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
  • A61K31/435—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
• • 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
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • 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
• • 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 provides methods and compositions for use in treating diseases associated with excessive cellular proliferation, such as cancer.
• Cancer is a term used to describe a wide variety of diseases that are each characterized by the uncontrolled, malignant growth of a particular type of cell. It begins in a tissue containing such a cell and, if the cancer has not spread to any additional tissues at the time of diagnosis, may be treated by, for example, surgery, radiation, or another type of localized therapy.
• different approaches to treatment are typically used. Indeed, because it is not possible to determine the extent of metastasis, systemic approaches to therapy are usually undertaken when any evidence of spread is detected. These approaches involve the administration of, for example,
• chemotherapeutic drugs that interfere with the growth of rapidly dividing cells, such as cancer cells.
• Halichondrin B is a structurally complex, macrocyclic compound that was originally isolated from the marine sponge Halichondria okadai, and subsequently was found in Axinella sp., Phakellia carteri, and Lissodendoryx sp. A total synthesis of halichondrin B was published in 1992 (Aicher et al., J. Am. Chem. Soc. 114:3162-3164, 1992). Halichondrin B has been shown to inhibit tubulin polymerization, microtubule assembly, beta s -tubulin crosslinking, GTP and vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis in vitro. This molecule has also been shown to have anti-cancer properties in vitro and in vivo. Halichondrin B analogs having anti-cancer activities are described in U.S. Patent No. 6,214,865 B1.
• Eribulin is a synthetic analog of halichondrin B. Eribulin is also known as ER-086526, and has been assigned CAS number 253128-41-5 and US NCI designation number NSC-707389.
• the mesylate salt of eribulin eribulin mesylate, which is marketed under the trade name
• HALAVEN® and is also known as E7389
• E7389 is approved for the treatment of patients with breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease that should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.
• the chemical name for eribulin mesylate is
• E7080 (also known as lenvatinib mesylate) is an active inhibitor of multiple receptor tyrosine kinases (e.g., receptor tyrosine kinases involved in angiogenesis and tumor proliferation) including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet- derived growth factor receptor a (PDGFRa), KIT, and RET proto-oncogene receptors. It has been assigned CAS number 857890-39-2 (also see 417716-92-8).
• VEGF vascular endothelial growth factor
• FGF fibroblast growth factor
• PDGFRa platelet- derived growth factor receptor a
• KIT RET proto-oncogene receptors
• lenvatinib mesylate is 4-[3-chloro-4-[[(cyclopropylamino)carbonyl]amino]phenoxy]-7-methoxy-6- quinolinecarboxamide, methanesulfonate (1 :1).
• [It is also named as 4-[3-chloro-4-(N'- cyclopropylureido)phenoxyl]-7-methoxyquinoline-6-carboxamide, and N- ⁇ 4-[(6-carbamoyl-7- methoxyquinolin-4-yl)oxy]-2-chlorophenyl ⁇ -A/'-cyclopropylurea monomethanesulfonate.]
• Lenvatinib mesylate can be depicted as:
• the invention is based on the observation that the combination of eribulin and lenvatinib shows improved (e.g., synergistic) antitumor effects. Therefore, the present invention features the co-administration of eribulin (or a pharmaceutically acceptable salt thereof, e.g., eribulin mesylate) and lenvatinib (or a pharmaceutically acceptable salt thereof, e.g., lenvatinib mesylate) in cancer treatment regimens, as well as the use of these agents for such treatment.
• eribulin or a pharmaceutically acceptable salt thereof, e.g., eribulin mesylate
• lenvatinib or a pharmaceutically acceptable salt thereof, e.g., lenvatinib mesylate
• the invention thus provides methods for treating a subject (e.g., a human patient) having or at risk of developing cancer.
• the methods involve administering to a subject (i) eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate), and (ii) lenvatinib or a pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate).
• eribulin or a pharmaceutically acceptable salt thereof e.g., eribulin mesylate
• lenvatinib or a pharmaceutically acceptable salt thereof e.g., lenvatinib mesylate.
• the invention also provides the use of these agents for the treatment of such a subject, as well as the use of these agents for the preparation of medicaments for the treatment of such a subject, as described herein. All descriptions of methods herein are applicable in the context of such uses.
• the subject may be diagnosed with cancer, in treatment for cancer, or in post-therapy recovery from cancer.
• the cancer may be a primary tumor, a metastasis, and/or a solid tumor.
• the cancer can be selected from the group consisting of breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, endometrial cancer, skin cancer (e.g., melanoma), prostate cancer, brain cancer, head and neck cancer, liver cancer, kidney cancer, bladder cancer, gastric cancer, gastrointestinal cancer, cancer of the blood (e.g., leukemia), cancer of the lymphatic system, thyroid cancer, bone cancer (e.g., osteosarcoma), and fibrosarcoma.
• the blood cancer e.g., leukemia
• cancer of the lymphatic system e.g., thyroid cancer, bone cancer (e.g., osteosarcoma), and fibrosarcoma.
• the eribulin or pharmaceutically acceptable salt thereof can be administered by intravenous infusion, for example, for about 1 to about 20 minutes, or for about 2 to about 5 minutes. Further, the eribulin or pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) can be administered in an amount in the range of about 0.1 mg/m 2 to about 20 mg/m 2 , or about 1.4 mg/m 2 or 1.1 mg/m 2 . In addition, the eribulin or pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) can be administered once on each of days 1 and 8 of a 21 -day cycle.
• the lenvatinib or pharmaceutically acceptable salt thereof can be administered orally, for example, in an amount in the range of about 0.1 mg to about 100 mg, or about 4 mg to about 24 mg. Further, in various examples, the lenvatinib or pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate) can be administered daily.
• eribulin or pharmaceutically acceptable salt thereof e.g., eribulin mesylate
• lenvatinib or pharmaceutically acceptable salt thereof e.g., lenvatinib mesylate
• Treatment according to the methods of the invention can: (i) reduce the number of cancer cells; (ii) reduce tumor volume; (iii) increase tumor regression rate; (iv) reduce or slow cancer cell infiltration into peripheral organs; (v) reduce or slow tumor metastasis; (vi) reduce or inhibit tumor growth; (vii) prevent or delay occurrence and/or recurrence of the cancer and/or extend disease- or tumor-free survival time; (viii) increase overall survival time; (ix) reduce the frequency of treatment; and/or (x) relieve one or more of symptoms associated with the cancer.
• the invention also includes methods for decreasing the size of a tumor in a subject.
• eribulin or a pharmaceutically acceptable salt thereof e.g., eribulin mesylate
• lenvatinib or a pharmaceutically acceptable salt thereof e.g., lenvatinib mesylate
• the invention includes the use of these agents for decreasing the size of a tumor in a subject, as described herein.
• kits for use in treating cancer, decreasing tumor size, or inducing or increasing an immune response to a tumor in a subject include (i) eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate), and (ii) lenvatinib or a pharmaceutically acceptable salt thereof (e.g., lenvatinib mesylate).
• these agents are present in dosage form.
• i.v. intravenous
• p.o. per os
• Q1 Dx14 once daily for 14 days
• Q7Dx2 once a week for 2 weeks.
• *P ⁇ 0.05 versus E7389 3.0 mg/kg single agent on day 30 one-way analysis of variance followed by the Dunnett's multiple comparison test).
• i.v. intravenous
• p.o. per os
• Q1 Dx14 once daily for 14 days
• Q7Dx2 once a week for 2 weeks.
• Body weight loss was observed after E7389 administered alone at 3.0 mg/kg and in the combination treatment groups. Partial recovery from body weight loss was observed in all mice upon completion of drug treatment.
• i.v. intravenous
• p.o. per os
• Q1 Dx12 once daily for 12 days
• Q7Dx2 once a week for 2 weeks.
• *P ⁇ 0.05 statically analysis of combination group vs. each single therapy group (repeated measured ANOVA test).
• the invention provides methods for treating cancer involving administration of eribulin and lenvatinib (or pharmaceutically acceptable salts thereof, e.g., mesylate salt), as well as the use of these agents for cancer treatment or the preparation of medicaments therefor.
• eribulin mesylate and lenvatinib mesylate when used in combination, potentiate the anti-cancer effects of one another.
• the combination therapy results in tumor regression.
• treatment of cancer by administering eribulin and lenvatinib (or pharmaceutically acceptable salts thereof, e.g., mesylate salt), can (i) reduce the number of cancer cells; (ii) reduce tumor volume; (iii) increase tumor regression rate; (iv) reduce or slow cancer cell infiltration into peripheral organs; (v) reduce or slow tumor metastasis; (vi) reduce or inhibit tumor growth; (vii) prevent or delay occurrence and/or recurrence of the cancer and/or extend disease or tumor-free survival time; (viii) increase overall survival time; (ix) reduce the frequency of treatment; and/or (x) relieve one or more of symptoms associated with cancer.
• eribulin and lenvatinib or pharmaceutically acceptable salts thereof, e.g., mesylate salt
• eribulin and/or lenvatinib can optionally be used in the present invention in a salt form.
• the salt may be selected from methansulfonic acid salt (e.g., eribulin mesylate or lenvatinib mesylate), hydrochloric acid salt, sulfuric acid salt, citric acid salt, hydrobromic acid salt, hydroiodine acid salt, nitric acid salt, bisulfate, phosphoric acid salt, super phosphoric acid salt, isonicotinic acid salt, acetic acid salt, lactic acid salt, salicic acid salt, tartaric acid salt, pantotenic acid salt, ascorbic acid salt, succinic acid salt, maleic acid salt, fumaric acid salt, gluconic acid salt, saccharinic acid salt, formic acid salt, benzoic acid salt, glutaminic acid salt, ethanesulf
• compositions including eribulin or lenvatinib can be prepared using standard methods known in the art (see, e.g., the patents noted above).
• Pharmaceutical compositions used in the invention can be prepared by, for example, mixing or dissolving the active ingredient(s), having the desired degree of purity, in a physiologically acceptable diluent, carrier, excipient, or stabilizer (see, e.g., Remington's Pharmaceutical Sciences (20 th edition), ed. A. Gennaro, 2000, Lippincott, Williams & Wilkins, Philadelphia, PA).
• Acceptable diluents include water and saline, optionally including buffers such as phosphate, citrate, or other organic acids; antioxidants including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, or other
• carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, PLURONICSTM, or PEG.
• chelating agents such as EDTA
• sugar alcohols such as mannitol or sorbitol
• salt-forming counterions such as sodium
• nonionic surfactants such as TWEENTM, PLURONICSTM, or PEG.
• the formulations of the invention contain a pharmaceutically acceptable preservative.
• the preservative concentration ranges from 0.1 to 2.0%, typically v/v.
• Suitable preservatives include those known in the pharmaceutical arts, such as benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben.
• the eribulin and/or lenvatinib (or pharmaceutically acceptable salts thereof, such as mesylate salts) formulations optionally include a pharmaceutically acceptable salt, such as sodium chloride at, for example, about physiological concentrations.
• eribulin or a pharmaceutically acceptable salt thereof, such as eribulin mesylate
• lenvatinib (or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate) is formulated for oral administration, e.g., in liquid, tablet, or capsule form.
• the formulations noted above can be used for parenteral administration of the drugs.
• the drugs can be administered by routes including intravenous, intra-tumoral, peri-tumoral, intra-arterial, intra-dermal, intra-vesical, ophthalmic, intramuscular, intradermal, intraperitoneal, pulmonary, subcutaneous, and transcutaneous routes.
• routes can also be used including, for example, transmucosal, transdermal, inhalation, intravaginal, rectal, and oral administration routes.
• the dosage of the eribulin and/or lenvatinib (or pharmaceutically acceptable salts thereof, such as mesylate salt) administered may differ markedly depending on the type of target disease, the choice of delivery method, as well as the age, sex, and weight of the patient, the severity of the symptoms, along with other factors, as can be assessed by those of skill in the art.
• the drugs are administered using amounts and regimens that obtain the desired effect (e.g., tumor regression; see also, e.g., the list of effects (i)-(x) set forth above).
• the amounts may have additive or synergistic effects on one or more features of cancer treatment (e.g., tumor regression), as is known in the art.
• the drugs can be administered to a patient substantially simultaneously or sequentially and in either order (e.g., administration of eribulin (or a pharmaceutically acceptable salt thereof, such as eribulin mesylate) prior to lenvatinib (or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate), or vice versa).
• Many regimens used to administer chemotherapeutic drugs involve, for example, administration of a drug (or drugs) followed by repetition of this treatment after a period (e.g., 1-4 weeks) during which the patient recovers from any adverse side effects of the treatment.
• the number of cycles of eribulin (or a pharmaceutically acceptable salt thereof, such as eribulin mesylate) and/or lenvatinib (or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate) administration are 4-8, e.g., 4-7, or 6. It may be desirable to use both drugs at each administration or, alternatively, to have some (or all) of the treatments include only one of the drugs.
• the daily dosage of eribulin may be in the range of, e.g., 0.001 mg/m 2 to about 100 mg/m 2 (e.g., in the range of about 0.01 mg/m 2 to about 50 mg/m 2 , 0.1 to about 5 mg/m 2 , or in the range of about 0.7 mg/m 2 to about 1.5 mg/m 2 , or in any single amount within these ranges (e.g., 1.4 or 1.1 mg/m 2 )).
• the drug may be administered as a single dose once a day, week, month, or year, or more than one dose of the drug may be administered per day, week, month, or year.
• the drug may be administered once daily on days 1 and 8 of a 21 -day cycle.
• the drug may be administered once daily on days 1 , 8, and 15 of a 28-day cycle.
• the drug can be administered over the course of, e.g., 1 minute to 1 hour (or longer), e.g., over 2 to 5 minutes.
• a recommended dose of eribulin mesylate is 1.4 mg/m 2 administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21 -day cycle.
• a recommended dose of eribulin mesylate in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m 2 administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21 -day cycle
• a recommended dose of eribulin mesylate in patients with moderate hepatic impairment is 0.7 mg/m 2 administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle.
• a recommended dose of eribulin mesylate in patients with moderate renal impairment is 1.1 mg/m 2 administered intravenously over 2 to 5 minutes on days 1 and 8 of a 21 -day cycle.
• 1.1 mg/m 2 eribulin mesylate is administered intravenously over 2 to 5 minutes on days 1 , 8, and 15 of a 28-day cycle.
• lenvatinib or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate
• the daily dosage of lenvatinib (or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate) for adults is not particularly restricted, although the drug may be
• the drug may be administered in the range of, e.g., about 0.1 mg to about 100 mg, e.g., about 4 mg to about 24 mg, or in any single amount within this range (e.g., 15 mg).
• the drug may be administered as a single dose once a day, week, month, or year, or more than one dose of the drug may be administered per day, week, month, or year.
• the drug may be administered once daily on days 1 and 8 of a 21 -day cycle.
• the drug may be administered once daily on days 1 , 8, and 15 of a 28-day cycle, or on days 1 , 8, 5, and 22 of a 35 day cycle.
• the drug may be administered once daily throughout the course of a cycle of administration of eribulin (or a pharmaceutically acceptable salt thereof, such as eribulin mesylate) and then, optionally, administered daily throughout the course of one or more additional cycles of eribulin (or a pharmaceutically acceptable salt thereof, such as eribulin mesylate) administration.
• lenvatinib (or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate) may be administered periodically (e.g., daily, weekly, or twice weekly) following the completion of one or more cycles of eribulin (or a pharmaceutically acceptable salt thereof, such as eribulin mesylate) treatment, optionally, for several additional weeks, months, or years (e.g., indefinitely).
• eribulin and lenvatinib typically start on the same "day 1" and different regimens (e.g., any one of those noted above) for the two drugs can be used together.
• different regimens e.g., any one of those noted above
• both drugs may be administered on days 1 and 8 of a 21 -day cycle
• both drugs may be administered on days 1, 8, and 15 of a 28-day cycle, etc.
• one drug e.g., eribulin, or a pharmaceutically acceptable salt thereof, such as eribulin mesylate
• the other drug e.g., lenvatinib, or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate
• eribulin or a pharmaceutically acceptable salt thereof, such as eribulin mesylate
• lenvatinib or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate
• lenvatinib or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate
• a pharmaceutically acceptable salt thereof e.g., eribulin mesylate
• the methods of the present invention may also include the administration of one or more additional therapeutic agents.
• additional therapeutic agents e.g., immunomodulatory agents (e.g., antibodies or vaccines), chemotherapeutic/antitumor agents, antibacterial agents, anti-emetics, and anti-inflammatory agents are suitable.
• the methods of the invention can be used to treat or prevent cancer in a subject (e.g., a human patient) and/or to decrease tumor size.
• the subject may be diagnosed with cancer, at risk for developing cancer, in treatment for cancer, or in post-therapy recovery from cancer. Further, the methods can be used to treat or prevent metastases and/or recurrence.
• the treatment may be chemotherapeutic alone, although treatment in combination with a surgical procedure to remove or reduce the size of a tumor, radiation therapy, and/or ablation therapy is also envisioned.
• cancer of the lymphatic system e.g., thyroid cancer
• bone cancer e.g., osteosarcoma
• fibrosarcoma fibrosarcoma
• kits that include a container with eribulin (or a
• kits can be provided in amounts sufficient to treat cancer in a patient in need thereof (e.g., amounts sufficient for a single administration or for multiple administrations).
• the kits may thus include multiple containers that each include effective amounts of single-dose eribulin (or a pharmaceutically acceptable salt thereof, such as eribulin mesylate) and/or lenvatinib (or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate) pharmaceutical composition(s).
• instruments, devices, and/or diluents necessary for administering the pharmaceutical composition(s) may also be included in the kits.
• the kits may include additional components, such as instructions or administration schedules, for treating a patient with cancer with the drugs.
• E7389 eribulin mesylate
• oral E7080 lenvatinib mesylate
• MTD maximum tolerable dose
• E7080 was dissolved in WFI at a concentration of 1.5 mg/mL. E7080 dosing solution was formulated for 7 days. The stock solution was aliquoted and stored at 4°C until use. 0.5 mg/mL E7389 was diluted with 3% ETOH in saline at concentrations of 0.005, 0.02, and 0.3 mg/mL. E7389 was freshly formulated for each day of dosing.
• A375 human malignant melanoma cells were maintained in monolayer cultures in Dulbecco's Modified Eagle's Medium (DMEM) growth medium supplemented with 10% Fetal Bovine Serum and 1 % of Penicillin-Streptomycin-Glutamine at 37°C in a 5% C0 2 humidified incubator. On the day of inoculation, cells were harvested by Trypsinization, washed, and mixed 1 :1 (v/v) with ice-cold Phosphate Buffered Saline (PBS)/Matrigel.
• DMEM Dulbecco's Modified Eagle's Medium
• PBS Phosphate Buffered Saline
• A375 malignant melanoma cells (5 x 10 6 cells per animal) were inoculated subcutaneously near the right axillary area using a 26-gauge needle in a 0.1 mL volume in 80 female immuncompromised mice (Mouse/Crl:NU- Foxn1 m ; Charles River Laboratories).
• the experiment consisted of a vehicle-treated control group, a single agent drug-treated group for either E7389 or E7080, and three combination drug-treated groups (summarized in Table 1 ). Each group was composed of six mice for a total of 48 mice on the first day of treatment. Forty eight out of 80 mice were selected based on their tumor volumes, and randomly divided into eight groups which resulted in approximately 300 mm 3 of mean tumor volume in each group 17 days after tumor implantation. Following randomization, drug treatment was initiated. E7080 was orally administered daily for 14 days (Q1 Dx14) at a volume of 0.1 mL per 10 g body weight. E7389 (0.05 mg/kg) was intravenously administered daily for 14 days.
• E7389 was administered three hours after oral administration of E7080.
• E7389 at 0.2 or 3.0 mg/kg was administered Q7Dx2 either as a single agent or in combination with E7080 (Q1 Dx14).
• the control group was treated with vehicle (WFI for oral daily dosing (Q1 Dx14) for 14 days and 3% ETOH in saline for intravenous dosing, on a Q7Dx2 schedule).
• the data generated consisted of group mean body weights at each measurement and group mean tumor volumes at each measurement.
• the mean ⁇ SEM for tumor volume and relative body weight for each experimental group was calculated.
• Table 1 Study Design for Investigation of Antitumor activity ofE7389 in combination with E7080 in A375 human malignant melanoma xenografts
• Figure 1 shows the effect of E7389 in combination with E7080 in A375 human malignant melanoma xenografts in mice.
• Single agent administration of either E7389 or E7080 at the highest dose of 3.0 mg/kg (MTD for E7389) and 15 mg/kg (MTD for E7080) resulted in tumor growth delay, but not tumor regression.
• the combination of E7389 with E7080 potentiated the antitumor activity of E7389 at all doses tested. Tumor growth inhibition was observed at all combination groups in a dose-dependent fashion (Figure 1 ).
• Administration of 3.0 mg/kg E7389 in combination with E7080 caused additional body weight loss. However, recovery from body weight loss was observed upon completion of drug treatment ( Figure 2).
• E7080 was administered orally once daily for 14 days.
• E7389 at 0.05 mg/kg was intravenously administered daily for 14 days.
• E7389 was dosed three hours after the oral administration of E7080.
• E7389 at 0.2 or 3.0 mg/kg was administered at Q7Dx2 either as a single agent or in combination.
• the study was terminated on 30 days after transplantation.
• Administration of 3.0 mg/kg (Q7Dx2) and 0.05 mg/kg E7389 (Q1 Dx14) combined with 15 mg/kg E7080 daily administration (Q1 Dx14) resulted in tumor regression in this study.
• E7389 alone at 3.0 mg/kg and combination treatment showed strong antitumor activity in the A375 human malignant melanoma xenograft model. Body weight loss appeared reversible as all animals partially recovered upon completion of drug treatment. E7389 administered at a low dose on a metronomic schedule (0.05 mg/kg Q1 Dx14) combined with 15 mg/kg E7080 daily dosing (Q1 Dx14) resulted in significant tumor regression compared to E7389 3.0 mg/kg single agent treatment.
• a patient with breast cancer is treated with a combination of E7389 (eribulin mesylate) and E7080 (lenvatinib mesylate) according to the following protocol.
• E7389 is administered at 1.4 mg/m 2 intravenously over 2 to 5 minutes on days 1 and 8 of a 21 -day cycle.
• E7080 is orally administered at 24 mg/day on each day of the 21-day cycle of E7389 treatment, starting on the same day.
• the patient is treated for a total of 4-6 cycles, depending upon factors such as the occurrence and severity of side effects, as well as clinical effects, as determined by a medical professional.
• E7080 treatment continues after the end of the E7389 treatment cycles.
• E7389 eribulin mesylate
• oral E7080 lenvatinib mesylate
• E7389 was administered at 1.5 mg/kg alone, or was co-administered with 10 mg/kg E7080.
• the combination of E7389 and E7080 showed significantly strong antitumor activity than that of each monotherapy.
• E7080 was dissolved in DW at a concentration of 1.0 mg/mL.
• 0.5 mg/mL E7389 was diluted with saline at concentrations of 0.15 mg/mL.
• Human non-small cell lung cancer cell lines NCI-H1993 and PC-9, were maintained in monolayer cultures in RPMI-1640 medium supplemented with 10% Fetal Bovine Serum and 1 % of Penicillin-Streptomycin-Amphotericin at 37°C in a 5% C0 2 humidified incubator. On the day of inoculation, cells were harvested by Trypsinization, washed, and mixed 1 :1 (v/v) with medium/GelTrex.
• NCI-H1993 and PC-9 human non-small cell lung cancer cells (10 x 10 6 cells per animal) were inoculated subcutaneously near the right axillary area using a 26-gauge needle in a 0.1 mL volume in female immuncompromised mice (Mouse: BALB/c Sic nu/nu; Japan SLC, Inc.).
• the experiment consisted of a no inject control group, a single agent drug-treated group for either E7389 (1.5 mg/kg) or E7080 (10 mg/kg), and combination drug-treated groups. Each group was composed of five mice. Mice were selected based on their tumor volumes, and randomly divided into groups which resulted in approximately 200 mm 3 (NCI-H1993: 191 mm 3 , PC-9: 227 mm 3 ) of mean tumor volume in each group 10 days (NCI-H1993) or 8 days (PC-9) after tumor cells inoculation. Following randomization, drug treatment was initiated. E7389 (1.5 mg/kg) was intravenously administered weekly for two weeks (Q7Dx2). E7080 was orally administered daily for 12 days (Q1 Dx12). Both drugs were administered at a volume of 0.1 mL per 10 g body weight.
• Tumor volume was determined by caliper measurements (mm) using the formula
• Tumor volume (mm 3 ) length (mm) ⁇ width 2 (mm 2 ) ⁇ 1/2
• Length largest diameter of tumor
• Width diameter perpendicular to length
• Figure 3 shows the effect of E7389 in combination with E7080 in NCI-H 993 (left) or PC- 9 (right) human non-small cell lung cancer xenografts in mice.
• Single treatment of E7389 (1.5 mg/kg) or E7080 (10 mg/kg) resulted significant antitumor activity in both xenograft models.
• a method for treating a subject having or at risk of developing cancer comprising administering to the subject (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) lenvatinib or a pharmaceutically acceptable salt thereof.
• said cancer is selected from the group consisting of breast cancer, pancreatic cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, ovarian cancer, endometrial cancer, skin cancer (e.g., melanoma), prostate cancer, brain cancer, head and neck cancer, liver cancer, kidney cancer, bladder cancer, gastric cancer,
• cancer of the blood e.g., leukemia
• cancer of the lymphatic system thyroid cancer
• bone cancer e.g., osteosarcoma
• fibrosarcoma e.g., fibrosarcoma
• a method for decreasing the size of a tumor in a subject comprising administering to the subject (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) lenvatinib or a pharmaceutically acceptable salt thereof.
• kits for use in treating cancer, decreasing tumor size, or inducing or increasing an immune response to a tumor in a subject comprising (i) eribulin or a pharmaceutically acceptable salt thereof, and (ii) lenvatinib or a pharmaceutically acceptable salt thereof.
• Eribulin or a pharmaceutically acceptable salt thereof for use in a method for treating a subject having or at risk of developing cancer, characterized in that said compound is administered to the subject with lenvatinib or a pharmaceutically acceptable salt thereof.
• Lenvatinib or a pharmaceutically acceptable salt thereof for use in a method for treating a subject having or at risk of developing cancer, characterized in that said compound is administered to the subject with eribulin or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition for treating a subject having or at risk of developing cancer comprising eribulin or a pharmaceutically acceptable salt thereof, characterized in that said pharmaceutical composition is administered to a subject with lenvatinib or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition for treating a subject having or at risk of developing cancer comprising lenvatinib or a pharmaceutically acceptable salt thereof, characterized in that said pharmaceutical composition is administered to a subject with eribulin or a pharmaceutically acceptable salt thereof.

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