WO2022042653A1 - 盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松的用途 - Google Patents

盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松的用途 Download PDF

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WO2022042653A1
WO2022042653A1 PCT/CN2021/114810 CN2021114810W WO2022042653A1 WO 2022042653 A1 WO2022042653 A1 WO 2022042653A1 CN 2021114810 W CN2021114810 W CN 2021114810W WO 2022042653 A1 WO2022042653 A1 WO 2022042653A1
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Prior art keywords
vincristine
mitoxantrone
prednisone
cyclophosphamide
ptcl
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PCT/CN2021/114810
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English (en)
French (fr)
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李春雷
夏雪芳
李彦辉
安娜
杜艳玲
李彤
王世霞
贾润露
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石药集团中奇制药技术（石家庄）有限公司
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Priority to EP21860487.4A priority Critical patent/EP4205747A4/en
Priority to JP2023513307A priority patent/JP2023539588A/ja
Priority to KR1020237010550A priority patent/KR20230058137A/ko
Priority to AU2021334710A priority patent/AU2021334710B2/en
Priority to CA3190922A priority patent/CA3190922A1/en
Priority to US18/023,161 priority patent/US20240024257A1/en
Priority to CN202180052842.XA priority patent/CN115955971A/zh
Publication of WO2022042653A1 publication Critical patent/WO2022042653A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention belongs to the field of anti-tumor, and particularly relates to the use of mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine and prednisone in preparing a medicament for the treatment of newly treated peripheral T-cell lymphoma (PTCL).
  • PTCL peripheral T-cell lymphoma
  • PTCL is a group of lymphoproliferative tumors originating from post-thymic mature T cells, with marked heterogeneity, and most of them are aggressive. According to the WHO classification standard revised in 2016 (Swerdlow SH, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood.
  • PTCL includes four categories More than 30 subtypes in total, including peripheral T-cell lymphoma unspecified, angioimmunoblastic T-cell lymphoma, extranodal nasal NK/T-cell lymphoma, ALK+ systemic anaplastic large T-cell lymphoma, ALK - Systemic anaplastic large T-cell lymphoma, mycosis fungoides/Sézary syndrome, etc.
  • the complex pathological typing reflects the heterogeneity of this group of diseases.
  • NHL non-Hodgkin's lymphoma
  • Mitoxantrone Hydrochloride is an anthracycline drug that has been used in more than 30 countries around the world. It has therapeutic effects on various solid tumors such as hematological tumors such as acute leukemia, lymphoma, and breast cancer. The main adverse reactions are bone marrow suppression, gastrointestinal reactions and cardiotoxicity. Clinically, it is mainly used for the treatment of acute myeloid leukemia.
  • Liposomes are a new form of drug delivery. Studies have shown that it can change the in vivo distribution of the encapsulated drug, so that the drug is mainly accumulated in 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 drug delivery in the research of antitumor drugs much valued.
  • Some researchers have studied mitoxantrone liposome preparations.
  • WO2008/080367A1 discloses a mitoxantrone liposome, the disclosure of which is incorporated herein by reference in its entirety. Studies have shown that, compared with common preparations of mitoxantrone, liposome preparations have lower toxicity (especially cardiotoxicity), and have the characteristics of passively targeting tumor tissue, improving antitumor activity.
  • the single-agent phase I of mitoxantrone hydrochloride liposome injection has completed dose escalation exploration and PK/PD studies in subjects with advanced solid tumors and lymphoma subjects. According to the test results, this product was safely tolerated in the dose range of 6-30 mg/m 2 and showed a certain curative effect.
  • the objective response rate (ORR) assessed by the committee (IRC) and confirmed by efficacy was 40.7%.
  • this study intends to further explore the combined administration of mitoxantrone hydrochloride liposome injection in patients with newly diagnosed PTCL.
  • Mitoxantrone includes mitoxantrone and pharmaceutically acceptable salts thereof, preferably mitoxantrone hydrochloride.
  • the mitoxantrone liposomes are preferably mitoxantrone hydrochloride liposomes.
  • the present invention provides the use of mitoxantrone liposome and cyclophosphamide, vincristine and prednisone in preparing a medicine for treating PTCL.
  • the PTCL is preferably selected from at least one of the following subtypes: peripheral T-cell lymphoma unspecified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK+ anaplastic large T-cell lymphoma (ALCL), ALK-anaplastic large T-cell lymphoma (ALCL).
  • PTCL-NOS peripheral T-cell lymphoma unspecified
  • AITL angioimmunoblastic T-cell lymphoma
  • ALK+ anaplastic large T-cell lymphoma ALCL
  • ALK-anaplastic large T-cell lymphoma ALK-anaplastic large T-cell lymphoma
  • the present invention provides the use of mitoxantrone liposome in preparing a medicine for improving the curative effect of cyclophosphamide, vincristine and prednisone in treating PTCL.
  • the invention also provides the use of the combination of cyclophosphamide, vincristine and prednisone in preparing a medicine for improving the curative effect of mitoxantrone liposome in treating PTCL.
  • the present invention provides a medicine for treating PTCL, which is characterized by comprising mitoxantrone liposome and cyclophosphamide, vincristine and prednisone.
  • the PTCL is preferably newly treated PTCL.
  • the mitoxantrone liposome is preferably mitoxantrone hydrochloride liposome.
  • mitoxantrone hydrochloride liposome, prednisone, cyclophosphamide and vincristine can be present in the same preparation, or can be prepared separately.
  • the dosage forms may be the same or different.
  • the dosage form can be any clinically accepted dosage form, such as injection dosage form, oral dosage form and the like.
  • the injection dosage forms include liquid injections, powders for injection, tablets for injection, and the like; the oral dosage forms include tablets, capsules, oral liquid preparations, and the like.
  • the active ingredient is 0.5-5 mg/ml, preferably 1-2 mg/ml, more preferably 1 mg/ml; when prednisone is When used as a tablet, the specification is 5mg/tablet; when cyclophosphamide is a powder for injection, the specification is 0.2g/bottle, and it is prepared as a 200mg/10ml solution when used; when vincristine is a powder for injection, the specification is 1mg/bottle, configured as 1mg/20ml solution when used.
  • prednisone is a tablet with a specification of 5mg/tablet, which means: each tablet contains 5mg of prednisone;
  • cyclophosphamide is a powder for injection with a specification of 0.2g/bottle, which means: each bottle of injection
  • the powder for injection contains 0.2g of cyclophosphamide;
  • the powder for injection with vincristine is 1mg/bottle, which means that each bottle of powder for injection contains 1mg of vincristine.
  • the medicines may further include other medicines for the treatment of PTCL, and the medicines refer to medicines approved by the drug administrations of China or other countries and regions (eg, the United States, the European Union, Japan, South Korea, etc.) for the treatment of PTCL.
  • the medicines refer to medicines approved by the drug administrations of China or other countries and regions (eg, the United States, the European Union, Japan, South Korea, etc.) for the treatment of PTCL.
  • the invention provides a method for treating PTCL, which is characterized in that: effective therapeutic doses of mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine and prednisone are used for PTCL patients.
  • the present invention also provides a method for improving the curative effect of cyclophosphamide, vincristine and prednisone treatment scheme on PTCL, which is characterized in that: on the basis of using cyclophosphamide, vincristine and prednisone for PTCL patients above, further combined use of effective therapeutic dose of mitoxantrone hydrochloride liposome.
  • the invention also provides a method for improving the curative effect of mitoxantrone hydrochloride liposome on PTCL, which is characterized in that: on the basis of using mitoxantrone hydrochloride liposome for PTCL patients, further combined use of an effective therapeutic dose of Cyclophosphamide, vincristine, prednisone.
  • the administration of mitoxantrone hydrochloride liposome, cyclophosphamide and vincristine is preferably by injection; prednisone is preferably administered orally.
  • the effective therapeutic dose of the mitoxantrone hydrochloride liposome refers to 8-30 mg/m 2 , more preferably 12-24 mg/m 2 ; for example, 12 mg/m 2 , 14mg/m 2 , 15mg/m 2 , 16mg/m 2 , 18mg/m 2 , 20mg/m 2 , 24mg/m 2 .
  • the dose of cyclophosphamide was 750 mg/m 2
  • the dose of vincristine was 1.4 mg/m 2 (calculated on the basis of body surface area, the maximum dose per case was not more than 2 mg)
  • the dose of prednisone was 100 mg/d.
  • the dosing cycle is once every 4 weeks or 3 weeks. In each dosing cycle, mitoxantrone hydrochloride liposome, cyclophosphamide and vincristine were administered once, and prednisone was administered 5 times continuously.
  • mitoxantrone hydrochloride liposome prednisone, vincristine and cyclophosphamide are administered to PTCL patients in any order on the first day of each dosing cycle, and continue on days 2-5 Prednisone was administered.
  • prednisone is administered before the administration of mitoxantrone hydrochloride liposomes
  • vincristine is administered after the administration of mitoxantrone hydrochloride liposomes
  • cyclophosphamide is administered .
  • the present invention further provides a composition for treating PTCL, comprising mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine, and prednisone, characterized in that, on the first day of each administration cycle, PTCL patients are treated according to the Effective therapeutic doses of mitoxantrone hydrochloride liposomes, prednisone, vincristine, and cyclophosphamide were administered in any sequential order, with continued prednisone administration on days 2-5.
  • prednisone is administered before the administration of mitoxantrone hydrochloride liposomes
  • vincristine is administered after the administration of mitoxantrone hydrochloride liposomes
  • cyclophosphamide is administered .
  • the dosing cycle is once every 4 weeks or 3 weeks.
  • the dosage of the mitoxantrone hydrochloride liposome is 8-30 mg/m 2 , more preferably 12-24 mg/m 2 .
  • the dose of cyclophosphamide is 750 mg/m 2
  • the dose of vincristine is 1.4 mg/m 2 (calculated based on body surface area, the maximum dose per case is not more than 2 mg)
  • the dose of prednisone is 100 mg/d.
  • the "administration in any order” here refers to the separate preparations of mitoxantrone hydrochloride liposome and cyclophosphamide, vincristine, and prednisone, which are administered separately in a clinically acceptable manner. There is no mandatory sequence; the drugs do not mix in vitro.
  • the present invention further provides a medicine for improving the curative effect of cyclophosphamide, vincristine and prednisone in the treatment of PTCL, characterized in that it contains mitoxantrone hydrochloride liposome, and the mitoxantrone hydrochloride lipid
  • the body was administered at any time after prednisone administration and before vincristine and cyclophosphamide administration.
  • effective therapeutic doses of mitoxantrone hydrochloride liposome, prednisone, vincristine and cyclophosphamide are administered to PTCL patients in any order on the first day of each dosing cycle, and continue on days 2-5 Prednisone was administered.
  • prednisone is administered before the administration of mitoxantrone hydrochloride liposomes
  • vincristine is administered after the administration of mitoxantrone hydrochloride liposomes
  • cyclophosphamide is administered .
  • the dosage of the mitoxantrone hydrochloride liposome is 8-30 mg/m 2 , more preferably 12-24 mg/m 2 , administered once every 4 weeks or 3 weeks.
  • the dose of cyclophosphamide is 750 mg/m 2
  • the dose of vincristine is 1.4 mg/m 2 (calculated based on body surface area, the maximum dose per case is not more than 2 mg)
  • the dose of prednisone is 100 mg/d.
  • the present invention further provides a medicine for improving the curative effect of mitoxantrone hydrochloride liposome in the treatment of PTCL, characterized in that it contains cyclophosphamide, vincristine and prednisone, and the mitoxantrone hydrochloride liposome is in Administer at any time after prednisone and before vincristine and cyclophosphamide.
  • effective therapeutic doses of mitoxantrone hydrochloride liposome, prednisone, vincristine and cyclophosphamide are administered to PTCL patients in any order on the first day of each dosing cycle, and continue on days 2-5 Prednisone was administered.
  • prednisone is administered before the administration of mitoxantrone hydrochloride liposomes
  • vincristine is administered after the administration of mitoxantrone hydrochloride liposomes
  • cyclophosphamide is administered .
  • the dosage of the mitoxantrone hydrochloride liposome is 8-30 mg/m 2 , more preferably 12-24 mg/m 2 , administered once every 4 weeks or 3 weeks.
  • the dose of cyclophosphamide is 750 mg/m 2
  • the dose of vincristine is 1.4 mg/m 2 (calculated based on body surface area, the maximum dose per case is not more than 2 mg)
  • the dose of prednisone is 100 mg/d.
  • the infusion administration time of the liposome pharmaceutical preparation is 30min-120min, preferably 60min-120min, more preferably 90 ⁇ 15min.
  • the doses of the mitoxantrone hydrochloride liposomes of the present invention are all based on mitoxantrone.
  • the mitoxantrone hydrochloride liposomes of the present invention can be prepared by conventional methods in the art, and can be mitoxantrone hydrochloride liposomes prepared by any method disclosed in the prior art, such as the method disclosed in WO2008/080367A1 prepared, the disclosure of this patent is hereby incorporated by reference in its entirety.
  • the mitoxantrone liposome of the present invention has a particle size of about 30-80 nm, and contains: 1) the active ingredient mitoxantrone or a pharmaceutically acceptable salt thereof, which can interact with the liposome
  • the polyvalent counter ions in the plastids form insoluble precipitates, 2) phospholipid bilayers, which contain phospholipids with a phase transition temperature (Tm) higher than body temperature, so that the phase transition temperature of liposomes is higher than body temperature.
  • Tm phase transition temperature
  • the phospholipid whose Tm is higher than body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, bis-palmitate or bis-stearate lecithin or any combination thereof, preferably, the mitoxanthen
  • the particle size of the quinone liposome is about 35-75 nm, preferably 40-70 nm, more preferably 40-60 nm, particularly preferably 60 nm.
  • the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of 3:1:1, and the liposome has a mass ratio of 3:1:1.
  • the particle size is about 60 nm and the counter ion is sulfate ion.
  • the preparation method of the mitoxantrone hydrochloride liposome of the present invention is as follows: HSPC (hydrogenated soybean lecithin), Chol (cholesterol) and DSPE-PEG2000 (polyethylene glycol 2000 modified dihard Fatty acylphosphatidylethanolamine) was weighed according to the mass ratio of (3:1:1), and dissolved in 95% ethanol to obtain a clear solution (ie, an ethanol solution of phospholipids). The ethanolic solution of phospholipids was mixed with 300 mM ammonium sulfate solution and shaken at 60-65 °C for 1 h to obtain heterogeneous multilamellar liposomes.
  • HSPC hydrogenated soybean lecithin
  • Chol cholesterol
  • DSPE-PEG2000 polyethylene glycol 2000 modified dihard Fatty acylphosphatidylethanolamine
  • the particle size of the liposomes is then reduced using a microfluidic device.
  • the obtained sample was diluted 200 times with 0.9% NaCl solution and detected by NanoZS.
  • the average particle size of the particles was about 60 nm, and the main peak was concentrated between 40 and 60 nm.
  • the ammonium sulfate in the outer phase of the blank liposome was then 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 blank liposomes, 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 product obtained with this prescription is named PLM 60.
  • the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in PLM60 was 9.58:3.19:3.19:1, and the osmotic pressure of sucrose-glycine solution was close to the physiological value.
  • mitoxantrone hydrochloride liposome of the present invention in combination with cyclophosphamide, vincristine and prednisone is safe and tolerated by patients, has less toxic and side effects, and can obtain a higher overall ORR rate in newly treated PTCL patients. It is expected that the efficacy will further improve with the increase of the dosing cycle, thereby improving the progression-free survival (PFS) and 5-year overall survival (OS) of the patients.
  • PFS progression-free survival
  • OS 5-year overall survival
  • Example 1 Clinical study of mitoxantrone hydrochloride liposome injection combined with cyclophosphamide, vincristine and prednisone in the treatment of newly diagnosed PTCL
  • This study is a single-arm, open-label, multi-center Phase Ib clinical study.
  • the subjects with newly diagnosed PTCL were enrolled and given different doses of mitoxantrone hydrochloride liposome injection and fixed doses of cyclophosphamide, vincristine Alkali and prednisone, aiming to explore the safety and tolerance of the above treatment regimens, determine the optimal dosage of mitoxantrone hydrochloride liposome injection in the combination regimen, evaluate the efficacy, and observe the pharmacokinetics feature.
  • the study was divided into a dose-escalation phase and a dose-expansion phase.
  • the study included a screening period, a treatment period, and a follow-up period.
  • Vincristine the dose is 1.4mg/m 2 (calculated based on body surface area, the maximum dose per case does not exceed 2mg), D1, intravenous injection, administered after mitoxantrone hydrochloride liposome administration.
  • Prednisone the dose is 100mg/d, D1-D5, orally, D1 is administered before the administration of mitoxantrone hydrochloride liposome; D2-D5 are only administered with prednisone, which is consistent with the clinical use of prednisone alone Dosing is required.
  • the original treatment regimen will be stopped, and the investigator will give corresponding treatment in accordance with clinical diagnosis and treatment standards, and monitor until the toxicity returns to ⁇ grade 1 or baseline level. If the investigator judges that the benefits of continuing the original regimen outweigh the risks, the subject can continue to enter the treatment period (with the same dose as the original dose) with the consent of the sponsor; if the investigator judges that the subject is not suitable to continue the original regimen treatment, and withdrawn from the study.
  • Non-hematologic toxicities regardless of whether medication is administered for drug toxicity, must return to ⁇ grade 1 or baseline levels.
  • the phase II recommended dose of mitoxantrone hydrochloride liposome in the combination regimen of mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine and prednisone was determined (RP2D) After that, the dose expansion phase can be entered.
  • the dose of mitoxantrone hydrochloride liposome injection was expanded by RP2D, and the doses of cyclophosphamide, vincristine and prednisone were in the same increasing stage.
  • the treatment was divided into two groups, the Q4W (28 days) group and the Q3W (21 days) group, with 10 to 20 cases in each group.
  • Eligible subjects were screened according to the research procedures and entered into the Q4W group or the Q3W group in a cross-group manner.
  • the Q4W group is a cycle of every 28 days
  • the Q3W group is a cycle of every 21 days. It is planned to dosing for 6 cycles until the completion of the 6-cycle treatment, disease progression, death, intolerable toxicity, and the investigator thinks that other treatments are needed Means (including changing chemotherapy regimens, ASCT, radiotherapy, etc.), subjects voluntarily withdraw from treatment (whichever occurs first).
  • PK blood collection and related examinations were carried out according to the requirements of the protocol to observe the safety and efficacy.
  • the follow-up period was entered.
  • End of study was defined as the last subject to complete his/her last visit.
  • Newly treated PTCL confirmed by histopathology, one of the following subtypes:
  • AITL angioimmunoblastic T-cell lymphoma
  • ALK Anaplastic large T-cell lymphoma
  • Fluorodeoxyglucose (FDG) affinity PTCL that can be evaluated by PET/CT;
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Consent to use an approved very effective contraceptive method throughout the study period and for at least 12 months after the last dose [defined as: able to be used consistently and correctly with a failure rate of less than 1% per year, for example: combined Hormones (including estrogen and progesterone) combined with ovulation suppression, progestin contraception combined with ovulation suppression, intrauterine device (IUD), intrauterine hormone releasing system (IUS), bilateral tubal ligation, vasectomy].
  • Histopathology is one of the following subtypes:
  • NKTCL Extranodal nasal NK/T cell lymphoma
  • Leukemia-type PTCL such as adult T-cell leukemia/lymphoma
  • Lymphoma leukemia stage the proportion of lymphoma cells in bone marrow examination is ⁇ 20%), or patients with central nervous system (CNS) involvement, or complicated with hemophagocytic syndrome.
  • glucocorticoids Received anti-lymphoma treatment, except for short-course or low-dose glucocorticoids (short-course glucocorticoids are defined as prednisone or converted to prednisone ⁇ 100mg/d less than 7d; low-dose glucocorticoids are defined as prednisone Or converted into prednisone ⁇ 30mg/d).
  • Impaired cardiac function or significant cardiac disease including but not limited to:
  • Cardiac function class II to IV New York Heart Association class of cardiac function NYHA
  • the cardiac ejection fraction (EF) detected by echocardiography is lower than 50% or the lower limit of the research center;
  • HCV hepatitis C
  • HAV human immunodeficiency virus
  • PLM 60 The dosage of mitoxantrone hydrochloride liposome (PLM 60) is shown in Table 1 below;
  • the dose of vincristine (the specification of powder for injection is 1 mg/bottle) is 1.4 mg/m 2 , intravenously injected on the first day of each cycle, and administered after the administration of mitoxantrone hydrochloride liposome;
  • cyclophosphamide (the specification of injection powder is 0.2g/bottle) is 750mg/m 2 , intravenously on the first day of each cycle, and given after the administration of mitoxantrone hydrochloride liposome and vincristine. Medicine;
  • prednisone tablette size is 5mg/tablet
  • dose of prednisone is 100mg/d, orally from the first day to the fifth day of each cycle, before the administration of mitoxantrone hydrochloride liposome on the first day of each cycle ;
  • Prednisone only is administered on days 2 to 5 of each cycle.
  • the mitoxantrone hydrochloride liposome of the present invention combined with cyclophosphamide, vincristine and prednisone at the above dose was safe and tolerated, with less toxic and side effects, and could obtain a higher level of efficacy in newly treated PTCL patients.

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Abstract

盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松在制备用于治疗外周T细胞淋巴瘤（PTCL）的药物中的用途。所述PTCL优选初治的PTCL。还可在上述基础上进一步使用其他治疗PTCL的一线、二线药物。一种治疗PTCL的方法，所述方法为给予患者治疗有效量的盐酸米托蒽醌脂质体和环磷酰胺、长春新碱及强的松。该药物的联合施用安全耐受，毒副作用小，并且能够在初治PTCL患者中获得较高的总客观缓解率（ORR）。

Description

盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松的用途 技术领域
本发明属于抗肿瘤领域，具体涉及盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松在制备用于治疗初治外周T细胞淋巴瘤(PTCL)的药物中的用途。
背景技术
PTCL是一组起源于胸腺后成熟T细胞的淋巴增殖性肿瘤，具有明显的异质性，大多侵袭性强。根据2016年修订的WHO分类标准(Swerdlow SH,et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Blood.2016 May 19；127(20):2375-2390.)，PTCL包括四大类总共30多个亚型，包括外周T细胞淋巴瘤非特指型、血管免疫母细胞性T细胞淋巴瘤、结外鼻型NK/T细胞淋巴瘤、ALK+系统性间变性大T细胞淋巴瘤、ALK-系统性间变性大T细胞淋巴瘤、蕈样霉菌病/Sézary综合征等，复杂的病理分型反映了这一组疾病的异质性。PTCL的发病和病理亚型分布存在地区差异。亚洲的发病率略高于欧美。在我国，PTCL约占非霍奇金淋巴瘤(NHL)的25％-35％，显著高于欧美国家(10％-15％)。
值得关注的是，PTCL的治疗不容乐观，一线应用CHOP(环磷酰胺、阿霉素、长春新碱、强的松)或CHOP类方案的总体反应率不高，且易复发，预后差。除了ALK+系统性间变性大T细胞淋巴瘤(ALCL)，其他亚型的PTCL五年生存率仅为14-32％(Vose J,et al.International peripheral T-cell and natural killer/T-cell lymphoma study:pathology findings and clinical outcomes.J Clin Oncol.2008 Sep 1；26(25):4124-4130.)。
国内外已经陆续有研究探索不含蒽环的方案治疗PTCL的一线疗效，然而尚未证实优于以蒽环类药物为主的CHOP类方案，故含蒽环方案的一线地位目前尚未能撼动。可见，对于PTCL来说，仍需进一步探索安全高效的一线治疗方案。
米托蒽醌(Mitoxantrone Hydrochloride)是一种蒽环类药物，至今已在全球30多个国家使用。其对于血液系统肿瘤如急性白血病、淋巴瘤以及乳腺 癌等多种实体肿瘤都具有治疗作用。其不良反应主要表现为骨髓抑制、胃肠道反应和心脏毒性。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，从而提高了药物的治疗指数、减少了药物的治疗剂量和降低了药物毒性。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WO2008/080367A1公开了一种米托蒽醌脂质体，其公开的内容在这里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，本品在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注射液单药的关键性Ⅱ期在复发/难治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客观缓解率(ORR)为40.7％。鉴于本品在复发/难治PTCL患者中较好的单药疗效，本研究拟在初治PTCL患者中进一步开展盐酸米托蒽醌脂质体注射液联合给药的探索。
发明内容
如无其它特殊说明，本发明中“初治”使用以下定义：
“初治”定义为新诊断，未经抗淋巴瘤治疗。
“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。
本发明提供米托蒽醌脂质体和环磷酰胺、长春新碱、强的松在制备治疗PTCL的药物中的用途。
所述PTCL优选选自以下亚型中的至少一种：外周T细胞淋巴瘤非特指型(PTCL-NOS)、血管免疫母细胞性T细胞淋巴瘤(AITL)、ALK+间变性大T细胞淋巴瘤(ALCL)、ALK-间变性大T细胞淋巴瘤(ALCL)。
同时，本发明提供米托蒽醌脂质体在制备改善环磷酰胺、长春新碱及强的松治疗PTCL的疗效的药物中的用途。
本发明还提供环磷酰胺、长春新碱及强的松的联用在制备改善米托蒽醌脂质体治疗PTCL的疗效的药物中的用途。
进一步的，本发明提供一种治疗PTCL的药物，其特征在于，包含米托蒽醌脂质体和环磷酰胺、长春新碱、强的松。
其中，所述PTCL优选为初治PTCL。所述米托蒽醌脂质体优选盐酸米托蒽醌脂质体。
优选的，盐酸米托蒽醌脂质体、强的松、环磷酰胺和长春新碱可以存在于同一制剂中，也可分别独立制剂。当上述4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。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；当强的松为片剂时，规格为5mg/片；当环磷酰胺为注射用粉针时，规格为0.2g/瓶，使用时配置成200mg/10ml溶液；当长春新碱为注射用粉针时，规格为1mg/瓶，使用时配置成1mg/20ml溶液。
其中，强的松为规格为5mg/片的片剂指的是：每片中含有5mg的强的松；环磷酰胺为规格为0.2g/瓶的注射用粉针指的是：每瓶注射用粉针含有0.2g的环磷酰胺；长春新碱为规格1mg/瓶的注射用粉针指的是：每瓶注射用粉针含有1mg的长春新碱。
所述药物中可进一步包含其他治疗PTCL的药物，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PTCL治疗的药物。
本发明提供了一种治疗PTCL的方法，其特征在于：对PTCL患者使用有效治疗剂量的盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松。
本发明还提供了一种改善环磷酰胺、长春新碱及强的松治疗方案对PTCL的疗效的方法，其特征在于：在对PTCL患者使用环磷酰胺、长春新碱、强的松的基础上，进一步联合使用有效治疗剂量的盐酸米托蒽醌脂质体。
本发明还提供一种改善盐酸米托蒽醌脂质体对PTCL的疗效的方法，其 特征在于：在对PTCL患者使用盐酸米托蒽醌脂质体的基础上，进一步联合使用有效治疗剂量的环磷酰胺、长春新碱、强的松。
上述方法中，盐酸米托蒽醌脂质体、环磷酰胺和长春新碱的施用优选注射给药；强的松优选口服给药。优选的，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8-30mg/m 2，更优选为12-24mg/m 2；具体例如，12mg/m 2，14mg/m 2，15mg/m 2，16mg/m 2，18mg/m 2，20mg/m 2，24mg/m 2。环磷酰胺剂量为750mg/m 2，长春新碱剂量为1.4mg/m 2(按体表面积计算，每个病例最大给药量不超过2mg)，强的松剂量为100mg/d。优选的，给药周期为每4周或3周给药一次。每个给药周期中，盐酸米托蒽醌脂质体、环磷酰胺和长春新碱给药一次，强的松连续给药5次。优选的，每个给药周期第1天对PTCL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、强的松、长春新碱和环磷酰胺，第2-5天继续施用强的松。优选的，每个给药周期第1天，在盐酸米托蒽醌脂质体给药前施用强的松，盐酸米托蒽醌脂质体给药后施用长春新碱，再施用环磷酰胺。
本发明进一步提供一种治疗PTCL的组合物，包含盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松，其特征在于，每个给药周期第1天对PTCL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、强的松、长春新碱和环磷酰胺，第2-5天继续施用强的松。优选的，每个给药周期第1天，在盐酸米托蒽醌脂质体给药前施用强的松，盐酸米托蒽醌脂质体给药后施用长春新碱，再施用环磷酰胺。优选的，给药周期为每4周或3周给药一次。优选的，以米托蒽醌计，所述盐酸米托蒽醌脂质体的剂量为8-30mg/m 2，更优选为12-24mg/m 2。优选的，环磷酰胺剂量为750mg/m 2，长春新碱剂量为1.4mg/m 2(按体表面积计算，每个病例最大给药量不超过2mg)，强的松剂量为100mg/d。
这里的“按照任意先后顺序施用”，是指盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松分别制剂，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。
本发明进一步提供一种改善环磷酰胺、长春新碱及强的松治疗方案治疗PTCL的疗效的药物，其特征在于，含有盐酸米托蒽醌脂质体，所述盐酸米托蒽醌脂质体在强的松给药后、长春新碱和环磷酰胺给药前的任意时间施用。 优选的，每个给药周期第1天对PTCL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、强的松、长春新碱和环磷酰胺，第2-5天继续施用强的松。优选的，每个给药周期第1天，在盐酸米托蒽醌脂质体给药前施用强的松，盐酸米托蒽醌脂质体给药后施用长春新碱，再施用环磷酰胺。优选的，以米托蒽醌计，所述盐酸米托蒽醌脂质体的剂量为8-30mg/m 2，更优选为12-24mg/m 2，每4周或3周给药一次。优选的，环磷酰胺剂量为750mg/m 2，长春新碱剂量为1.4mg/m 2(按体表面积计算，每个病例最大给药量不超过2mg)，强的松剂量为100mg/d。
本发明进一步提供一种改善盐酸米托蒽醌脂质体治疗PTCL的疗效的药物，其特征在于，含有环磷酰胺、长春新碱及强的松，所述盐酸米托蒽醌脂质体在强的松给药后、长春新碱和环磷酰胺给药前的任意时间施用。优选的，每个给药周期第1天对PTCL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、强的松、长春新碱和环磷酰胺，第2-5天继续施用强的松。优选的，每个给药周期第1天，在盐酸米托蒽醌脂质体给药前施用强的松，盐酸米托蒽醌脂质体给药后施用长春新碱，再施用环磷酰胺。优选的，以米托蒽醌计，所述盐酸米托蒽醌脂质体的剂量为8-30mg/m 2，更优选为12-24mg/m 2，每4周或3周给药一次。优选的，环磷酰胺剂量为750mg/m 2，长春新碱剂量为1.4mg/m 2(按体表面积计算，每个病例最大给药量不超过2mg)，强的松剂量为100mg/d。
优选的，每次静脉给药，所述脂质体药物制剂的滴注给药时间为30min-120min，优选60min-120min，进一步优选90±15min。
本发明所述盐酸米托蒽醌脂质体的剂量均以米托蒽醌计。
本发明所述的盐酸米托蒽醌脂质体可以采用本领域常规方法制备，可以是现有技术公开任意一种方法制备的盐酸米托蒽醌脂质体，例如采用WO2008/080367A1公开的方法制备，该专利公开的内容在这里被全文引入作为参考。
在一些实施例中，本发明所述米托蒽醌脂质体，其粒径为约30-80nm，含有：1)活性成分米托蒽醌或其药学上可接受的盐，它可以和脂质体内的多价反离子形成难以溶解的沉淀，2)磷脂双分子层，其含有相转变温度(Tm)高于体温的磷脂，从而脂质体的相转变温度高于体温。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，优选地，所述米托蒽醌脂质体的粒径为约35-75nm，优选40-70nm，进一步优选40-60nm，特别优选60nm。在一些实施例中，所述磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，质量比为3:1:1，所述脂质体的粒径为约60nm，所述反离子为硫酸根离子。
在一些实施例中，本发明所述盐酸米托蒽醌脂质体的制备方法如下：将HSPC(氢化大豆卵磷脂)、Chol(胆固醇)和DSPE-PEG2000(聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺)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％。此处方得到的产品被命名为PLM 60。PLM60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。
有益效果
使用本发明的盐酸米托蒽醌脂质体联合环磷酰胺、长春新碱及强的松对于患者安全耐受，毒副作用小，并且能够在初治PTCL患者中获得较高的总ORR率。预期随着给药周期的增加，疗效会进一步提高，从而改善患者的无进展生存期(PFS)和5年总生存率(OS)。
具体实施方式
以下实施例是对本发明的具体说明，不应对本发明的范围构成限制。
实施例1 盐酸米托蒽醌脂质体注射液联合环磷酰胺、长春新碱及强的松治疗初治PTCL的临床研究
本研究是一项单臂、开放、多中心的Ib期临床研究，纳入初治PTCL受试者，给予不同剂量的盐酸米托蒽醌脂质体注射液和固定剂量的环磷酰胺、长春新碱、强的松，旨在探索上述治疗方案的安全耐受性，确定该联合用药方案中盐酸米托蒽醌脂质体注射液的最佳给药剂量，同时评估疗效，观察药代动力学特征。研究分为剂量递增阶段与剂量扩展阶段。
一、试验设计
1.剂量递增阶段
(1)总体设计
研究包含筛选期、治疗期和随访期。
受试者签署知情同意书并在筛选期内完善所有基线评估，筛选合格的受试者将进入治疗期，盐酸米托蒽醌脂质体注射液的给药剂量将从低剂量组逐渐递增到高剂量组，每4W(28天)为一个周期，第一个给药周期观察DLT。所有受试者依据方案在给药前后的不同时间点采集PK血样，并在治疗过程中完善方案规定的相关检查，以观察安全性、耐受性和疗效。同一受试者在研究期间只能接受一种剂量的治疗和给药安排。治疗期结束之后进入随访期。
(2)剂量递增和给药方案
盐酸米托蒽醌脂质体(PLM 60)剂量递增阶段以12mg/m 2作为初始剂量(以米托蒽醌计)，预设12mg/m 2、15mg/m 2、18mg/m 2三个剂量组。每周期第一天(D1)静脉滴注。
长春新碱，剂量为1.4mg/m 2(按体表面积计算，每个病例最大给药量不超过2mg)，D1，静脉注射，在盐酸米托蒽醌脂质体给药后给药。
环磷酰胺，剂量为750mg/m 2，D1，静脉滴注，在盐酸米托蒽醌脂质体、长春新碱给药后给药。
强的松，剂量为100mg/d，D1-D5，口服，D1在盐酸米托蒽醌脂质体给药前给药；D2-D5只施用强的松，符合强的松单独使用时的临床给药要求即可。
受试者一旦出现DLT，将停止原治疗方案，由研究者按照临床诊疗规范给与相应处理，并监测至毒性恢复至≤1级或基线水平。如果研究者判断该受试者继续原方案治疗的获益大于风险，经申办方同意后，可以继续进入治疗期(给药剂量同原剂量)；如果研究者判断受试者不适合继续原方案治疗， 则退出研究。
(3)继续用药的规定
1)需满足中性粒细胞计数≥1.5×10 9/L，血红蛋白≥80g/L，血小板计数≥75×10 9/L。
2)非血液学毒性(脱发除外)，无论是否针对药物毒性进行用药治疗，必须恢复到≤1级或基线水平。
3)若以上条件无法满足，原则上不减量，可延迟给药，但不超过14天。
4)若毒性未恢复至满足1、2要求的给药条件，和/或延迟给药超过14天，若研究者判断患者仍可获益，与申办方沟通后可继续用药。
2.剂量扩展阶段
根据剂量递增阶段的研究结果，确定盐酸米托蒽醌脂质体在盐酸米托蒽醌脂质体、环磷酰胺、长春新碱及强的松联用方案中的Ⅱ期推荐剂量(RP2D)后，可进入剂量扩展阶段。
研究包含筛选期、治疗期和随访期。盐酸米托蒽醌脂质体注射液以RP2D剂量进行扩展，环磷酰胺、长春新碱、强的松剂量同递增阶段。治疗分为两组，Q4W(28天)组和Q3W(21天)组，每组扩展10～20例。
按照研究程序筛选合格的受试者，以交叉入组的方式分别进入Q4W组或Q3W组。治疗期间Q4W组每28天为一个周期，Q3W方案组每21天为一个周期，计划给药6周期，直至完成6周期治疗、疾病进展、死亡、不可耐受的毒性、研究者认为需要其他治疗手段(包括更换化疗方案、ASCT、放疗等)、受试者自愿退出治疗(以先发生者为准)。治疗期间按照方案要求进行PK采血和相关检查，观察安全性和疗效。治疗期结束进入随访期。
3.研究结束时间
研究结束的定义是最后一例受试者完成他/她的最后一次访视。
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.患者充分了解本研究，自愿参加并签署知情同意书(ICF)；
2.年龄18～70岁(含上下限)；
3.初治的经组织病理学确诊的PTCL，为以下亚型之一：
(1)外周T细胞淋巴瘤非特指型(PTCL-NOS)
(2)血管免疫母细胞性T细胞淋巴瘤(AITL)
(3)间变性大T细胞淋巴瘤(ALCL)，ALK+
(4)间变性大T细胞淋巴瘤(ALCL)，ALK-
(5)研究者认为可以入组并且经过申办方同意的其他亚型PTCL
4.可以应用PET/CT进行评价的氟脱氧葡萄糖(FDG)亲和PTCL；
5.ECOG评分0～1分；
6.实验室检查符合以下标准：
(1)中性粒细胞绝对值(ANC)≥1.5×10 9/L；
(2)血小板(PLT)≥75×10 9/L；
(3)血红蛋白(HB)≥80g/L；
(4)血清总胆红素(TBIL)≤1.5倍正常值上限(ULN)；
(5)丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤2.5倍ULN；
(6)血肌酐(Scr)≤1.5倍ULN；
7.女性患者必须满足以下条件之一：
(1)已绝经者，停经至少1年以上；
(2)育龄期需满足下列条件：
a)入组本试验前血妊娠检查结果阴性；
b)整个研究期间及末次给药结束后至少12个月，同意采取一种被认可的非常有效的避孕措施【定义为：能够坚持且正确地使用，每年失败率低于1％，例如：联合激素(含雌激素和孕激素)结合抑制排卵的、孕激素避孕结合抑制排卵的、宫内节育器(IUD)、宫内激素释放系统(IUS)、双侧输卵管结扎术、输精管切除术】。
8.男性患者或其伴侣在研究期间同意采取第7条中所述的非常有效的避孕措施之一，整个治疗期间及末次给药结束后至少12个月内有效避孕。
(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.组织病理学为以下亚型之一：
(1)结外鼻型NK/T细胞淋巴瘤(NKTCL)
(2)蕈样霉菌病(MF)/Sézary综合征(SS)、原发皮肤间变性大细胞淋巴瘤等原发皮肤T细胞淋巴瘤
(3)成人T细胞白血病/淋巴瘤等白血病型PTCL
2.淋巴瘤白血病期(骨髓检查淋巴瘤细胞比例≥20％)、或中枢神经系统(CNS)受累、或并发噬血细胞综合征患者。
3.预计生存期<6个月。
4.对蒽环类药物或脂质体类药物有过敏史。
5.存在环磷酰胺、长春新碱、强的松使用禁忌。
6.接受过抗淋巴瘤治疗，短程或小剂量糖皮质激素除外(短程糖皮质激素定义为强的松或换算成强的松≤100mg/d小于7d；小剂量糖皮质激素定义为强的松或换算成强的松≤30mg/d)。
7.心脏功能受损或具有显著的心脏疾病，包括但不限于：
(1)在筛选前6个月内发生过心肌梗死、充血性心力衰竭、病毒性心肌炎；有症状需要治疗干预的心脏病，如不稳定心绞痛、心律失常等；
(2)心功能Ⅱ～Ⅳ级(纽约心脏病学会心功能分级NYHA)；
(3)超声心动图检测心脏射血分数(EF)低于50％或研究中心下限；
(4)持续存在的心肌病史；
(5)QTc>450毫秒，或患有先天性QT间期延长综合症。
8.乙型表面抗原阳性且HBV-DNA滴度高于研究中心上限，或丙型肝炎(HCV)抗体阳性，或人免疫缺陷病毒(HIV)抗体初筛阳性。
9.筛选前4～6周内进行过外科大手术或预计在研究期间进行大手术。
10.筛选前4周内出现过严重的感染，经研究者判定不适合化疗。
11.筛选时存在控制不佳的高血压。
12.筛选时存在控制不佳的糖尿病。
13.筛选前3个月内有活动性内脏出血病史。
14.五年内有恶性肿瘤病史，可能影响试验方案的实施或结果分析(已治愈的皮肤基底细胞癌、宫颈原位癌、乳腺原位癌、原位胃肠道粘膜内癌、局限性前列腺癌除外)。
15.实体器官移植术后。
16.精神疾病病史或认知障碍病史。
17.有药物(非医疗目的使用麻醉药品或精神药品)滥用史和药物(镇静催眠药、镇痛药、麻醉药、兴奋药及拟精神病性药物等)依赖史者。
18.妊娠或哺乳期妇女。
19.研究者认为不适合参加本研究。
三、研究结果
本研究目前在剂量递增阶段，已完成预设12mg/m 2、15mg/m 2、18mg/m 2三个剂量组的爬坡，未出现导致停止剂量递增的情况，经研究者和申办方沟通讨论后，增加21mg/m 2剂量组(已入组3例)。
按照2014年版Lugano标准，利用PET-CT进行疗效评价
本研究总共入组了22例初治PTCL受试者，其中有18例受试者在治疗中，4例退出研究(3例疾病进展退出、1例疗效不佳退出)。其中，将进行了一次疗效评价(84天)的受试者13例入组进行以下考察：
盐酸米托蒽醌脂质体(PLM 60)的剂量如下表1所示；
长春新碱(注射用粉针的规格为1mg/瓶)的剂量为1.4mg/m 2，每周期第一天静脉注射，在盐酸米托蒽醌脂质体给药后给药；
环磷酰胺(注射用粉针的规格为0.2g/瓶)的剂量为750mg/m 2，每周期第一天静脉滴注，在盐酸米托蒽醌脂质体、长春新碱给药后给药；
强的松(片剂的规格为5mg/片)的剂量为100mg/d，每周期第一天至第五天口服，每周期第一天在盐酸米托蒽醌脂质体给药前给药；每周期第二天至第五天只施用强的松。
评价结果如下表1所示：
表1
Figure PCTCN2021114810-appb-000001
结果：使用上述剂量下的本发明的盐酸米托蒽醌脂质体联合环磷酰胺、长春新碱及强的松，安全耐受，毒副作用小，能够在初治PTCL患者中获得较高的总ORR率，并且随着米托蒽醌脂质体剂量的提高，疗效呈增加趋势。目前大部分患者仅进行了1次疗效评价，预期随着给药周期的增加，疗效会进一步提高，其中，盐酸米托蒽醌脂质体较高剂量组，疗效将优于临床标准治疗(CHOP样方案)。

Claims (13)

  1. 米托蒽醌脂质体和环磷酰胺、长春新碱、强的松在制备治疗PTCL的药物中的用途。
  2. 米托蒽醌脂质体在制备改善环磷酰胺、长春新碱及强的松治疗方案治疗PTCL的疗效的药物中的用途。
  3. 如权利要求1或2所述的用途，其特征在于，所述PTCL为初治PTCL，所述米托蒽醌脂质体优选盐酸米托蒽醌脂质体。
  4. 如权利要求3所述的用途，其特征在于，所述盐酸米托蒽醌脂质体、强的松、环磷酰胺和长春新碱可以存在于同一制剂中，也可分别独立制剂；当上述4种药物分别制剂时，剂型可以相同，也可以不同；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；当强的松为片剂时，规格为5mg/片；当环磷酰胺为注射用粉针时，规格为0.2g/瓶；当长春新碱为注射用粉针时，规格为1mg/瓶。
  5. 如权利要求1-4任一所述的用途，其特征在于，所述药物中进一步包含其他治疗PTCL的药物。
  6. 一种治疗PTCL的药物，其特征在于，包含米托蒽醌脂质体和环磷酰胺、长春新碱、强的松；所述米托蒽醌脂质体优选盐酸米托蒽醌脂质体；所述盐酸米托蒽醌脂质体、强的松、环磷酰胺和长春新碱可以存在于同一制剂中，也可分别独立制剂；当上述4种药物分别制剂时，剂型可以相同，也可以不同；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；当强的松为片剂时，规格为5mg/片；当环磷酰胺为注射用粉针时，规格为0.2g/瓶；当长春新碱为注射用粉针时，规格为1mg/瓶。
  7. 一种治疗PTCL的方法，其特征在于：对PTCL患者使用有效治疗剂量的盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松；盐酸米托蒽醌脂质体、环磷酰胺和长春新碱的施用优选注射给药；强的松优选口服给药；优选的，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8-30mg/m 2，更优选为12-24mg/m 2；环磷酰胺剂量为750mg/m 2，长春新碱剂量为1.4mg/m 2，强的松剂量为100mg/d。
  8. 一种改善环磷酰胺、长春新碱及强的松治疗方案对PTCL的疗效的方 法，其特征在于：在对PTCL患者使用环磷酰胺、长春新碱、强的松的基础上，进一步联合使用有效治疗剂量的盐酸米托蒽醌脂质体。
  9. 一种治疗PTCL的组合物，包含盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松，其特征在于，每个给药周期第一天对PTCL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、强的松、长春新碱和环磷酰胺；优选盐酸米托蒽醌脂质体给药前施用强的松，盐酸米托蒽醌脂质体给药后施用长春新碱，再施用环磷酰胺；优选的，给药周期为每4周或3周给药一次。
  10. 一种改善环磷酰胺、长春新碱及强的松治疗方案治疗PTCL的疗效的药物，其特征在于，含有盐酸米托蒽醌脂质体，每个给药周期第一天所述盐酸米托蒽醌脂质体在强的松给药后、长春新碱和环磷酰胺给药前的任意时间施用，剂量为8-30mg/m 2，更优选为12-24mg/m 2，每4周或3周给药一次。
  11. 根据权利要求1-5任一项所述的用途，其中，所述米托蒽醌脂质体粒径为约30-80nm，优选为约35-75nm，更优选为约40-70nm，进一步优选为约40-60nm，含有：1)活性成分米托蒽醌或其药学上可接受的盐，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。
  12. 根据权利要求6或10所述的药物，或根据权利要求9所述的组合物，其中，所述米托蒽醌脂质体粒径为约30-80nm，优选为约35-75nm，更优选为约40-70nm，进一步优选为约40-60nm，含有：1)活性成分米托蒽醌或其药学上可接受的盐，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。
  13. 根据权利要求7或8所述的方法，其中，所述米托蒽醌脂质体粒径为约30-80nm，优选为约35-75nm，更优选为约40-70nm，进一步优选为约40-60nm，含有：1)活性成分米托蒽醌或其药学上可接受的盐，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。
PCT/CN2021/114810 2020-08-27 2021-08-26 盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松的用途 WO2022042653A1 (zh)

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AU2021334710A AU2021334710B2 (en) 2020-08-27 2021-08-26 Use of mitoxantrone hydrochloride liposome and cyclophosphamide, vincristine and prednisone
CA3190922A CA3190922A1 (en) 2020-08-27 2021-08-26 Use of mitoxantrone hydrochloride liposome and cyclophosphamide, vincristine and prednisone
US18/023,161 US20240024257A1 (en) 2020-08-27 2021-08-26 Use of mitoxantrone hydrochloride liposome and cyclophosphamide, vincristine and prednisone
CN202180052842.XA CN115955971A (zh) 2020-08-27 2021-08-26 盐酸米托蒽醌脂质体和环磷酰胺、长春新碱、强的松的用途

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