WO2021011488A1 - Compositions comprenant du chlorhydrate d'aldoxorubicine et de l'ifosfamide et leur utilisation pour le traitement d'un sarcome de tissu mou - Google Patents

Compositions comprenant du chlorhydrate d'aldoxorubicine et de l'ifosfamide et leur utilisation pour le traitement d'un sarcome de tissu mou Download PDF

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WO2021011488A1
WO2021011488A1 PCT/US2020/041831 US2020041831W WO2021011488A1 WO 2021011488 A1 WO2021011488 A1 WO 2021011488A1 US 2020041831 W US2020041831 W US 2020041831W WO 2021011488 A1 WO2021011488 A1 WO 2021011488A1
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aldoxorubicin
administration
ifosfamide
pharmaceutical composition
hydrochloride
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PCT/US2020/041831
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English (en)
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John Lee
Patrick Soon-Shiong
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Nantkwest, Inc.
Nantcell, Inc.
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Publication of WO2021011488A1 publication Critical patent/WO2021011488A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides

Definitions

  • Anthracyclines are a class of antibiotics derived from certain types of Streptomyces bacteria. Anthracyclines are often used as cancer therapeutics and function in part as nucleic acid intercalating agents and inhibitors of the DNA repair enzyme topoisomerase II, thereby damaging nucleic acids in cancer cells and preventing the cells from replicating.
  • An anthracycline cancer therapeutic is doxorubicin, which is used to treat a variety of cancers including breast cancer, lung cancer, ovarian cancer, lymphoma, and leukemia.
  • the 6-maleimidocaproyl hydrazone of doxorubicin (aldoxorubicin hydrochloride (HC1) also known as DOXO-EMCH or INNO-206) was synthesized to provide an acid- sensitive linker that could be used to prepare immunoconjugates of doxorubicin and monoclonal antibodies directed against tumor antigens (Winner et ah, Bioconjugate Chem 4:521-527 (1993)).
  • antibody disulfide bonds are reduced with dithiothreitol to form free thiol groups, which in turn react with the maleimide group of aldoxorubicin HC1 to form a stable thioether bond.
  • the doxorubicin-antibody conjugate When administered, the doxorubicin-antibody conjugate is targeted to tumors containing the antigen recognized by the antibody. Following antigen-antibody binding, the conjugate is internalized within the tumor cell and transported to lysosomes. In the acidic lysosomal environment, doxorubicin is released from the conjugate intracellularly by hydrolysis of the acid-sensitive hydrazone linker. Upon release, the doxorubicin reaches the cell nucleus and is able to kill the tumor cell.
  • aldoxorubicin HC1 A subsequent use of aldoxorubicin HC1 was developed by reacting the molecule in vitro with the free thiol group (Cys-34) on human serum albumin (HSA) to form a stable thioether conjugate with this circulating protein (Kratz et ah, J Med Chem 45:5523-5533 (2002)). Based on these results, it was hypothesized that intravenously-administered aldoxorubicin HC1 would rapidly conjugate to HSA in vivo and that this macromolecular conjugate would preferentially accumulate in tumors due to an "enhanced permeability and retention" (EPR) intratumor effect (Maeda et ah, J Control Release 65:271-284 (2000)).
  • EPR enhanced permeability and retention
  • aldoxorubicin HC1 Acute and repeat-dose toxicology studies with aldoxorubicin HC1 in mice, rats, and dogs identified no toxicity beyond that associated with doxorubicin, and showed that all three species had significantly higher tolerance for aldoxorubicin HC1 compared to doxorubicin (Kratz et al., Hum Exp Toxicol 26: 19-35 (2007)). Based on the favorable toxicology profile and positive results from animal tumor models, a Phase 1 clinical trial of aldoxorubicin HC1 was conducted in 41 advanced cancer patients (Unger et al., Clin Cancer Res 13 :4858-4866 (2007)). This trial found aldoxorubicin HC1 to be safe for clinical use and in some cases induced tumor regression.
  • High-grade, advanced, soft-tissue sarcoma is an aggressive disease with poor prognosis.
  • soft-tissue sarcoma encompasses a broad diversity of tumors.
  • gastrointestinal stromal tumors effective targeted treatment is available (Verweij J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364: 1127-34).
  • translocations or amplifications have been associated with an increasing number of sarcoma subtypes, these findings have led to innovative treatment for only a minority of cases.
  • Histological diagnosis can be used to guide treatment for some sarcomas— e.g., taxanes for angiosarcoma, (Penel N, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol 2008; 26: 5269-74; Skubitz KM, Haddad PA. Paclitaxel and pegylated-liposomal doxorubicin are both active in angiosarcoma. Cancer 2005; 104: 361-66) or gemcitabine-containing treatment for leiomyosarcoma and un-differentiated pleomorphic sarcoma (Hensley ML, et al.
  • doxorubicin and ifosfamide which have been used to treat soft-tissue sarcoma for more than 30 years— still have an important role; however, whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. Few studies have directly addressed this question and none have shown that overall survival is improved by dose intensification or combination treatment compared with doxorubicin alone. Ifosfamide has a clear dose-response relationship (van Oosterom AT, et al, and the EORTC Soft Tissue and Bone Sarcoma Group.
  • progression-free survival might be equally important as overall survival, although improved overall survival is still a key goal of treatment (Van Glabbeke M, et al. app and the EORTC Soft Tissue and Bone Sarcoma Group. Progression-free rate as the principal end point for phase II trials in soft-tissue sarcomas. Eur J Cancer 2002; 38: 543-49).
  • One embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (a) 15 to 35 parts of aldoxorubicin hydrochloride (HC1) or a pharmaceutically acceptable salt thereof; and (b) 80 to 120 parts of ifosfamide.
  • the pharmaceutical composition further comprises 80 to 120 parts of mesna.
  • the aldoxorbicin hydrochloride is prepared by reconstituting a lyophilized composition of aldoxorubicin hydrochloride in a reconstitution liquid comprising ethanol and water.
  • the volumne: volume ratio of ethanol water is about 10:90 to about 90: 10.
  • the pharmaceutical composition is formulated for an administration route selected from the group consisting of intravaneous, oral, parenteral, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intraci sternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, and administration by suppository.
  • an administration route selected from the group consisting of intravaneous, oral, parenteral, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intraci sternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, and administration by suppository.
  • the aldoxorubicin hydrochloride is administered together with or separately from the ifosfamide administration as an injection or infusion.
  • the pharmaceutical composition comprises about 25 parts aldoxorubicin hydrochloride.
  • the pharmaceutical composition comprises about 100 parts ifosfamide.
  • the pharmaceutical composition comprises about 100 parts mesna.
  • Another embodiment of the invention relates to a method of treating soft tissue sarcoma comprising administering to a subject a therapeutically effective amount of pharmaceutical composition comprising (a) a therapeutically effective amount of aldoxorubicin hydrochloride or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of ifosfamide.
  • the soft tissue sarcoma is selected from the group consisting of leiomyosarcoma and liposarcoma
  • the subject is further administered mesna.
  • the pharmaceutical composition is administered to the subject by an administration route selected from the group consisting of intravaneous, oral, parenteral, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, and administration by suppository.
  • an administration route selected from the group consisting of intravaneous, oral, parenteral, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, and administration by suppository.
  • the aldoxorubicin hydrochloride is administered together with or separately from the ifosfamide administration as an injection or infusion.
  • the therapeutically effective amount of aldoxorubicin hydrochloride is about 250 mg/m2 when the composition is formulated for intravenous administration.
  • the therapeutically effective amount of ifosfamide is about 1 gm/m2/day when the composition is formulated for intravenous administration.
  • the therapeutically effective amount of aldoxorubicin hydrochloride is administered every day for 28 days starting on day 1 of an administration cycle for six cycles.
  • the therapeutically effective amount of ifosfamide is administered every day for 10 to 14 days starting on day 1 of an administration cycle for six cycles.
  • the subject is further administered an anti-cancer agent.
  • the anti-cancer agent is selected from the group consisting of cisplatin, carboplatin, paclitaxel, docetaxel, temozolomide, nitrosoureas, bortezomib, gemcitabine, etoposide, and topptecan.
  • Fig. 1 is a Kaplan-Meier Figure showing progression free survival (PFS). Aldoxorubicin HC1 administered at 250 mg/m 2 (250) or 170 mg/m 2 (170).
  • Fig. 2 is a graph showing percent change in target lesion measurements. Arms-darker is for Aldoxorubicin HC1 at 170 mg/m 2 ; lighter is for Aldoxorubicin HC1 at 250 mg/m 2 .
  • patient refers to either a human or a non-human animal.
  • mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats).
  • livestock animals e.g., bovines, porcines
  • companion animals e.g., canines, felines
  • rodents e.g., mice and rats.
  • pharmaceutically effective amount refers to an amount effective to treat cancer in a patient, e.g., effecting a beneficial and/or desirable alteration in the general health of a patient suffering from a disease (e.g., cancer).
  • treating cancer includes, hut is not limited to, killing cancer ceils, preventing the growth of new cancer cells, causing tumor regression (a decrease in tumor size), causing a decrease in metastasis, improving vital functions of a patient, improving the well-being of the patient, decreasing pain, improving appetite, improving the patient's weight, and arty combination thereof
  • a “pharmaceutically effective amount” or“therapeutically effective amount” also refers to the amount required to improve the clinical symptoms of a patient.
  • the therapeutic methods or methods of treating cancer described herein are not to be interpreted or otherwise limited to "curing" cancer.
  • treating includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a subject's condition.
  • treatment is an approach far obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • a pharmaceutical composition comprising aldoxorubicin HC1 and ifosfamide has improved efficacy compared to a composition comprising doxorubicin alone or in combination with ifosfamide in treating subjects having certain cancers, such as soft tissue sarcomas.
  • a pharmaceutical composition of the present invention comprises about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 to about 35 parts of aldoxorubicin HC1 and about 80, 81, 82, 83, 84, 85, 86, 87,
  • the pharmaceutical composition can further comprise about 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107,
  • the composition comprises about 25 parts aldoxorubicin HC1. In another aspect of the invention, the composition comprises about 100 parts of ifosfamide and in still another aspect of the invention, the composition comprises about 100 parts of mesna.
  • the aldoxorubicin HC1 in the pharmaceutical composition of the present invention can be prepared by reconstituting a lyophilized composition of aldoxorubicin HC1 in a reconstitution liquid comprising ethanol and water. Such reconstitution may comprise adding the reconstitution liquid and mixing, for example, by swirling or vortexing the mixture.
  • the reconstituted formulation then can be made suitable for injection by mixing e.g., Lactated Ringer's solution with the formulation to create an injectable composition.
  • the volume.volume ratio of ethanol : water for use as a reconstitution liquid can be from about 10:90 to about 90: 10, e.g., about 10:90, about 20:80, about 30:70, about 40:60, about 41 :59, about 42: 58, about 43 :57, about 44:56, about 45:55, about 46:54, about 47:53, about 48:52, about 49:51, about 50:50 (e.g., 50 ⁇ 5:5Q ⁇ 5), about 51 :49, about 52:48, about 53:47, about 54:46, about 55:45, about 56:44, about 57:43, about 58:42, about 59:41 , about 60:40, about 70:30, about 80:20, about 90: 10, or any intermediate ratio thereof.
  • the pharmaceutical composition can be formulated into suitable routes of administration including, but are not limited to intravenous, oral, parenteral, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intraci sternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, and administration by suppository.
  • the composition is formulated for intravenous administration including intravenous injection and/or intravenous infusion.
  • a method of administering a pharmaceutical composition of the invention would depend on factors such as the age, weight, and physical condition of the patient being treated, and the disease or condition being treated. The skilled worker would, thus, be able to select a method of administration optimal for a patient on a case-by- case basis.
  • the pharmaceutical composition is formulated for administration as an injection or infusion.
  • the aldoxorubicin HC1 can be administered together with or separately from the ifosfamide.
  • the mesna can be administered together with or separately from the aldoxorubicin HC1 and the ifosfamide.
  • compositions and kits of the present invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • compositions may be administered in a variety of conventional ways.
  • routes of administration include intravenous, oral, parenteral, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, or administration by suppository.
  • routes of administration include intravenous, oral, parenteral, intra-arterial, cutaneous, subcutaneous, intramuscular, topical, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, central nervous system (CNS) administration, or administration by suppository.
  • the compositions are injected intravenously.
  • the present invention provides a kit comprising a therapeutically effective substance (e.g., aldoxorubicin HC1, ifosfamide, mesna) as described herein and, a pharmaceutically acceptable excipient, a carrier, and/or a diluent.
  • a therapeutically effective substance e.g., aldoxorubicin HC1, ifosfamide, mesna
  • one or more excipients may be included in the composition.
  • One of skill in the art would appreciate that the choice of any one excipient may influence the choice of any other excipient. For example, the choice of a particular excipient may preclude the use of one or more additional excipients because the combination of excipients would produce undesirable effects.
  • Excipients may include, but are not limited to, co-solvents, solubilizing agents, buffers, pH adjusting agents, bulking agents, surfactants, encapsulating agents, tonicity-adjusting agents, stabilizing agents, protectants, and viscosity modifiers.
  • a solubilizing agent can be included in the pharmaceutical compositions.
  • Solubilizing agents may be useful for increasing the solubility of any of the components of the composition, including a therapeutically effective substance (e.g., aldoxorubicin HC1, ifosfamide, mesna) or an excipient.
  • a therapeutically effective substance e.g., aldoxorubicin HC1, ifosfamide, mesna
  • the solubilizing agents described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary solubilizing agents that may be used in the compositions.
  • solubilizing agents include, but are not limited to, ethyl alcohol, tert-butyl alcohol, polyethylene glycol, glycerol, methylparaben, propylparaben, polyethylene glycol, polyvinyl pyrrolidone, and any pharmaceutically acceptable salts and/or combinations thereof.
  • the pH of the compositions may be any pH that provides desirable properties for the composition. Desirable properties may include, for example, therapeutically effective substance (e.g., aldoxorubicin HC1, ifosfamide, mesna) stability, increased therapeutically effective substance retention as compared to compositions at other pHs, and improved filtration efficiency.
  • the pH of the compositions can be from about 3.0 to about 9.0, e.g., from about 5.0 to about 7.0.
  • the pH of the compositions can be 5.5.+-.0.1, 5.6.+-.0.1, 5.7.+-.0.1, 5.8.+-.0.1, 5.9.+-.0.1, 6.0.+-.0.1, 6.1.+-.0.1, 6.2.+-.0.1, 6.3.+-.0.1, 6.40,1, or 6.5.+-.0.1.
  • a buffer may have a pKa of, for example, about 5.5, about 6.0, or about 6.5.
  • a buffer may have a pKa of, for example, about 5.5, about 6.0, or about 6.5.
  • Buffers are well known in the art. Accordingly, the buffers described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary buffers that may be used in the formulations or compositions of the invention.
  • a buffer includes, but is not limited to Tris, Tris HC1, potassium phosphate, sodium phosphate, sodium citrate, sodium ascorbate, combinations of sodium and potassium phosphate, Tris/Tris HC1, sodium bicarbonate, arginine phosphate, arginine hydrochloride, histidine hydrochloride, cacodylate, succinate, 2-(N-morpholino) ethanesulfonic acid (MES), maleate, bis-tris, phosphate, carbonate, and any pharmaceutically acceptable salts and/or combinations thereof.
  • Tris Tris HC1, potassium phosphate, sodium phosphate, sodium citrate, sodium ascorbate, combinations of sodium and potassium phosphate, Tris/Tris HC1, sodium bicarbonate, arginine phosphate, arginine hydrochloride, histidine hydrochloride, cacodylate, succinate, 2-(N-morpholino) ethanesulfonic acid (MES), maleate, bis-tris,
  • a pH-adjusting agent may be included in the compositions. Modifying the pH of a composition may have beneficial effects on, for example, the stability or solubility of a therapeutically effective substance, or may be useful in making a composition suitable for parenteral administration.
  • pH-adjusting agents are well known in the art. Accordingly, the pH-adjusting agents described herein are not intended to constitute an exhaustive list but are provided merely as exemplary pH-adjusting agents that may be used in the compositions. pH-adjusting agents may include, for example, acids and bases.
  • a pH-adjusting agent includes, but is not limited to, acetic acid, hydrochloric acid, phosphoric acid, sodium hydroxide, sodium carbonate, and combinations thereof.
  • a bulking agent may be included in the compositions.
  • Bulking agents are commonly used in lyophilized compositions to provide added volume to the composition and to aid visualization of the composition, especially in instances where the lyophilized pellet would otherwise be difficult to see. Bulking agents also may help prevent drug loss due to blowout of the active component(s) of a pharmaceutical composition and/or to aid cryoprotection of the composition. Bulking agents are well known in the art. Accordingly, the bulking agents described herein are not intended to constitute an exhaustive list but are provided merely as exemplary bulking agents that may be used in the compositions.
  • Exemplary bulking agents may include carbohydrates, monosaccharides, disaccharides, polysaccharides, sugar alcohols, amino acids, and sugar acids, and combinations thereof.
  • Carbohydrate bulking agents include, but are not limited to, mono-, di-, or poly-carbohydrates, starches, aldoses, ketoses, amino sugars, glyceraldehyde, arabinose, lyxose, pentose, ribose, xylose, galactose, glucose, hexose, idose, mannose, talose, heptose, glucose, fructose, methyl a-D-glucopyranoside, maltose, lactone, sorbose, erythrose, threose, arabinose, allose, altrose, gulose, idose, talose, erythrulose, ribulose, xylulose, psicose, tag
  • Sugar alcohol bulking agents include, but are not limited to, alditols, inositols, sorbitol, and mannitol.
  • Amino acid bulking agents include, but are not limited to, glycine, histidine, and proline.
  • Sugar acid bulking agents include, but are not limited to, aldonic acids, uronic acids, aldaric acids, gluconic acid, isoascorbic acid, ascorbic acid, glucaric acid, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, neuraminic acid, pectic acids, and alginic acid.
  • a surfactant may be included in the compositions.
  • Surfactants in general, reduce the surface tension of a liquid composition. This may provide beneficial properties such as improved ease of filtration. Surfactants also may act as emulsifying agents andlor solubilizing agents. Surfactants are well known in the art. Accordingly, the surfactants described herein are not intended to constitute an exhaustive list but are provided merely as exemplary surfactants that may be used in the formulations or compositions of the invention.
  • Surfactants that may be included include, but are not limited to, sorbitan esters such as polysorbates (e.g., polysorbate 20 and polysorbate 80), lipopolysaccharides, polyethylene glycols (e.g., PEG 400 and PEG 3000), poloxamers (i.e., pluronics), ethylene oxides and polyethylene oxides (e.g., Triton X-100), saponins, phospholipids (e.g., lecithin), and combinations thereof.
  • sorbitan esters such as polysorbates (e.g., polysorbate 20 and polysorbate 80), lipopolysaccharides, polyethylene glycols (e.g., PEG 400 and PEG 3000), poloxamers (i.e., pluronics), ethylene oxides and polyethylene oxides (e.g., Triton X-100), saponins, phospholipids (e.g., lecithin), and combinations thereof.
  • an encapsulating agent may be included in the compositions.
  • Encapsulating agents can sequester molecules and help stabilize or solubilize them.
  • Encapsulating agents are well known in the art. Accordingly, the encapsulating agents described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary encapsulating agents that may be used in the compositions.
  • Encapsulating agents that may be included in compositions include, but are not limited to, dimethyl-beta- cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and trimethl-beta-cyclodextrin, and combinations thereof.
  • Atonicity-adjusting agent may be included in the compositions.
  • the tonicity of a liquid composition is an important consideration when administering the composition to a patient, for example, by parenteral administration. Tonicity-adjusting agents, thus, may be used to help make a composition suitable for administration. Tonicity-adjusting agents are well known in the art. Accordingly, the tonicity-adjusting agents described herein are not intended to constitute an exhaustive list but are provided merely as exemplary tonicity-adjusting agents that may be used in the compositions.
  • Tonicity-adjusting agents may be ionic or non-ionic and include, but are not limited to, inorganic salts, amino acids, carbohydrates, sugars, sugar alcohols, and carbohydrates.
  • Exemplary inorganic salts may include sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate.
  • An exemplary amino acid is glycine.
  • Exemplary sugars may include sugar alcohols such as glycerol, propylene glycol, glucose, sucrose, lactose, and mannitol.
  • stabilizing agent may be included in the compositions
  • Stabilizing agents help increase the stability of a therapeutically effective substance in the compositions. This may occur by, for example, reducing degradation or preventing aggregation of a therapeutically effective substance.
  • mechanisms for enhancing stability may include sequestration of the therapeutically effective substance from a solvent or inhibiting free radical oxidation of the anthracycline compound.
  • Stabilizing agents are well known in the art. Accordingly, the stabilizing agents described herein are not intended to constitute an exhaustive list but are provided merely as exemplary stabilizing agents that may be used in the compositions.
  • Stabilizing agents may include, but are not limited to, emulsifiers and surfactants.
  • a protectant may be included in the compositions.
  • Protectants are agents that protect a pharmaceutically active ingredient (e.g., a therapeutically effective substance) from an undesirable condition (e.g., instability caused by freezing or lyophilization, or oxidation).
  • Protectants can include, for example, cryoprotectants, lyoprotectants, and antioxidants.
  • Cryoprotectants are useful in preventing loss of potency of an active pharmaceutical ingredient (e.g., an anthracycline compound) when a composition is exposed to a temperature below its freezing point.
  • a cryoprotectant could be included in a reconstituted lyophilized formulation so that the formulation could be frozen before dilution for intravenous (IV) administration.
  • cryoprotectants are well known in the art. Accordingly, the cryoprotectants described herein are not intended to constitute an exhaustive list, but are provided merely as exemplary cryoprotectants that may be used in the compositions. Cryoprotectants include, but are not limited to, solvents, surfactants, encapsulating agents, stabilizing agents, viscosity modifiers, and combinations thereof.
  • Cryoprotectants may include, for example, disaccharides (e.g., sucrose, lactose, maltose, and trehalose), polyols (e.g., glycerol, mannitol, sorbitol, and dulcitol), glycols (e.g., ethylene glycol, polyethylene glycol and propylene glycol).
  • disaccharides e.g., sucrose, lactose, maltose, and trehalose
  • polyols e.g., glycerol, mannitol, sorbitol, and dulcitol
  • glycols e.g., ethylene glycol, polyethylene glycol and propylene glycol.
  • Lyoprotectants are useful in stabilizing the components of a composition.
  • a therapeutically effective substance could be lyophilized with a lyoprotectant prior to reconstitution.
  • Lyoprotectants are well known in the art. Accordingly, the lyoprotectants described herein are not intended to constitute an exhaustive list but are provided merely as exemplary lyoprotectants that may be used in the compositions.
  • Lyoprotectacts include, but are not limited to, solvents, surfactants, encapsulating agents, stabilizing agents, viscosity modifiers, and combinations thereof.
  • Exemplary lyoprotectants may be, for example, sugars and polyols.
  • Trehalose, sucrose, dextran, and hydroxypropyl- beta-cyclodextrin are non-limiting examples of lyoprotectants.
  • Antioxidants are useful in preventing oxidation of the components of a composition. Oxidation may result in aggregation of a drug product or other detrimental effects to the purity of the drug product or its potency.
  • Antioxidants are well known in the art. Accordingly, the antioxidants described herein are not intended to constitute an exhaustive list but are provided merely as exemplary antioxidants that may be used in the compositions.
  • Antioxidants may be, for example, sodium ascorbate, citrate, thiols, metabi sulfite, and combinations thereof
  • a viscosity modifying agent may be included in the composition.
  • Viscosity modifiers change the viscosity of liquid compositions. This may be beneficial because viscosity plays an important role in the ease with which a liquid composition is filtered. A composition may be filtered prior to lyophilization and reconstitution, or after reconstitution. Viscosity modifiers are well known in the art. Accordingly, the viscosity modifiers described herein are not intended to constitute an exhaustive list but are provided merely as exemplary viscosity modifiers that may be used in the compositions. Viscosity modifiers include solvents, solubilizing agents, surfactants, and encapsulating agents. Exemplary viscosity modifiers that may be included in compositions include, but are not limited to, N-acetyl-DL-tryptophan and N-acetyl- cysteine.
  • each of the methods or uses of the present invention comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition as described herein, to treat soft tissue sarcoma.
  • the soft tissue sarcoma is leiomyosarcoma or liposarcoma.
  • the method comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of aldoxorubicin HC1 or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of ifosfamide.
  • the method further comprises administering to the subject a therapeutically effective amount of mesna.
  • the therapeutically effective amount of aldoxorubicin HC1 is about 250 mg/m 2 when the composition is formulated for intravenous administration.
  • the therapeutically effective amount of ifosfamide is about 1 gm/m 2 /day when the composition is formulated for intravenous administration.
  • the therapeutically effective amount of mesna is about 1 gm/m 2 /day when the composition is formulated for intravenous administration.
  • the therapeutically effective amount of aldoxorubicin HC1 can be administered every day for 28 days starting on day 1 of an administration cycle for six cycles.
  • the therapeutically effective amount of ifosfamide is administered every day for 10 to 14 days starting on day 1 of an administration cycle for six cycles.
  • the pharmaceutical composition may be administered alone. In some embodiments, the pharmaceutical composition may be administered in combination with an anti-cancer agent. In some embodiments, the pharmaceutical composition may be administered in combination with other medications such platinum-containing anti-cancer compounds or agents, taxanes, alkylating agents, proteasome inhibitors, nucleoside analogs, topoisomerase inhibitors, immunosuppressive agents for the treatment of immune-mediated brain disorders.
  • the anti-cancer compound or agent is selected from the group consisting of cisplatin, carboplatin, paclitaxel, docetaxel, temozolomide, nitrosoureas, bortezomib, gemcitabine, etoposide, and topptecan.
  • the method comprises administering the pharmaceutical composition disclosed herein either alone or in combination with an anti-cancer agent for treating cancers or tumors.
  • This example describes a phase 3 randomized open-label study comparing aldoxorubicin/ifosfamide versus doxorubicin in patients with recurrent and metastatic leiomyosarcoma and liposarcoma.
  • the efficacy of aldoxorubicin HC1, aldoxorubicin HC1 plus ifosfamide as well as aldoxorubicin HC1 plus ifosfamide plus mesna versus doxorubicin in metastatic or recurrent leiomyosarcoma and liposarcoma is assessed by PFS.
  • tumor molecular profiles, therapy-induced changes in immune responses, and molecular changes in ctDNA and ctRNA; and their correlations with subject outcomes is also assessed.
  • IV intravenously
  • aldoxorubicin HC1 is administered every 3 weeks in subjects with (complete response (CR), partial response (PR), or stable disease (SD)) to initial combination therapy may continue with aldoxorubicin alone until disease progression, unacceptable toxicity or withdrawal of consent.
  • the comparison arm uses FDA approved dosing of doxorubicin to be administered up to 8 cycles until disease progression.
  • G-CSF granulocyte colony-stimulating factor
  • Tumors are assessed at screening, and tumor response is assessed every 8 weeks during the initial 6 months and then every 12 weeks by computed tomography (CT) or magnetic resonance imaging (MRI) CT of target and non-target lesions in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the initial phase of treatment consists of 6 repeated 28 day cycles of aldoxorubicin HCl/ifosfamide/mesna. After 6 cycles, aldoxorubicin HC1 is administered every 3 weeks in subjects with (CR, PR, or SD) to initial combination therapy may continue with aldoxorubicin alone until disease progression, unacceptable toxicity or withdrawal of consent.
  • the study treatment is conducted in accordance with the following dosing regimen: Days 1-14 every 28 days for 6 cycles:
  • Doxorubicin in the control arm is administered per FDA approved guidelines outlined below:
  • DCR Disease Control Rate
  • Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), two forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and abstinence.
  • Exclusion Criteria 1. Within 5 years prior to first dose of study treatment, any evidence of other active malignancies except controlled basal cell carcinoma; prior history of in situ cancer (e.g., breast, melanoma, cervical); prior history of prostate cancer that is not under active systemic treatment (except hormonal therapy) and with undetectable prostate- specific antigen (PSA) ( ⁇ 0.2 ng/mL); and bulky (> 1.5 cm) disease with metastasis in the central hilar area of the chest and involving the pulmonary vasculature.
  • PSA prostate- specific antigen
  • ALT [SGPT] alanine aminotransferase > 3.0 c ULN (> 5 c ULN in subjects with liver metastases).
  • Serum anion gap > 16 mEq/L or arterial blood with pH ⁇ 7.3.
  • HAV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • Subjects are treated for up to 2 years (up to 1 year in each treatment phase) or until they experience PD or unacceptable toxicity (not corrected with dose reduction), withdraw consent, or the Investigator feels it is no longer in the subject’s best interest to continue treatment.
  • Safety endpoints include assessments of treatment-emergent AEs, SAEs, and clinically significant changes in safety laboratory tests, physical examinations, electrocardiograms (ECGs), and vital signs. All subjects are evaluable for toxicity from the time of their first study treatment. Toxicities will be graded using the NCI CTCAE Version 4.03
  • ORR and PFS are assessed by CT, MRI, or PET-CT of target and non-target lesions every 8 weeks during first 6 months and every 12 weeks thereafter in accordance with RECIST Version 1.1. OS, DOR, and DCR is also assessed.
  • Tumor Molecular Profiling Genomic sequencing of tumor cells from tissue relative to non-tumor cells from whole blood is conducted to identify tumor-specific genomic variances that can contribute to disease progression and/or response to treatment RNA sequencing is conducted to provide expression data and give relevance to DNA mutations.
  • This randomized phase 3 study examines the overall efficacy doxorubicin versus aldoxorubicin HCl/ifosfamide/mesna in the treatment of unresectable and metastatic leiomyosarcoma and liposarcoma.
  • PFS is evaluated in accordance with RECIST Version 1.1 by BIRC. The percentage of subjects (and 95% confidence interval [Cl]) who achieve a confirmed response are summarized. DCR is evaluated similar to ORR. PFS, OS, and DOR is analyzed using Kaplan-Meier methods. Descriptive statistics of PROs is then presented. While various embodiments of the present invention have been described in detail, it is apparent that modifications and adaptations of those embodiments will occur to those skilled in the art. It is to be expressly understood, however, that such modifications and adaptations are within the scope of the present invention, as set forth in the following exemplary claims.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant de l'aldoxorubicine HCl et de l'ifosfamide et un procédé de traitement d'un sarcome de tissu mou avec une quantité thérapeutiquement efficace de la composition pharmaceutique.
PCT/US2020/041831 2019-07-18 2020-07-13 Compositions comprenant du chlorhydrate d'aldoxorubicine et de l'ifosfamide et leur utilisation pour le traitement d'un sarcome de tissu mou WO2021011488A1 (fr)

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PCT/US2020/041831 WO2021011488A1 (fr) 2019-07-18 2020-07-13 Compositions comprenant du chlorhydrate d'aldoxorubicine et de l'ifosfamide et leur utilisation pour le traitement d'un sarcome de tissu mou

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FREDERICK C. EILBER ET AL: "Administration of aldoxorubicin and 14 days continuous infusion of ifosfamide/mesna in metastatic or locally advanced sarcomas. | Journal of Clinical Oncology", JOURNAL OF CLINICAL ONCOLOGY, vol. 35, no. 15 suppl., 1 January 2017 (2017-01-01), pages 11051, XP055732117, DOI: 10.1200/JCO.2017.35.15_suppl.11051 *

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