WO2023237055A1 - 一种cdk4/6抑制剂治疗去分化脂肪肉瘤的用途 - Google Patents

一种cdk4/6抑制剂治疗去分化脂肪肉瘤的用途 Download PDF

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Publication number
WO2023237055A1
WO2023237055A1 PCT/CN2023/099164 CN2023099164W WO2023237055A1 WO 2023237055 A1 WO2023237055 A1 WO 2023237055A1 CN 2023099164 W CN2023099164 W CN 2023099164W WO 2023237055 A1 WO2023237055 A1 WO 2023237055A1
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formula
compound
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
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PCT/CN2023/099164
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English (en)
French (fr)
Inventor
于鼎
王训强
崔思思
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正大天晴药业集团股份有限公司
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Publication of WO2023237055A1 publication Critical patent/WO2023237055A1/zh

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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
    • A61K31/495—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present disclosure belongs to the field of medical technology and relates to the use of a CDK4/6 inhibitor to treat dedifferentiated liposarcoma, and specifically to the use of the compound of formula (I) to treat dedifferentiated liposarcoma.
  • Cyclin-dependent kinase (CDK) 4/6 is a key regulator of the cell cycle and can trigger the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S1 phase).
  • CDK4/6 and cyclin D can phosphorylate retinoblastoma protein (Rb).
  • Rb retinoblastoma protein
  • E2F activates further transcription to promote the cell cycle through the restriction point (R point) and progress from the G1 phase to the S phase.
  • WO2016141881 discloses substituted 2-hydro-pyrazole derivatives as selective CDK4/6 inhibitors, and specifically discloses compounds of formula (I) with the following structure,
  • DDLS Dedifferentiated liposarcoma
  • NCDB US National Cancer Database
  • DDLS cases were new primary tumors, and the remaining 15% cases were secondary to well-differentiated liposarcoma (WDLS), with an average recurrence interval of 7.7 years.
  • the most common primary site of DDLS is the retroperitoneum. Less common sites include the limbs, paratesticular area, head and neck, chest, and rarely in soft tissue.
  • DDLS is less aggressive than other pleomorphic sarcomas, with a local recurrence rate of approximately 41% to 52%, a metastasis rate of 15% to 30%, and a 5-year disease-related mortality rate of 28% to 30%.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of dedifferentiated liposarcoma,
  • the present disclosure provides a pharmaceutical composition for the treatment or prevention of dedifferentiated liposarcoma, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is packaged in a kit further comprising a compound of formula (I) or Description of pharmaceutically acceptable salts thereof for use in the treatment or prevention of dedifferentiated liposarcoma.
  • the pharmaceutically acceptable salt of the compound of Formula (I) is a maleate salt, such as the monomaleate salt of the compound of Formula (I).
  • the pharmaceutical composition contains 20 to 240 mg, 40 to 180 mg, 60 to 180 mg, 80 to 180 mg, 100 to 180 mg, 120 to 180 mg or 150 to 180 mg based on the compound of formula (I).
  • the pharmaceutical composition contains 150 to 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I).
  • the pharmaceutical composition contains 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg or 180 mg of a compound of Formula (I) or a pharmaceutically acceptable compound thereof. of salt.
  • the pharmaceutical composition contains 60 mg, 120 mg, 150 mg or 180 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 60 mg, 150 mg or 180 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 150 mg or 180 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I).
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, is in single or multiple dose form. In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in multiple dosage form.
  • the pharmaceutical composition contains a daily dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains a once daily dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, is a once daily dose, and each dose is a single dose or multiple doses, usually multiple doses. .
  • the pharmaceutical composition contains a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is in the form of a single administration preparation, the pharmaceutical composition containing 50 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I).
  • the pharmaceutical composition contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).
  • the pharmaceutical composition is in the form of a single administration preparation, the pharmaceutical composition containing 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof based on the compound of formula (I).
  • a treatment cycle is every 28 days.
  • the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), the formulation comprising: a total dose of a compound of formula (I)
  • a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof of 1680 to 5040 mg for example, 1680 mg, 3360 mg, 4200 mg, 5040 mg or the range formed by any two of the above values).
  • the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), the formulation comprising: a total of a compound of formula (I) A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a dosage of 4200 mg or 5040 mg.
  • the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (eg, a treatment cycle of 28 days), the formulation comprising: a total dose of a compound of formula (I) A pharmaceutical composition containing 5040 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a kit, which contains the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a kit of a pharmaceutical composition for treating or preventing dedifferentiated liposarcoma, which contains the compound of formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg or 60 mg calculated as the compound of formula (I).
  • Compounds of formula (I) or pharmaceutically acceptable salts thereof are prepared into a unit preparation containing 50 mg or 60 mg calculated as the compound of formula (I).
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 60 mg of the compound of formula (I) calculated as the compound of formula (I).
  • the present disclosure also provides a method of treating or preventing dedifferentiated liposarcoma, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need thereof, e.g., to an individual in need thereof.
  • the subject is administered a therapeutically effective amount of a pharmaceutical composition of the present disclosure, as described above.
  • the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of dedifferentiated liposarcoma, for example, the pharmaceutical composition of the present disclosure is used in the preparation of Use in drugs for the treatment or prevention of dedifferentiated liposarcoma.
  • the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing dedifferentiated fat.
  • the pharmaceutical composition of the present disclosure is used for treating or preventing dedifferentiated fat. Meat uses.
  • the pharmaceutical composition contains a daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is administered by :
  • the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day.
  • the pharmaceutical composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in a daily dose, wherein the compound of formula (I) Or a pharmaceutically acceptable salt thereof is administered in a single dose or a multiple dose manner, usually in a multiple dose manner; further, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a multiple dose manner daily.
  • Medicine 1 time the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose, wherein the compound of formula (I) Or a pharmaceutically acceptable salt thereof is administered in a single dose or a multiple dose manner, usually in a multiple dose manner; further, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a multiple dose manner daily.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered by: a daily dose of 60 mg; alternatively, a daily dose of 120 mg; alternatively, the daily dose is 150 mg; alternatively, the daily dose is 180 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered by: a daily dose of 150 mg; alternatively, a daily dose of 180mg.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered in a daily dose of 180 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is administered in multiple doses, the multiple doses consisting of a single The dose consists of 50 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered as a continuous daily administration.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is administered in multiple doses, the multiple doses consisting of a single The dose consists of 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered as a continuous daily administration.
  • the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a dose per treatment cycle, which is determined by Mode of Administration: Daily administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared in a single aliquot or multiple aliquots (for example, 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more). equal portions) for packaging.
  • a treatment cycle is 28 days, and the compound of formula (I) or a pharmaceutically acceptable compound thereof is administered daily on days 1-28 of each treatment cycle. of salt.
  • a treatment cycle is 28 days, and the compound of formula (I) is administered once daily on days 1-28 of each treatment cycle or Its pharmaceutically acceptable salt.
  • a 28-day treatment cycle is administered once a day for 28 consecutive days, and each treatment cycle is administered with a compound containing the compound of formula (I) or
  • the total dosage of the pharmaceutical composition of its pharmaceutically acceptable salt is 1680 to 5040 mg.
  • the total dosage of the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof The amount is selected from the range formed by 1680 mg, 3360 mg, 4200 mg, 5040 mg or any two of the above values.
  • the total dosage of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 4200 mg or 5040 mg.
  • the total dosage of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5040 mg.
  • the treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.
  • the dedifferentiated liposarcoma is selected from dedifferentiated liposarcoma that is refractory to surgery or dedifferentiated liposarcoma that refuses surgery.
  • the dedifferentiated liposarcoma is a dedifferentiated liposarcoma whose pathological and imaging review results indicate the presence of dedifferentiated liposarcoma components that are difficult to remove with surgery or a dedifferentiated liposarcoma that refuses surgery.
  • the dedifferentiated liposarcoma is newly diagnosed dedifferentiated liposarcoma; and/or dedifferentiated liposarcoma with postoperative residual disease; and/or locally recurrent or metastatic dedifferentiated liposarcoma; and/or dedifferentiated liposarcoma confirmed by imaging results within the past 6 months.
  • the dedifferentiated liposarcoma is a patient with dedifferentiated liposarcoma who is difficult to remove by surgery or who refuses surgery.
  • Pathological and imaging review results suggest the presence of dedifferentiated liposarcoma components, and the subject also needs to meet the following requirements: Any of the following categories: 1) newly diagnosed dedifferentiated liposarcoma; 2) patients with residual disease after surgery; 3) locally recurrent or metastatic dedifferentiated liposarcoma; 4) patients with disease progression confirmed by imaging results within the past 6 months.
  • the term "difficult to resect” refers to the inability to achieve R0/R1 resection through surgery as assessed by the researcher, specifically including: the tumor is huge or involves important organs; and/or the tumor is located in an important vascular pathway; and/or the tumor is multiple. Metastasis is difficult to control by surgery; and/or combined with serious medical diseases that may pose a fatal surgical risk; and/or recurrence after multiple surgeries is not suitable for immediate surgery.
  • the “newly diagnosed” subjects are treatment-naive subjects, and the treatment-naive subjects refer to subjects who have not received systemic drug treatment or postoperative adjuvant treatment and have not relapsed within 6 months.
  • the "disease progression" refers to treated subjects, and the treated subjects refer to subjects who relapse within 6 months after receiving first-line systemic drug treatment or postoperative adjuvant treatment.
  • the dedifferentiated liposarcoma has at least one measurable lesion according to RECIST 1.1 criteria.
  • the dedifferentiated liposarcoma has at least one measurable lesion according to RECIST 1.1 criteria, and the measurable lesion, if located within the area of previous radiation therapy, should be clearly defined as progressive status.
  • the patient with dedifferentiated liposarcoma has recovered to ⁇ Grade 1 or baseline (per Common Terminology Criteria for Adverse Events version 5.0) from all acute toxic effects of prior treatment or surgery prior to the first dose. , except for alopecia and grade 2 peripheral neuropathy.
  • the patient with dedifferentiated liposarcoma has been previously treated with surgical resection (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has been previously treated with epirubicin or a pharmaceutically acceptable salt thereof and/or ifosfamide (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has been previously treated with extensive resection of tumor tissue and/or vascular exploration (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has been previously treated (eg, failed) with a tyrosine kinase inhibitor (eg, anlotinib).
  • a tyrosine kinase inhibitor eg, anlotinib
  • the patient with dedifferentiated liposarcoma has been previously treated (eg, failed) with systemic chemotherapy (eg, eribulin).
  • systemic chemotherapy eg, eribulin
  • the patient with dedifferentiated liposarcoma has been previously treated with adjuvant chemotherapy with an injectable eribulin regimen (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has been previously treated with radiation therapy (eg, failed treatment).
  • the patient with dedifferentiated liposarcoma has been previously treated (eg, failed) with an immune checkpoint inhibitor (eg, anti-PD-1 antibody or anti-PD-L1 antibody).
  • an immune checkpoint inhibitor eg, anti-PD-1 antibody or anti-PD-L1 antibody.
  • the immune checkpoint inhibitor is selected from camrelizumab.
  • the patient with dedifferentiated liposarcoma has been previously treated with pirarubicin (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has previously undergone surgical resection, epirubicin hydrochloride + ifosfamide, extended tumor tissue resection + vascular exploration, and anlotinib treatment (e.g. treatment failure).
  • the patient with dedifferentiated liposarcoma has previously undergone surgical resection and treatment with anlotinib (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has been previously treated with surgical resection and adjuvant chemotherapy with injectable eribulin regimen (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has been previously treated with surgical resection, radiation therapy, and pirarubicin (eg, treatment failure).
  • the patient with dedifferentiated liposarcoma has previously undergone surgical resection and treatment with anlotinib + camrelizumab (eg, treatment failure).
  • the active components in the pharmaceutical combinations of the present disclosure may be each independently formulated, or some or all of them may be formulated together with pharmaceutically acceptable carriers and/or excipients.
  • Pharmaceutical combinations of the present disclosure may also include additional therapeutic agents.
  • the additional therapeutic agent may be a therapeutic agent known in the art for cancer, preferably for dedifferentiated liposarcoma.
  • the period is 28 days.
  • the amount of compound of formula (I) or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicities, the age and health status of the patient.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered through a variety of routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatal, intraarticular, intraperitoneal and intrathecal.
  • routes including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatal, intraarticular, intraperitoneal and intrathecal.
  • routes including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered as a continuous daily oral administration.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered once daily in the form of a multi-dose oral solid formulation.
  • the compounds of formula (I) of the present disclosure can be administered in the form of their free bases, or in the form of pharmaceutically acceptable salts, hydrates and prodrugs, which are converted into compounds of formula (I) in the body. form.
  • pharmaceutically acceptable salts of compounds of formula (I) are within the scope of the present disclosure and can be produced from various organic and inorganic acids according to methods well known in the art.
  • the molar ratio of the compound of formula (I) to the acid ion forming the pharmaceutically acceptable salt may be 1:1.
  • a pharmaceutically acceptable salt of a compound of formula (I) may be a maleate salt of a compound of formula (I) (eg, a monomaleate salt of a compound of formula (I)).
  • the pharmaceutically acceptable salt of the compound of Formula (I) exists as a salt of the compound of Formula (I).
  • the compound of formula (I) or its pharmaceutically acceptable salt used in the present disclosure can be prepared by methods in the prior art, for example, with reference to the method of WO2016141881.
  • compositions of compounds of formula (I) or pharmaceutically acceptable salts thereof are provided.
  • the single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg or 60 mg based on the compound of formula (I).
  • the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is prepared into a unit preparation containing 50 mg or 60 mg of the compound of formula (I) or its pharmaceutically acceptable salt. Take that with a grain of salt.
  • the single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 60 mg based on the compound of formula (I).
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Salt.
  • the method of administration can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc.
  • the pharmaceutical compositions include, but are not limited to, formulations suitable for oral, parenteral, topical administration.
  • the pharmaceutical composition is a formulation suitable for oral administration.
  • the pharmaceutical composition is a solid formulation suitable for oral administration.
  • the pharmaceutical compositions include, but are not limited to, tablets and capsules.
  • the pharmaceutical composition is a solid pharmaceutical combination.
  • the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is a capsule containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or The core of the sugar coating.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the “clinical benefits” of the compounds of formula (I) disclosed in the present disclosure include, but are not limited to: higher 12-week progression-free survival rate for clinical patients, prolongation of progression-free survival (PFS), prolongation of overall survival (OS), and objective response.
  • the disease control rate (ORR) is improved, the disease control rate (DCR) is improved, the number and/or severity of adverse reactions is reduced, the distant metastasis rate and local control rate are reduced, etc.
  • patient or “individual/subject” refers to a mammal, such as a primate (human, macaque, chimpanzee, etc.), rodent (mouse, rat, rabbit, etc.), feline, canine Animals, etc., preferably humans.
  • a primate human, macaque, chimpanzee, etc.
  • rodent mouse, rat, rabbit, etc.
  • feline canine Animals, etc., preferably humans.
  • the patient and the individual are patients who have failed or are lacking standard treatments.
  • pharmaceutically acceptable refers to a carrier, excipient or excipient used in the preparation of a pharmaceutical composition that is generally safe, non-toxic and not bioavailable. Scientifically or otherwise undesirable, including acceptable use in human medicines.
  • terapéuticaally effective amount means an amount of a compound sufficient to effect treatment of a disease when administered to a human for the treatment of the disease.
  • treating means administering a compound or formulation of the present disclosure to ameliorate, alleviate, or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) inhibiting a disease or disease state, i.e. To arrest or retard the progression of a disease or disease state; (ii) To alleviate a disease or disease state, i.e. to cause the disease or disease state to subside.
  • prevention means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with said disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such disease A mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • an "adverse event” is any adverse and generally unintentional or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment.
  • adverse events may be associated with activation of the immune system or expansion of immune system cells (eg, T cells) in response to treatment.
  • a medical treatment can have one or more associated AEs, and each AE can have the same or different severity levels.
  • References to methods that "modify adverse events” refer to treatment regimens that reduce the incidence and/or severity of one or more AEs associated with the use of different treatment regimens.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • administration refers to the physical introduction of a composition containing a therapeutic agent to an individual using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral administration.
  • daily dose refers to the daily dose administered to a patient.
  • single dose or "unit preparation” refers to the smallest packaging unit of a medicine containing a certain amount of active ingredient. For example, if a box of medicine has seven capsules, each capsule is a single dose or unit preparation; for example, a box of medicine has seven capsules. tablets, each tablet is a single-dose unit preparation.
  • multiple doses consists of a plurality of single doses.
  • “combination” or “used in combination” means that two or more active substances may be administered to an individual simultaneously, each as a single formulation, in parallel, or each as a single formulation, sequentially in any order.
  • composition refers to a mixture of one or more active ingredients of the present disclosure or a pharmaceutical combination thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an individual of a compound of the present disclosure or a pharmaceutical combination thereof.
  • day When referring to a dosing regimen, the terms "day”, “daily” and the like refer to the time within a calendar day starting at midnight and ending at the next midnight.
  • recurrent cancer is a cancer that reappears at the original site or at a distant site after responding to initial treatment, such as surgery.
  • a “locally recurrent” cancer is a cancer that appears after treatment in the same location as a previously treated cancer.
  • metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • Age 18-75 years old (calculated based on the date of signing the informed consent form); ECOG PS score: 0 to 1 point; body mass index (BMI) > 18.5 and weight > 40 kg; expected survival period > 3 months;
  • Routine blood examination standards no blood transfusion or correction with hematopoietic stimulating factor drugs within 7 days before the examination:
  • Total bilirubin (TBIL) 1.5 times the upper limit of normal (ULN); patients with Gilbert syndrome ⁇ 3 ⁇ ULN;
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Routine urine examination standards Routine urine examination indicates urine protein ⁇ ++; if urine protein ⁇ ++, it is necessary to confirm that the 24-hour urine protein quantification is ⁇ 1.0g;
  • Coagulation function standards prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ⁇ 1.5 ⁇ ULN (no anticoagulant treatment);
  • LVEF left ventricular ejection fraction
  • Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study period and within 6 months after the end of the study; have a negative serum pregnancy test within 7 days before study enrollment , and must be non-lactating subjects; male subjects should agree to use contraceptive measures during the study period and within 6 months after the end of the study period.
  • contraceptive measures such as intrauterine devices, birth control pills or condoms
  • Capsules of compounds of formula (I) specifications of 50 mg or 60 mg, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
  • Capsule of compound of formula I 180 mg/time (based on compound of formula (I)), taken orally on an empty stomach, once a day, and taken continuously for 28 days as a treatment cycle.
  • Compound of formula I capsule placebo 0 mg/time (based on compound of formula (I)), taken orally on an empty stomach, once a day, for 28 consecutive days as a treatment cycle.
  • Effectiveness evaluation criteria RECIST 1.1 criteria are used to determine disease status.
  • Safety evaluation standard NCI-CTC AE 5.0 standard is used to judge the severity of adverse events. During the trial, the adverse event record form should be filled in truthfully, including the time of occurrence, severity, correlation with study treatment, duration, measures taken and outcome of the adverse event.
  • Gastrointestinal reactions are mainly grade 1 to 2 and can be controlled after symptomatic treatment.
  • the overall incidence of grade 3 and above TEAEs is 9%, and the overall safety is good.

Abstract

本公开属于医药技术领域，涉及一种CDK4/6抑制剂治疗去分化脂肪肉瘤的用途，具体涉及式(I)化合物治疗去分化脂肪肉瘤的用途。

Description

一种CDK4/6抑制剂治疗去分化脂肪肉瘤的用途
相关申请的交叉引用
本申请要求于2022年06月09日向中国国家知识产权局提交的第202210650673.6号中国发明专利申请的优先权和权益，所述申请公开的全部内容通过引用整体并入本文中。
技术领域
本公开属于医药技术领域，涉及一种CDK4/6抑制剂治疗去分化脂肪肉瘤的用途，具体涉及式(I)化合物治疗去分化脂肪肉瘤的用途。
背景技术
周期蛋白依赖性激酶(CDK)4/6是细胞周期的关键调节因子，能够触发细胞周期从生长期(G1期)进入DNA复制期(S1期)。在细胞增殖过程中，CDK4/6与细胞周期素D(CyclinD)形成的复合物能够磷酸化视网膜母细胞瘤蛋白(Rb)。肿瘤抑制蛋白Rb一旦发生磷酸化，可释放其在未被磷酸化的状态下紧密结合的转录因子E2F，E2F激活进一步转录而推动细胞周期通过限制点(R点)并从G1期进展到S期。因此，抑制CDK4/6使之无法形成CyclinD-CDK4/6复合物，能够阻滞细胞周期自G1期向S期的进程，从而达到抑制肿瘤增殖的目的。WO2016141881公开了作为选择性的CDK4/6抑制剂取代的2-氢-吡唑衍生物，并具体公开了如下结构的式(I)化合物，
去分化脂肪肉瘤(DDLS)好发年龄为60至80岁，性别分布较平衡。但美国国家癌症数据库(NCDB)对3573例病例分析发现，65％的病例是男性。研究发现85％的DDLS为新发的原发性肿瘤，其余15％病例则继发于高分化脂肪肉瘤(WDLS)，复发间隔平均7.7年。DDLS最主要的原发部位是腹膜后，较少见的部位包括四肢，睾丸旁区域，头颈部，胸部，极少见于软组织。DDLS较其他多形性肉瘤的侵袭性较小，其局部复发率约为41％～52％，转移率为15～30％，5年疾病相关死亡率28％～30％。
目前根治性手术切除仍是DDLS治疗的主要手段，在提高局部控制率方面，无放疗的3年局部复发率为49％，而有放疗的为34％，但对总体生存率没有影响。对于肢体/躯干壁较大(＞5cm)，浸润程度较深的DDLS患者，应考虑使用全身疗法(新辅助疗法)。但由于DDLS对一线化疗药物的反应往往较差，对于复发性患者可用的选择相对有限。因此，开发对于DDLS的药物十分必要。
发明内容
一方面，本公开提供了用于治疗或预防去分化脂肪肉瘤的式(I)化合物或其药学上可接受的盐，
另一方面，本公开提供了用于治疗或预防去分化脂肪肉瘤的药物组合物，其包含式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物包装于试剂盒中，所述试剂盒还包含将式(I)化合物或 其药学上可接受的盐用以治疗或预防去分化脂肪肉瘤的说明。
在本公开的一些实施方案中，在所述药物组合物中，所述式(I)化合物的药学上可接受的盐是马来酸盐，例如式(I)化合物的单马来酸盐。
在本公开的一些实施方案中，所述药物组合物含有以式(I)化合物计为20～240mg、40～180mg、60～180mg、80～180mg、100～180mg、120～180mg或150～180mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物含有以式(I)化合物计为150～180mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物含有以式(I)化合物计为20mg、40mg、60mg、80mg、100mg、120mg、150mg或180mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物含有以式(I)化合物计为60mg、120mg、150mg或180mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物含有以式(I)化合物计为60mg、150mg或180mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物含有以式(I)化合物计为150mg或180mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物含有以式(I)化合物计为180mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物中，式(I)化合物或其药学上可接受的盐为单剂量或多剂量形式。在本公开的一些实施方案中，所述药物组合物中式(I)化合物或其药学上可接受的盐为多剂量形式。
在本公开的一些实施方案中，所述药物组合物中，式(I)化合物或其药学上可接受的盐为每日剂量。
在本公开的一些实施方案中，所述药物组合物中，式(I)化合物或其药学上可接受的盐为每日一次剂量。
在本公开的一些实施方案中，所述药物组合物中，式(I)化合物或其药学上可接受的盐为每日一次剂量，且每次剂量为单剂量或多剂量，通常为多剂量。
在本公开的一些实施方案中，所述药物组合物中，其含有单剂量以式(I)化合物计为50mg或60mg的式(I)化合物或其药学上可接受的盐。或者，所述药物组合物处于单次给予制剂的形式，所述药物组合物含有以式(I)化合物计为50mg或60mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物中，其含有单剂量以式(I)化合物计为60mg的式(I)化合物或其药学上可接受的盐。或者，所述药物组合物处于单次给予制剂的形式，所述药物组合物含有以式(I)化合物计为60mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，每28天为一个治疗周期。
在本公开的一些实施方案中，所述药物组合物为适用于在单个治疗周期(例如28天的一个治疗周期)内施用的制剂，所述制剂包括：以式(I)化合物计的总剂量为1680～5040mg(例如1680mg、3360mg、4200mg、5040mg或所述任意两个值所形成的范围)的含有式(I)化合物或其药学上可接受的盐的药物组合物。
在本公开的另一些实施方案中，所述药物组合物为适用于在单个治疗周期(例如28天的一个治疗周期)内施用的制剂，所述制剂包括：以式(I)化合物计的总剂量为4200mg或5040mg的含有式(I)化合物或其药学上可接受的盐的药物组合物。
在本公开的一些实施方案中，所述药物组合物为适用于在单个治疗周期(例如28天的一个治疗周期)内施用的制剂，所述制剂包括：以式(I)化合物计的总剂量为5040mg的含有式(I)化合物或其药学上可接受的盐的药物组合物。
另一方面，本公开还提供一种试剂盒，其中含有本公开所述的式(I)化合物或其药学上可接受的盐。
另一方面，本公开还提供一种用于治疗或预防去分化脂肪肉瘤的药物组合物的试剂盒，其中含有本公开所述的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物中，所述式(I)化合物或其药学上可接受的盐被制备成单位制剂中含有以式(I)化合物计为50mg或60mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述药物组合物中，所述式(I)化合物或其药学上可接受的盐被制备成单位制剂中含有以式(I)化合物计为60mg的式(I)化合物或其药学上可接受的盐。
另一方面，本公开还提供了治疗或预防去分化脂肪肉瘤的方法，其包括向有需要的个体施用治疗有效量的式(I)化合物或其药学上可接受的盐，例如向有需要的个体施用治疗有效量的本公开的上文所述的药物组合物。
另一方面，本公开还提供了式(I)化合物或其药学上可接受的盐在制备用于治疗或预防去分化脂肪肉瘤的药物中的用途，例如本公开所述药物组合物在制备用于治疗或预防去分化脂肪肉瘤的药物中的用途。
另一方面，本公开还提供了式(I)化合物或其药学上可接受的盐用于治疗或预防去分化脂肪肉的用途，例如本公开所述药物组合物用于治疗或预防去分化脂肪肉的用途。
在本公开的一些实施方案中，在所述方法或用途中，所述药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其通过如下方式给药：式(I)化合物或其药学上可接受的盐每日给药1次。
在本公开的一些实施方案中，在所述方法或用途中，所述药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其中式(I)化合物或其药学上可接受的盐以单剂量或多剂量方式给药，通常以多剂量方式给药；进一步地，其中式(I)化合物或其药学上可接受的盐以多剂量方式每日给药1次。
在本公开的一些实施方案中，在所述方法或用途中，所述式(I)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为60mg；或者，每日剂量为120mg；或者，每日剂量为150mg；或者，每日剂量为180mg。
在本公开的一些实施方案中，在所述方法或用途中，所述式(I)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为150mg；或者，每日剂量为180mg。
在本公开的一些实施方案中，在所述方法或用途中，所述式(I)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为180mg。
在本公开的一些实施方案中，在所述方法或用途中，所述药物组合物中的式(I)化合物或其药学上可接受的盐以多剂量方式给药，所述多剂量由单剂量为50mg的式(I)化合物或其药学上可接受的盐组成。在本公开的一些实施方案中，在所述方法或用途中，所述式(I)化合物或其药学上可接受的盐以连续每日给药的方式给药。
在本公开的一些实施方案中，在所述方法或用途中，所述药物组合物中的式(I)化合物或其药学上可接受的盐以多剂量方式给药，所述多剂量由单剂量为60mg的式(I)化合物或其药学上可接受的盐组成。在本公开的一些实施方案中，在所述方法或用途中，所述式(I)化合物或其药学上可接受的盐以连续每日给药的方式给药。
在本公开的一些实施方案中，在所述方法或用途中，所述药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每个治疗周期的剂量，其通过如下方式给药：每天施用式(I)化合物或其药学上可接受的盐。其中，式(I)化合物或其药学上可接受的盐以单等份或多个等份(例如2等份、4、等份、7个等份、14等份、28等份或更多等份)进行包装。
在本公开的一些实施方案中，在所述方法或用途中，28天为一个治疗周期，在每个治疗周期的第1-28天每天施用所述式(I)化合物或其药学上可接受的盐。
在本公开的一些具体的实施方案中，在所述方法或用途中，28天为一个治疗周期，在每个治疗周期的第1-28天每日1次施用所述式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，在所述方法或用途中，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为1680～5040mg。在部分的实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物的总剂 量选自1680mg、3360mg、4200mg、5040mg或所述任意两个值所形成的范围。在部分的实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物的总剂量优选为4200mg、5040mg。在部分的实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物的总剂量优选为5040mg。
本公开的实施方案中，只要疾病仍处于控制之下和给药方案具有临床耐受性，就重复所述治疗周期。
在本公开的一些实施方案中，所述去分化脂肪肉瘤选自手术难以切除的去分化脂肪肉瘤或拒绝手术的去分化脂肪肉瘤。
在本公开的一些实施方案中，所述去分化脂肪肉瘤为病理及影像学复核结果提示存在去分化脂肪肉瘤成分的手术难以切除的去分化脂肪肉瘤或拒绝手术的去分化脂肪肉瘤。
在本公开的一些实施方案中，所述去分化脂肪肉瘤为新诊断的去分化脂肪肉瘤；和/或术后残留病灶的去分化脂肪肉瘤；和/或局部复发、转移性去分化脂肪肉瘤；和/或近6个月内经影像结果证实疾病进展的去分化脂肪肉瘤。
在本公开的一些实施方案中，所述去分化脂肪肉瘤为手术难以切除或拒绝手术的去分化脂肪肉瘤患者，病理及影像学复核结果提示存在去分化脂肪肉瘤成分，且受试者还需满足以下任一类别：1)新诊断的去分化脂肪肉瘤；2)术后残留病灶者；3)局部复发、转移性去分化脂肪肉瘤；4)近6个月内经影像结果证实疾病进展者。
本公开中，所述手术难以切除是指经研究者评估无法通过手术达到R0/R1切除，具体包括：肿瘤巨大或累及重要脏器；和/或肿瘤位于重要血管途径部位；和/或肿瘤多发转移，难以通过外科手术来控制；和/或合并严重内科疾病可造成致命外科手术风险；和/或多次手术后复发不适合立即手术。
本公开中，所述“新诊断”为初治受试者，所述初治受试者是指未接受过***药物治疗或术后辅助治疗后6个月内未复发的受试者。
本公开中，所述“疾病进展”为经治受试者，所述经治受试者是指接受过一线***药物治疗或术后辅助治疗后6个月内复发的受试者。
在本公开的一些实施方案中，所述去分化脂肪肉瘤根据RECIST 1.1标准至少有一个可测量病灶。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤根据RECIST 1.1标准至少有一个可测量病灶，所述可测量病灶如位于既往放疗区域内的，应明确为进展状态。
在本公开的一些实施方案中，所述去分化脂肪肉瘤患者在首次用药之前既往治疗或外科手术的所有急性毒性效应均已恢复至≤1级或基线(根据不良事件通用术语标准第5.0版)，脱发和2级周围神经病变除外。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过手术切除的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过表柔比星或其药学上可接受的盐和/或异环磷酰胺的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过肿瘤组织扩大切除术和/或血管探查术的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过酪氨酸激酶抑制剂(例如安罗替尼)的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过全身化疗(例如艾日布林)的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过注射用艾日布林方案辅助化疗的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过放疗的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过免疫检查点抑制剂(例如抗PD-1抗体或抗PD-L1抗体)的治疗(例如治疗失败)。在本公开的另一些实施方案中，所述免疫检查点抑制剂选自卡瑞丽珠单抗。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过吡柔比星的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过手术切除、盐酸表柔比星+异环磷酰胺、肿瘤组织扩大切除术+血管探查术以及安罗替尼的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过手术切除和安罗替尼的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过手术切除和注射用艾日布林方案辅助化疗的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过手术切除、放疗和吡柔比星的治疗(例如治疗失败)。
在本公开的另一些实施方案中，所述去分化脂肪肉瘤患者既往接受过手术切除、安罗替尼+卡瑞丽珠单抗的治疗(例如治疗失败)。
本公开的药物组合中的活性组分可以各自独立地，或者其中的部分或全部地共同与药学上可接受的载体和/或赋形剂配制。本公开的药物组合还可以包含另外的治疗剂。本公开的一些实施方案，所述另外的治疗剂可以是本领域已知的用于癌症的治疗剂，优选用于去分化脂肪肉瘤的治疗剂。
在本公开的一些实施方案中，所述周期为28天。
施用式(I)化合物或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。
式(I)化合物或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于以下途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、***、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一个具体的实施方案中，式(I)化合物或其药学上可接受的盐通过口服给药。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐以连续每日口服给药的方式给药。
在本公开的一些实施方案中，式(I)化合物或其药学上可接受的盐以多剂量的口服固体制剂形式每天给药1次。
式(I)化合物或其药学上可接受的盐
本公开的式(I)化合物可以以其游离碱形式给药，也可以以其药学上可接受的盐、水合物和前药的形式给药，该前药在体内转换成式(I)化合物形式。例如，式(I)化合物的药学上可接受的盐在本公开的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
关于本公开所述的式(I)化合物的药学上可接受的盐，式(I)化合物与形成可药用盐的酸根离子的摩尔比可为1∶1。
式(I)化合物的药学上可接受的盐可以是式(I)化合物的马来酸盐(例如式(I)化合物的单马来酸盐)。
本公开中涉及的式(I)化合物或其药学上可接受的盐的剂量，除非另有说明，均基于式(I)化合物的量。
在本公开的一些实施方案中，所述式(I)化合物的药学上可接受的盐以式(I)化合物的盐形式存在。
本公开所用的式(I)化合物或其药学上可接受的盐可以通过现有技术的方法制备，例如参照WO2016141881的方法进行制备。
式(I)化合物或其药学上可接受的盐的药物组合物
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物的单剂量以式(I)化合物计为50mg或60mg。或者，所述式(I)化合物或其药学上可接受的盐的药物组合物被制备成单位制剂中含有以式(I)化合物计为50mg或60mg的式(I)化合物或其药学上可接受的盐。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物的单剂量以式(I)化合物计为60mg。或者，所述式(I)化合物或其药学上可接受的盐的药物组合物被制备成单位制剂中含有以式(I)化合物计为60mg的式(I)化合物或其药学上可接受的盐。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在本公开的一些实施方案中，所述含有式(I)化合物或其药学上可接受的盐的药物组合物还含有药学上可接受的辅料。药学上可接受的辅料包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。在本公开的一些实施方案中，所述药物组合物包括但不限于适合口服、肠道外、局部给药的制剂。在一些实施方案中，所述药物组合物为适合口服的制剂。在一些实施方案中，所述药物组合物为适合口服的固体制剂。在一些实施方案中，所述药物组合物包括但不限于片剂、胶囊。
在本公开的一些实施方案中，所述药物组合物为固体药物组合。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物为含有式(I)化合物或其药学上可接受的盐的固体药物组合物。
在本公开的一些实施方案中，所述式(I)化合物或其药学上可接受的盐的药物组合物为含有式(I)化合物或其药学上可接受的盐的胶囊。
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
技术效果
通常，使用所述的本公开的式(I)化合物将有助于：
(1)在减少肿瘤的生长或甚至消除肿瘤方面产生较好的疗效；
(2)提供在患者中具有良好耐受的治疗，不良反应和/或并发症少；
(3)提供在所治疗患者之中的较好的疾病控制率(DCR)；
(4)提供在所治疗的患者中具有较长的生存期(例如中位生存期、无进展生存期或总生存期)；
(5)提供相比于标准的化疗而言，所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(6)提供较长时间的疾病缓解持续时间(DOR)。
本公开的式(I)化合物“临床有收益”包括但不限于：临床患者12周无进展生存率较高、无进展生存期(PFS)得到延长、总生存期(OS)得到延长、客观缓解率(ORR)得到提高、疾病控制率(DCR)得到提高、不良反应数量减少和/或程度降低、远处转移率以及局部控制率下降等。
定义和说明
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising以及其等同物应理解为开放的、非排他性的意义，即“包括但不限于”，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
术语“患者”或“个体/受试者”是指哺乳动物，例如灵长类动物(人、猕猴、黑猩猩等)、啮齿动物(小鼠、大鼠、兔等)、猫科动物、犬科动物等，优选人。在本公开的一些实施方案中，所述患者和所述个体为经标准治疗失败或缺乏标准治疗的患者。
术语“药学上可接受的”或“可药用的”是指用于制备药物组合物的载体、赋形剂或辅料，该载体、赋形剂或辅料通常是安全、无毒的并且不在生物学上或其它方面不合乎需要，而且包括其对于人类药物的使用是可接受的。
术语“治疗有效量”意指化合物被施用于人来治疗疾病时，足以实现对该疾病的治疗的量。
术语“治疗”意为将本公开所述化合物或制剂进行给药以改善、减轻或消除疾病或与所述疾病相关的一个或多个症状，且包括：(i)抑制疾病或疾病状态，即遏制或迟滞其发展；(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本公开所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
本文中使用的“不良事件”(AE)是与医学治疗的应用有关的任何不利的和通常非故意的或不希望的迹象(包括异常的实验室发现)、征状或疾病。例如，不利事件可以与响应于治疗的免疫***的激活或免疫***细胞(例如，T细胞)的扩增相关。医学治疗可以具有一种或多种相关的AE，并且每种AE可以具有相同或不同的严重性水平。对能够“改变不利事件”的方法的提及是指降低与不同治疗方案的应用相关的一种或多种AE的发生率和/或严重性的治疗方案。
备选方案(例如，“或”)的应用应当被理解为是指备选方案中的任一个、两个或它们的任意组合。本文中使用的不定冠词“一个”或“一种”应当理解为表示任何列举或枚举的组分中的“一个或多个/一种或多种”。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“施用”和“给药”表示使用本领域技术人员已知的多种方法和递送***中的任一种向个体物理引入包含治疗剂的组合物。在某些实施方案中，施用为口服施用。
术语“每日剂量”是指每日施用于患者的剂量。
术语“单剂量”或“单位制剂”是指含有一定量活性成分的药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量或单位制剂；例如一盒药有七片药品，则每片药为单剂量单位制剂。
术语“多剂量”由多个单剂量组成。如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、并行地或各自作为单一制剂以任何顺序依次地施用于个体。
术语“药物组合物”是指一种或多种本公开的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对个体施用本公开的化合物或其药物组合。
涉及给药方案时，术语“天(日)”、“每天(每日)”等指一个日历日内的时间，开始于午夜且终止于下一个午夜。
术语“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后，在与先前治疗的癌症相同的位置出现的癌症。
术语“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”，反之亦然。
除非另有说明，在本文中，代表成分的量或理化性质或者反应条件等的参数值应当被理解为在所有情况下均由术语“约”修饰。当用术语“约”描述本公开时，术语“约”表示存在的误差值，例如表示在某一特定值的±5％、例如±1％或±0.1％的范围内变化。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本公开的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的 正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
实施例
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本公开。它们不应该被认为是对本公开范围的限制，而只是本公开的示例性说明和典型代表。
实验例1临床试验
本研究采用随机、双盲、安慰剂平行对照试验设计或者单臂试验设计。对于平行对照试验，所有患者签署知情同意书后，经过筛选检查符合入组条件的受试者将被随机(1∶1)分成两组，分为试验组和对照组，试验组给予式I化合物胶囊，对照组给予式I化合物胶囊安慰剂，4周(28天)为1个周期；对于单臂试验，给药方案同平行对照试验的试验组。通过本公开的临床试验以评价式I化合物胶囊治疗去分化脂肪肉瘤的有效性和安全性。
1.1入选标准：
1)受试者自愿加入本研究，签署知情同意书，依从性好；
2)年龄：18-75周岁(以签署知情同意书日期计算)；ECOG PS评分：0～1分；身体质量指数(BMI)＞18.5且体重＞40kg；预计生存期＞3个月；
3)经多学科会诊确诊为手术难以切除或拒绝手术的去分化脂肪肉瘤患者，病理及影像学复核结果提示存在去分化脂肪肉瘤成分，且受试者还需满足以下任一类别：
1)新诊断的去分化脂肪肉瘤；
2)术后残留病灶者；
3)局部复发、转移性去分化脂肪肉瘤；
4)近6个月内经影像结果证实疾病进展者；
4)根据RECIST 1.1标准至少有一个可测量病灶，可测量病灶如位于既往放疗区域内的，应明确为进展状态；
5)受试者在首次用药之前既往治疗或外科手术的所有急性毒性效应均已恢复至≤1级或基线(根据不良事件通用术语标准第5.0版[CTCAE v 5.0])，脱发和2级周围神经病变除外；
6)主要器官功能良好，符合下列标准：
1)血常规检查标准(检查前7天内未输血、未使用造血刺激因子类药物纠正)：
a.血红蛋白(HGB)≥90.0g/L；
b.中性粒细胞绝对值(ANC)≥1.5×109/L；
c.血小板计数(PLT)≥90×109/L；
2)生化检查标准：
a.总胆红素(TBIL)≤1.5倍正常值上限(ULN)；Gilbert综合症患者≤3×ULN；
b.丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤3×ULN。若伴肝转移，则
ALT和AST≤5×ULN；
c.血清肌酐(CR)≤178μmol/L或肌酐清除率(CCR)＞50ml/min；
3)尿常规检查标准：尿常规提示尿蛋白＜++；若尿蛋白≥++，需证实24小时尿蛋白定量≤1.0g；
4)凝血功能标准：凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、国际标准化比值(INR)≤1.5×ULN(未接受过抗凝治疗)；
5)心脏彩超评估：左室射血分数(LVEF)≥50％；
6)12-导联心电图评估：QTc＜450ms(男)，QTc＜470ms(女)
7)育龄女性受试者应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器、避孕药或避孕套)；在研究入组前的7天内血清妊娠试验阴性，且必须为非哺乳期受试者；男性受试者应同意在研究期间和研究期结束后6个月内必须采用避孕措施。
1.2试验药
式(I)化合物的胶囊：规格50mg或60mg，由正大天晴药业集团股份有限公司提供。
1.3给药方案
式I化合物胶囊：180mg/次(以式(I)化合物计)，空腹口服，每日一次，连续服用28天为一个治疗周期。
式I化合物胶囊安慰剂：0mg/次(以式(I)化合物计)，空腹口服，每日一次，连续服用28天为一个治疗周期。
1.4评价标准
有效性评价标准：采用RECIST 1.1标准判定疾病状态。
安全性评价标准：采用NCI-CTC AE 5.0标准判断不良事件严重程度。试验期间应如实填写不良事件记录表，包括不良事件的发生时间、严重程度、与研究治疗的相关性、持续时间、采取的措施和转归等。
1.5试验结果
1.5.1安全性
胃肠道反应(腹泻、呕吐等)，1～2级为主，经对症处理后可控，3级及以上TEAEs总体发生率为9％，总体安全性较好。
1.5.2有效性
15例已达到C3(12周)疗效评估的受试者中，9例患者达到12周PFS，12周PFS率为60％。可评估患者无进展生存期(PFS)、总生存期(OS)、客观缓解率ORR)、疾病控制率(DCR)、缓解持续时间DOR均较好。结果发现本公开的式(I)化合物具有临床收益。
以下为代表性病例：
本领域技术人员将认识到，本公开的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本公开的精神和构思的情况下，进行各种修改、替换、或重新组合，这都落入了本公开的保护范围内。

Claims (14)

  1. 用于治疗或预防去分化脂肪肉瘤的式(I)化合物或其药学上可接受的盐，
  2. 用于治疗或预防去分化脂肪肉瘤的药物组合物，其包含式(I)化合物或其药学上可接受的盐，
  3. 根据权利要求2所述的药物组合物，所述药物组合物包装于试剂盒中，所述试剂盒还包含将式(I)化合物或其药学上可接受的盐用以治疗或预防去分化脂肪肉瘤的说明。
  4. 根据权利要求2所述的药物组合物，所述药物组合物含有以式(I)化合物计为20～240mg、40～180mg、60～180mg、80～180mg、100～180mg、120～180mg或150～180mg的式(I)化合物或其药学上可接受的盐；
    或者，所述药物组合物含有以式(I)化合物计为150～180mg的式(I)化合物或其药学上可接受的盐；
    或者，所述药物组合物含有以式(I)化合物计为20mg、40mg、60mg、80mg、100mg、120mg、150mg或180mg的式(I)化合物或其药学上可接受的盐；
    或者，所述药物组合物含有以式(I)化合物计为60mg、150mg或180mg的式(I)化合物或其药学上可接受的盐；
    或者，所述药物组合物含有以式(I)化合物计为150mg或180mg的式(I)化合物或其药学上可接受的盐。
  5. 根据权利要求2所述的药物组合物，所述药物组合物中，式(I)化合物或其药学上可接受的盐为单剂量或多剂量形式；
    或者，所述药物组合物中，式(I)化合物或其药学上可接受的盐为多剂量形式。
  6. 根据权利要求2所述的药物组合物，所述药物组合物中，式(I)化合物或其药学上可接受的盐为每日剂量；
    或者，所述药物组合物中，式(I)化合物或其药学上可接受的盐为每日一次剂量；
    或者，所述药物组合物中，式(I)化合物或其药学上可接受的盐为每日一次剂量，且每次剂量为单剂量或多剂量；
    或者，所述药物组合物中，式(I)化合物或其药学上可接受的盐为每日一次剂量，且每次剂量为多剂量。
  7. 根据权利要求2所述的药物组合物，所述药物组合物为适用于在单个治疗周期内施用的制剂，所述制剂包括：以式(I)化合物计的总剂量为1680～5040mg的含有式(I)化合物或其药学上可接受的盐的药物组合物；
    或者，所述药物组合物为适用于在单个治疗周期内施用的制剂，所述制剂包括：以式(I)化合物计的总剂量为1680mg、3360mg、4200mg、5040mg或所述任意两个值所形成的范围的含有式(I)化合物或其药学上可接受的盐的药物组合物；
    或者，所述药物组合物为适用于在单个治疗周期内施用的制剂，所述制剂包括：以式(I)化合物计的总剂量为4200mg或5040mg的含有式(I)化合物或其药学上可接受的盐的药物组合物。
  8. 根据权利要求2所述的药物组合物，所述式(I)化合物或其药学上可接受的盐被制备成单位制剂中含有以式(I)化合物计为50mg或60mg的式(I)化合物或其药学上可接受的盐。
  9. 治疗或预防去分化脂肪肉瘤的方法，其包括向有需要的个体施用治疗有效量的权利要求1所述的式(I)化合物或其药学上可接受的盐或权利要求2-8任一项所述的药物组合物。
  10. 根据权利要求9所述的方法，所述药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其通过如下方式给药：式(I)化合物或其药学上可接受的盐每日给药1次；
    或者，所述药物组合物中的式(I)化合物或其药学上可接受的盐的含量为每日剂量，其通过如下方式给药：式(I)化合物或其药学上可接受的盐以多剂量方式每日给药1次。
  11. 根据权利要求9所述的方法，所述式(I)化合物或其药学上可接受的盐通过如下方式给药：每日剂量为60mg；或者，每日剂量为120mg；或者，每日剂量为150mg；或者，每日剂量为180mg。
  12. 根据权利要求9所述的方法，28天为一个治疗周期，在每个治疗周期的第1-28天每天施用所述式(I)化合物或其药学上可接受的盐；
    或者，28天为一个治疗周期，在每个治疗周期的第1-28天每日1次施用所述式(I)化合物或其药学上可接受的盐；
    或者，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为1680～5040mg；
    或者，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为1680mg、3360mg、4200mg、5040mg或所述任意两个值所形成的范围；
    或者，28天为一个治疗周期，每天给药1次，连续给药28天，每个治疗周期施用含有所述式(I)化合物或其药学上可接受的盐的药物组合物的总剂量为4200mg、5040mg。
  13. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐或权利要求2-8任一项所述的药物组合物、权利要求9-12任一项所述的方法，所述去分化脂肪肉瘤选自手术难以切除的去分化脂肪肉瘤或拒绝手术的去分化脂肪肉瘤。
  14. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐或权利要求2-8任一项所述的药物组合物、权利要求9-12任一项所述的方法，所述去分化脂肪肉瘤为新诊断的去分化脂肪肉瘤；和/或术后残留病灶的去分化脂肪肉瘤；和/或局部复发、转移性去分化脂肪肉瘤；和/或近6个月内经影像结果证实疾病进展的去分化脂肪肉瘤。
PCT/CN2023/099164 2022-06-09 2023-06-08 一种cdk4/6抑制剂治疗去分化脂肪肉瘤的用途 WO2023237055A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016141881A1 (zh) * 2015-03-11 2016-09-15 南京明德新药研发股份有限公司 作为抗癌药物的取代的2-氢-吡唑衍生物
WO2018045993A1 (zh) * 2016-09-09 2018-03-15 正大天晴药业集团股份有限公司 一种取代的2-氢-吡唑衍生物的晶型、盐型及其制备方法
WO2021259203A1 (zh) * 2020-06-22 2021-12-30 正大天晴药业集团股份有限公司 一种cdk4/6抑制剂的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016141881A1 (zh) * 2015-03-11 2016-09-15 南京明德新药研发股份有限公司 作为抗癌药物的取代的2-氢-吡唑衍生物
WO2018045993A1 (zh) * 2016-09-09 2018-03-15 正大天晴药业集团股份有限公司 一种取代的2-氢-吡唑衍生物的晶型、盐型及其制备方法
WO2021259203A1 (zh) * 2020-06-22 2021-12-30 正大天晴药业集团股份有限公司 一种cdk4/6抑制剂的制备方法

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