WO2023284790A1 - 选择性雌激素受体共价拮抗剂与cdk4/6抑制剂联合在制备治疗乳腺癌药物中的用途 - Google Patents

选择性雌激素受体共价拮抗剂与cdk4/6抑制剂联合在制备治疗乳腺癌药物中的用途 Download PDF

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WO2023284790A1
WO2023284790A1 PCT/CN2022/105484 CN2022105484W WO2023284790A1 WO 2023284790 A1 WO2023284790 A1 WO 2023284790A1 CN 2022105484 W CN2022105484 W CN 2022105484W WO 2023284790 A1 WO2023284790 A1 WO 2023284790A1
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pharmaceutically acceptable
acceptable salt
formula
compound represented
day
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PCT/CN2022/105484
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English (en)
French (fr)
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邹建军
张晓静
张蕾
龚彦玲
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江苏恒瑞医药股份有限公司
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Priority to CN202280049326.6A priority Critical patent/CN117642169A/zh
Publication of WO2023284790A1 publication Critical patent/WO2023284790A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosure relates to the use of a selective estrogen receptor covalent antagonist combined with a CDK4/6 inhibitor in the preparation of a drug for treating breast cancer, and belongs to the field of pharmacy.
  • Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer, and endocrine therapy is the mainstay of treatment for ER+ breast cancer. Although endocrine therapy has greatly reduced breast cancer recurrence and mortality, primary and secondary drug resistance remain major challenges.
  • the SERD drug fulvestrant is the only clinically approved drug molecule that has shown efficacy in the treatment of drug-resistant ER+ breast cancer. The antiestrogenic activity of fulvestrant and its ability to degrade ER protein make it an effective treatment for patients with ER-positive breast cancer, including those who have developed resistance to TAM or aromatase inhibitors.
  • the present disclosure provides the use of a selective estrogen receptor covalent antagonist in the preparation of a drug for treating breast cancer.
  • the present disclosure provides a use of a selective estrogen receptor covalent antagonist in the preparation of a medicament for treating ER+ or HER2- breast cancer.
  • the present disclosure provides a use of a selective estrogen receptor covalent antagonist in the preparation of a medicament for treating ER+, HER2- breast cancer.
  • the present disclosure provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer.
  • the present disclosure provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ER+ or HER2- breast cancer.
  • the present disclosure provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating ER+, HER2- breast cancer.
  • Another aspect of the present disclosure provides a combination of a selective estrogen receptor covalent antagonist and a CDK4/6 inhibitor in a drug for treating breast cancer.
  • the present disclosure provides the use of a selective estrogen receptor covalent antagonist in combination with a CDK4/6 inhibitor in the treatment of ER+ or HER2- breast cancer.
  • the present disclosure provides the use of a selective estrogen receptor covalent antagonist in combination with a CDK4/6 inhibitor in the treatment of ER+, HER2- breast cancer.
  • the CDK 4/6 inhibitors described in the present disclosure are selected from palbociclib or a pharmaceutically acceptable salt thereof, bomazenil or a pharmaceutically acceptable salt thereof, ribociclib, 2 '-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9 '-Pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6'-one dihydrochloride, G1T-28, AT-7519, FLX-925, A Fuxidi.
  • Palbociclib in this disclosure is: 6-acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-(piperazin-1-yl)pyridin-2-yl]amino ⁇ pyridine And[2,3-d]pyrimidin-7(8H)-one;
  • Bomazenil compound name N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin 2-yl )-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine;
  • Ribociclib chemical name 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;
  • G1T- 28 Chemical name: 2'-((5-(4-methylpiperazin-1-yl)pyridin-2
  • the present disclosure provides a combination of a pharmaceutically acceptable salt of a compound represented by formula (I) and a compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer use,
  • the present disclosure provides a pharmaceutically acceptable salt of a compound represented by formula (I) in combination with a compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the preparation of treating ER+ or HER2- breast cancer use in medicines.
  • the present disclosure provides a pharmaceutically acceptable salt of a compound represented by formula (I) in combination with a compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the preparation for treating ER+, HER2- breast cancer use in medicines,
  • the breast cancer described in the present disclosure is metastatic or locally advanced breast cancer.
  • the ER+ or HER2- breast cancer described in the present disclosure is metastatic or locally advanced breast cancer.
  • the ER+, HER2- breast cancer described in the present disclosure is metastatic or locally advanced breast cancer.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malic acid salt, adipate, methanesulfonate, phosphate, acetate, mandelate, or sulfate.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from maleate or hydrochloride.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from maleate.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from hydrochloride.
  • the pharmaceutically acceptable salt of the compound represented by formula (II) in the present disclosure is isethionate.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in this co-disclosure is selected from 1-1000 mg, and the optional dose is: 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg , 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg , 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg,
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg or 600mg, the administration frequency is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 75 mg, 150 mg, 300 mg, 450 mg or 600 mg; the administration frequency is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 25 mg, and the administration frequency is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 75 mg, and the administration frequency is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 150 mg;
  • the frequency of administration is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 300 mg; the administration frequency is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 450 mg; the administration frequency is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 600 mg; the administration frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 1-500 mg, and the dosage frequency is selected from once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265m
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 25 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 50 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 75 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 100 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 125 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 150 mg, and the dosage is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 175 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 200 mg, and the dosage frequency is once a day or twice a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg or 600mg, the administration frequency is once a day; From 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, the dosing frequency is once a day.
  • the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 25 mg, 75 mg, 150 mg, 300 mg, 450 mg or 600 mg, and the administration frequency is once a day; the compound represented by formula (II)
  • the dosage of the pharmaceutically acceptable salt thereof is selected from 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, and the dosage is once a day.
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 25 mg, and the administration frequency is once a day; the administration of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, and the administration frequency is once a day.
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 75 mg, and the administration frequency is once a day; the administration of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, and the administration frequency is once a day.
  • the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is 150 mg, and the administration frequency is once a day; the administration of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, and the administration frequency is once a day.
  • the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is 300 mg, and the administration frequency is once a day; the administration of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, and the administration frequency is once a day.
  • the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 450 mg, and the administration frequency is once a day; the administration of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, and the administration frequency is once a day.
  • the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is 600 mg, and the administration frequency is once a day; the administration of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75mg, 100mg, 125mg, 150mg, 175mg or 200mg, and the administration frequency is once a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 50 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 75 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 100 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 125 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 150 mg, and the dosage is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 175 mg, and the dosage frequency is once a day or twice a day.
  • the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 200 mg, and the dosage frequency is once a day or twice a day.
  • one administration cycle of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is 28 days, wherein the administration is administered on the first 21 days and the administration is stopped on the last 7 days.
  • Another aspect of the present disclosure provides a method for treating breast cancer patients, giving patients a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a compound represented by formula (II) or its Pharmaceutically acceptable salts.
  • Another aspect of the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treating breast cancer, which is used in combination with a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof for treating breast cancer, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • compositions comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical
  • pharmaceutically acceptable excipients include but are not limited to fillers, disintegrants, binders or lubricants.
  • compositions described in the present disclosure can be prepared as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays and the like.
  • the administration route of the combination in the present disclosure is selected from oral administration, parenteral administration, and transdermal administration, and said parenteral administration includes but not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • the "combination" described in this disclosure is a mode of administration, which refers to the administration of at least one dose of selective estrogen receptor covalent antagonist (SERCA) or a pharmaceutically acceptable salt thereof within a certain period of time and CDK4/6 inhibitors, both of which show pharmacological effects.
  • the time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • the selective estrogen receptor covalent antagonist (SERCA) or a pharmaceutically acceptable salt thereof and the CDK4/6 inhibitor can be administered simultaneously or sequentially. This term includes treatments wherein the selective estrogen receptor covalent antagonist (SERCA) or a pharmaceutically acceptable salt thereof and the CDK4/6 inhibitor are administered by the same route of administration or by different routes of administration.
  • Example 1 Drug A (maleate salt of compound represented by formula (I), refer to WO2020253762A) single drug, fulvestrant single drug and combined drug B (compound isethionate represented by formula (I) , can refer to WO2014183520A) in human breast cancer cell MCF-7 (Y537S, mutant) cell breast cancer animal model of drug effect
  • Drug B was provided by Jiangsu Hengrui Medicine Co., Ltd.
  • the mutant human breast cancer cell MCF-7(Y537S) was provided by Shanghai Hengrui Molecular Cell Department.
  • Fulvestrant is prepared with ethanol/olive oil (1:9) solution to make 40mg/mL (free base) solution, the dosage is 200mg/kg, twice a week, and the subcutaneous injection volume is 5mL/kg;
  • Drug A is formulated with 9% PEG400+0.5% Tween-80+90.5% (0.5% CMC-Na) aqueous solution to make 2.5mg/mL (free base) aqueous solution, and the dosage is 20.50mg/kg, once a day, orally The volume of gavage is 10mL/kg.
  • Drug B is formulated with 9% PEG400+0.5% Tween-80+90.5% (0.5% CMC-Na) aqueous solution to make 2.5mg/mL (free base) aqueous solution, and the dosage is 25mg/kg, once a day, oral gavage volume 10mL/kg.
  • Vehicle is 9% PEG400+0.5% Tween-80+90.5% (0.5% CMC-Na) aqueous solution, once a day, oral gavage volume 10mL/kg.
  • mice Inoculate 200 ⁇ L of MCF-7 (Y537S) cells (1.0 ⁇ 10 7 cells) subcutaneously in the right flank of 110 Scid Beige mice. After 20 days of inoculation, remove the body weight, tumor size and size after the tumor volume is ⁇ 180mm3 . According to the tumor volume, the mice were randomly divided into 10 groups, with 8 mice in each group, as shown in Table 1. After 21 days of administration, the tumor volume was measured twice a week, the body weight was weighed, and the data was recorded. The grouping and drug administration are shown in Table 1.
  • V tumor volume
  • T/C (%) (TT 0 )/(CC 0 ) ⁇ 100, wherein T, C are the tumor volumes of the treatment group and the control group at the end of the experiment; T 0 , C 0 are the tumor volumes at the beginning of the experiment tumor volume.
  • Tumor inhibition rate TGI(%) 100-T/C(%).
  • Table 2 shows the growth inhibitory effects of the administered compounds on MCF-7(Y537S) tumors.
  • the tumor inhibition rates of drug A at doses of 20 and 50 mg/kg were 102% and 108%, respectively. There was no significant difference between.
  • the tumor inhibition rate of the reference compound fulvestrant-200mg/kg was 89%.
  • the tumor inhibition rate of CDK4/6 inhibitor drug B at 25mg/kg was 88%.
  • drug A was administered in combination with drug B-25 mg/kg at doses of 20 and 50 mg/kg, the tumor inhibition rates were 121% and 125%, respectively, which were significantly higher than those of the single-use groups (p ⁇ 0.001).
  • Fulvestrant-200mg/kg combined with drug B-25mg/kg has a tumor inhibition rate of 100%, which is significantly higher than that of the single-administration group (p ⁇ 0.01).
  • the tumors of mice in each group were stripped and weighed.
  • the weight of tumors in each administration group was significantly smaller than that in Vehicle group (p ⁇ 0.001), and each administration group could significantly inhibit the growth of MCF-7(Y537S) tumors (p ⁇ 0.001).
  • the body weight of mice in each group increased slightly, suggesting that there is no obvious toxic effect under the current administration dose.
  • drug A can significantly inhibit the growth of MCF-7(Y537S) tumors, and its efficacy alone is better than that of the reference compound.
  • Drug A is administered in combination with CDK4/6 inhibitor drug B to further enhance the anti-tumor effect.
  • Embodiment 2 drug A (compound maleate shown in formula (I)) single drug and combined drug B (compound isethionate shown in formula (I)) in ER positive, HER2 negative metastatic or local Single-arm, open-label, multi-center phase I clinical study of safety, tolerability and pharmacokinetics in patients with advanced breast cancer
  • DLT dose-limiting toxicity
  • the main research endpoints include MTD and RP2D, as well as safety endpoints (laboratory indicators, electrocardiogram, vital signs, adverse events. The incidence and severity of adverse events/serious adverse events are judged according to NCI-CTCAE V5.0 standards) ; Secondary study endpoints include PK parameters and primary efficacy endpoints.
  • Study population patients with ER-positive, HER2-negative, metastatic or locally advanced breast cancer who have no standard treatment, have failed standard treatment, or are not suitable for standard treatment.
  • This trial is a single-arm, open-label, multicenter phase I clinical study of drug A single drug and combination drug B dose escalation and dose expansion.
  • Group A is drug A single drug dose escalation
  • Group B is a single dose expansion of drug A
  • Group C is drug A combined with drug B in increasing doses
  • Group D is drug A combined with drug B treatment dose expansion.
  • the single-drug dose escalation of group A drug A is carried out, and the safety monitoring committee (Safety monitoring committee, SMC) decides when to start the single-drug expansion of group B after obtaining preliminary safety data; After the treatment and expansion, the SMC discussed and decided to increase the combined treatment of group C and expand the combined treatment of group D.
  • SMC Safety monitoring committee
  • Group A The principle of i3+3 was adopted to carry out single-drug dose escalation.
  • Drug A presets 6 dosage groups based on preclinical test data: 25mg, 75mg, 150mg, 300mg, 450mg and 600mg, and subjects can only receive one of the dosages.
  • Group B Select 2-3 dosage groups for extended research to further clarify the pharmacokinetic characteristics and RP2D of drug A, and expand to 10-12 subjects in each dosage group.
  • the preset dose of drug A is the previous dose of RP2D (RP2D-1) and the PR2D of drug A, and the preset dose of drug B.
  • 100mg qd and 125mg qd adopt the "3+3" principle to increase the combined dose of the two drugs, and take 28 days as a cycle. After completing one cycle of combined continuous administration, the subjects will undergo a safety assessment during the DLT observation period, and only after the safety is confirmed can they enter the next dose group trial.
  • Group D According to the comprehensive safety and efficacy data of the climbing results of Group C, select 1-2 dose groups of drug A and drug B combined for dose expansion, each dose group expanded to 10-12 subjects .
  • Drug A administration method oral administration, every morning on an empty stomach, once a day during continuous administration, and continuous administration for 4 weeks as a cycle.
  • Drug A tablet specification 25mg/tablet; 150mg/tablet.
  • Single-dose lead-in period Subjects took drug A orally on an empty stomach and took it with warm water. Do not eat or drink (except water) 2 hours before and 1 hour after taking the medicine. After a single dose, PK blood samples were collected, and the next dose was taken after 3 days of washout. This phase is only applicable to the drug A monotherapy phase (groups A and B), and there is no single-dose lead-in phase for combination drug B.
  • Drug B administration method orally, once a day, every 28 days is a treatment cycle, in which the first 3 weeks (day 1 to 21) are taken continuously, and the next week (day 22 to 28) is rested (without medication).
  • Drug B tablet specifications 150mg/tablet, 125mg/tablet, 50mg/tablet, 25mg/tablet.
  • ER positive and HER2 negative confirmed by histological examination
  • ER positive standard immunohistochemical staining shows that no less than 10% of tumor cell nuclei are stained to varying degrees.
  • HER2 Negative standard Immunohistochemical staining [IHC, staining intensity range 0-3] intensity is 0, 1+; if the intensity is 2+, fluorescent in situ hybridization [FISH] must be carried out to confirm that it is negative).

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Abstract

选择性雌激素受体共价拮抗剂与CDK4/6抑制剂联合在制备治疗乳腺癌药物中的用途。具体而言，选择性雌激素受体共价拮抗剂选自式(I)所示化合物或其药学上可接受的盐，CDK4/6抑制剂选自式(II)所示化合物或其药学上可接受的盐。

Description

选择性雌激素受体共价拮抗剂与CDK4/6抑制剂联合在制备治疗乳腺癌药物中的用途
本申请要求申请日为2021年7月13日的中国专利申请2021107886085的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种选择性雌激素受体共价拮抗剂与CDK4/6抑制剂联合在制备治疗乳腺癌的药物中的用途，属于制药领域。
背景技术
雌激素受体阳性(ER+)乳腺癌是最常见的乳腺癌亚型，内分泌治疗是ER+乳腺癌的主要治疗手段。尽管内分泌疗法已大大降低了乳腺癌的复发率和死亡率,但原发性耐药和继发性耐药仍然是主要挑战。SERD药物氟维司群是唯一经过临床批准的显示治疗ER+乳腺癌耐药疗效的药物分子。氟维司群的抗雌激素活性及其降解ER蛋白的能力，使其成为可以有效治疗ER阳性乳腺癌患者(包括对TAM或芳香化酶抑制剂已产生耐药的患者)。但是由于氟维司群溶解度差等特征，导致口服生物利用度极低，需每月肌肉注射给药，且需要低温(2～8℃)保存，相比于口服药物他莫昔芬和AI类药物，临床应用受到限制。基于此，新一代生物利用度更高、药动学特征更理想且在乳腺中具有强效抗雌激素活性的口服SERD以及选择性雌激素受体共价拮抗剂(SERCA)的研发正火热进行中，多个化合物已处于临床不同阶段。
发明内容
本公开提供一种选择性雌激素受体共价拮抗剂在制备治疗乳腺癌的药物中的用途。
一些实施方案中，本公开提供一种选择性雌激素受体共价拮抗剂在制备治疗ER+或HER2-乳腺癌的药物中的用途。
一些实施方案中，本公开提供一种选择性雌激素受体共价拮抗剂在制备治疗ER+、HER2-乳腺癌的药物中的用途。
一些实施方案中，本公开提供一种式(I)所示化合物或其药学上可接受的盐在制备治疗乳腺癌的药物中的用途。
Figure PCTCN2022105484-appb-000001
一些实施方案中，本公开提供一种式(I)所示化合物或其药学上可接受的盐在制备治疗ER+或HER2-乳腺癌的药物中的用途。
一些实施方案中，本公开提供一种式(I)所示化合物或其药学上可接受的盐在制备治疗ER+、HER2-乳腺癌的药物中的用途。
本公开另一方面提供一种选择性雌激素受体共价拮抗剂与CDK4/6抑制剂联合在治疗乳腺癌的药物中的用途。
一些实施方案中，本公开提供一种选择性雌激素受体共价拮抗剂与CDK4/6抑制剂联合在治疗ER+或HER2-乳腺癌的药物中的用途。
一些实施方案中，本公开提供一种选择性雌激素受体共价拮抗剂与CDK4/6抑制剂联合在治疗ER+、HER2-乳腺癌的药物中的用途。
一些实施方案中，本公开中所述CDK 4/6抑制剂选自帕博西尼或其药学上可接受的盐、玻玛西尼或其药学上可接受的盐、瑞博西尼、2'-((5-(4-异丙基哌嗪-1-基)吡啶-2-基)氨基)-7',8'-二氢-6'H-螺[环己烷-1,9'-吡嗪并[1',2':1,5]吡咯并[2,3-d]嘧啶]-6'-酮二盐酸盐、G1T-28、AT-7519、FLX-925、阿伏西地。
本公开中帕博西尼化学名为：6-乙酰基-8-环戊基-5-甲基-2-{[5-(哌嗪-1-基)吡啶-2-基]氨基}吡啶并[2,3-d]嘧啶-7(8H)-酮；玻玛西尼化合物名为：N-(5-((4-乙基哌嗪-1-基)甲基)吡啶2-基)-5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-胺；瑞博西尼化学名为：7-环戊基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-7H-吡咯并[2,3-d]嘧啶-6-甲酸二甲基酰胺；G1T-28化学名为：2’-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-7',8’-二氢-6’H-螺[环己烷-1,9’-吡嗪并[1’,2’:1,5]吡咯并[2,3-d]嘧啶]-6’-酮；AT-7519化学名为：N-(4-哌啶基)-4-(2,6-二氯苯甲酰基氨基)-1H-吡唑-3-甲酰胺；FLX-9252化学名为：2-羟基-1-[2-[[9-(反式-4-甲基环己基)-9H-吡啶并[4',3':4,5]吡咯并[2,3-d]嘧啶-2-基]氨基]-7,8-二氢-1,6-萘啶-6(5H)-基]乙酮；阿伏西地化学名为：2-(2-氯苯基)-5,7-二羟基-8-((3S,4R)-3-羟基-1-甲基哌啶-4-基)-4H-色烯-4-酮。
一些实施方案中，本公开提供一种式(I)所示化合物的药学上可接受的盐与式(II)所示化合物或其药学上可接受的盐联合在制备治疗乳腺癌的药物中的用途，
Figure PCTCN2022105484-appb-000002
一些实施方案中，本公开提供一种式(I)所示化合物的药学上可接受的盐与式(II)所示化合物或其药学上可接受的盐联合在制备治疗ER+或HER2-乳腺癌的药物中的用途。
一些实施方案中，本公开提供一种式(I)所示化合物的药学上可接受的盐与式(II)所示化合物或其药学上可接受的盐联合在制备治疗ER+、HER2-乳腺癌的药物中的用途，
一些实施方案中，本公开中所述乳腺癌为转移性或局部晚期乳腺癌。
一些实施方案中，本公开中所述ER+或HER2-乳腺癌为转移性或局部晚期乳腺癌。
一些实施方案中，本公开中所述ER+、HER2-乳腺癌为转移性或局部晚期乳腺癌。
一些实施方案中，本公开中式(I)所示化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐。
一些实施方案中，本公开中式(I)所示化合物的药学上可接受的盐选自马来酸盐或盐酸盐。
一些实施方案中，本公开中式(I)所示化合物的药学上可接受的盐选自马来酸盐。
一些实施方案中，本公开中式(I)所示化合物的药学上可接受的盐选自盐酸盐。
一些实施方案中，本公开中式(II)所示化合物的药学上可接受的盐为羟乙基磺酸盐。
一些实施方案中，本共公开中式(I)所示化合物或其药学上可接受的盐的剂量选自1-1000mg，可选的剂量为：1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、 95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg、605mg、610mg、615mg、620mg、625mg、630mg、635mg、640mg、645mg、650mg、655mg、660mg、665mg、670mg、675mg、680mg、685mg、690mg、695mg、700mg、705mg、710mg、715mg、720mg、725mg、730mg、735mg、740mg、745mg、750mg、755mg、760mg、765mg、770mg、775mg、780mg、785mg、790mg、795mg、800mg、805mg、810mg、815mg、820mg、825mg、830mg、835mg、840mg、845mg、850mg、855mg、860mg、865mg、870mg、875mg、880mg、885mg、890mg、895mg、900mg、905mg、910mg、915mg、920mg、925mg、930mg、935mg、940mg、945mg、950mg、955mg、960mg、965mg、970mg、975mg、980mg、985mg、990mg、995mg或1000mg；给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg或600mg，给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量选自25mg、75mg、150mg、300mg、450mg或600mg；给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为25mg给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为75mg，给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为150mg；
给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为300mg；给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量450mg；给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为600mg；给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自1-500mg，给药频次选自一日一次或一日二次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg或500mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自25mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自50mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选 自100mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自125mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自150mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自175mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自200mg，给药频次为一日一次或一日两次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg或600mg，给药频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为25mg、75mg、150mg、300mg、450mg或600mg，给药频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为25mg，给药频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为75mg，给药频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为150mg，给药频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为300mg，给药 频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为450mg，给药频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，式(I)所示化合物或其药学上可接受的盐的剂量为600mg，给药频次为一日一次；式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自50mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自100mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自125mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自150mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自175mg，给药频次为一日一次或一日两次。
一些实施方案中，本公开中式(II)所示化合物或其药学上可接受的盐的给药剂量选自200mg，给药频次为一日一次或一日两次。
一些实施方案中，式(II)所示化合物或其药学上可接受的盐的一个给药周期为28天，其中前21天给药，后7天停止给药。
本公开另一方提供一种治疗乳腺癌患者的方法，给与患者治疗有效量的式(I)所示化合物或其药学上可接受的盐及治疗有效量的式(II)所示化合物或其药学上可接受的盐。
本公开另一方提供一种用于治疗乳腺癌的式(I)所示化合物或其药学上可接受的盐，其与式(II)所示化合物或其药学上可接受的盐联合使用。
本公开另一方提供一种用于治疗乳腺癌的式(II)所示化合物或其药学上可接受的盐， 其与式(I)所示化合物或其药学上可接受的盐联合使用。
本公开另一方面提供一种药物组合物，包含式(I)所示化合物或其药学上可接受的盐和式(II)所示化合物或其药学上可接受的盐，及至少一种药学上可接受的赋形剂，所述赋形剂包括但不限于填充剂、崩解剂、粘合剂或润滑剂。
本公开中所述的药物组合物可以制备为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂、栓剂、吸入剂或喷雾剂等。
本公开所述联合的给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
本公开中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的选择性雌激素受体共价拮抗剂(SERCA)或其药学上可接受的盐和CDK4/6抑制剂，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内。可以同时或依次给予选择性雌激素受体共价拮抗剂(SERCA)或其药学上可接受的盐和CDK4/6抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予选择性雌激素受体共价拮抗剂(SERCA)或其药学上可接受的盐和CDK4/6抑制剂。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1、药物A(式(I)所示化合物马来酸盐，可参考WO2020253762A)单药、氟维司群单药及联合药物B(式(I)所示化合物羟乙基磺酸盐，可参考WO2014183520A)在人乳腺癌细胞MCF-7(Y537S，突变型)细胞乳腺癌动物模型的药效
1.1药物信息
氟维司群，由上海恒瑞医药有限公司提供；
药物A，由江苏恒瑞医药股份有限公司提供；
药物B，由江苏恒瑞医药股份有限公司提供。
1.2实验动物和细胞
Scid Beige小鼠，SPF，16-19g，♀，购自北京维通利华实验动物有限责任公司。
突变的人乳腺癌细胞MCF-7(Y537S)由上海恒瑞分子细胞部提供。
1.3实验仪器：
TESA电子防水卡尺IP67，特萨测量仪器(上海)有限公司；
电子天平PL2001-L(0.1g-2100g)，梅特勒-托利多仪器上海有限公司；
电子天平AL204-IC(0.1mg-220g)，梅特勒-托利多仪器上海有限公司。
1.4药物配制
氟维司群用乙醇/橄榄油(1:9)溶液配制成40mg/mL(游离碱)溶液，给药剂量为200mg/kg，每周2次，皮下注射体积为5mL/kg；
药物A用9％PEG400+0.5％Tween-80+90.5％(0.5％CMC-Na)水溶液配制成2、5mg/mL(游离碱)水溶液，给药剂量为20、50mg/kg，每天一次，口服灌胃体积10mL/kg。
药物B用9％PEG400+0.5％Tween-80+90.5％(0.5％CMC-Na)水溶液配制成2.5mg/mL(游离碱)水溶液，给药剂量为25mg/kg，每天一次，口服灌胃体积10mL/kg。
Vehicle为9％PEG400+0.5％Tween-80+90.5％(0.5％CMC-Na)水溶液，每天一次，口服灌胃体积10mL/kg。
1.5实验方法：
将MCF-7(Y537S)细胞(1.0×10 7个)200μL接种于110只Scid Beige小鼠右肋部皮下，接种20天后，待肿瘤体积在～180mm 3后去除体重、肿瘤过大和过小的，按肿瘤体积将小鼠随机分为10组，每组8只，如表1所示。给药21天，每周测2次瘤体积，称体重，记录数据。分组及给药情况见表1。
给药具体给药方案见表1。
表1.实验分组及给药情况
Figure PCTCN2022105484-appb-000003
1.6数据统计
使用Excel统计软件记录数据：平均值以avg计算；SD值以STDEV计算；SEM值以STDEV/SQRT(每组动物数)计算；采用GraphPad Prism软件分析，采用Two-way ANOVA或One-way ANOVA对数据进行统计学分析。
肿瘤体积(V)计算公式为：V＝1/2×L 长×L 短 2
相对肿瘤增殖率T/C(％)＝(T-T 0)/(C-C 0)×100，其中T、C为实验结束时治疗组和对照组的肿瘤体积；T 0、C 0为实验开始时的肿瘤体积。
抑瘤率TGI(％)＝100-T/C(％)。
1.7实验结果
给药化合物对MCF-7(Y537S)肿瘤的生长抑制作用如表2所示。
表2.给药化合物对MCF-7(Y537S)小鼠移植瘤的疗效
Figure PCTCN2022105484-appb-000004
给药21天，与Vehicle组相比，药物A在20、50mg/kg剂量的抑瘤率分别为102％、108％，随着剂量的升高，抑瘤率逐渐升高，但两组之间没有显著性差别。参比化合物氟维司群-200mg/kg的抑瘤率为89％。
CDK4/6抑制剂药物B在25mg/kg的抑瘤率为88％。药物A在20、50mg/kg剂量与药物B-25mg/kg联合给药，抑瘤率分别为121％、125％，显著高于各单用组的抑瘤率(p<0.001)。氟维司群-200mg/kg与药物B-25mg/kg联合给药，抑瘤率为100％，显著高于单用组的抑瘤率(p<0.01)。剥离各组小鼠肿瘤称取重量，各给药组肿瘤重量显著小于Vehicle组(p<0.001)，各给药组均能明显抑制MCF-7(Y537S)肿瘤的生长(p<0.001)。各组小鼠体重均略有增加，提示目前给药剂量下没有明显的毒性作用。
综上所述，在本次实验中，药物A能显著抑制MCF-7(Y537S)肿瘤的生长，单用药效优于参比化合物。药物A与CDK4/6抑制剂药物B联合给药，进一步增强抑瘤作用。
实施例2、药物A(式(I)所示化合物马来酸盐)单药及联合药物B(式(I)所示化合物羟乙基磺酸盐)在ER阳性、HER2阴性转移性或局部晚期乳腺癌患者中的安全性、耐受性及药代动力学的单臂、开放、多中心I期临床研究
主要研究目的：
1)确定药物A单药及联合药物B在转移性或局部晚期乳腺癌患者中的剂量限制性毒性(DLT)，确定最大耐受剂量(MTD)和II期临床研究推荐剂量(RP2D)；
2)评价药物A单药及联合药物B在转移性或局部晚期乳腺癌患者中的安全性。
次要研究目的包括药代动力学(PK)参数和初步疗效。
研究终点：主要研究终点包括MTD和RP2D，以及安全性终点(实验室指标、心电图、生命体征、不良事件。依据NCI-CTCAE V5.0标准判断不良事件/严重不良事件的发生率以及严重程度)；次要研究终点包括PK参数指标和初步疗效终点。
初步疗效终点：
客观缓解率(ORR：完全缓解[CR]+部分缓解[PR])、最佳总体疗效(BOR)、缓解持续时间(DoR)、疾病控制率(DCR：CR+PR+疾病稳定[SD])、无进展生存期(PFS)；
研究人群：无标准治疗、标准治疗失败或者不适合接受标准治疗的ER阳性、HER2阴性、转移性或局部晚期乳腺癌患者。
本试验为单臂、开放、多中心药物A单药和联合药物B的剂量递增和剂量拓展I期临床研究。
A组为药物A单药剂量递增；
B组为药物A单药剂量拓展；
C组为药物A联合药物B治疗剂量递增；
D组为药物A联合药物B治疗剂量拓展。
首先进行A组药物A单药剂量递增，在获得初步的安全性数据后由安全监测委员会(Safety monitoring committee,SMC)决定何时开展B组单药拓展；在完成A组和B组单药递增和拓展后，经SMC讨论决定进行C组联合治疗递增以及D组联合治疗拓展。
A组：采用i3+3原则进行单药剂量爬坡。药物A根据临床前试验数据预设6个剂量组：25mg、75mg、150mg、300mg、450mg和600mg，受试者只能接受其中一种的剂量。
B组：选择2-3个剂量组进行拓展研究，进一步明确药物A的药代动力学特征和RP2D，每个剂量组拓展至10-12例受试者。
C组：本研究采用“3+3”原则进行联合剂量爬坡试验。药物A预设剂量为RP2D前一剂量(RP2D-1)以及药物A的PR2D，药物B预设。
100mg qd和125mg qd，采用“3+3”原则进行两药联合剂量递增，以28天为一周期。受试者完成联合连续给药1周期后，进行DLT观察期安全性评估，在确定安全后方可递增进入下一剂量组试验。
D组：根据C组的爬坡结果综合安全性和有效性数据，选择药物A与药物B联用的1-2个剂量组进行剂量拓展，每个剂量组拓展至10-12例受试者。
药物A给药方式：口服给药，每天早晨空腹口服，连续给药期间每日给药1次，连续服药4周为一个周期。
药物A片规格：25mg/片；150mg/片。
单次给药导入期：受试者空腹口服药物A，温水送服。服药前2小时和服药后1小时禁食或饮料(水除外)。单次给药后，收集PK血样，3天洗脱后进行下一次服药。该阶段仅适用于药物A单药阶段(A和B组)，联合药物B没有单次给药导入期。
多次给药：单次给药洗脱3天后连续口服药物A片，每日一次，空腹温水送服，服药前2小时和服药后1小时禁食或饮料(水除外)。4周(28天)为1个周期。服药直至出现疾病进展、不可耐受、撤销知情同意或研究者判断受试者不再适合继续接受治疗。
药物B给药方式：口服，每日一次，每28天为一个治疗周期，其中前3周(第1天至第21天)连续服药，后1周(第22天至第28天)休息(不服药)。
药物B片规格：150mg/片，125mg/片，50mg/片，25mg/片。
入组标准：
年龄18-75岁(含两端值)女性；
经组织学确诊的转移性或局部晚期乳腺癌患者：组织学检查证实的ER阳性、HER2阴性(ER阳性的标准：免疫组化染色显示不少于10％的肿瘤细胞核呈现不同程度的着色。HER2阴性的标准：免疫组化染色[IHC，染色强度范围0～3]强度为0，1+；如果强度显示为2+，须进行荧光原位杂交[FISH]确认是阴性)。
绝经状态：
a)既往进行过双侧卵巢切除术，或年龄≥60岁；或
b)年龄＜60岁，自然绝经后状态(定义为连续至少12个月规律月经自发性停止且无其他病理或生理原因)，雌二醇和FSH在绝经后水平；或
c)绝经前或围绝经期患者，但在研究期间必须接受LHRH激动剂治疗
既往晚期阶段至少接受过1线内分泌治疗进展；既往接受针对晚期疾病的≤2线的化疗；
入组前最后一次系统治疗中或后，发生经临床或影像学证实的疾病进展；
既往治疗：本研究首次用药前，接受亚硝基脲或丝裂霉素的间隔≥6周；接受细胞毒性药物、任何其他抗癌内分泌治疗、免疫治疗、靶向治疗、手术间隔或其他临床研究末次用药≥4周；距离放疗结束间隔≥2周。

Claims (8)

  1. 一种式(I)所示化合物或其药学上可接受的盐在制备治疗乳腺癌的药物中的用途，所述乳腺癌优选ER+或HER2-乳腺癌，最优选ER+、HER2-乳腺癌，
    Figure PCTCN2022105484-appb-100001
  2. 根据权利要求1所述的用途，所述的用途进一步包括联合CDK 4/6抑制剂，所述的CDK 4/6抑制剂优选帕博西尼或其药学上可接受的盐、玻玛西尼或其药学上可接受的盐、瑞博西尼、2'-((5-(4-异丙基哌嗪-1-基)吡啶-2-基)氨基)-7',8'-二氢-6'H-螺[环己烷-1,9'-吡嗪并[1',2':1,5]吡咯并[2,3-d]嘧啶]-6'-酮二盐酸盐、G1T-28、AT-7519、FLX-925、阿伏西地或式(II)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022105484-appb-100002
    最优选式(II)所示化合物或其药学上可接受的盐。
  3. 根据权利要求1-2任一项所述的用途，所述乳腺癌为转移性或局部晚期乳腺癌。
  4. 根据权利要求1-3任一项所述的用途，所述式(I)所示的化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐；优选马来酸盐或盐酸盐，最优选盐酸盐。
  5. 根据权利要求2-4任一项所述的用途，所述式(II)所示化合物的药学上可接受的盐为羟乙基磺酸盐。
  6. 根据权利要求1-5任一项所述的用途，所述式(I)所示化合物或其药学上可接受的盐的剂量选自1-1000mg；给药频次为一日一次或一日两次；优选地，式(I)所示化合 物或其药学上可接受的盐的剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg或600mg，给药频次为一日一次；最优选地，式(I)所示化合物或其药学上可接受的盐的剂量选自25mg、75mg、150mg、300mg、450mg或600mg，给药频次为一日一次。
  7. 根据权利要求6所述的用途，所述式(II)所示化合物或其药学上可接受的盐的给药剂量选自1-500mg，给药频次选自一日一次或一日二次；优选地，式(II)所示化合物或其药学上可接受的盐的给药剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次；最优选地，式(II)所示化合物或其药学上可接受的盐的给药剂量选自75mg、100mg、125mg、150mg、175mg或200mg，给药频次为一日一次。
  8. 一种药物组合物，包含根据权利要求2-7任一项所述的式(I)所示化合物或其药学上可接受的盐和式(II)所示化合物或其药学上可接受的盐，及至少一种药学上可接受的赋形剂。
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