WO2023036161A1 - 米托蒽醌脂质体、硼替佐米和地塞米松治疗多发性骨髓瘤的用途 - Google Patents

米托蒽醌脂质体、硼替佐米和地塞米松治疗多发性骨髓瘤的用途 Download PDF

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WO2023036161A1
WO2023036161A1 PCT/CN2022/117434 CN2022117434W WO2023036161A1 WO 2023036161 A1 WO2023036161 A1 WO 2023036161A1 CN 2022117434 W CN2022117434 W CN 2022117434W WO 2023036161 A1 WO2023036161 A1 WO 2023036161A1
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mitoxantrone
dexamethasone
bortezomib
liposome
multiple myeloma
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PCT/CN2022/117434
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English (en)
French (fr)
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李春雷
刘延平
李彦辉
梁敏
张兰
贾润露
张阳
王世霞
田海伟
Original Assignee
石药集团中奇制药技术（石家庄）有限公司
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Publication of WO2023036161A1 publication Critical patent/WO2023036161A1/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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the invention relates to the field of antitumor, in particular to the use of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of medicines for treating relapsed/refractory multiple myeloma (MM).
  • MM multiple myeloma
  • MM Multiple myeloma
  • MM is a malignant disease in which monoclonal plasma cells abnormally proliferate, and it often occurs in the elderly, with a median age of onset of 66 years (Robert A Kyle, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc.2003 Jan; 78(1):21-33), the male incidence rate is slightly higher.
  • MM is the second most malignant tumor of the blood system in terms of epidemiology, with the highest incidence in Australia, North America, and Western Europe. In my country, the incidence rate of MM is 1-2/100,000. In 2016, there were 16,500 new cases and 10,400 deaths.
  • Anthracyclines are an important part of MM treatment.
  • the use of anthracyclines has declined as newer drugs have become available.
  • Mayo guidelines 2020 recommend anthracycline-containing multi-drug combination regimens for patients with aggressive relapses such as plasma cell leukemia and extramedullary lesions (S Vincent Rajkumar. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
  • a multi-center clinical trial included 64 patients with relapsed/refractory multiple myeloma, all of whom received PAD regimen (bortezomib+doxorubicin/adriamycin liposome+dexamethasone) , 43 patients achieved at least PR (67%), including CR (9%) and VGPR (16%); during the treatment of PAD regimen, the most common grade 1-2 adverse event was anemia (42% ), decreased neutrophil count (30%), decreased platelet count (27%), peripheral neuropathy (27%), nausea (14%), diarrhea (11%), and unexplained fever (11%); The most common grade 3 adverse events were decreased platelet count (23%), decreased neutrophil count (20%), anemia (11%), peripheral neuropathy (10%), and pneumonia (9%); grade 4 adverse events Events included decreased platelet count (25%), decreased neutrophil count (16%), and anemia (2%), acute heart failure (2%), and pneumonia (3%).
  • Adverse reactions of anthracyclines mainly include cardiotoxicity, bone marrow toxicity, and gastrointestinal reactions.
  • anthracyclines such as epirubicin and doxorubicin liposome appeared one after another, with improved safety but no difference in curative effect.
  • a randomized controlled phase 3 clinical study included 646 patients with relapsed/refractory MM, and compared the efficacy of doxorubicin liposome combined with bortezomib and bortezomib monotherapy (Robert Z Orlowski, et al., Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol.
  • Mitoxantrone is an anthracycline drug that has been used in more than 30 countries around the world. At the end of the 1970s, the United States began clinical research on mitoxantrone. A series of clinical trials showed that mitoxantrone, whether used as a single drug or in combination with other drugs, is effective for hematological tumors such as acute leukemia, lymphatic Tumors and a variety of solid tumors such as breast cancer have therapeutic effects. Its adverse reactions are mainly bone marrow suppression, gastrointestinal reactions and cardiotoxicity. Mitoxantrone is mainly used clinically for the treatment of acute myeloid leukemia.
  • Liposome is a new form of drug loading. Studies have shown that it can change the distribution of the encapsulated drug in the body, so that the drug is mainly accumulated in the tumor tissue, thereby improving the therapeutic index of the drug, reducing the therapeutic dose of the drug and reducing the toxicity of the drug. These characteristics make the application of liposome-loaded drugs in the research of anti-tumor drugs attract much attention.
  • the phase I of mitoxantrone hydrochloride liposome injection monotherapy has completed dose escalation exploration and PK/PD research in subjects with advanced solid tumors and lymphoma subjects. According to the test results, mitoxantrone hydrochloride liposome injection is safe and tolerated in the dose range of 6-30mg/ m2 , and shows a certain curative effect.
  • PTCL relapsed/refractory peripheral T-cell lymphoma
  • Relapse/refractory MM is still a difficult problem for clinicians.
  • anthracyclines are still one of the important components of drug combination.
  • Mitoxantrone liposome is an anthracycline (quinone) drug with high efficiency and low toxicity, and its combination with bortezomib and dexamethasone is expected to become a treatment option for relapsed/refractory MM, especially for aggressive relapsed patients. patient.
  • the invention relates to the application of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of medicine for treating multiple myeloma.
  • the present invention also relates to the use of the mitoxantrone liposome in the preparation of medicines for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma.
  • the invention also relates to the use of bortezomib and dexamethasone in the preparation of medicines for improving the curative effect of mitoxantrone liposomes in treating multiple myeloma.
  • the present invention also provides a method for treating multiple myeloma, which comprises administering effective therapeutic doses of mitoxantrone liposome, bortezomib and dexamethasone to multiple myeloma patients.
  • the present invention also provides a method for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma.
  • Therapeutically effective doses of liposomal mitoxantrone are provided.
  • the present invention also provides a method for improving the curative effect of mitoxantrone liposomes in the treatment of multiple myeloma, said method comprising administering mitoxantrone liposomes to patients with multiple myeloma on the basis of further combined administration Bortezomib and dexamethasone at therapeutically effective doses.
  • the present invention also provides a drug combination product for treating multiple myeloma, the drug combination product comprising mitoxantrone liposome, bortezomib and dexamethasone.
  • the present invention also provides a medicine for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma, and the medicine comprises mitoxantrone liposome.
  • the present invention also provides a medicine for improving the curative effect of mitoxantrone liposome in treating multiple myeloma, the medicine comprises bortezomib and dexamethasone.
  • Relapse was defined as minimal response (MR) or better from prior therapy followed by disease progression.
  • Refractory was defined as failure to achieve MR with any first-line treatment.
  • Mitoxantrone includes mitoxantrone and pharmaceutically acceptable salts thereof, and the pharmaceutically acceptable salt of mitoxantrone is preferably mitoxantrone hydrochloride.
  • the mitoxantrone liposomes are preferably mitoxantrone hydrochloride liposomes.
  • administering in any order means that mitoxantrone liposomes, bortezomib and dexamethasone are prepared separately and administered in a clinically acceptable manner, and there is no mandatory requirement for the order of administration; Mixing does not occur in vitro.
  • the invention provides the application of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of medicine for treating multiple myeloma.
  • the present invention also provides the use of the mitoxantrone liposome in the preparation of medicines for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma.
  • the present invention also provides the use of bortezomib and dexamethasone in preparing a medicine for improving the curative effect of mitoxantrone liposome in treating multiple myeloma.
  • the present invention provides the use of mitoxantrone hydrochloride liposome, bortezomib and dexamethasone in the preparation of a drug for treating multiple myeloma.
  • the present invention provides the application of mitoxantrone hydrochloride liposomes in the preparation of drugs for improving the efficacy of bortezomib and dexamethasone in the treatment of multiple myeloma.
  • the present invention provides the use of bortezomib and dexamethasone in the preparation of a drug for improving the curative effect of mitoxantrone hydrochloride liposomes in treating multiple myeloma.
  • the multiple myeloma is preferably relapsed/refractory multiple myeloma.
  • the invention provides a method for treating multiple myeloma, which comprises administering effective doses of mitoxantrone liposome, bortezomib and dexamethasone to patients with multiple myeloma.
  • the present invention also provides a method for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma.
  • Therapeutically effective doses of liposomal mitoxantrone are provided.
  • the present invention also provides a method for improving the curative effect of mitoxantrone liposomes in the treatment of multiple myeloma, said method comprising administering mitoxantrone liposomes to patients with multiple myeloma on the basis of further combined administration Bortezomib and dexamethasone at therapeutically effective doses.
  • the multiple myeloma is preferably relapsed/refractory multiple myeloma.
  • the administration of mitoxantrone liposome and bortezomib is preferably administered by injection; dexamethasone is preferably administered orally.
  • the effective therapeutic dose of the mitoxantrone liposome is 12-30 mg/m 2 , more preferably 12-20 mg/m 2 . Specific examples: 12mg/m 2 , 16mg/m 2 , 20mg/m 2 .
  • the mitoxantrone liposome is administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dose is 20 mg/day.
  • the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times.
  • multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the present invention provides a method for treating multiple myeloma, said method comprising administering effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone to patients with multiple myeloma.
  • the present invention provides a method for improving the curative effect of bortezomib and dexamethasone in the treatment of multiple myeloma, said method comprising on the basis of administering bortezomib and dexamethasone to patients with multiple myeloma, further A therapeutically effective dose of mitoxantrone hydrochloride liposomes is administered in combination.
  • the present invention provides a method for improving the curative effect of mitoxantrone hydrochloride liposomes in treating multiple myeloma, said method comprising administering mitoxantrone hydrochloride liposomes to multiple myeloma patients on the basis of , further administering therapeutically effective doses of bortezomib and dexamethasone in combination.
  • the multiple myeloma is preferably relapsed/refractory multiple myeloma.
  • the administration of mitoxantrone hydrochloride liposome and bortezomib is preferably administered by injection; the administration of dexamethasone is preferably administered orally.
  • the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 12-30 mg/m 2 , more preferably 12-20 mg/m 2 . Specific examples: 12mg/m 2 , 16mg/m 2 , 20mg/m 2 .
  • the mitoxantrone hydrochloride liposome is administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dose is 20 mg/day.
  • the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times.
  • the multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order, and on the fourth and eighth days.
  • Bortezomib was continued on days 1 and 11
  • dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the present invention also provides a drug combination product for treating multiple myeloma, the drug combination product comprising mitoxantrone liposome, bortezomib and dexamethasone.
  • the liposomes of mitoxantrone, bortezomib and dexamethasone can be present in the same preparation, or can be separately prepared in the form of combined packaging.
  • the dosage forms may be the same or different.
  • the dosage form can be any clinically acceptable dosage form, such as injection dosage form, oral dosage form and the like.
  • the injection dosage form includes liquid injection, powder for injection, tablet for injection, etc.; the oral dosage form includes tablet, capsule, oral liquid preparation, etc.
  • the active ingredient when the mitoxantrone liposome is a liquid injection, based on mitoxantrone, the active ingredient contains 0.5-5 mg/ml, preferably 1-2 mg/ml, more preferably 1 mg/ml; when bortezol When rice is powder for injection, the specification is 3.5mg/bottle, and it is prepared into a 2.5mg/ml solution when used; when dexamethasone is tablet, the specification is 0.75mg/tablet.
  • the drug combination product may further contain other second-line and above drugs for the treatment of multiple myeloma, and the drugs refer to drugs approved by the drug management department in China or other countries and regions (such as the United States, the European Union, Japan, South Korea, etc.) Second-line and above drugs in the treatment of multiple myeloma.
  • the present invention also provides a pharmaceutical composition for treating multiple myeloma, said pharmaceutical composition comprising mitoxantrone liposome, bortezomib and dexamethasone, said treatment includes treating multiple myeloma patients Use therapeutically effective liposomes of mitoxantrone, and administer bortezomib and dexamethasone at any time before, during, and after administration of liposomes with mitoxantrone.
  • the effective therapeutic dose of the mitoxantrone liposome refers to 12-30 mg/m 2 , more preferably 12-20 mg/m 2 .
  • the mitoxantrone liposome is administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dose is 20 mg/day.
  • the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times.
  • multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and third days. Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the present invention also provides a medicine for improving the curative effect of bortezomib and dexamethasone in the treatment of multiple myeloma, said medicine contains mitoxantrone liposome, and said mitoxantrone liposome Administer at any time before, during or after the administration of rice and dexamethasone.
  • the effective therapeutic dose of the mitoxantrone liposome is 12-30 mg/m 2 , more preferably 12-20 mg/m 2 .
  • 12mg/m 2 , 16mg/m 2 , 20mg/m 2 are administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dose is 20 mg/day.
  • the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times.
  • multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the present invention also provides a medicine for improving the curative effect of mitoxantrone liposome in treating multiple myeloma, said medicine contains bortezomib and dexamethasone, and said bortezomib and dexamethasone are in the mitoxantrone Administration of anthraquinone liposome at any time before, during and after administration.
  • the effective therapeutic dose of the mitoxantrone liposome is 12-30 mg/m 2 , more preferably 12-20 mg/m 2 . Specific examples: 12mg/m 2 , 16mg/m 2 , 20mg/m 2 .
  • the mitoxantrone liposome is administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dose is 20 mg/day.
  • the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times.
  • multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the present invention provides a drug combination product for treating multiple myeloma
  • the drug combination product comprises mitoxantrone hydrochloride liposome, bortezomib and dexamethasone.
  • the liposomes of mitoxantrone hydrochloride, bortezomib and dexamethasone can be present in the same preparation, or can be separately prepared in the form of combined packaging.
  • the dosage forms may be the same or different.
  • the dosage form can be any clinically acceptable dosage form, such as injection dosage form, oral dosage form and the like.
  • the injection dosage form includes liquid injection, powder for injection, tablet for injection, etc.; the oral dosage form includes tablet, capsule, oral liquid preparation, etc.
  • the mitoxantrone hydrochloride liposome when the mitoxantrone hydrochloride liposome is a liquid injection, the mitoxantrone contains 0.5-5 mg/ml active ingredient, preferably 1-2 mg/ml, more preferably 1 mg/ml; when boron When tezomib is powder for injection, the specification is 3.5mg/bottle, and it is prepared into a 2.5mg/ml solution when used; when dexamethasone is tablet, the specification is 0.75mg/tablet.
  • the drug combination product may further contain other second-line and above drugs for the treatment of multiple myeloma, and the drugs refer to drugs approved by the drug management department in China or other countries and regions (such as the United States, the European Union, Japan, South Korea, etc.) Second-line and above drugs in the treatment of multiple myeloma.
  • the present invention provides a pharmaceutical composition for the treatment of multiple myeloma, the pharmaceutical composition comprising mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone, the treatment includes the treatment of multiple myeloma Myeloma patients were treated with an effective therapeutic dose of mitoxantrone hydrochloride liposomes, and bortezomib and dexamethasone were administered at any time before, during and after the administration of mitoxantrone hydrochloride liposomes.
  • the effective therapeutic dose of the mitoxantrone hydrochloride liposome refers to 12-30 mg/m 2 , more preferably 12-20 mg/m 2 . Specific examples: 12mg/m 2 , 16mg/m 2 , 20mg/m 2 .
  • the mitoxantrone hydrochloride liposome is administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dose is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day.
  • the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times.
  • multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the present invention provides a medicine for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma
  • the medicine contains mitoxantrone hydrochloride liposome, and the mitoxantrone hydrochloride lipid
  • the body was administered at any time before, during and after the administration of bortezomib and dexamethasone.
  • the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 12-30 mg/m 2 , more preferably 12-20 mg/m 2 . Specific examples: 12mg/m 2 , 16mg/m 2 , 20mg/m 2 .
  • the mitoxantrone hydrochloride liposome is administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dose is 20 mg/day.
  • the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times.
  • the multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order, and on the fourth and eighth days. Bortezomib was continued on days 1 and 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the present invention provides a kind of medicine that is used for improving the curative effect of mitoxantrone hydrochloride liposome treatment multiple myeloma
  • described medicine contains bortezomib and dexamethasone, and described bortezomib and dexamethasone Administer at any time before, during and after the administration of mitoxantrone hydrochloride liposomes.
  • the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 12-30 mg/m 2 , more preferably 12-20 mg/m 2 . Specific examples: 12mg/m 2 , 16mg/m 2 , 20mg/m 2 .
  • the mitoxantrone hydrochloride liposome is administered intravenously.
  • the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90 ⁇ 15 minutes.
  • the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m 2 .
  • the administration method of dexamethasone is oral administration, and the dose is 20 mg/day.
  • the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times.
  • the multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order, and on the fourth and eighth days. Bortezomib was continued on days 1 and 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.
  • the multiple myeloma is preferably relapsed/refractory multiple myeloma.
  • the mitoxantrone liposome can be a mitoxantrone ester prepared by a conventional method in the art or any method disclosed in the prior art
  • the plastid for example, can be a liposome of mitoxantrone hydrochloride prepared by the method disclosed in WO2008/080367 A1, the disclosure of which is hereby incorporated by reference in its entirety.
  • the particle size of the mitoxantrone hydrochloride liposome is about 30-80nm, and it contains: 1) the active ingredient mitoxantrone, which can form a polyvalent counterion difficult to form with the liposome Dissolved precipitates, and 2) phospholipid bilayers containing phospholipids with a phase transition temperature (Tm) higher than body temperature, so that the phase transition temperature of the liposome is higher than body temperature.
  • Tm phase transition temperature
  • the multivalent counter ion is, for example, an organic acid radical, for example, an acid radical selected from the following organic acids: citric acid, tartaric acid, fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid, and maleic acid, etc., or Inorganic acid radicals, such as sulfate radicals, phosphate radicals, or ionized forms of amino acids such as cystine, preferably citrate radicals, sulfate radicals or phosphate radicals; the phospholipids whose Tm is higher than body temperature are phosphatidylcholine, hydrogenated soybean lecithin , hydrogenated egg yolk lecithin, dispalmitate lecithin or distearate lecithin, or any combination thereof.
  • organic acid radical for example, an acid radical selected from the following organic acids: citric acid, tartaric acid, fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid, and maleic acid, etc
  • the particle diameter of the liposome is about 35-75 nm, preferably 40-70 nm, more preferably 40-60 nm, especially preferably 60 nm.
  • the liposomes also contain cholesterol.
  • the phospholipid bilayer of the liposome may also contain other excipients, especially excipients that can further modify the surface characteristics of the liposome, such as lipids modified with hydrophilic polymers , which can be selected from, for example, polyethylene glycol-modified distearoylphosphatidylethanolamine (DSPE-PEG), polyethylene glycol-modified distearoylphosphatidylglycerol (DSPG-PEG), polyethylene glycol-modified Cholesterol (chol-PEG), povidone-modified distearoylphosphatidylethanolamine (DSPE-PVP), polyethylene glycol-modified distearoylphosphatidylglycerol (DSPG-PVP), polyethylene glycol-modified Cholesterol (chol-PVP) or its combination, preferably distearoylphosphatidylethanolamine modified with polyethylene glycol 2000.
  • DSPE-PEG polyethylene glycol-modified
  • the phospholipid bilayer contains hydrogenated soybean lecithin (HSPC), cholesterol (Chol) and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine ( DSPE-PEG2000), the particle diameter of the liposome is about 60nm, and the counterion is sulfate ion.
  • the phospholipid bilayer contains HSPC, Chol and DSPE-PEG2000 in a mass ratio of 3:1:1, the particle size of the liposome is about 60 nm, and the counterion is sulfate ion , and the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in the liposome is 9.58:3.19:3.19:1.
  • the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes (trade name: Doenda) approved by the National Pharmaceutical Standard H20220001.
  • the mitoxantrone liposomes can be prepared by conventional methods in the art, or can be prepared by any method disclosed in the prior art, for example, by the method disclosed in WO2008/080367 A1, the content disclosed in this patent is hereby It is incorporated by reference in its entirety.
  • the mitoxantrone liposomes are prepared as follows: HSPC, Chol and DSPE-PEG2000 are weighed according to a mass ratio of 3:1:1, dissolved in 95% ethanol to obtain a clear solution (i.e. ethanol solution of phospholipids). Mix the ethanol solution of phospholipids with 300 mM ammonium sulfate solution, shake and hydrate at 60-65° C.
  • the liposomes are then reduced in size using a microfluidic device.
  • the obtained sample was diluted 200 times with 0.9% NaCl solution, it was detected by NanoZS, the average particle size of the particles was about 60nm, and the main peak was concentrated between 40nm and 60nm.
  • the ammonium sulfate in the outer phase of the blank liposome was removed using an ultrafiltration device, and the outer phase was replaced with 290 mM sucrose and 10 mM glycine to form a transmembrane ammonium sulfate gradient.
  • mitoxantrone hydrochloride solution (10 mg/mL) was added to the blank liposome, and the drug was loaded at 60-65°C. After about 1 h of incubation, the encapsulation efficiency was demonstrated to be about 100% using gel exclusion chromatography.
  • the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone is 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose glycine solution is close to the physiological value.
  • amino acid species that can be substituted for glycine in the outer phase of the transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, alanine.
  • the mass ratio of HSPC, Chol and DSPE-PEG2000 can be adjusted appropriately.
  • those skilled in the art can design, test and finally obtain a suitable lipid-drug ratio to maximize the drug loading while reducing drug leakage.
  • the lipid-drug ratio that can be used is in a wide range, such as as low as 2:1 or as high as 30:1, 40:1 or 50:1, which is more suitable
  • the lipid-to-drug ratio can be about (15-20):1, such as about 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1.
  • Example 1 Clinical study of mitoxantrone hydrochloride liposome combined with bortezomib and dexamethasone in the treatment of relapsed/refractory multiple myeloma
  • This study is an open, multi-center, multi-cohort phase I clinical study. 60 subjects with relapsed/refractory MM were randomly assigned to three dose groups according to the ratio of 1:1:1 (20 cases in each group). , were given different doses of mitoxantrone hydrochloride liposomes and fixed doses of bortezomib and dexamethasone. The purpose of this study is to explore the safety and effectiveness of mitoxantrone hydrochloride liposome combined with bortezomib and dexamethasone, and to determine the optimal dosage of mitoxantrone hydrochloride liposome in the combined drug regimen.
  • the study consisted of a screening period, a treatment period and a follow-up period.
  • the screening period is up to 28 days. During this period, the inclusion/exclusion criteria will be reviewed, and the subjects will provide information related to tumor diagnosis and treatment, and complete clinical assessment within the specified time window. Those who pass the screening will enter the treatment period. Mitoxantrone hydrochloride liposomal (study drug) application on the first day (D1) of each cycle, bortezomib application on D1, D4, D8, D11, D1, D2, D4, D5, D8, D9, D11, D12 Apply dexamethasone. Every 4 weeks (28 days) is a treatment cycle, and 8 cycles of treatment are planned.
  • the investigator and the sponsor can negotiate to determine whether the treatment can be continued.
  • blood routine, blood biochemical and other laboratory tests, electrocardiogram, echocardiogram, physical examination, vital signs, ECOG score, etc. will be used to evaluate the safety of the subjects until 28 days after the last administration of the study drug, and according to the international According to the evaluation criteria of the Myeloma Working Group (IMWG), the curative effect was evaluated every 2 cycles. Dose adjustments and dosing delays per protocol were allowed from the second treatment cycle onwards.
  • Mitoxantrone hydrochloride liposome injection (1.0mg/ml), provided by CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. (Guoyao Zhunzi H20220001), the dosages are 12mg/m 2 and 16mg respectively /m 2 , 20mg/m 2 , intravenous infusion on the first day (D1) of each cycle.
  • Dexamethasone is commercially available, and the dosage is 20 mg/d, orally on D1, D2, D4, D5, D8, D9, D11, and D12.
  • Non-hematological toxicity must return to ⁇ grade 1 or baseline level (except hair loss, pigmentation, peripheral neuropathy).
  • the dose of mitoxantrone hydrochloride liposome is reduced by 4mg/m 2 each time, the lowest can be reduced to 8mg/m 2 ; the dose of bortezomib is reduced by 0.3mg/m 2 each time, and the lowest can be reduced to 1.0mg/m 2 .
  • the subsequent treatment of the two drugs will be carried out according to the adjusted dose, or further reduced if necessary, and no increase in dose is allowed.
  • the dosage of dexamethasone is allowed to be adjusted according to the actual clinical situation, and the minimum dosage is 10mg/time.
  • Cytology or tissue biopsy meets the diagnostic criteria for multiple myeloma (according to IMWG criteria), and relapsed or refractory patients who have received at least one line of treatment.
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Female subjects must have a negative blood HCG test result before enrolling in this trial, and agree to take a recognized very effective contraceptive measure from signing the ICF to at least 7 months after the end of the last dose [for example: combined hormone ( Containing estrogen and progesterone) combined with ovulation suppression, progesterone contraception combined with ovulation suppression, intrauterine device, intrauterine hormone releasing system, bilateral tubal ligation, vasectomy, etc.]. Except those who have been menopausal (stopping menstruation for at least 1 year); except those who have undergone hysterectomy or bilateral oophorectomy.
  • combined hormone Containing estrogen and progesterone
  • Impaired cardiac function or significant cardiac disease including but not limited to:
  • Heart diseases that need to be treated during screening, such as unstable angina, chronic congestive heart failure (NYHA ⁇ 2), arrhythmia, valvular disease, or persistent cardiomyopathy.
  • Cardiac ejection fraction is lower than 50% or lower than the lower limit of the inspection value range of the research center at the time of screening.
  • Bacterial infection, fungal infection or viral infection requiring systemic treatment within 1 week before study drug administration.
  • IMWG complete response
  • CR complete response
  • VGPR very good partial response
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • Case 1 After the diagnosis of multiple myeloma, the effect of thalidomide was not good, and the TD (thalidomide + dexamethasone) program was evaluated as VGPR. After re-examination and evaluation of PD, he participated in a clinical trial and was given CPT/placebo + Thalidomide + dexamethasone was treated for 4 courses, and after the disease progression was evaluated, mitoxantrone liposome + bortezomib + dexamethasone was given for 2 courses, and the evaluation was sCR.
  • TD thalidomide + dexamethasone
  • Case 2 After the diagnosis of multiple myeloma, bortezomib + doxorubicin liposome + dexamethasone was given for 4 courses of treatment, and it was evaluated as CR, and then ixapride + doxorubicin liposome + dexamethasone was given for treatment 1 course of treatment, after assessment of disease progression, 2 courses of mitoxantrone liposome + bortezomib + dexamethasone were given, and the assessment was VGPR.
  • Case 3 After diagnosis of multiple myeloma, TBCD (thalidomide + bortezomib + cyclophosphamide + dexamethasone) program 1 course, BCD (bortezomib + cyclophosphamide + dexamethasone) program 3 After a course of treatment, it was evaluated as PR, and after 4 courses of BCD regimen, 2 courses of BD (bortezomib + dexamethasone) regimen, and 1 course of BRD (bortezomib + lenalidomide + dexamethasone) regimen, it was evaluated as disease recurrence , BRD regimen was given for 2 courses, and after the assessment of disease progression, mitoxantrone liposome + bortezomib + dexamethasone was given for 2 courses of treatment, and the assessment was VGPR.
  • BCD thalidomide + bortezomib + cyclophosphamide + de
  • VADT vincristine + doxorubicin + dexamethasone + thalidomide

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Abstract

米托蒽醌脂质体、硼替佐米和地塞米松在制备治疗多发性骨髓瘤的药物中的用途，用于治疗多发性骨髓瘤的包含米托蒽醌脂质体、硼替佐米和地塞米松的药物组合产品，以及使用米托蒽醌脂质体、硼替佐米和地塞米松治疗多发性骨髓瘤的方法。所述多发性骨髓瘤优选为复发/难治多发性骨髓瘤。所述米托蒽醌脂质体优选为盐酸米托蒽醌脂质体。

Description

米托蒽醌脂质体、硼替佐米和地塞米松治疗多发性骨髓瘤的用途 技术领域
本发明涉及抗肿瘤领域，具体涉及米托蒽醌脂质体、硼替佐米和地塞米松在制备用于治疗复发/难治多发性骨髓瘤(MM)的药物中的用途。
背景技术
多发性骨髓瘤(MM)是一种单克隆浆细胞异常增殖的恶性疾病，好发于老年人，中位发病年龄66岁(Robert A Kyle，et al.Review of 1027 patients with newly diagnosed multiple myeloma.Mayo Clin Proc.2003 Jan；78(1)：21-33)，男性发病率稍高。MM作为全球性疾病，从流行病学来看，是血液系统第二大恶性肿瘤，澳大利亚、北美、西欧的发病率最高。在我国，MM发病率为1～2/10万，2016年新发病例为1.65万人，死亡病例为1.04万人，发病/死亡人数均位列全球第二位(Andrew J Cowan，et al.，Global Burden of Multiple Myeloma：A Systematic Analysis for the Global Burden of Disease Study 2016.JAMA Oncol.2018 Sep 1；4(9)：1221-1227)。新药的不断出现，改变了MM的治疗模式和预后，中位OS约6年(S Vincent Rajkumar.Multiple myeloma：2020 update on diagnosis，risk-stratification and management.Am J Hematol.2020 May；95(5)：548-567)。然而，MM仍具有反复复发、耐药的特点，无法治愈，复发/难治仍是难题。
在MM的治疗里，不管是传统治疗时代蒽环类药物联合长春新碱、地塞米松(VAD方案)，还是新药时代蒽环类药物与硼替佐米、地塞米松的联合(PAD方案)，蒽环类药物都是MM治疗的重要组成部分。随着新药的不断问世，蒽环类药物的使用有所减少。梅奥指南2020推荐含蒽环的多药组合方案用于浆细胞白血病、髓外病变等侵袭性复发的患者(S Vincent Rajkumar.Multiple myeloma：2020 update on diagnosis，risk-stratification and management.Am J Hematol.2020 May；95(5)：548-567)。2020中国MM诊治指南里含蒽环的方案如PAD、TAD(沙利度胺+阿霉素+地塞米松)仍在一线推荐行列，伴有髓外病变的复发MM也推荐应用含细胞毒药物的联合方案(《(中国多发性骨髓瘤诊 治指南(2020年修订)》[J].中华医学信息导报，2020，35(11)：12-12)。硼替佐米+阿霉素脂质体+地塞米松(PAD方案)、硼替佐米+地塞米松(PD方案)治疗复发/难治MM，仍是2021版NCCN指南1类推荐(NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines).multiple myeloma.Version 3.2021)。一项多中心临床试验纳入了64例复发/难治多发性骨髓瘤患者，均接受PAD方案(硼替佐米+阿霉素/阿霉素脂质体+地塞米松)治疗，有43例患者的疗效至少达到了PR(67％)，包括CR(9％)和VGPR(16％)；在PAD方案治疗过程中，最常见的1-2级不良事件为贫血(42％)，中性粒细胞计数降低(30％)，血小板计数降低(27％)，周围神经病变(27％)，恶心(14％)，腹泻(11％)以及不明原因的发热(11％)；最常见的3级不良事件为血小板计数降低(23％)，中性粒细胞计数降低(20％)，贫血(11％)，周围神经病变(10％)以及肺炎(9％)；4级不良事件包括血小板计数降低(25％)、中性粒细胞计数降低(16％)及贫血(2％)、急性心力衰竭(2％)和肺炎(3％)，没有患者出现4级周围神经病变(A Palumbo，et al.，Bortezomib，doxorubicin and dexamethasone in advanced multiple myeloma.Ann Oncol.2008 Jun；19(6)：1160-5)。另一项ENDEAVOR研究中，对于252例既往应用过硼替佐米的复发/难治MM患者，PD方案的客观缓解率(ORR)为60.3％，中位无进展生存期(PFS)为8.1个月；对于177例既往应用过来那度胺的复发/难治MM患者，PD方案的ORR为59.3％，中位PFS为7.3个月(P Moreau，et al.，Impact of prior treatment on patients with relapsed multiple myeloma treated with carfifilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study，Leukemia.2017 Jan；31(1)：115-122)。
蒽环类药物的不良反应主要包括心脏毒性、骨髓毒性、胃肠道反应等。在阿霉素之后，相继出现了表阿霉素、阿霉素脂质体等蒽环类药物，安全性有所提高，但疗效并无差异。一项随机对照的3期临床研究纳入646例复发/难治MM患者，比较了阿霉素脂质体联合硼替佐米与硼替佐米单药治疗的疗效(Robert Z Orlowski，et al.，Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma：combination therapy improves time to progression.J Clin Oncol.2007 Sep  1；25(25)：3892-901)。研究结果表明阿霉素脂质体联合硼替佐米的中位PFS为9个月，缓解≥VGPR的占27％，均显著优于硼替佐米单药，提示两药的联合有协同增效作用。基于此项研究，阿霉素脂质体于2007年经FDA批准与硼替佐米联合用于复发/难治MM治疗。以两药为基础的3～4药组合对于复发/难治MM也有一定疗效(A Palumbo，et al.，Bortezomib，doxorubicin and dexamethasone in advanced multiple myeloma.Ann Oncol.2008 Jun；19(6)：1160-5；Stefania Ciolli，et al.，The addition of liposomal doxorubicin to bortezomib，thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma.Br J Haematol.2008 Jun；141(6)：814-9；Massimo Offidani，et al.，Thalidomide，dexamethasone，Doxil and Velcade(ThaDD-V)followed by consolidation/maintenance therapy in patients with relapsed-refractory multiple myeloma.Ann Hematol.2011 Dec；90(12)：1449-56；JR Berenson，et al.，A phase 2 study of pegylated liposomal doxorubicin，bortezomib，dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma，Leukemia.2012 Jul；26(7)：1675-80)，包括对于既往应用过蒽环类药物和硼替佐米治疗的患者。
米托蒽醌(Mitoxantrone)是一种蒽环类药物，至今已在全球30多个国家使用。二十世纪七十年代末，美国就开始了米托蒽醌的相关临床研究，一系列临床试验表明，米托蒽醌不管是单药还是与其他药物联合，对于血液系统肿瘤如急性白血病、淋巴瘤以及多种实体肿瘤如乳腺癌等都具有治疗作用。其不良反应主要表现为骨髓抑制、胃肠道反应和心脏毒性。米托蒽醌临床上主要用于治疗急性髓系白血病。
脂质体是一种新型载药形式。研究显示，其可改变包封药物的体内分布，使药物主要在肿瘤组织中积蓄，从而提高药物的治疗指数、减少药物的治疗剂量和降低药物毒性。这些特性使得脂质体载药在抗肿瘤药物研究中的应用备受重视。有研究人员针对米托蒽醌脂质体制剂进行了研究。例如，2006年12月29日提交的中国专利申请200610102339.8和2007年12月29日提交的PCT申请WO2008/080367A1公开了一种米托蒽醌脂质体，其公开内容在此被全文引入作为参考。研究显示，相对于米托蒽醌普通制剂，脂质体制剂 的毒性(特别是心脏毒性)更低，并具备了被动靶向肿瘤组织的特性，提高了抗肿瘤活性。
盐酸米托蒽醌脂质体注射液单药I期已在晚期实体瘤受试者及淋巴瘤受试者中完成了剂量爬坡的探索和PK/PD研究。根据试验结果，盐酸米托蒽醌脂质体注射液在6～30mg/m 2剂量范围内安全耐受，且显示了一定疗效。盐酸米托蒽醌脂质体单药的关键性II期在复发/难治外周T细胞淋巴瘤(PTCL)患者中进行并已完成入组(n＝108例，给药剂量20mg/m 2)，目前经独立评审委员会(IRC)评估并经疗效确认的ORR为40.7％。
鉴于米托蒽醌脂质体在复发/难治PTCL患者中较好的单药疗效，在复发/难治MM患者中进一步开展了米托蒽醌脂质体联合用药的探索。初步临床研究结果表明，米托蒽醌脂质体联合硼替佐米和地塞米松的方案安全耐受，提高了复发/难治MM患者的客观缓解率(ORR)，延长了缓解持续时间(DoR)，改善了PFS和OS，从而提高了患者生活质量，使MM患者受益。
MM的复发/难治仍是临床医生所面临的难题。在新药时代，作为MM治疗的传统药物，蒽环类药物仍是联合用药的重要组成部分之一。米托蒽醌脂质体作为高效低毒的蒽环(醌)类药物，其与硼替佐米和地塞米松的联合用药有望成为复发/难治MM的治疗选择，特别是对于侵袭性复发的患者。
发明内容
本发明涉及米托蒽醌脂质体、硼替佐米和地塞米松在制备治疗多发性骨髓瘤的药物中的用途。
本发明还涉及米托蒽醌脂质体在制备改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的药物中的用途。
本发明还涉及硼替佐米和地塞米松在制备改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物中的用途。
本发明还提供一种治疗多发性骨髓瘤的方法，所述方法包括对多发性骨髓瘤患者施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松。
本发明还提供一种改善硼替佐米和地塞米松治疗多发性骨髓瘤的 疗效的方法，所述方法包括在对多发性骨髓瘤患者施用硼替佐米和地塞米松的基础上，进一步联合施用有效治疗剂量的米托蒽醌脂质体。
本发明还提供一种改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的方法，所述方法包括在对多发性骨髓瘤患者施用米托蒽醌脂质体的基础上，进一步联合施用有效治疗剂量的硼替佐米和地塞米松。
本发明还提供一种用于治疗多发性骨髓瘤的药物组合产品，所述药物组合产品包含米托蒽醌脂质体、硼替佐米和地塞米松。
本发明还提供一种用于改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的药物，所述药物包含米托蒽醌脂质体。
本发明还提供一种用于改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物，所述药物包含硼替佐米和地塞米松。
具体实施方式
如无其它特殊说明，本发明中使用的术语具有以下定义：
“复发”定义为既往治疗达到微小缓解(MR)及以上缓解，之后疾病进展。
“难治”定义为一线应用任何治疗都没有达到MR。
“米托蒽醌”包括米托蒽醌及其药学上可接受的盐，所述米托蒽醌药学上可接受的盐优选为米托蒽醌盐酸盐。米托蒽醌脂质体优选为盐酸米托蒽醌脂质体。
“按照任意先后顺序施用”是指米托蒽醌脂质体、硼替佐米和地塞米松分别制剂，并以临床可接受的方式分别给药，对给药的先后顺序无强制规定；各药物在体外不发生混合。
本发明提供米托蒽醌脂质体、硼替佐米和地塞米松在制备治疗多发性骨髓瘤的药物中的用途。
本发明还提供米托蒽醌脂质体在制备改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的药物中的用途。
本发明还提供硼替佐米和地塞米松在制备改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物中的用途。
进一步地，本发明提供盐酸米托蒽醌脂质体、硼替佐米和地塞米松在制备治疗多发性骨髓瘤的药物中的用途。
进一步地，本发明提供盐酸米托蒽醌脂质体在制备改善硼替佐米 和地塞米松治疗多发性骨髓瘤的疗效的药物中的用途。
进一步地，本发明提供硼替佐米和地塞米松在制备改善盐酸米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物中的用途。
在上述用途中，所述多发性骨髓瘤优选是复发/难治多发性骨髓瘤。
本发明提供一种治疗多发性骨髓瘤的方法，所述方法包括对多发性骨髓瘤患者施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松。
本发明还提供一种改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的方法，所述方法包括在对多发性骨髓瘤患者施用硼替佐米和地塞米松的基础上，进一步联合施用有效治疗剂量的米托蒽醌脂质体。
本发明还提供一种改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的方法，所述方法包括在对多发性骨髓瘤患者施用米托蒽醌脂质体的基础上，进一步联合施用有效治疗剂量的硼替佐米和地塞米松。
在上述方法中，所述多发性骨髓瘤优选是复发/难治多发性骨髓瘤。
在上述方法中，米托蒽醌脂质体和硼替佐米的施用优选注射给药；地塞米松优选口服给药。优选地，以米托蒽醌计，所述米托蒽醌脂质体的有效治疗剂量是12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周期为4周或3周，进一步优选为4周；每个给药周期中，米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
进一步地，本发明提供一种治疗多发性骨髓瘤的方法，所述方法包括对多发性骨髓瘤患者施用有效治疗剂量的盐酸米托蒽醌脂质体、硼替佐米和地塞米松。
进一步地，本发明提供一种改善硼替佐米和地塞米松治疗多发性 骨髓瘤的疗效的方法，所述方法包括在对多发性骨髓瘤患者施用硼替佐米和地塞米松的基础上，进一步联合施用有效治疗剂量的盐酸米托蒽醌脂质体。
进一步地，本发明提供一种改善盐酸米托蒽醌脂质体治疗多发性骨髓瘤的疗效的方法，所述方法包括在对多发性骨髓瘤患者施用盐酸米托蒽醌脂质体的基础上，进一步联合施用有效治疗剂量的硼替佐米和地塞米松。
在上述方法中，所述多发性骨髓瘤优选是复发/难治多发性骨髓瘤。
在上述方法中，盐酸米托蒽醌脂质体和硼替佐米的施用优选注射给药；地塞米松优选口服给药。优选地，以米托蒽醌计，所述盐酸米托蒽醌脂质体的有效治疗剂量是12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，盐酸米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周期为4周或3周，进一步优选为4周；每个给药周期中，盐酸米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的盐酸米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
本发明还提供一种用于治疗多发性骨髓瘤的药物组合产品，所述药物组合产品包含米托蒽醌脂质体、硼替佐米和地塞米松。优选地，米托蒽醌脂质体、硼替佐米和地塞米松可以存在于同一制剂中，也可分别独立制剂，以组合包装的形式存在。当上述3种药物分别制剂时，剂型可以相同，也可以不同。所述剂型可以是临床可接受的任意一种剂型，例如注射剂型、口服剂型等。所述注射剂型包括液体注射剂、注射用粉剂、注射用片剂等等；所述口服剂型包括片剂、胶囊剂、口服液体制剂等。优选地，当所述米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml；当硼替佐米为注射用粉针时，规格为3.5mg/瓶，使用时配制成2.5mg/ml 溶液；当地塞米松为片剂时，规格为0.75mg/片。
所述药物组合产品中可进一步包含其他治疗多发性骨髓瘤的二线及以上药物，所述药物是指中国或其它国家和地区(例如美国、欧盟、日本、韩国等等)药物管理部门批准用于多发性骨髓瘤治疗的二线及以上药物。
本发明还提供一种用于治疗多发性骨髓瘤的药物组合物，所述药物组合物包含米托蒽醌脂质体、硼替佐米和地塞米松，所述治疗包括对多发性骨髓瘤患者使用有效治疗剂量的米托蒽醌脂质体，并在米托蒽醌脂质体给药前、中、后的任意时间施用硼替佐米和地塞米松。优选地，以米托蒽醌计，所述米托蒽醌脂质体的有效治疗剂量是指12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周期为4周或3周，进一步优选为4周；每个给药周期中，米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松，第4、第8和第11天继续施用硼替佐米，第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
本发明还提供一种用于改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的药物，所述药物含有米托蒽醌脂质体，所述米托蒽醌脂质体在硼替佐米和地塞米松给药前、中、后的任意时间施用。优选地，以米托蒽醌计，所述米托蒽醌脂质体的有效治疗剂量是12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周期为4周或3周，进一步优 选为4周；每个给药周期中，米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
本发明还提供一种用于改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物，所述药物含有硼替佐米和地塞米松，所述硼替佐米和地塞米松在米托蒽醌脂质体给药前、中、后的任意时间施用。优选地，以米托蒽醌计，所述米托蒽醌脂质体的有效治疗剂量是12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周期为4周或3周，进一步优选为4周；每个给药周期中，米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
进一步地，本发明提供一种用于治疗多发性骨髓瘤的药物组合产品，所述药物组合产品包含盐酸米托蒽醌脂质体、硼替佐米和地塞米松。
优选地，盐酸米托蒽醌脂质体、硼替佐米和地塞米松可以存在于同一制剂中，也可分别独立制剂，以组合包装的形式存在。当上述3种药物分别制剂时，剂型可以相同，也可以不同。所述剂型可以是临床可接受的任意一种剂型，例如注射剂型、口服剂型等。所述注射剂型包括液体注射剂、注射用粉剂、注射用片剂等等；所述口服剂型包括片剂、胶囊剂、口服液体制剂等。优选地，当所述盐酸米托蒽醌脂质体为液体注射剂时，以米托蒽醌计，含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml；当硼替佐米为注射用粉针时，规格为3.5mg/瓶，使用时配制成2.5mg/ml溶液；当地塞米松为片剂时，规格为0.75mg/ 片。
所述药物组合产品中可进一步包含其他治疗多发性骨髓瘤的二线及以上药物，所述药物是指中国或其它国家和地区(例如美国、欧盟、日本、韩国等等)药物管理部门批准用于多发性骨髓瘤治疗的二线及以上药物。
进一步地，本发明提供一种用于治疗多发性骨髓瘤的药物组合物，所述药物组合物包含盐酸米托蒽醌脂质体、硼替佐米和地塞米松，所述治疗包括对多发性骨髓瘤患者使用有效治疗剂量的盐酸米托蒽醌脂质体，并在盐酸米托蒽醌脂质体给药前、中、后的任意时间施用硼替佐米和地塞米松。优选地，以米托蒽醌计，所述盐酸米托蒽醌脂质体的有效治疗剂量是指12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，盐酸米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周期为4周或3周，进一步优选为4周；每个给药周期中，盐酸米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的盐酸米托蒽醌脂质体、硼替佐米和地塞米松，第4、第8和第11天继续施用硼替佐米，第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
进一步地，本发明提供一种用于改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的药物，所述药物含有盐酸米托蒽醌脂质体，所述盐酸米托蒽醌脂质体在硼替佐米和地塞米松给药前、中、后的任意时间施用。优选地，以米托蒽醌计，所述盐酸米托蒽醌脂质体的有效治疗剂量是12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，盐酸米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周 期为4周或3周，进一步优选为4周；每个给药周期中，盐酸米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的盐酸米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
进一步地，本发明提供一种用于改善盐酸米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物，所述药物含有硼替佐米和地塞米松，所述硼替佐米和地塞米松在盐酸米托蒽醌脂质体给药前、中、后的任意时间施用。优选地，以米托蒽醌计，所述盐酸米托蒽醌脂质体的有效治疗剂量是12～30mg/m 2，更优选为12～20mg/m 2。具体例如：12mg/m 2，16mg/m 2，20mg/m 2。优选地，盐酸米托蒽醌脂质体的给药方式为静脉给药。优选地，每次静脉给药，所述脂质体制剂的滴注给药时间为30min～120min，优选60min～120min，进一步优选90±15min。优选地，硼替佐米的给药方式为注射给药，剂量为1.3mg/m 2。优选地，地塞米松的给药方式为口服给药，剂量为20mg/天。优选地，治疗的给药周期为4周或3周，进一步优选为4周；每个给药周期中，盐酸米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。优选地，在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的盐酸米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
在上述涉及治疗多发性骨髓瘤使用的药物组合产品、药物组合物和药物中，所述多发性骨髓瘤优选是复发/难治多发性骨髓瘤。
在上述用途、方法、药物组合产品、药物组合物和药物中，所述米托蒽醌脂质体可以是采用本领域常规方法或现有技术公开的任意一种方法制备的米托蒽醌脂质体，例如可以是采用WO2008/080367 A1公开的方法制备的盐酸米托蒽醌脂质体，该专利公开的内容在此被全文引入作为参考。
在一些实施方案中，所述盐酸米托蒽醌脂质体的粒径为约30～80nm，其含有：1)活性成分米托蒽醌，它可以和脂质体内的多价反离子形成难以溶解的沉淀，和2)磷脂双分子层，其含有相转变温度(Tm) 高于体温的磷脂，从而使脂质体的相转变温度高于体温。其中，所述多价反离子例如为有机酸根，例如选自以下有机酸的酸根：柠檬酸、酒石酸、富马酸、草酸、丙二酸、琥珀酸、苹果酸，以及马来酸等，或无机酸根，例如硫酸根、磷酸根，或氨基酸例如胱氨酸的离子化形式，优选为柠檬酸根、硫酸根或者磷酸根；所述Tm高于体温的磷脂为磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或双硬脂酸卵磷脂或者其任何组合。
在一些实施方案中，所述脂质体的粒径为约35～75nm，优选40～70nm，进一步优选40～60nm，特别优选60nm。
在一些实施方案中，所述脂质体还含有胆固醇。在一些实施方案中，所述脂质体的磷脂双分子层中也可含有其他的辅料，特别是可以进一步修饰脂质体的表面特征的辅料，例如用亲水性聚合物修饰的脂类物质，其可选自例如聚乙二醇修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG)、聚乙二醇修饰的二硬脂酰磷脂酰甘油(DSPG-PEG)、聚乙二醇修饰的胆固醇(chol-PEG)、聚维酮修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PVP)、聚乙二醇修饰的二硬脂酰磷脂酰甘油(DSPG-PVP)、聚乙二醇修饰的胆固醇(chol-PVP)或者其组合，优选为聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺。
在一些实施方案中，所述磷脂双分子层含有质量比为3∶1∶1的氢化大豆卵磷脂(HSPC)、胆固醇(Chol)和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)，所述脂质体的粒径为约60nm，所述反离子为硫酸根离子。在一些实施方案中，所述磷脂双分子层含有质量比为3∶1∶1的HSPC、Chol和DSPE-PEG2000，所述脂质体的粒径为约60nm，所述反离子为硫酸根离子，且脂质体中HSPC∶Chol∶DSPE-PEG2000∶米托蒽醌的重量比为9.58∶3.19∶3.19∶1。在一些实施方案中，所述米托蒽醌脂质体为国药准字H20220001的盐酸米托蒽醌脂质体(商品名：多恩达)。
所述米托蒽醌脂质体可以采用本领域常规方法制备，也可以采用现有技术公开的任意一种方法制备，例如采用WO2008/080367 A1公开的方法制备，该专利公开的内容在此被全文引入作为参考。在一些实施方案中，所述米托蒽醌脂质体如下制备：将HSPC、Chol和DSPE-PEG2000按照3∶1∶1的质量比称重，溶解于95％乙醇中，得到澄 明溶液(即磷脂的乙醇溶液)。将磷脂的乙醇溶液与300mM的硫酸铵溶液混合，在60～65℃震荡水化lh，得到不均匀的多室脂质体。之后使用微射流设备降低脂质体的粒度。将所获得的样品用浓度0.9％的NaCl溶液稀释200倍后，用NanoZS进行检测，粒子的平均粒度约为60nm，主峰集中在40～60nm之间。之后使用超滤装置移去空白脂质体外相的硫酸铵，将外相置换成290mM蔗糖及10mM甘氨酸，以便形成跨膜硫酸铵梯度。按照脂药比16∶1的比例，在空白脂质体中加入米托蒽醌盐酸盐溶液(10mg/mL)，在60～65℃进行载药。孵育约lh后，使用凝胶排阻色谱可证明包封效率约为100％。其中HSPC∶Chol∶DSPE-PEG2000∶米托蒽醌的重量比为9.58∶3.19∶3.19∶1，蔗糖甘氨酸溶液的渗透压与生理值接近。
应当理解的是，上述示例性制备方法中的多个技术细节和参数可以由本领域技术人员在合理的范围内进行调试和确定。例如，用于形成跨膜硫酸铵梯度的外相中的甘氨酸可替换的氨基酸种类包括但不限于组氨酸、天冬酰胺、谷氨酸、亮氨酸、脯氨酸、丙氨酸。再例如，HSPC、Chol和DSPE-PEG2000的质量比可以进行适当的调整。还例如，对于制备具体脂质体药物制剂中的脂药比参数，本领域技术人员可以设计、测试并最终得出合适的脂药比，以尽量提高载药量的同时减少药物漏出量。对于本申请的米托蒽醌脂质体制剂而言，可以使用的脂药比是宽范围的，例如低至2∶1或高至30∶1、40∶1或50∶1，更为适合的脂药比可以为约(15-20)∶1，例如约15∶1、16∶1、17∶1、18∶1、19∶1或20∶1。
实施例
以下实施例旨在对本发明进行具体说明，而不应解释为对本发明的范围构成限制。
实施例1盐酸米托蒽醌脂质体联合硼替佐米和地塞米松治疗复发/难治多发性骨髓瘤的临床研究
本研究是一项开放、多中心、多队列的I期临床研究，纳入60例复发/难治MM受试者，按照1∶1∶1比例随机分配到三个剂量组(每组20例)，分别给予不同剂量的盐酸米托蒽醌脂质体和固定剂量的硼替佐米、地塞米松。本研究旨在探索盐酸米托蒽醌脂质体联合硼替佐米、地塞米 松方案的安全性和有效性，确定该联合用药方案中盐酸米托蒽醌脂质体的最佳给药剂量。
一、试验设计
1、总体设计
研究包含筛选期、治疗期和随访期。
筛选期最长为28天，在此期间，针对入选/排除标准进行审查，受试者提供肿瘤诊断及治疗相关资料，并在规定的时间窗内进行完整的临床评估。筛选合格的受试者将进入治疗期。每周期的第一天(D1)应用盐酸米托蒽醌脂质体(研究药物)，D1、D4、D8、D11应用硼替佐米，D1、D2、D4、D5、D8、D9、D11、D12应用地塞米松。每4周(28天)为一个治疗周期，计划治疗8个周期。对于已完成8个周期治疗的受试者，如存在继续获益可能并且耐受治疗，可由研究者与申办者共同协商确定是否可以继续治疗。治疗期间将应用血常规、血生化等实验室检查、心电图、超声心动图、体格检查、生命体征、ECOG评分等对受试者进行安全性评价至研究药物末次给药后28天，并按照国际骨髓瘤工作组(IMWG)的评效标准每2个周期进行一次疗效评价。从第二个治疗周期开始，允许按照方案进行剂量调整和给药延迟。治疗结束继续对受试者进行生存状态随访：每8周(±7d)进行一次疾病状态评估直至疾病进展/复发；出现疾病进展/复发或者开始其他抗肿瘤治疗的受试者继续随访生存状态，每8周(±7d)一次访视或电话随访。
2、给药方案
盐酸米托蒽醌脂质体，注射液(1.0mg/ml)，由石药集团中诺药业(石家庄)有限公司提供(国药准字H20220001)，给药剂量分别为12mg/m 2、16mg/m 2、20mg/m 2，每周期第一天(D1)静脉滴注。
硼替佐米，商购，给药剂量为1.3mg/m 2，D1、D4、D8、D11皮下注射。
地塞米松，商购，给药剂量为20mg/d，D1、D2、D4、D5、D8、D9、D11、D12口服。
3、继续用药的规定
(1)下一周期(CnD1)给药标准
1)中性粒细胞绝对值(ANC)≥1.5x10 9/L、血小板≥75x10 9/L。
2)非血液学毒性必须恢复至≤1级或基线水平(脱发、色素沉着、 周围神经病变除外)。
3)若因不能满足1或2给药标准而导致延迟给药，原则上不超过14天。
4)如果不能满足1或2给药标准，或者延迟给药＞14天，若研究者判断受试者仍可获益，与申办者沟通后可考虑继续用药。
(2)剂量调整
研究治疗期间，允许进行剂量调整。盐酸米托蒽醌脂质体每次减量4mg/m 2，最低可减至8mg/m 2；硼替佐米每次减量0.3mg/m 2，最低可减至1.0mg/m 2。一旦减量，两药的后续治疗将按调整后剂量执行，或者在必要时进一步减量，不允许增加剂量。地塞米松允许根据临床实际情况进行剂量调整，最低给药剂量10mg/次。
二、试验人群：
(一)入选标准：
符合下列全部标准的患者方可入选本研究：
1.受试者充分了解本研究，自愿参加并签署知情同意书(ICF)。
2.年龄18～75周岁，男女不限。
3.细胞学或组织活检符合多发性骨髓瘤诊断标准(根据IMWG标准)，并至少接受过一线治疗的复发或难治患者。
4.至少有下列一项可评价指标：
(1)血M蛋白水平≥10g/L
(2)24小时尿M蛋白水平≥200mg
(3)受累和非受累血清游离轻链差值(dFLC)≥100mg/L
5.ECOG评分0～2分。
6.实验室检查符合以下标准：
(1)中性粒细胞绝对值(ANC)≥1.5x10 9/L(检查前1周内未接受G-CSF治疗)。
(2)血小板(PLT)≥75x10 9/L(检查前1周内未接受输注血小板治疗)。
(3)总胆红素≤1.5倍正常值上限(ULN)。
(4)丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)≤2.5倍ULN。
(5)肌酐清除率(Ccr)≥30ml/min。
7.女性受试者入组本试验前血HCG检测结果必须阴性，且从签署ICF至末次给药结束后至少7个月同意采取一种被认可的非常有效的避孕措施【例如：联合激素(含雌激素和孕激素)结合抑制排卵、孕激素避孕结合抑制排卵、宫内节育器、宫内激素释放系统、双侧输卵管结扎术、输精管切除术等】。已绝经者(停经至少1年)除外；已行子宫切除或双侧卵巢切除者除外。
8.男性受试者及其伴侣同意在签署ICF至末次给药结束后至少4个月采取第8条中所述的避孕措施之一。
(二)排除标准：
符合下列任何一项排除标准，不可入选本研究：
1.伴发淀粉样变性或中枢神经系统侵犯或进行透析治疗的受试者。
2.预计生存时间＜3个月。
3.对米托蒽醌或脂质体类药物有过敏史；或者既往接受过蒽环类药物治疗，蒽环类药物总累积剂量换算成阿霉素≥350mg/m 2(蒽环类药物等效剂量换算：1mg阿霉素＝2mg表阿霉素/吡喃阿霉素/柔红霉素＝0.5mg去甲氧柔红霉素＝0.45mg米托蒽醌；阿霉素脂质体除外)。
4.对硼替佐米有过敏史(局部注射反应除外)或不耐受；或者既往含硼替佐米方案规范治疗出现以下情况之一：无治疗反应(未达到MR)；末次用药结束后6个月内疾病进展。
5.对地塞米松有使用禁忌或不耐受。
6.在研究药物首次给药前4周内接受过任何临床常规抗骨髓瘤药物治疗(沙利度胺为首次给药前3周，全身糖皮质激素为首次给药前2周)或放疗；或研究药物首次给药前3个月内接受过研究性抗骨髓瘤药物治疗。
7.筛选前6个月内接受过自体造血干细胞移植。
8.异基因造血干细胞移植或异体器官移植术后。
9.既往抗肿瘤治疗毒性未恢复至≤1级(脱发、色素沉着除外)。
10.持续存在≥2级的周围神经病变或1级周围神经病变伴疼痛。
11.心脏功能受损或患有显著的心脏疾病，包括但不限于：
(1)在筛选前6个月内发生过心肌梗死、病毒性心肌炎。
(2)筛选时存在需要治疗的心脏病，如不稳定心绞痛、慢性充血性心力衰竭(NYHA≥2级)、心律失常、瓣膜病等或持续存在的心肌 病。
(3)筛选时QTc间期＞480ms或患有长QTc综合征。
(4)筛选时心脏射血分数低于50％或低于研究中心检查值范围下限。
12.HBsAg或HBcAb阳性且HBV-DNA滴度高于研究中心检测值下限、或HCV抗体阳性且HCV-RNA滴度高于研究中心检测值下限、或HIV抗体阳性。
13.有明显的消化系统功能异常，可能影响药物的摄入、转运、吸收(如无法吞咽、全胃切除、肠梗阻等)。
14.研究药物给药前1周内患有需要全身治疗的细菌感染、真菌感染或病毒感染。
15.首次给药前6周内接受过重大手术，或者计划在研究治疗期间进行重大手术者。
16.既往5年内患有其他恶性肿瘤(已治愈的局部可治愈性肿瘤除外，例如基底或鳞状细胞皮肤癌或原位前列腺癌、宫颈癌或乳腺癌)。
17.患有经研究者判定不适宜参加本研究的其他疾病，包括但不限于药物控制未达标的高血压(多次测量收缩压≥140mmHg和/或舒张压≥90mmHg)、药物控制不达标的糖尿病(空腹血糖＞7mmol/L或糖化血红蛋白≥7.0％)、慢性阻塞性肺疾病、肺栓塞、6个月内发生过脑血栓或脑出血。
18.妊娠或正在哺乳的妇女。
19.存在其他研究者判定不适宜参加本研究的情况。
三、研究结果
疗效评价
按照IMWG标准进行疗效评价，分为严格意义的完全缓解(sCR)、完全缓解(CR)、非常好的部分缓解(VGPR)、部分缓解(PR)、疾病稳定(SD)和疾病进展(PD)。
总缓解率(ORR)＝(sCR+CR+VGPR+PR)/总的可评价病例数*100％。
Figure PCTCN2022117434-appb-000001
截至2022年8月17日，本项目共入组12例多发性骨髓瘤受试者。5例受试者进行过至少一次疗效评估，其中，1例受试者评估PR(部分缓解)，3例受试者评估VGPR(非常好的部分缓解)，1例受试者 评估sCR(严格意义的完全缓解)，ORR＝100％(5/5)。
上述结果表明，盐酸米托蒽醌脂质体联合硼替佐米和地塞米松的方案显著提高了复发/难治MM患者的ORR。
四.典型病例
病例1：确诊多发性骨髓瘤后，给予沙利度胺效果不佳，给予TD(沙利度胺+地塞米松)方案评估为VGPR，复查评估PD后参与临床试验，给予CPT/安慰剂+沙利度胺+地塞米松方案治疗4疗程，评估疾病进展后给予米托蒽醌脂质体+硼替佐米+地塞米松治疗2疗程，评估为sCR。
病例2：确诊多发性骨髓瘤后，给予硼替佐米+阿霉素脂质体+地塞米松治疗4疗程后评估为CR，给予伊沙比利+阿霉素脂质体+地塞米松治疗1疗程，评估疾病进展后给予米托蒽醌脂质体+硼替佐米+地塞米松治疗2疗程，评估为VGPR。
病例3：确诊多发性骨髓瘤后，给予TBCD(沙利度胺+硼替佐米+环磷酰胺+地塞米松)方案1疗程、BCD(硼替佐米+环磷酰胺+地塞米松)方案3疗程后评估为PR，继续给予4疗程BCD方案、2疗程BD(硼替佐米+地塞米松)方案、1疗程BRD(硼替佐米+来那度胺+地塞米松)方案后评估为疾病复发，给予BRD方案2疗程，评估疾病进展后给予米托蒽醌脂质体+硼替佐米+地塞米松治疗2疗程，评估为VGPR。
病例4：确诊多发性骨髓瘤后，给予VADT(长春新碱+阿霉素+地塞米松+沙利度胺)方案治疗8疗程后评估为SD，后给予地塞米松+沙利度胺治疗2疗程后评估为PD，后参与临床试验，给予CPT/安慰剂+沙利度胺+地塞米松方案治疗4疗程，评估疾病进展后给予米托蒽醌脂质体+硼替佐米+地塞米松治疗2疗程，评估为VGPR。

Claims (28)

  1. 米托蒽醌脂质体、硼替佐米和地塞米松在制备治疗多发性骨髓瘤的药物中的用途。
  2. 米托蒽醌脂质体在制备改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的药物中的用途。
  3. 硼替佐米和地塞米松在制备改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物中的用途。
  4. 如权利要求1-3中任一项所述的用途，其特征在于所述多发性骨髓瘤为复发/难治多发性骨髓瘤。
  5. 如权利要求1-3中任一项所述的用途，其中所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
  6. 如权利要求5所述的用途，其中所述盐酸米托蒽醌脂质体的粒径为30～80nm，其含有：1)活性成分米托蒽醌，其与脂质体内的多价反离子形成难以溶解的沉淀，和2)磷脂双分子层，其含有相转变温度(Tm)高于体温的磷脂，所述磷脂选自磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或双硬脂酸卵磷脂或者其任何组合。
  7. 一种用于治疗多发性骨髓瘤的药物组合产品，所述药物组合产品包含米托蒽醌脂质体、硼替佐米和地塞米松。
  8. 一种用于改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的药物，所述药物含有米托蒽醌脂质体。
  9. 一种用于改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的药物，所述药物含有硼替佐米和地塞米松。
  10. 如权利要求7-9中任一项所述的药物组合产品或药物，其特征在于所述多发性骨髓瘤为复发/难治多发性骨髓瘤。
  11. 如权利要求7-10中任一项所述的药物组合产品或药物，其中所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
  12. 如权利要求11所述的药物组合产品或药物，其中所述盐酸米托蒽醌脂质体的粒径为30～80nm，其含有：1)活性成分米托蒽醌，其与脂质体内的多价反离子形成难以溶解的沉淀，和2)磷脂双分子层，其含有相转变温度(Tm)高于体温的磷脂，所述磷脂选自磷脂酰胆碱、 氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或双硬脂酸卵磷脂或者其任何组合。
  13. 如权利要求7-12中任一项所述的药物组合产品或药物，其中米托蒽醌脂质体静脉给药，以米托蒽醌计，有效治疗剂量为12～30mg/m 2。
  14. 如权利要求7-13中任一项所述的药物组合产品或药物，其中硼替佐米注射给药，剂量为1.3mg/m 2。
  15. 如权利要求7-14中任一项所述的药物组合产品或药物，其中地塞米松口服给药，剂量为20mg/天。
  16. 如权利要求7-15中任一项所述的药物组合产品或药物，其中给药周期为4周或3周，每个给药周期中，米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。
  17. 如权利要求16所述的药物组合产品或药物，其中在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，和在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
  18. 一种治疗多发性骨髓瘤的方法，所述方法包括对多发性骨髓瘤患者施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松。
  19. 一种改善硼替佐米和地塞米松治疗多发性骨髓瘤的疗效的方法，所述方法包括在对多发性骨髓瘤患者施用硼替佐米和地塞米松的基础上，进一步联合施用有效治疗剂量的米托蒽醌脂质体。
  20. 一种改善米托蒽醌脂质体治疗多发性骨髓瘤的疗效的方法，所述方法包括在对多发性骨髓瘤患者施用米托蒽醌脂质体的基础上，进一步联合施用有效治疗剂量的硼替佐米和地塞米松。
  21. 如权利要求18-20中任一项所述的方法，其特征在于所述多发性骨髓瘤为复发/难治多发性骨髓瘤。
  22. 如权利要求18-20中任一项所述的方法，其中所述米托蒽醌脂质体为盐酸米托蒽醌脂质体。
  23. 如权利要求22所述的方法，其中所述盐酸米托蒽醌脂质体的粒径为30～80nm，其含有：1)活性成分米托蒽醌，其与脂质体内的多价反离子形成难以溶解的沉淀，和2)磷脂双分子层，其含有相转变 温度(Tm)高于体温的磷脂，所述磷脂选自磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或双硬脂酸卵磷脂或者其任何组合。
  24. 如权利要求18-20中任一项所述的方法，其中米托蒽醌脂质体静脉给药，以米托蒽醌计，有效治疗剂量为12～30mg/m 2。
  25. 如权利要求18-20中任一项所述的方法，其中硼替佐米注射给药，剂量为1.3mg/m 2。
  26. 如权利要求18-20中任一项所述的方法，其中地塞米松口服给药，剂量为20mg/天。
  27. 如权利要求18-20中任一项所述的方法，其中给药周期为4周或3周，每个给药周期中，米托蒽醌脂质体给药1次，硼替佐米给药4次，地塞米松给药8次。
  28. 如权利要求27所述的方法，其中在每个给药周期第1天对多发性骨髓瘤患者按照任意先后顺序施用有效治疗剂量的米托蒽醌脂质体、硼替佐米和地塞米松，在第4、第8和第11天继续施用硼替佐米，和在第2、第4、第5、第8、第9、第11和第12天继续施用地塞米松。
PCT/CN2022/117434 2021-09-07 2022-09-07 米托蒽醌脂质体、硼替佐米和地塞米松治疗多发性骨髓瘤的用途 WO2023036161A1 (zh)

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