US20180169101A1 - Methods for treating cancer - Google Patents

Methods for treating cancer Download PDF

Info

Publication number
US20180169101A1
US20180169101A1 US15/794,861 US201715794861A US2018169101A1 US 20180169101 A1 US20180169101 A1 US 20180169101A1 US 201715794861 A US201715794861 A US 201715794861A US 2018169101 A1 US2018169101 A1 US 2018169101A1
Authority
US
United States
Prior art keywords
rad1901
dose
palbociclib
tumor
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/794,861
Other languages
English (en)
Inventor
Gary Hattersley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Radius Pharmaceuticals Inc
Original Assignee
Radius Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Radius Pharmaceuticals Inc filed Critical Radius Pharmaceuticals Inc
Priority to US15/794,861 priority Critical patent/US20180169101A1/en
Publication of US20180169101A1 publication Critical patent/US20180169101A1/en
Priority to US16/580,914 priority patent/US11413258B2/en
Assigned to RADIUS PHARMACEUTICALS, INC. reassignment RADIUS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HATTERSLEY, GARY
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
Assigned to MIDCAP FUNDING IV TRUST, AS AGENT reassignment MIDCAP FUNDING IV TRUST, AS AGENT REAFFIRMATION, JOINDER & AMENDMENT TO SECURITY AGREEMENT (REVOLVING) Assignors: RADIUS HEALTH VENTURES, INC., RADIUS HEALTH, INC., RADIUS PHARMACEUTICALS, INC.
Assigned to MIDCAP FINANCIAL TRUST, AS AGENT reassignment MIDCAP FINANCIAL TRUST, AS AGENT REAFFIRMATION, JOINDER & AMENDMENT TO SECURITY AGREEMENT (TERM) Assignors: RADIUS HEALTH VENTURES, INC., RADIUS HEALTH, INC., RADIUS PHARMACEUTICALS, INC.
Priority to US17/852,673 priority patent/US20220339126A1/en
Assigned to RADIUS HEALTH, INC., RADIUS PHARMACEUTICALS, INC. reassignment RADIUS HEALTH, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MIDCAP FINANCIAL TRUST
Assigned to RADIUS HEALTH, INC., RADIUS PHARMACEUTICALS, INC. reassignment RADIUS HEALTH, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MIDCAP FUNDING IV TRUST
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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, 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.
  • CDKs Cell cycle regulators such as cyclins and cyclin-dependent kinases
  • CDKs cyclin-dependent kinases
  • Selective CDK4/6 inhibitors e.g., ribociclib, abemaciclib and palbociclib
  • CDK4/6 has a pivotal role in the G1-to-S-phase cell cycle transition to be targeted with improved effectiveness and fewer adverse effects to normal cells.
  • Palbociclib in combination with the aromatase inhibitor letrozole (PALoMA-1/TRIO 18 study) was approved for the treatment of hormone receptor (HR)-positive (HR+), HER2-negative (HER2 ⁇ ) advanced breast cancer as initial endocrine based therapy in postmenopausal women in February 2015.
  • palbociclib in combination with the SERD fulvestrant (PALOMA-3 study) was approved for the treatment of ER+, HER2 ⁇ advanced or metastatic breast cancer patients that had progressed on prior endocrine therapy.
  • CDK4/6 inhibitor abemaciclib LY2835219
  • endocrine therapies e.g., AIs, SERMs and SERDs
  • CDK4/6 inhibitors demonstrate toxicities that may require intermittent therapy (O'Leary). Furthermore, there remains a need for more durable and effective ER-targeted therapies that can overcome challenges associated with the current endocrine therapies, while providing additional benefits by combining with CDK4/6 inhibitors to combat cancer in advanced stage and/or with resistance to prior treatments.
  • FIG. 1 RAD1901-palbociclib combination showed improved tumor growth inhibition (TGI) compared to RAD1901 single agent treatment in various patient-derived xenograft (PDx) models regardless of ESR1 status and prior endocrine therapy. Percentage of TGI in PDx models treated with RAD1901 alone or in combination with palbociclib is shown.
  • TGI tumor growth inhibition
  • FIGS. 2A-C The combination of RAD1901 and palbociclib demonstrated tumor growth inhibition and regression in wild-type (WT) ER ⁇ MCF-7 xenograft models (PR+, HER2 ⁇ ).
  • A Tumor growth of MCF-7 xenograft models treated with vehicle control, palbociclib (45 mg/kg, p.o., q.d), fulvestrant (3 mg/dose, s.c., qwk), a combination of fulvestrant (3 mg/dose, s.c., qwk) and palbociclib (45 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 palbociclib (45 mg/kg, p.o., q.d); One-way ANOVA, “ns” is not significant, *p-way A
  • FIGS. 3A-B The combination of RAD1901 and palbociclib demonstrated tumor growth inhibition and regression in WT ER ⁇ PDx-11 models (PR+, Her2+, previously treated with aromatase inhibitor, fulvestrant, and chemotherapy).
  • n 8-10/
  • FIGS. 4A-B The combination of RAD1901 and palbociclib demonstrated tumor growth inhibition in WT ER+ PDx-2 models (PR+, Her2+, treatment na ⁇ ve).
  • A 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);
  • B Tumor growth of PDx-2 models treated with vehicle control, palbociclib (75 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 palbociclib (75 mg/kg,
  • 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. 6A-C The combination of RAD1901 and palbociclib demonstrated tumor growth inhibition in mutant (Y537S) ER ⁇ PDx-5 models (PR+, Her2+, previously treated with aromatase inhibitors).
  • A Tumor growth of PDx-5 models treated with vehicle control, fulvestrant (3 mg/dose, s.c., qwk), RAD1901 (60 mg/kg, p.o., q.d.), palbociclib (75 mg/kg, p.o., q.d), and a combination of RAD1901 (60 mg/kg, p.o., q.d.) and palbociclib (75 mg/kg, p.o., q.d);
  • B Change in individual tumor size from baseline to day 17 for fulvestrant (3 mg/dose, s.c., qwk), palbociclib (75 mg/kg, p.o., q.d), and a combination of RAD1901
  • FIGS. 7A-B The combination of RAD1901 and palbociclib demonstrated tumor growth inhibition in mutant (Y537S) ER ⁇ PDx-5 models (PR+, Her2+, previously treated with aromatase inhibitors).
  • A Tumor growth of PDx-5 models treated with vehicle control, fulvestrant (3 mg/dose, s.c., qwk), RAD1901 (60 mg/kg, p.o., q.d.), palbociclib (p.o., q.d), and a combination of RAD1901 (60 mg/kg, p.o., q.d.) and palbociclib (p.o., q.d);
  • B Tumor growth of PDx-5 models treated with vehicle control, fulvestrant (3 mg/dose, s.c., qwk), RAD1901 (120 mg/kg, p.o., q.d.), palbociclib (p.o., q.d), and
  • FIG. 8 The combination of RAD1901 and palbociclib demonstrated tumor growth inhibition in mutant (Y537S) ER ⁇ PDx-5 models (PR+, Her2+, previously treated with aromatase inhibitors).
  • n 8-10/group.
  • FIG. 9 Pharmacokinetic analysis of fulvestrant in nude mice. The plasma concentration of fulvestrant at 1 mg/dose (solid diamond), 3 mg/dose (solid circle), and 5 mg/dose (solid triangle) is shown. The nude mice were dosed subcutaneously with fulvestrant on Day 1 and the second dose on Day 8. The plasma concentration of fulvestrant was monitored at the indicated time points for up to 168 hours after the second dose.
  • FIG. 10 Effect of RAD1901 and fulvestrant (Faslodex) on mouse survival in an intracranial MCF-7 tumor model.
  • FIGS. 11A-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.
  • FIGS. 12A-B A representative image of FES-PET scan of the uterus (A) and pituitary (B) before (Baseline) and after (Post-treatment) RAD1901 treatment (500 mg).
  • FIG. 13 PR and ER expression in MCF-7 xenograft models treated with vehicle control, RAD1901, palbociclib, a combination of RAD1901 and palbociclib, fulvestrant, and a combination of fulvestrant and palbociclib.
  • FIGS. 14A-B RAD1901 treatment resulted in complete ER degradation and inhibited ER signaling in MCF-7 cell lines (A) and T47D cell lines (B) 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. 15A-C RAD1901 treatment resulted in ER degradation and abrogation of ER signaling in MCF-7 xenograft models.
  • A Western blot showing PR and ER expression in the MCF-7 xenograft models treated with vehicle control, RAD1901 at 30 and 60 mg/kg, and fulvestrant at 3 mg/dose, 2 hour or 8 hour after the last dose;
  • B ER protein expression in the MCF-7 xenograft models treated with vehicle control, RAD1901 at 30 and 60 mg/kg, and fulvestrant at 3 mg/dose, 2 hour after the last dose;
  • C PR protein expression in the MCF-7 xenograft models treated with vehicle control, RAD1901 at 30 and 60 mg/kg, and fulvestrant at 3 mg/dose, 8 hour after last dose.
  • FIGS. 16A-C RAD1901 treatment resulted in a rapid decrease in PR in MCF-7 xenograft models.
  • A 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
  • B 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
  • C Dose-dependent decrease in PR expression in MCF-7 xenograft models treated with RAD1901 at 30, 60, and 90 mg/kg.
  • FIGS. 17A-B RAD1901 treatment resulted in a rapid decrease in proliferation in MCF-7 xenograft models.
  • A 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;
  • B 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. 18 RAD1901 treatment at 30, 60, and 120 mg/kg decreased Ki67 more significantly than fulvestrant (1 mg/animal) in end of study tumors of PDx-4 models four hours on the last day of a 56 day efficacy study.
  • FIG. 19 RAD1901 treatment at 60 and 120 mg/kg resulted in reduced ER signaling in vivo in PDx-5 models with decreased PR expression.
  • FIGS. 20A-D Effect of RAD1901 on uterine tissue in newly weaned female Sprague-Dawley rats.
  • A Uterine wet weights of rats euthanized 24 hours after the final dose;
  • B Epithelial height in tissue sections of the uterus;
  • C Representative sections of Toluidine Blue O-stained uterine tissue at 400 ⁇ magnification, arrows indicate uterine epithelium;
  • D Total RNA extracted from uterine tissue and analyzed by quantitative RT-PCR for the level of complement C3 expression relative to the 18S ribosomal RNA housekeeping gene.
  • FIG. 21 Plasma pharmacokinetic results of RAD1901 at 200, 500, 750, and 1000 mg/kg after dosing on Day 7.
  • FIG. 22 3ERT (I).
  • FIG. 23 3ERT (II).
  • FIG. 24 Superimpositions of the ER ⁇ LBD-antagonist complexes summarized in Table 10.
  • FIGS. 25A-B Modeling of (A) RAD1901-1R5K; and (B) GW5-1R5K.
  • FIGS. 26A-B Modeling of (A) RAD1901-1SJ0; and (B) E4D-1SJ0.
  • FIGS. 27A-B Modeling of (A) RAD1901-2JFA; and (B) RAL-2JFA.
  • FIGS. 28A-B Modeling of (A) RAD1901-2BJ4; and (B) OHT-2BJ4.
  • FIGS. 29A-B Modeling of (A) RAD1901-2IOK; and (B) IOK-2IOK.
  • FIG. 30 Superimpositions of the RAD1901 conformations resulted from IFD analysis with 1R5K and 2OUZ.
  • FIG. 31 Superimpositions of the RAD1901 conformations resulted from IFD analysis with 2BJ4, and 2JFA.
  • FIGS. 32A-B Superimpositions of the RAD1901 conformations resulted from IFD analysis with 2BJ4, 2JFA and 1SJ0.
  • FIGS. 33A-C IFD of RAD1901 with 2BJ4.
  • FIGS. 34A-C Protein Surface Interactions of RAD1901 docked in 2BJ4 by IFD.
  • FIGS. 35A-C IFD of Fulvestrant with 2BJ4.
  • FIGS. 36A-B IFD of Fulvestrant and RAD1901 with 2BJ4.
  • FIGS. 37A-B Superimposions of IFD of Fulvestrant and RAD1901 with 2BJ4.
  • FIG. 38 RAD1901 in vitro binding assay with ER ⁇ constructs of WT and LBD mutant.
  • FIG. 39 Location of exemplary mutations of ER ⁇ and frequencies thereof.
  • 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 palbociclib demonstrated greater tumor growth inhibition than RAD1901 alone in breast cancer xenograft models, regardless of ESR1 status, PR status and prior endocrine therapy (Example I(A)).
  • the xenograft models treated had tumor expressing wild-type (WT) or mutant (e.g., Y537S) ER ⁇ , with or without PR expression, with high or low Her2 expression, and with or without prior endocrine therapy (e.g., tamoxifen (tam), AI, fulvestrant), chemotherapy (chemo), Her2 inhibitors (Her2i, e.g., trastuzumab, lapatinib), bevacizumab, and/or rituximab ( FIG. 1 ).
  • RAD1901-palbo combinations showed greater tumor growth inhibition (TGI of 65% or higher) in xenograft models wherein RAD1901 alone achieved a TGI of 26-64%; and RAD1901-palbo combinations showed greater tumor growth inhibition (TGI of 26-64%) in xenograft models wherein RAD1901 alone achieved a TGI of less than 25%.
  • RAD1901-palbo combinations showed greater tumor regression than RAD1901 alone in xenograft models that are highly responsive to RAD1901 treatment (TGI of 65% or higher), e.g., PDx-11 ( FIGS. 3A-B )
  • ER WT PDx models and ER mutant PDx models may have different level of responsiveness to treatment with fulvestrant alone, palbociclib alone, and/or a combination of fulvestrant and palbociclib (a ful-palbo combination).
  • RAD1901-palbo combinations demonstrated improved tumor growth inhibition and/or tumor regression compared to treatment with RAD1901 alone or palbociclib alone, regardless of whether the PDx models were responsive to fulvestrant treatment and/or ful-palbo combination treatment.
  • RAD1901-palbo combination may inhibit tumor growth and/or produce tumor regression in fulvestrant resistant cancers.
  • RAD1901-palbo combination treatment demonstrated improved tumor growth inhibition and/or tumor regression compared to treatment with fulvestrant alone or with the ful-palbo combination.
  • the RAD1901-palbo combination caused more significant tumor regression in more WT ER+ xenograft models than treatment with fulvestrant alone, RAD1901 alone, or palbociclib alone, even though these xenograft models have varied responsiveness to fulvestrant treatment (e.g., MCF7 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-palbo combination also caused more significant tumor regression in more WT ER+MCF7 cell line xenograft models and PDx-11 models than treatment with a ful-palbo combination ( FIGS. 2A-C and 3 A-B).
  • the RAD1901-palbo 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-palbo 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-palbo combination demonstrated tumor regression or improved tumor growth inhibition in mutant ER+(e.g., Y537S) PDx models hardly responsive to fulvestrant treatment.
  • PDx-5 is an ER Y537S mutant PDx model (PR+, Her2+, prior treatment with AI) hardly responsive to fulvestrant treatment.
  • RAD1901-palbo combination demonstrated tumor regression in PDx-5 model, while palbociclib alone or RAD1901 alone only inhibited tumor growth without causing tumor regression ( FIGS. 6A-C and 7 A-B).
  • the RAD1901-palbo combination provided similar effects with RAD1901 at a dose of 60 mg/kg or 120 mg/kg ( FIGS.
  • RAD1901-palbo combination with a lower dose of RAD1901 (e.g., 60 mg/kg) was sufficient to maximize the tumor growth inhibition/tumor regression effects in said PDx models.
  • the RAD1901-palbo combination caused more significant tumor growth inhibition than RAD1901 alone, palbociclib alone, fulvestrant alone, or the ful-palbo combination in mutant PDx-5 models ( FIG. 8 ).
  • the ful-palbo combination did not enhance tumor growth inhibition significantly compared to treatment with palbociclib alone in PDx-5 models ( FIG. 8 ).
  • RAD1901-palbo combinations provide powerful anti-tumor therapy for ER+ breast cancer expressing WT or mutant ER, with or without 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 said delivery improved mouse survival in an intracranial tumor model expressing wild-type ER ⁇ (MCF-7 xenograft model, Example I(B)).
  • MCF-7 xenograft model Example I(B)
  • a RAD1901-palbo combination is likely to also be able to cross brain-blood barrier and treat ER+ tumors in brain. This represents an additional advantage over the ful-palbo combination for treating ER+ tumors in the brain, as fulvestrant cannot cross the blood-brain barrier (Vergotel et al., “Fulvestrant, a new treatment option for advanced breast cancer: tolerability versus existing agents,” Ann.
  • a combination of RAD1901 with other CDK4/6 inhibitor(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 treatment ended while estradiol treatment continued (e.g., PDx-4 model).
  • estradiol treatment continued e.g., PDx-4 model.
  • a RAD1901-palbo combination is likely to benefit patients by inhibiting tumor growth after treatment ends, especially when CDK4/6 inhibitors (e.g., ribociclib, abemaciclib and palbociclib) can only be administered intermittently due to their side effects (O'Leary).
  • CDK4/6 inhibitors e.g., ribociclib, abemaciclib and palbociclib
  • a RAD1901-palbo combination is likely to have lower side-effects than treatment with palbociclib alone or a combination of palbociclib 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 dose of about 200 mg up to about 500 mg q.d.(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-palbo combination may be especially useful for patients having osteoporosis or a higher risk of osteoporosis.
  • RAD1901 was found to degrade wild-type ER ⁇ and abrogate ER signaling in vivo in MCF7 cell line xenograft models, and showed a dose-dependent decrease in PR in these MCF7 cell line xenograft models (Example III(B)).
  • RAD1901 decreased proliferation in MCF7 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 III(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).
  • CDK4 and/or CDK6 inhibitors as described herein e.g., ribociclib, abemaciclib and palbociclib
  • RAD1901 or solvates e.g., hydrate
  • salts thereof is likely to have therapeutic effects with relatively low side effects similar to RAD1901-palbo combinations as disclosed herein.
  • 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 CDK4/6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib) may provide strong anti-tumor therapy with relatively low side effects similar to RAD1901-palbo combinations as disclosed herein.
  • a CDK4/6 inhibitor e.g., ribociclib, abemaciclib and palbociclib
  • RAD1901 or solvates e.g., hydrate
  • CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib).
  • administration of RAD1901 or solvates (e.g., hydrate) or salts thereof 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 does not provide negative effects to muscles, bones, breast, and/or uterus.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof modulates and/or degrades ER ⁇ and mutant ER ⁇ .
  • 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 one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or a solvate (e.g., hydrate) or salt thereof.
  • the salt thereof is RAD1901 dihydrochloride having the structure:
  • the CDK4 and/or CDK6 inhibitors include, without limitation, palbociclib, abemaciclib, ribociclib, AMG925, Formula II compounds, Formula III compounds and Formula IV compounds as disclosed below, solvates thereof, salts thereof, and combinations thereof.
  • Formula II compounds have a structure of Formula II, including pharmaceutically acceptable solvates (e.g., hydrates) thereof, and pharmaceutically acceptable salts thereof:
  • a lower alkyl as used herein is an alkyl having 1, 2, 3, 4, 5, or 6 carbons.
  • Formula III compounds have a structure of Formula III, including pharmaceutically acceptable solvates (e.g., hydrates) thereof, and pharmaceutically acceptable salts thereof:
  • Formula IV compounds have a structure of Formula IV as disclosed in EP1295878B1, which is herein incorporated by reference, further including pharmaceutically acceptable solvates (e.g., hydrates) thereof, and pharmaceutically acceptable salts thereof:
  • “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 CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof may result in a decrease in tumor size versus baseline (i.e., size prior to initiation of treatment), or even eradication or partial eradication of a tumor.
  • the methods of tumor regression provided herein may be alternatively characterized as methods of reducing tumor size versus baseline.
  • 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 patient has one or more cells within the tumor expressing one or more forms of ER ⁇ .
  • the ER ⁇ -positive tumor and/or cancer is associated with breast, uterine, ovarian, or pituitary cancer.
  • the patient has a tumor located in breast, uterine, ovarian, or pituitary tissue.
  • the tumor may be associated with luminal breast cancer that may or may not be positive for HER2, and for HER2+ tumors, the tumors may express high or low HER2 (e.g., FIG. 1 ).
  • the patient has a tumor located in another tissue or organ (e.g., bone, muscle, brain), but is nonetheless associated with breast, uterine, ovarian, or pituitary cancer (e.g., tumors derived from migration or metastasis of breast, uterine, ovarian, or pituitary cancer).
  • the tumor being targeted is a metastatic tumor and/or the tumor has an overexpression of ER in other organs (e.g., bones and/or muscles).
  • the tumor being targeted is a brain tumor and/or cancer.
  • the tumor being targeted is more sensitive to a treatment of RAD1901 and a CDK4 and/or CDK 6 inhibitor 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, tax
  • the methods further comprise a step of determining whether a patient has a tumor expressing ER ⁇ prior to administering a combination of one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • the methods further comprise a step of determining whether the patient has a tumor expressing mutant ER ⁇ prior to administering a combination of one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • the methods further comprise a step of determining whether a patient has a tumor expressing ER ⁇ that is responsive or non-responsive to fulvestrant treatment prior to administering a combination of one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • 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, V392I, 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 CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof.
  • LBD ligand-binding domain
  • RAD1901 or solvates (e.g., hydrate) or salts thereof “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 or solvates (e.g., hydrate) or salts thereof preferably accumulate in tumor at a T/P (RAD1901 concentration in tumor/RAD1901 concentration in plasma) ratio of about 15 or higher, about 18 or higher, about 19 or higher, about 20 or higher, about 25 or higher, about 28 or higher, about 30 or higher, about 33 or higher, about 35 or higher, or about 40 or higher.
  • T/P RAD1901 concentration in tumor/RAD1901 concentration in plasma
  • 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 CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) 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.
  • CDK4 and/or CDK6 inhibitor(s) as described herein e.g., ribociclib, abemaciclib and palbociclib
  • RAD1901 or solvates e.g., hydrate
  • tamoxifen may be associated with bone loss in premenopausal women, and fulvestrant may impair the bone structures due to its mechanism of action
  • a combination of one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof can be particularly useful for premenopausal women, tumors resistant to tamoxifen or antiestrogen therapy, and patients having osteoporosis and/or high risk of osteoporosis.
  • RAD1901 antagonized estradiol stimulation of uterine tissues in ovariectomized rats show that RAD1901 antagonized estradiol stimulation of uterine tissues in ovariectomized rats (Example IV(A)). Furthermore, in human subjects treated with RAD1901 at a dosage of 200 mg or up to 500 mg q.d., standardized uptake value (SUV) for uterus, muscle, and bone tissues that did not significantly express ER showed hardly any changes in signals pre- and post-treatment (Example III(A)). Accordingly, in certain embodiments, such administration also does not result in undesirable effects on other tissues, including for example uterine, muscle, or breast tissue.
  • SUV standardized uptake value
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib) disclosed herein are administered in combination to a subject in need.
  • the phrase “in combination” means RAD1901 or solvates (e.g., hydrate) or salts thereof may be administered before, during, or after the administration of the CDK4 and/or CDK6 inhibitor.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib) disclosed herein 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 apart
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib) disclosed herein are administered to the subject simultaneously or substantially simultaneously.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib) disclosed herein may be administered as part of a single formulation.
  • the combination of RAD1901 or solvates (e.g., hydrate) or salts thereof and a single CDK4 and/or CDK6 inhibitor is administered to a subject.
  • the combination of RAD1901 or solvates (e.g., hydrate) or salts thereof and more than one CDK4 and/or CDK6 inhibitor is administered to a subject.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof can be combined with two or more CDK4 and/or CDK6 inhibitors for treating cancers/tumors.
  • a therapeutically effective amount of a combination of one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein is an amount that, when administered over a particular time interval, results in achievement of one or more therapeutic benchmarks (e.g., slowing or halting of tumor growth, resulting in tumor regression, cessation of symptoms, etc.).
  • the combination for use in the presently disclosed methods may be administered to a subject one time or multiple times.
  • the compounds may be administered at a set interval, e.g., daily, every other day, weekly, or monthly. Alternatively, they can be administered at an irregular interval, for example on an as-needed basis based on symptoms, patient health, and the like.
  • a therapeutically effective amount of the combination may be administered q.d. for one day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, or at least 15 days.
  • the status of the cancer or the regression of the tumor is monitored during or after the treatment, for example, by a FES-PET scan of the subject.
  • the dosage of the combination administered to the subject can be increased or decreased depending on the status of the cancer or the regression of the tumor detected.
  • the 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.
  • Examples of therapeutically effective amounts of a RAD1901 or solvates (e.g., hydrate) or salts thereof for use in the methods disclosed herein include, without limitation, about 150 to about 1,500 mg, about 200 to about 1,500 mg, about 250 to about 1,500 mg, or about 300 to about 1,500 mg dosage q.d. for subjects having resistant ER-driven tumors or cancers; about 150 to about 1,500 mg, about 200 to about 1,000 mg or about 250 to about 1,000 mg or about 300 to about 1,000 mg dosage q.d.
  • the dosage of a compound of Formula I (e.g., RAD1901) or a salt or solvate thereof for use in the presently disclosed methods general for an adult subject may be approximately 200 mg, 400 mg, 30 mg to 2,000 mg, 100 mg to 1,500 mg, or 150 mg to 1,500 mg p.o., q.d.
  • This daily dosage may be achieved via a single administration or multiple administrations.
  • a therapeutically effective amount or dosage of a CDK4 and/or CDK6 inhibitor as described herein depends on its particular type.
  • the daily dosage of a CDK4 and/or CDK6 inhibitor as described herein 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
  • Dosing of RAD1901 with abemaciclib can be accomplished with RAD1901 at 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1,000 mg per day. In particular, 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1,000 mg per day are noted. Under certain circumstances a BID dosing schedule is preferred. The surprisingly long half-life of RAD1901 in humans after PO dosing make this option particularly viable. Accordingly, the drug may be administered as 200 mg bid (400 mg total daily), 250 mg bid (500 mg total daily), 300 mg bid (600 mg total daily), 400 mg bid (800 mg daily) or 500 mg bid (1,000 mg total daily). Preferably the dosing is oral.
  • the dose of abemaciclib may be 50 mg to 500 mg daily, or 150 mg to 450 mg daily and the dosing can be daily in 28 day cycles or less than 28 days per 28 day cycles such as 21 days per 28 day cycle or 14 days per 28 day cycle or 7 days per 28 day cycles.
  • the abemaciclib is dosed once daily or preferably on a bid schedule where dosing is oral. In the case of bid dosing, the doses can be separated by 4 hours, 8 hours or 12 hours.
  • the abemaciclib is dosed at 150 mg bid via oral where the doses are recommended to be spaced out by 12 hours.
  • RAD1901 may be recommended for monotherapy treatment at doses of 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1,000 mg or more specifically at 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1,000 mg per day.
  • a reduction of the specified dose by a given fraction means that doses of 25% to 75% less than the usual dose are possible.
  • a recommended dose of RAD1901 of 400 mg per day may be reduced to between a final dose of 100 mg and 300 mg per day, or 100 mg per day, 200 mg per day or 300 mg per day. If the RAD1901 dose is reduced as described, the same percent reduction is generally applied whether the dosing is bid or once daily. For example, a 400 mg bid dose reduced by 50% would be administered on a 200 mg bid schedule. In some exceptions, a reduction of a daily recommended bid dose may be sufficient to allow for the total daily dose to be administered as a once daily dose. For example, a normal bid dose of 300 mg that is given in combination with abemaciclib may be reduced by 50%. Accordingly, the dose may be given as 150 mg bid or 300 mg once daily.
  • the normal recommended dose of abemaciclib may be reduced when used in combination with RAD1901.
  • the dose of abemaciclib may be reduced and combined with the normal recommended monotherapy dose of RAD1901 or a reduced RAD1901 dose wherein the reduced dose is 25% to 75% less than the normal recommended dose as exemplified immediately above.
  • a recommended dose of abemaciclib of 150 mg bid might be given as a bid dose of 25% to 75% less than the 150 mg bid dose.
  • 150 mg bid of abemaciclib may be reduced to a bid dose of 37.5 mg to 112.5 mg (total daily dose of 75 mg to 225 mg).
  • the dosing frequency can be reduced to 22 days to 27 days out of a 28 day cycle or to 21 days out of a 28 day cycle, or the dosing frequency may be reduced to 15 days to 20 days out of a 28 day cycle or to 14 days out of a 28 day cycle, or the dosing frequency may be reduced to 8 days to 13 days out of a 28 day cycle or to just 7 days out of a 28 day cycle.
  • the days dosed may be consecutive or combined as needed under the circumstance.
  • the total dose over a dosing interval is reduced by 25% to 75% of the recommended dose and that reduction may come as a result of less frequent dosing, reduced dosage or a combination thereof.
  • a recommended dosing cycle of 28 days of abemaciclib at a dose of 150 mg bid (300 mg total daily) results in a total dose over 28 days of 8,400 mg (28 days times 300 mg total per day). This amount can be reduced to between from 2,100 mg per 28 day to 6,300 mg per 28 day.
  • Dosing of RAD1901 with ribociclib can be accomplished with RAD1901 at 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1,000 mg per day. In particular, 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1,000 mg per day are noted. Under certain circumstances a BID dosing schedule preferred. The surprisingly long half-life of RAD1901 in humans after PO dosing make this option particularly viable. Accordingly, the drug may be administered as 200 mg bid (400 mg total daily), 250 mg bid (500 mg total daily), 300 mg bid (600 mg total daily), 400 mg bid (800 mg daily) or 500 mg bid (1,000 mg total daily). Preferably the dosing is oral.
  • the dose of ribociclib may be 200 mg to 1,000 mg daily, or 250 mg to 750 mg daily and the dosing can be daily in 28 day cycles or less than 28 days per 28 day cycles such as 21 days per 28 day cycle or 14 days per 28 day cycle or 7 days per 28 day cycles.
  • the ribociclib is dosed once daily where dosing is oral.
  • the dose of ribociclib to be used in combination with RAD1901 is 600 mg once daily and the dosing interval is 21 days out of a 28 day cycle.
  • RAD1901 may be recommended for monotherapy treatment at doses of 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1,000 mg or more specifically at 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1,000 mg per day.
  • a reduction of the specified dose by a given fraction means that doses of 25% to 75% less than the usual dose are possible.
  • a recommended dose of RAD1901 of 400 mg per day may be reduced to between a final dose of 100 mg and 300 mg per day, or 100 mg per day, 200 mg per day or 300 mg per day. If the RAD1901 dose is reduced as described, the same percent reduction is generally applied whether the dosing is bid or once daily. For example, a 400 mg bid dose reduced by 50% would be administered on a 200 mg bid schedule. In some exceptions, a reduction of a daily recommended bid dose may be sufficient to allow for the total daily dose to be administered as a once daily dose. For example, a normal bid dose of 300 mg that is given in combination with ribociclib may be reduced by 50%. Accordingly, the dose may be given as 150 mg bid or 300 mg once daily.
  • the normal recommended dose of ribociclib may be reduced when used in combination with RAD1901.
  • the dose of ribociclib may be reduced and combined with the normal recommended monotherapy dose of RAD1901 or a reduced RAD1901 dose wherein the reduced dose is 25% to 75% less than the normal recommended dose as exemplified immediately above.
  • a recommended dose of ribociclib of 600 mg qd might be given as a qd dose of 25% to 75% less than the 600 mg dose.
  • 600 mg of a recommended ribociclib dose may be reduced to a dose of between 150 mg to 450 mg.
  • the dosing frequency can be reduced to 15 to 20 days to out of a 28 day cycle or to 14 days out of a 28 day cycle, or the dosing frequency may be reduced to 8 days to 13 days out of a 28 day cycle or to 7 days out of a 28 day cycle.
  • the days dosed may be consecutive or combined as needed under the circumstance.
  • the total dose over a dosing interval is reduced by 25% to 75% of the recommended dose and that reduction may come as a result of less frequent dosing, reduced dosage or a combination thereof.
  • a recommended dosing cycle of 28 days of ribociclib results in a total dose over 28 days of 12,600 mg (21 dosing days times 600 mg total per day). This amount can be reduced to between from 3,150 mg per 28 day cycle to 9,450 mg per 28 day cycle.
  • Dosing of RAD1901 with palbociclib can be accomplished with RAD1901 at 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1,000 mg per day. In particular, 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1,000 mg per day are noted. Under certain circumstances a BID dosing schedule preferred. The surprisingly long half-life of RAD1901 in humans after PO dosing make this option particularly viable. Accordingly, the drug may be administered as 200 mg bid (400 mg total daily), 250 mg bid (500 mg total daily), 300 mg bid (600 mg total daily), 400 mg bid (800 mg daily) or 500 mg bid (1,000 mg total daily). Preferably the dosing is oral.
  • the dose of palbociclib may be 25 mg to 250 mg daily, or 50 mg to 125 mg daily or from 75 mg to 125 mg daily or 75 mg daily or 100 mg daily or 125 mg daily.
  • the dosing can be daily in 28 day cycles or less than 28 days per 28 day cycles such as 21 days per 28 day cycle or 14 days per 28 day cycle or 7 days per 28 day cycles.
  • the palbociclib is dosed once daily where dosing is oral.
  • the dose of palbociclib to be used in combination with RAD1901 is 125 mg once daily and the dosing interval is 21 days out of a 28 day cycle, or 100 mg once daily and the dosing interval is 21 days out of a 28 day cycle or 75 mg once daily and the dosing interval is 21 days out of a 28 day cycle.
  • RAD1901 may be recommended for monotherapy treatment at doses of 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1,000 mg or more specifically at 200 mg, 400 mg, 500 mg, 600 mg, 800 mg and 1,000 mg per day.
  • a reduction of the specified dose by a given fraction means that doses of 25% to 75% less than the usual dose are possible.
  • a recommended dose of RAD1901 of 400 mg per day may be reduced to between a final dose of 100 mg and 300 mg per day, or 100 mg per day, 200 mg per day or 300 mg per day. If the RAD1901 dose is reduced as described, the same percent reduction is generally applied whether the dosing is bid or once daily. For example, a 400 mg bid dose reduced by 50% would be administered on a 200 mg bid schedule. In some exceptions, a reduction of a daily recommended bid dose may be sufficient to allow for the total daily dose to be administered as a once daily dose. For example, a normal bid dose of 300 mg that is given in combination with palbociclib may be reduced by 50%. Accordingly, the dose may be given as 150 mg bid or 300 mg once daily.
  • the normal recommended dose of palbociclib may be reduced when used in combination with RAD1901.
  • the dose of palbociclib may be reduced and combined with the normal recommended monotherapy dose of RAD1901 or a reduced RAD1901 dose wherein the reduced dose is 25% to 75% less than the normal recommended dose as exemplified immediately above.
  • a recommended dose of palbociclib of 125 mg qd might be given as a qd dose of 25% to 75% less than the 125 mg dose.
  • 125 mg of a recommended palbociclib dose may be reduced to a dose of between 31.25 mg to 93.75 mg.
  • a specific pre-specified reduction dose of from 125 mg to 100 mg daily or from 125 mg to 75 mg daily may be used.
  • the dosing frequency can be reduced to 15 to 20 days to out of a 28 day cycle or to 14 days out of a 28 day cycle, or the dosing frequency may be reduced to 8 days to 13 days out of a 28 day cycle or to 7 days out of a 28 day cycle.
  • the days dosed may be consecutive or combined as needed under the circumstance.
  • the total dose over a dosing interval is reduced by 25% to 75% of the recommended dose and that reduction may come as a result of less frequent dosing, reduced dosage or a combination thereof.
  • a recommended dosing cycle of 28 days of palbociclib results in a total dose over 28 days of 2,625 mg (21 dosing days times 125 mg total per day). This amount can be reduced to between from 656.25 mg per 28 day cycle to 1,968.75 mg per 28 day cycle.
  • a recommended 28 day total cycle dose of 2,625 mg be reduced to 2,100 mg per 28 day cycle.
  • 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 CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) 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 CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) 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 combination therapy achieves a significantly improved effect by reducing the dosage of at least one or all of RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib), thereby eliminating or alleviating undesirable toxic side effects.
  • RAD1901 or solvates e.g., hydrate
  • CDK4 and/or CDK6 inhibitor(s) as described herein e.g., ribociclib, abemaciclib and palbociclib
  • 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 CDK4 and/or CDK6 inhibitor as described herein 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
  • 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 dosage of RAD1901 or solvates (e.g., hydrate) or salts thereof in a combination with a CDK4 and/or CDK6 inhibitor as described herein (e.g., ribociclib, abemaciclib and palbociclib) for use in the presently disclosed methods general for an adult subject may be approximately 30 mg to 2,000 mg, 100 mg to 1,500 mg, or 150 mg to 1,500 mg p.o., q.d. This daily dosage may be achieved via a single administration or multiple administrations.
  • a combination of one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof may be administered to a subject one time or multiple times.
  • the compounds may be administered at a set interval, e.g., daily, every other day, weekly, or monthly.
  • they can be administered at an irregular interval, for example on an as-needed basis based on symptoms, patient health, and the like.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor(s) as described herein 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 CDK4 and/or CDK6 inhibitor(s) as described herein 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 CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib) described herein are administered as part of a single formulation.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor(s) as described herein are formulated in a single pill for oral administration or in a single dose for injection.
  • combination formulations comprising RAD1901 or solvates (e.g., hydrate) or salts thereof and one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib).
  • CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib).
  • administration of the compounds in a single formulation improves patient compliance.
  • the therapeutically effective amount of each compound when administered in combination may be lower than the therapeutically effective amount of each compound administered alone.
  • a formulation comprising RAD1901 or solvates (e.g., hydrate) or salts thereof, one or more to the CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib), or both RAD1901 or solvates (e.g., hydrate) or salts thereof and the one or more CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib) may further comprise one or more pharmaceutical excipients, carriers, adjuvants, and/or preservatives.
  • the RAD1901 or solvates (e.g., hydrate) or salts thereof and the CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib) for use in the presently disclosed methods can be formulated into unit dosage forms, meaning physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times q.d.). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • the compounds may be formulated for controlled release.
  • the RAD1901 or solvates (e.g., hydrate) or salts thereof and salts or solvates and the CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib) for use in the presently disclosed methods can be formulated according to any available conventional method.
  • Examples of 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.
  • compositions include, for example, (1) an oil such as a soybean oil, a beef tallow and synthetic glyceride; (2) hydrocarbon such as liquid paraffin, squalane and solid paraffin; (3) ester oil such as octyldodecyl myristic acid and isopropyl myristic acid; (4) higher alcohol such as cetostearyl alcohol and behenyl alcohol; (5) a silicon resin; (6) a silicon oil; (7) a surfactant such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, a solid polyoxyethylene castor oil and polyoxyethylene polyoxypropylene block co-polymer; (8) water soluble macromolecule such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethyleneglycol, polyvinylpyrrolidone and methylcellulose; (9) lower alcohol such as ethanol and
  • Additives for use in the above formulations may include, for example, 1) lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide as the diluent; 2) polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatine, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polypropylene glycol-poly oxyethylene-block co-polymer, meglumine, calcium citrate, dextrin, pectin and the like as the binder; 3) starch, agar, gelatine powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectic, carboxymethylcellulose/calcium and the like as the disintegrant; 4) magnesium stearate, talc, polyethyleneglycol, silica,
  • the one or more CDK4 and/or CDK6 inhibitor(s) as described herein e.g., ribociclib, abemaciclib and palbociclib
  • RAD1901 or solvates e.g., hydrate
  • solvates e.g., hydrate
  • salts thereof for use in the presently disclosed methods
  • 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).
  • 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.
  • compositions are prepared in accordance with acceptable pharmaceutical procedures such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference.
  • pharmaceutically acceptable carrier refers to a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered and are compatible with the other ingredients in the formulation.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent.
  • the one or more CDK4 and/or CDK6 inhibitor(s) as described herein e.g., ribociclib, abemaciclib and palbociclib
  • RAD1901 or solvates e.g., hydrate
  • salts thereof in a free form can be converted into a salt by conventional methods.
  • 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, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), a quatern
  • Isomers of RAD1901 or solvates (e.g., hydrate) or salts thereof and/or the CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib) disclosed herein (e.g., geometric isomers, optical isomers, rotamers, tautomers, and the like) can be purified using general separation means, including for example recrystallization, optical resolution such as diastereomeric salt method, enzyme fractionation method, various chromatographies (for instance, thin layer chromatography, column chromatography, glass chromatography and the like) into a single isomer.
  • 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 CDK4 and/or CDK6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib), and all crystal polymorphs thereof are included in the present invention.
  • the crystal polymorph is sometimes single and sometimes a mixture, and both are included herein.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and/or CDK4 and/or CDK6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib) may be in a prodrug form, meaning that it must undergo some alteration (e.g., oxidation or hydrolysis) to achieve its active form.
  • RAD1901 or solvates (e.g., hydrate) or salts thereof and/or CDK4 and/or CDK6 inhibitor (e.g., ribociclib, abemaciclib and palbociclib) may be a compound generated by alteration of a parental prodrug to its active form.
  • Administration routes of RAD1901 or solvates (e.g., hydrate) or salts thereof and/or CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib) 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
  • this invention provides a method of treating a subpopulation of breast cancer patients wherein said sub-population has increased expression of one or more of the genes disclosed supra, and treating said sub-population with an effective dose of a combination of one or more CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof according to the dosing embodiments as described in this disclosure.
  • CDK4 and/or CDK6 inhibitor(s) as described herein (e.g., ribociclib, abemaciclib and palbociclib) and RAD1901 or solvates (e.g., hydrate) or salts thereof according to the dosing embodiments as described in this disclosure.
  • 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 RAD1901 or salt or solvate (e.g., hydrate) 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 RAD1901 or solvates (e.g., hydrate) or salts thereof and/or CDK4 and/or CDK6 inhibitor(s) (e.g., ribociclib, abemaciclib and palbociclib) disclosed herein in a therapeutically effective amount as disclosed herein for the combination methods set forth herein.
  • CDK4 and/or CDK6 inhibitor(s) e.g., ribociclib, abemaciclib and palbociclib
  • 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.
  • 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 p.o.
  • 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.
  • FFPE formalin fixed paraffin embedded
  • 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-Palbo 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-palbo combinations demonstrated improved tumor growth inhibition in PDx models (PDx-1 to PDx-12) regardless of ER status and prior endocrine therapy
  • PDx models were treated with vehicle (negative control), RAD1901 at a dosage of 60 mg/kg p.o., q.d., or a RAD1901-palbo combination with 60 mg/kg RAD1901 and palbociclib p.o., q.d. for 60 days.
  • 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 na ⁇ ve (Rx-na ⁇ ve), 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
  • RAD1901-palbo combinations demonstrated enhanced tumor growth inhibition in PDx models in which RAD1901 single agent treatment achieved TGI of 64% or lower (PDx-2, PDx-5, PDx-7, PDx-8, PDx-9, and PDx-10).
  • Said PDx models include treatment na ⁇ ve models (PDx-2, ER++, PR++ and Her2+), and models with prior treatments of aromatase inhibitor (AI, tamoxifen (tam), chemotherapy (chemo), Her2 inhibitors (Her2i, e.g., trastuzumab, lapatinib), bevacizumab, fulvestrant, and/or rituximab (PDx-5, PDx-7, PDx-8, PDx-9, and PDx-10).
  • PDx-5 models expressed mutant ESR1, while other PDx models expressed WT ESR1.
  • PDx-2, and PDx-5 models were PR+ and Her2+, while other PDx models were PR ⁇ and HER2+.
  • RAD1901 single agent treatment provided TGI of 65% or higher in PDx-6 and PDx-11 models, the differences between RAD1901 treatment with and without palbociclib could not be demonstrated in FIG. 1 . See, e.g., Example (I)(A)(ii), and FIG. 3B showing RAD1901-palbo combinations caused more significant tumor regression than RAD1901 alone in PDx11 models.
  • I(A)(ii)(1) RAD1901-palbo drove more regression than RAD1901 alone in MCF-7 xenografts that were responsive to fulvestrant treatments.
  • mice Two days before cell implantation, Balb/C-Nude mice were inoculated with 0.18/90-day release 17 ⁇ -estradiol pellets. MCF7 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.
  • vehicle control, p.o., q.d.
  • fulvestrant Fravestrant
  • RAD1901 (30 mg/kg or 60 mg/kg of the subject, p.o., q.d. to the endpoint
  • palbociclib 45 mg/kg or 75 mg/kg or 100 mg/kg, p.o., q.d. to the end point
  • RAD1901-palbo combination at doses specified from day 0. The treatment period lasted for 28 days.
  • FIGS. 2A-C demonstrate that in MCF7 Xenograft Model, RAD1901-palbo combination with RAD1901 at 60 mg/kg p.o., q.d. and palbociclib at 45 mg/kg p.o., q.d. RAD1901 (60 mg/kg p.o., q.d.) significantly reduced tumor size by about 50% by day 14. RAD1901 and palbociclib when administered alone exhibited efficacy in inhibiting tumor growth.
  • MCF7 xenograft mice were treated with vehicle (negative control), RAD1901 (30 or 60 mg/kg, p.o., q.d), palbociclib (45 mg/kg, p.o., q.d), a combination of RAD1901 (30 or 60 mg/kg, p.o., q.d) and palbociclib (45 mg/kg, p.o., q.d), fulvestrant (3 mg/dose, s.c., qwk) or a combination of fulvestrant (3 mg/dose, s.c., qwk) and palbociclib (45 mg/kg, p.o., q.d.).
  • Tumor size was measured at various time points for 27 days.
  • Results are shown in FIGS. 2A-B .
  • Treatment with the combination of RAD1901 (60 mg/kg) and palbociclib (45 mg/kg) once again resulted in significant tumor regression, with superior results to treatment with RAD1901, palbociclib, or fulvestrant alone, or with a combination of fulvestrant and palbociclib ( FIGS. 2A-B ).
  • FIG. 2C demonstrates that RAD1901-palbo 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-palbo 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 palbociclib was also more effective at decreasing ER and PR expression in vivo in the MCF7 xenograft models than treatment with RAD1901, palbociclib, or fulvestrant alone, or treatment with a combination of fulvestrant and palbociclib ( FIG. 13 ); tumors harvested two hours after the last dosing).
  • I(A)(ii)(2) RAD1901-palbo drove more tumor 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, p.o., q.d.) and palbociclib (75 mg/kg, p.o., q.d.), RAD1901 alone (60 mg/kg, p.o., q.d.), palbociclib alone (75 mg/kg, p.o., q.d.), or fulvestrant alone (3 mg/dose, s.c., qwk).
  • PDx-11 models were also treated with a combination of palbociclib (75 mg/kg, p.o., q.d.), and fulvestrant (3 mg/dose, s.c., qwk).
  • 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 RAD1901-palbo combination is likely to benefit a patient in inhibiting tumor growth after treatment ends, especially when CDK4/6 inhibitors (e.g., ribociclib, abemaciclib and palbociclib) can only be administered intermittently due to their side effects (O'Leary).
  • CDK4/6 inhibitors e.g., ribociclib, abemaciclib and palbociclib
  • I(A)(iii) RAD1901-palbo drove more regression than RAD1901 alone in xenograft models expressing mutant ER (ER ⁇ Y537S)
  • 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.
  • combination treatment of RAD1901 and palbociclib was more effective in inhibiting tumor growth than treatment with either agent alone ( FIG. 6A )).
  • These PDx models were not sensitive to fulvestrant (3 mg/dose) treatment ( FIG. 6A ).
  • Combination treatment of RAD1901 and palbociclib was more effective than treatment with either agent alone in driving tumor regressions in the RDx-5 models ( FIGS. 6B-C ),showing the change of the individual tumor size from baseline on day 17 and day 56, respectively).
  • PDx-5 was treated with vehicle (negative control), fulvestrant (faslodex 3 mg/dose, s.c., qwk), RAD1901 (60 mg/kg or 120 mg/kg, p.o., q.d.), palbociclib (100 mg/kg, p.o., q.d., dropped to 75 mg/kg mid-study due to tolerability issues), or the combination of RAD1901 (60 or 120 mg/kg, p.o., q.d.) and palbociclib (100 mg/kg, p.o., q.d., dropped to 75 mg/kg mid-study due to tolerability issues).
  • the tumor sizes measured were shown in ( FIGS. 7A-B ).
  • PDx-5 models were resistant to fulvestrant treatment, but RAD1901 and palbociclib either alone or in combination inhibited tumor growth.
  • RAD1901 alone had substantially the same efficacy as palbociclib alone at 100 mg/kg ( FIG. 7A ); while at a dose of 120 mg/kg, RAD1901 alone had an improved efficacy comparing to palbociclib alone at 100 mg/kg ( FIG. 7B ).
  • RAD1901 at 60 mg/kg p.o. achieved significant inhibition of tumor growth ( FIG. 8 ).
  • administration of palbociclib alone or in combination with fulvestrant significantly inhibited tumor growth in the mutant PDx model, although the combination did not further enhance the inhibition ( FIG. 8 ).
  • RAD1901 alone or in combination with palbociclib achieved even more significant tumor inhibition, with the combination almost completely inhibited tumor growth in the mutant PDx model; and a RAD1901-palbo combination with a lower dose of RAD1901(e.g., 60 mg/kg) was sufficient to maximize the tumor growth inhibition/tumor regression effects in PDx-5 models ( FIGS. 7A-B ).
  • 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.
  • I(B) RAD1901 promoted survival in a mouse xenograft model of brain metastasis (MCF-7 intracranial models).
  • 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)-Foxn1nu) 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 7 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 q.d.), or RAD1901 (120 mg/kg q.d.), 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).
  • RAD1901 Preferably Accumulated in Tumor and Can be Delivered to Brain
  • MCF-7 xenografts as described in Example I(A)(i) were further evaluated for RAD1901 concentration in plasma and tumor using LC-MS/MS.
  • concentration of RAD1901 in plasma was 344 ⁇ 117 ng/mL and in tumor in 11,118 ⁇ 3,801 ng/mL for the 60 mg/kg dose level.
  • a similar tumor to plasma ratio was also observed at lower dose levels where tumor concentrations were approximately 20-30 fold higher than in plasma.
  • RAD1901 levels in plasma, tumor, and brain for mice treated for 40 days are summarized in Table 1.
  • 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 labeled-estradiol to both the uterus and pituitary after RAD1901 treatment with 200 mg or 500 mg (p.o., q.d, 6 days).
  • FIGS. 11A-B 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. 11(C) ), 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).
  • FIG. 12 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., q.d., for six days.
  • FIG. 12A 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. 12A , Post-treatment) and at pituitary ( FIG. 12B , 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., q.d. in Tables 2 and 3, respectively.
  • Post-dose uterine signals were at or 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 palbociclib was also more effective at decreasing ER and PR expression in vivo in the MCF7 xenograft models (as described in Example I(A)(ii)) than treatment with RAD1901, palbociclib, or fulvestrant alone, or treatment with a combination of fulvestrant and palbociclib ( FIG. 13 ); tumors harvested two hours after the last dosing).
  • RAD1901 and fulvestrant were compared using MCF7 and T47D cell lines, both are human breast cancer cell lines, at various concentrations, 0.01 ⁇ M, 0.1 ⁇ M and 1 ⁇ M ( FIG. 14A for MCF7 cell line assays; and FIG. 14B for T47D cell lines).
  • Three ER target genes, progesterone receptor (PgR), growth regulation by estrogen in breast cancer 1 (GREB 1) and trefoil factor 1 (TFF 1) were used as markers.
  • RAD1901 caused ER degradation and inhibited ER signaling ( FIG. 14 ).
  • 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. 15A-C student's t-test: *p-value ⁇ 0.05, **p-value ⁇ 0.01
  • FIGS. 15A and 15C student's t-test: *p-value ⁇ 0.05, **p-value ⁇ 0.01
  • tumor harvested from MCF7 xenograft 8 hours after the final dose of RAD1901 treatment showed reduced PR and ER expression ( FIGS. 15A and 15C ).
  • RAD1901 treatment caused a rapid decrease in proliferation in MCF7 xenograft models.
  • tumor harvested from MCF7 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. 17A-B ).
  • 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. 18 ).
  • 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, s.c., qwk, FIG. 6A for 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. 19 ).
  • 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. 20A-D .
  • Fresh uterine tissue from each rat was fixed in 4% paraformaldehyde, dehydrated with ethanol, and embedded into JB4 plastic resin. Sections were cut at 8 ⁇ m and stained with 0.1% Toluidine Blue O. Thickness of the endometrial epithelium was measured using a Zeiss Axioskop 40 microscope using the Spot Advanced program; the mean of 9 measurements per specimen was calculated.
  • 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. 20D )).
  • RAD1901 did not increase C3 gene expression at any of the doses tested (0.3 to 100 mg/kg).
  • Immature female rats were administered p.o., q.d., for 3 consecutive days with vehicle (VEH), estradiol (E2), Raloxifene (RAL), Tamoxifen (TAM), RAD1901 or RAD1901+E2.
  • VH vehicle
  • E2 estradiol
  • RAL Raloxifene
  • TAM Tamoxifen
  • RAD1901 or RAD1901+E2 Wet uterine weights were measured.
  • Example II(A)(2) Treatment with RAD1901 Protected Against Bone Loss in Ovariectomized Rats
  • 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 q.d. 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 6)
  • the subjects were treated with placebo or at least one dose p.o., q.d. 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 7.
  • 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 8, “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 toxicities 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. 21 ).
  • the dotted box in FIG. 22 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. 24-28 ). 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.
  • FIG. 24 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. 25 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. 26 shows the modeling of RAD1901-2JFA (a) and RAL-2JFA (b). RAD1901 bound with p-interaction with F404.
  • FIG. 27 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. 28 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, 1SJ0, 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 ( FIG. 29-31 , shown in stick model). All bonds in each RAD1901 conformation were shown in the same color in FIGS. 29, 30 and 31 ( a ).
  • 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. 29 ).
  • 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. 30 ).
  • 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. 31( a ) and ( b ) ).
  • the RAD1901 IFD docking scores are summarized in V(A)-Table 5.
  • FIG. 32( a )-( c ) The IFD of RAD1901 with 2BJ4 showed hydrogen bond interactions with E353 and D351 and pi-interactions with F404 ( FIG. 32( a )-( c ) ).
  • FIG. 32( a ) 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.
  • FIG. 33( a )-( c ) show a protein-surface interactions of the IFD of RAD1901 with 2BJ4.
  • V(A)- FIGS. 33( a ) and ( b ) are the front view, and FIG.
  • FIG. 33( c ) is the side view.
  • the molecular surface of RAD1901 was blue in FIG. 33( a ) , and green in FIG. 33( c ) .
  • FIG. 33( b )-( c ) are electrostatic representation of the solvent accessible surface of ER ⁇ , wherein red represented electronegative and blue represented electropositive.
  • FIG. 34( a )-( c ) 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 ( FIG. 34( a )-( c ) ).
  • FIG. 34( a ) 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.
  • FIG. 35( a )-( b ) 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. 35( b ) ), while fulvestrant had hydrogen bond interactions with Y526, and H524 (green representing fulvestrant molecular surface, FIG. 35( c ) ). Superimpositions of 2BJ4 docked with RAD1901 and fulvestrant are shown in FIG. 36( a )-( b ) . In FIG. 36( a ) , green represents fulvestrant molecular surface and blue represents RAD1901 molecular surface. In FIG. 36( b ) , 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.
  • Y537N is common in ER ⁇ -negative metastatic breast cancer. A mutation at this site may allow ER ⁇ to escape phosphorylation-mediated controls and provide a cell with a potential selective tumorigenic advantage. Specifically, Y537N substitution induces conformational changes in the ER ⁇ that might mimic hormone binding, not affecting the ability of the receptor to dimerize, but conferring a constitutive transactivation function to the receptor (Zhang et al. Cancer Res 57:1244-1249 (1997)).
  • 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 IC 50 for different ER ⁇ constructs ( FIG. 38 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
US15/794,861 2015-04-29 2017-10-26 Methods for treating cancer Abandoned US20180169101A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US15/794,861 US20180169101A1 (en) 2015-04-29 2017-10-26 Methods for treating cancer
US16/580,914 US11413258B2 (en) 2015-04-29 2019-09-24 Methods for treating cancer
US17/852,673 US20220339126A1 (en) 2015-04-29 2022-06-29 Methods for treating cancer

Applications Claiming Priority (15)

Application Number Priority Date Filing Date Title
US201562154699P 2015-04-29 2015-04-29
US201562155451P 2015-04-30 2015-04-30
US201562158469P 2015-05-07 2015-05-07
US201562192940P 2015-07-15 2015-07-15
US201562192944P 2015-07-15 2015-07-15
US201562252085P 2015-11-06 2015-11-06
US201562252916P 2015-11-09 2015-11-09
US201562265774P 2015-12-10 2015-12-10
US201562265658P 2015-12-10 2015-12-10
US201562265696P 2015-12-10 2015-12-10
US201562265663P 2015-12-10 2015-12-10
US201662323572P 2016-04-15 2016-04-15
US201662323576P 2016-04-15 2016-04-15
PCT/US2016/030321 WO2016176666A1 (en) 2015-04-29 2016-04-29 Methods of treating cancer
US15/794,861 US20180169101A1 (en) 2015-04-29 2017-10-26 Methods for treating cancer

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/030321 Continuation WO2016176666A1 (en) 2015-04-29 2016-04-29 Methods of treating cancer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/580,914 Continuation US11413258B2 (en) 2015-04-29 2019-09-24 Methods for treating cancer

Publications (1)

Publication Number Publication Date
US20180169101A1 true US20180169101A1 (en) 2018-06-21

Family

ID=57198783

Family Applications (10)

Application Number Title Priority Date Filing Date
US15/794,910 Abandoned US20180214393A1 (en) 2015-04-29 2017-10-26 Methods for treating cancer
US15/794,774 Abandoned US20180153828A1 (en) 2015-04-29 2017-10-26 Methods for treating cancer
US15/794,861 Abandoned US20180169101A1 (en) 2015-04-29 2017-10-26 Methods for treating cancer
US16/545,859 Abandoned US20200046655A1 (en) 2015-04-29 2019-08-20 Methods For Treating Cancer
US16/580,914 Active US11413258B2 (en) 2015-04-29 2019-09-24 Methods for treating cancer
US16/985,021 Active 2036-11-29 US11819480B2 (en) 2015-04-29 2020-08-04 Methods for treating cancer
US17/510,050 Granted US20220110890A1 (en) 2015-04-29 2021-10-25 Methods for treating cancer
US17/852,673 Pending US20220339126A1 (en) 2015-04-29 2022-06-29 Methods for treating cancer
US18/367,103 Pending US20240099996A1 (en) 2015-04-29 2023-09-12 Methods for treating cancer
US18/511,036 Pending US20240091177A1 (en) 2015-04-29 2023-11-16 Methods for treating cancer

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US15/794,910 Abandoned US20180214393A1 (en) 2015-04-29 2017-10-26 Methods for treating cancer
US15/794,774 Abandoned US20180153828A1 (en) 2015-04-29 2017-10-26 Methods for treating cancer

Family Applications After (7)

Application Number Title Priority Date Filing Date
US16/545,859 Abandoned US20200046655A1 (en) 2015-04-29 2019-08-20 Methods For Treating Cancer
US16/580,914 Active US11413258B2 (en) 2015-04-29 2019-09-24 Methods for treating cancer
US16/985,021 Active 2036-11-29 US11819480B2 (en) 2015-04-29 2020-08-04 Methods for treating cancer
US17/510,050 Granted US20220110890A1 (en) 2015-04-29 2021-10-25 Methods for treating cancer
US17/852,673 Pending US20220339126A1 (en) 2015-04-29 2022-06-29 Methods for treating cancer
US18/367,103 Pending US20240099996A1 (en) 2015-04-29 2023-09-12 Methods for treating cancer
US18/511,036 Pending US20240091177A1 (en) 2015-04-29 2023-11-16 Methods for treating cancer

Country Status (14)

Country Link
US (10) US20180214393A1 (ja)
EP (4) EP3288382A4 (ja)
JP (8) JP6926065B2 (ja)
KR (6) KR102676629B1 (ja)
CN (5) CN108024540B (ja)
AU (3) AU2016256469B2 (ja)
BR (3) BR112017023228A2 (ja)
CA (3) CA2984200C (ja)
HK (3) HK1251408A1 (ja)
IL (7) IL255148B2 (ja)
MX (6) MX2021005561A (ja)
RU (3) RU2747228C2 (ja)
SG (4) SG11201708861VA (ja)
WO (3) WO2016176666A1 (ja)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020112765A1 (en) 2018-11-30 2020-06-04 Radius Pharmaceuticals, Inc. Elacestrant in combination with abemaciclib in women with breast cancer
WO2020118213A1 (en) * 2018-12-06 2020-06-11 Radius Pharmaceuticals, Inc. Methods for treating cancer resistant to cdk4/6 inhibitors
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
US11708318B2 (en) 2017-01-05 2023-07-25 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2943611A1 (en) 2014-03-28 2015-10-01 Duke University Method of treating cancer using selective estrogen receptor modulators
US9421264B2 (en) 2014-03-28 2016-08-23 Duke University Method of treating cancer using selective estrogen receptor modulators
AR107616A1 (es) 2016-02-15 2018-05-16 Sanofi Sa Compuestos de 6,7-dihidro-5h-benzo[7]anuleno sustituidos, procesos para su preparación y usos terapéuticos de los mismos
TWI794171B (zh) 2016-05-11 2023-03-01 美商滬亞生物國際有限公司 Ｈｄａｃ抑制劑與ｐｄ-ｌ１抑制劑之組合治療
TWI808055B (zh) 2016-05-11 2023-07-11 美商滬亞生物國際有限公司 Hdac 抑制劑與 pd-1 抑制劑之組合治療
IL265537B2 (en) * 2016-09-27 2023-04-01 Radius Health Inc Methods of treating ovarian cancer
CA3040266A1 (en) 2016-10-11 2018-05-24 Duke University Lasofoxifene treatment of er+ breast cancer
KR102477513B1 (ko) 2016-11-17 2022-12-16 사노피 신규 치환된 n-(3-플루오로프로필)-피롤리딘 화합물, 그의 제조 방법 및 그의 치료 용도
WO2018170447A1 (en) * 2017-03-16 2018-09-20 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of breast cancer
US12012421B2 (en) 2017-07-07 2024-06-18 Hoffmann-La Roche Inc. Solid forms of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate
EP3434272A1 (en) * 2017-07-25 2019-01-30 Sanofi Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid
JP2021503448A (ja) 2017-11-16 2021-02-12 ノバルティス アーゲー Ｌｓｚ１０２及びリボシクリブを含む医薬組合せ
US12012420B2 (en) 2017-11-21 2024-06-18 Hoffmann-La Roche, Inc. Solid forms of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate
EP3716969A1 (en) 2017-12-01 2020-10-07 Novartis AG Pharmaceutical combination comprising lsz102 and alpelisib
US11497730B2 (en) 2018-04-10 2022-11-15 Duke University Lasofoxifene treatment of breast cancer
CN110585429B (zh) * 2018-06-12 2022-10-21 江苏恒瑞医药股份有限公司 酪氨酸激酶抑制剂联合单克隆抗体以及紫杉醇类药物治疗肿瘤疾病的用途
CN112638869A (zh) 2018-09-07 2021-04-09 赛诺菲 6-(2,4-二氯苯基)-5-[4-[(3s)-1-(3-氟丙基)吡咯烷-3-基]氧基苯基]-8,9-二氢-7h-苯并[7]轮烯-2-甲酸甲酯的盐及其制备方法
WO2020118202A1 (en) * 2018-12-06 2020-06-11 Radius Pharmaceuticals, Inc. Methods for treating cancer in models harboring esr1 mutations
KR102341347B1 (ko) * 2019-11-28 2021-12-20 의료법인 성광의료재단 암 치료제에 대한 내성 암의 진단을 위한 조성물, 키트 및 방법
WO2021178846A1 (en) * 2020-03-06 2021-09-10 Olema Pharmaceuticals, Inc. Methods of treating estrogen receptor-associated diseases
WO2021231250A1 (en) * 2020-05-12 2021-11-18 Genentech, Inc. Treatment of breast cancer using combination therapies comprising gdc-9545 and a cdk4/6 inhibitor
CN113662942B (zh) * 2021-08-19 2023-02-07 中国人民解放军陆军军医大学第一附属医院 药物组合物及其在smo突变性髓母细胞瘤中的应用
WO2023064519A1 (en) 2021-10-14 2023-04-20 Teva Pharmaceuticals International Gmbh Solid state forms of elacestrant and processes for preparation thereof
GB202116903D0 (en) 2021-11-18 2022-01-05 Sermonix Pharmaceuticals Inc Lasofoxifene treatment of aromatase-resistant er+ cancer
WO2024104268A1 (zh) * 2022-11-15 2024-05-23 苏州科睿思制药有限公司 艾拉司群二盐酸盐的共晶及其制备方法和用途
KR20240105964A (ko) * 2022-12-29 2024-07-08 주식회사 삼양홀딩스 약동학적 특성이 우수한 풀베스트란트의 약학 조성물 및 그 제조 방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110124617A1 (en) * 2008-05-09 2011-05-26 Lyttle C Richard Combination Therapy for BreastCancer Comprising an Antiestrogenic Agent
US20150274640A1 (en) * 2014-03-28 2015-10-01 Duke University Method of treating cancer using selective estrogen receptor modulators
US20160279142A1 (en) * 2015-03-26 2016-09-29 Genentech, Inc. Combinations of a phosphoinositide 3-kinase inhibitor compound and a cdk4/6 inhibitor compound for the treatment of cancer

Family Cites Families (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3939346A1 (de) 1989-11-29 1991-06-06 Behringwerke Ag Arzneimitel zur subkutanen oder intramuskulaeren applikation enthaltend polypeptide
US5589452A (en) 1992-07-14 1996-12-31 Syntex (U.S.A.) Inc. Analogs of parathyroid hormone and parathyroid hormone related peptide: synthesis and use for the treatment of osteoporosis
US5977070A (en) 1992-07-14 1999-11-02 Piazza; Christin Teresa Pharmaceutical compositions for the nasal delivery of compounds useful for the treatment of osteoporosis
US5821225A (en) 1992-07-14 1998-10-13 Syntex (U.S.A.) Inc. Method for the treatment of corticosteroid induced osteopenia comprising administration of modified PTH or PTHrp
DE19517430A1 (de) 1995-05-12 1996-11-14 Boehringer Mannheim Gmbh Pharmazeutische Darreichungsform von Parathormon mit einer zwei- bis sechsstündigen Wirkstoff-Freisetzungsperiode
IT1285405B1 (it) 1995-06-06 1998-06-03 Alza Corp Modificazione di farmaci polipeptidici per accrescere il flusso per elettrotrasporto.
US5723577A (en) 1995-07-13 1998-03-03 Biomeasure Inc. Analogs of parathyroid hormone
US6544949B1 (en) 1995-07-13 2003-04-08 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Analogs of parathyroid hormone
US7410948B2 (en) 1995-07-13 2008-08-12 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Analogs of parathyroid hormone
US5955574A (en) 1995-07-13 1999-09-21 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. Analogs of parathyroid hormone
US5969095A (en) 1995-07-13 1999-10-19 Biomeasure, Inc. Analogs of parathyroid hormone
DE19538687A1 (de) 1995-10-17 1997-04-24 Boehringer Mannheim Gmbh Stabile pharmazeutische Darreichungsformen enthaltend Parathormon
DE19539574A1 (de) 1995-10-25 1997-04-30 Boehringer Mannheim Gmbh Zubereitungen und Verfahren zur Stabilisierung biologischer Materialien mittels Trocknungsverfahren ohne Einfrieren
TWI240627B (en) 1996-04-26 2005-10-01 Chugai Pharmaceutical Co Ltd Erythropoietin solution preparation
TW505654B (en) 1996-07-30 2002-10-11 Hoffmann La Roche Synthesis of analogs of PTH and PTHrP
JP2002509431A (ja) 1996-12-23 2002-03-26 イミュネックス・コーポレーション ＮＦ−κＢのレセプター活性化因子−レセプターはＴＮＦレセプタースーパーファミリーの一員である−
US6136784A (en) 1997-01-08 2000-10-24 Amylin Pharmaceuticals, Inc. Amylin agonist pharmaceutical compositions containing insulin
US6316408B1 (en) 1997-04-16 2001-11-13 Amgen Inc. Methods of use for osetoprotegerin binding protein receptors
CZ298701B6 (cs) 1997-09-09 2007-12-27 F. Hoffman-La Roche Ag Lécivo pro hojení kostí a reparaci zlomenin
US6770623B1 (en) 1997-12-09 2004-08-03 Eli Lilly And Company Stabilized teriparatide solutions
MY120063A (en) 1997-12-09 2005-08-30 Lilly Co Eli Stabilized teriparatide solutions
DE69806963T2 (de) 1997-12-11 2002-11-21 Alza Corp., Mountain View Vorrichtung zur erhöhung des transdermalen wirkstoffeflusses
ATE302041T1 (de) 1997-12-11 2005-09-15 Alza Corp Vorrichtung zur erhöhung des transdermalen wirkstoffeflusses
EP0922467A3 (en) 1997-12-12 2000-05-24 Takeda Chemical Industries, Ltd. Iontophoretic drug delivery
JP4154017B2 (ja) 1997-12-30 2008-09-24 久光製薬株式会社 イオントフォレーシス装置および薬物ユニット
US6091975A (en) 1998-04-01 2000-07-18 Alza Corporation Minimally invasive detecting device
SE9801495D0 (sv) 1998-04-28 1998-04-28 Astra Ab Protein formulationa
US6316410B1 (en) 1999-09-22 2001-11-13 National Research Council Of Canada Parathyroid hormone analogues for the treatment of osteoporosis
AU1280701A (en) 1999-11-17 2001-05-30 Novartis Ag Iontophoretic transdermal delivery of peptides
GB9930882D0 (en) 1999-12-30 2000-02-23 Nps Allelix Corp GLP-2 formulations
US20010044431A1 (en) 2000-03-21 2001-11-22 Rodriguez Gustavo C. Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium
US6756480B2 (en) 2000-04-27 2004-06-29 Amgen Inc. Modulators of receptors for parathyroid hormone and parathyroid hormone-related protein
US20050124537A1 (en) 2000-04-27 2005-06-09 Amgen Inc. Modulators of receptors for parathyroid hormone and parathyroid hormone-related protein
AU8206401A (en) 2000-08-03 2002-02-18 Antares Pharma Ipl Ag Novel composition for transdermal and/or transmucosal administration of active compounds that ensures adequate therapeutic levels
ATE309208T1 (de) 2000-08-23 2005-11-15 Akzo Nobel Nv 10-aryl-11h-benzo(b)fluoren-derivate und analoga als östrogene mittel
US7186683B2 (en) 2000-09-18 2007-03-06 Sanos Bioscience A/S Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders
US7371721B2 (en) 2000-09-18 2008-05-13 Sanos Bioscience A/S Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes
JP4659336B2 (ja) 2000-10-26 2011-03-30 アルザ・コーポレーシヨン 被覆された微細突出物を有する経皮的薬剤配達装置
BR0209046A (pt) 2001-04-20 2004-11-09 Alza Corp Disposição de microprojeção que possui um agente benéfico contendo revestimento
MXPA04000134A (es) 2001-06-26 2005-06-06 Abgenix Inc Anticuerpos para ligandos de osteoprotegerina.
US6881203B2 (en) 2001-09-05 2005-04-19 3M Innovative Properties Company Microneedle arrays and methods of manufacturing the same
US8853266B2 (en) 2001-12-06 2014-10-07 University Of Tennessee Research Foundation Selective androgen receptor modulators for treating diabetes
HUP0402605A2 (hu) 2001-12-20 2005-06-28 Alza Corporation Eszköz mikroszkopikus bemetszések ejtésére állat bőrszövetén
WO2003063859A1 (en) 2002-01-14 2003-08-07 Nordic Bioscience A/S Suppression of cartilage degradation via the estrogen receptor
CA2472956A1 (en) 2002-02-14 2003-08-21 Bayer Pharmaceuticals Corporation Formulation strategies in stabilizing peptides in organic solvents and in dried states
WO2003099849A2 (en) 2002-05-23 2003-12-04 Michael Holick Use of a parathyroid hormone peptide analogs for the treatment of vaginal atrophy
TW200307553A (en) 2002-05-24 2003-12-16 Akzo Nobel Nv Treatment of post-menopausal complaints in breast cancer patients
AU2003251527A1 (en) 2002-06-13 2003-12-31 Beth Israel Deaconess Medical Center, Inc. Analogs of parathyroid hormone and pth-related protein as bone anabolic agents
WO2004007520A2 (en) 2002-07-12 2004-01-22 Medarex, Inc. Methods and compositions for preventing oxidative degradation of proteins
EP1523367A1 (en) 2002-07-19 2005-04-20 3M Innovative Properties Company Microneedle devices and microneedle delivery apparatus
US7411039B2 (en) 2002-10-14 2008-08-12 Novo Nordisk A/S GLP-2 compounds, formulations, and uses thereof
BR0314920A (pt) 2002-10-14 2005-08-02 Novo Nordisk As Peptìdeo glp-2, construto de polinucleotìdeo, célula hospedeira, derivado de glp-2 compreendendo um peptìdeo glp-2, composição farmacêutica, uso de um derivado de glp-2, método para o tratamento de uma insuficiência intestinal ou outra condição acarretando a má absorção de nutrientes no intestino, método para o tratamento de doenças, e, método para produzir o peptìdeo glp-2
US7662404B2 (en) 2002-10-31 2010-02-16 Transpharma Medical Ltd. Transdermal delivery system for dried particulate or lyophilized peptides and polypeptides
US8133505B2 (en) 2002-10-31 2012-03-13 Transpharma Medical Ltd. Transdermal delivery system for dried particulate or lyophilized medications
US7383084B2 (en) 2002-10-31 2008-06-03 Transpharma Medical Ltd. Transdermal delivery system for dried particulate or lyophilized medications
IL152574A (en) 2002-10-31 2009-09-22 Transpharma Medical Ltd A system for passing through the skin of dry items or dried medicines
EP1567178A4 (en) 2002-11-01 2009-07-15 Amgen Inc MODULATORS OF RECEPTORS FOR NEUTRAL THERAPY HORMONE AND SIDE-HORSE HORMONE-RELATED PROTEINS
CA2512000C (en) * 2002-12-26 2011-08-09 Eisai Co., Ltd. Selective estrogen receptor modulator
WO2005000795A2 (en) 2003-06-10 2005-01-06 Smithkline Beecham Corporation Aniline derivatived androgen-, glucocorticoid-, mineralcorticoid- and progesterone- receptor modulators
US20060142387A1 (en) 2003-06-10 2006-06-29 Rodolfo Cadilla Chemical compounds
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
EP1638468B1 (en) 2003-06-30 2007-08-15 Alza Corporation Method for coating skin piercing microprojections
CA2530531A1 (en) 2003-06-30 2005-01-20 Alza Corporation Formulations for coated microprojections containing non-volatile counterions
WO2005014034A1 (en) 2003-07-14 2005-02-17 Nps Allelix Corp. Stabilized formulation of parathyroid hormone
US7141544B2 (en) 2003-10-10 2006-11-28 Baxter International, Inc. Stabilization of pharmaceutical protein formulations with small peptides
GB0324551D0 (en) 2003-10-21 2003-11-26 Karobio Ab Novel compounds
US20050124625A1 (en) 2003-10-21 2005-06-09 Salvati Mark E. Piperazine derivatives and their use as modulators of nuclear hormone receptor function
CA2543280A1 (en) 2003-10-28 2005-05-19 Alza Corporation Delivery of polymer conjugates of therapeutic peptides and proteins via coated microporjections
EP1680154B1 (en) 2003-10-31 2012-01-04 ALZA Corporation Self-actuating applicator for microprojection array
AU2004292954A1 (en) 2003-11-13 2005-06-09 Alza Corporation Composition and apparatus for transdermal delivery
US20070129409A1 (en) 2003-11-20 2007-06-07 Lain-Yen Hu Androgen receptor modulators
BRPI0416822A (pt) 2003-11-21 2007-03-06 Alza Corp método e sistema de liberação de vacina transdérmica com ultra-som
IL159273A0 (en) 2003-12-09 2004-06-01 Transpharma Medical Ltd Transdermal delivery system for sustained release of polypeptides
AU2003297904A1 (en) 2003-12-12 2005-07-14 University Of Maryland, Baltimore Immunomodulatory compounds that target and inhibit the py+3 binding site of tyrosene kinase p56 lck sh2 domain
CA2551737C (en) 2004-01-07 2009-11-10 Endorecherche, Inc. Helix 12 directed steroidal pharmaceutical products
IL160033A0 (en) 2004-01-25 2004-06-20 Transpharma Medical Ltd Transdermal delivery system for polynucleotides
TWI359026B (en) 2004-02-12 2012-03-01 Sankyo Co Pharmaceutical composition for the osteoclast rela
GB0405033D0 (en) 2004-03-05 2004-04-07 Karobio Ab Novel pharmaceutical compositions
WO2005099707A1 (en) 2004-04-08 2005-10-27 Merck & Co., Inc. 17 beta-acetamide-4-azasteroids as androgen receptor modulators
CN101151048A (zh) 2004-05-10 2008-03-26 纳斯泰克制药公司 增强甲状旁腺激素粘膜递送的组合物和方法
WO2005108351A1 (en) 2004-05-11 2005-11-17 Pfizer Products Inc. Benzonitrile derivatives to treat musculoskeletal frailty
AU2005244734A1 (en) 2004-05-13 2005-12-01 Alza Corporation Apparatus and method for transdermal delivery of parathyroid hormone agents
EP1765406A4 (en) 2004-05-21 2012-11-28 Mediplex Corp ADDITIVES FOR IMPROVED MUCOSAL ABSORPTION OF THERAPEUTIC AGENTS
US7906137B2 (en) 2004-05-21 2011-03-15 Mediplex Corporation, Korea Delivery agents for enhancing mucosal absorption of therapeutic agents
US20090069226A1 (en) 2004-05-28 2009-03-12 Amylin Pharmaceuticals, Inc. Transmucosal delivery of peptides and proteins
TW200621282A (en) 2004-08-13 2006-07-01 Wyeth Corp Stabilizing formulations
EP1807076A4 (en) 2004-10-29 2010-06-02 Merck Sharp & Dohme N- (PYRIDIN-3-YL) -2-PHENYLBUTANAMIDES AS ANDROGEN RECEPTOR MODULATORS
US8057842B2 (en) 2004-11-18 2011-11-15 3M Innovative Properties Company Method of contact coating a microneedle array
JP4927751B2 (ja) 2004-11-18 2012-05-09 スリーエム イノベイティブ プロパティズ カンパニー マイクロニードルアレイのコーティング方法
EP1848498A4 (en) 2004-11-18 2009-12-16 Transpharma Medical Ltd ASSOCIATED MICRO-CHANNEL PRODUCTION AND IONTOPHORESIS FOR TRANSDERMAL DELIVERY OF PHARMACEUTICAL AGENTS
WO2006079019A2 (en) 2005-01-21 2006-07-27 Alza Corporation Therapeutic peptide formulations for coating microneedles with improved stabitity containing at least one counterion
EP1871379A4 (en) 2005-04-15 2010-06-02 Glaxosmithkline Llc CYANOARYLAMINE
KR100700869B1 (ko) 2005-06-03 2007-03-29 재단법인 목암생명공학연구소 Ｐｔｈ, 완충제 및 안정제를 포함하는 안정한 ｐｔｈ조성물
US20090170907A1 (en) 2005-06-06 2009-07-02 Smithkline Beecham Corporation Chemical Compounds
WO2007005887A2 (en) 2005-07-01 2007-01-11 Ligand Pharmaceuticals Incorporated Androgen receptor modulator compounds, compositions and uses thereof
US20070021216A1 (en) 2005-07-19 2007-01-25 Sony Ericsson Mobile Communications Ab Seamless gaming method and apparatus
JP2008303145A (ja) 2005-09-22 2008-12-18 Takeda Chem Ind Ltd Ｇｒｋ阻害剤からなる強心薬
CA2629193C (en) 2005-11-18 2016-03-29 3M Innovative Properties Company Coatable compositions, coatings derived therefrom and microarrays having such coatings
US8632801B2 (en) 2005-12-28 2014-01-21 Alza Corporation Stable therapeutic formulations
WO2007106597A2 (en) 2006-03-15 2007-09-20 Alza Corporation Method for the transdermal delivery of parathyroid hormone agents for treating osteopenia
US9119945B2 (en) 2006-04-20 2015-09-01 3M Innovative Properties Company Device for applying a microneedle array
JP5362552B2 (ja) 2006-04-20 2013-12-11 ヴェロシス，インク． マイクロチャネルプロセス技術を用いて非ニュートン流体を処理し、および／または形成させるためのプロセス
CN101437490A (zh) 2006-04-20 2009-05-20 安美基公司 稳定乳液配方
CN101085743B (zh) 2006-06-06 2012-02-15 浙江大德药业集团有限公司 含氟烷氧基康普立停衍生物及制法和用途
CA2656067C (en) 2006-06-23 2014-08-12 Radius Health, Inc. Treatment of vasomotor symptoms with selective estrogen receptor modulators
PL2038252T3 (pl) 2006-07-12 2017-03-31 University Of Tennessee Research Foundation Podstawione acyloanilidy i sposoby ich zastosowania
EA016853B1 (ru) 2006-08-24 2012-08-30 Юниверсити Оф Теннесси Рисерч Фаундейшн Замещенные ациланилиды и их применение
AU2007287510B2 (en) 2006-08-25 2012-08-30 Ares Trading S.A. Treatment of cartilage disorders with FGF-18
CN1927815A (zh) 2006-09-25 2007-03-14 天津理工大学 邻苄胺基苯基醚化合物、化合物的衍生物及其制备方法与用途
US7803770B2 (en) 2006-10-03 2010-09-28 Radius Health, Inc. Method of treating osteoporosis comprising administration of PTHrP analog
DK2957278T3 (en) 2006-10-03 2017-07-31 Radius Health Inc STABLE COMPOSITION COMPREHENSIVE PTHRP AND APPLICATIONS THEREOF
WO2008044033A1 (en) 2006-10-11 2008-04-17 Astrazeneca Ab Amide derivatives
US20100030100A1 (en) 2007-02-06 2010-02-04 Hisamitsu Pharmaceutical Co., Inc. Microneedle Device For Diagnosis Of Allergy
WO2008121602A1 (en) 2007-03-29 2008-10-09 Smithkline Beecham Corporation Chemical compounds
WO2008124000A2 (en) 2007-04-02 2008-10-16 Ligand Pharmaceuticals Incorporated Thiazole derivatives as androgen receptor modulator compounds
AU2008241470B2 (en) 2007-04-16 2013-11-07 Corium Pharma Solutions, Inc. Solvent-cast microneedle arrays containing active
GB0707938D0 (en) 2007-04-25 2007-05-30 Univ Strathclyde Precipitation stabilising compositions
EP2155905A1 (en) 2007-05-31 2010-02-24 Dako Denmark A/S Methods for utilizing esr copy number changes in breast cancer treatments and prognoses
MX2009013575A (es) 2007-06-12 2010-07-02 Schering Corp Biomarcador de histona h2ax (hh2ax) para sensibilidad de inhibidores de farnesil proteina transferasa.
EP2155226A4 (en) 2007-06-14 2010-07-28 Univ California COMPOUNDS FOR INHIBITING AGGREGATION OF PROTEINS AND METHODS OF MAKING AND USING SAME
US20120150023A1 (en) 2007-08-06 2012-06-14 Kaspar Roger L Microneedle arrays for active agent delivery
WO2009040548A1 (en) 2007-09-28 2009-04-02 The Queen's University Of Belfast Delivery device and method
WO2009054988A1 (en) 2007-10-23 2009-04-30 Alza Corporation Transdermal sustained release drug delivery
EP2052736A1 (en) 2007-10-26 2009-04-29 Nycomed Danmark ApS Parathyroid hormone formulations und uses thereof
WO2009065126A2 (en) 2007-11-16 2009-05-22 Boston Protein Solutions Excipients for protein stabilization
WO2009133861A1 (ja) 2008-04-28 2009-11-05 武田薬品工業株式会社 環状アミン化合物
WO2010022176A1 (en) 2008-08-19 2010-02-25 Ferring International Center S.A. Methods of treatment for skeletal conditons
CN106539756A (zh) 2008-10-15 2017-03-29 精达制药公司 高浓缩药物颗粒、制剂、混悬剂及其应用
ES2548378T3 (es) 2008-11-04 2015-10-16 Aska Pharmaceutical Co., Ltd. Composición acuosa que contiene hormona foliculoestimulante
JP2012509106A (ja) 2008-11-18 2012-04-19 スリーエム イノベイティブ プロパティズ カンパニー 中空のマイクロニードルアレイ及び方法
WO2010074239A1 (ja) 2008-12-26 2010-07-01 久光製薬株式会社 マイクロニードルデバイス
US20100203014A1 (en) 2009-02-04 2010-08-12 Aegis Therapeutics Llc Zwitterionic buffered acidic peptide and protein formulations
US20100226966A1 (en) 2009-03-03 2010-09-09 Daddona Peter E Method for transdermal controlled release drug delivery
WO2010118287A1 (en) 2009-04-10 2010-10-14 Radius Health, Inc. Selective androgen receptor modulators
JP5820805B2 (ja) 2009-04-24 2015-11-24 コリウム インターナショナル， インコーポレイテッド マイクロプロジェクションのアレイの製造のためのプロセス
CA2769102C (en) 2009-07-31 2017-09-19 3M Innovative Properties Company Hollow microneedle arrays
WO2011051916A2 (en) 2009-11-02 2011-05-05 Universite De Geneve Stabilized protein formulations and use thereof
US20110172609A1 (en) 2010-01-08 2011-07-14 Ratio, Inc. Microneedle component assembly for drug delivery device
CN101912600B (zh) 2010-01-11 2014-01-29 杨国汉 改善胰岛素在溶液中稳定性的方法
IE20100174A1 (en) 2010-03-25 2012-02-29 Trinity College Dublin Transdermal administration of peptides
AU2011248108B2 (en) 2010-05-04 2016-05-26 Corium Pharma Solutions, Inc. Method and device for transdermal delivery of parathyroid hormone using a microprojection array
CA2800253C (en) 2010-05-28 2022-07-12 3M Innovative Properties Company Aqueous formulations for coating microneedle arrays
MX2012014579A (es) * 2010-06-16 2013-05-22 Endorech Inc Procedimientos de tratamiento o pevencion de enfermedades relacionadas con estrogenos.
WO2012075375A1 (en) 2010-12-02 2012-06-07 Lanco Biosciences, Inc. Delivery of parathyroid hormones by microinjection systems
EP2680871A4 (en) 2011-03-01 2015-04-22 Sloan Kettering Inst Cancer SYMBOLS HORMONE ANALOGUE, COMPOSITIONS THEREOF AND USES THEREOF
AU2012245301B2 (en) 2011-04-22 2016-05-19 3M Innovative Properties Company, A Wholly Owned Subsidiary Of 3M Company Method of drug delivery for PTH, PTHrP and related peptides
CN104080441B (zh) 2011-11-30 2020-02-28 3M创新有限公司 包括肽治疗剂和氨基酸的微针装置、制备和使用其的方法
GB201217439D0 (en) 2012-09-28 2012-11-14 Topotarget As Combination therapy
CA2915534A1 (en) 2013-06-19 2014-12-24 Seragon Pharmaceuticals, Inc. Azetidine estrogen receptor modulators and uses thereof
WO2014203129A1 (en) * 2013-06-19 2014-12-24 Olema Pharmaceuticals, Inc. Combinations of benzopyran compounds, compositions and uses thereof
CN104436194B (zh) 2013-09-18 2018-03-30 北京大学 具有协同增效作用的抗癌组合物
EP3099305A4 (en) * 2014-01-27 2017-12-06 DNA-Seq, Inc. Methods and systems for determination of an effective therapeutic regimen and drug discovery
JP2017507964A (ja) 2014-03-13 2017-03-23 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト エストロゲン受容体モジュレーターを用いた治療的組合せ
CA2943611A1 (en) * 2014-03-28 2015-10-01 Duke University Method of treating cancer using selective estrogen receptor modulators
WO2015160986A2 (en) 2014-04-16 2015-10-22 Infinity Pharmaceuticals, Inc. Combination therapies
WO2016097071A1 (en) 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Estrogen receptor modulators and uses thereof
IL255148B2 (en) 2015-04-29 2023-04-01 Radius Pharmaceuticals Inc 1901 rad for use in a method to inhibit a cancerous growth or induce tumor regression in a patient who is resistant to the drug and/or has cancer positive for an estrogen receptor alpha mutation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110124617A1 (en) * 2008-05-09 2011-05-26 Lyttle C Richard Combination Therapy for BreastCancer Comprising an Antiestrogenic Agent
US20150274640A1 (en) * 2014-03-28 2015-10-01 Duke University Method of treating cancer using selective estrogen receptor modulators
US20160279142A1 (en) * 2015-03-26 2016-09-29 Genentech, Inc. Combinations of a phosphoinositide 3-kinase inhibitor compound and a cdk4/6 inhibitor compound for the treatment of cancer

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11819480B2 (en) 2015-04-29 2023-11-21 Radius Pharmaceuticals, Inc. Methods for treating cancer
US11708318B2 (en) 2017-01-05 2023-07-25 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCL
US11643385B2 (en) 2018-07-04 2023-05-09 Radius Pharmaceuticals, Inc. Polymorphic forms of RAD1901-2HCl
WO2020112765A1 (en) 2018-11-30 2020-06-04 Radius Pharmaceuticals, Inc. Elacestrant in combination with abemaciclib in women with breast cancer
WO2020118213A1 (en) * 2018-12-06 2020-06-11 Radius Pharmaceuticals, Inc. Methods for treating cancer resistant to cdk4/6 inhibitors

Also Published As

Publication number Publication date
KR20240110098A (ko) 2024-07-12
IL307983A (en) 2023-12-01
EP3288382A4 (en) 2019-01-30
AU2016256469A1 (en) 2017-12-14
AU2016256471A1 (en) 2017-12-21
MX2017013794A (es) 2018-08-15
RU2017140675A3 (ja) 2019-09-27
CN108024540B (zh) 2021-09-17
EP3288382A1 (en) 2018-03-07
EP4039253A1 (en) 2022-08-10
JP2024120996A (ja) 2024-09-05
JP7146992B2 (ja) 2022-10-04
KR20180011780A (ko) 2018-02-02
JP2018514549A (ja) 2018-06-07
IL255189B2 (en) 2024-04-01
RU2017140675A (ru) 2019-05-29
CA2984200A1 (en) 2016-11-03
CA2984357A1 (en) 2016-11-03
AU2016256470A1 (en) 2017-12-14
RU2017140676A (ru) 2019-05-29
RU2017140676A3 (ja) 2019-09-27
RU2017140674A3 (ja) 2019-09-27
MX2021003389A (es) 2021-05-28
CN108135177A (zh) 2018-06-08
CN108024541A (zh) 2018-05-11
IL255261A0 (en) 2017-12-31
US20240099996A1 (en) 2024-03-28
CN113750091A (zh) 2021-12-07
EP3288383A1 (en) 2018-03-07
MX2017013802A (es) 2018-08-15
KR102676629B1 (ko) 2024-06-18
JP6926065B2 (ja) 2021-08-25
WO2016176666A1 (en) 2016-11-03
JP7019422B2 (ja) 2022-02-15
IL297369B2 (en) 2024-06-01
MX2017013801A (es) 2018-08-15
SG10202104177VA (en) 2021-05-28
IL310069A (en) 2024-03-01
JP2021102640A (ja) 2021-07-15
BR112017023233A2 (pt) 2018-11-06
CA2984195C (en) 2023-10-24
US11413258B2 (en) 2022-08-16
US20220339126A1 (en) 2022-10-27
US20200368183A1 (en) 2020-11-26
AU2016256470B2 (en) 2020-10-15
KR20240095372A (ko) 2024-06-25
IL255148B2 (en) 2023-04-01
IL255189A0 (en) 2017-12-31
IL255261B1 (en) 2023-11-01
SG11201708858WA (en) 2017-11-29
JP2022172039A (ja) 2022-11-14
IL255261B2 (en) 2024-03-01
BR112017023228A2 (pt) 2018-11-06
US20180214393A1 (en) 2018-08-02
EP3294065A4 (en) 2019-03-20
JP6926066B2 (ja) 2021-08-25
HK1251407A1 (zh) 2019-02-01
JP2023052631A (ja) 2023-04-11
JP2018518529A (ja) 2018-07-12
HK1251408A1 (zh) 2019-02-01
JP2018514593A (ja) 2018-06-07
AU2016256469B2 (en) 2020-12-10
AU2016256469A8 (en) 2017-12-21
AU2016256471B2 (en) 2020-09-10
WO2016176665A1 (en) 2016-11-03
US11819480B2 (en) 2023-11-21
EP3288383A4 (en) 2019-01-23
CN108024540A (zh) 2018-05-11
WO2016176664A1 (en) 2016-11-03
CN113288887A (zh) 2021-08-24
JP7516472B2 (ja) 2024-07-16
CN108135177B (zh) 2021-06-01
EP3294065A1 (en) 2018-03-21
IL255148A0 (en) 2017-12-31
HK1251409A1 (zh) 2019-02-01
CA2984200C (en) 2024-03-19
RU2017140674A (ru) 2019-05-29
RU2747228C2 (ru) 2021-04-29
US20200046655A1 (en) 2020-02-13
IL255189B1 (en) 2023-12-01
JP7262508B2 (ja) 2023-04-21
KR20180043202A (ko) 2018-04-27
KR20240097966A (ko) 2024-06-27
IL255148B (en) 2022-12-01
KR20180042155A (ko) 2018-04-25
SG11201708860SA (en) 2017-11-29
SG11201708861VA (en) 2017-11-29
JP2021105064A (ja) 2021-07-26
MX2021004881A (es) 2021-07-21
CN108024541B (zh) 2021-07-20
RU2737496C2 (ru) 2020-12-01
US20220110890A1 (en) 2022-04-14
US20200038343A1 (en) 2020-02-06
IL297369B1 (en) 2024-02-01
IL297369A (en) 2022-12-01
CA2984195A1 (en) 2016-11-03
RU2745678C2 (ru) 2021-03-30
BR112017023269A2 (pt) 2018-11-06
US20180153828A1 (en) 2018-06-07
MX2021005561A (es) 2022-07-01
KR102682763B1 (ko) 2024-07-05
IL307981A (en) 2023-12-01
KR102676705B1 (ko) 2024-06-18
US20240091177A1 (en) 2024-03-21

Similar Documents

Publication Publication Date Title
US11413258B2 (en) Methods for treating cancer

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

AS Assignment

Owner name: RADIUS PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HATTERSLEY, GARY;REEL/FRAME:050476/0098

Effective date: 20190617

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: RADIUS HEALTH, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNORS:MIDCAP FINANCIAL TRUST;MIDCAP FUNDING IV TRUST;REEL/FRAME:053315/0231

Effective date: 20200723

Owner name: RADIUS PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNORS:MIDCAP FINANCIAL TRUST;MIDCAP FUNDING IV TRUST;REEL/FRAME:053315/0231

Effective date: 20200723

AS Assignment

Owner name: MIDCAP FINANCIAL TRUST, AS AGENT, MARYLAND

Free format text: REAFFIRMATION, JOINDER & AMENDMENT TO SECURITY AGREEMENT (TERM);ASSIGNORS:RADIUS HEALTH, INC.;RADIUS PHARMACEUTICALS, INC.;RADIUS HEALTH VENTURES, INC.;REEL/FRAME:055632/0017

Effective date: 20210303

Owner name: MIDCAP FUNDING IV TRUST, AS AGENT, MARYLAND

Free format text: REAFFIRMATION, JOINDER & AMENDMENT TO SECURITY AGREEMENT (REVOLVING);ASSIGNORS:RADIUS HEALTH, INC.;RADIUS PHARMACEUTICALS, INC.;RADIUS HEALTH VENTURES, INC.;REEL/FRAME:055632/0316

Effective date: 20210303

AS Assignment

Owner name: RADIUS PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FINANCIAL TRUST;REEL/FRAME:061176/0938

Effective date: 20220815

Owner name: RADIUS HEALTH, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FINANCIAL TRUST;REEL/FRAME:061176/0938

Effective date: 20220815

Owner name: RADIUS PHARMACEUTICALS, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FUNDING IV TRUST;REEL/FRAME:061176/0914

Effective date: 20220815

Owner name: RADIUS HEALTH, INC., MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FUNDING IV TRUST;REEL/FRAME:061176/0914

Effective date: 20220815