[go: up one dir, main page]

WO2014142220A1 - Agent antitumoral - Google Patents

Agent antitumoral Download PDF

Info

Publication number
WO2014142220A1
WO2014142220A1 PCT/JP2014/056602 JP2014056602W WO2014142220A1 WO 2014142220 A1 WO2014142220 A1 WO 2014142220A1 JP 2014056602 W JP2014056602 W JP 2014056602W WO 2014142220 A1 WO2014142220 A1 WO 2014142220A1
Authority
WO
WIPO (PCT)
Prior art keywords
sepantronium
lymphoma
bendamustine
day
rituximab
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2014/056602
Other languages
English (en)
Japanese (ja)
Inventor
金子　直樹
伸明 網野
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Pharma Inc
Original Assignee
Astellas Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2013050641A external-priority patent/JP2016104703A/ja
Priority claimed from JP2013122759A external-priority patent/JP2016104704A/ja
Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc
Publication of WO2014142220A1 publication Critical patent/WO2014142220A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method for treating non-Hodgkin's lymphoma using a combination of pharmaceuticals, particularly sepantronium and bendamustine, and a pharmaceutical composition for use therein.
  • Malignant lymphoma is a malignant tumor arising from blood cancer and lymphoid tissue, roughly divided into Hodgkin's lymphoma (HL or Hodgkin's disease, HD) and non-Hodgkin's lymphoma (NHL).
  • non-Hodgkin lymphoma is classified into lymphoma with B-cell cancer (B-cell non-Hodgkin lymphoma) and lymphoma with T-cell or NK-cell cancer (T / NK cell non-Hodgkin lymphoma).
  • B cell non-Hodgkin lymphoma examples include diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, follicular Lymphoma (Follicular center lymphoma, FCL), MALT lymphoma (MALT lymphoma, HL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), etc.
  • DLBCL diffuse large B cell lymphoma
  • MCL mantle cell lymphoma
  • Burkitt's lymphoma Burkitt's lymphoma
  • FCL follicular Lymphoma
  • FCL follicular center lymphoma
  • MALT lymphoma MALT lymphoma
  • CLL / SLL chronic lymphocytic leukemia / small lymphocytic lymphoma
  • T / NK cell non-Hodgkin lymphoma examples include T / NK cell non-Hodgkin lymphoma
  • T-cell lymphoma Adult T-Cell Lymphoma, ATL
  • peripheral T-cell lymphoma peripheral T-cell lymphoma
  • lymphoblastic lymphoma and the like.
  • non-Hodgkin's lymphoma has a low-grade group (progresses slowly in a year, often in follicular lymphomas), a moderate-grade group (progresses in a month, diffuse large, due to its rapid progression.
  • Cell type and high-grade groups (common in Burkitt lymphoma, lymphoblastic lymphoma, etc., which progress rapidly in units of one week).
  • lymphoid tissue is found throughout the body, unlike other cancers, radiation therapy and chemotherapy are mainly applied instead of surgical resection. Although it is judged that the tumor has not been detected due to treatment, it has been judged to have been in complete remission, but there are many cases of recurrence, and improvement of the complete remission rate and prolongation of progression-free survival have become issues in clinical practice of lymphoma. Yes. On the other hand, bendamustine is considered to be the main mechanism of action of DNA alkylation, but is an antitumor agent reported to have other mechanisms of action due to its various actions (Non-patent Document 1), and is low malignant.
  • Non-patent Document 2 B-cell non-Hodgkin lymphoma (follicular lymphoma, small cell lymphoma), mantle cell lymphoma, chronic lymphocytic leukemia, and intermediate-grade non-Hodgkin lymphoma (diffuse large cell lymphoma, peripheral) It has been reported that clinical trials for expanding indications to (T-cell lymphoma) have also started (Non-patent Document 2). Further, it was known that it was commercialized in 1971 in the former East Germany and was used for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma, breast cancer and lung cancer (Non-patent Document 2).
  • Bendamustine has a strong effect of shrinking a tumor even with a single agent, and clinical trials for non-Hodgkin's lymphoma have confirmed a good complete remission rate and an extension of progression-free survival (Non-patent Document 3).
  • Rituximab is an anti-CD20 chimeric antibody that binds to CD20 antigen, which is one of the human B cell surface antigens, to bind B cells by antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.
  • CD20 antigen is present in the majority of B-cell non-Hodgkin's lymphomas and includes rituximab or various combination therapies including rituximab (R-ICE (Rituximab, Ifosfamide, Carboplatin and Etoposide), R-DHAP (Rituximab, Dexamethasone, Alla- C (cytarabine) and cisplatin) and R-CHOP) have become one of the standard treatments for B-cell non-Hodgkin lymphoma.
  • Sepantronium especially its bromide, 1- (2-methoxyethyl) -2-methyl-4,9-dioxo-3- (pyrazin-2-ylmethyl) -4,9 -Dihydro-1H-naphtho [2,3-d] imidazol-3-ium (generic name: Sepantronium bromide, hereinafter sometimes referred to as YM155) has good cancer growth inhibitory activity in vivo Moreover, it is disclosed that it is expected as an anticancer agent because of its low toxicity (Patent Documents 1 and 2).
  • Sepantronium is the first compound found to selectively suppress survivin. Sepantronium exhibits a time-dependent anticancer effect, and human hormone-resistant prostate cancer (HRPC) transplantation model (Non-patent document 5), human non-Hodgkin lymphoma model (Non-patent document) Cancer regression was induced in 6) and human non-small cell lung cancer (NSCLC) transplantation model and various other carcinomas (Non-patent Document 7). Furthermore, in patients with advanced solid cancer and non-Hodgkin's lymphoma, it showed a good anticancer effect (Non-patent Documents 8 and 9). Sepantronium has few side effects such as weight loss and hematotoxicity frequently observed in the treatment with paclitaxel, cisplatin and doxorubicin (Non-patent Documents 8 and 9).
  • Sepantronium contains several existing anticancer drugs, specifically carboplatin, cisplatin, paclitaxel, vinorelbine, gemcitabine, irinotecan, docetaxel, doxorubicin, dacarbazine, rituximab, or Rituximab such as R-ICE and R-DHAP It has been reported that when used in combination with combination therapy, it has an antitumor effect. In particular, in the combined use of sepantronium and rituximab or a combination therapy containing rituximab, an excellent combined effect including a tumor disappearance example has been confirmed in an animal model transplanted with lymphoma cells (Patent Document 3).
  • the present inventors have found that by using sepantronium in combination with bendamustine for non-Hodgkin's lymphoma, it is possible to achieve a stronger and lasting cancer growth-inhibiting effect compared to each monotherapy, and sepantronium And bendamustine were found to be a new combination therapy for non-Hodgkin lymphoma. Furthermore, when rituximab is used in combination with sepantronium and bendamustine, it is confirmed that the antitumor action is further enhanced, and a therapy using these three agents is an excellent treatment method for B-cell non-Hodgkin lymphoma. The present invention was completed with this knowledge. That is, the present invention relates to a composition for malignant tumor treatment containing sepantronium as an active ingredient, which is used in combination with bendamustine.
  • a composition for treating malignant tumor comprising sepantronium as an active ingredient, which is used in combination with bendamustine.
  • the composition according to (1), wherein the malignant tumor is lymphoma, leukemia, multiple myeloma or solid cancer.
  • the composition according to (1), wherein the malignant tumor is non-Hodgkin lymphoma, multiple myeloma, breast cancer or lung cancer.
  • the composition according to (1), wherein the malignant tumor is non-Hodgkin lymphoma.
  • the composition according to (4), wherein the non-Hodgkin lymphoma is a B-cell non-Hodgkin lymphoma.
  • composition according to (5), wherein the B-cell non-Hodgkin lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small cell lymphoma, or mantle cell lymphoma.
  • the composition according to (5), wherein the B-cell non-Hodgkin lymphoma is a diffuse large B-cell lymphoma.
  • the present invention also relates to the following inventions.
  • (11) Use of sepantronium for the manufacture of a composition for malignant tumor treatment, which is used in combination with bendamustine.
  • (12) Use of sepantronium according to (11) for the manufacture of a composition for treating B-cell non-Hodgkin lymphoma, which is further used in combination with rituximab.
  • (13) Use of sepantronium for the treatment of malignant tumors, characterized by being used in combination with bendamustine.
  • (14) Use of sepantronium according to (13) for the treatment of B-cell non-Hodgkin lymphoma, which is further used in combination with rituximab.
  • Sepantronium for the treatment of malignant tumors characterized by being used in combination with bendamustine (16) The sepantronium according to (15) for the treatment of B-cell non-Hodgkin lymphoma, which is further used in combination with rituximab.
  • a method for treating a malignant tumor comprising administering a therapeutically effective amount of sepantronium to a patient, which is used in combination with a therapeutically effective amount of bendamustine.
  • a composition for treating malignant tumor comprising sepantronium as an active ingredient, which is used for administration to a patient undergoing malignant tumor treatment with bendamustine.
  • a composition for treating B-cell non-Hodgkin lymphoma containing sepantronium as an active ingredient, wherein the composition is used for administration to a patient undergoing treatment for B-cell non-Hodgkin lymphoma with bendamustine and rituximab (19) The composition which is a thing.
  • a malignant treatment kit comprising a therapeutically effective amount of bendamustine and a therapeutically effective amount of sepantronium.
  • chronic lymphocytic leukemia and small cell lymphoma are classified as a single disease, in the present specification, both may be collectively referred to as “chronic lymphocytic leukemia / small cell lymphoma”. is there.
  • the composition for malignant tumor treatment containing sepantronium as an active ingredient can be used for the treatment of various malignant tumors.
  • it can be used for the treatment of lymphoma, leukemia, multiple myeloma, and solid cancer such as breast cancer and lung cancer.
  • non-Hodgkin lymphomas such as B-cell non-Hodgkin lymphoma (diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, MALT lymphoma, and chronic lymphocytic leukemia / small cell Can be used for the treatment of lymphoma.
  • FIG. 1 is a graph showing the results of Example 1.
  • (a) shows the change in mean tumor volume (mm 3 ) in the sepantronium-administered group (YM155), bendamustine-administered group (BEM), and the combination-administered group of sepantronium and bendamustine (YM155 + BEM), and
  • (b) Changes in mean body weight (g) are shown relative to the control group (CON), respectively.
  • # and *** indicate that #: P ⁇ 0.05 (less than 5% risk) and ***: P ⁇ 0.001 (risk rate 0.1) when the combination group is compared with the sepantronium group and bendamustine group, respectively. Less than%) indicates a significant difference.
  • FIG. 2 is a graph showing the results of Example 2.
  • (a), (b) and (c) are apoptotic cells after 48 hours by combined treatment with sepantronium and bendamustine (YM155 + BEM) in DB cells, SU-DHL-8 cells and WSU-DLCL-2 cells, respectively. The percentage (%) is shown together with the results of the comparative examples (control, YM155 and BEM).
  • FIG. 3 is a graph showing the results of Example 3.
  • FIG. 4 is a graph showing the results of Example 4.
  • Sepantronium, bendamustine and rituximab combination treatment group (YM155 + BEM + RTX) survival time, comparative sepantronium administration group (YM155), sepantronium and rituximab combination administration group (YM155 + RTX) and bendamustine
  • the results are shown together with the results of the combined administration group of rituximab (BEM + RTX).
  • the vertical axis represents the survival rate (%), and the horizontal axis represents the survival period (days) after the start of administration.
  • sepantronium means sepantronium ion (cation moiety: 1- (2-methoxyethyl) -2-methyl-4,9-dioxo-3- (pyrazin-2-ylmethyl) -4,9-dihydro-1H-naphtho [2,3-d] imidazol-3-ium) or its anion salt, where the anion includes halogen ion, organic sulfonate ion, acetate ion, etc.
  • Examples of the pharmaceutically acceptable monovalent or divalent anion include a halogen ion as one embodiment, a chloro ion or a bromine ion as another embodiment, and a bromine ion as another embodiment. is there.
  • Some embodiments of sepantronium include sepantronium bromide (1- (2-methoxyethyl) -2-methyl-4,9-dioxo-3- (pyrazin-2-ylmethyl) -4,9-dihydro-1H bromide). -Naphtho [2,3-d] imidazol-3-ium, YM155). Sepantronium described in the present specification can be easily obtained by the production methods disclosed in International Publication No.
  • WO01 / 60803 and International Publication No. WO2004 / 092160 Sepantronium is administered parenterally, but intravenous administration is preferred.
  • injections for intravenous administration include those containing sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • the aqueous solvent include distilled water for injection and physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of bactericides, or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • sepantronium bromide When sepantronium bromide is administered intravenously, it is usually 0.1 to 20 mg / m 2 / day, and in one embodiment, 1 to 10 mg / m 2 / day is appropriate. Dosage in divided doses or continuous infusion. In one embodiment, the infusion is continuously administered at a dose of 1 to 10 mg / m 2 / day for 4 to 14 days or 7 days. In another embodiment, 3 to 10 mg / m 2 / day is used for 4 to 20 days, and in another embodiment, 4 to 14 days, or 5 days, 7 days, 10 days, or 14 days. In this embodiment, continuous infusion is administered for 7 days.
  • a dosing cycle is employed.
  • 3 to 8 mg / m 2 / day is continuously infused for 7 days, and then a 7-day, 14-day, or 21-day withdrawal period is defined as one cycle, and this is repeated depending on symptoms.
  • the method is adopted.
  • the dose should be determined appropriately with reference to the dose of the bromide.
  • the anticancer agent used in combination has a specific administration cycle, it is preferable to set the administration cycle of sepantronium and the anticancer agent.
  • Specific administration frequency, dosage, infusion administration time, administration cycle, and the like are appropriately determined according to individual cases in consideration of the anticancer drug to be used in combination, the patient's symptoms, age, sex, and the like.
  • bendamustine described in the present specification is bendamustine (free form) or a salt thereof, and in one embodiment, bendamustine hydrochloride.
  • Drugs containing bendamustine hydrochloride as an active ingredient are already marketed in various countries under trade names such as Treakisym (registered trademark), Ribomustin (registered trademark), Levact (registered trademark) or Treanda (registered trademark),
  • a drug containing bendamustine as an active ingredient including these commercially available drugs, can be used as appropriate.
  • rituximab The general name of rituximab described in the present specification is rituximab (genetical recombination), which is an anti-human CD20 human / mouse chimeric antibody.
  • Drugs containing rituximab as an active ingredient have already been launched in various countries under trade names such as Rituxan (registered trademark) Note, MabThera (registered trademark), and Zytux (registered trademark).
  • pharmaceuticals containing rituximab as an active ingredient including these commercially available drugs, can be used as appropriate.
  • another anticancer agent may be used in combination as long as the combined effect of sepantronium and bendamustine is not significantly attenuated.
  • the cancer agent include other anticancer agents used for non-Hodgkin lymphoma treatment.
  • rituximab and combination therapies involving rituximab, such as R-ICE (rituximab, ifosfamide, carboplatin and etoposide), R-DHAP (rituximab, dexamethasone, ara-C (cytarabine) and cisplatin) and R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisolone).
  • R-ICE rituximab, ifosfamide, carboplatin and etoposide
  • R-DHAP rituximab, dexamethasone, ara-C (cytarabine) and cisplatin
  • R-CHOP rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and predni
  • ICE ifosfamide, carboplatin and etoposide
  • DHAP dihydroxy amethasone
  • ara-C cytarabine
  • CHOP cyclophosphamide, doxorubicin hydrochloride, sulfate
  • Combination therapy such as, but not limited to, vincristine and prednisolone.
  • ICE ifosfamide, carboplatin and etoposide
  • DHAP diexamethasone
  • ara-C cytarabine
  • CHOP cyclophosphamide, doxorubicin hydrochloride, sulfate
  • Combination therapy such as, but not limited to, vincristine and prednisolone.
  • rituximab or a combination therapy comprising rituximab
  • another embodiment is rituximab.
  • Anticancer agents such as bendamustine used in combination with sepantronium and rituximab that may be used in combination have already been clinically used, and their administration route, administration cycle, and dosage are apparent to those skilled in the art.
  • the appropriate dosage and administration varies depending on the type of cancer, symptoms, and concomitant drugs.
  • Detailed information is available from various databases provided by the FDA, such as "Drugs @ FDA" ( http://www.accessdata.fda.gov /scripts/cder/drugsatfda/index.cfm ) and the Japanese medical device information provision homepage (http://www.info.pmda.go.jp/).
  • 100 mg for intravenous administration of treaxin (registered trademark: containing 100 mg of bendamustine hydrochloride) has the following indications: “Indication or effect Relapsed or refractory disease Low grade B Cellular Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma; Usage and Dosage
  • bendamustine hydrochloride 120 mg / m 2 body surface area
  • the drug is withdrawn for 19 days, and this is taken as one cycle, and the administration is repeated.
  • NDL non-Hodgkin lymphoma
  • the recommended dose for non-Hodgkin lymphoma is 375 mg / m 2 given once a week by intravenous infusion.
  • the frequency of administration is indicated between 4 and 16 times depending on the type of lymphoma.
  • the same dosage and frequency as those usually administered alone, or lower doses and Set to low frequency (for example, 0.10 to 0.99 times the maximum dose when administered alone and / or 0.10 to 0.99 times the frequency when administered alone) be able to.
  • the administration time can be combined so as to be suitable for combined use with sepantronium.
  • the administration cycle may be adjusted as necessary. Specific administration frequency, dose, infusion administration time, administration cycle, and the like are appropriately determined according to individual cases in consideration of patient symptoms, age, sex, and the like.
  • the administration form when sepantronium and bendamustine (and optionally one or more other anticancer agents) are administered in combination is not particularly limited as long as an appropriate administration route, administration frequency and dosage are adopted.
  • a combination therapy including only sepantronium and bendamustine (1) a composition containing sepantronium and bendamustine, that is, administration as a single preparation, (2) sepantronium and bendamustine Simultaneous administration of two preparations obtained by separate formulation by the same administration route, (3) Time difference in the same administration route of two preparations obtained by separately formulating sepantronium and bendamustine (E.g., administration of sepantronium and bendamustine or vice versa), (4) sepantronium and Simultaneous administration of two preparations obtained by separately formulating ndamustine in different administration routes, (5) Time difference in different administration routes of two preparations obtained by separately formulating sepantronium and bendamustine (For example, administration of sepantronium and bendamustine in the order,
  • Preferred dosage forms for the combination therapy described herein include a plurality of formulations obtained by separately formulating sepantronium and bendamustine (and optionally one or more other anticancer agents), respectively. It is a method of administration at a suitable administration route and administration frequency, including at the same time (including part at the same time) or at a time difference. In the case of administration with a time lag, it is necessary to administer at intervals sufficient to enhance the antitumor effect. In one embodiment, administration is started within 2 weeks, in another embodiment within 7 days, and in another embodiment within 3 days from the end of administration of the previous drug.
  • bendamustine and any one or more other anticancer agents When there is a concern about drug interaction between sepantronium, bendamustine and any one or more other anticancer agents, it is preferable to administer them at intervals necessary to avoid the interaction.
  • bendamustine (and rituximab) and sepantronium are administered in combination in a 21-day or 28-day dosing cycle.
  • bendamustine (and rituximab) is administered in a 21-day or 28-day dosing cycle while sepantronium is administered in a 14-day dosing cycle.
  • the dose of sepantronium is as described above, and in one embodiment, 1 to 10 mg / m 2 / day as sepantronium bromide.
  • the dose of sepantronium is as described above, and in one embodiment, 1 to 10 mg / m 2 / day as sepantronium bromide.
  • sepantronium is continuously infused intravenously for 7 days from the first day of the 14-day cycle, and this cycle is repeated. 6).
  • sepantronium is continuously infused intravenously for 7 days from the second day of the 14-day cycle, and this cycle is repeated. 7).
  • sepantronium is continuously infused intravenously for 7 days from the third day of the 14-day cycle, and this cycle is repeated.
  • Bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on days 1 and 2 of the 21-day or 28-day cycle, and rituximab was administered on days 1, 8, and 15 ( 21-day cycle) or on days 1, 8, 15 and 22 (28-day cycle), 200-375 mg / m 2 of each is infused intravenously, and sepantronium is continuously applied for 7 days from the second day of the cycle. Intravenously infused. Repeat this cycle. 3.
  • Bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on days 1 and 2 of the 21-day or 28-day cycle, and rituximab was administered on days 1, 8, and 15 ( 21-day cycle) or 200-375 mg / m 2 intravenously on days 1, 8, 15 and 22 (28-day cycle), and sepantronium continuously infused for 7 days from the third day of the cycle Inject intravenously. Repeat this cycle. 4).
  • Bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on days 2 and 3 of the 21- or 28-day cycle, and rituximab was administered on days 1, 8, and 15 ( 21-day cycle) or 200-375 mg / m 2 intravenously on days 1, 8, 15 and 22 (28-day cycle), and sepantronium continuously infused for 7 days from the first day of the cycle. Inject intravenously. Repeat this cycle. 5.
  • Bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on days 2 and 3 of the 21- or 28-day cycle, and rituximab was administered on days 1, 8, and 15 ( 21-day cycle) or 200-375 mg / m 2 each on days 1, 8, 15 and 22 (28-day cycle), and sepantronium is continuously infused for 7 days from the second day of the cycle. Inject intravenously. Repeat this cycle. 6).
  • Bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on days 2 and 3 of the 21- or 28-day cycle, and rituximab was administered on days 1, 8, and 15 ( 21-day cycle) or 200-375 mg / m 2 intravenously on days 1, 8, 15 and 22 (28-day cycle), and sepantronium continuously infused for 7 days from the third day of the cycle Inject intravenously. Repeat this cycle. 7).
  • Sepantronium was continuously infused intravenously for 7 days from the first day of the 21-day cycle, and bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on the 8th and 9th day, and rituximab On the 8th and 15th day of the same cycle, 200-375 mg / m 2 of each is instilled. Repeat this cycle. 8).
  • Bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on days 1 and 2 of the 21-day or 28-day cycle, and rituximab was administered on days 1, 8, and 15 ( 21-day cycle) or 200-375 mg / m 2 each on days 1, 8, 15, and 22 (28-day cycle), and repeat this cycle.
  • sepantronium is continuously infused intravenously for 7 days from the first day of the 14-day cycle, and this cycle is repeated. 9.
  • Bendamustine was infused intravenously over 80 to 120 mg / m 2 over 40 to 60 minutes on days 1 and 2 of the 21-day or 28-day cycle, and rituximab was administered on days 1, 8, and 15 ( 21-day cycle) or 200-375 mg / m 2 each on days 1, 8, 15, and 22 (28-day cycle), and repeat this cycle.
  • sepantronium is continuously infused intravenously for 7 days from the second day of the 14-day cycle, and this cycle is repeated.
  • the composition for malignant tumor treatment containing sepantronium as an active ingredient characterized in that it is used in combination with bendamustine described in the present specification, has various malignant tumors, in particular, bendamustine has an antitumor effect. It is useful for the treatment of malignant tumors.
  • Such malignant tumors include, for example, lymphoma; leukemia; multiple myeloma; skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, gastric cancer, etc. Cancer is mentioned.
  • Some embodiments are non-Hodgkin lymphoma, multiple myeloma, breast cancer and lung cancer.
  • the malignant tumor treatment composition described herein can be used for the treatment of various non-Hodgkin lymphomas.
  • non-Hodgkin lymphoma examples include B-cell non-Hodgkin lymphoma and T / NK cell non-Hodgkin lymphoma.
  • B-cell non-Hodgkin lymphoma specifically, diffuse large cell type B Cellular lymphoma, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, MALT lymphoma, chronic lymphocytic leukemia / small cell lymphoma, etc.
  • T / NK cell non-Hodgkin lymphoma includes adult T cell lymphoma, peripheral T Examples include cell lymphoma and lymphoblastic lymphoma.
  • the non-Hodgkin lymphoma that can be used in the composition for treating malignant tumors containing sepantronium as an active ingredient described herein is a B-cell non-Hodgkin lymphoma, and in another embodiment, it is a diffuse Large B-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, MALT lymphoma and chronic lymphocytic leukemia / small cell lymphoma.
  • Yet another embodiment is diffuse large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma. Yet another embodiment is diffuse large B-cell lymphoma.
  • the malignant tumor is a malignant tumor resistant to an existing anticancer agent, and in another aspect, a recurrent or refractory malignant tumor. Yet another embodiment is a malignant tumor of a patient who cannot obtain a sufficient therapeutic effect in treatment with bendamustine.
  • Non-Hodgkin's lymphoma is classified into a low-grade group, a middle-grade group, and a high-grade group because of its rapid progression, but it contains a malignant substance containing sepantronium as described herein as an active ingredient.
  • Tumor therapeutic compositions can be used to treat any non-Hodgkin lymphoma.
  • the non-Hodgkin lymphoma that can be used for the composition for treating malignant tumors containing sepantronium as an active ingredient described in this specification includes B-cell non-Hodgkin lymphoma in the low-grade group or the middle-grade group Another embodiment is low-grade B-cell non-Hodgkin lymphoma, and yet another embodiment is a medium-grade B-cell non-Hodgkin lymphoma.
  • composition for malignant tumor treatment containing sepantronium as an active ingredient described in this specification may be used in combination with rituximab in addition to bendamustine. When used in combination with rituximab, it is preferably used for a CD20 positive malignant tumor. .
  • B-cell non-Hodgkin lymphomas 95% or more are known to be CD20 positive, and the triple combination therapy of sepantronium, bendamustine and rituximab is suitable for the treatment of various B-cell non-Hodgkin lymphomas
  • Can be used for Non-Hodgkin's lymphoma that can be used in combination therapy with sepantronium, bendamustine and rituximab is, in one aspect, B-cell non-Hodgkin's lymphoma, and in another aspect, low-grade B-cell non-Hodgkin's lymphoma, Medium-grade B-cell non-Hodgkin lymphoma and high-grade B-cell non-Hodgkin lymphoma, and in another aspect, low-grade B-cell non-Hodgkin lymphoma, medium-grade B-cell non-Hodgkin lymphoma, Yet another embodiment is moderate-grade B-cell non-Hodgkin lymphoma.
  • Other embodiments are diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, MALT lymphoma, and chronic lymphocytic leukemia / small cell lymphoma.
  • Another embodiment is CD20 positive B-cell non-Hodgkin lymphoma
  • yet another embodiment is diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, MALT lymphoma, And CD20 positive in chronic lymphocytic leukemia / small cell lymphoma.
  • CD20-positive diffuse large B-cell lymphoma CD20-positive mantle cell lymphoma, CD20-positive follicular lymphoma, and CD20-positive chronic lymphocytic leukemia / small cell lymphoma.
  • CD20-positive diffuse large B-cell lymphoma CD20-positive medium-grade B-cell non-Hodgkin lymphoma.
  • Example 1 Test substance Sepantronium bromide was produced by a method according to the production method disclosed in International Publication No. WO01 / 60803 and International Publication No. WO2004 / 092160. Bendamustine hydrochloride (Levact®) was purchased from Mundi Pharma Inc. (Cambridge, UK).
  • Cells Human diffuse large B cell lymphoma-derived DB cells were obtained from the American Type Culture Collection (VA, USA). The cells were cultured under conditions of 37 ° C. and 5% CO 2 using RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS). The collected cells were suspended in PBS (Phosphate Buffered Saline) at 6 ⁇ 10 7 cells / mL and mixed with an equal amount of Matrigel TM Basement Membrane Matrix (Becton Dickinson Co., MA, USA).
  • PBS Phosphate Buffered Saline
  • an osmotic pump containing sepantronium solution was implanted subcutaneously on the back of the mouse under anesthesia.
  • Sepantronium was administered subcutaneously for 7 days from day 0 to 1 mg / kg / day in the sepantronium administration group.
  • Bendamustine was administered as an intravenous bolus at a dose of 50 mg / kg on day 0 to the bendamustine administration group.
  • both drugs were administered in the same manner as the sepantronium administration group and bendamustine administration group.
  • Body weight and tumor diameter were measured every 3-4 days. Tumor volume was calculated as described above.
  • the antitumor activity was expressed as a tumor growth inhibition rate (% inhibition) and a tumor regression rate (% regression) of each group.
  • the tumor growth inhibition rate on day 21 was 100 ⁇ [1- (average tumor volume on day 21 in each group ⁇ average tumor volume on day 0 in each group) / (average tumor volume on day 21 in the control group) for each group. -Average tumor volume on day 0 of the control group)].
  • the tumor regression rate was calculated from 100 ⁇ [1- (average tumor volume on day 21 of each group / average tumor volume on day 0 of each group)].
  • CR complete disappearance
  • Example 2 Test substance Sepantronium bromide was obtained in the same manner as in Example 1, and bendamustine hydrochloride was purchased from Sigma-Aldrich (MO, USA). 2) Preparation of test substance A sepantronium solution and a bendamustine solution were prepared to 10 mmol / L with dimethyl sulfoxide and PBS, respectively, and then diluted with the same solvent.
  • DB cells CRL-2289
  • SU-DHL-8 cells CL-2961
  • VA American Type Culture Collection
  • -DLCL-2 cells ACC575
  • DSMZ Brainschweig, Germany
  • the cells were cultured under the conditions of 37 ° C. and 5% CO 2 using RPMI1640 medium supplemented with 10% heat-inactivated FBS.
  • Test method Cells were seeded in a 12-well plate at a concentration of about 1 ⁇ 10 5 cells / mL at 1 mL / well and cultured overnight. The next day, the cells were treated with sepantronium (YM155) and bendamustine (BEM) alone or in combination so that the drug concentrations shown in Table 2 were obtained. The added solvent was prepared so that all samples were the same, and cells treated with the solvent alone were used as controls. After 48 hours of treatment, the cells were collected, washed once with PBS, fixed with ice-cold 70% ethanol, and stored at 4 ° C. After washing once with PBS on the measurement day, 150 ⁇ L of Guava Cell Cycle Reagent (Merck Co., Ltd.
  • Example 3 Apoptosis induction test using human diffuse large B-cell lymphoma-derived cells by the combination treatment of sepantronium and bendamustine and the combination treatment of sepantronium, bendamustine and rituximab was conducted in combination with the comparative examples described later.
  • Rituxan Injection registered trademark
  • Rituximab was diluted with PBS and treated with Example 2 except that Sepantronium (YM155), Bendamustine (BEM), and Rituximab (RTX) were added alone or in combination to achieve the drug concentrations shown in Table 4. The test was conducted in the same manner.
  • YM155 + BEM Sepantronium and bendamustine combined treatment
  • YM155 + BEM + RTX Sepantronium, bendamustine and rituximab combined treatment
  • Control Solvent treatment YM155: Sepantronium alone treatment
  • BEM Bendamustine alone treatment
  • RTX Rituximab alone treatment
  • YM155 + RTX Sepantronium and rituximab combination treatment
  • BEM + RTX Bendamustine and rituximab treatment
  • any human diffuse large B-cell lymphoma-derived cell showed a better apoptosis-inducing action than each single agent treatment when treated with sepantronium and bendamustine.
  • rituximab alone treatment had a slight effect on apoptosis, but the group treated with rituximab in addition to sepantronium and bendamustine showed excellent apoptosis-inducing ability, and the degree was induced by each single agent treatment. It was more than the sum of the percentage of apoptotic cells.
  • the combination of sepantronium and bendamustine showed better apoptosis-inducing ability than the combined treatment of bendamustine and rituximab, and the results were comparable or better than the combined use of sepantronium and rituximab. Furthermore, the group treated with rituximab in addition to sepantronium and bendamustine showed superior apoptosis-inducing ability as compared with the combined treatment of bendamustine and rituximab or sepantronium and rituximab.
  • Example 4 Test substance Sepantronium bromide and bendamustine hydrochloride were obtained in the same manner as in Example 1, and rituximab was obtained in the same manner as in Example 3.
  • Cells SU-DHL-8 (CRL-2961) derived from human diffuse large B-cell lymphoma was obtained from the American Type Culture Collection (VA, USA). The cells were cultured under the conditions of 37 ° C. and 5% CO 2 using RPMI1640 medium supplemented with 10% heat-inactivated FBS. The collected cells were suspended in PBS at 1 ⁇ 10 7 cells / mL.
  • YM155 Sepantronium administration; Sepantronium bromide 1 mg / kg / day (continuous subcutaneous administration from day 0 and 19 to 7 days)
  • YM155 + RTX combination use of sepantronium and rituximab; sepantronium bromide 1 mg / kg / day (continuous subcutaneous administration for 7 days from days 0 and 19) + rituximab 50 mg / kg (venous on days 0, 2, 19, and 22) (Internal bolus administration)
  • BEM + RTX Bendamustine combined with rituximab; bendamustine hydrochloride 25 mg / kg (intravenous bolus on days 0, 1, 19 and 20) + rituximab 50 mg / kg (intravenous on days 0, 2, 19 and 22)
  • an osmotic pump containing sepantronium solution was implanted subcutaneously on the back of the mouse under anesthesia
  • YM155 + BEM + RTX administration group sepantronium was administered subcutaneously for 7 days from day 0 and 19 to 1 mg / kg / day, and bendamustine was administered at 25 mg / kg on days 0, 1, 19, and 20, and Rituximab was administered as an intravenous bolus at 50 mg / kg on days 0, 2, 19, and 22.
  • Sepantronium, rituximab and / or bendamustine were administered to the YM155 administration group, the YM155 + RTX administration group and the BEM + RTX administration group of the comparative example in the same manner as in the YM155 + BEM + RTX administration group.
  • the survival period of the mice was observed until Day 82. Animals with a weight loss of 20% or more and animals with a weak state of no recovery (such as decreased activity and decreased body temperature) were considered dead at that time.
  • the results are shown in FIG.
  • the YM155, BEM + RTX and YM155 + RTX administration groups which are comparative examples, significantly increased the survival time compared to the CON group.
  • the median survival of the CON group was 45.5 days, while the median survival of the YM155, BEM + RTX and YM155 + RTX administration groups was 68, 57.5 and 78 days, respectively.
  • the YM155 + BEM + RTX administration group further treated with septantronium and bendamustine of the present invention in combination with rituximab significantly increased the survival time compared to the YM155, BEM + RTX and YM155 + RTX administration groups of the comparative examples. It was extended (see Fig. 4). From the results observed up to day 88, it was confirmed that the median survival time of the YM155 + BEM + RTX administration group was 86 days.
  • composition for malignant tumor treatment containing sepantronium as an active ingredient which is used in combination with bendamustine described in the present specification, is used for various malignant tumors, particularly diffuse large B-cell lymphoma.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention vise à fournir une polythérapie efficace sous forme d'agent thérapeutique pour des tumeurs malignes. Les inventeurs ont réalisé la présente invention en démontrant qu'un effet thérapeutique amélioré contre des tumeurs malignes est obtenu au moyen de l'utilisation simultanée de bendamustine et de sépantronium. Cette composition pour le traitement de tumeurs malignes, qui est caractérisée comme étant utilisée en polythérapie avec de la bendamustine et contient du sépantronium comme principe actif, peut être utilisée pour le traitement de lymphome, de leucémie, de myélome multiple, de tumeurs solides ou de diverses autres tumeurs malignes, et en particulier de lymphome non hodgkinien.
PCT/JP2014/056602 2013-03-13 2014-03-13 Agent antitumoral Ceased WO2014142220A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2013-050641 2013-03-13
JP2013050641A JP2016104703A (ja) 2013-03-13 2013-03-13 抗腫瘍剤
JP2013122759A JP2016104704A (ja) 2013-06-11 2013-06-11 抗腫瘍剤
JP2013-122759 2013-06-11

Publications (1)

Publication Number Publication Date
WO2014142220A1 true WO2014142220A1 (fr) 2014-09-18

Family

ID=51536871

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2014/056602 Ceased WO2014142220A1 (fr) 2013-03-13 2014-03-13 Agent antitumoral

Country Status (1)

Country Link
WO (1) WO2014142220A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10604580B2 (en) 2014-09-09 2020-03-31 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US10668149B2 (en) 2015-06-22 2020-06-02 Janssen Biotech, Inc. Combination therapies for heme malignancies with anti-CD38 antibodies and survivin inhibitors
US10766965B2 (en) 2015-05-20 2020-09-08 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of light chain amyloidosis and other CD38-positive hematological malignancies
US10781261B2 (en) 2015-11-03 2020-09-22 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US10793630B2 (en) 2014-12-04 2020-10-06 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute myeloid leukemia
US10800851B2 (en) 2014-02-28 2020-10-13 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US11021543B2 (en) 2015-06-24 2021-06-01 Janssen Biotech, Inc. Immune modulation and treatment of solid tumors with antibodies that specifically bind CD38
US11566079B2 (en) 2015-11-03 2023-01-31 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11618787B2 (en) 2017-10-31 2023-04-04 Janssen Biotech, Inc. Methods of treating high risk multiple myeloma
US11713355B2 (en) 2014-02-28 2023-08-01 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia
WO2023168908A1 (fr) 2022-03-07 2023-09-14 上海交通大学 Quinone oxime imidazole fusionné, son dérivé onium, préparation correspondante et utilisation associée
US12163193B2 (en) 2018-08-13 2024-12-10 Beijing Percans Oncology Co., Ltd. Biomarkers for cancer therapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008081927A1 (fr) * 2006-12-29 2008-07-10 Astellas Pharma Inc. Procédé de traitement d'un cancer utilisant un agent anti-cancer en combinaison
WO2009011897A1 (fr) * 2007-07-17 2009-01-22 Combinatorx, Incorporated Combinaisons pour le traitement des troubles prolifératifs des lymphocytes b
WO2009011893A2 (fr) * 2007-07-17 2009-01-22 Combinatorx, Incorporated Traitements de troubles prolifératifs des lymphocytes b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008081927A1 (fr) * 2006-12-29 2008-07-10 Astellas Pharma Inc. Procédé de traitement d'un cancer utilisant un agent anti-cancer en combinaison
WO2009011897A1 (fr) * 2007-07-17 2009-01-22 Combinatorx, Incorporated Combinaisons pour le traitement des troubles prolifératifs des lymphocytes b
WO2009011893A2 (fr) * 2007-07-17 2009-01-22 Combinatorx, Incorporated Traitements de troubles prolifératifs des lymphocytes b

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A. W. TOLCHER ET AL.: "A phase I study of YM155, a novel survivin suppressant, administered by 168 hour continuous infusion to patients with advanced solid tumors.", JOURNAL OF CLINICAL ONCOLOGY, vol. 24, no. 18S, 2006, pages 124S, 3014 *
A. W. TOLCHER ET AL.: "YM155, A Novel Survinvin Suppressant, Demonstrates Anti-tumor Activity in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphoma", ANNALS OF ONCOLOGY, vol. 17, no. SUPPL., May 2006 (2006-05-01), pages P.III23, 0.403 *
KANEKO, NAOKI ET AL.: "Combination of YM155, a survivin suppressant, with bendamustine and rituximab: A new combination therapy to treat relapsed/refractory diffuse large B- cell lymphoma.", CLINICAL CANCER RESEARCH, vol. 20, no. 7, pages 1814 - 1822 *
TREVOR W. DENNIE ET AL.: "Bendamustine for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B- cell non- hodgkin lymphoma", CLINICAL THERAPEUTICS, vol. 31, 2009, pages 2290 - 2311, XP026872238 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11713355B2 (en) 2014-02-28 2023-08-01 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia
US10800851B2 (en) 2014-02-28 2020-10-13 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US12060432B2 (en) 2014-02-28 2024-08-13 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US10604580B2 (en) 2014-09-09 2020-03-31 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US12286474B2 (en) 2014-12-04 2025-04-29 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute myeloid leukemia
US10793630B2 (en) 2014-12-04 2020-10-06 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute myeloid leukemia
US10766965B2 (en) 2015-05-20 2020-09-08 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of light chain amyloidosis and other CD38-positive hematological malignancies
US12091466B2 (en) 2015-05-20 2024-09-17 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of light chain amyloidosis and other CD38-positive hematological malignancies
US10668149B2 (en) 2015-06-22 2020-06-02 Janssen Biotech, Inc. Combination therapies for heme malignancies with anti-CD38 antibodies and survivin inhibitors
US11021543B2 (en) 2015-06-24 2021-06-01 Janssen Biotech, Inc. Immune modulation and treatment of solid tumors with antibodies that specifically bind CD38
US11732051B2 (en) 2015-11-03 2023-08-22 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11708419B2 (en) 2015-11-03 2023-07-25 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11708420B2 (en) 2015-11-03 2023-07-25 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11566079B2 (en) 2015-11-03 2023-01-31 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US10781261B2 (en) 2015-11-03 2020-09-22 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11618787B2 (en) 2017-10-31 2023-04-04 Janssen Biotech, Inc. Methods of treating high risk multiple myeloma
US12163193B2 (en) 2018-08-13 2024-12-10 Beijing Percans Oncology Co., Ltd. Biomarkers for cancer therapy
WO2023168908A1 (fr) 2022-03-07 2023-09-14 上海交通大学 Quinone oxime imidazole fusionné, son dérivé onium, préparation correspondante et utilisation associée

Similar Documents

Publication Publication Date Title
WO2014142220A1 (fr) Agent antitumoral
JP7562296B2 (ja) がんの処置のための併用治療
JP4788774B2 (ja) 抗癌剤の併用による癌治療方法
TWI786044B (zh) 藉由投予ｐｄ-１抑制劑治療皮膚癌之方法
CN111065411B (zh) Pd-1抗体和vegfr抑制剂联合治疗小细胞肺癌的用途
JP6426706B2 (ja) がん処置で使用するためのｇｌａ単剤療法
CA2926771C (fr) Traitement du cancer avec une association de plinabuline et de taxane
DK2944323T3 (en) Means for the treatment of tumors, their use and their method
JP2012067116A5 (fr)
WO2016204193A1 (fr) Agent anticancéreux
WO2019072220A1 (fr) Utilisation d'un anticorps pd-1 combiné à un régulateur épigénétique dans la préparation d'un médicament pour le traitement de tumeurs
JP2023542093A (ja) 抗腫瘍治療におけるチアウラニブと免疫チェックポイント阻害剤との組み合わせの使用
CN111166878B (zh) 靶向肿瘤抗原的抗体与iNKT细胞的组合的制备方法与用途
JP2016104703A (ja) 抗腫瘍剤
KR20220114532A (ko) 암의 치료를 위한 방법 및 조성물
WO2017176565A1 (fr) Combinaisons d'un anticorps anti-b7-h1 et d'un agoniste du peptide cxcr4 pour le traitement d'une tumeur solide
CN119055767A (zh) 包含抗her2双特异性抗体的联合治疗药物及其用途
JP7311177B2 (ja) Ａ－ＮＯＲ－５αアンドロスタン薬物と抗がん薬物との併用
TWI798243B (zh) 治療癌症的方法
JP2016104704A (ja) 抗腫瘍剤
JP2021508699A (ja) トリプルネガティブ乳がんを処置するためのｐｄ−１抗体及びアパチニブの併用処置の使用
JP6992984B2 (ja) 腫瘍内静脈形成促進剤
KR20250146947A (ko) 암 예방 또는 치료를 위한 병용 투여용 약학 조성물 세트
CN117281902A (zh) 一种药物组合物在制备治疗黑色素瘤产品中的应用
CN119074887A (zh) 一种治疗肿瘤的综合靶向药物复合物及其制剂和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14765011

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14765011

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP