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
  • A61K31/56—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
  • A61K31/33—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
  • 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
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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

• the disclosure relates to the field of treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer in patients previously treated with a CDK4 and 6 inhibitor.
• HR+ hormone receptor-positive
• HER2- human epidermal growth factor receptor 2-negative
• the disclosure provides a method of treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who has been previously treated with a CDK4 and 6 inhibitorcontaining therapy, the method comprising administering to the patient a CDK4 and 6 inhibitor in combination with fulvestrant.
• the method comprises administering to the patient a CDK4 and 6 inhibitor comprising abemaciclib, palbociclib, or ribociclib in combination with fulvestrant.
• the method comprises administering to the patient abemaciclib in combination with fulvestrant.
• the method comprises administering to the patient palbociclib in combination with fulvestrant.
• the method comprises administering to the patient ribociclib in combination with fulvestrant.
• the patient may have been administered a prior CDK4 and 6 inhibitor-containing therapy as a monotherapy. In some other embodiments, the patient may have been administered a prior CDK4 and 6 inhibitor-containing therapy in combination with an additional therapy.
• the prior CDK4 and 6 inhibitor-containing therapy comprises abemaciclib, palbociclib, or ribociclib. In further embodiments, the prior CDK4 and 6 inhibitor-containing therapy comprises abemaciclib. In some further embodiments, the prior CDK4 and 6 inhibitor-containing therapy comprises palbociclib. In yet some further embodiments, the prior CDK4 and 6 inhibitor-containing therapy comprises ribociclib.
• the patient may have been administered a prior CDK4 and 6 inhibitor-containing therapy in combination with an endocrine therapy.
• the prior endocrine therapy comprises tamoxifen.
• the prior endocrine therapy comprises an aromatase inhibitor.
• the aromatase inhibitor comprises letrozole, anastrozole, or exemestane.
• the patient may have been administered a combination of a CDK4 and 6 inhibitor with an endocrine therapy for the first line (or initial) treatment of HR+, HER2- advanced or metastatic breast cancer.
• the first line treatment comprises an endocrine therapy selected from tamoxifen and an aromatase inhibitor.
• the first line treatment comprises ribociclib as the CDK4 and 6 inhibitor.
• the first line treatment comprises palbociclib as the CDK4 and 6 inhibitor.
• the first line treatment comprises abemaciclib as the CDK 4 and 6 inhibitor.
• the patient may have been administered a prior CDK4 and 6 inhibitor-containing therapy as a monotherapy. In some other embodiments, the patient may have been administered a prior CDK4 and 6 inhibitor-containing therapy in combination with an additional therapy. In some further embodiments, the prior CDK4 and 6 inhibitor-containing therapy comprises abemaciclib, palbociclib, or ribociclib. [0008] In further embodiments, the prior CDK4 and 6 inhibitor-containing therapy comprises abemaciclib. In some further embodiments, the prior CDK4 and 6 inhibitor-containing therapy comprises palbociclib. In yet some further embodiments, the prior CDK4 and 6 inhibitorcontaining therapy comprises ribociclib.
• the method of treating comprises a patient with advanced or metastatic breast cancer and who has received a prior CDK4 and 6 inhibitor therapy comprising abemaciclib.
• the prior therapy comprising abemaciclib may have been administered: (i) in combination with endocrine therapy (e.g., tamoxifen or an aromatase inhibitor) for the adjuvant treatment in an adult patient with HR+, HER2- node positive, early breast cancer at high risk of recurrence and a Ki-67 score >20% as determined by an FDA approved test; (ii) in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR+, HER2- advanced or metastatic breast cancer; (iii) in combination with fulvestrant for the treatment of women with HR+, HER2- advanced or metastatic breast cancer; or (iv) as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic
• the method of treating comprises a patient with advanced or metastatic breast cancer and who has received a prior CDK4 and 6 inhibitor therapy comprising palbociclib.
• the prior therapy comprising palbociclib may have been administered: (i) in combination with an aromatase inhibitor as initial endocrinebased therapy for the treatment of postmenopausal women with HR+, HER2- advanced or metastatic breast cancer; or (ii) in combination with fulvestrant for the treatment of women with HR+, HER2- advanced or metastatic breast cancer following endocrine therapy.
• the method of treating comprises a patient with advanced or metastatic breast cancer and who has received a prior CDK4 and 6 inhibitor therapy comprising ribociclib.
• the prior therapy comprising ribociclib may have been administered: (i) in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of pre/perimenopausal or postmenopausal women with HR+, HER2- advanced or metastatic breast cancer; or (ii) in combination with fulvestrant for the treatment of postmenopausal women with HR+, HER2- advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy.
• the method according to any of the above aspects and embodiments comprises administering abemaciclib as a 150 mg oral dose twice daily on days 1- 28 of each 28 day cycle.
• the above method comprises administering fulvestrant as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle (cycle 1), and on day 1 of a second and any subsequent 28 day cycle (cycle 2 and subsequent cycles).
• the disclosure provides a method of treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer previously treated with a CDK4 and 6 inhibitor-containing therapy selected from abemaciclib, ribociclib, and palbociclib, the method comprising administering to the patient an effective amount of abemaciclib in combination with fulvestrant, wherein abemaciclib is administered twice daily as a 150 mg oral dose on days 1-28 of each 28 day cycle, and wherein fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle, and on day 1 of a second and any subsequent 28 day cycle.
• HR+ hormone receptor-positive
• HER2- human epidermal growth factor receptor 2-negative
• the method may comprise administering the CDK4 and 6 inhibitor in simultaneous, separate, or sequential combination with fulvestrant.
• the method may be administered for a time sufficient to provide the patient progression-free survival.
• the patient is human.
• the patient may be an adult male, or an adult premenopausal, perimenopausal, or postmenopausal woman.
• the disclosure provides a CDK4 and 6 inhibitor for use in simultaneous, separate or sequential combination with fulvestrant, in the treatment of a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer wherein the patient had received a prior CDK4 and 6 inhibitor-containing therapy.
• HR+ hormone receptor positive
• HER2- human epidermal growth factor receptor 2 negative
• advanced or metastatic breast cancer wherein the patient had received a prior CDK4 and 6 inhibitor-containing therapy.
• the disclosure provides a combination comprising a therapeutically effective amount of CDK4 and 6 inhibitor and fulvestrant for simultaneous, separate or sequential use in providing treatment to a patient with HR+, HER2- advanced or metastatic breast cancer with disease progression on or after a prior therapy of a CDK4 and 6 inhibitor, for a time period sufficient to provide progression free survival.
• the disclosure provides a CDK4 and 6 inhibitor for use in simultaneous, separate or sequential combination with fulvestrant for the treatment of a patient with HR+, HER2- advanced or metastatic breast cancer with disease progression on or after a prior therapy of a CDK4 and 6 inhibitor.
• the disclosure provides for the use of a CDK4 and 6 inhibitor in the manufacture of a medicament for the treatment of a patient with HR+, HER2- advanced or metastatic breast cancer who has received a prior therapy of a CDK4 and 6 inhibitor, wherein the medicament is to be administered in simultaneous, separate or sequential combination with fulvestrant.
• the patient experienced disease progression on the prior therapy of a CDK4 and 6 inhibitor.
• the disclosure provides for the use of a CDK4 and 6 inhibitor in the manufacture of a medicament for the treatment of a patient with HR+, HER2- advanced or metastatic breast cancer with disease recurrence on or after a prior therapy of a combination of a CDK4 and 6 inhibitor with endocrine therapy for the adjuvant treatment of early breast cancer, wherein the medicament is to be administered in simultaneous, separate or sequential combination with fulvestrant.
• the 2020 ESMO and 2021 NCCN clinical guidelines support use of options that include (i) endocrine therapy alone (e.g., aromatase inhibitors (Al), selective estrogen receptor modulators or degraders (SERMs or SERDs)); (ii) endocrine therapy in combination with PI3K pathway blockade (e.g., with everolimus or alpelisib, if an actionable PIK3CA mutation is detected); (iii) cytotoxic therapy; and (iv) clinical trial participation.
• endocrine therapy alone
• SERMs or SERDs selective estrogen receptor modulators or degraders
• the disclosure relates to a method of treating a patient with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who has previously been treated with a CDK4 and 6 inhibitorcontaining therapy, comprising administering a CDK4 and 6 inhibitor in combination with fulvestrant.
• HR+ hormone receptor-positive
• HER2- human epidermal growth factor receptor 2-negative
• Methods of treatment and methods of treating a patient in accordance with various aspects and embodiments of the disclosure comprise a patient who has received a previous therapy comprising a CDK4 and 6 inhibitor.
• "Previously treated” or "previous therapy” with a CDK4 and 6 inhibitor in accordance with the aspects and embodiments disclosed herein encompasses any prior administration of a therapy for the treatment of HR+, HER2- breast cancer (e.g., early stage, advanced, or metastatic breast cancer) that comprises a CDK4 and 6 inhibitor.
• a previous CDK4 and 6 inhibitor-containing therapy comprises treatment of early stage HR+, HER2- breast cancer.
• a prior CDK4 and 6 inhibitor treatment of early stage HR+, HER2- breast cancer comprises an adjuvant treatment, comprising administering to the patient a CDK4 and 6 inhibitor optionally in combination with an endocrine therapy.
• the prior adjuvant treatment is administered to a patient with node positive, early breast cancer at a high risk of recurrence.
• the prior adjuvant treatment is administered to a patient with early breast cancer with a Ki-67 score of at least 20% or more as determined by an FDA approved test.
• the prior adjuvant treatment is administered to a patient with node positive, early breast cancer at high risk of recurrence as determined by four or more positive axillary lymph nodes (>4 pALN), or one to three positive axillary lymph nodes (1-3 pALN) and with a tumor grade 3 and/or tumor size >5 cm.
• the prior adjuvant treatment is administered to a patient with node positive, early breast cancer at high risk of recurrence as determined by one to three positive axillary lymph nodes (1-3 pALN), a Ki -67 >20%, and no grade 3 tumor and tumor size not >5 cm.
• a previous CDK4 and 6 inhibitor-containing therapy comprises an initial or first line treatment of advanced or metastatic HR+, HER2- breast cancer.
• the initial or first line treatment of advanced or metastatic HR+, HER2- breast cancer comprises administering to the patient a CDK4 and 6 inhibitor optionally in combination with an endocrine therapy.
• the first line treatment is administered with palbociclib in combination with an endocrine therapy.
• the first line treatment is administered with ribociclib in combination with an endocrine therapy.
• the first line treatment is administered with abemaciclib in combination with an endocrine therapy.
• a previous CDK4 and 6 inhibitor-containing therapy may be an incomplete course of therapy.
• a previous CDK4 and 6 inhibitor-containing therapy may be an incomplete course of therapy wherein disease progression occurs during treatment of advanced or metastatic breast cancer.
• a previous CDK4 and 6 inhibitor-containing therapy may be an incomplete course of therapy wherein disease recurs on adjuvant treatment of early breast cancer.
• a previous CDK4 and 6 inhibitor-containing therapy may be a completed course of therapy.
• a previous CDK4 and 6 inhibitorcontaining therapy may be a completed course of therapy wherein disease recurs after adjuvant treatment of early breast cancer.
• a previous CDK4 and 6 inhibitorcontaining therapy is halted for a period of time sufficient to provide clearance of the previous therapy from the patient (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 14, 21 days or more), before the administration of the sequential CDK4 and 6 inhibitor in accordance with the disclosure.
• a CDK4 and 6 inhibitor-containing therapy refers to a treatment or therapeutic intervention that comprises administration of a CDK4 and 6 inhibitor to a patient.
• a CDK4 and 6 inhibitor-containing therapy can comprise administration of the CDK4 and 6 inhibitor as a monotherapy.
• a CDK4 and 6 inhibitor-containing therapy can comprise administration of a CDK4 and 6 inhibitor in combination with one or more other active agents.
• the CDK4 and 6 inhibitor-containing therapy comprises a CDK4 and 6 inhibitor in combination with endocrine therapy.
• a “CDK4 and 6 inhibitor” or alternatively a “CDK4/6 inhibitor” refers to molecules that inhibit the activity of D-type cyclins (e.g., cyclin D3) and cyclin-dependent kinases (CDK4 and 6) protein complexes (e.g., cyclinD:CDK4 and 6 complexes), and generally function to block transition from the G1 to S phase of cell cycle through inhibition of kinase activity.
• the CDK4 and 6 inhibitor is palbociclib, ribociclib, or abemaciclib.
• Palbociclib [6-acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(piperazin-l-yl)pyridine-2- yl]amino ⁇ pyrido[2,3,-t ]pyrimidin-7(8J7)-one] is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer (i) in combination with an aromatase inhibitor as an initial endocrine based therapy in postmenopausal women or in men, or (ii) in combination with fulvestrant in patients with disease progression following endocrine therapy. It has the chemical structure:
• Palbociclib is taken orally and is available as capsules (125 mg, 100 mg, and 75 mg) with a recommended starting dosage of 125 mg, once daily for 21 days followed by 7 days of off treatment.
• Palbociclib may be prepared as the free base or as pharmaceutically acceptable salts, including mono- and di-acid addition salts such as, for example, the mono-isethionate salt, polymorphic forms of the isethionate salt, or the hydrochloride salt (see, e.g., WO 2003/062236, WO 2005/005426, WO 2008/032157, U.S. Pat. Nos. 6,936,612; 7,208,489; 7,345,171;
• Palbociclib in its free base form may be anhydrous or may contain varying amounts of water or one or more solvents, (see, e.g., U.S. Pat. No. 10,723,730).
• Ribociclib [7-cy cl open tyl-M -di methyl -2- ⁇ [5-(piperazin-l-yl)pyridine-2-yl]amino ⁇ - 7H-pyrrolo[2,3-t ]pyrimidine-6-carboxamide] is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer (i) in combination with an aromatase inhibitor as an initial endocrine-based therapy in pre/perimenopausal or postmenopausal women, or (ii) in combination with fulvestrant in postmenopausal women as an initial endocrine-based therapy or following disease progression on endocrine therapy. It has the chemical structure:
• Ribociclib is taken orally and is available as tablets (200 mg, equivalent to 254.40 mg ribociclib succinate) with a recommended starting dosage of 600 mg, (3x 200 mg tablets) taken once daily for 21 days followed by 7 days of off treatment.
• Ribociclib may be prepared as the free base or as pharmaceutically acceptable salts, including as ribociclib succinate (see, e.g., U.S. Pat. Nos. 9,868,739; 9,193,732).
• Abemaciclib has the following structure:
• Abemaciclib is approved for the treatment of several breast cancer indications, including (i) in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with HR+, HER2- node-positive, early breast cancer at high risk of recurrence and a Ki -67 score >20% as determined by an FDA approved test; (ii) in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women, and men, with HR+, HER2- advanced or metastatic breast cancer; (iii) in combination with fulvestrant for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy; and (iv) as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
• endocrine therapy tamoxifen or an aromatase
• abemaciclib is administered at a dose of 50 mg to 200 mg twice a day.
• abemaciclib, or a pharmaceutically acceptable salt thereof is administered at a dose of 100 mg to 150 mg twice a day.
• abemaciclib, or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg twice a day.
• abemaciclib, or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg twice a day in a 28-day cycle.
• abemaciclib is administered at a dose of 100 mg twice a day in a 28-day cycle. More preferably, abemaciclib, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg twice a day in a 28-day cycle.
• abemaciclib is administered orally.
• abemaciclib is administered by capsule.
• abemaciclib is administered by tablet.
• Fulvestrant is indicated for the treatment of advanced or metastatic breast cancer and is formulated as an injectable (intravenous (IV) or intramuscular (IM)), having the chemical structure:
• fulvestrant is administered as described on the approved label, for example, at 500 mg injection once a month, with an additional single 500 mg loading dose on day 15 of the first dose cycle. More preferably fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle, and on day 1 of a second and any subsequent 28 day cycles.
• the methods and uses are administered to a patient who has received prior therapy comprising a CDK4 and 6 inhibitor.
• the prior therapy comprising a CDK4 and 6 inhibitor is in combination with an endocrine therapy such as, for example, one or more endocrine therapies that may be indicated for the treatment of advanced or metastatic breast cancer with abemaciclib, ribociclib, or palbociclib.
• an endocrine therapy includes tamoxifen or a pharmaceutically acceptable salt thereof, anastrozole, letrozole, or exemestane.
• an endocrine therapy can include fulvestrant.
• the endocrine therapy is previously administered in accordance with the guidance and direction on the approved label of the particular endocrine therapy.
• tamoxifen or a pharmaceutically acceptable salt thereof may be administered at 20-40 mg/day.
• the dose should be administered in a divided dose of morning and evening.
• Doses are preferably oral.
• anastrazole may be administered at 1 mg/day.
• Doses are preferably oral.
• letrozole may be administered at 2.5 mg/day.
• Doses are preferably oral.
• exemestane may be administered at 25 mg/day.
• Doses are preferably oral.
• the previously administered CDK4 and 6 therapy can be administered as described on the approved label for the particular CDK4 and 6 inhibitor and in combination with an endocrine therapy according to the approved label for the particular endocrine therapy.
• a CDK4 and 6 inhibitor in accordance with the aspects and embodiments of the disclosure may be prepared and administered as the inhibitor compound, or as a pharmaceutically acceptable salt thereof.
• abemaciclib may be prepared and/or administered as the free base.
• abemaciclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, the hydrochloride or mesylate salt.
• ribociclib may be prepared and/or administered as the free base.
• or ribociclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, ribociclib succinate.
• palbociclib may be prepared and/or administered as the free base.
• palbociclib may be prepared and/or administered as a pharmaceutically acceptable salt such as, for example, the isethionate or the hydrochloride salt.
• a pharmaceutically acceptable salt such as, for example, the isethionate or the hydrochloride salt.
• the formation of pharmaceutically acceptable salts is generally well known. See, for example, Gould, P. L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al.
• the term "patient” refers to a human.
• the patient may be an adult male, or an adult premenopausal, perimenopausal, or postmenopausal woman, who has or is diagnosed with HR+, HER2- advanced or metastatic breast cancer.
• the patient has HR+, HER2- advanced or metastatic breast cancer and has been previously treated with a CDK4 and 6 inhibitor-containing therapy, in accordance with the disclosure.
• cancer and “cancerous” refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation.
• the term "effective amount” refers to the amount or dose of a CDK4 and 6 inhibitor (such as e.g., abemaciclib, palbociclib, or ribociclib) and the amount or dose of fulvestrant which provides an effective response in the patient under treatment.
• a CDK4 and 6 inhibitor such as e.g., abemaciclib, palbociclib, or ribociclib
• the term "effective response" of a patient or a patient's “responsiveness” to treatment with a combination of agents refers to the clinical or therapeutic benefit imparted to a patient upon administration of a CDK4 and 6 inhibitor (such as e.g., abemaciclib, palbociclib, or ribociclib) or a pharmaceutically acceptable salt thereof, and fulvestrant.
• a CDK4 and 6 inhibitor such as e.g., abemaciclib, palbociclib, or ribociclib
• a pharmaceutically acceptable salt thereof such as e.g., abemaciclib, palbociclib, or ribociclib
• an effective response can include, but is not limited to, any one or more of progression free survival (PFS) (e.g., based on investigator assessment or blinded independent review (BICR)), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), safety, patient-reported outcomes (PRO), pharmacokinetics (PK), or a best overall response (BOR) that may include complete response (CR), partial response (PR), or stable disease (SD).
• PFS progression free survival
• OS overall survival
• ORR objective response rate
• CBR clinical benefit rate
• DCR disease control rate
• DoR duration of response
• PRO patient-reported outcomes
• PK pharmacokinetics
• BOR best overall response
• an effective response is not limited to curing, eliminating, or ameliorating the disease or the clinical symptoms associated with the disease.
• the term "in combination with” refers to the administration of a CDK4 and 6 inhibitor (e.g., abemaciclib), or a pharmaceutically acceptable salt thereof, and an endocrine therapy (e.g., fulvestrant) either simultaneously or sequentially in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.
• a CDK4 and 6 inhibitor e.g., abemaciclib
• an endocrine therapy e.g., fulvestrant
• the term "early stage” means cancers that may have spread to nearby lymph nodes but not to distant parts of the body.
• treatment of early stage breast cancer can be referred to as “adjuvant treatment” .
• the term “advanced” or “metastatic” means cancers that have spread to one or more parts of the body that were not the site of the original cancerous tissue.
• a first treatment of advanced or metastatic breast cancer with a CDK4 and 6 inhibitor therapy can be referred to as “initial treatment” or "first line treatment”.
• treating means the administration of a drug or drugs to a patient.
• the terms can also be used in connection with diminishing, inhibiting, reducing, arresting, or ameliorating the disease, or to delay the onset of the biological manifestation of disease progression.
• adjuvant treatment means the administration of a drug or drugs to a patient after surgical resection of one or more cancerous tumors, where all detectable and resectable disease (for example, cancer) has been removed from the patient, but where there remains a statistical risk of relapse due to occult disease, for the purpose of diminishing the likelihood or the severity of reoccurance of the disease, or to delay the onset of the biological manifestation of the reoccurance of the disease.
• all detectable and resectable disease for example, cancer
• Ki67 antigen or simply “Ki67” (also known as antigen identified by monoclonal antibody Ki-67) means a nuclear protein encoded by the MK167 gene that is expressed in all phases of the cell cycle other than the Go phase and has been reported as an independent prognostic factor in early breast cancer (Dowsett et al. 2011).
• HR+ breast cancer patients with high levels (e.g., a threshold value of Ki67 within the range of 20% to 29%) of Ki67 have been shown to have higher disease recurrence rates while receiving adjuvant endocrine therapy following surgery.
• CDK4 and 6 inhibitor in the manufacture of a medicament for the treatment of a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer after a prior CDK4 and 6 inhibitorcontaining therapy, wherein the medicament is to be administered in simultaneous, separate or sequential combination with fulvestrant.
• HR+ hormone receptor positive
• HER2- human epidermal growth factor receptor 2 negative
• advanced or metastatic breast cancer after a prior CDK4 and 6 inhibitorcontaining therapy, wherein the medicament is to be administered in simultaneous, separate or sequential combination with fulvestrant.
• aromatase inhibitor is selected from letrozole, anastrozole, or exemestane.
• CDK4 and 6 inhibitor administered in combination with fulvestrant is selected from abemaciclib, palbociclib, and ribociclib. 14. The use according to aspect 13, wherein the CDK4 and 6 inhibitor is abemaciclib.
• fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle (cycle 1), and on day 1 of a second and any subsequent 28 day cycle (cycle 2 and subsequent cycles).
• abemaciclib in the manufacture of a medicament for the treatment of a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer after a prior CDK4 and 6 inhibitor-containing therapy, wherein abemaciclib is administered twice daily as a 150 mg oral dose on days 1-28 of each 28 day cycle, wherein fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle, and on day 1 of a second and any subsequent 28 day cycle, and wherein the prior CDK4 and 6 inhibitor-containing therapy is a combination of abemaciclib and tamoxifen or an aromatase inhibitor.
• HR+ hormone receptor positive
• HER2- human epidermal growth factor receptor 2 negative
• fulvestrant is administered as a 500 mg intramuscular dose on day 1 and 15 of a first 28 day cycle, and on day 1 of a second and any subsequent 28 day cycle
• the prior CDK4 and 6 inhibitor-containing therapy is a
• Example 1 Sequential treatment with abemaciclib with endocrine therapy inhibits cell proliferation in cells with prior resistance to CDK4 and 6 inhibitors
• Resistant breast cancer cells are prepared by treating breast cancer cell lines with amounts of a CDK4 and 6 inhibitor (either abemaciclib or palbociclib) in combination with 4- OH-tamoxifen (tamoxifen) for 120-144 h.
• the cells are sorted and screened for resistant cells, defined as geminin positive (GEM+), a marker of S/G2/M cell cycle accumulation.
• GEM+ geminin positive
• cell lines are treated with tamoxifen plus the CDK4 and 6 inhibitor used to drive resistance (either abemaciclib or palbociclib).
• Resistant cancer cells generated by the above method are treated with abemaciclib in combination with an endocrine therapy (ET) comprising either fulvestrant or tamoxifen; or with palbociclib in combination with either fulvestrant or tamoxifen.
• E endocrine therapy
• Cell proliferation and viability are evaluated by Geminin/Ki67, annexin V, and colony formation assays.
• Mechanisms of resistance and the effects of sequential treatment of the CDK4 and 6 inhibitor in combination with either fulvestrant or tamoxifen are characterized by western blot and RNAseq analysis.
• Cancer cell lines that are resistant to palbociclib and tamoxifen show decreased %GEM+ and colony formation ability, decreased Ki67 levels, and increased apoptosis when sequentially treated with a combination of abemaciclib and ET.
• cell lines resistant to abemaciclib and tamoxifen do not show similar inhibition effects when sequentially treated with a combination of palbociclib and ET.
• Western blot analysis demonstrates that both palbociclib and abemaciclib-resistant cells exhibit increases in levels of CDK6 and pERK relative to control.
• Treatment of palbociclib-resistant cells with abemaciclib and ET is effective to decrease F0XM1, a regulator of senescence and apoptosis, as well as to decrease cyclin A, a marker of mitosis, which is consistent with a decreased %GEM+ cell subpopulation in palbociclib and ET- resistant cells.
• Treatment of abemaciclib-resistant cells with a combination of palbociclib and ET do not exhibit similar effects.
• Cancer cell lines that are resistant to palbociclib and tamoxifen show proliferation decrease, decreased pRb signaling, and androgen response induction when sequentially treated with a combination of abemaciclib and ET. Treatment of abemaciclib-resistant cells with a combination of palbociclib and ET do not exhibit similar effects on proliferation, pRb signaling, or androgen response.
• Example 2 Randomized, Phase 3 study of fulvestrant with or without abemaciclib in participants with HR+, HER2- advanced or metastatic breast cancer with disease progression on or after either an adjuvant or a first-line treatment with a CDK4 and 6 inhibitor plus endocrine therapy.
• ET e.g., tamoxifen
• a clinical trial is conducted as a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled study in participants with HR+, HER2- advanced or metastatic breast cancer.
• the study will enroll adults who experienced disease progression on a CDK4 and 6 inhibitor and an aromatase inhibitor (Al) therapy in the first-line setting (initial therapy for advanced or metastatic breast cancer), or recurrence on or after a CDK4 and 6 inhibitor with endocrine therapy (ET) in the adjuvant setting.
• Al aromatase inhibitor
• the trial will include approximately 350 participants that will be randomly assigned to one of two intervention arms that include an investigational arm A: abemaciclib and fulvestrant and a control arm B: placebo and fulvestrant.
• Patient randomization will be 1 : 1 and stratified by factors including: geography (USA, East Asia, or Other (including EU)); presence of visceral metastases (yes or no); and duration on prior CDK4 and 6 inhibitor-based regimen (2 levels, based on adjuvant/first line therapy), wherein duration of ⁇ 12 months if prior treatment was in metastatic setting; or disease recurrence during CDK4 and 6 inhibitor-based regimen if treated in adjuvant setting, or duration of >12 months if prior treatment was in first line/metastatic setting; or disease recurrence after completing CDK4 and 6 inhibitor-based regimen if treated in adjuvant setting.
• the primary endpoint will be progression free survival (PFS) based on investigator assessment. Participants will be treated until disease progression or other discontinuation criteria are met. Secondary endpoints will include overall survival (OS), PFS by blinded independent central review (BICR), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), Safety, patient-reported outcomes (PRO), and pharmacokinetics (PK).
• OS overall survival
• BICR blinded independent central review
• ORR objective response rate
• CBR clinical benefit rate
• DCR disease control rate
• DoR duration of response
• Safety patient-reported outcomes
• PK pharmacokinetics
• the primary endpoint, PFS by investigator assessment, is defined as the time from randomization until the first occurrence of documented disease progression as determined by investigator assessment per RECIST 1.1, or death from any cause in the absence of documented progressive disease.
• PFS will be compared between treatment arms using a stratified log-rank test, stratified by the randomization strata. The corresponding hazard ratio between treatment arms will be estimated using a stratified Cox regression model (Cox 1972), stratified by randomization strata.
• PFS curves, median PFS, and PFS rates at various time points with 95% CI for each treatment arm will be estimated using the Kaplan-Meier method (Kaplan and Meier 1958).
• ORR Objective Response Rate
• DCR Disease Control Rate
• CBR Clinical Benefit Rate
• Objective response rate is defined as the number of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the total number of participants randomized to the corresponding treatment arm. Confirmation of CR and PR is not required.
• DCR Disease control rate
• CBR Clinical benefit rate
• Duration of response is defined as the time from the date that measurement criteria for CR or PR (whichever is first recorded) are first met until the first date that disease is recurrent or documented disease progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the absence of documented disease progression or recurrence.
• OS Overall survival
• BICR blinded independent central review
• CBR clinical benefit rate
• DCR disease control rate
• DoR duration of response
• EORTC IL-19 European Organisation for Research and Treatment of Cancer Item Library 19
• mBPI-SF modified Brief Pain Inventory -short form
• ORR objective response rate
• OS overall survival
• PRO patient-reported outcome
• PFS progression-free survival
• RECIST Response Evaluation Criteria in Solid Tumors
• SAE serious adverse event
• TEAE treatment-emergent adverse event.
• a treatment cycle will be defined as an interval of 28 days.
• the 28-day cycle length will be maintained throughout the treatment phase regardless of dose interruptions. Participants will begin dosing assigned treatment on CID 1. Every attempt will be made to maintain a 28-day +/- 7-day cycle for fulvestrant administration. When delays are required, doses will be resumed at earliest medically appropriate opportunity based on investigator judgment. Additional clinic visits may be required for administration. Treatment will continue until progression, unacceptable toxicity, or other discontinuation criteria are met.
• abemaciclib For the approved indication in HR+, HER2- MBC, the recommended starting dose of abemaciclib in combination with fulvestrant is 150 mg BID, which is based on the Phase 3 study, MONARCH 2 (Sledge et al. 2017), in which abemaciclib 150 mg BID in combination with fulvestrant exhibited a manageable safety profile and resulted in clinically meaningful PFS and OS benefit compared to fulvestrant/placebo in patients with HR+, HER2- advanced or metastatic breast cancer (Verzenio package insert, 2019; Verzenios SmPC, 2018). [0078] Fulvestrant.
• the recommended dose of fulvestrant in combination with abemaciclib is consistent with the approved monotherapy dose of fulvestrant. Study participants will receive fulvestrant 500 mg IM on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and beyond according to the dosing information provided in the approved local label.
• Tumor Response Tumor response per RECIST 1.1 should be assessed approximately every 8 weeks for the first 12 months (relative to Cycle 1 Day 1), and thereafter approximately every 12 weeks until the participant has objective disease progression, death, or study completion (following evaluation of final OS data).
• Short- and Long-Term follow-Up Participants discontinuing study intervention will return for an in-clinic short-term follow-up visit.
• the short-term follow-up visit will take place 30 days ( ⁇ 7 days) after the decision is made to discontinue all study treatment.
• all participants will enter the long-term follow-up period.
• Long-term follow-up begins the day after the short-term follow-up visit is completed and continues until participant’s death, withdrawal from study, or study completion.
• Long-term follow-up visits should occur approximately every 2-3 months (Q60-90D) during long-term follow-up. The duration of this study period is not pre-defined as participants will remain in long-term follow-up until death, withdrawal from study, or study completion.
• Treatment in the investigation arm (combination of abemaciclib and fulvestrant) is expected to be well tolerated and to achieve a statistically significant primary endpoint and/or delay disease progression. Prolonged disease control may also delay the need for cytotoxic chemotherapy.
• Age >18 years of age (or of an acceptable age according to local regulations, whichever is older) at the time of signing the informed consent.
• a participant will have radiologic evidence of disease progression or recurrence either (a) on treatment with a CDK4 and 6 inhibitor (palbociclib, ribociclib, or abemaciclib) plus Al as initial therapy for advanced disease, or on or after treatment with a CDK4 and 6 inhibitor (palbociclib, ribociclib, or abemaciclib) plus ET administered as adjuvant therapy for early-stage breast cancer.
• a participant will have either measurable disease or non-measurable but evaluable disease. Measurable, non-measurable, and evaluable disease are defined according to the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1 [vl.l], Eisenhauer et al. 2009).
• a participant will have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al. 1982).
• PS performance status
• ECOG Eastern Cooperative Oncology Group
• a participant must be deemed appropriate for treatment with ET.
• a participant will have discontinued previous treatments and recovered from the acute effects of therapy to at least Grade 1, except for residual alopecia and peripheral neuropathy, with the therapy washout periods required prior to receiving study drug summarized in Table 3. Table 3. Prior treatment washout periods
• ALT alanine aminotransferase
• ANC absolute neutrophil count
• AST aspartate aminotransferase
• G-CSF granulocyte colony-stimulating factor
• ULN upper limit of normal.
• Female participants must have postmenopausal status due to either surgical/natural menopause or ovarian suppression (received monthly and initiated at least 28 days prior to Cycle 1 Day 1) with a gonadotropin-releasing hormone agonist, such as goserelin or leuprolide.
• a gonadotropin-releasing hormone agonist such as goserelin or leuprolide.
• Postmenopausal status due to surgical/natural menopause requires at least 1 of the following: (a) prior bilateral oophorectomy, (b) age >55 years and amenorrhoeic for at least 12 months or with a diagnosis of menopause, or (c) age >40 and ⁇ 55 years, amenorrhoeic for at least 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression), and FSH in the postmenopausal range (>40 mIU/mL).
• WOCBP Women of childbearing potential
• WOCBP must test negative for pregnancy prior to initiation of treatment with a negative serum pregnancy test at the screening visit, followed by a negative urine pregnancy test within 48 hours prior to first exposure to study drug.
• WOCBP must agree to use 2 forms of effective contraception where at least one form must be highly effective (less than 1% failure rate) to prevent pregnancy while receiving study treatment, for 3 weeks after the last dose of blinded study drug and for 2 years after the last dose of fulvestrant (or according to local approved fulvestrant label).
• Participants are excluded if they have certain medical conditions or are receiving certain prior or concomitant therapy. Participants are excluded if they are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study. Women who are pregnant or breastfeeding are excluded. Any patient who has a known or suspected hypersensitivity reactions or intolerance to the study drug or to any of the excipients (e.g., lactose), unless otherwise deemed appropriate by the investigator.
• the excipients e.g., lactose
• Exclusionary medical conditions include participants who:
• Visceral crisis is not the mere presence of visceral metastases but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of the disease.
• CNS central nervous system
• a known active systemic infection for example, bacterial, fungal, or detectable viral infection requiring systemic therapy.
• Participants with uncontrolled human immunodeficiency virus (HIV) infection or an acquired immunodeficiency syndrome (AIDS) defining illness are not eligible.
• Participants with known HIV infection and CD4+ T-cell (CD4+) counts >350 cells/pL are eligible.
• Participants with hepatitis B are not eligible unless viral load is below the level of quantification.
• Participants with known hepatitis C are not eligible unless they have completed curative anti-viral therapy and viral load is below the level of quantification.
• Screening for HIV, coronavirus disease 2019 (COVID-19), hepatitis B, or hepatitis C is not required.
• Exclusionary prior or concomitant therapy include participants who:

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