US20210330653A1 - Dosage Regimen for the Treatment of Cancer - Google Patents

Dosage Regimen for the Treatment of Cancer Download PDF

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US20210330653A1
US20210330653A1 US17/237,112 US202117237112A US2021330653A1 US 20210330653 A1 US20210330653 A1 US 20210330653A1 US 202117237112 A US202117237112 A US 202117237112A US 2021330653 A1 US2021330653 A1 US 2021330653A1
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cancer
azd9833
dose
compound
administered
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Pablo MORENTIN GUTIERREZ
Camila DE ALMEIDA
Eric Todd GANGL
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AstraZeneca AB
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Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASTRAZENECA UK LIMITED
Assigned to ASTRAZENECA UK LIMITED reassignment ASTRAZENECA UK LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASTRAZENECA PHARMACEUTICALS LP
Assigned to ASTRAZENECA UK LIMITED reassignment ASTRAZENECA UK LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUTIERREZ, PABLO MORENTIN, DE ALMEIDA, Camila
Publication of US20210330653A1 publication Critical patent/US20210330653A1/en
Priority to US18/152,255 priority patent/US12364689B2/en
Priority to US19/240,036 priority patent/US20250352531A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/33—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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present specification relates to N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine (AZD9833, Compound (I) below) for use in the treatment of cancer, characterised in that the compound is for once daily oral administration in a specified dose.
  • the specification also relates to methods of treatment involving once daily oral administration of AZD9833 in a specified dose to a patient in need thereof, the use of AZD9833 for the production of a medicament where the medicament is for once daily oral administration in a specified dose, pharmaceutical compositions comprising certain amounts of AZD9833 and kits of such pharmaceutical compositions.
  • Estrogen receptor alpha (ER ⁇ , ESR1, NR3A) and estrogen receptor beta (ER ⁇ , ESR2, NR3b) are steroid hormone receptors which are members of the large nuclear receptor family. Structured similarly to all nuclear receptors, ER ⁇ is composed of six functional domains (named A-F) (Dahlman-Wright, et al., Pharmacol.
  • Estrogen Receptor Elements The ER ⁇ gene is located on 6q25.1 and encodes a 595AA protein and multiple isoforms can be produced due to alternative splicing and translational start sites.
  • the receptor In addition to the DNA binding domain (Domain C) and the ligand binding domain (Domain E) the receptor contains a N-terminal (A/B) domain, a hinge (D) domain that links the C and E domains and a C-terminal extension (F domain). While the C and E domains of ER ⁇ and ER ⁇ are quite conserved (96% and 55% amino acid identity respectively) conservation of the A/B, D and F domains is poor (below 30% amino acid identity). Both receptors are involved in the regulation and development of the female reproductive tract and in addition play roles in the central nervous system, cardiovascular system and in bone metabolism.
  • ERs The genomic action of ERs occurs in the nucleus of the cell when the receptor binds EREs directly (direct activation or classical pathway) or indirectly (indirect activation or non-classical pathway).
  • ERs are associated with heat shock proteins, Hsp90 and Hsp70, and the associated chaperone machinery stabilizes the ligand binding domain (LBD) making it accessible to ligand.
  • LBD ligand binding domain
  • Liganded ER dissociates from the heat shock proteins leading to a conformational change in the receptor that allows dimerization, DNA binding, interaction with co-activators or co-repressors and modulation of target gene expression.
  • AP-1 and Sp-1 are alternative regulatory DNA sequences used by both isoforms of the receptor to modulate gene expression.
  • ER does not interact directly with DNA but through associations with other DNA bound transcription factors e.g. c-Jun or c-Fos (Kushner et al., Pure Applied Chemistry 2003, 7a:1757-1769).
  • c-Jun or c-Fos DNA bound transcription factors
  • the precise mechanism whereby ER affects gene transcription is poorly understood but appears to be mediated by numerous nuclear factors that are recruited by the DNA bound receptor.
  • the recruitment of co-regulators is primarily mediated by two protein surfaces, AF2 and AF which are located in the E-domain and the A/B domain respectively.
  • AF1 is regulated by growth factors and its activity depends on the cellular and promoter environment whereas AF2 is entirely dependent on ligand binding for activity.
  • the two domains can act independently, maximal ER transcriptional activity is achieved through synergistic interactions via the two domains (Tzukerman, et al., Mol. Endocrinology 1994, 8:21-30).
  • ERs are considered transcription factors they can also act through non-genomic mechanisms as evidenced by rapid ER effects in tissues following E2 administration in a timescale that is considered too fast for a genomic action.
  • ER ⁇ has been shown to have ligand independent activity through AF-1 which has been associated with stimulation of MAPK through growth factor signalling e.g. insulin like growth factor 1 (IGF-1) and epidermal growth factor (EGF).
  • IGF-1 insulin like growth factor 1
  • EGF epidermal growth factor
  • Activity of AF-1 is dependent on phosphorylation of Ser118 and an example of cross-talk between ER and growth factor signalling is the phosphorylation of Ser 118 by MAPK in response to growth factors such as IGF-1 and EGF (Kato, et al., Science. 1995, 270:1491-1494).
  • SERMs selective estrogen receptor modulators
  • tamoxifen have the ability to act as both receptor agonists and antagonists depending on the cellular and promoter context as well as the ER isoform targeted.
  • tamoxifen acts as an antagonist in breast but acts as a partial agonist in bone, the cardiovascular system and uterus. All SERMs appear to act as AF2 antagonists and derive their partial agonist characteristics through AF1.
  • a second group fulvestrant being an example, are classified as full antagonists and are capable of blocking estrogen activity via the complete inhibition of AF1 and AF2 domains through induction of a unique conformation change in the ligand binding domain (LBD) on compound binding which results in complete abrogation of the interaction between helix 12 and the remainder of the LBD, blocking co-factor recruitment (Wakeling, et al., Cancer Res., 1991, 51:3867-3873; Pike, et al., Structure, 2001, 9:145-153).
  • LBD ligand binding domain
  • Intracellular levels of ER ⁇ are downregulated in the presence of E2 through the ubiquitin/proteasome (Ub/26S) pathway.
  • Polyubiquitinylation of liganded ER ⁇ is catalysed by at least three enzymes; the ubiquitin-activating enzyme E1 activated ubiquitin is conjugated by E2 with lysine residues through an isopeptide bond by E3 ubiquitin ligase and polyubiquitinated ER ⁇ is then directed to the proteasome for degradation.
  • ER and/or progesterone receptors implying the hormone dependence of these tumor cells for growth.
  • Other cancers such as ovarian and endometrial are also thought to be dependent on ER ⁇ signalling for growth.
  • Therapies for such patients can inhibit ER signalling either by antagonising ligand binding to ER e.g. tamoxifen which is used to treat early and advanced ER positive breast cancer in both pre- and post-menopausal setting; antagonising and down-regulating ER ⁇ e.g. fulvestrant which is used to treat breast cancer in women which have progressed despite therapy with tamoxifen or aromatase inhibitors; or blocking estrogen synthesis e.g.
  • aromatase inhibitors which are used to treat early and advanced ER positive breast cancer. Although these therapies have had an enormously positive impact on breast cancer treatment, a considerable number of patients whose tumors express ER display de novo resistance to existing ER therapies or develop resistance to these therapies over time.
  • Several distinct mechanisms have been described to explain resistance to first-time tamoxifen therapy which mainly involve the switch from tamoxifen acting as an antagonist to an agonist, either through the lower affinity of certain co-factors binding to the tamoxifen-ER ⁇ complex being off-set by over-expression of these co-factors, or through the formation of secondary sites that facilitate the interaction of the tamoxifen-ER ⁇ complex with co-factors that normally do not bind to the complex.
  • Resistance could therefore arise as a result of the outgrowth of cells expressing specific co-factors that drive the tamoxifen-ER ⁇ activity.
  • growth factor signalling pathways directly activate the ER receptor or co-activators to drive cell proliferation independently of ligand signalling.
  • mutations in ESR1 have been identified as a possible resistance mechanism in metastatic ER-positive patient derived tumor samples and patient-derived xenograft models (PDX) at frequencies varying from 17-25%. These mutations are predominantly, but not exclusively, in the ligand-binding domain leading to mutated functional proteins; examples of the amino acid changes include Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn and Asp538Gly, with changes at amino acid 537 and 538 constituting the majority of the changes currently described. These mutations have been undetected previously in the genomes from primary breast samples characterised in the Cancer Genome Atlas database.
  • AZD9833 N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine, optionally provided as a pharmaceutically acceptable salt thereof, has been identified as a compound with the ability to act as a selective estrogen receptor down-regulator (SERD).
  • AZD9833 is described as example 17 in WO2018/077630A1 wherein methods for the synthesis of the compound and its biological activity in in vitro and in vivo experiments are disclosed.
  • the only SERD currently approved for clinical use that is administered by intramuscular injection, preclinical work indicated that AZD9833 has a physicochemical profile compatible with oral administration.
  • AZD9833 administered orally on a daily basis might achieve superior estrogen receptor degradation than that delivered by fulvestrant.
  • preliminary results from clinical trials on daily oral administration of AZD9833 has led to the discovery of a range of doses that in heavily pre-treated patients have elicited partial response as established according to the RECIST criteria (for example according to RECIST 1.1 criteria, see https://recist.eortc.org/; Eur. J. Cancer 2016, 62, Pages 132-137).
  • AZD9833 for use in the treatment of cancer where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • a method of treatment for cancer comprising administration of AZD9833 in a dose between 25 mg and 450 mg once daily to a patient in need thereof.
  • AZD9833 in the manufacture of a medicament for the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • a pharmaceutical composition for once daily oral administration comprising between 25 mg and 450 mg of AZD9833 and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition for once daily oral administration comprising between 25 mg and 450 mg of AZD9833 and a pharmaceutically acceptable excipient for use in the treatment of cancer.
  • kits comprising a pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient and instructions for the use of the pharmaceutical composition in the treatment of cancer, where the AZD9833 is for once daily administration at a dose between 25 mg and 450 mg.
  • FIG. 1 Schematic of the dose-escalation phase of a phase I clinical trial in heavily pre-treated patients breast cancer patients suitable to demonstrate the benefits of AZD9833 treatments across the dose range.
  • FIG. 2 Swimmer plot of patient responses after treatment with ascending doses of AZD9833.
  • FIG. 3 Composite waterfall plot showing best change in tumor size from baseline in patients treated with varying doses of AZD9833.
  • FIG. 4 Mean plasma concentration over time plot following administration of AZD9833 at varying doses.
  • A” or “an” mean “at least one”. In any embodiment where “a” or “an” are used to denote a given element, “a” or “an” may mean one. In any embodiment where “a” or “an” are used to denote a given element, “a” or “an” may mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • a certain feature may be present, the feature may be present in a suitable embodiment in any part of the specification, not just a suitable embodiment in the same section or textual region of the specification.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • AZD9833 for use in producing an anti-proliferative effect, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • AZD9833 for selectively inhibiting ER ⁇ , where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • AZD9833 in the manufacture of a medicament for the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • AZD9833 in the manufacture of a medicament for producing an anti-proliferative effect, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • AZD9833 in the manufacture of a medicament for selectively inhibiting ER ⁇ , where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg.
  • a method of treating cancer in a human or animal patient in need of such treatment comprising administering to the patient AZD9833 orally once daily at a dose between 25 mg and 450 mg.
  • a method of producing an anti-proliferative effect in a human or animal patient in need of such an effect comprising administering to the patient AZD9833 orally once daily at a dose between 25 mg and 450 mg.
  • a method of selectively inhibiting ER ⁇ in a human or animal patient in need of such an effect comprising administering to the patient AZD9833 orally once daily at a dose between 25 mg and 450 mg.
  • AZD9833 may be N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine or a pharmaceutically acceptable salt thereof.
  • N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine has the structure of compound (I) above.
  • AZD9833 may be N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetra hydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine in a salt-free form (for example in a neutral or zwitterionic form, or for example in a free base form).
  • AZD9833 may be a pharmaceutically acceptable salt of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine.
  • pharmaceutically acceptable is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients.
  • An example list of pharmaceutically acceptable salts can be found in the “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VFiCA, 2002 or subsequent editions.
  • a suitable pharmaceutically acceptable salt of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine is, for example, an acid-addition salt.
  • An acid addition salt of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from acetic acid, adipic acid, benzene sulfonic acid, benzoic acid, cinnamic acid, citric acid, D,L-lactic acid, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, hydrochloric acid, L-tartaric acid, maleic acid, malic acid, malonic acid, methane sulfonic acid, napadisylic acid, phosphoric acid, saccharin, succinic acid, sulfuric acid, p-toluene sulfonic acid, toluene sulfonic acid and trifluoroacetic acid.
  • a further suitable pharmaceutically acceptable salt of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine is, for example, a salt formed within the human or animal body after administration of N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine to said human or animal body.
  • the dose of AZD9833 may be selected from 25 mg, 75 mg, 150 mg, 300 mg and 450 mg.
  • the dose of AZD9833 may be 25 mg.
  • the dose of AZD9833 may be 75 mg.
  • the dose of AZD9833 may be 150 mg.
  • the dose of AZD9833 may be 300 mg.
  • the dose of AZD9833 may be 450 mg.
  • the dose of AZD9833 may be an oral daily dose.
  • oral daily dose is the amount of AZD9833 administered by mouth in a 24-hour period.
  • the AZD9833 may be administered as a single dose.
  • the AZD9833 may be administered as a divided dose.
  • a “divided dose” is one where the total dose (for example the oral daily dose) is administered in multiple (for example 1, 2, 3, 4 or 5) portions.
  • the AZD9833 may be administered as a single dose unit or as multiple dose units.
  • a “dose unit” is a discrete dosage form, for example a specified number (for example 1, 2, 3, 4 or 5) of tablets or capsules.
  • the AZD9833 may be administered as a single tablet.
  • the AZD9833 may be administered as a single tablet once daily.
  • the AZD9833 may be administered orally as a single tablet once daily.
  • a range of doses for AZD9833 for example, a dose between 25 mg and 450 mg
  • the range includes the doses at the endpoints of the range as well as doses falling in between those endpoints, i.e. 25 mg and 450 mg and quantities in between.
  • Cancer is used synonymously with tumor and lesion in this specification. Cancer may include primary cancer as well as secondary cancers and metastases.
  • treatment of cancer encompass treating an existing cancer and/or preventing cancer.
  • the treatment of cancer or treating cancer may mean treating and preventing cancer.
  • the treatment of cancer or treating cancer may mean treating cancer.
  • the treatment of cancer or treating cancer may mean preventing cancer.
  • cancer may be selected from breast cancer and gynaecological cancer.
  • “Gynaecological cancer” includes womb cancer, ovarian cancer, cervical cancer, vulva cancer and vaginal cancer.
  • cancer may be selected from breast cancer, womb cancer, ovarian cancer, cervical cancer, vulva cancer and vaginal cancer.
  • cancer may be ER-positive HER2-negative breast cancer.
  • ER-positive HER2-negative breast cancer comprises tumors with estrogen receptors (are ER-positive) that do not have high levels of the HER2 gene or the HER2 protein (are HER2-negative). ER-positive and HER2-negative status can be determined by methods known in the art, including the use of commercial kits.
  • breast cancer may be ER-positive breast cancer.
  • breast cancer may be HER2-negative breast cancer.
  • cancer may be ER-positive HER2-negative advanced breast cancer.
  • breast cancer may be ER-positive advanced breast cancer.
  • breast cancer may be HER2-negative advanced breast cancer.
  • AZD9833 may be administered to a pre- or post-menopausal woman.
  • AZD9833 may be administered to a pre-menopausal woman.
  • AZD9833 may be administered to a post-menopausal woman.
  • AZD9833 may be administered to a pre- or post-menopausal woman whose cancer is ER-positive.
  • AZD9833 may be administered to a pre- or post-menopausal woman whose cancer is HER2-negative.
  • AZD9833 may be administered to a pre- or post-menopausal woman whose cancer is ER-positive and HER2-negative.
  • AZD9833 may be administered to a pre- or post-menopausal woman whose cancer has an ESR1 mutation.
  • AZD9833 may be administered to a pre- or post-menopausal woman whose cancer does not have an ESR1 mutation.
  • AZD9833 may be administered to a patient whose cancer has previously been treated with between 1 and 15 anti-cancer therapies.
  • AZD9833 may be administered to a patient whose cancer has previously been treated with between 1 and 10 anti-cancer therapies.
  • AZD9833 may be administered to a patient whose cancer has previously been treated with between 1 and 5 anti-cancer therapies.
  • AZD9833 may be administered to a patient whose cancer has previously been treated with between 5 and 10 anti-cancer therapies.
  • a patient has “previously been treated”, this refers to any treatment administered to the patient prior to them being dosed with AZD9833.
  • Previous treatment does not imply that the therapy in question was successful or curative, only that a patient received treatment with the therapy (for example, as a result of being prescribed the therapy by a suitably qualified healthcare professional).
  • Anti-cancer therapies include medicaments, drugs, compounds or other medical approaches (for example treatments using a patient's own immunological agents) aimed at the treatment of cancer.
  • Example anti-cancer therapies are endocrine therapies and chemotherapies.
  • Endocrine therapies are those which work by modulating a patient's hormonal pathways. Examples include estrogen inhibitors (such as tamoxifen or fulvestrant), aromatase inhibitors (such as letrozole, anastrozole, vorazole or exemestane), progestogens (such as megestrol acetate) and luteinising hormone blockers (such as leuprolide or goserelin).
  • estrogen inhibitors such as tamoxifen or fulvestrant
  • aromatase inhibitors such as letrozole, anastrozole, vorazole or exemestane
  • progestogens such as megestrol acetate
  • luteinising hormone blockers such as leuprolide or goserelin
  • “Chemotherapies” are cancer therapies which are not endocrine therapies. They include for example:
  • AZD9833 may be administered to a patient whose cancer has previously been treated with ⁇ 1 endocrine therapy and ⁇ 2 chemotherapies.
  • AZD9833 may be administered to a patient whose cancer has previously been treated with ⁇ 1 endocrine therapy and ⁇ 2 chemotherapies for ER-positive HER2-negative breast cancer.
  • “Chemotherapies for ER-positive HER2-negative breast cancer” may include any anti-cancer regimen(s) comprising at least one cytotoxic agent given for 21 days or longer.
  • AZD9833 may be administered to a patient whose cancer has previously been treated with ⁇ 1 endocrine therapy and ⁇ 2 chemotherapies for ER-positive HER2-negative advanced breast cancer.
  • the ⁇ 1 endocrine therapy may be selected from an estrogen inhibitor, an aromatase inhibitor, a progestogen and a luteinising hormone blocker.
  • the ⁇ 1 endocrine therapy may be selected from tamoxifen, toremifene, raloxifene, droloxifene, idoxifene, fulvestrant, letrozole, anastrozole, vorazole, exemestane, megestrol acetate, leuprolide and goserelin.
  • the ⁇ 2 chemotherapies may be selected from a CDK inhibitor (such as a CD4, CDK6, or CDK4/CDK6 dual inhibitor) and an mTOR inhibitor.
  • a CDK inhibitor such as a CD4, CDK6, or CDK4/CDK6 dual inhibitor
  • an mTOR inhibitor such as a CD4, CDK6, or CDK4/CDK6 dual inhibitor
  • the ⁇ 2 chemotherapies may be selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib and everolimus.
  • AZD9833 may be administered to a patient whose cancer is resistant to aromatase inhibitors.
  • AZD9833 may be administered to a patient whose cancer is resistant to non-steroidal aromatase inhibitors.
  • AZD9833 may be administered to a patient whose cancer is resistant to an aromatase inhibitor selected from letrozole and anastrozole.
  • AZD9833 may be administered to a patient whose cancer is resistant to tamoxifen.
  • AZD9833 may be administered to a patient whose cancer is resistant to fulvestrant.
  • AZD9833 may be administered to a patient whose cancer is resistant to CDK inhibitors.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a mean peak blood plasma concentration in a cancer patient of between 10 and 1000 ng/mL.
  • peak mean blood plasma concentration refers to the maximum amount of AZD9833 achieved in a patient's plasma following treatment.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a median terminal half-life of between 8 h and 14 h in a cancer patient.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a median terminal half-life of 12 h in a cancer patient.
  • the “median terminal half-life” is the median time for a patient's drug blood plasma concentration to halve after reaching pseudo-equilibrium.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves an objective response rate between 10% and 20%.
  • “Objective response rate” is the percentage of patients with measurable disease at baseline and who have a date of first dose of 217 weeks or a date of post-treatment scan of 215 weeks that indicates a confirmed response as measured by the RECIST criteria.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a clinical benefit rate between 25% and 100%.
  • “Clinical benefit rate” is the percentage of patients who have a date of first dose of 225 weeks or a date of post-treatment scan of 223 weeks that indicates a confirmed response or stable disease as measured by the RECIST criteria for >23 weeks post treatment.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a clinical benefit rate greater than 25%.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a clinical benefit rate between 25% and 90%.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a clinical benefit rate between 25% and 80%.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and achieves a clinical benefit rate between 25% and 75%.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg and does not cause any serious side-effects in a cancer patient.
  • serious side-effects may be defined as grade 4 or 5 adverse events.
  • AZD9833 for use in the treatment of cancer, where the AZD9833 is administered orally once daily at a dose between 25 mg and 450 mg in combination with a further anti-cancer therapy.
  • the combination may comprise the separate, sequential, or simultaneous administration of the drugs.
  • the interval between the dose of AZD9833 and the dose of the further anti-cancer therapy may be chosen to ensure the production of a combined therapeutic effect.
  • the administration of the AZD9833 and a further anti-cancer therapy is separate.
  • the administration of the AZD9833 and a further anti-cancer therapy is sequential.
  • the administration of the AZD9833 and a further anti-cancer therapy is separate and sequential.
  • the further anti-cancer therapy may be a CDK inhibitor.
  • the further anti-cancer therapy may be a CDK4 inhibitor.
  • the further anti-cancer therapy may be a CDK6 inhibitor.
  • the further anti-cancer therapy may be a dual CDK4/CDK6 inhibitor.
  • the further anti-cancer therapy may be a CDK inhibitor selected from palbociclib, ribociclib, abemaciclib, lerociclib or trilaciclib.
  • the further anti-cancer therapy may be palbociclib.
  • the further anti-cancer therapy may be an mTOR inhibitor.
  • the further anti-cancer therapy may be an mTOR inhibitor selected from sirolimus, deforolimus, everolimus and temsirolimus.
  • the further anti-cancer therapy may be everolimus.
  • the further anti-cancer therapy may be everolimus which is administered orally once daily at a dose of up to 10 mg.
  • the further anti-cancer therapy may be selected from palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib and everolimus.
  • the further anti-cancer therapy may be selected from palbociclib, ribociclib, abemaciclib, lerociclib and trilaciclib.
  • the further anti-cancer therapy may be an AKT inhibitor.
  • the further anti-cancer therapy may be selected from capivasertib, afuresertib, miransertib, ARQ751, ipataserib, MK-2206 or perifosine.
  • composition for once daily oral administration comprising between 25 mg and 450 mg of AZD9833 and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipients may be selected from inert diluents (for example microcrystalline cellulose or dicalcium phosphate anhydrous), granulating agents, disintegrating agents (for example sodium starch glycolate), binding agents, lubricating agents (for example magnesium stearate), preservative agents, antioxidants and chelating agents.
  • inert diluents for example microcrystalline cellulose or dicalcium phosphate anhydrous
  • disintegrating agents for example sodium starch glycolate
  • binding agents for example sodium starch glycolate
  • lubricating agents for example magnesium stearate
  • preservative agents antioxidants and chelating agents.
  • the composition for once daily oral administration comprises between 25 mg and 450 mg of AZD9833, for example 25 mg, 75 mg or 100 mg of AZD9833, and at least one diluent selected from microcrystalline cellulose (MCC), dicalcium phosphate anhydrous (DCPA), mannitol, lactose, dicalcium phosphate, calcium sulfate dihydrate, tribasic calcium phosphate, dibasic calcium phosphates dihydrate, silicified microcrystalline cellulose, their co-processed combinations, polydextrose, trehalose, sucrose, glucose, cyclodextrin and hydroxypropyl cellulose.
  • MCC microcrystalline cellulose
  • DCPA dicalcium phosphate anhydrous
  • mannitol lactose
  • dicalcium phosphate calcium sulfate dihydrate
  • tribasic calcium phosphate dibasic calcium phosphates dihydrate
  • silicified microcrystalline cellulose their co-processed combinations, polydextrose,
  • composition for once daily oral administration may further comprise at least one disintegrant selected from croscarmellose sodium, crospovidone, sodium starch glycolate (SSG) and low substituted hydroxypropyl cellulose (L-HPC).
  • disintegrant selected from croscarmellose sodium, crospovidone, sodium starch glycolate (SSG) and low substituted hydroxypropyl cellulose (L-HPC).
  • composition for once daily oral administration may further comprise at least one lubricant selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate and stearic acid.
  • at least one lubricant selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate and stearic acid.
  • a pharmaceutical composition comprising between 25 mg and 450 mg of AZD9833 and a pharmaceutically acceptable excipient in the form of a tablet or a capsule for once daily oral administration.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures known in the art.
  • tablet formulations may be treated such that they release active ingredients immediately.
  • a pharmaceutical composition comprising between 25 mg and 450 mg of AZD9833, for example between 25 and 100 mg of AZD9833, and a pharmaceutically acceptable excipient, which composition is an immediate release composition.
  • a pharmaceutical composition comprising between 25 mg and 450 mg of AZD9833, for example between 25 and 100 mg of AZD9833, and a pharmaceutically acceptable excipient in the form of a single tablet for once daily oral administration.
  • compositions for oral use may alternatively be in the form of hard gelatine capsules in which the active ingredient is mixed with an inert solid diluent, or as soft gelatine capsules in which the active ingredient is mixed with water or an oil.
  • a pharmaceutical composition comprising between 25 mg and 450 mg of AZD9833, for example between 25 and 100 mg of AZD9833, and a pharmaceutically acceptable excipient in the form of a single capsule for once daily oral administration.
  • a pharmaceutical composition comprising between 25 mg and 450 mg of AZD9833, for example between 25 and 100 mg of AZD9833, and a pharmaceutically acceptable excipient in the treatment of cancer, where the pharmaceutical composition is administered once daily.
  • kits comprising a pharmaceutical composition comprising AZD9833 and at least one pharmaceutically acceptable excipient and instructions for the use of the pharmaceutical composition in the treatment of cancer, where the AZD9833 is for once daily administration at a dose between 25 mg and 450 mg.
  • HER2 negative advanced breast cancer Phase 1 dose-escalation and expansion in patients with ER positive, HER2 negative advanced breast cancer was carried out according to the following basic protocol.
  • AZD9833 has the potential to provide superior clinical benefit to existing endocrine therapies through enhanced bioavailability (compared to fulvestrant, which is administered intramuscularly) and target (estrogen receptor) engagement and modulation in patients with estrogen receptor positive (ER+) breast cancer.
  • the study's primary objective is to determine the safety and tolerability of AZD9833 in women with ER+ human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
  • HER2- human epidermal growth factor receptor 2 negative
  • Solid Tumour RECIST
  • Objective response rate ORR
  • DoR Duration of response
  • CBR 24weeks Percentage change in tumour size
  • PFS Progression-free survival
  • AZD9833 To characterise the Plasma and urine AZD9833 single- and multiple-dose concentrations and derived pharmacokinetics of pharmacokinetic parameters.
  • AZD9833 To investigate AZD9833 activity Assessment of biomarker in tumour cells. changes, which include expression levels of estrogen receptor (ER), progesterone receptor (PgR) and Ki67 protein.
  • ER estrogen receptor
  • PgR progesterone receptor
  • biomarker changes which circulating tumour cells may include but are not (CTCs), and blood, limited to expression including plasma levels of estrogen circulating tumour DNA receptor-regulated gene (ctDNA). expression, and gene mutational status.
  • CTCs cancer cells
  • ctDNA estrogen circulating tumour DNA receptor-regulated gene
  • biomarkers including but not limited to gene expression.
  • biomarkers that may influence development of breast cancer and/or response to treatment.
  • Part A of the study allow for dose escalation of AZD9833 alone.
  • a ‘cohort’ will constitute all the patients dosed at that particular dose level in the dose escalation scheme as illustrated in FIG. 1 .
  • eligible subjects will be randomised to receive selected doses of AZD9833 based on the findings in Part A.
  • Eligible pre- and post-menopausal subjects will receive AZD9833.
  • the first patient in each cohort will be followed to Day 8 before further patients are allocated to that dose level cohort; see Section 6.1.5.5.
  • the cohort may be optionally expanded to include additional subjects (to have up to 12 evaluable subjects in a cohort) and/or a cohort may be opened at the next dose level.
  • a maximum of 8 dose-level cohorts is anticipated in Part A of the study. Escalation will stop at the MTD/MFD. Part A will include at least 2 subjects with paired tumour biopsies at each dose level.
  • the dose escalation phase of the study will determine the MTD or MFD of AZD9833 based on the assessment of the safety, tolerability, and PK data collected during the first 28 days of daily dosing.
  • the dose escalation and de-escalation plan for evaluating AZD9833 will follow a Bayesian adaptive design scheme (Neuenschwander et al., Stat Med. 2008, 15:2420), which combines prior expectations about the dose-toxicity relationship and applies the data at the end of each cohort to recommend a dose for the next cohort.
  • Once safety and tolerability have been established following at least 7 days of treatment of the first subject in each dose level cohort, up to 3 additional subjects will be enrolled to ensure at least 3 evaluable subjects at 28 days.
  • AZD9833 doses where those doses have a pre-clinically predicted pharmacodynamic effect on ER greater than or equal to fulvestrant, a reasonable standard of care in this disease setting. This will provide an early opportunity for subjects to receive the drug at potentially therapeutic doses and to permit further investigation of the safety, tolerability, and the pharmacologic and biological activity profile of AZD9833. Dose level(s) to be expanded will be based on emerging data and will be approved by the Safety Review Committee (SRC).
  • SRC Safety Review Committee
  • Part A of the study also provides for the recruitment of at least 2 subjects suitable for paired on-study tumour biopsies to enable a preliminary assessment of tumour pharmacodynamics across a wider range of doses than will be examined in Part B.
  • Part B will include at least 5 paired biopsy-evaluable subjects in each of the 4 treatment groups (pre-menopausal dose 300 mg, post-menopausal dose 300 mg, post-menopausal dose 150 mg, post-menopausal dose 75 mg).
  • Part B will permit further evaluation of the safety profile of AZD9833 in a larger group of post-menopausal subjects at 3 distinct dose levels.
  • the objective of the examination of 3 dose levels is to permit a robust selection of recommended doses for further clinical exploration in future AZD9833 studies, both in the advanced breast cancer setting and, potentially, in the early disease/adjuvant setting.
  • a randomised design is applied to the allocation of 36 subjects to 1 of 3 tolerated dose levels from part A, to facilitate a robust comparison of the safety profile by avoiding allocation or any other potential experimental bias.
  • Part B will also allow for up to 12 pre-menopausal subjects to be allocated to the highest of the 3 doses considered safe and well tolerated in Part A (300 mg).
  • Protocol waivers or exemptions Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as protocol waivers or exemptions, is not permitted.
  • Each subject should meet all of the inclusion criteria and none of the exclusion criteria to be assigned/randomised to AZD9833. Under no circumstances can there be exceptions to this rule. Subjects who do not meet the entry requirements are screen failures.
  • Enrolled subjects are defined as those who sign informed consent. Treated subjects are those who receive at least 1 dose of AZD9833. In Parts B and D, enrolled subjects are randomised into their treatment group. Randomised subjects are defined as those who undergo randomisation and receive a randomisation number.
  • AZD9833 administered as 25 mg and 100 mg tablets.
  • AZD9833 will be administered as an oral dose, initially once daily. It should be taken in the morning, with or without food, at approximately the same time of day.
  • the SRC may decide to require fed or fasted dosing of AZD9833 (i.e., no food for a minimum of 2 hours prior to and 1 hour after each AZD9833 dose), depending on emerging study data.
  • Alternative dosing frequencies or intermittent schedules of AZD9833 may be initiated following recommendation by the SRC in response to emerging safety, tolerability, and PK data.
  • Dosing will begin at 75 mg once daily. At each dose level, 1 subject will be exposed and monitored until Day 8; for details. After each dose level during the dose escalation phase of the study, the SRC will evaluate all available safety information. The dose for subsequent cohorts or a decision to stop recruitment will be agreed by the SRC after review of the data from each cohort. Dose escalation and de-escalation will be decided by the SRC. The proposed dose escalation scheme will allow for a doubling in dose with each cohort in principle, e.g. 75 mg, 150 mg, 300 mg, etc. However, alternative or intermediate dose levels may be tested following review of safety data by the SRC.
  • At least 2 subjects in each dose level in Part A and at least 5 subjects in each cohort in Part B will be selected such that they are suitable for and consent to provide one pre-treatment and one on-treatment paired tumour biopsy sample.
  • the individual cohorts may be expanded by recruiting additional biopsy-eligible subjects until the required number of evaluable biopsy pairs in each cohort have been collected.
  • AZD9833 There is no maximum duration of treatment, and subjects may continue to receive AZD9833 as long as they are continuing to show clinical benefit, as judged by the investigator. If AZD9833 is discontinued for reasons other than disease progression, the subject must continue tumour assessments until disease progression, or until a further line of anti-cancer therapy is administered.
  • a DLT is defined as an AE or abnormal laboratory value that occurs from the first dose of AZD9833 up to and including Day 28, Cycle 1 (the DLT period) that is assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and that, despite optimal therapeutic intervention, meets any of the following criteria:
  • Pre-menopausal women must have commenced treatment with an LHRH agonist at least 4 weeks prior to starting AZD9833 and continue LHRH agonist therapy throughout the duration of the study.
  • Baseline tumour assessments should encompass all areas of known predilection for metastases in the disease under evaluation and should additionally investigate areas that may be involved based on signs and symptoms of individual subjects. Baseline assessments should be performed no more than 28 days before the start of AZD9833, ideally, as close as possible to the start of AZD9833. The methods of assessment used at baseline should be used at each subsequent assessment during treatment and follow-up part of the study. Any other sites at which new disease is suspected should also be appropriately imaged.
  • AZD9833 The safety and tolerability of AZD9833 is the primary objective of this study. Related outcome measures are DLTs, AEs/SAEs, vital signs, clinical chemistry/haematology, and ECGs.
  • Clinical chemistry, haematology, and urinalysis and coagulation will be performed at a local laboratory at or near to the investigator study site. Sample tubes and sample sizes may vary depending on laboratory method used and routine practice at the study site.
  • AZD9833 The characterisation of the pharmacokinetics of single and multiple doses of AZD9833 is a secondary objective of this study. Any residual sample remaining after PK analysis has been performed may be used to identify, characterise, and establish the concentration of AZD9833 metabolites and drug-related products in plasma, and/or to conduct exploratory biomarker research. Analysis of AZD9833 in plasma and urine will be performed using appropriate bioanalytical methods. Full details of the analytical methods used will be described in separate bioanalytical reports.
  • PK samples may be subjected to further analyses to identify, characterise, and establish the concentration of metabolites in plasma. Any results from such analyses will be reported separately from the clinical study report. Incurred sample reproducibility analysis, if any, will be performed with the bioanalysis of the test samples. The results from the evaluation will not be reported in the clinical study report but, separately, in a bioanalytical report.
  • Biomarkers e. g., optional tumour biopsies, plasma ctDNA, CTC, and archival tumour tissue.
  • Biological samples archival tumour tissue, mandatory and optional biopsies where applicable will be collected for the analysis of tumour DNA as an exploratory objective in this study.
  • a 2-mL blood sample for DNA isolation will be collected prior to administration of the first dose of AZD9833 from subjects who have consented to participate in the genetic analysis component of this study. If for any reason the sample is not drawn prior to dosing, it may be taken at any visit until the last study visit. Only one sample for genetic research should be collected per subject during the study. Participation is optional. Subjects who do not wish to participate in the genetic research may still participate in the study.
  • paired tumour biopsy samples will be taken from at least 2 subjects at each dose level.
  • these biopsies will be taken from at least 5 post-menopausal subjects at each AZD9833 dose level, 300 mg, 150 mg and 75 mg and at least 5 from pre-menopausal subjects at 300 mg. If subjects are willing to participate in this part of the study, they will sign a biopsy-specific written informed consent. Paired tumour biopsies will be obtained from subjects with accessible tumours who have consented to biopsies. Accessible lesions are defined as tumour lesions that are biopsiable, and amenable to repeat biopsy.
  • the pre-treatment biopsy will be taken during screening as close as possible to starting treatment.
  • the on-treatment sample should be taken on Day 1 ( ⁇ 7 days) of Cycle 2 but can be taken outside this time window, if agreed with AstraZeneca.
  • a further (optional) tumour biopsy should also be taken on disease progression or at the end of treatment.
  • the biomarkers to be investigated using tumour samples may include, but will not necessarily be limited to: ER, PgR, Ki67, genomic/genetic alterations, and other ER-regulated gene expression. Where feasible, collection of a tumour biopsy at disease progression is encouraged. This sample will be used to investigate changes in pathway signalling and potential mechanisms of resistance (i. e., genetic alterations or evidence of alternative pathway activation).
  • Formalin-fixed archival tumour tissue embedded in paraffin blocks are to be retrieved for all subjects, where available. If baseline biopsy samples can also be collected, retrieval of the archival diagnostic tumour material is still required to provide data on how the tumour has evolved since diagnosis.
  • the archival samples can be derived from the primary tumour and/or metastatic site and, where possible, the most recently acquired archival sample is required. Freshly prepared unstained slides from the archival tumour block are accepted, if tumour blocks cannot be submitted. From submitted archival tumour blocks, cores may be removed to construct tissue microarrays for later biomarker analysis. The remaining part of the tumour block may be returned to the institution.
  • One 2-mL blood sample will be taken at each of the timepoints, for cancer antigen CA15-assessment.
  • Blood samples will be taken at each of the timepoints. These samples will be taken to obtain a preliminary assessment of AZD9833 activity in the tumour by evaluation of pharmacodynamic biomarker changes, which may include but are not limited to total counts, and expression levels of ER, Ki67 protein, and ER-regulated genes.
  • One 10-mL blood sample will be taken at the timepoints below to provide 2 samples of plasma and one sample of serum per timepoint.
  • the samples will be collected and stored to permit retrospective exploratory biomarker analysis and will be analysed for a range of oncology biomarkers that may correlate with drug response.
  • RNA and microRNA/RNA samples preparation Two 2.5-mL whole blood samples will be collected in PAXgene tubes for RNA and microRNA/RNA samples preparation. Analysis of RNA may be conducted to generate hypotheses associated with the mechanisms of action of the molecule evaluated in the study and to potentially identify changes in gene expression that correlate with treatment response.
  • One 20-mL blood sample will be taken at screening, and 10-mL blood sample will be taken at all of the other timepoints to provide plasma. It will be used for the extraction and analysis of ctDNA for the analysis of predictive and pharmacodynamic biomarkers to interrogate changes in genetic alterations and potential mechanisms of resistance.
  • AZD9833 exposure was dose proportional after multiple doses, with a median terminal t1/2 of 12 h.
  • AZD9833 has an encouraging efficacy and dose-dependent safety profile.
  • Evidence of clinical benefit and target engagement was observed at all dose levels in women with ER+ ABC, including patients pre-treated with CDK4/6 inhibitors and fulvestrant, and those with ESR1 mutations.

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