sometimes single and sometimes a mixture, and both are included herein. In certain embodiments, RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611 may be in a prodrug form, meaning that it must undergo some alteration (e.g., oxidation or hydrolysis) to achieve its active form. Alternative, RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611 may be a compound generated by alteration of a parental prodrug to its active form. Pharmaceutical Combinations and Compositions The components of the pharmaceutical combination disclosed herein are each formulated separately into suitable pharmaceutical compositions. In one aspect, the present disclosure relates to a combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3- kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use. Most preferably, the selective degrader and modulator of the estrogen receptor (SERD) is RAD1901, and the PI3K class I is MEN1611. In some embodiments, RAD1901 or solvates (e.g., hydrate) or salts thereof and the PI3K class I inhibitor such as MEN1611 or solvates (e.g., hydrate) or salts thereof may be administered as part of a single formulation. For example, RAD1901 or solvates (e.g., hydrate) or salts thereof and the PI3K class I inhibitor such as MEN1611 or solvates (e.g., hydrate) or salts thereof are formulated in a pharmaceutical composition. In a most preferable embodiments, the pharmaceutical combination and each component thereof are adapted for oral administration. The pharmaceutical combinations and compositions of the present invention can be formulated and administered by oral or parenteral route (such as by intravenous, intramuscular, subcutaneous, rectal, nasal, intracisternal, vaginal, abdominal, intracystic route or locally). Examples of pharmaceutical compositions for oral administration include tablets, capsules, granules, powders, pills, solutions and aqueous and non-aqueous oral suspensions. Examples of pharmaceutical compositions for the parental administration include aqueous or oily solution for intravenous, intramuscular, subcutaneous injections. Other formulations such as ointments, gels, creams, suppositories, sprays by oral or nasal route, emulsions, oily agents and suspending agents, can be equally used if suitable to the contingent situation. The solutions for parental use usually are distributed in containers suitable for the administration in small individual doses. The formulation of the various active principles such as the PI3K class I inhibitor and the SERD should be so as to allow the administration of customized quantities of the medicament and not the administration of standard quantities. Moreover, the administration form can be adapted to the various administration methods for controlled or delayed release formulation. In some embodiments, the first and/or the second pharmaceutical composition are adapted for oral administration. In some embodiments, the first pharmaceutical composition provides a delayed release of the SERD. In some embodiments, the second pharmaceutical composition provides a delayed release of the PI3K class I inhibitor. In particular, both the PI3K class I inhibitor and the particular SERD RAD1901 are usually administered by oral route and therefore it will be formulated in any form suitable for such administration route. However, other administration routes are not excluded. In some embodiments, the pharmaceutical composition comprising the SERD and the pharmaceutical composition comprising the PI3K may be of the same type. For example, both pharmaceutical compositions may be adapted for oral administration (e.g., via two separate pills) or for injection (e.g., via two separate injectable formulations). In some embodiments, the pharmaceutical compositions may be adapted for different routes of administration. For example, one compound may be in a pharmaceutical composition adapted for oral administration, while the other is in a pharmaceutical composition adapted for injection. Examples of dosage forms include a tablet, a powder, a subtle granule, a granule, a coated tablet, a capsule, a syrup, a troche, an inhalant, a suppository, an injectable, an ointment, an ophthalmic ointment, an eye drop, a nasal drop, an ear drop, a cataplasm, a lotion and the like. In the pharmaceutical composition, generally used additives such as a diluent, a binder, an disintegrant, a lubricant, a colorant, a flavoring agent, and if necessary, a stabilizer, an emulsifier, an absorption enhancer, a surfactant, a pH adjuster, an antiseptic, an antioxidant and the like can be used. The oral pharmaceutical compositions as disclosed herein can be formulated readily by combining the components (SERD or PI3K class I inhibitor) with pharmaceutically acceptable carriers for oral administration that are well known in the art. Such carriers enable the compounds of embodiments herein to be formulated as nanoparticles, nanoparticle suspension, tablets, troches, pills, dragees, capsules, powders, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Oral compositions can also be prepared using a fluid carrier, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutical combinations and compositions for oral administration can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross- linked PVP, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, PVP, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical compositions which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient in an admixture with one or more fillers (e.g., lactose), one or more binders (e.g., starches), and/or one or more lubricants (e.g., talc or magnesium stearate) and, optionally, one or more stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid PEG. In addition, stabilizers can be added. All compositions for oral administration should be in dosages (e.g., about 5 mg to about 500 mg) suitable for such administration. In some embodiments, the oral compositions may take the form of, e.g., lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, PVP or HPMC); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art with, e.g., sugars, films or enteric coatings. Additionally, the pharmaceutical compositions containing one of the components as disclosed herein can be in any form suitable for oral use, including, e.g., troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. In one embodiment, the oral pharmaceutical composition as disclosed herein is a tablet. Tablets may contain one of the components of the pharmaceutical combination in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents (e.g., corn starch, or alginic acid); binding agents (for example starch, gelatin or acacia); and lubricating agents (for example magnesium stearate, stearic acid or talc). The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. In some embodiments, the tablet is formulated for immediate release. In some embodiments, the tablet is formulated for controlled release. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release. The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. In some embodiments, the oral pharmaceutical composition may comprise one of the components of the pharmaceutical combination and a buffer. In some embodiments, the buffer may be selected from the group consisting of citric acid monohydrate, sodium phosphate, water, and a combination thereof. In some embodiments, the oral composition comprises one of the components of the pharmaceutical combination and a stabilizer. In some embodiments, the stabilizer is selected from a group consisting of povidone, sodium benzoate, water, sodium lauryl sulfate, and a combination thereof. In some embodiments, the oral composition further includes a buffer, an acid, sodium benzoate, sodium phosphate, citric acid, or a combination thereof. In some embodiments, the oral composition comprises one of the components of the pharmaceutical combination and a stabilizer and a buffer. In some embodiments, the oral composition further comprises a lubricant, a pH modifier, a binder, a diluent, a granulating agent, a glidant, a disintegrant, a filler, a sorbent, an anti-adherent, a coloring agent, a compression aid, a coating material, a sweetener, a preservative, an antioxidant, or a combination thereof. In some embodiments, one of the components of the pharmaceutical combination is in a therapeutically effective amount (e.g., about 5 mg to about 500 mg). In some embodiments, the oral composition is a suspension, tablet, capsule, nanoparticle powder, nanoparticle suspension, cachet, pellet, pill, powder, granules, or a combination thereof. In some embodiments, the lubricant may be selected from the group consisting of stearic acid or its salts (e.g., magnesium stearate, calcium stearate), sodium lauryl sulfate, PEG, mineral oil, sodium benzoate, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, and a combination thereof. In some embodiments, the pH modifier may be an acid (e.g., hydrochloric acid, acetic acid, citric acid, phosphoric acid, sulfuric acid, or a combination thereof). In some embodiments, the binder may be selected from the group consisting of a natural or synthetic polymer (e.g., starches, sugars, sugar alcohols, or cellulose derivatives) such as gelatin, glucose, lactose, sorbitol, xylitol, maltitol, methyl cellulose, microcrystalline cellulose (MCC), ethyl cellulose, HPMC, hydroxypropyl cellulose (HPC), starch, PVP, PEG, sodium alginate, CMC, and a combination thereof. In some embodiments, the compression aid may be selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, a physical mixture of MCC-colloidal silicon dioxide, and a combination thereof. In some embodiments, the disintegrant may be selected from the group consisting of starch, cellulose derivatives and alginates, PVP, croscarmellose sodium, sodium starch glycolate, and a combination thereof. In some embodiments, the filler may be selected from the group consisting of lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate, plant cellulose, dibasic calcium phosphate, dibasic sodium phosphate, vegetable fats and oils, and a combination thereof. In some embodiments, the diluent may be selected from the group consisting of sugar compounds (e.g., sucrose, lactose, dextrin, glucose, sorbitol, or the like), inorganic compounds (e.g., silicates, calcium salts, or magnesium salts), sodium chloride, potassium chloride, and a combination thereof. In some embodiments, the preservative may be selected from the group consisting of an antioxidant (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), an amino acid (e.g., cysteine, or methionine), citric acid, sodium citrate, a synthetic preservative (e.g., a paraben such as methyl paraben or propyl paraben), and a combination thereof. In some embodiments, the glidant may be selected from the group consisting of colloidal anhydrous silicon and other silica compounds, such as fumed silica, magnesium carbonate, colloidal silicon dioxide (AEROSIL™), cornstarch, talc, and a combination thereof. In some embodiments the oral pharmaceutical composition comprising one of the components of the pharmaceutical combination is a tablet. In some embodiments the tablet contains one of the components of the pharmaceutical combination in the form of nanoparticles. In some embodiments, the tablet may be coated. In some embodiments, the tablet may be coated with an enteric coating. In some embodiments, the tablet may be coated with a coating selected from a sugar coating, film coating, organic film coating, aqueous film coating, pan coating, dip coating, electrostatic coating, compression coating, plasticizer dry coating, heat dry coating, electrostatic dry coating, or the like. Some ingredients used for coating may include aqueous acrylic enteric system such as that sold under the trade name ACRYL-EZE™, film coating system sold under the trade name OPADRY™, HPMC, methyl hydroxyethyl cellulose, ethylcellulose, povidone, cellulose acetate phthalate, acrylate polymers (such as those sold under the trade name EUDRAGIT™ & EUDRAGIT™), HPMC phthalate, or a combination thereof. A tablet may be manufactured by spraying the nanosuspension (above) onto sucrose to form a spray granulate intermediate, granulating the spray granulate intermediate with excipients to form a final granulation, and compressing the final granulation to form a tablet. The sucrose could be any sugar, including, e.g., glucose, fructose, maltose, galactose, lactose, or the like. In some embodiments, the excipients for the tablet formulation may include lactose monohydrate, PVP, silicified microcrystalline cellulose (e.g., sold under the trade name PROSOLV.RTM. SMCC HD 90), magnesium stearate, or a combination thereof. In some embodiments, the tablet comprises about 5 mg to about 300 mg of Compound I. Other excipients included in the pharmaceutical compositions disclosed herein may contain, for example, (1) an oil such as a soybean oil, a beef tallow and synthetic glyceride; (2) hydrocarbon such as liquid paraffin, squalane and solid paraffin; (3) ester oil such as octyldodecyl myristic acid and isopropyl myristic acid; (4) higher alcohol such as cetostearyl alcohol and behenyl alcohol; (5) a silicon resin; (6) a silicon oil; (7) a surfactant such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, a solid polyoxyethylene castor oil and polyoxyethylene polyoxypropylene block co-polymer; (8) water soluble macromolecule such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethyleneglycol, polyvinylpyrrolidone and methylcellulose; (9) lower alcohol such as ethanol and isopropanol; (10) multivalent alcohol such as glycerin, propyleneglycol, dipropyleneglycol and sorbitol; (11) a sugar such as glucose and cane sugar; (12) an inorganic powder such as anhydrous silicic acid, aluminum magnesium silicicate and aluminum silicate; (13) purified water, and the like. Additives for use in the above formulations may include, for example, 1) lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide as the diluent; 2) polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polypropylene glycol-poly oxyethylene-block co-polymer, meglumine, calcium citrate, dextrin, pectin and the like as the binder; 3) starch, agar, gelatine powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectic, carboxymethylcellulose/calcium and the like as the disintegrant; 4) magnesium stearate, talc, polyethyleneglycol, silica, condensed plant oil and the like as the lubricant; 5) any colorants whose addition is pharmaceutically acceptable is adequate as the colorant; 6) cocoa powder, menthol, aromatizer, peppermint oil, cinnamon powder as the flavoring agent; 7) antioxidants whose addition is pharmaceutically accepted such as ascorbic acid or alpha-tophenol. Although pharmaceutical compositions adapted for oral administration are most preferable, other pharmaceutical compositions adapted for other routes of administration are not excluded. The SERD such as Elacestrant or solvates (e.g., hydrate) or salts thereof and the PI3K class I inhibitor such as MEN1161 or solvates (e.g., hydrate) or salts thereof for use in the presently disclosed methods can be formulated into a pharmaceutical composition comprising a physiologically acceptable carrier (also referred to as a pharmaceutically acceptable carrier or solution or diluent) adapted for any administrative route. Such compositions are prepared in accordance with acceptable pharmaceutical procedures such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference. The term “pharmaceutically acceptable carrier” refers to a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered and are compatible with the other ingredients in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices. For example, solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent. Dosages and dosage forms of the components of the pharmaceutical combination The SERD such as Elacestrant (RAD1901) or solvates (e.g., hydrate) or salts thereof and the PI3K class I inhibitor such as MEN1161 for use in the presently disclosed methods can be formulated into unitary dosage forms, meaning physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times q.d.). When multiple daily doses are used, the unit dosage form can be the same or different for each dose. In certain embodiments, the compounds may be formulated for controlled or delayed release. The typical dosage of PI3K inhibitor of formula I effective for a patient in case of oral preparation preferably is from 0.1 to 1000 mg and more preferably from 1 to 100 mg, per kg of body weight daily. Preferred dosages are from 1 to 10 mg/Kg for example 3, 4, 5, 6, 7, 8 or 9 mg/Kg body weight. In some embodiments, the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from 1 to 10 mg/Kg body weight. In some embodiments, the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from 5 to 7 mg/Kg body weight. In some embodiments, the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor of 3, 4, 5, 6, 7, 8 or 9 mg/Kg body weight. In some embodiments, the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD from about 10 to about 100 mg/Kg body weight. In some embodiments, the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD from about 10 to about 40 mg/Kg body weight. In some embodiments, the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD from about 50 to about 100 mg/Kg body weight. In some embodiments, the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD of about 30 mg/Kg body weight, or about 60 mg/Kg body weight. The dosages of the PI3K inhibitor as well as of the SERD can be suitably modified based upon symptoms, age, body weight, relative health state, presence of other drugs, administration route and the like. Methods of treatment, dosages, and administration routes In one aspect, the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering to the patient a pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use. In some embodiments, the SERD is suitable for oral administration. In some embodiments, the SERD is suitable for oral administration. In some embodiments, the PI3K and PI3K class I inhibitor class I inhibitor are suitable for oral administration. In some embodiments, the pharmaceutical combination of any one of the preceding claims, wherein component (a) and/or (b) are each formulated as pharmaceutical compositions adapted for oral administration. In another aspect, the present disclosure relates to a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor. In another aspect, the present disclosure relates to a pharmaceutical composition for use in a method of treating a patient suffering from a cancer, comprising administering a pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor. In another aspect, the present disclosure relates to a pharmaceutical composition for use in a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor. In another aspect, the present disclosure relates to use of a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor in the preparation of a medicament for treating a cancer in a subject, wherein the use comprises administering to the subject a therapeutically effective amount of the SERD and the PI3K class I inhibitor. In some embodiments, the first and second pharmaceutical composition are administered simultaneously. In some embodiments, wherein the first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD) is administered prior to, during, or after the second pharmaceutical composition a PI3K class I inhibitor. As used herein, "treatment" refers to clinical intervention in an attempt to alter the natural course of the subject or cell being treated, and may be performed for prophylactic purposes or during clinical pathology. Desirable therapeutic effects include prevention of onset or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or slowing of the disease state, and remission or improved prognosis. In some embodiments, the development of a disease or disorder is delayed using a pharmaceutical composition of the invention. “Inhibiting growth” of a tumor or cancer cells as used herein may refer to slowing the rate of tumor or cancer cell growth, or halting tumor or cancer cell growth entirely. The terms "individual (individual)", "subject", or “patient” are used interchangeably herein. In some embodiments the patient or subject is a vertabrate. In certain embodiments, the vertebrate is a mammal. The term "mammal" for therapeutic purposes refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc. In certain embodiments, the mammal is a human. Hence, the subject or patient may include, but is not limited to, farm animals (such as cattle), sport animals, pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the subject or patient is human. As used herein, "tumor" refers to the growth and proliferation of all neoplastic cells (malignant or benign), and all precancerous and cancerous cells and tissues. As referred to herein, the terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder" and "tumor" are not mutually exclusive. The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation. Examples of cancer include, but are not limited to, carcinoma, lymphoma (such as Hodgkin's lymphoma and non-Hodgkin's lymphoma), blastoma, sarcoma, and leukemia. More specific examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, leukemia, and other lymphoproliferative disorders, as well as various types of head and neck cancer. In preferred embodiments, the patient is suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer, and even more preferable, the cancer is breast cancer. In some embodiments, the breast cancer is Hormone receptor-positive and HER2- negative (HR+/HER2-) breast cancer. In some embodiments, the breast cancer is estrogen receport prositive (ER+) and HER2 negative (ER+/HER2-). In some embodiments, the breast cancer comprises PI3KCA mutations. In some embodiments, the breast cancer is resistant to endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or resistant to CDK4/6 inhibitors. In some embodiments, the breast cancer is advanced or metastatic. “Tumor regression” or “regression” of an tumor (e.g. HR-/HER2+ tumor) as used herein may refer to reducing the size or maximum size of a tumor. Tumor size can be determined by bioluminescence as shown in the working examples herein. Other methods of monitor tumor regression includes gene profiling. In certain embodiments, the methods of tumor growth inhibition or tumor regression provided herein further comprise gene profiling the subject, wherein the gene to be profiled is one or more genes selected from the group consisting of ABL1, AKT1, AKT2, ALK, APC, AR, ARID1A, ASXL1, ATM, AURKA, BAP, BAP1, BCL2L11, BCR, BRAF, BRCA1, BRCA2, CCND1, CCND2, CCND3, CCNE1, CDH1, CDK4, CDK6, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CEBPA, CTNNB1, DDR2, DNMT3A, E2F3, EGFR, EML4, EPHB2, ERBB2, ERBB3, ESR1, EWSR1, FBXW7, FGF4, FGFR1, FGFR2, FGFR3, FLT3, FRS2, HIF1A, HRAS, IDH1, IDH2, IGF1R, JAK2, KDM6A, KDR, KIF5B, KIT, KRAS, LRP1B, MAP2K1, MAP2K4, MCL1, MDM2, MDM4, MET, MGMT, MLL, MPL, MSH6, MTOR, MYC, NF1, NF2, NKX2-1, NOTCH1, NPM, NRAS, PDGFRA, PIK3CA, PIK3R1, PML, PTEN, PTPRD, RARA, RB1, RET, RICTOR, ROS1, RPTOR, RUNX1, SMAD4, SMARCA4, SOX2, STK11, TET2, TP53, TSC1, TSC2, and VHL. In some embodiments, this invention provides a method of treating a subpopulation of breast cancer patients wherein said sub-population has increased expression of one or more of the genes disclosed supra, and treating said sub-population with an effective dose of a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof according to the dosing embodiments as described in this disclosure. In certain embodiments, administration of a combination as described herein, or solvates (e.g., hydrate) or salts thereof may result in a decrease in tumor size versus baseline (i.e., size prior to initiation of treatment), or even eradication or partial eradication of a tumor. Accordingly, in certain embodiments the methods of tumor regression provided herein may be alternatively characterized as methods of reducing tumor size versus baseline Although both the SERD Elacestrant and the PI3K class I inhibitor MEN1611 can individual inhibit tumor growth, it was surprising discovered that the combination of Elacestrant and MEN1611 synergistically inhibited tumor growth in breast cancer models that are resistant to or progresses over a first line therapy as shown in the working examples herein. Moreover, no toxicity, in terms of body weight changes or death events, was observed in any group treated with the combination of Elacestrant and MEN1611. See working example 2. In particular, the combination, compositions and methods disclosed herein were surprisingly effective in inhibiting tumor growth of: ^ the breast cancer ER+/HER2- PDX model HBCx-3 that is resistant to or progressed over a prior treatment with Palbociclib and Fulvestrant and harbors the mutation P246 fs8aa in the PTEN gene (see Fig. 2); ^ the breast cancer ER+/HER2- PDX model CTG-2308 that is resistant to or progressed over a prior treatment with Palbociclib, and Fulvestrant (Fig. 3); ^ the breast cancer ER+/HER2- PDX model CTG-1260 is resistant to or progressed over a prior treatment with Palbociclib and Fulvestrant, and it harbors the double mutations D350H and H1047R in the PIK3CA gene, and the D538G mutation in ESR1 gene (Fig. 4); and ^ the breast cancer ER+/HER2-cell-derived xenograft model MCF7 red F-luc harbors the E545K mutation in the PIK3CA gene (Fig. 5). The methods and compositions disclosed herein are particularly useful for treating hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer, preferably Estrogen receport positive and HER2-negative (ER+/HER2-) breast cancer, but are not limited to treating this type of cancer. In some embodiments, the methods and compositions disclosed herein can treat a patient suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer. Examples of cancer treated with the combinations of the present invention include solid tumors, whereas examples of solid tumors include breast cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer and non-small cell lung cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the breast cancer is Hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer, preferably Estrogen receport positive and HER2-negative (ER+/HER2-) breast cancer. In some embodiments, the breast cancer comprises PI3KCA mutations. In some embodiments, the breast cancer is resistant to or progressed over a previous treatment with: endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or resistant to CDK4/6 inhibitors. In some embodiments, the breast cancer is advanced or metastatic. In those embodiments where the patient has a tumor located in the breast, the tumor may be associated with luminal breast cancer that may or may not be positive for HER2, and for HER2+ tumors, the tumors may express high or low HER2. In other embodiments, the patient has a tumor located in another tissue or organ (e.g., bone, muscle, brain), but is nonetheless associated with breast, uterine, ovarian, or pituitary cancer (e.g., tumors derived from migration or metastasis of breast, uterine, ovarian, or pituitary cancer). Accordingly, in certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, the tumor being targeted is a metastatic tumor and/or the tumor has an overexpression of ER in other organs (e.g., bones and/or muscles). In certain embodiments, the tumor being targeted is a brain tumor and/or cancer. In certain embodiments, the tumor being targeted is more sensitive to a treatment of RAD1901 and a PI3K class I inhibitor than treatment with another SERD (e.g., fulvestrant, TAS-108 (SR16234), ZK191703, RU58668, GDC-0810 (ARN-810), GW5638/DPC974, SRN-927, ICI182782 and AZD9496), Her2 inhibitors (e.g., trastuzumab, lapatinib, ado- trastuzumab emtansine, and/or pertuzumab), chemo therapy (e.g., abraxane, adriamycin, carboplatin, cytoxan, daunorubicin, doxil, ellence, fluorouracil, gemzar, helaven, lxempra, methotrexate, mitomycin, micoxantrone, navelbine, taxol, taxotere, thiotepa, vincristine, and xeloda), aromatase inhibitor (e.g., anastrozole, exemestane, and letrozole), selective estrogen receptor modulators (e.g., tamoxifen, raloxifene, lasofoxifene, and/or toremifene), angiogenesis inhibitor (e.g., bevacizumab), and/or rituximab. In another aspect of the tumor growth inhibition or tumor regression methods provided herein, the methods further comprise a step of determining whether a patient has a tumor expressing ERα, HR, and/or HER2 prior to administering a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof. In certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, the methods further comprise a step of determining whether the patient has a tumor expressing mutant ERα prior to administering a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof. In certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, the methods further comprise a step of determining whether a patient has a tumor expressing ERα, HR, or HER2 that is responsive or non-responsive to fulvestrant treatment prior to administering a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof. These determinations may be made using any method of expression detection known in the art, and may be performed in vitro using a tumor or tissue sample removed from the subject. In some embodiments, methods are provided herein for inhibiting growth or producing regression of a tumor that is positive for ERα having one or more mutants within the ligand-binding domain (LBD), selected from the group consisting of Y537X1 wherein X1 is S, N, or C, D538G, L536X2 wherein X2 is R or Q, P535H, V534E, S463P, V3921, E380Q, especially Y537S ERα, in a subject with cancer by administering to the subject a therapeutically effective amount of a combination of MEN1611 and RAD1901 or solvates (e.g., hydrate) or salts thereof. “Mutant ERα” as used herein refers to ERα comprising one or more substitutions or deletions, and variants thereof comprising, consisting of, or consisting essentially of an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or at least 99.5% identity to the amino acid sequence of wild type ERα. RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 or solvates (e.g., hydrate) or salts thereof are administered in combination to a subject in need. The phrase “in combination” means RAD1901 or solvates (e.g., hydrate) or salts thereof may be administered before, during, simultaneously, or after the administration of MEN1611. For example, RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 can be administered in about one week apart, about 6 days apart, about 5 days apart, about 4 days apart, about 3 days apart, about 2 days apart, about 24 hours apart, about 23 hours apart, about 22 hours apart, about 21 hours apart, about 20 hours apart, about 19 hours apart, about 18 hours apart, about 17 hours apart, about 16 hours apart, about 15 hours apart, about 14 hours apart, about 13 hours apart, about 12 hours apart, about 11 hours apart, about 10 hours apart, about 9 hours apart, about 8 hours apart, about 7 hours apart, about 6 hours apart, about 5 hours apart, about 4 hours apart, about 3 hours apart, about 2 hours apart, about 1 hour apart, about 55 minutes apart, about 50 minutes apart, about 45 minutes apart, about 40 minutes apart, about 35 minutes apart, about 30 minutes apart, about 25 minutes apart, about 20 minutes apart, about 15 minutes apart, about 10 minutes apart, or about 5 minutes apart. In other embodiments RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 or solvates (e.g., hydrate) or salts thereof are administered to the subject simultaneously or substantially simultaneously. In certain of these embodiments, RAD1901 or solvates (e.g., hydrate) or salts thereof and MEN1611 or solvates (e.g., hydrate) or salts thereof may be administered as part of a single formulation. A therapeutically effective amount of a combination of MEN1611 or solvates (e.g., hydrate) or salts thereof and RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein is an amount that, when administered over a particular time interval, results in achievement of one or more therapeutic benchmarks (e.g., slowing or halting of tumor growth, resulting in tumor regression, cessation of symptoms, etc.). The combination for use in the presently disclosed methods may be administered to a subject one time or multiple times. In those embodiments wherein the compounds are administered multiple times, they may be administered at a set interval, e.g., daily, every other day, weekly, or monthly. Alternatively, they can be administered at an irregular interval, for example on an as-needed basis based on symptoms, patient health, and the like. A therapeutically effective amount of the combination may be administered for one day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 50 days, at least 55 days, at least 60 days, at least 65 days, at least 70 days, at least 75 days, at least 80 days, at least 85 days, or at least 90 days. A therapeutically effective amount of the combination may be administered for from one day to 90 days, from one day to 7, from 7 days to 14 days, from 14 days to 21 days, from 7 days to 28 days, from 14 days to 36 days, from 21 days to 36 days, from 36 days to 48 days, from 32 days to 58 days, from 48 days to 60 days, from 36 days to 80 days, from 7 days to 90 days, from 14 days to 90 days, from 21 days to 90 days, from 42 days to 90 days, or from one day to 28 days, from one day to 21 days. A therapeutically effective amount of the combination may be administered for from one month to three month, from two months to four months, from one month to six months, from one month to twelve months, or for more than a year. In other embodiments, the therapeutically effective amount of the combination may be administered for one week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 10 weeks, or at least 15 weeks. In other embodiments, the therapeutically effective amount of the combination may be administered for one to five weeks, one to six weeks, one to seven weeks, two to five weeks, two to six weeks, three to six weeks, or four to eight weeks. Optionally, the status of the cancer or the regression of the tumor is monitored during or after the treatment, for example, by a FES- PET scan of the subject. The dosage of the combination administered to the subject can be increased or decreased depending on the status of the cancer or the regression of the tumor detected. In some embodiments, the pharmaceutical combinations disclosed herein are administered once daily. In some embodiments, the PI3K class I inhibitor can be administered once a day for 7, 10, 12, 15 or 20 days (qldx7, 10, 12, 15 o 20), and the SERD can be administered according to an identical or different regime, but on alternate days with respect to the PI3K class I inhibitor. For example the first section will include a number of unitary doses (tablets, capsules, etc) sufficient for the daily administration for a period ranging from 7 to 40 days or from 10 to 30 days or from 12 to 20 days (qldx7-40 or qldx 10- 30 or qldx 12-20). The second section will include unitary doses sufficient for one administration or daily or weekly or bi-weekly or monthly administration for a period, according to prescription, overlapped to the period of treatment with the first medicament. For example by starting the two overlapped treatments on the same day 1, the second medicament could be subsequently administered every 4, 5, 7, 10 or 12 days. When the second medicament is an antibody usually a limited number (2-4) of administrations are sufficient for a complete cycle. In some embodiments, SERD is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period. In some embodiments, the PI3K class I inhibitor is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period. The first time period may be for one day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 55 days, at least about 56 days, at least about 57 days, at least about 58 days, at least about 59 days, at least about 60 days, or at least about 65 days. The first time period may be for about 1 to about 7 days, about 1- about 14 days, about 1- about 90 days, about 7- about 14 days, about 14- about 21 days, about 14- about 28 days, about 21- about 36 days, about 21- about 42 days, about 7- about 90 days or about 14- about 90 days or about 21- about 90 days, or about 42- about 90 days. Similarly, the second time period may be for about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 55 days, at least about 56 days, at least about 57 days, at least about 58 days, at least about 59 days, at least about 60 days, or at least about 65 days. The second time period may be for about 1 to about 7 days, about 1- about 14 days, about 1- about 90 days, about 7- about 14 days, about 14- about 21 days, about 14- about 28 days, about 21- about 36 days, about 21- about 42 days, about 7- about 90 days or about 14- about 90 days or about 21- about 90 days, or about 42- about 90 days. The "therapeutically effective amount" or “effective amount” of a substance/molecule such as RAD1901 or MEN1611 of the invention may vary depending on factors such as: the disease state, age, sex and weight of the individual, and the ability of the substance/molecule to induce a desired response in the individual. A therapeutically effective amount is also an amount that has a therapeutically beneficial effect over any toxic or detrimental effect of the substance/molecule. A "prophylactically effective amount" refers to an amount of dosage and time necessary to effectively achieve the desired prophylactic result. Since prophylactic doses are used in individuals prior to or early in the disease, the prophylactically effective amount is typically (but not necessarily) less than the therapeutically effective amount. In a preferred embodiment, the therapeutically effective amount does not exceed the maximum tolerated dosage at which 50% or more of treated subjects experience nausea or other toxicity reactions that prevent further drug administrations. A therapeutically effective amount may vary for a subject depending on a variety of factors, including variety and extent of the symptoms, sex, age, body weight, or general health of the subject, administration mode and salt or solvate type, variation in susceptibility to the drug, the specific type of the disease, and the like. In certain embodiments, treatment can be paused due to illness, adverse event, etc., and is resumed upon resolution, reduction or amelioration of such illness, adverse event, etc. In some embodiments, a therapeutically effective amount of the SERD is administered to the patient. In some embodiments, the therapeutically effective amount comprises from about 1 to about 10 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 5 to about 15mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 10 to about 100 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 10 to about 40 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 0.1 to about 1, from about 10 to about 15, about 5 to about 10, about 10 to about 25, or about 30 to 50 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 50 to about 150 mg, about 100 to about 200 mg, about 250 to about 500 mg, or about 300 to about 600 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises from about 50 to about 100 mg/Kg body weight. In some embodiments, the therapeutically effective amount comprises about 30 mg/Kg body weight, or about 60 mg/Kg body weight. In certain embodiments, the dosage of RAD1901 or solvates (e.g., hydrate) or salts thereof in a combination with MEN1611 or solvates (e.g., hydrate) or salts thereof for use in the presently disclosed methods general for an adult subject may be approximately 30 mg to 2,000 mg, 100 mg to 1,500 mg, or 150 mg to 1,500 mg p.o., q.d. This daily dosage may be achieved via a single administration or multiple administrations Further examples of therapeutically effective amounts of a RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein include, without limitation, about 150 to about 1,500 mg, about 200 to about 1,500 mg, about 250 to about 1,500 mg, or about 300 to about 1,500 mg dosage q.d. In some embodiments, the therapeutically effective amounts of a RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein include, without limitation, from about 50 to about 150 mg, from about 300 to about 500 mg, about 300 to about 550 mg, about 300 to about 600 mg, about 250 to about 500 mg, about 250 to about 550 mg, about 250 to about 600 mg, about 200 to about 500 mg, about 200 to about 550 mg, about 200 to about 600 mg, about 150 to about 500 mg, about 150 to about 550 mg, or about 150 to about 600 mg q.d. dosage. In certain embodiments, the dosage of a compound of Formula II (e.g., RAD1901) or a salt or solvate thereof for use in the presently disclosed methods general for an adult subject may be about 10 mg, about 50 mg, about 100 mg, about 150 mg, 200 mg, about 400 mg, about 30 mg to about 2,000 mg, about 100 mg to about 1,500 mg, or about 150 mg to about 1,500 mg p.o., q.d. This daily dosage may be achieved via a single administration or multiple administrations. In some preferable embodiments, RAD1901 (Elacestrant) is used at a dosage of 800 mg/day, 700 mg/day, 600 mg/day, 500 mg/day, 400 mg/day, 300 mg/day, 200 mg/day, 100 mg/day, or 50 mg/day. In some preferable embodiments, RAD1901 (Elacestrant) is used at a dosage of 50 to 800 mg/day. In some preferable embodiments, RAD1901 (Elacestrant) is used at a dosage of 100 to 500 mg/day. Most preferably, RAD1901 (Elacestrant) is used at a dosage of 400 mg/day. The typical dosage of PI3K inhibitor of formula I effective for a patient in case of oral preparation preferably is from about 0.1 to about 1, from about 0.1 to 1000 mg and more, or from 1 to 100 mg, per kg of body weight daily. Preferred dosages are from 1 to 10 mg/Kg for example 3, 4, 5, 6, 7, 8 or 9 mg/Kg body weight. In particular, daily dosages from about 40 mg/day to about 100 mg/day are administered. In one embodiment, two 48-mg capsules daily (total 96 mg daily) are administered. In case of parental administration, the typical effective quantity preferably is from about 0.1 to about 1000 mg and more preferably from about 1 to about 100 mg per kg of body weight daily. In some embodiments, a therapeutically effective amount of the PI3K class I inhibitor is administered to the patient. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises from about 1 to about 10 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises from about 5 to about 7 mg/Kg body weight, or preferably about 6.5 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises from about 0.1 to about 0.5, from about 1 to about 5, about 2 to about 7, about 6 to about 12, about 7 to about 12, about 8 to about 12, about 9 to about 15, about 10 to about 15, or about 11 to about 15 mg/Kg body weight. In some embodiments, the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from 10 to 100 mg. In some embodiments, the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor of about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, or about 22 mg. Most preferably, the pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor of about 16 mg. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises from about 50 to about 150 mg/day, or preferably about 96 mg/day. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises from about 60, about 64, about 68, about 72, about 76, about 80, about 84, about 88, about 92, about 96, about 100, about 104, about 108, or about 112 mg/day. Most preferably, the therapeutically effective amount of the PI3K class I inhibitor comprises about 96 mg/day. The dose can be adjusted by monitoring tumor growth as described elsewhere herein. In some embodiments, the dose can be adjusted by measuring effects of the SERD on estradiol-ER binding. In some embodiments, the therapeutically effective amount of the SERD is determined based on monitoring binding of estradioal to the estrogen-receptor-alpha (ERα). In these methods, estradiol-ER binding can serve as a proxy for tumor growth inhibition, or a supplemental means of evaluating growth inhibition. If estradiol-ER binding is not affected or exhibits a decrease below a predetermined threshold (e.g., a decrease in binding versus baseline of less than 5%, less than 10%, less than 20%, less than 30%, or less than 50%), the first dosage is deemed to be too low. In other embodiments, the dosage can be adjusted by measuring PI3K activity or downstream effects of the PI3K signaling pathway. In these methods, PI3K activity can serve as a proxy for tumor growth inhibition, or a supplemental means of evaluating growth inhibition. In certain embodiments, these methods comprise an additional step of administering an increased second dosage of the compounds (e.g. the SERD or the PI3K class I inhibitor). Hence, the methods herein includes a method comprising a) administering a first dosage of the SERD, measuring estradiol-ER binding, and if estradiol-ER binding is detectable or above a threshold, then increase the first dosage to a second dosage; b) administering a first dosage of the PI3K class I inhibitor, measuring PI3K activity, and if PI3K activity is detectable or above a threshold, then increase the first dosage to a second dosage; optionally repeat steps a and b to optimize the dosage of the SERD and the PI3K class I inhibitor, thereby determine the optimal dosage of the SERD and the PI3K class I inhibitor. Another aspect of the invention relates to a pharmaceutical composition comprising RAD1901 or solvates (e.g., hydrate) or salts thereof and/or MEN1611 or solvates (e.g., hydrate) or salts thereof in a therapeutically effective amount as disclosed herein for the combination methods set forth herein. Kits An additional embodiment of the invention consists in a kit of parts, that is a package ready for use containing in a first section the first medicament that is the PI3K class I inhibitor of formula I, in a second section the second medicament that is the SERD, and a package leaflet with instructions for the combined, contemporary, consecutive or alternated administration of the two medicaments. The kit comprises a number of mono-doses of the first and the second medicament required and sufficient for a complete treatment cycle. In particular the first section will include a blister of mono-doses of the first medicament for oral administration, for example tablets, stiff or soft capsules or phials of lyophilised medicament or powder sachets or granulate sufficient for a complete cycle, whereas the second section will equally include blisters or phials or sachets, as in the first section, including the second medicament for oral use or phials including the solution or phials including the lyophilizate of the second medicament for parental use. In case of lyophilised formulations of the first or the second medicament the respective sections will include the required disposable amounts of the solvent suitable to bring the lyophilizate back to solution. In some embodiments, the present disclosure relates to a kit comprising a pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor as described elsewhere herein. In some embodiments, the present disclosure relates to a kit comprising a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor. The kits disclosed herein may further comprise the following embodiments: In some embodiments, the first and second pharmaceutical composition are administered simultaneously. In some embodiments, wherein the first pharmaceutical composition is administered prior to, during, or after the second pharmaceutical composition. In some embodiments, the patient is suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer. In some embodiments, the cancer is a breast cancer. In some embodiments, the breast cancer is Hormone receptor-positive and HER2- negative (HR+/HER2-) breast cancer, preferably Estrogen receport positive and HER2- negative (ER+/HER2-) breast cancer. In some embodiments, the breast cancer comprises PI3KCA mutations. In some embodiments, the breast cancer is resistant to or progressed over a previous treatment with: endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or CDK4/6 inhibitors. In some embodiments, the breast cancer is advanced or metastatic. In some embodiments, SERD is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period. In some embodiments, the PI3K class I inhibitor is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period. In some embodiments, a therapeutically effective amount of the SERD is administered to the patient. In some embodiments, both the first and the second pharmaceutical compositions are adapted for oral administration. In some embodiments, the second pharmaceutical composition comprising a PI3K class I inhibitor is adapted for oral administration, and comprises hypromellose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. In some embodiments, the therapeutically effective amount of the SERD comprises from about 10 to about 100 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD comprises from about 10 to about 40 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD comprises from about 50 to about 100 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD comprises about 30 mg/Kg body weight, or about 60 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the SERD is determined based on monitoring binding of estradioal to the estrogen-receptor-alpha (ERα). In some embodiments, the PI3K class I inhibitor comprises 5-(7-methanesulfonyl-2- morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or a pharmaceutically acceptable salt thereof. In some embodiments, the PI3K class I inhibitor comprises a 2-morpholin-4-yl-6,7- dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro- pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof. In some embodiments, PI3K class I inhibitor is a PI3K class Ia inhibitor. In some embodiments, a therapeutically effective amount of the PI3K class I inhibitor is administered to the patient. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises from about 1 to about 10 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor comprises from about 5 to about 7 mg/Kg body weight, or preferably about 6.5 mg/Kg body weight. In some embodiments, the therapeutically effective amount of the PI3K class I inhibitor is determined based on monitoring PI3K activity. In some embodiments, the first and/or the second pharmaceutical composition are adapted for oral administration. In some embodiments, wherein the first pharmaceutical composition provides a delayed release of the SERD. In some embodiments, the first pharmaceutical composition provides a delayed release of the SERD. In some embodiments, the second pharmaceutical composition provides a delayed release of the PI3K class I inhibitor. In some embodiments, the first and/or the second pharmaceutical composition is administered once daily. In some embodiments, the patient is a mammal. In some embodiments, the patient is human. Definitions As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art and which are not otherwise defined herein, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term. As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a” component includes embodiments having two or more such components, unless the context clearly indicates otherwise. Also, the word “or” when used without a preceding “either” (or other similar language indicating that “or” is unequivocally meant to be exclusive – e.g., only one of x or y, etc.) shall be interpreted to be inclusive (e.g., “x or y” means one or both x or y). The term “and/or” shall also be interpreted to be inclusive (e.g., “x and/or y” means one or both x or y). In situations where “and/or” or “or” are used as a conjunction for a group of three or more items, the group should be interpreted to include one item alone, all the items together, or any combination or number of the items. Moreover, terms used in the specification and claims such as have, having, include, and including should be construed to be synonymous with the terms comprise and comprising. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. As a non-limiting example, a reference to “X and/or Y” may refer, in one embodiment, to X only (optionally including elements other than Y); in some embodiments, to Y only (optionally including elements other than X); in yet some embodiments, to both X and Y (optionally including other elements). As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof, inclusive of the endpoints. As such, all disclosed ranges are to be understood to encompass and provide support for claims that recite any and all subranges or any and all individual values subsumed by each range. For example, a stated range of 1 to 10 should be considered to include and provide support for claims that recite any and all subranges or individual values that are between and/or inclusive of the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more and ending with a maximum value of 10 or less (e.g., 5.5 to 10, 2.34 to 3.56, and so forth) or any values from 1 to 10 (e.g., 3, 5.8, 9.9994, and so forth). Any listed range may be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein may be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which may be subsequently broken down into subranges as discussed herein. Further, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 layers refers to groups having 1, 2, or 3 layers. Similarly, a group having 1-5 layers refers to groups having 1, 2, 3, 4, or 5 layers, and so forth. The embodiments illustratively disclosed herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified. The term "inhibit" or its grammatical equivalent, such as "inhibiting," is not intended to require complete reduction in biological activity of a target (e.g., PI3K or SERD). Such reduction is preferably by at least about 50%, at least about 75%, at least about 90%, and more preferably by at least about 95% of the activity of the molecule in the absence of the inhibitory effect, e.g., in the absence of an inhibitor, such as a SERD or PI3K inhibitor disclosed in the invention. More preferably, the term refers to an observable or measurable reduction in activity. In treatment scenarios, preferably the inhibition is required to produce a therapeutic benefit in the condition being treated (e.g., cancer). Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure. WORKING EXAMPLES The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention. It will be understood that many variations can be made in the procedures herein described while still remaining within the bounds of the present invention. It is the intention of the inventors that such variations are included within the scope of the invention. Materials and methods Preparation of the active agents The PI3K class I inhibitor MEN1611 was synthesized by MENARINI RICERCHE SPA Pisa. For in vitro studies, the powder was dissolved in DMSO. For in vivo studies, the powder was dissolved in a DMSO/Cremophor EL solution (50%/50% v/v), divided into aliquots and stored at 4°C until use. MEN1611 stock solution at 6.5 mg/ml was prepared by dissolving hydroxypropyl-beta cyclodextrin (HPCD) and polyethylene Glycol 400 in distilled water as 10% (w/v) and 10% (v/v) respectively (formulation media). The solution was stored at 4°C for a maximum of 6 months. MEN1611 stock solution was diluted 10-fold in formulation media to obtain the dosing solution at 0,65 mg/ml. Elacestrant (RAD1901) was obtained by MENARINI RICERCHE SPA Pisa. For in vitro studies, the powder was dissolved in a DMSO. For in vivo studies, the powder was dissolved in a 0.5% solution of carboxymethylcellulose Animal studies In vivo study on the breast cancer PDX model was performed at XenTech. The authorization to use animals in the CERFE facility was obtained by The Direction Départementale de la Protection des Populations, Ministère de l'Agriculture et de l'Alimentation,France "Direction of the Veterinarìan Services, Ministry of Agriculture and Food, France" (agreement No. D-91-228-107). In vivo study on the breast cancer PDX model was performed by transplanting tumor fragments from the patient subcutaneously into immunocompromised mice. The breast tumor-bearing mice received estrogen diluted in drinking water (3-oestradiol, 8.5 mg/l) from the date of tumor implant to the end of the study. The tumor growth was evaluated by measuring tumor diameters with a caliper by using the following formula: [length (mm) × width2 (mm) × d]/2. The weight of the mice was monitored during the study. The treatment was started when the tumor masses achieved an average volume of 150-200 mm3. Treatment effectiveness was assessed as TVI% in treated versus control mice. TVI is short for tumor volume inhibition percentage. In vivo study on breast cancer PDX model CTG-2308 and CTG-1260 were performed at Champions Oncology. The breast cancer PDX models CTG-2308 and CTG-1260 were obtained by transplanting the tumor fragments from the patient subcutaneously into immunocompromised mice. The tumor growth was evaluated by measuring tumor diameters with a caliper, using the following formula: [length (mm) × width2 (mm) × d]/2 (two times a week). The weight of the mice was monitored during the study. The treatment was started when the tumor masses achieved an average volume of 150-200 mm3. Treatment effectiveness was assessed as TVI% in treated versus control mice. In vivo study on breast cancer cell-derived xenograft MCF7 red F-luc model was performed at Menarini Ricerche. For the breast cancer cell-derived xenograft model, 10 x 106 MCF7 red F-luc cells were re-suspended in 0.2 ml of BME type III (Trevigen) at 5.6 mg/ml, and then injected subcutaneously into the right flank of 6-8 weeks old female CD-1 mice. The MCF7 red F-luc cells are genetically modified to express the luciferase protein, which in presence of its substrate luciferin can generate a bioluminescence signal detected by the in vivo imaging tool IVIS®-CT Spectrum. Thus, the tumor growth can be followed in vivo by measuring bioluminescence signal from the MCF7 red F-luc in the whole animal. The breast tumor-bearing mice were implanted subcutaneously with 17-β estradiol pellet (0.72 mg/pellet), from the date of tumor implant to the end of the study. The tumor growth was followed by measuring the bioluminescence produced by the tumor cells expressed in Total Flux photons per second (p/s). Also the weight of the mice was monitored during the study. The treatment was started when the tumor masses achieved an average bioluminescence signal of 1.96 x107 and 8.1 x 108 p/s. Each group was composed of 5 mice. Treatment effectiveness was assessed as TVI% in treated versus control mice. Determination of Synergy using the Chou-Talalay combination index (Cl- Chou-Talalay combination index Cl). Synergism may be quantified using the Chou-Talalay combination index (CI) (see “Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses”, Zhao L, et al. Clin Cancer Res. (2004) Dec. 1; 10(23):7994-8004; and “Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design”, Chou T C, Motzer R J, Tong Y, Bosl G J., J. Natl. Cancer Inst. (1994) Oct. 19; 86(20):1517-24, Chou TC. Leuk. Lymphoma,2008;49(l l):2059-2080; all incorporated herein in their entirety. The Chou-Talalay combination index (CI) method is based on the multiple drug effect equation derived from the median-effect principle of the mass-action law. Such index provides a quantitative definition of the synergy and in particular: Cl <0.3 designates a strong synergy, 0.3 < Cl <0.9 designates synergy, 0.9 < CI< 1.1 designates an additive effect, and CI> 1.1 designates antagonism. It takes into account both the potency (the D(m) value) and the shape of the dose- effect curve (the m value) of each drug alone and their combination. The Chou-Talalay combination index (CI) may be estimated using the Synergy R package (see “Preclinical versus Clinical Drugs Combination Studies”, Chou T C. Leuk. Lymphoma. (2008); 49(11):2059-2080, and references therein, all of which are specifically incorporated herein by reference). The CI of the combination may be tested in a suitable cell-line, e.g. in MCF7 cells, e.g. under the conditions used in Example 9. according to what designated in Preclinical versus Clinical Drugs Combination Studies. Working Example 1 showed synergistic effect of Elacestrant and MEN1611 in vitro The in vitro antitumor activity of Elacestrant in combination with MEN1611 was investigated in ER+/HER2- breast cancer cell lines. The in vitro cytotoxic activity of the combination Elacestrant and MEN1611 was evaluated in terms of Combination Index (CI) in breast cancer cell line MCF7. The MCF7 cells were treated with Elacestrant and MEN1611 at different concentration as shown in Table 1 below. To determine synergistic effects, the comparative effects of single agent treatments were also measured as shown in Table 2 below.
Table 1: Effects of different combinations of Elacestrant and MEN1611 (ELA is
Figure imgf000052_0001
short for Elacestrant and 1611 is short for MEN1611) Table 2: Effects of single agent treatments The CI value for each of the combinations of Elacestrant and MEN1611 shown in Table 1 was determined based on the inhibitory effects on MCF7 cells of the combinations, and the effects of the single agents as shown in Table 2. The CI values shown in Table 1 were plotted in Fig. 1, and the different combinations of Elacestrant and MEN1611 are indicated with a Figure Ref number as shown in Table 1. As shown in Fig. 1 and Table 1, combining Elacestrant and MEN1611 at different resulted in a synergistic effect, and most of the combinations had a CI < 0.9 indicating synergy. Working Example 2 showed synergistic effect of the combination between Elacestrant and MEN1611 in vivo We evaluated the antitumor activity of MEN1611 in combination with Elacestrant in different breast cancer ER+/HER2- models, resistant to endocrine therapy, aromatase inhibitors, Fulvestrant (ESR selective degrader/modulator), and CDK4/6 inhibitors. The clinically relevant dosages and schedules used for testing MEN1611 and Elacestrant in the breast cancer models are shown in Table 3 below.
Figure imgf000053_0001
Figure imgf000054_0001
Treatment effectiveness was assessed as tumor volume inhibition (TVI%) in treated versus control mice. The breast cancer ER+/HER2- PDX model HBCx-3 is resistant to Palbociclib and Fulvestrant and harbors the mutation P246 fs8aa in the PTEN gene. This breast cancer model was treated with the combination of MEN1611 and Elacestrant as shown in Table 3 above. As shown in Fig. 2, the treatment with both MEN1611 with Elacestrant showed a synergistic effect at the end of the treatment. In particular, the combination treatment showed a 71.7% of TVI compared to vehicle group (combo group vs vehicle group p-value= 0.0005), whereas the MEN1611 and Elacestrant as single agent treatment induced respectively, 56.2% and 48.7% of TVI (MEN1611 group vs vehicle group p-value= 0.002; Elacestrant group vs vehicle group p-value= 0.01) (Fig. 2A-B). The breast cancer ER+/HER2- PDX model CTG-2308 is resistant to endocrine therapy, Palbociclib, and Fulvestrant. This model harbors the mutation E545K in the PIK3CA gene. As shown in Fig. 3, the combination of MEN1611 and Elacestrant showed a synergistic effect at the end of the study. In particular, the combination treatment resulted in 61.4% of TVI compared to vehicle group (combo group vs vehicle group p-value= 0.0002; combo group vs MEN1611 group p-value= 0.008; combo group vs Elacestrant group p-value < 0.0001), whereas the MEN1611 and Elacestrant as single agent treatment induced respectively, 27.2 and 0% of TVI (no statistically differences compare to the vehicle group) (Fig. 3A-B). No toxicity, in terms of body weight changes or death events, was observed in any treated group. The breast cancer ER+/HER2- PDX model CTG-1260 is resistant to Palbociclib and Fulvestrant, and it harbors the double mutations D350H and H1047R in the PIK3CA gene, and the D538G mutation in ESR1 gene. As shown in Fig. 4, treating the CTG-1260 model with the combination of MEN1611 and Elacestrant showed a synergistic effect at the end of the treatment. In particular, the combination treatment resulted in 86.9% of TVI compared to vehicle group (combo group vs vehicle group p-value < 0.0001; combo group vs MEN1611 group p-value= 0.004; combo group vs Elacestrant group p-value < 0.0001), whereas the MEN1611 and Elacestrant as single agent treatment induced, respectively, 63.2 and 52.3% of TVI (MEN1611 group vs vehicle group p-value= 0.0003; Elacestrant group vs vehicle group p-value= 0.005) (Fig. 4). No toxicity, in terms of body weight changes or death events, was observed in any treated group. The breast cancer ER+/HER2-cell-derived xenograft model MCF7 red F-luc harbors the E545K mutation in the PIK3CA gene. Treating this MCF7 xenograft model with the combination of MEN1611 and Elacestrant showed a synergistic effect at the end of the treatment. In particular, the combination treatment resulted in 92% of TVI compared to the vehicle group (combo group vs vehicle group p-value= 0.007; combo group vs MEN1611 group p-value= 0.007), whereas the MEN1611 and Elacestrant as single agent treatment induced, respectively, 50.3% and 67.2% of TVI (Elacestrant group vs vehicle group p-value= 0.03) (Fig. 5). No toxicity, in terms of body weight changes or death events, was observed in any treated group.

Claims

WHAT IS CLAIMED IS: 1. A pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3- kinase (PI3K) class I inhibitor, wherein the components of the pharmaceutical combination are formulated separately or are each formulated into a suitable pharmaceutical composition to allow simultaneous, separate or sequential use.
2. The pharmaceutical combination of claim 1, wherein the SERD is suitable for oral administration.
3. The pharmaceutical combination of claim 1, wherein the SERD is nonsteroidal.
4. The pharmaceutical combination of claim 1, wherein the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical combination of claim 4, wherein the Elacestrant is in the form of a dihydrochloride salt. 6. The pharmaceutical combination of claim 1, comprising an amount of the SERD sufficient for a unitary dosage of the SERD of about 400 mg . 7. The pharmaceutical combination of claim 1, comprising an amount of the SERD sufficient for a unitary dosage of the SERD from about 100 mg to about 500 mg. 8. The pharmaceutical combination of any one of the preceding claims, wherein the PI3K class Ia inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3- d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,
6,
7,
8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
9. The pharmaceutical combination of any one of the preceding claims, wherein the PI3K class Ia inhibitor is suitable for oral administration.
10. The pharmaceutical combination of any one of the preceding claims, wherein the PI3K class Ia inhibitor comprises 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-amine or the pharmaceutically acceptable salt thereof.
11. The pharmaceutical combination of any one of the preceding claims, wherein the PI3K class I inhibitor is selective for PI3K class Ia over PI3K class Id, optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for PI3K class Ia, class Ib, and class Ig over PI3K class Id.
12. The pharmaceutical combination of any one of the preceding claims, comprising an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from about 10 to 100 mg, or preferably about 16 mg.
13. The pharmaceutical combination of any one of the preceding claims, wherein component (a) and/or (b) additionally comprise one or more pharmaceutically-acceptable diluents, excipients or carriers.
14. The pharmaceutical combination of any one of the preceding claims, wherein component (a) and/or (b) are each formulated as pharmaceutical compositions adapted for oral administration.
15. A method of treating a patient suffering from a cancer, comprising administering a therapeutically effective amounts of component (a) and component (b) of a pharmaceutical combination according to any one of claims 1-14.
16. A method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a phosphatidylinositol 3-kinase (PI3K) class I inhibitor.
17. The method of claim 16, wherein the first and second pharmaceutical composition are administered simultaneously.
18. The method of claim 16, wherein the first pharmaceutical composition is administered prior to or after the second pharmaceutical composition.
19. The method of any one of claims 16-18, wherein the patient is suffering from colon cancer, prostate cancer, breast cancer, lung cancer, or ovarian cancer.
20. The method of any one of claims 16-18, wherein the cancer is a breast cancer.
21. The method of claim 20, wherein the breast cancer is Hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer; preferably Estrogen receptor positive and HER2 negative (ER+/HER2-) breast cancer.
22. The method of claims 20 or 21, wherein the breast cancer comprises PI3KCA mutations.
23. The method of any one of claims 20-22, wherein the breast cancer is resistant to or progressed over a previous treatment with: endocrine therapy, an aromatase inhibitor, Fulvestrant, and/or CDK4/6 inhibitors.
24. The method of any one of claims 20-23, wherein the breast cancer is advanced or metastatic.
25. The method of any one of claims 16-24, wherein SERD is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
26. The method of any one of claims 16-25, wherein PI3K class I inhibitor is administered at a first dosage for a first time period, and subsequently, at a second dosage for a second time period.
27. The method of any one of claims 16-26, wherein the SERD is suitable for oral administration.
28. The method of any one of claims 16-27, wherein the SERD is nonsteroidal.
29. The method of any one of claims 16-28, wherein the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof.
30. The method of claim 29, wherein Elacestrant is in the form of a dihydrochloride salt.
31. The method of any one of claims 16-30, wherein both the first and the second pharmaceutical compositions are adapted for oral administration.
32. The method of any one of claims 16-31, wherein the second pharmaceutical composition comprising a PI3K class I inhibitor is adapted for oral administration, and comprises hypromellose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.
33. The method of any one of claims 15-32, wherein the therapeutically effective amount of the SERD comprises about 400 mg/day.
34. The method of any one of claims 15-32, wherein the therapeutically effective amount of the SERD comprises from about 100 mg/day to about 500 mg/day.
35. The method of any one of claims 15-33, wherein the therapeutically effective amount of the SERD is determined based on monitoring binding of estradioal to the estrogen- receptor-alpha (ERα).
36. The method of any one of claims 16-35, wherein the PI3K class I inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4- yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
37. The method of any one of claims 16-35, wherein the PI3K class I inhibitor comprises 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)- pyrimidin-2-amine or the pharmaceutically acceptable salt thereof.
38. The method of any one of claims 16-35, wherein the PI3K class I inhibitor is selective for PI3K class Ia over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id..
39. The method of any one of claims 15-38, wherein the therapeutically effective amount of the PI3K class I inhibitor comprises from about 50 to 150 mg/day, or preferably about 96 mg/day.
40. The method of any one of claims 15-38, wherein the therapeutically effective amount of the PI3K class I inhibitor is determined based on monitoring PI3K activity.
41. The method of any one of claims 16-40, wherein the first and/or the second pharmaceutical composition are adapted for oral administration.
42. The method of any one of claims 16-41, wherein the first pharmaceutical composition provides a delayed release of the SERD.
43. The method of any one of claims 16-42, wherein the second pharmaceutical composition provides a delayed release of the PI3K class I inhibitor.
44. The method of any one of claims 16-43, wherein the first and/or the second pharmaceutical composition is administered once daily.
45. The method of any one of claims 15-44, wherein the patient is a mammal.
46. The method of any one of claims 15-44, wherein the patient is human.
47. A pharmaceutical combination according to any one of claims 1-14 for use in a method of treating a patient suffering from a cancer, wherein components: (a) and (b) are sequentially, simultaneously, separately administered to the patient.
48. A pharmaceutical combination for use in a method of treating a patient suffering from a cancer, comprising administering a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a PI3K class I inhibitor.
49. Use of a selective degrader and modulator of the estrogen receptor (SERD) and a PI3K class I inhibitor in the preparation of a pharmaceutical combination for simultaneous, separate or sequential use for treating a cancer in a subject, wherein the use comprises administering to the subject a therapeutically effective amount of the SERD and the PI3K class I inhibitor.
50. A kit comprising a first pharmaceutical composition comprising a selective degrader and modulator of the estrogen receptor (SERD), and a second pharmaceutical composition comprising a phosphatidylinositol 3-kinase (PI3K) class I inhibitor.
51. The kit of claim 50, wherein the SERD is suitable for oral administration.
52. The kit of any one of the claims 50-51, wherein the SERD is nonsteroidal.
53. The kit of any one of the claims 50-52, wherein the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof.
54. The kit of claim 53, wherein the Elacestrant is in the form of a dihydrochloride salt.
55. The kit of any one of the claims 50-54, wherein the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD of about 400 mg.
56. The kit of any one of the claims 50-55, wherein the first pharmaceutical composition comprises an amount of the SERD sufficient for a unitary dosage of the SERD from about 100 to 500 mg.
57. The kit of any one of the claims 50-56, wherein the PI3K class I inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4- yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
58. The kit of any one of the claims 50-56, wherein the PI3K class I inhibitor comprises 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)- pyrimidin-2-amine or the pharmaceutically acceptable salt thereof.
59. The kit of any one of the claims 50-58, wherein the is selective for PI3K class Ia over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id.
60. The kit of any one of the claims 50-59, wherein the second pharmaceutical composition comprises an amount of the PI3K class I inhibitor sufficient for a unitary dosage of the PI3K class I inhibitor from 10 to 100 mg, or preferably about 16 mg.
61. The kit of any one of the claims 50-60, wherein the first or the second pharmaceutical composition is adapted for oral administration.
62. The kit of any one of claims 50-60, wherein both the first and the second pharmaceutical composition are adapted for oral administration.
63. The kit of any one of claims 50-62, wherein the second pharmaceutical composition comprising a PI3K class I inhibitor is adapted for oral administration, and comprises hypromellose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.
64. The kit of any one of claims 50-63, further comprising instructions for treating a cancer in a subject in need thereof.
65. An oral pharmaceutical combination comprising the following components: (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor, wherein the components of the oral pharmaceutical combination are formulated separately or are each formulated into an oral pharmaceutical composition to allow simultaneous, separate or sequential use.
66. A pharmaceutical composition comprising (a) a selective degrader and modulator of the estrogen receptor (SERD) and (b) a phosphatidylinositol 3-kinase (PI3K) class I inhibitor.
67. The pharmaceutical composition of claim 66, wherein the pharmaceutical composition is adapted for oral administration.
68. The pharmaceutical composition of any one of claims 66-67, wherein the SERD is Elacestrant, or a pharmaceutically acceptable salt thereof, preferably wherein the Elacestrant is in the form of a dihydrochloride salt.
69. The pharmaceutical composition of any one of claims 66-68, wherein the PI3K class Ia inhibitor comprises a 2-morpholin-4-yl-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidine derivative, or a 2-morpholin-4-yl- 5,6,7,8-tetrahydro-pyrrido[2,3-d]pyrimidine derivative or the pharmaceutically acceptable salt thereof.
70. The pharmaceutical composition of any one of claims 66-69, wherein the PI3K class Ia inhibitor comprises 5-(7-methanesulfonyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-4-yl)-pyrimidin-2-amine or the pharmaceutically acceptable salt thereof.
71. The pharmaceutical composition of any one of claims 66-70, wherein the PI3K class I inhibitor is selective for PI3K class Ia over PI3K class Id, optionally wherein the PI3K class I inhibitor is selective for both PI3K class Ia and class Ig over PI3K class Id, or optionally wherein the PI3K class I inhibitor is selective for PI3K class Ia, class Ib, and class Ig over PI3K class Id.
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