US20180214393A1 - Methods for treating cancer - Google Patents

Methods for treating cancer Download PDF

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US20180214393A1
US20180214393A1 US15/794,910 US201715794910A US2018214393A1 US 20180214393 A1 US20180214393 A1 US 20180214393A1 US 201715794910 A US201715794910 A US 201715794910A US 2018214393 A1 US2018214393 A1 US 2018214393A1
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rad1901
everolimus
tumor
treatment
fulvestrant
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Gary Hattersley
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Radius Pharmaceuticals Inc
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Assigned to RADIUS PHARMACEUTICALS, INC. reassignment RADIUS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HATTERSLEY, GARY
Publication of US20180214393A1 publication Critical patent/US20180214393A1/en
Priority to US16/545,859 priority patent/US20200046655A1/en
Assigned to RADIUS PHARMACEUTICALS, INC., RADIUS HEALTH, INC. reassignment RADIUS PHARMACEUTICALS, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MIDCAP FINANCIAL TRUST, MIDCAP FUNDING IV TRUST
Priority to US17/510,050 priority patent/US20220110890A1/en
Priority to US18/511,036 priority patent/US20240091177A1/en
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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
    • A61K31/13—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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

  • Provisional Application No. 62/192,940 filed Jul. 15, 2015, U.S. Provisional Application No. 62/265,658, filed Dec. 10, 2015, and U.S. Provisional Application No. 62/323,572, filed Apr. 15, 2016, U.S. Provisional Application No. 62/192,944, filed Jul. 15, 2015, U.S. Provisional Application No. 62/265,663, filed Dec. 10, 2015, and U.S. Provisional Application No. 62/323,576, filed Apr. 15, 2016, all of which are incorporated herein by reference in their entireties.
  • Breast cancer is divided into three subtypes based on expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Overexpression of ERs is found in many breast cancer patients. ER-positive (ER+) breast cancers comprise two-thirds of all breast cancers. Other than breast cancer, estrogen and ERs are associated with, for example, ovarian cancer, colon cancer, prostate cancer and endometrial cancer.
  • ERs can be activated by estrogen and translocate into the nucleus to bind to DNA, thereby regulating the activity of various genes. See, e.g., Marino et al., “Estrogen Signaling Multiple Pathways to Impact Gene Transcription,” Curr. Genomics 7(8): 497-508 (2006); and Heldring et al., “Estrogen Receptors: How Do They Signal and What Are Their Targets,” Physiol. Rev. 87(3): 905-931 (2007).
  • Agents that inhibit estrogen production such as aromatase inhibitors (AIs, e.g., letrozole, anastrozole and aromasin), or those that directly block ER activity, such as selective estrogen receptor modulators (SERMs, e.g., tamoxifen, toremifene, droloxifene, idoxifene, raloxifene, lasofoxifene, arzoxifene, miproxifene, levormeloxifene, and EM-652 (SCH 57068)) and selective estrogen receptor degraders (SERDs, e.g., fulvestrant, TAS-108 (SR16234), ZK191703, RU58668, GDC-0810 (ARN-810), GW5638/DPC974, SRN-927, ICI182782 and AZD9496), have been used previously or are being developed in the treatment of ER-positive breast cancers.
  • SERMs selective estrogen receptor modulators
  • SERMs e.g., tamoxifen
  • AIs are often used as a first-line adjuvant systemic therapy for ER-positive breast cancer. Tamoxifen is commonly used for ER-positive breast cancer. AIs suppress estrogen production in peripheral tissues by blocking the activity of aromatase, which turns androgen into estrogen in the body. However, AIs cannot stop the ovaries from making estrogen, Thus, AIs are mainly used to treat postmenopausal women. Furthermore, as AIs are much more effective than tamoxifen with fewer serious side effects, AIs may also be used to treat premenopausal women with their ovarian function suppressed. See, e.g., Francis et al., “Adjuvant Ovarian Suppression in Premenopausal Breast Cancer,” N. Engl. J. Med., 372:436-446 (2015).
  • Fulvestrant is currently the only SERD approved for the treatment of ER-positive metastatic breast cancers with disease progression following antiestrogen therapy. Despite its clinical efficacy, the utility of fulvestrant has been limited by the amount of drug that can be administered in a single injection and by reduced bioavailability. Imaging studies using 18F-fluoroestradiol positron emission tomography (FES-PET) suggest that even at the 500 mg dose level, some patients may not have complete ER inhibition, and insufficient dosing may be a reason for therapeutic failure.
  • FES-PET 18F-fluoroestradiol positron emission tomography
  • estrogen-directed therapies may have undesirable effects on uterine, bone, and other tissues.
  • the ER directs transcription of estrogen-responsive genes in a wide variety of tissues and cell types. These effects can be particularly pronounced as endogenous levels of estrogen and other ovarian hormones diminish during menopause.
  • tamoxifen can cause bone thinning in premenopausal women and increase the risk of endometrial cancer because it acts as a partial agonist on the endometrium.
  • AIs can cause more bone loss and more broken bones than tamoxifen. Patients treated with fulvestrant may also be exposed to the risk of osteoporosis due to its mechanism of action.
  • PI3K phosphoinositide 3-kinase
  • AKT protein kinase B
  • mTOR mimerase B pathway
  • the frequent activation of the PI3K/AKT/mTOR pathway in cancer and its crucial role in cell growth and survival provide a challenge in finding an appropriate amount of proliferation versus differentiation in order to utilize this balance in the development of various therapies. See, e.g., Gitto et al., “Recent insights into the pathophysiology of mTOR pathway dysregulation,” Res. Rep. Bio., 2:1-16 (2015).
  • Inhibitors of the PI3K pathway have shown the most promise when given in combination with other therapies.
  • everolimus an allosteric mTOR inhibitor
  • HR+ advanced hormone receptor positive
  • HER2-breast cancer BOLERO-2 study.
  • Agents targeting other components of the PI3K pathway are under development for treating HR+ cancer, e.g., ATP-competitive dual inhibitors of PI3K and mTOR (e.g., BEZ235, GDC-0980), pan-PI3K inhibitors which inhibit all four isoforms of class I PI3K (e.g., BKM120, GDC-0941), isoform-specific inhibitors of the various PI3K isoforms (e.g., BYL719, GDC-0032), allosteric and catalytic inhibitors of AKT (MK2206, GDC-0068, GSK2110183, GSK2141795, AZD5363), and ATP-competitive inhibitors of mTOR only (AZD2014, MLN0128, and CC-223).
  • ATP-competitive dual inhibitors of PI3K and mTOR e.g., BEZ235, GDC-0980
  • One aspect of the invention relates to a method for treating one or more cancers and/or tumors in a subject comprising administering to the subject a therapeutically effective amount of a combination of RAD1901 or solvates (e.g., hydrate) or salts thereof and one or more second therapeutic agent(s) (e.g., everolimus) as described herein.
  • a combination of RAD1901 or solvates e.g., hydrate
  • one or more second therapeutic agent(s) e.g., everolimus
  • the cancer is an estrogen-dependent cancer, such as breast cancer, ovarian cancer, colon cancer, endometrial cancer, or prostate cancer. In some embodiments, the cancer is ER-positive breast cancer.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) are administered in combination to a subject in need.
  • the phrase “in combination” means that RAD1901 or solvates (e.g., hydrate) or salts thereof may be administered before, during, or after the administration of the second therapeutic agent(s) (e.g., everolimus).
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) are administered to the subject simultaneously or substantially simultaneously.
  • the compounds may be administered as part of a single formulation.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) are administered in separate formulations.
  • the formulations may be of the same type.
  • both formulations may be designed for oral administration (e.g., via two separate pills) or for injection (e.g., via two separate injectable formulations).
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) may be formulated in different types of formulations.
  • one compound may be in a formulation designed for oral administration, while the other is in a formulation designed for injection.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) are administered as part of a single formulation.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) are formulated in a single pill for oral administration or in a single dose for injection.
  • formulations comprising RAD1901 or solvates (e.g., hydrate) or salts thereof and one or more second therapeutic agents.
  • Administration routes of RAD1901 or solvates (e.g., hydrate) or salts thereof and/or the second therapeutic agent(s) include but are not limited to topical administration, oral administration, intradermal administration, intramuscular administration, intraperitoneal administration, intravenous administration, intravesical infusion, subcutaneous administration, transdermal administration, and transmucosal administration.
  • FIG. 1 RAD1901 inhibited tumor growth in various patient-derived xenograft (PDx) models regardless of ESR1 status and prior endocrine therapy. Percentage of tumor growth inhibition (TGI) in PDx models treated with RAD1901 is shown.
  • TGI tumor growth inhibition
  • FIGS. 2A-C The combination of RAD1901 and everolimus demonstrated tumor growth inhibition and regression in wild-type (WT) ER ⁇ MCF-7 xenograft models (PR+, HER2 ⁇ ).
  • FIG. 2A Tumor growth of MCF-7 xenograft models treated with vehicle control, everolimus (2.5 mg/kg, p.o., q.d), fulvestrant (3 mg/dose, s.c., qwk), a combination of fulvestrant (3 mg/dose, s.c., qwk) and everolimus (2.5 mg/kg, p.o., q.d), RAD1901 (60 mg/kg, p.o., q.d.), and a combination of RAD1901 (60 mg/kg, p.o., q.d.) and everolimus (2.5 mg/kg, p.o., q.d); One-way ANOVA, “ns” is not significant, *p-way ANOVA
  • FIGS. 3A-B The combination of RAD1901 and everolimus demonstrated tumor growth inhibition and regression in WT ER ⁇ PDx-11 models (PR+, Her2+, previously treated with aromatase inhibitor, fulvestrant, and chemotherapy).
  • 3A Tumor growth of PDx-11 models treated with vehicle control, fulvestrant (3 mg/dose, s.c., qwk), everolimus (2.5 mg/kg, p.o., q.d), RAD1901 (60 mg/kg, p.o., q.d.), and a combination of RAD1901 (60 mg/kg, p.o., q.d.) and everolimus (2.5 mg/kg, p.o., q.d); ( FIG.
  • FIGS. 4A-B The combination of RAD1901 and everolimus demonstrated tumor growth inhibition in WT ER+PDx-2 models (PR+, Her2+, treatment na ⁇ ve).
  • FIG. 4A Tumor growth of PDx-2 models treated with vehicle control, RAD1901 (60 mg/kg, p.o., q.d.), fulvestrant (3 mg/dose, s.c., qwk), and a combination of RAD1901 (60 mg/kg, p.o., q.d.) and fulvestrant (3 mg/dose, s.c., qwk);
  • FIG. 4A Tumor growth of PDx-2 models treated with vehicle control, RAD1901 (60 mg/kg, p.o., q.d.), fulvestrant (3 mg/dose, s.c., qwk);
  • FIG. 4A Tumor growth of PDx-2 models treated with vehicle control, RAD1901 (60 mg/kg, p.o.
  • FIG. 5 Efficacy of RAD1901 sustained at least two months after RAD1901 treatment ended while estradiol treatment continued in WT ER ⁇ PDx-4 models (PR+, Her2+, treatment na ⁇ ve).
  • FIGS. 9A-C A representative image of FES-PET scan of the uterus of a subject treated with 200 and 500 mg RAD1901 p.o., q.d., and change of the ER engagement after the RAD1901 treatments.
  • FIG. 9A Transversal view of uterus CT scan before 200 mg RAD1901 treatment (a) and after (c), and transversal view of uterus FES-PET scan before the RAD1901 treatment (b) and after (d);
  • FIG. 9A Transversal view of uterus CT scan before 200 mg RAD1901 treatment
  • b transversal view of uterus FES-PET scan before the RAD1901 treatment
  • FIG. 9B Sagittal view of uterus CT scan before 500 mg RAD1901 treatment (top (a) panel) and after (bottom (a) panel), sagittal view of uterus FES-PET scan before the RAD1901 treatment (top (b) panel) and after (bottom (b) panel), transversal view of uterus CT scan before the RAD1901 treatment (top (c) panel) and after (bottom (c) panel), transversal view of uterus FES-PET scan before the RAD1901 treatment (top (d) panel) and after (bottom (d) panel);
  • FIG. 9C Sagittal view of uterus CT scan before 500 mg RAD1901 treatment (top (a) panel) and after (bottom (a) panel), sagittal view of uterus FES-PET scan before the RAD1901 treatment (top (b) panel) and after (bottom (b) panel), transversal view of uterus CT scan before the RAD1901 treatment (top (c) panel) and after (bottom (c
  • FIG. 11 PR and ER expression in MCF-7 xenograft models treated with vehicle control, RAD1901, everolimus, a combination of RAD1901 and everolimus, fulvestrant, and a combination of fulvestrant and everolimus.
  • FIGS. 12A-B RAD1901 treatment resulted in complete ER degradation and inhibited ER signaling in MCF-7 cell lines ( FIG. 12A ) and T47D cell lines ( FIG. 12B ) in vitro.
  • the ER expression was shown in both cell lines treated with RAD1901 and fulvestrant at various concentrations of 0.001 ⁇ M, 0.01 ⁇ M, 0.1 ⁇ M and 1 ⁇ M, respectively.
  • ER signaling was shown by three ER target genes tested: PGR, GREB1 and TFF1.
  • FIGS. 14A-C RAD1901 treatment resulted in a rapid decrease in PR in MCF-7 xenograft models.
  • FIG. 14A Western blot showing PR expression in MCF-7 xenograft models treated with vehicle control and RAD1901 at 30, 60, and 90 mg/kg, at 8 hours or 12 hours after single dose
  • FIG. 14B Western blot showing PR expression in MCF-7 xenograft models treated with vehicle control and RAD1901 at 30, 60, and 90 mg/kg, at 4 hours or 24 hours after the 7th dose
  • FIG. 14C Dose-dependent decrease in PR expression in MCF-7 xenograft models treated with RAD1901 at 30, 60, and 90 mg/kg.
  • FIGS. 15A-B RAD1901 treatment resulted in a rapid decrease in proliferation in MCF-7 xenograft models.
  • FIG. 15A A representative photograph of a sectioned tumor harvested from MCF-7 xenograft models treated with vehicle control and RAD1901 at 90 mg/kg, 8 hours after single dose and 24 hours after the 4th dose, stained for proliferation marker Ki-67;
  • FIG. 15B Histogram showing decrease of proliferation marker Ki-67 in MCF-7 xenograft models treated with vehicle control and RAD1901 at 90 mg/kg, 8 hours after single dose and 24 hours after the 4th dose.
  • FIG. 17 RAD1901 treatment at 60 and 120 mg/kg resulted in reduced ER signaling in vivo in PDx-5 models with decreased PR expression.
  • FIG. 19 Plasma pharmacokinetic results of RAD1901 at 200, 500, 750, and 1000 mg/kg after dosing on Day 7.
  • FIG. 21 3ERT (II).
  • FIG. 22 Superimpositions of the ER ⁇ LBD-antagonist complexes summarized in Table 11 .
  • FIGS. 24A-B Modeling of ( FIG. 24A ) RAD1901-1SJ0; and ( FIG. 24B ) E4D-1SJ0.
  • FIGS. 25A-B Modeling of ( FIG. 25A ) RAD1901-2JFA; and ( FIG. 25B ) RAL-2JFA.
  • FIGS. 26A-B Modeling of ( FIG. 26A ) RAD1901-2BJ4; and ( FIG. 26B ) OHT-2BJ4.
  • FIGS. 27A-B Modeling of ( FIG. 27A ) RAD1901-2IOK; and ( FIG. 27B ) IOK-2IOK.
  • FIG. 28 Superimpositions of the RAD1901 conformations resulted from IFD analysis with 1R5K and 2OUZ.
  • FIG. 29 Superimpositions of the RAD1901 conformations resulted from IFD analysis with 2BJ4, and 2JFA.
  • FIGS. 30A-B Superimpositions of the RAD1901 conformations resulted from IFD analysis with 2BJ4, 2JFA and 1SJ0.
  • FIGS. 31A-C IFD of RAD1901 with 2BJ4.
  • FIGS. 32A-C Protein Surface Interactions of RAD1901 docked in 2BJ4 by IFD.
  • FIGS. 33A-C IFD of Fulvestrant with 2BJ4.
  • FIGS. 34A-B IFD of Fulvestrant and RAD1901 with 2BJ4.
  • FIGS. 35A-B Superimposions of IFD of Fulvestrant and RAD1901 with 2BJ4.
  • FIG. 36 RAD1901 in vitro binding assay with ER ⁇ constructs of WT and LBD mutant.
  • ABD apparent bone density
  • BV/TV bone volume density
  • ConnD connectivity density
  • E2 beta estradiol
  • OVX ovariectomized
  • TbN trabecular number
  • TbTh trabecular thickness
  • TbSp trabecular spacing
  • Veh vehicle.
  • RAD1901 and everolimus demonstrated greater tumor growth inhibition than RAD1901 alone in several breast cancer xenograft models, including a wild-type (WT) ER ⁇ MCF-7 xenograft model ( FIGS. 2A-C ), WT ER ⁇ PDx-2 ( FIGS. 4A-B ) and PDx-11 models ( FIGS. 3A-B ), and a mutant (e.g., Y537S) ER ⁇ PDx-5 model ( FIGS. 6A-B ), regardless of ESR1 status, and prior endocrine therapy as described in Example I.
  • WT wild-type
  • ER ⁇ PDx-2 FIGS. 4A-B
  • PDx-11 models FIGS. 3A-B
  • mutant e.g., Y537S
  • PDx-2, PDx-5 and PDx-11 models had tumor expressing WT or mutant (e.g., Y537S) ER ⁇ , with PR expression, with high or low Her2 expression, and with or without prior endocrine therapy (e.g., AI, fulvestrant), and/or chemotherapy (chemo) ( FIG. 1 ).
  • WT or mutant e.g., Y537S
  • PR expression e.g., PR expression
  • Her2 expression e.g., Her2 expression
  • chemo chemotherapy
  • WT or mutant e.g., Y537S
  • PR expression with high or low Her2 expression
  • Her2 inhibitors Her2i, e.g., trastuzumab, lapatinib), bevacizumab, and/or rituximab.
  • ER WT PDx models and ER mutant PDx models may have different level of responsiveness to treatment with fulvestrant alone, everolimus alone, and/or a combination of fulvestrant and everolimus (a ful-everolimus combination).
  • RAD1901-everolimus combinations demonstrated improved tumor growth inhibition and/or tumor regression compared to treatment with RAD1901 alone or everolimus alone, regardless of whether the PDx models were responsive to fulvestrant treatment and/or ful-everolimus combination treatment.
  • RAD1901-everolimus combination may inhibit tumor growth and/or produce tumor regression in fulvestrant resistant cancers.
  • RAD1901-everolimus combination treatment demonstrated improved tumor growth inhibition and/or tumor regression compared to treatment with fulvestrant alone or with the ful-everolimus combination.
  • the RAD1901-everolimus combination caused more significant tumor regression in more WT ER+xenograft models than treatment with fulvestrant alone, RAD1901 alone, or everolimus alone, even though these xenograft models have varied responsiveness to fulvestrant treatment (e.g., MCF-7 cell line xenograft model responsive to fulvestrant treatment ( FIGS. 2A-C ); PDx-11 model responsive to fulvestrant treatment ( FIGS. 3A-B ); and PDx-2 model least responsive to fulvestrant treatment ( FIGS.
  • the RAD1901-everolimus combination also caused more significant tumor regression in more WT ER+MCF-7 cell line xenograft models and PDx-11 models than treatment with a ful-everolimus combination ( FIGS. 2A-C and 3 A-B).
  • the RAD1901-everolimus combination provided similar effects with RAD1901 at a dose of 30 mg/kg or 60 mg/kg, although RAD1901 alone at 30 mg/kg was not as effective as RAD1901 alone at 60 mg/kg in inhibiting tumor growth ( FIG. 2C ).
  • Said results suggest a RAD1901-everolimus combination with a lower dose of RAD1901 (e.g., 30 mg/kg) was sufficient to maximize the tumor growth inhibition/tumor regression effects in said xenograft models.
  • the RAD1901-everolimus combination demonstrated tumor regression or improved tumor growth inhibition in mutant ER+(e.g., Y537S) PDx models hardly responsive to fulvestrant treatment ( FIG. 6A ).
  • PDx-5 is an ER Y537S mutant PDx model (PR+, Her2-, prior treatment with AI) hardly responsive to fulvestrant treatment.
  • RAD1901-everolimus combination demonstrated tumor regression in PDx-5 model, while everolimus alone or RAD1901 alone only inhibited tumor growth without causing tumor regression ( FIG. 6B ).
  • the RAD1901-everolimus combination caused more significant tumor growth inhibition than RAD1901 alone, everolimus alone, or fulvestrant alone in mutant PDx-5 models ( FIG.
  • RAD1901-everolimus combinations provide powerful anti-tumor therapy for ER+breast cancer expressing WT or mutant ER, with PR expression, with high or low Her2 expression, and with or without resistance to fulvestrant.
  • RAD1901 can be delivered to the brain (Example II), and that said delivery improved mouse survival in an intracranial tumor model expressing wild-type ER ⁇ (MCF-7 xenograft model, Example I(B)).
  • Everolimus was approved to treat subependymal giant cell astrocytoma (SEGA), a brain tumor seen with tuberous sclerosis (TS).
  • SEGA subependymal giant cell astrocytoma
  • TS tuberous sclerosis
  • a combination of RAD1901 with other second therapeutic agent(s) that can cross the blood-brain barrier may also have similar therapeutic effects on ER+ tumors in brain.
  • RAD1901 showed sustained efficacy in inhibiting tumor growth after RAD1901 treatment ended while estradiol treatment continued (e.g., PDx-4 model).
  • estradiol treatment continued (e.g., PDx-4 model).
  • a RAD1901-everolimus combination is likely to benefit patients by inhibiting tumor growth after treatment ends, especially when the second therapeutic agent(s) treatment may be discontinued (e.g., 29% for everolimus) or reduced or delayed (70% for everolimus-treated patients) for adverse reactions. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm488028.htm.
  • a RAD1901-everolimus combination is likely to have fewer and/or less severe side-effects than treatment with everolimus alone or a combination of everolimus with other hormone therapies (e.g., AIs such as letrozole and SERDs such as fulvestrant). For example, both AIs and fulvestrant may cause bone loss in treated patients.
  • RAD1901 is unlikely to have similar side effects.
  • RAD1901 was found to preferentially accumulate in tumor, with a RAD1901 level in tumor v. RAD1901 level in plasma (T/P ratio) of up to about 35 (Example II).
  • Standardized uptake values (SUV) for uterus, muscle and bone were calculated for human subjects treated with RAD1901 at a daily dose of about 200 mg up to about 500 mg (Example III(A)).
  • Post-dose uterine signals were close to levels from “non-target tissues” (tissues that do not express estrogen receptor), suggesting a complete attenuation of FES-PET uptake post-RAD1901 treatment. Almost no change was observed in pre-versus post-treatment PET scans in tissues that did not significantly express estrogen receptor (e.g., muscles, bones) (Example IIIA).
  • RAD1901 treatments antagonized estradiol stimulation of uterine tissues in ovariectomized (OVX) rats (Example IV(A)), and largely preserved bone quality of the treated subjects.
  • OVX rats treated with RAD1901 showed maintained BMD and femur microarchitecture (Example IV(A)).
  • the RAD1901-everolimus combination may be especially useful for patients having osteoporosis or a higher risk of osteoporosis.
  • genes disclosed herein may further comprise gene profiling of subjects to be treated in order to identify subjects with greater response and/or longer responsive time.
  • RAD1901 was found to degrade wild-type ER ⁇ and abrogate ER signaling in vivo in MCF-7 cell line xenograft models, and produced a dose-dependent decrease in PR in these MCF-7 cell line xenograft models (Example 111(B)).
  • RAD1901 decreased proliferation in MCF-7 cell line xenograft models and PDx-4 models as evidenced by a decrease in proliferation marker Ki67 in tumors harvested from the treated subjects.
  • RAD1901 also decreased ER signaling in vivo in an ER mutant PDx model that was hardly responsive to fulvestrant treatment (Example 111(B)).
  • RAD1901-ER ⁇ interactions are not likely to be affected by mutations in the LBD of ER ⁇ , e.g., Y537X mutant wherein X was S, N, or C; D538G; and S463P, which account for about 81.7% of LBD mutations found in a recent study of metastatic ER positive breast tumor samples from patients who received at least one line of endocrine treatment (Table 9, Example V).
  • a combination of one or more second therapeutic agent(s) e.g., everolimus
  • RAD1901 or salt or solvate e.g., hydrate
  • the computer modeling resulted in identification of specific residues in the C-terminal ligand-binding domains of ER ⁇ that are critical to binding, information that can be used to develop compounds that bind and antagonize not only wild-type ER ⁇ but also certain mutants and variants thereof, which when combined with a second therapeutic agent (e.g., everolimus) may provide strong anti-tumor therapy with relatively low side effects similar to RAD1901-everolimus combinations as disclosed herein.
  • a second therapeutic agent e.g., everolimus
  • methods for inhibiting growth or producing regression of an ER ⁇ -positive tumor in a subject in need thereof by administering to the subject a therapeutically effective amount of a combination of RAD1901 or solvates (e.g., hydrates) or salts thereof, plus one or more second therapeutic agent(s) as described herein (e.g., everolimus).
  • a combination of RAD1901 or solvates e.g., hydrates
  • second therapeutic agent(s) as described herein (e.g., everolimus).
  • administering has additional therapeutic benefits in addition to inhibiting tumor growth, including for example inhibiting cancer cell proliferation or inhibiting ER ⁇ activity (e.g., by inhibiting estradiol binding or by degrading ER ⁇ ).
  • the method produces little or no negative effects on non-targeted tissues (e.g., muscles, bones).
  • a second therapeutic agent for use in the methods provided herein can be a chemotherapeutic agent, or an inhibitor of AKT, androgen receptor, angiogenesis, aromatase, aurora A kinase, BCL2, EGFR, the estrogen pathway, estrogen signaling pathway, estrogen receptor, HER2, HER3, heat shock protein 90 (Hsp90), hedgehog (Hh) signaling pathway, histone deacetylase (HDAC), KIT pathways, mTOR (e.g., TORC1 and/or TORC2), microtubule, MYC, nucleoside metabolism, PARP, pan PI3K, PI3K, protein kinase CK2, the RAS pathway, steroid sulfatase (STS), TK, Top2A, tyrosine kinase, VEGF receptor tyrosine kinase, or any combinations thereof.
  • the second therapeutic agent may also be an antibody such as an anti-TGF beta antibody, anti-type-1 insulin
  • second therapeutic agents include, without limitation, abiraterone acetate, ADI-PEG 20, ado-trastuzumab emtansine, afatinib, alisertib, anastrozole, paclitaxel, and paclitaxel derivatives (e.g., ANG1005, paclitaxel polymeric micelle), ARN-810, azacitidine, AZD2014, AZD5363, bevacizumab, BP-C1, buparlisib (BKM120), BYL719, capecitabine, carboplatin, cediranib Maleate, cetuximab, cisplatin/AC4-CDDP4, CR1447, CX-4945, dasatinib, denosumab, docetaxel, doxorubicin, eniluracil, entinostat, enzalutamide, epirubicin, eribulin, exemestane, ever
  • goserelin acetate GRN1005, GSK 2141795, ibandronate, IMMU-132, irinotecan, irosustat, epothilone (e.g., ixabepilone), lapatinib, sonidegib (LDE225), letrozole, LGK974, LJM716, lucitanib, methotrexate, MK-2206, MK-3475, MLN0128, MM-302, neratinib, niraparib, olaparib, anti-androgen (e.g., orteronel), oxaliplatin, pazopanib, pertuzumab, PF-05280014, PM01183, progesterone, pyrotinib, romidepsin, ruxolitinib, sorafenib, sunitinib, talazoparib, tamoxifen, tax
  • the second therapeutic agents are selected from the group consisting of ado-trastuzumab emtansine, aurora A kinase inhibitors (e.g., alisertib), AIs (e.g., anastrozole; exemestane, letrozole), ARN-810, mTOR inhibitors (e.g., everolimus, AZD2014, BEZ235, GDC-0980, CC-223, MLN0128), AKT inhibitors (e.g., AZD5363, GDC-0068, GSK2110183, GSK2141795, GSK690693, MK2206), PI3K inhibitors (e.g., BKM120, BYL719, GDC-0032, GDC-0941), selective histone deacetylase (HDAC) inhibitors (e.g., entinostat), GnRH agonist (e.g., goserelin acetate), GRN1005
  • HDAC
  • the second therapeutic agent can be an AI (e.g., anastrozole, aromasin, and letrozole), another SERM (e.g., arzoxifene, droloxifene, EM-652 (SCH 57068), idoxifene, lasofoxifene, levormeloxifene, miproxifene, raloxifene, tamoxifen, and toremifene), or another SERD (e.g., fulvestrant, GDC-0810 (ARN-810), GW5638/DPC974, ICI182782, RU58668, SRN-927, TAS-108 (SR16234), and ZK191703), including solvates (e.g., hydrates) and salts thereof.
  • AI e.g., anastrozole, aromasin, and letrozole
  • SERM e.g., arzoxifene, droloxifene, EM-652 (
  • the second therapeutic agents include, without limitation, abraxane, AMG 386, cabazitaxel, caelyx, capecitabine, docetaxel, eribulin, gemcitabine, herceptin, neratinib, pazopanib (GW786034), rapalogs (rapamycin and its analogs), taxol (including analogs/alternative formulations), TDM1, temozolamide, tykerb, veliparib (ABT-888), and vinorelbine, including solvates (e.g., hydrates) and salts thereof.
  • solvates e.g., hydrates
  • the second therapeutic agent targets the PI3K/AKT/mTOR pathway and can be a mTOR inhibitor, a dual mTOR inhibitor, a PI3K/mTOR inhibitor.
  • the second therapeutic agent is a rapamycin derivative (aka rapalog) such as rapamycin (sirolimus or rapamune, Pfizer), everolimus (Afinitor or RAD001, Novartis), ridaforolimus (AP23573 or MK-8669, Merck and ARIAD Pharmaceuticals), temsirolimus (Torisel or CCI779, Pfizer), including solvates (e.g., hydrates) and salts thereof.
  • rapamycin derivative such as rapamycin (sirolimus or rapamune, Pfizer), everolimus (Afinitor or RAD001, Novartis), ridaforolimus (AP23573 or MK-8669, Merck and ARIAD Pharmaceuticals), temsirolimus (Torisel or
  • the second therapeutic agent is a dual mTOR inhibitor that inhibits both mTORC1 and mTORC2, such as MLN0128 (castration-resistant prostate cancer (CRPC), Memorial Sloan Kettering Cancer Center), CC115 and CC223 (Celgene), OSI-027 (OSI Pharmaceuticals), and AZD8055 and AZD2014 (AstraZeneca), including solvates (e.g., hydrates) and salts thereof.
  • MLN0128 castration-resistant prostate cancer (CRPC), Memorial Sloan Kettering Cancer Center
  • CC115 and CC223 Celgene
  • OSI-027 OSI Pharmaceuticals
  • AZD8055 and AZD2014 AZD8055 and AZD2014
  • the second therapeutic agent is a PI3K/mTOR inhibitor such as GDC-0980, SAR245409 (XL765), LY3023414 (Eli Lilly), NVP-BEZ235 (Novartis), NVP-BGT226 (Novartis), SF1126, and PKI-587 (Pfizer), including solvates (e.g., hydrates) and salts thereof
  • more than one of the second therapeutic agents disclosed above may be used in combination with RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • an mTOR inhibitor can be used together with another mTOR inhibitor or with a PI3K/mTOR inhibitor.
  • the second therapeutic agents disclosed above including mTOR inhibitors, dual mTOR inhibitors, and PI3K/mTOR inhibitors, can be administered with other active agents to enhance the efficacy of the treatment.
  • an mTOR inhibitor can be used in combination with JAK2 inhibitors (Bogani et al., PLOS One, 8(1): e54826 (2013)), chemotherapeutic agents (Yardley, Breast Cancer ( Auckl ) 7: 7-22 (2013)), or endocrine therapies such as tamoxifen or exemestane (Vinayak et al., “mTOR inhibitors in the treatment of breast cancer,” Oncology , published Jan. 15, 2013 (http://www.cancernetwork.com/breast-cancer/mtor-inhibitors-treatment-breast-cancer)).
  • the second therapeutic agents also include these auxiliary active agents.
  • “Inhibiting growth” of an ER ⁇ -positive tumor as used herein may refer to slowing the rate of tumor growth, or halting tumor growth entirely.
  • Tumor regression or “regression” of an ER ⁇ -positive tumor as used herein may refer to reducing the maximum size of a tumor.
  • administration of a combination of one or more second therapeutic agent(s) e.g., everolimus
  • second therapeutic agent(s) e.g., everolimus
  • RAD1901 or a solvate e.g., hydrate
  • a solvate e.g., hydrate
  • the methods of tumor regression provided herein may be alternatively characterized as methods of reducing tumor size versus baseline.
  • Tumor as used herein is a malignant tumor, and is used interchangeably with “cancer.”
  • Tumor growth inhibition or regression may be localized to a single tumor or to a set of tumors within a specific tissue or organ, or may be systemic (i.e., affecting tumors in all tissues or organs).
  • Estrogen receptor alpha refers to a polypeptide comprising, consisting of, or consisting essentially of the wild-type ER ⁇ amino acid sequence, which is encoded by the gene ESR1.
  • a tumor that is “positive for estrogen receptor alpha,” “ER ⁇ -positive,” “ER+,” or “ER ⁇ +” as used herein refers to a tumor in which one or more cells express at least one isoform of ER ⁇ . In certain embodiments, these cells overexpress ER ⁇ .
  • the tumor being targeted is more sensitive to a treatment of RAD1901 and a second therapeutic agent as disclosed herein 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
  • RAD1901 In addition to demonstrating the ability of RAD1901 to inhibit tumor growth in tumors expressing wild-type ER ⁇ , the results provided herein show that RAD1901 exhibited the unexpected ability to inhibit the growth of tumors expressing a mutant form of ER ⁇ , namely Y537S ER ⁇ (Example I(A)).
  • Computer modeling evaluations of examples of ER ⁇ mutations showed that none of these mutations were expected to impact the LBD or specifically hinder RAD1901 binding (Example V(A)), e.g., ER ⁇ having one or more mutants selected from the group consisting of ER ⁇ with Y537X mutant wherein X is S, N, or C, ER ⁇ with D538G mutant, and ER ⁇ with S463P mutant.
  • ligand-binding domain selected from the group consisting of Y537X 1 wherein X 1 is S, N, or C, D538G, L536X 2 wherein X 2 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 one or more one or more second therapeutic agent(s) (e.g., everolimus) 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 ER ⁇ .
  • the results disclosed herein show that RAD1901 exhibits significant accumulation within tumor cells, and is capable of penetrating the blood-brain barrier (Example II).
  • the ability to penetrate the blood-brain barrier was confirmed by showing that RAD1901 administration significantly prolonged survival in a brain metastasis xenograft model (Example I(B)).
  • the ER ⁇ -positive tumor being targeted is located in the brain or elsewhere in the central nervous system. In certain of these embodiments, the ER ⁇ -positive tumor is primarily associated with brain cancer.
  • the ER ⁇ -positive tumor is a metastatic tumor that is primarily associated with another type of cancer, such as breast, uterine, ovarian, or pituitary cancer, or a tumor that has migrated from another tissue or organ.
  • the tumor is a brain metastases, such as breast cancer brain metastases (BCBM).
  • BCBM breast cancer brain metastases
  • RAD1901 or solvates (e.g., hydrate) or salts thereof accumulate in one or more cells within a target tumor.
  • RAD1901 administration protects against bone loss in ovariectomized rats (Example IV(A)). Accordingly, in certain embodiments of the tumor growth inhibition or tumor regression methods provided herein, administration of a combination of one or more second therapeutic agent(s) (e.g., everolimus) and RAD1901 or solvates (e.g., hydrate) or salts thereof does not have undesirable effects on bone, including for example undesirable effects on bone volume density, bone surface density, bone mineral density, trabecular number, trabecular thickness, trabecular spacing, connectivity density, and/or apparent bone density of the treated subject.
  • second therapeutic agent(s) e.g., everolimus
  • RAD1901 or solvates e.g., hydrate
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) are administered in combination to a subject in need.
  • the phrase “in combination” means that RAD1901 or solvates (e.g., hydrate) or salts thereof may be administered before, during, or after the administration of the second therapeutic agent(s) (e.g., everolimus).
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) 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.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) are administered to the subject simultaneously or substantially simultaneously.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) may be administered as part of a single formulation.
  • the combination of RAD1901 or solvates (e.g., hydrate) or salts thereof and a single second therapeutic agent (e.g., everolimus) is administered to a subject.
  • the combination of RAD1901 or solvates (e.g., hydrate) or salts thereof and more than one second therapeutic agent (e.g., everolimus) is administered to a subject.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof can be combined with two or more second therapeutic agent(s) (e.g., everolimus) for treating cancers/tumors.
  • a therapeutically effective amount of a combination of RAD1901 or solvates (e.g., hydrate) or salts thereof and one or more second therapeutic agent(s) (e.g., everolimus) 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.
  • 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.
  • a therapeutically effective amount or dosage of a second therapeutic agent depends on its particular type.
  • the daily dosage of a second therapeutic agent ranges from about 1 mg to about 1,500 mg, from about 1 mg to about 1,200 mg, from about 1 mg to about 1,000 mg, from about 1 mg to about 800 mg, from about 1 mg to about 600 mg, from about 1 mg to about 500 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, from about 1 mg to about 5 mg, from about 50 mg to about 1,500 mg, from about 100 mg to about 1,200 mg, from about 150 mg to about 1,000 mg, from about 200 mg to about 800 mg, from about 300 mg to about 600 mg, from about 350 mg to about 500 mg.
  • the daily dosage of a second therapeutic agent may range from about 1 to about 100 mg/kg, from about 1 to about 75 mg/kg, from about 1 to about 50 mg/kg, from about 1 to about 45 mg/kg, from about 1 to about 40 mg/kg, from about 1 to about 30 mg/kg, from about 1 to about 20 mg/kg, from about 1 to about 10 mg/kg, from about 2 to about 100 mg/kg, from about 2 to about 75 mg/kg, from about 2 to about 50 mg/kg, from about 2 to about 45 mg/kg, from about 2 to about 40 mg/kg, from about 2 to about 30 mg/kg, from about 2 to about 20 mg/kg, from about 2 to about 10 mg/kg, from about 2.5 to about 100 mg/kg, from about 2.5 to about 75 mg/kg, from about 2.5 to about 50 mg/kg, from about 2.5 to about 45 mg/kg, from about 2.5 to about 40 mg/kg, from about 2.5 to about 30 mg/kg, from about 2.5 to about 20 mg/kg, or from about 2.5
  • a therapeutically effective amount of the combination may utilize a therapeutically effective amount of either compound administered alone.
  • the therapeutically effective amounts of RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) when administered in the combination may be smaller than the therapeutically effective amounts of RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) required when administered alone; and one or both compounds may be administered at a dosage that is lower than the dosage at which they would normally be administered when given separately.
  • the therapeutically effective amount of RAD1901 or solvates (e.g., hydrate) or salts thereof when administered as part of the combination is about 30% to about 200%, about 40% to about 200%, about 50% to about 200%, about 60% to about 200%, about 70% to about 200%, about 80% to about 200%, about 90% to about 200%, about 100% to about 200%, 30% to about 150%, about 40% to about 150%, about 50% to about 150%, about 60% to about 150%, about 70% to about 150%, about 80% to about 150%, about 90% to about 150%, about 100% to about 150%, about 30% to about 120%, about 40% to about 120%, about 50% to about 120%, about 60% to about 120%, about 70% to about 120%, about 80% to about 120%, about 90% to about 120%, about 100% to about 120%, 30% to about 110%, about 40% to about 110%, about 50% to about 110%, about 60% to about 110%, about 70% to about 110%, about 80% to about 110%, about 90% to
  • the therapeutically effective amount of the second therapeutic agent(s) (e.g., everolimus) when administered as part of the combination is about 30% to about 200%, about 40% to about 200%, about 50% to about 200%, about 60% to about 200%, about 70% to about 200%, about 80% to about 200%, about 90% to about 200%, about 100% to about 200%, 30% to about 150%, about 40% to about 150%, about 50% to about 150%, about 60% to about 150%, about 70% to about 150%, about 80% to about 150%, about 90% to about 150%, about 100% to about 150%, about 30% to about 120%, about 40% to about 120%, about 50% to about 120%, about 60% to about 120%, about 70% to about 120%, about 80% to about 120%, about 90% to about 120%, about 100% to about 120%, 30% to about 110%, about 40% to about 110%, about 50% to about 110%, about 60% to about 110%, about 70% to about 110%, about 80% to about 110%, about 90% to about 110%,
  • the cancers or tumors are resistant ER-driven cancers or tumors (e.g. having mutant ER binding domains (e.g. ER ⁇ comprising one or more mutations including, but not limited to, Y537X 1 wherein X 1 is S, N, or C, D538G, L536X 2 wherein X 2 is R or Q, P535H, V534E, S463P, V392I, E380Q and combinations thereof), overexpressors of the ERs or tumor and/or cancer proliferation becomes ligand independent, or tumors and/or cancers that progress with treatment of 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, a
  • the therapeutically effective amount of each compound when administered in combination may be lower than the therapeutically effective amount of each compound administered alone.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the second therapeutic agent(s) (e.g., everolimus) for use in the presently disclosed methods can be formulated according to any available conventional method.
  • preferred 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 formulation is also carried out by combining compositions that are generally used as a raw material for pharmaceutical formulation, according to the conventional methods.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and one or more second therapeutic agent(s) (e.g., everolimus) for use in the presently disclosed methods can be formulated into a pharmaceutical composition as any one or more of the active compounds described herein and a physiologically acceptable carrier (also referred to as a pharmaceutically acceptable carrier or solution or diluent).
  • a physiologically acceptable carrier also referred to as a pharmaceutically acceptable carrier or solution or diluent.
  • Such carriers and solutions include pharmaceutically acceptable salts and solvates of compounds used in the methods of the instant invention, and mixtures comprising two or more of such compounds, pharmaceutically acceptable salts of the compounds and pharmaceutically acceptable solvates of the compounds.
  • Such compositions are prepared in accordance with acceptable pharmaceutical procedures such as described in Remington's Pharmaceutical Sciences, 18th edition, ed. Alfonso R. Gennaro, Mack Printing Company, Eaton, Pa. (1990), which is incorporated herein by reference.
  • the one or more second therapeutic agent(s) e.g., everolimus
  • RAD1901 or solvates e.g., hydrate
  • salts thereof in a free form can be converted into a salt by conventional methods.
  • 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, 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,
  • Isomers of RAD1901 or solvates (e.g., hydrate) or salts thereof and/or the second therapeutic agent(s) e.g., everolimus
  • the second therapeutic agent(s) e.g., everolimus
  • the second therapeutic agent(s) e.g., everolimus
  • the second therapeutic agent(s) e.g., everolimus
  • 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.
  • 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 a second therapeutic agent (e.g., everolimus), 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.
  • Administration routes of RAD1901 or solvates (e.g., hydrate) or salts thereof and/or second therapeutic agent(s) (e.g., everolimus) disclosed herein include but not limited to topical administration, oral administration, intradermal administration, intramuscular administration, intraperitoneal administration, intravenous administration, intravesical infusion, subcutaneous administration, transdermal administration, and transmucosal administration.
  • 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
  • RAD1901 inhibits estradiol binding to ER in the uterus and pituitary (Example III(A)).
  • estradiol binding to ER in uterine and pituitary tissue was evaluated by FES-PET imaging. After treatment with RAD1901, the observed level of ER binding was at or below background levels.
  • binding is measured at some point following one or more administrations of a first dosage of the compound. 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 certain embodiments, these methods comprise an additional step of administering an increased second dosage of the compound.
  • 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%
  • estradiol-ER binding can serve as a proxy for tumor growth inhibition, or a supplemental means of evaluating growth inhibition.
  • these methods can be used in conjunction with the administration of RAD1901 or solvates (e.g., hydrate) or salts thereof for purposes other than inhibition of tumor growth, including for example inhibition of cancer cell proliferation.
  • the methods provided herein for adjusting the dosage of a RAD1901 or solvates (e.g., hydrate) or salts thereof in a combination therapy comprise:
  • the invention includes the use of PET imaging to detect and/or dose ER sensitive or ER resistant cancers.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more RAD1901 or solvates (e.g., hydrate) or salts thereof and/or second therapeutic agent(s) (e.g., everolimus) disclosed herein in a therapeutically effective amount as disclosed herein for the combination methods set forth herein.
  • second therapeutic agent(s) e.g., everolimus
  • the mutant ER ⁇ comprises one or more mutations including, but not limited to, Y537X 1 wherein X 1 is S, N, or C, D538G, L536X 2 wherein X 2 is R or Q, P535H, V534E, S463P, V392I, E380Q and combinations thereof.
  • the LBD of ER ⁇ and a mutant ER ⁇ comprises AF-2.
  • the LBD comprises, consists of, or consists essentially of amino acids 299-554 of ER ⁇ .
  • the LBD of the mutant ER ⁇ comprises one or more mutations including, but not limited to, Y537X 1 wherein X 1 is S, N, or C, D538G, L536X 2 wherein X 2 is R or Q, P535H, V534E, S463P, V392I, E380Q and combinations thereof.
  • the term “and/or” as used herein includes both the “and” case and the “or” case.
  • a condition associated with ER ⁇ and/or a mutant ER ⁇ activity or expression in a subject in need thereof comprising administering to the subject a combination of one or more second therapeutic agent(s) (e.g., everolimus) and one or more compounds capable of binding to ER ⁇ and/or a mutant ER ⁇ via LBD.
  • the subject is a mammal, and in certain of these embodiments the subject is human.
  • the condition is tumor and/or cancer, including but not limited to ER positive tumor and/or cancer as disclosed herein.
  • the LBD of ER ⁇ and a mutant ER ⁇ comprises AF-2.
  • the LBD comprises, consists of, or consists essentially of amino acids 299-554 of ER ⁇ .
  • the LBD of the mutant ER ⁇ comprises one or more mutations including, but not limited to, Y537X1 wherein X 1 is S, N, or C, D538G, L536X 2 wherein X 2 is R or Q, P535H, V534E, S463P, V392I, E380Q and combinations thereof.
  • the compound capable of binding to ER ⁇ and/or mutant ER ⁇ via LBD is a selective estrogen receptor degrader (SERD) or selective estrogen receptor modulator (SERM).
  • SEMD selective estrogen receptor degrader
  • SERM selective estrogen receptor modulator
  • the compound capable of binding to ER ⁇ and/or mutant ER ⁇ via LBD does so via one or more interactions selected from the group consisting of H-bond interactions with residues E353, D351, R349, and/or L536 and pi-interactions with residue F404 of ER ⁇ and/or mutant ER ⁇ .
  • One example of such a compound is RAD1901.
  • a condition associated with activity or expression of a mutant ER ⁇ comprising one or more mutations including, but not limited to, Y537X 1 wherein X 1 is S, N, or C, D538G, L536X 2 wherein X2 is R or Q, P535H, V534E, S463P, V3921, E380Q and combinations thereof, wherein the method comprises administering to the subject a combination of one or more second therapeutic agent(s) (e.g., everolimus) and one or more compounds capable of binding to ER ⁇ via the LBD.
  • a second therapeutic agent(s) e.g., everolimus
  • the condition is cancer, including but not limited to ER positive cancer, breast cancer, ER positive breast cancer, and metastatic breast cancer, and in certain embodiments the compound is RAD1901 or a pharmaceutically acceptable solvate (e.g., hydrate) or pharmaceutically acceptable salt thereof.
  • RAD1901 used in the examples below was (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride, manufactured by IRIX Pharmaceuticals, Inc. (Florence, S.C.).
  • RAD1901 was stored as a dry powder, formulated for use as a homogenous suspension in 0.5% (w/v) methylcellulose in deionized water, and for animal models was administered by oral gavage.
  • Tamoxifen, raloxifene and estradiol (E2) were obtained from Sigma-Aldrich (St. Louis, Mo.), and administered by subcutaneous injection.
  • Fulvestrant was obtained from Tocris Biosciences (Minneapolis, Minn.) and administered by subcutaneous injection.
  • Other laboratory reagents were purchased from Sigma-Aldrich
  • MCF-7 cells human mammary metastatic adenocarcinoma
  • MCF-7 cells human mammary metastatic adenocarcinoma
  • MEM phenol red-free minimal essential medium
  • bovine insulin 0.01 mg/ml bovine insulin and 10% fetal bovine serum (Invitrogen, Carlsbad, Calif.), at 5% CO 2 .
  • T47D cells were cultured in 5% CO 2 incubator in 10 cm dishes to approximately 75% confluence in RPMI growth media supplemented with 10% FBS and 5 ⁇ g/mL human insulin.
  • mice All mice were housed in pathogen-free housing in individually ventilated cages with sterilized and dust-free bedding cobs, access to sterilized food and water ad libitum, under a light dark cycle (12-14 hour circadian cycle of artificial light) and controlled room temperature and humidity. Tumors were measured twice weekly with Vernier calipers and volumes were calculated using the formula: (L*W 2 )*0.52.
  • PDx models patient-derived xenograft models
  • FIG. 1 Some examples of patient-derived xenograft models (PDx models) are shown in FIG. 1 .
  • PDx models with patient derived breast cancer tumor were established from viable human tumor tissue or fluid that had been serially passaged in animals (athymic nude mice (Nu (NCF)-Foxn1nu)) a limited number of times to maintain tumor heterogeneity. Pre-study tumor volumes were recorded for each experiment beginning approximately one week prior to its estimated start date. When tumors reached the appropriate Tumor Volume Initiation (TVI) range (150-250 mm 3 ), animals were randomized into treatment and control groups and dosing initiated (Day 0, 8-10 subjects in each group); animals in all studies followed individually throughout each experiment.
  • TVI Tumor Volume Initiation
  • TV Tumor Volume
  • time endpoint was 60 days; and volume endpoint was group mean 2 cm 3 ); individual mice reaching a tumor volume of 2 cm 3 or more were removed from the study and the final measurement included in the group mean until the mean reached volume endpoint or the study reached time endpoint.
  • Tumors were harvested and protein expression was analyzed using standard practice. Tumors were harvested at the indicated time points after the last day of dosing, homogenized in RIPA buffer with protease and phosphatase inhibitors using a Tissuelyser (Qiagen). Equal amounts of protein were separated by MW, transferred to nitrocellulose membranes and blotted with the following antibodies using standard practice:
  • qPCR analyses were performed as follows: Cells were harvested, mRNA was extracted, and equal amounts used for cDNA synthesis and qPCR with primers specific for progesterone receptor, GREB1, and TFF1 (LifeTech). Bands were quantified using 1D Quant software (GE).
  • Tumors were harvested, formalin-fixed and embedded into paraffin. Embedded tumors were sectioned (6 ⁇ M) and stained with antibodies specific for ER, PR, and Her2. Quantitation was performed as follows: Five fields were counted for positive cells (0-100%) and intensity of staining (0-3+). H-scores (0-300) were calculated using the following formula: % positivity*intensity.
  • RAD1901-Everolimus Combinations Provided Enhanced Tumor Growth Inhibition in Tumor and/or Cancer Expressing WT ER or Mutant ER (e.g., Y537S), with Different Prior Endocrine Therapy
  • I(A)(i) RAD1901 inhibited tumor growth in PDx models (PDx-1 to PDx-12) regardless of ER status and prior endocrine therapy
  • PDx models in which the growth was driven by ER and an additional driver benefited from the RAD1901 treatments.
  • RAD1901 was efficacious in inhibiting tumor growth in models with ER mutations and/or high level expression of Her2 (PDx), regardless of prior treatment, either treatment naive (Rx-naive), or treated with aromatase inhibitor, tamoxifen (tam), chemotherapy (chemo), Her2 inhibitors (Her2i, e.g., trastuzumab, lapatinib), bevacizumab, fulvestrant, and/or rituximab.
  • Her2i Her2i, e.g., trastuzumab, lapatinib
  • bevacizumab fulvestrant
  • rituximab Her2 inhibitors
  • I(A)(ii) RAD1901-everolimus combination drove more regression than RAD1901 alone in xenograft models expressing WT ER
  • mice Two days before cell implantation, Balb/C-Nude mice were inoculated with 0.18/90-day release 17 ⁇ -estradiol pellets. MCF-7 cells (PR+, Her2-) were harvested and 1 ⁇ 10 7 cells were implanted subcutaneously in the right flank of Balb/C-Nude mice. When the tumors reached an average of 200 mm 3 , the mice were randomized into treatment groups by tumor volume and treated with the test compounds.
  • Each group was treated with vehicle (control, p.o., q.d., to the endpoint), fulvestrant (Faslodex®; 3 mg/subject, s.c., qwk X 5 and extended if necessary), RAD1901 (30 mg/kg or 60 mg/kg of the subject, p.o., q.d., to the endpoint), everolimus (2.5 mg/kg, p.o., to the end point), or RAD1901-everolimus combination at doses specified from day 0. The treatment period lasted for 28 days.
  • MCF-7 xenograft mice were treated with vehicle (negative control), RAD1901 (60 mg/kg, PO daily), everolimus (2.5 mg/kg, p.o.), a combination of RAD1901 (30 or 60 mg/kg, PO daily) and everolimus (2.5 mg/kg, p.o.), fulvestrant (3 mg/dose, s.c., weekly) or a combination of fulvestrant (3 mg/dose, s.c., weekly) and everolimus (2.5 mg/kg, p.o.).
  • Tumor size was measured at various time points for 27 days.
  • Results are shown in FIGS. 2A-2B .
  • FIG. 2C demonstrates that RAD1901-everolimus combinations with RAD1901 at a dose of 30 mg/kg or 60 mg/kg both provided similar effects, although RAD1901 alone at 30 mg/kg was not as effective as RAD1901 alone at 60 mg/kg in inhibiting tumor growth. Said results suggest a RAD1901-everolimus combination with a lower dose of RAD1901(e.g., 30 mg/kg) was sufficient to maximize the tumor growth inhibition/tumor regression effects in said xenograft models.
  • Treatment with the combination of RAD1901 and everolimus was also more effective at decreasing ER and PR expression in vivo in the MCF-7 xenograft models than treatment with RAD1901, everolimus, or fulvestrant alone, or treatment with a combination of fulvestrant and everolimus ( FIG. 11 ); tumors harvested two hours after the last dosing).
  • RAD1901-everolimus drove more regression than RAD1901 alone in PDx-11 and PDx-2 models that were responsive to fulvestrant treatments.
  • PDx-2 and PDx-11 models were treated with a combination of RAD1901 (60 mg/kg, q.d., p.o.) and everolimus (2.5 mg/kg, p.o.), RAD1901 alone (60 mg/kg, q.d., p.o.), everolimus alone (2.5 mg/kg, p.o.), or fulvestrant alone (3 mg/dose, qwk, s.c.).
  • RAD1901-mediated tumor growth inhibition was maintained in the absence of treatment at least two months after RAD1901 treatment (30 mg/kg, p.o., q.d.) period ended, while estradiol treatment continued ( FIG. 5 ).
  • a combination of one or more second therapeutic agent (s) with RAD1901 is likely to benefit a patient in inhibiting tumor growth after treatment ends, especially when the one or more second therapeutic agent (s) (e.g., everolimus) can be reduced or delayed for adverse reactions. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm488028.htm.
  • PDx-5 models were prepared following similar protocol as described supra for PDx models.
  • the tumor sizes of each dosing group were measured twice weekly with Vernier calipers, and volumes were calculated using the formula (L*W2)*0.52.
  • RAD1901 was an effective endocrine backbone that potentiated the tumor growth inhibition of targeted agents. Furthermore, RAD1901 showed potent anti-tumor activity in PDx models derived from patients that have had multiple prior endocrine therapies including those that are insensitive to fulvestrant.
  • the potential ability of RAD1901 to cross the blood-brain barrier and inhibit tumor growth was further evaluated using an MCF-7 intracranial tumor xenograft model.
  • mice Female athymic nude mice (Crl:NU(NCr)-Foxnlmu) were used for tumor xenograft studies. Three days prior to tumor cell implantation, estrogen pellets (0.36 mg E2, 60-day release, Innovative Research of America, Sarasota, Fla.) were implanted subcutaneously between the scapulae of all test animals using a sterilized trochar.
  • MCF-7 human breast adenocarcinoma cells were cultured to mid-log phase in RPMI-1640 medium containing 10% fetal bovine serum, 100 units/mL penicillin G, 100 ⁇ g/mL streptomycin sulfate, 2 mM glutamine, 10 mM HEPES, 0.075% sodium bicarbonate and 25 g/mL gentamicin.
  • the cells were trypsinized, pelleted, and resuspended in phosphate buffered saline at a concentration of 5 ⁇ 10′ cells/mL.
  • Each test mouse received 1 ⁇ 10 6 MCF-7 cells implanted intracranially.
  • mice Five days after tumor cell implantation (designated as day 1 of the study), mice were randomized into three groups of 12 animals each and treated with vehicle, fulvestrant (0.5 mg/animal daily), or RAD1901 (120 mg/kg daily), as described above.
  • the endpoint was defined as a mortality or 3 ⁇ survival of the control group, whichever comes first.
  • Treatment tolerability was assessed by body weight measurements and frequent observation for clinical signs of treatment-related adverse effects. Animals with weight loss exceeding 30% for one measurement, or exceeding 25% for three measurements, were humanely euthanized and classified as a treatment-related death. Acceptable toxicity was defined as a group-mean body weight loss of less than 20% during the study and not more than one treatment-related death among ten treated animals, or 10%.
  • At the end of study animals were euthanized by terminal cardiac puncture under isoflurane anesthesia. RAD1901 and fulvestrant concentration in plasma and tumor were determined using LC-MS/MS.
  • Concentration of RAD1901 in the plasma was 738 ⁇ 471 ng/mL and in the intracranial tumor was 462 ⁇ 105 ng/g supporting the hypothesis that RAD1901 is able to effectively cross the blood-brain barrier.
  • concentrations of fulvestrant were substantially lower in the plasma (21 ⁇ 10 ng/mL) and in the intracranial tumor (8.3 ⁇ 0.8 ng/g).
  • TEAEs were recorded throughout the study. Preliminary data are summarized in Table 12. “n” is number of subjects with at least one treatment-related AE in a given category, AEs graded as per the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and any patient with multiple scenarios of a same preferred term was counted only once to the most severe grade. No death or dose limiting toxicities were observed, maximum tolerated dose (MTD) was not established. Most AEs were grade 1 or 2. Most common treatment-related AEs were dyspepsia (5 ⁇ 8 patients) and nausea (3 ⁇ 8 patients). Two serious AEs (SAES) were observed, one a grade 3 treatment-related constipation, and the other shortness of breath (pleural effusion) not related to the treatment.
  • CCAE Common Terminology Criteria for Adverse Events
  • the heavily pretreated subjects of this phase 1 study included subjects previously treated with multiple endocrine and targeted agents, e.g., CDK4/6, PI3K and mTOR inhibitors. No dose limiting toxicities were observed after RAD1901 treatment at 200 mg daily oral dose up to 6 months, and at 400 mg daily oral dose up to two months. Thus, RAD1901 showed potential for treating ER+advanced breast cancer, especially in subjects previously treated with endocrine and/or targeted agents such as CDK4/6, PI3K and mTOR inhibitors.
  • RAD1901 Preferably Accumulated in Tumor and Can be Delivered to Brain
  • RAD1901 A significant amount of RAD1901 was delivered to the brain of the treated mice (e.g., see the B/P ratio (RAD1901 concentration in brain/the RAD1901 concentration in plasma)), indicating that RAD1901 was able to cross the blood-brain barrier (BBB).
  • BBB blood-brain barrier
  • RAD1901 preferably accumulated in the tumor. See, e.g., the T/P (RAD1901 concentration in tumor/RAD1901 concentration in plasma) ratio shown in Table 1.
  • RAD1901 decreased ER-engagements in uterus and pituitary in healthy postmenopausal female human subjects.
  • the subjects had an amenorrhea duration of at least 12 months and serum FSH consistent with menopause.
  • the subjects were 40-75 years old with BMI of 18.0-30 kg/m 2 .
  • Subjects had intact uterus.
  • Subjects having evidence of clinically relevant pathology, increased risk of stroke or of history venous thromboembolic events, or use of concomitant medication less than 14 days prior to admission to clinical research center (paracetamol allowed up to 3 days prior) were excluded.
  • FES-PET was performed at baseline and after 6 days of exposure to RAD1901 to evaluate ER engagement in the uterus.
  • RAD1901 occupied 83% and 92% of ER in the uterus at the 200 mg (7 subjects) and 500 mg (6 subjects) dose levels, respectively.
  • FES-PET imaging showed significant reduction in binding of labelled-estradiol to both the uterus and pituitary after RAD1901 treatment with 200 mg or 500 mg (once/day, p.o., 6 days).
  • FIGS. 9A and 9B also include CT scan of the uterus scanned by FES-PET showing the existence of the uterus before and after RAD1901 treatment.
  • the FES-PET uterus scan results were further quantified to show the change of post-dose ER-binding from baseline for 7 subjects ( FIG. 9C ), showing Subjects 1-3 and Subjects 4-7 as examples of the 200 mg dose group and 500 mg dose group, respectively.
  • RAD1901 showed robust ER engagement at the lower dose level (200 mg).
  • FIGS. 10A-B showed a representative image of FES-PET scan of the uterus (A) and pituitary (B) before (Baseline) and after (Post-treatment) RAD1901 treatment at 500 mg p.o. once a day, after six days.
  • FIG. 10A showed the FES-PET scan of the uterus by (a) Lateral cross-section; (b) longitude cross-section; and (c) longitude cross-section.
  • the subject's post dose FES-PET scan of uterus and pituitary showed no noticeable signal of ER binding at uterus ( FIG. 10A , Post-treatment) and at pituitary ( FIG. 10B , Post-treatment), respectively.
  • Standard uptake value (SUV) for uterus, muscle and bone were calculated and summarized for RAD1901 treatments at 200 mg and 500 mg p.o. daily in Tables 2 and 3, respectively.
  • Post-dose uterine signals were a tor close to levels from “non-target tissues,” suggesting a complete attenuation of FES-PET uptake post RAD1901 treatment. Almost no change was observed in pre-versus post-treatment PET scans in tissues that did not significant express estrogen receptor.
  • RAD1901 or salt or solvate (e.g., hydrate) thereof may be used in treating cancer and/or tumor cells having overexpression of ER (e.g., breast cancer, uterus cancer, and ovary cancer), without negative effects to other organs (e.g. bones, muscles).
  • ER e.g., breast cancer, uterus cancer, and ovary cancer
  • RAD1901 or salt or solvate (e.g., hydrate) thereof may be especially useful in treating metastatic cancers and/or tumors having overexpression of ER in other organs, e.g., the original breast cancer, uterus cancer, and/or ovary cancer migrated to other organs (e.g., bones, muscles), to treat breast cancer, uterus cancer, and/or ovary cancer lesions in other organs (e.g., bones, muscles), without negative effect to said organs.
  • organs e.g., the original breast cancer, uterus cancer, and/or ovary cancer migrated to other organs (e.g., bones, muscles), to treat breast cancer, uterus cancer, and/or ovary cancer lesions in other organs (e.g., bones, muscles), without negative effect to said organs.
  • Treatment with the combination of RAD1901 and everolimus was also more effective at decreasing ER and PR expression in vivo in the MCF-7 xenograft models (as described in Example I(A)(ii)) than treatment with RAD1901, everolimus, or fulvestrant alone, or treatment with a combination of fulvestrant and everolimus ( FIG. 11 ); tumors harvested two hours after the last dosing).
  • RAD1901 and fulvestrant were compared using MCF-7 and T47D cell lines, both are human breast cancer cell lines, at various concentrations, 0.01 ⁇ M, 0.1 ⁇ M and 1 M ( FIG. 12A for MCF-7 cell line assays; and FIG. 12B for T47D cell lines).
  • Three ER target genes, progesterone receptor (PgR), growth regulation by estrogen in breast cancer 1 (GREB1) and trefoil factor 1 (TFF 1) were used as markers.
  • RAD1901 caused nearly complete ER degradation and inhibited ER signaling ( FIGS. 12A-B ).
  • fulvestrant showed comparable or even slightly higher efficacies in inhibiting ER signaling when administered at the same concentration.
  • RAD1901 was comparable or more effective than fulvestrant in inhibiting tumor growth, and driving tumor regression as disclosed supra in Example I(A) and Example I(B).
  • FIGS. 13A and 13B student's t-test: *p-value ⁇ 0.05, **p-value ⁇ 0.01
  • FIGS. 13A and 13C student's t-test: *p-value ⁇ 0.05, **p-value ⁇ 0.01
  • tumor harvested from MCF-7 xenograft 8 hours after the final dose of RAD1901 treatment showed reduced PR and ER expression ( FIGS. 13A and 13C ).
  • RAD1901 treatment caused a rapid decrease in proliferation in MCF-7 xenograft models.
  • tumor harvested from MCF-7 xenograft models 8 hours after the single dose of RAD1901 (90 mg/kg, p.o., q.d.) and 24 hours after the 4th dose of RAD1901 (90 mg/kg, p.o., q.d.) were sectioned and stained to show a rapid decrease of the proliferation marker Ki67 ( FIGS. 15A and 15B ).
  • RAD1901 treatment caused a rapid decrease in proliferation in the PDx-4 models. For example, four hours after the final dose on the last day of a 56 day efficacy study, tumor harvested from PDx-4 models treated with RAD1901 (30, 60, or 120 mg/kg, p.o., q.d.) or fulvestrant (1 mg/animal, qwk) were sectioned and showed a rapid decrease of the proliferation marker Ki67 compared to PDx-4 models treated with fulvestrant ( FIG. 16 ).
  • Tumors were harvested at the indicated time points after the last day of dosing (unless otherwise specified), homogenized in RIPA buffer with protease and phosphatase inhibitors using a Tissuelyser (Qiagen). Equal amounts of protein were separated by MW, transferred to nitrocellulose membranes and blotted with the following antibody as described in the Materials and methods section: progesterone receptor (PR, Cell Signaling Technologies; 3153).
  • PR progesterone receptor
  • RAD1901 was more effective than fulvestrant at inhibiting the tumor growth, especially effective in inhibiting the growth of tumors which were hardly responsive to fulvestrant treatment (e.g., at a dosage of 3 mg/dose, qwk, s.c., FIG. 6A PDx-5). Furthermore, for the tumors which did not respond well to fulvestrant treatment (e.g., PDx-5), RAD1901 was effective in reducing PR expression in vivo, while fulvestrant was not ( FIG. 17 ).
  • the uterotropic effects of RAD1901 were investigated by assessing changes in uterine weight, histology, and C3 gene expression in immature rats. Results from a representative study are shown in FIGS. 18A-D .
  • Quantitative PCR was performed using the ABI Prism 7300 System (Applied Biosystems). PCR was done using the Taqman Universal Master Mix with probe sets for C3 and for the 18S ribosomal RNA as a reference gene. Thermal cycling conditions comprised an initial denaturation step at 95° C. for 10 min, followed by 40 cycles at 95° C. for 15 second and 60° C. for 1 minute.
  • RAD1901 antagonized E2-mediated uterine stimulation in a dose-dependent manner, exhibiting significant inhibition of uterotropic activity at doses of 0.1 mg/kg and greater and complete inhibition at 3 mg/kg.
  • the EC 50 for RAD1901 was approximately 0.3 mg/kg. Similar results were obtained in mice where RAD1901 doses 0.03 to 100 mg/kg also had no effect on uterine wet weight or epithelial thickness (data not shown).
  • E2 tamoxifen, and raloxifene all significantly increased the expression of the estrogen-regulated complement gene, C3 ( FIG. 18D ).
  • RAD1901 did not increase C3 gene expression at any of the doses tested (0.3 to 100 mg/kg).
  • the bone-specific effects of RAD1901 was examined in ovariectomized rats.
  • ovariectomy was performed on anesthetized adult female Sprague-Dawley rats, with sham surgery as a control. Following surgery, ovariectomized rats were treated once daily for 4 weeks with vehicle, E2 (0.01 mg/kg), or RAD1901 (0.1, 0.3, 1, 3 mg/kg), administered as described above, with 20 animals per group. Animals in the sham surgery group were vehicle treated. All animals were euthanized by carbon dioxide inhalation 24 hours after the final dose. Bone mineral density was assessed at baseline and again after 4 weeks of treatment using PIXImus dual emission x-ray absorptiometry.
  • the left femur of each animal was removed, dissected free of soft tissue and stored in 70% ethanol before analysis.
  • a detailed qualitative and quantitative 3-D evaluation was performed using a micro-CT40 system (Scanco Systems, Wayne, Pa.). For each specimen, 250 image slices of the distal femur metaphysis were acquired. Morphometric parameters were determined using a direct 3-D approach in pre-selected analysis regions. Parameters determined in the trabecular bone included bone volume density, bone surface density, trabecular number, trabecular thickness, trabecular spacing, connectivity density, and apparent bone density.
  • Micro-CT analysis of the distal femur demonstrated that ovariectomy induced significant changes in a number of key micro-architectural parameters when compared to sham surgery animals. These changes were consistent with a decrease in bone mass and include decreased bone volume, reduced trabecular number, thickness and density, and increased trabecular separation. Consistent with the preservation of bone mineral density observed after treatment with RAD1901, significant preservation of trabecular architecture was observed in key micro-structural parameters (Table 5)
  • the subjects were treated with placebo or at least one oral dose daily after a light breakfast for 7 days at dose levels of 200 mg, 500 mg, 750 mg and 1000 mg, respectively.
  • the key baseline demographics of the 44 healthy postmenopausal females enrolled in the phase 1 study are summarized in Table 6.
  • TEAEs were recorded, and the most frequent (>10% of patients in the total active group who had any related TEAEs) adverse events (AEs) are summarized in Table 7, “n” is number of subjects with at least one treatment-related AE in a given category, AEs graded as per the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and any patient with multiple scenarios of a same preferred term was counted only once to the most severe grade. No dose limiting toxicites were observed, maximum tolerated dose (MTD) was not established.
  • CTCAE Common Terminology Criteria for Adverse Events
  • each end of a bond is colored with the same color as the atom to which it is attached, wherein grey is carbon, red is oxygen, blue is nitrogen and white is hydrogen.
  • ER ⁇ ligand-binding domain LBD complexed with various ER ligands
  • 3ERT human ER ⁇ LBD bound to 4-hydroxytamoxifen (OHT)
  • OHT is the active metabolite of tamoxifen and a first generation SERM that functions as an antagonist in breast tissue.
  • the ER ⁇ binding site adopts a three layer “helical sandwich” forming a hydrophobic pocket which includes Helix 3 (H3), Helix 5 (H5), and Helix 11 (H11) ( FIG. 20 ).
  • the dotted box in FIG. 21 represents the binding site and residues within the binding site that are important or are effected by OHT binding.
  • OHT functions as an antagonist by displacing H12 into the site where LXXLL coactivator(s) binds.
  • OHT occupies the space normally filled by L540 and modifies the conformation of four residues on the C-terminal of Helix 11 (G521, H524, L525, and M528).
  • OHT also forms a salt bridge with D351, resulting in charge neutralization.
  • Root-mean-square deviation (RMSD) calculations of any pair of the fourteen models are summarized in Table 11. Structures were considered to be overlapping when their RMSD was ⁇ 2 ⁇ . Table 11 shows that all fourteen models had a RMSD ⁇ 1.5 ⁇ . Using conditional formatting analysis suggested that 1R5K and 3UUC were the least similar to the other models (analysis not shown). Therefore, 1R5K and 3UUC were considered a unique, separate structural cluster to be examined.
  • ER ⁇ residues bound by ligand in the fourteen models are summarized in Table 12.
  • Table 12 also shows the EC 50 in the ER ⁇ LBD-antagonist complexes.
  • thirteen showed H-bond interactions between the ligand and E353; twelve showed pi interactions between the ligand and F404; five showed H-bond interactions between the ligand and D351; six showed H-bond interactions between the ligand and H524; four showed H-bond interactions between the ligand and R394; and one (3UUC) showed interactions between the ligand and T347.
  • Each of the fourteen models was used to dock a random library of 1,000 compounds plus the ligand the model was published with (the known antagonist) to determine whether the model could identify and prioritize the known antagonist. If the model could identify the known antagonist, the model was determined to be able to predict the pose of its own published ligand. EF 50 was then calculated to quantify the model's strength to see how much better it was than a random selection.
  • RAD1901 was docked in the selected models (e.g., FIGS. 23A &B- 27 A&B). Docking scores of the published ligand and RAD1901 in the models were determined. EC 50 was also determined.
  • RAD1901 had a higher docking score than the published ligand.
  • FIGS. 23A &B shows the modeling of RAD1901-1R5K (A) and GW5-1R5K (B).
  • RAD1901 bound with H-bond interactions to E353, R394, and L536; and with p-interaction with F404.
  • FIG. 24A &B shows the modeling of RAD1901-1SJ0 (A) and E4D-1SJ0 (B). RAD1901 bound with H-bond interactions to E353, and D351; and with p-interaction with F404.
  • FIG. 25A &B shows the modeling of RAD1901-2JFA (A) and RAL-2JFA (B). RAD1901 bound with p-interaction with F404.
  • FIG. 26A &B shows the modeling of RAD1901-2BJ4 (A) and OHT-2BJ4 (B).
  • RAD1901 bound with H-bond interactions with E353 and R394; and p-interaction with F404.
  • FIG. 27A &B shows the modeling of RAD1901-2IOK (A) and IOK-2IOK (B).
  • RAD1901 bound with H-bond interactions with E353, R394, and D351; and p-interaction with F404.
  • Binding conformation of RAD1901 in ER ⁇ was further optimized by IFD analysis of the five ER ⁇ crystal structures 1R5K, 1SJO, 2JFA, 2BJ4, and 2OUZ. IFD analysis accounted for the receptor flexibility (upon ligand binding) to accommodate its correct binding conformation.
  • a library of different conformations for each ligand (e.g., RAD1901 and fulvestrant) was generated by looking for a local minima as a function of rotations about rotatable bonds.
  • the library for RAD1901 had 25 different conformations.
  • the five ER ⁇ crystal structures were prepared and minimized.
  • the corresponding ligand in the published X-ray structures were used to define the ER ⁇ binding pocket.
  • RAD1901 conformations were docked into the prepared ER ⁇ structures wherein they were allowed to induce side-chain or back-bone movements to residues located in the binding pocket. Those movements allowed ER ⁇ to alter its binding site so that it was more closely conformed to the shape and binding mode of the RAD1901 conformation. In some examples, small backbone relaxations in the receptor structure and significant side-chain conformation changes were allowed in the IFD analysis.
  • Gscore is also known as GlideScore, which may be used interchangeably with docking score in this example.
  • the docking score was an estimate of the binding affinity. Therefore, the lower the value of the docking score, the “better” a ligand bound to its receptor.
  • a docking score of ⁇ 13 to ⁇ 14 corresponded to a very good binding interaction.
  • the RAD1901 conformations resulted from the IFD analysis with 1R5K, 1SJ0, 2JFA, 2BJ4, and 2OUZ respectively were superimposed to show their differences ( FIGS. 28-30A &B, shown in stick model). All bonds in each RAD1901 conformation were shown in the same color in FIGS. 28, 29 and 30A .
  • the RAD1901 conformations resulted from the IFD analysis with1R5K (blue) and 2OUZ (yellow) had N-benzyl-N-ethylaniline group of RAD1901 on the front ( FIG. 28 ).
  • the RAD1901 conformations resulted from the IFD analysis with 2BJ4 (green) and 2JFA (pink) had N-benzyl-N-ethylaniline group of RAD1901 on the back ( FIG. 29 ).
  • the RAD1901 conformations resulted from the IFD analysis with 2BJ4 (green), 2JFA (pink) and 1SJ0 (brown) were quite similar as shown by their superimpositions ( FIGS. 30A and 30B ).
  • the RAD1901 IFD docking scores are summarized in Table 14.
  • FIGS. 31A-31C The IFD of RAD1901 with 2BJ4 showed hydrogen bond interactions with E353 and D351 and pi-interactions with F404 ( FIGS. 31A-31C ).
  • FIG. 31A showed regions within the binding site suitable for H-bond acceptor group (red), H-bond donor group (blue) and hydrophobic group (yellow).
  • FIGS. 31A and 31B light blue was for carbon for RAD1901.
  • FIGS. 32A-32C show a protein-surface interactions of the IFD of RAD1901 with 2BJ4.
  • FIGS. 32A and 32B are the front view, and FIG. 32C is the side view.
  • the molecular surface of RAD1901 was blue in FIG. 32A , and green in FIG. 32C .
  • FIGS. 32B and 32C are electrostatic representation of the solvent accessible surface of ER ⁇ , wherein red represented electronegative and blue represented electropositive.
  • FIGS. 33A-33C Similar IFD analysis was carried out for fulvestrant with 2BJ4 as described supra.
  • the fulvestrant-2BJ4 IFD resulted in a Gscore of ⁇ 14.945 and showed hydrogen bond interactions with E353, Y526, and H524 and pi-interactions with F404 ( FIGS. 33A-33C ).
  • FIG. 33A showed regions within the binding site suitable for H-bond acceptor group (red), H-bond donor group (blue) and hydrophobic group (yellow).
  • light blue was for carbon for RAD1901.
  • FIGS. 34A and 34B showed RAD1901 and fulvestrant docked in 2BJ4 by IFD both had pi-interactions with F404 and hydrogen bond interactions with E353. Furthermore, RAD1901 had hydrogen bond interaction with D351 (blue representing RAD1901 molecular surface, FIG. 34B ), while fulvestrant had hydrogen bond interactions with Y526, and H524 (green representing fulvestrant molecular surface, FIG. 34C ).
  • Superimpositions of 2BJ4 docked with RAD1901 and fulvestrant are shown in FIGS. 35A and 35B .
  • green represents fulvestrant molecular surface
  • blue represents RAD1901 molecular surface.
  • the brown structure is fulvestrant and the blue structure is RAD1901.
  • Y537 resides in Helix 12. It may regulate ligand binding, homodimerization, and DNA binding once it is phosphorylated, and may allow ER ⁇ to escape phosphorylation-mediated controls and provide a cell with a potential selective tumorigenic advantage. In addition, it may cause conformational changes that makes the receptor constitutively active.
  • the Y537S mutation favors the transcriptionally active closed pocket conformation, whether occupied by ligand or not.
  • the closed but unoccupied pocket may account for ER ⁇ 's constitutive activity (Carlson et al. Biochemistry 36:14897-14905 (1997)).
  • Ser537 establishes a hydrogen-bonding interaction with Asp351 resulting in an altered conformation of the helix 11-12 loop and burial of Leu536 in a solvent-inaccessible position. This may contribute to constitutive activity of the Y537S mutant protein.
  • the Y537S surface mutation has no impact on the structure of the LBD pocket.
  • Y537C has a similar effect to Y537N.
  • D538G may shift the entire energy landscape by stabilizing both the active and inactive conformations, although more preferably the active. This may lead to constitutive activity of this mutant in the absence of hormones as observed in hormone-resistant breast cancer (Huang et al., “A newfound cancer-activating mutation reshapes the energy landscape of estrogen-binding domain,” J. Chem. Theory Comput. 10:2897-2900 (2014)).
  • Y537 and D538 may cause conformational changes that leads to constitutive receptor activation independent of ligand binding.
  • ER ⁇ constructs of WT and LBD mutant were prepared by expressing and purifying the corresponding LBD residues 302-552 with N-terminal thioredoxin and 6 ⁇ His tags which were cleaved by TEV protease.
  • Fluorescence polarization was used to determine binding of test compounds (RAD1901, fulvestrant, apeloxifene, tamoxifene, and AZD9496) to ER ⁇ as per manufacturer's instructions (Polar Screen, Invitrogen) with 2 nM fluoromone, 100 nM ER ⁇ construct of WT or LBD mutant. Each set was carried out in duplicate and tested one test compound to determine the IC50 for different ER ⁇ constructs ( FIG. 36 for RAD1901 binding essay).
  • BMD was measured by dual emission x-ray absorptiometry at baseline and after 4 weeks of treatment. Data are expressed as mean ⁇ SD. *P ⁇ 0.05 versus the corresponding OVX + Veh control. BMD, bone mineral density; E2, beta estradiol; OVX, ovariectomized; Veh, vehicle.
  • Bone microarchitecture was evaluated using microcomputed tomography. Data are expressed as mean ⁇ SD. *P ⁇ 0.05 versus the corresponding OVX + Veh control.
  • ABD apparent bone density
  • BV/TV bone volume density
  • ConnD connectivity density
  • E2 beta estradiol
  • OVX ovariectomized
  • TbN trabecular number
  • TbTh trabecular thickness
  • TbSp trabecular spacing
  • Veh vehicle.

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