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WO2018148555A1 - Utilisation d'agents vasculoclastiques (vda) pour améliorer des traitements immunomodulateurs contre des tumeurs - Google Patents

Utilisation d'agents vasculoclastiques (vda) pour améliorer des traitements immunomodulateurs contre des tumeurs Download PDF

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Publication number
WO2018148555A1
WO2018148555A1 PCT/US2018/017639 US2018017639W WO2018148555A1 WO 2018148555 A1 WO2018148555 A1 WO 2018148555A1 US 2018017639 W US2018017639 W US 2018017639W WO 2018148555 A1 WO2018148555 A1 WO 2018148555A1
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antibody
tumor
cancer
combretastatin
ctla
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David J. Chaplin
Kimberly Perkins
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Mateon Therapeutics Inc
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Mateon Therapeutics Inc
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid

Definitions

  • the present application relates generally to cancer treatments.
  • VDAs Vascular Disrupting Agents
  • VTAs Vascular Targeting Agents
  • VDAs The primary mechanism of action of VDAs is "vascular targeting", in which the neovasculature of solid tumors is selectively disrupted, resulting in a transient decrease or complete shutdown of tumor blood flow that results in secondary tumor cell death due to hypoxia, acidosis, and/or nutrient deprivation (Dark et al., Cancer Res., 57: 1829-34, (1997); Chaplin et al., Anticancer Res., 19: 189-96, (1999); Hill et al., Anticancer Res.,
  • VDAs Vascular disrupting agents
  • a viable rim of tumor tissue typically surrounds a massive necrotic tumor center after treatment. Rapid tumor regrowth can resume from this residual viable rim, driven by an acute systemic mobilization of bone marrow derived circulating endothelial precursor cells (CEPs) which home to the viable tumor rim and stimulate revascularization.
  • CEPs bone marrow derived circulating endothelial precursor cells
  • the present invention relates to methods for treating cancer.
  • the methods can include producing an anti-tumor effect in a subject suffering from cancer or a tumor.
  • the methods can include administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody, programmed cell death protein 1 (anti-PD-1) antibody, programmed death-ligand 1 (anti-PD-Ll) antibody, and programmed death-ligand 2 (anti-PD-L2) antibody in amounts effective therefor.
  • VDA Vascular Disrupting Agent
  • anti-CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • anti-PD-1 programmed cell death protein 1
  • anti-PD-Ll programmed death-ligand 1
  • anti-PD-L2 programmed death-ligand 2
  • a method for producing an anti-tumor effect in a subject suffering from cancer or a tumor including administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti- PD-Ll antibody, and an anti-PD-L2 antibody in amounts effective therefor.
  • VDA Vascular Disrupting Agent
  • a method for preventing tumor regrowth in a subject suffering from cancer or a tumor including administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, and an anti-PD-L2 antibody in amounts effective therefor.
  • VDA Vascular Disrupting Agent
  • VDA Vascular Disrupting Agent
  • PD-L1 antibody and an anti-PD-L2 antibody in amounts effective therefor.
  • a method for the treatment of cancer including: administering to a subject in need of a synergistic, therapeutically effective amount of (1) a Vascular Disrupting Agent that is a combretastatin agent; and (2) one or more antibodies selected from the group consisting of: an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti- PD-L1 antibody, and an anti-PD-L2 antibody.
  • the method can include administering two or more antibodies selected from the group consisting of: an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, and an anti-PD-L2 antibody.
  • the method can include administering an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, and an anti-PD-L2 antibody in a therapeutically effective amount.
  • the combretastatin agent can be combretastatin Al diphosphate (CA1P) or
  • the anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD- LI antibody, and anti-PD-L2 antibody can be selected from the group consisting of:
  • the compounds can be simultaneously or sequentially administered.
  • the combretastatin agent can be administered prior to the antibody.
  • the combretastatin agent can be administered more than about 12 hours prior to the antibody.
  • Said cancer can be selected from the group consisting of: ovarian cancer, fallopian tube cancer, cervical cancer, breast cancer, lung cancer, melanoma, kidney, and primary cancer of the peritoneum.
  • the tumor can be a solid tumor selected from the group consisting of: a melanoma, an ovarian tumor, a cervical tumor, a breast tumor, small cell lung tumor, a non-small cell lung tumor, a fallopian tube tumor, a primary tumor of the peritoneum, a glioblastoma multiforme, gliomas, astrocytomas, thyroid carcinoma, neuroendocrine tumors, soft tissue sarcomas, hepatocellular carcinoma, and gastrointestinal stromal tumors.
  • Said cancer can be selected from the group consisting of: hematologic malignancies, acute leukemias, chronic leukemias, lymphomas, and myelomas.
  • the tumor can have a diameter or length that can be greater than about 5 cm.
  • the tumor can have a diameter or length that can be greater than about 7 cm.
  • the tumor can have a diameter or length that can be greater than about 10 cm.
  • the combretastatin agent can be a compound of Formula II:
  • R a can be H, phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl; and R b can be phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate,
  • the combretastatin agent can be a compound of Formula lib:
  • R a can be H or OP(0)(OR 3 )OR 4 ; and OR 1 , OR 2 , OR 3 and OR 4 can be each, independently, H, -O- QH + or -O- M + , wherein M + can be a monovalent or divalent metal cation, and Q can be, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, can form a quaternary ammonium cation QH + ; or b) an organic amine containing at least one nitrogen atom which, together with a proton, can form a quaternary ammonium cation, QH + .
  • R 3 can be H or OP(0)(OR 3 )OR 4
  • R 1 , R 2 , R 3 and R 4 can be each, independently, an aliphatic organic amine, alkali metals, transition metal, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic.
  • R 1 , R 2 , R 3 and R 4 can be each, independently, Na, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4- imidazolyl)-ethylamine, choline, or hydrabamine.
  • Formula II or Formula lib can be represented by a compound of Formula III:
  • a method of treating a tumor in a subject in need thereof by administering to the subject a pharmaceutical composition including combretastatin Al diphosphate (CA1P) and one or more compound selected from the group consisting of:
  • a method of treating a tumor in a subject in need thereof by administering to the subject a pharmaceutical composition including combretastatin A4 phosphate (CA4P) and one or more compound selected from the group consisting of:
  • the subject can be a human.
  • the tumor can have a diameter or length that can be greater than about 5 cm.
  • the tumor can have a diameter or length that can be greater than about 7 cm.
  • the tumor can have a diameter or length that can be greater than about 10 cm.
  • a pharmaceutical composition for producing an antitumor effect in a subject suffering from cancer or a tumor including a Vascular Disrupting Agent (VDA) including a combretastatin agent and one or more antibodies selected from the group consisting of: an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, and an anti-PD-L2 antibody in amounts effective therefore in a pharmaceutical carrier.
  • VDA Vascular Disrupting Agent
  • the anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-Ll antibody, and anti-PD-L2 antibody can be selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL3280A, and AMP-224.
  • the composition can include two or more antibodies selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL3280A, and AMP- 224.
  • the VDA can be combretastatin Al diphosphate (CA1P) or combretastatin A4 phosphate (CA4P).
  • the combretastatin agent can be a compound of Formula II:
  • R a can be H, phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl; and R b can be phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate,
  • the combretastatin agent can be a compound of Formula
  • R a can be H or OP(0)(OR 3 )OR 4 ; and OR 1 , OR 2 , OR 3 and OR 4 can each, independently, H, -O- QH + or -O- M + , wherein M + can be a monovalent or divalent metal cation, and Q can be, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, can form a quaternary ammonium cation QH + ; or b) an organic amine containing at least one nitrogen atom which, together with a proton, can form a quaternary ammonium cation, QFT.
  • R 3 can be H or OP(0)(OR 3 )OR 4
  • R 1 , R 2 , R 3 and R 4 can each, independently, an aliphatic organic amine, alkali metals, transition metal, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic.
  • R 1 , R 2 , R 3 and R 4 can each, independently, Na, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)-ethylamine, choline, or hydrabamine.
  • Formula II or lib can be represented by a compound of Formula III:
  • the pharmaceutical composition can include CA1P and one or more compounds selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL3280A, and AMP-224.
  • the pharmaceutical composition can include CA4P and one or more compounds selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL3280A, and AMP-224.
  • the methods and compositions described herein for treating cancer including the use of a VDA that is a combretastatin agent and one or more of anti- CTLA-4 antibody, anti-PD-1 antibody, anti-PD-Ll antibody, and anti-PD-L2 antibody may result in an enhanced immune response, in addition to reductions in tumor volume after treatment.
  • a VDA e.g., a combretastatin such as C41P or CA4P
  • anti-CTLA-4 in a combination therapy may be used.
  • a combretastatin such as CA4P induces an immediate, rapid and extensive tumor cell necrosis which can stimulate the immune system, while antibodies to CTLA-4 stimulate the immune system through a different mechanism, by blocking immunosuppression (similar to the approved drug marketed under the trade name Yervoy).
  • the combination of the VDA (e.g., CA4P) and anti-CTLA-4 stimulate the immune system and enhance the efficacy of a checkpoint inhibitor such as CA4P.
  • the combination therapy of CA4P and anti-CTLA-4 results in an enhanced immune response, showing increases in the median number of tumor-associated white blood cells (WBC's), T cells, and effector cytotoxic CD8+ T Cells, indicating a heightened immunologic response to the tumor in the presence of the two-drug combination.
  • WBC's tumor-associated white blood cells
  • T cells T cells
  • effector cytotoxic CD8+ T Cells indicating a heightened immunologic response to the tumor in the presence of the two-drug combination.
  • treatment with both CA4P and anti-CTLA-4 generally maintains an elevated tumor-associated median effector T cell/regulatory T cell ratio, which also indicates a heightened immune response.
  • FIG. 1 is a graph illustrating tumor volume versus time post tumor induction for mice in a study.
  • FIG. 2 is a graph illustrating body weight versus time post tumor induction for mice in a study.
  • FIG. 3A shows a graph illustrating median tumor growth versus time in mice receiving treatment with a PD-1 antibody alone and a PD-1 antibody with CA4P along with a graph showing survival versus time.
  • FIG. 3B shows a graph illustrating median tumor growth versus time in mice receiving treatment with a PD-Ll antibody alone and a PD-Ll antibody with CA4P along with a graph showing survival versus time.
  • FIG. 4 is a graph illustrating tumor volume versus time for mice receiving various treatments.
  • FIG. 5 illustrates the number of days until the endpoint of the study for mice receiving various treatments.
  • FIG. 6 and FIG. 7 are graphs illustrating tumor volume versus time for mice with large CT-26 colon tumors receiving various treatments.
  • FIG. 8A is a graph illustrating tumor volume versus time for mice receiving various treatments.
  • FIG. 8B is a graph illustrating tumor volume versus time for mice receiving various treatments.
  • FIG. 9A is a graph showing the tumor volume versus study day for each individual animal receiving the vehicle treatment.
  • FIG. 9B is a graph showing the tumor volume versus study day for each individual animal receiving the anti-PD-1 treatment alone.
  • FIG. 9C is a graph showing the tumor volume versus study day for each individual animal receiving the CA4P treatment alone.
  • FIG. 9D is a graph showing the tumor volume versus study day for each individual animal receiving the combination treatment of C A4P and anti-PD- 1.
  • FIG. 10A is a table showing results of the combination treatment of C4AP and anti- CTLA-4, compared to CA4P (test item) alone, anti-CTLA-4 alone, and control (e.g., vehicle).
  • FIGS. 10B shows CD45+ cell count (e.g., WBCs) between vehicle, anti-CTLA-4 and combination therapy (anti-CTLA-4 and the VDA).
  • FIG. IOC shows CD3+ cells among CD45+ cells (e.g., T cells) between vehicle, anti-CTLA-4 and combination therapy.
  • FIG. 10D shows by
  • CD8+ cells among CD3+ cells (Treff, e.g., Effector cytotoxic CD8+ T Cells).
  • the present application relates to the surprising and unexpected discovery of the synergistic combination of a VDA that is a combretastatin agent and one or more of anti-CTLA- 4 antibody, anti-PD-1 antibody, anti-PD-Ll antibody, and anti-PD-L2 antibody.
  • a VDA that is a combretastatin agent
  • anti-CTLA- 4 antibody anti-PD-1 antibody
  • anti-PD-Ll antibody anti-PD-L2 antibody
  • anti-PD-L2 antibody anti-PD-L2 antibody
  • the combination of necrotic cell death caused by the VDA in combination with the antibodies blocking one or more of the CTLA-4, PD-1, PD-Ll, and PD-L2 receptors on the T-call can provide greatly improved immune system responses against the tumor.
  • the improved immune system response against the cancer or tumor can be reflected in a variety of different ways.
  • the treatment includes tumor regression.
  • the treatment includes producing an anti-tumor effect in the subject suffering from the cancer or a tumor.
  • the treatment includes preventing tumor regrowth in a subject suffering from the cancer or a tumor.
  • the treatment includes inhibiting tumor-associated angiogenesis in the subject suffering from the cancer or tumor.
  • treatment includes producing a synergistic effect against the tumor that is greater than the combined effects of the individual therapies administered to the patient.
  • the synergistic anti-tumor therapies described herein can also allow for lower drug dosages that can minimize side effects while exhibiting good anti-tumor effects.
  • CTLA-4 and PD-1 receptors on T cells can down regulate T cell function.
  • Callahan et al. (“CTLA-4 and PD-1 pathway blockade: combinations in the clinic” Frontiers in Oncology; January 2015, volume 4, article 385, pages 1-6) studied checkpoint blocking antibodies that target regulatory molecules on T cells like CTLA-4 and PD-1. A number of anti-CTLA-4, anti-PD-1, and anti-PD-Ll antibodies are currently being evaluated.
  • necrotic cell death (caused by the VDA) and immune system response modifications from anti-CTLA-4, anti-PD-1, and anti-PD-Ll antibodies can increase anti-tumor effects.
  • VDA ZD6126 indicated that this VDA may reduce T-cell mediated immune response ("Necrotic Tumor Cell Death in Vivo Impairs Tumor-Specific Immune Responses" J. Immunol. 2007; 178: 1573-1580).
  • the present application unexpectedly found a synergistic combination with a combretastatin agent and anti-
  • CTLA-4 anti-PD-1, and anti-PD-Ll antibodies.
  • Cytotoxic T-lymphocyte-associated protein 4 which is also known as CD 152 (cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint that down regulates the immune system.
  • Anti-CTLA-4 antibodies can be used to target CTLA-4 and provide a boost to the immune system during cancer treatments.
  • Examples of anti-CTLA-4 antibodies include Tremelimumab formerly known as ticilimumab / CP-675,206 (Medlmmune / AstraZeneca) and Ipilumab (Bristol-Myers Squibb). Ipilumab has FDA approval for treatment of melanoma.
  • Programmed cell death protein 1 is also known as PD-1 and CD279 (cluster differentiation 279).
  • PD-1 is a cell surface receptor that is expressed on T cells and pro-B cells.
  • PD-1 can bind between two ligands, PD-Ll and PD-L2.
  • PD-1 functions as an immune checkpoint.
  • Anti-PD-1 antibodies can be used to target PD-1 to provide a boost to the immune system during cancer treatments. Examples of anti-PD-1 antibodies that are approved for use include Nivolumab (Opdivo, BMS-936558, Bristol-Myers Squibb) and Pembrolizumab
  • anti-PD-1 antibodies that are in early stage development include Pidilizumab (CT-011, Cure Tech).
  • the PD-Ll and PD-L2 ligands can also be targeted with antibodies.
  • Programmed death-ligand 1 also known as CD279 (cluster differentiation 279), is a transmembrane protein that can bind to PD-1.
  • Examples of anti-PD-Ll antibodies in clinical development included MEDI4736 (Medimmune / AstraZeneca), BMS 936559 (MDX-1105, Bristol-Myers Squibb), and MPDL3280A (Roche).
  • Examples of anti-PD-L2 antibodies in clinical development include AMP-224 (Medimmune).
  • checkpoint inhibitors besides the anti-CTLA-4, anti-PD- 1, anti-PD-Ll, and anti-PD-L2 antibodies can be used in combination with the combretastatin agents described herein.
  • checkpoint inhibitors include IMP321 (Immutep) and TRX518 (GITR, Inc).
  • IMP321 (Immutep) is a soluble lymphocyte activation gene-3
  • TRX518 (GITR, Inc) is a monoclonal antibody against glucocorticoid-inducted tumor necrosis factor receptor-related gene.
  • the treatment methods disclosed herein can include one or more anti-CTLA-4, anti- PD-1, anti-PD-Ll, and anti-PD-L2 antibodies and other checkpoint inhibitors.
  • one antibody can be provided to the patient selected from the group consisting of: anti-CTLA-4, anti-PD-1, anti-PD-Ll, and anti-PD-L2 antibodies.
  • two antibodies can be provided to the patient selected from the group consisting of: anti-CTLA-4, anti-PD-1, anti-PD-Ll, and anti-PD-L2 antibodies.
  • all three anti-CTLA-4, anti-PD-1, anti-PD-Ll, and anti-PD-L2 antibodies can be provided to the patient.
  • multiple different anti-CTLA-4 antibodies can be provided to the patient.
  • multiple different anti-PD- 1 antibodies can be provided to the patient.
  • multiple different anti-PD-Ll antibodies can be provided to the patient.
  • multiple different anti-PD-L2 antibodies can be provided to the patient.
  • multiple different checkpoint inhibitors can be provided to the patient.
  • the checkpoint inhibitors are used in combination with one or more of the other antibodies disclosed herein.
  • the checkpoint inhibitors are used with the combretastatin agent alone without the other antibodies disclosed herein.
  • combretastatin agents can be used with the anti-CTLA-4, anti-PD-1, anti-PD-Ll, and anti-PD-L2 antibodies and checkpoint inhibitors described herein.
  • a number of combretastatin agents are described herein.
  • the combretastatin agent is combretastatin Al diphosphate (CA1P).
  • the combretastatin agent is combretastatin A4 phosphate (CA4P).
  • the cancer is selected from the group consisting of: ovarian cancer, fallopian tube cancer, cervical cancer, breast cancer, lung cancer, melanoma, kidney, and primary cancer of the peritoneum.
  • the tumor is a solid tumor selected from the group consisting of: a melanoma, an ovarian tumor, a cervical tumor, a breast tumor, small cell lung tumor, a non- small cell lung tumor, a fallopian tube tumor, a primary tumor of the peritoneum, a glioblastoma multiforme, gliomas,
  • the cancer is selected from the group consisting of: hematologic malignancies, acute leukemias, chronic leukemias, lymphomas, and myelomas.
  • combretastatin or “combretastatin compound” denotes at least one of the combretastatin family of compounds, derivatives or analogs thereof, their prodrugs (preferably phosphate prodrugs) and derivatives thereof, and salts of these compounds.
  • Combretastatins include those anti-cancer compounds isolated from the South African tree
  • Combretum cqffrum including without limitation, Combretastatins A-l, A-2, A-3, A-4, B-l, B- 2, B-3, B-4, D-l, and D-2 , and various prodrugs thereof, exemplified by Combretastatin A-4 phosphate (CA4P) compounds, Combretastatin A-l diphosphate (CAldP) compounds and salts thereof (see for example Pettit et al, Can. J. Chem., (1982); Pettit et al., J. Org. Chem., 1985; Pettit et al., J. Nat.
  • CA4P Combretastatin A-4 phosphate
  • CAldP Combretastatin A-l diphosphate
  • CA4P combretastatin A-4 phosphate
  • CAIP combretastatin A-1 diphosphate
  • CAIP combretastatin A-1 diphosphate prodrugs
  • the combretastatin agent is a compound of Formula II:
  • R a is H, phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl;
  • R b is phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic
  • R b is a phosphate of formula:
  • OR 1 , OR 2 , OR 3 and OR 4 are each, independently, H, -O- QH+ or -O- M+, wherein M+ is a monovalent or divalent metal cation, and Q is, independently:
  • the combretastatin agent is a compound of the Formula
  • R a is H or OP(0)(OR 3 )OR 4 ;
  • OR 1 , OR 2 , OR 3 and OR 4 are each, independently, H, -O- QH+ or -O- M+, wherein M+ is a monovalent or divalent metal cation, and Q is, independently:
  • R a is H, one of OR 1 and OR 2 is hydroxyl, and the other is -O- QH+ where Q is L-histidine.
  • R a is H, one of OR 1 and OR 2 is hydroxyl and the other is -O- QH+ and Q is tris(hydroxymethyl)amino methane ("TRIS").
  • R a is H or OP(0)(OR 3 )OR 4
  • R 1 , R 2 , R 3 and R 4 are each, independently, an aliphatic organic amine, alkali metals, transition metals, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic.
  • R 1 , R 2 , R 3 and R 4 are each, independently, Na, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine,
  • Formula lib is represented by a compound of Formula III:
  • OR 1 , OR 2 , OR 3 and OR 4 are each, independently, H, -O- QH+ or -O- M+, wherein M+ is a monovalent or divalent metal cation, and Q is, independently:
  • At least one of OR 1 , OR 2 , OR 3 and OR 4 is hydroxyl, and at least one of OR 1 , OR 2 , OR 3 and OR 4 is -O- QH+, where Q is L-histidine.
  • at least one of OR 1 , OR 2 , OR 3 and OR 4 is hydroxyl, and at least one of OR 1 , OR 2 , OR 3 and OR 4 is TRIS.
  • combination therapy (or “co-therapy”) embraces the administration of a anti-CTLA-4, anti-PD-1, anti-PD-Ll, and/or anti-PD-L2 antibody and a VDA such as a combretastatin agent, as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of the antibody and the VDA.
  • a VDA such as a combretastatin agent
  • Administration of the anti-CTLA-4, anti-PD- 1 , anti-PD-Ll , and/or anti-PD-L2 antibody and the VDA in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” generally is not intended to encompass the administration of an anti-CTLA-4, anti-PD- 1, anti-PD-Ll, anti-PD-L2 antibody and VDA as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations described herein.
  • Combination therapy is intended to embrace administration of an anti-CTLA-4, anti-PD-1, anti-PD-Ll, and/or anti-PD- L2 antibody and VDA in a sequential manner, that is, wherein the anti-CTLA-4, anti-PD-1, anti- PD-Ll, and/or anti-PD-L2 antibody and the VDA are administered at different times, as well as administration of the anti-CTLA-4, anti-PD-1, anti-PD-Ll, and/or anti-PD-L2 antibody and
  • VDA in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject concurrently a single dosage having a fixed ratio of each therapeutic agent or in multiple, single dosage for each therapeutic agent.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents if more than one, can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • composition therapy also can embrace the administration of the anti-CTLA-4, anti-PD-1, anti-PD-Ll antibody and VDA as described above in further combination with other biologically active ingredients and non- drug therapies (such as, but not limited to, surgery).
  • the combretastatin agent can be administered simultaneously or sequentially with the anti-CTLA-4, anti-PD-1, anti-PD-Ll, and/or anti-PD-L2 antibodies. In some cases the combretastatin agent can be administered prior to the anti-CTLA-4, anti-PD-1, anti-PD-Ll, and/or anti-PD-L2 antibodies. For example, the combretastatin agent can be administered about 12 or more hours prior to the anti-CTLA-4, anti-PD-1, anti-PD-Ll, and/or anti-PD-L2 antibodies. In some cases the combretastatin agent can be administered about 24 or more hours prior to the anti-CTLA-4, anti-PD-1, anti-PD-Ll, and/or anti-PD-L2 antibodies.
  • the dosing schedule for the antibodies and VDA can be daily, every other day, multiple times per week, or as otherwise recommended.
  • the agents can be administered for multiple weeks.
  • the antibodies and VDA can be administered twice weekly for two or more consecutive weeks.
  • any of the compounds and combinations disclosed herein can be formulated into pharmaceutical compositions for administration to the subject.
  • any of the combination therapies described herein can be combined with other therapies: radiation therapy, surgery, chemotherapy, etc.
  • a suitable dose per day for each of the compounds can be, individually, in the range of from about 1 ng to about 10,000 mg, about 5 ng to about 9,500 mg, about 10 ng to about 9,000 mg, about 20 ng to about 8,500 mg, about 30 ng to about 7,500 mg, about 40 ng to about 7,000 mg, about 50 ng to about 6,500 mg, about 100 ng to about 6,000 mg, about 200 ng to about 5,500 mg, about 300 ng to about 5,000 mg, about 400 ng to about 4,500 mg, about 500 ng to about 4,000 mg, about 1 ⁇ g to about 3,500 mg, about 5 ⁇ g to about 3,000 mg, about 10 ⁇ g to about 2,600 mg, about 20 ⁇ g to about 2,575 mg, about 30 ⁇ g to about 2,550 mg, about 40
  • suitable doses for the compounds include, for example, 0.1 mg/kg to about 100 mg/kg; from about 1 mg/kg to about 100 mg/kg; from about 5 mg/kg to about 50 mg/kg; from about 10 to about 25 mg/kg; about 10 mg/kg; about 15 mg/kg; about 20 mg/kg; about 25 mg/kg; about 30 mg/kg; about 40mg/kg; about 50 mg/kg; about 60 mg/kg; about 70 mg/kg; about 80 mg/kg; about 90 mg/kg; and about lOOmg/kg.
  • the VDA e.g., a combretastatin agent such as CA4P
  • the VDA is administered at a dose ranging from between 20 mg/m 2 and 80 mg/m 2 .
  • the methods disclosed herein can include providing the manufacturer's recommended dosage level for one or more of the antibodies selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL3280A, and AMP-224.
  • the dosage levels for the combretastatin agent and the antibody can be provided in an effective amount.
  • the term "effective amount" of a compound or pharmaceutical composition refers to an amount sufficient to provide the desired anti-cancer effect or anti-tumor effect in an animal, preferably a human, suffering from cancer. Desired anti-tumor effects include, without limitation, the modulation of tumor growth (e.g.
  • tumor growth delay the reduction of toxicity and side effects associated with a particular anti-cancer agent
  • the enhancement of tumor necrosis or hypoxia the reduction of tumor angio genesis, the reduction of tumor re-growth, reduced tumor retention of CEPs and other pro-angiogenic cells, the amelioration or minimization of the clinical impairment or symptoms of cancer, extending the survival of the subject beyond that which would otherwise be expected in the absence of such treatment, and the prevention of tumor growth in an animal lacking any tumor formation prior to administration, i.e., prophylactic administration.
  • the terms “modulate”, “modulating” or “modulation” refer to changing the rate at which a particular process occurs, inhibiting a particular process, reversing a particular process, and/or preventing the initiation of a particular process. Accordingly, if the particular process is tumor growth or metastasis, the term “modulation” includes, without limitation, decreasing the rate at which tumor growth and/or metastasis occurs; inhibiting tumor growth and/or metastasis, including tumor re-growth following treatment with an anticancer agent; reversing tumor growth and/or metastasis (including tumor shrinkage and/or eradication) and/or preventing tumor growth and/or metastasis.
  • tumor tumor growth
  • tumor tissue tumor tissue
  • subject is intended to include mammals suffering from or afflicted with a tumor.
  • exemplary subjects include humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a cancer.
  • the combination therapies described herein can be particularly effective for treating larger tumor sizes. Larger tumor sizes can have greater amounts of vasculature relative to smaller tumors.
  • the vascular disrupting agents described herein such as CA1P and CA4P, can provide an improved response against larger tumor sizes by disrupting the increased vasculature present in larger tumors.
  • the improved vascular disruption of the larger tumor in combination with the antibody treatments described herein can provide a synergistic effect to boost the immune therapy response against the tumor to more effectively treat the targeted tumor.
  • the tumor size can be expressed as a maximum length or maximum diameter for a dominant dimension of the tumor.
  • the combination therapies described herein are provided to a patient with a tumor having a maximum length or diameter of greater than about 5 cm.
  • the combination therapies described herein are provided to a patient with a tumor having a maximum length or diameter of greater than about 7 cm. In some embodiments the combination therapies described herein are provided to a patient with a tumor having a maximum length or diameter of greater than about 10 cm.
  • lung cancer tumors can be considered large tumors (non- small tumors) when the tumor has a diameter or length that is greater than about 5 cm.
  • ovarian cancer tumors can be considered large tumors (non-small tumors) when the tumor has a diameter or length that is greater than about 5 cm.
  • the methods disclosed herein are used to treat solid tumors.
  • solid tumors are quite distinct from non-solid tumors, such as those found in hematopoietic -related cancers.
  • a solid tumor can be malignant, e.g. tending to metastasize and being life threatening, or benign.
  • solid tumors that can be treated or prevented according to the methods described herein include sarcomas and carcinomas such as, but not limited to: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangio sarcoma,
  • sarcomas and carcinomas such as, but not limited to: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangio sarcoma,
  • lymphangioendotheliosarcoma synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, ovarian cancer, fallopian tube cancer, primary carcinoma of the peritoneum, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas,
  • cystadenocarcinoma medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, liver metastases, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, thyroid carcinoma such as anaplastic thyroid cancer, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma such as small cell lung carcinoma and non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
  • tumors comprising dysproliferative changes can be treated or prevented with a pharmaceutical composition or the methods described herein in epithelial tissues such as those in the cervix, esophagus, and lung.
  • a pharmaceutical composition or the methods described herein in epithelial tissues such as those in the cervix, esophagus, and lung.
  • the present disclosure provides for treatment of conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 68 to 79).
  • Hyperplasia is a form of controlled cell proliferation involving an increase in cell number in a tissue or organ, without significant alteration in structure or function. For example, endometrial hyperplasia often precedes endometrial cancer. Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplasia can occur in epithelial or connective tissue cells. Atypical metaplasia involves a somewhat disorderly metaplastic epithelium.
  • Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells.
  • Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism.
  • Dysplasia characteristically occurs where there exists chronic irritation or inflammation, and is often found in the cervix, respiratory passages, oral cavity, and gall bladder.
  • AV arteriovenous
  • U.S. Patent No. 9,040,500 discloses methods for treating hematopoietic neoplasms including the use of a combretastatin compound. The methods described herein for
  • administering a combretastatin agent in combination with an antibody for anti-CTLA-4, anti-PD- 1, and/or anti-PD-Ll can be used to treat hematopoietic neoplasms as described in U.S. Patent No. 9,040,500. Accordingly, one aspect of the present disclosure provides a method of treating a hematopoietic neoplasm, the method comprising administering, to a mammal suffering from a hematopoietic neoplasm, a therapeutically effective amount of a combretastatin compound and one or more of the antibodies for anti-CTLA-4, anti-PD- 1, and/or anti-PD-Ll.
  • solid tumors are quite distinct from non-solid tumors, such as those found in hematopoietic-related cancers.
  • non-solid tumors include leukemias, such as myeloid leukemias and lymphoid leukemias, myelomas, and lymphomas.
  • the non-solid tumor is a hematopoietic neoplasm, which is aberrant growth of cells of the hematopoietic system.
  • Hematopoietic malignancies can have their origins in pluripotent stem cells, multipotent progenitor cells, oligopotent committed progenitor cells, precursor cells, and terminally differentiated cells involved in hematopoiesis.
  • hematopoietic stem cells which have the ability for self renewal.
  • AML acute myeloid leukemia
  • hematopoietic stem cells which have the ability for self renewal.
  • AML acute myeloid leukemia
  • hematopoietic stem cells implicating hematopoietic stem cells as the source of leukemic cells.
  • hematopoietic neoplasms often originate from stem cells, committed progenitor cells or more terminally differentiated cells of a developmental lineage can also be the source of some leukemias.
  • fusion protein Bcr/Abl associated with chronic myelogenous leukemia
  • common myeloid progenitor or granulocyte/macrophage progenitor cells produces a leukemic-like condition.
  • Hematopoietic neoplasms differ from solid tumors in being capable of circulating and having access to various organs through interaction with activated vascular cells. Indeed, some hematopoietic neoplastic cells may adhere to vascular cells, establishing perivascular infiltrates, and as such may be endowed with a unique mechanism of resistance to chemotherapy. Both circulating and vascular-adherent hematopoietic neoplasms require cytoskeletal stability to maintain mitochondrial and cellular function and avoid cell death.
  • the hematopoietic neoplasm treated is a lymphoid neoplasm, where the abnormal cells are derived from and/or display the characteristic phenotype of cells of the lymphoid lineage. Lymphoid neoplasms can be subdivided into B-cell neoplasms,
  • B-cell neoplasms can be further subdivided into precursor B-cell neoplasm and mature/peripheral B-cell neoplasm.
  • B-cell neoplasms are precursor B -lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) while exemplary mature/peripheral B-cell neoplasms are B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-cell lymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of MALT type, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, primary effusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia.
  • T-cell and NK-cell neoplasms are further subdivided into precursor T-cell neoplasm and mature (peripheral) T-cell neoplasms.
  • Exemplary precursor T-cell neoplasm is precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia) while exemplary mature (peripheral) T-cell neoplasms are T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell lymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type, enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosis fungoides/Sezary syndrome, Anaplastic large-cell
  • the third member of lymphoid neoplasms is Hodgkin's lymphoma, also referred to as Hodgkin's disease.
  • Exemplary diagnosis of this class that can be treated with the compounds include, among others, nodular lymphocyte -predominant Hodgkin's lymphoma, and various classical forms of Hodgkin's disease, exemplary members of which are Nodular sclerosis Hodgkin's lymphoma (grades 1 and 2), Lymphocyte -rich classical Hodgkin's lymphoma, Mixed cellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin's lymphoma.
  • any of the lymphoid neoplasms can be treated with the combretastatin compounds and antibodies as described herein.
  • the hematopoietic neoplasm treated is a myeloid neoplasm.
  • This group comprises a large class of cell proliferative disorders involving or displaying the characteristic phenotype of the cells of the myeloid lineage.
  • Myeloid neoplasms can be subdivided into myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes, and acute myeloid leukemias.
  • Exemplary myeloproliferative diseases are chronic myelogenous leukemia (e.g. , Philadelphia chromosome positive
  • leukemia/hypereosinophilic syndrome chronic idiopathic myelofibrosis, polycythemia vera, and essential thrombocythemia.
  • Exemplary myelodysplastic/myeloproliferative diseases are chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, and juvenile
  • myelomonocytic leukemia myelomonocytic leukemia.
  • myelodysplastic syndromes are refractory anemia, with ringed sideroblasts and without ringed sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multilineage dysplasia, refractory anemia (myelodysplastic syndrome) with excess blasts, 5q- syndrome, and myelodysplastic syndrome.
  • any of the myeloid neoplasms can be treated with the combretastatin compounds and antibodies described herein.
  • the combination therapies described herein can be used to treat acute myeloid leukemias (AML), which represent a large class of myeloid neoplasms having its own subdivision of disorders. These subdivisions include, among others, AMLs with recurrent cytogenetic translocations, AML with multilineage dysplasia, and other AML not otherwise categorized.
  • AML acute myeloid leukemias
  • Exemplary AMLs with recurrent cytogenetic translocations include, among others, AML with t(8;21)(q22;q22), AMLl(CBF-alpha)/ETO, Acute promyelocytic leukemia (AML with t(15; 17)(q22;ql l- 12) and variants, PML/RAR- alpha), AML with abnormal bone marrow eosinophils (inv(16)(pl3q22) or t(16; 16)(pl3;ql l), CBFb/MYHl IX), and AML with 1 lq23 (MLL) abnormalities.
  • AML with t(8;21)(q22;q22) AMLl(CBF-alpha)/ETO
  • Acute promyelocytic leukemia AML with t(15; 17)(q22;ql l- 12) and variants, PML/RAR- alpha
  • Exemplary AML with multilineage dysplasia are those that are associated with or without prior myelodysplastic syndrome.
  • Other acute myeloid leukemias not classified within any definable group include, AML minimally differentiated, AML without maturation, AML with maturation, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryocytic leukemia, acute basophilic leukemia, and acute panmyelosis with myelofibrosis.
  • the combination therapy methods disclosed herein can also be used to treat carcinoid syndrome and neuroendocrine tumors.
  • U.S. 2015/0141349 discloses using combretastatin compounds to treat carcinoid syndrome and neuroendocrine tumors, the disclosure of which is incorporated by reference herein in its entirety.
  • Neuroendocrine tumors refers to a cell proliferative disorder arising from secretary cells of the endocrine and nervous system, and develop from different endocrine glands (such as the pituitary, the parathyroid or the neuroendocrine adrenal glands), from endocrine islets (for example in the pancreas) or from endocrine cells dispersed between exocrine cells throughout the digestive and respiratory tracts
  • Carcinoid syndrome is rare and is caused by carcinoid tumors— small, malignant or benign tumors that most commonly arise in the submucosa of the gastrointestinal tract. Carcinoid syndrome is the set of symptoms that may occur in patients who have carcinoid tumors.
  • the syndrome occurs when carcinoid tumors overproduce substances, such as serotonin and chromogranin A, that normally circulate throughout the body.
  • substances such as serotonin and chromogranin A
  • the serotonin produced by the carcinoid tumor is further metabolized to the most important serotonin metabolite, 5- hydroxyindoleacetic acid (5-HIAA).
  • the term "treating" carcinoid syndrome, or other symptoms associated with a hormone-producing neuroendocrine tumor is intended to mean inhibiting production of a tumor-generated hormone, decreasing levels of tumor-induced hormone and causing the regression and palliation of carcinoid syndrome, i.e., reducing the number of flushing or diarrheal events and/or increase quality of life.
  • Other desired effects include, without limitation, decreases in abdominal pain, heart disease, wheezing, bloating, or sweating, and extending the survival of the subject beyond that which would otherwise be expected in the absence of such treatment.
  • some embodiments provide a method of treating carcinoid syndrome, the method comprising administering, to a mammal suffering from one or more symptoms of carcinoid syndrome, a therapeutically effective amount of a vascular disrupting agent that is a combretastatin agent along with one or more antibodies for anti-CTLA-4, anti-PD-1, anti-PD-Ll, and anti-PD-L2.
  • Diseases which can be treated in accordance with the methods described herein include, but are not limited: Accelerated Phase Chronic Myelogenous Leukemia; Acute
  • Erythroid Leukemia Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Lymphocytic Leukemia; Acute Monoblastic and Acute Monocytic Leukemia;
  • Acute Myelogenous Leukemia Acute Myeloid Leukemia; Adenocarcinoma; Adenocarcinoma of the Colon; Adenocarcinoma of the Esophagus; Adenocarcinoma of the Lung; Adenocarcinoma of the Pancreas; Adenocarcinoma of the Prostate; Adenocarcinoma of the Rectum;
  • Adenocarcinoma of the Stomach Adenoid Cystic Carcinoma of the Head and Neck;
  • Adenosquamous Cell Lung Cancer including Cancer; Autism Glioblastoma; Advanced Adult Primary Liver Cancer; Advanced Gastrointestinal Stromal Tumor; Advanced Non-Nasopharyngeal Head and Neck Carcinoma; Advanced NSCLC; Advanced Solid Tumors; Agnogenic Myeloid;
  • Metaplasia Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Thyroid Cancer; Astrocytoma; Atypical Chronic Myelogenous Leukemia; B- Cell Adult Acute
  • Lymphoblastic Leukemia Bladder Cancer; Blastic Phase Chronic Myelogenous Leukemia; Bone Metastases; Brain Tumor; Breast Cancer; Breast Cancer in situ; Breast Neoplasms; Brenner Tumor; Bronchoalveolar Cell Lung Cancer; Cancer of the Fallopian Tube; Carcinoma,
  • Lymphoblastic Leukemia Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Brain Tumor; Childhood Central Nervous System Germ Cell Tumor; Childhood Cerebellar Astrocytoma; Childhood Chronic Myelogenous Leukemia; Childhood Ependymoma; Childhood Malignant Germ Cell Tumor; Childhood Oligodendroglioma; Childhood Soft Tissue Sarcoma; Chordoma; Chronic Eosinophilic Leukemia (CEL); Chronic Idiopathic Myelofibrosis; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia;
  • Esophageal Cancer Epidemic Kaposi's Sarcoma; Epithelial Mesothelioma; Esophageal Cancer; Esophagogastric Cancer; Essential Thrombocythemia; Ewing's Family of Tumors; Extensive
  • Hematopoietic and Lymphoid Cancer Hepatocellular Carcinoma; High-Grade Childhood Cerebral Astrocytoma; Hypereosinophilic Syndrome; Hypopharyngeal Cancer; Idiopathic Pulmonary Fibrosis; Inflammatory Myofibroblastic Tumor; Inoperable Locally Advanced Squamous Cell Carcinoma of Head and Neck; Insulinoma; Intraductal Breast Carcinoma; Islet Cell Carcinoma; Kidney and Urinary Cancer; LI Adult Acute Lymphoblastic Leukemia; L2
  • Bronchiole- Alveolar Feature Lung Cancer; Male Breast Cancer; Malignant Fibrous
  • Histiocytoma Malignant Melanoma; Mastocytosis; Medullary Thyroid Cancer; Melanoma; Meningeal Tumors; Meningeal Hemangiopericytoma; Meningioma; Meningioma; Meningioma; Mesothelioma; Metastatic Cancer; Metastatic Solid Tumors; Metastatic Colorectal Cancer;
  • Metastatic Gastrointestinal Carcinoid Tumor Metastatic Pancreatic Carcinoma; Mixed Gliomas; Multiple Myeloma; Musculoskeletal Tumors; Myelodysplastic Syndrome; Myelogenous Leukemia, Acute; Myelofibrosis; Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic Accelerated-Phase; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Metaplasia;
  • MPD Myeloproliferative Disorder
  • Lymphoblastic Leukemia Non-Metastatic (T2-T4, N0-N3, MO; Stages II and III) and
  • Adrenocortical Carcinoma Non-Small Cell Lung Cancer; Nose Cancer; Oligodendroglioma; Oligodendroglial Tumors; Oral Cancer; Oropharyngeal Cancer; Osteosarcoma; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Ovarian Neoplasms; Pancreatic Cancer; Papillary Thyroid Cancer; Pelvic Neoplasms; Peritoneal Cavity Cancer; Peritoneal Carcinoma; Peritoneal Neoplasms; Pharynx Cancer; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia Positive Acute
  • P-ADC Pneumonic-Type Adenocarcinoma
  • P-ADC Polycythemia Vera
  • Pulmonary Fibrosis Primary Hepatocellular Carcinoma; Primary Liver Cancer; Prostate Cancer; Prostate Cancer, Antigen Independent; Rectal Cancer; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Adult Primary Liver Cancer; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Cancer, Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Glioblastoma; Recurrent Glioblastoma Multiforme (GBM); Recurrent Kaposi's Sarcoma; Recurrent Melanoma; Recurrent Merkel Cell Carcinoma;
  • Recurrent Ovarian Epithelial Cancer Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Skin Cancer; Recurrent Small Cell Lung Cancer; Recurrent Tumors of the Ewing's Family; Recurrent Uterine Sarcoma; Refractory Germ Cell Tumors Expressing EGRF; Relapsing Chronic Myelogenous Leukemia;
  • Renal Cell Cancer Renal Cell Cancer; Renal Cell Carcinoma; Renal Papillary Carcinoma; Rhabdomyosarcomas; Salivary Gland Adenoid Cystic Carcinoma; Sarcoma; Sarcomatous Mesothelioma; Skin Cancer; Small Cell Lung Cancer; Soft Tissue Sarcoma; Squamous Cell Carcinoma; Squamous Cell Carcinoma of the Esophagus; Squamous Cell Carcinoma of the Head and Neck; Squamous Cell Carcinoma of the Skin; Squamous Cell Lung Cancer; Stage II Esophageal Cancer; Stage III Esophageal Cancer, Stage II Melanoma; Stage II Merkel Cell Carcinoma; Stage III Adult Soft Tissue Sarcoma; Stage III Esophageal Cancer; Stage III Merkel Cell Carcinoma; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Salivary Gland Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Soft Tissue
  • Gastrointestinal Stromal Tumor GIST
  • Unspecified Childhood Solid Tumor Unspecified Adult Solid Tumor
  • Untreated Childhood Brain Stem Glioma Untreated Childhood Brain Stem Glioma
  • Urethral Cancer Uterine
  • a randomized trial was conducted to evaluate the antitumor activity of fosbretabulin tromethamine (CA4P) in mice bearing subcutaneous EMT-6 mouse mammary tumor cells in combination with other treatments.
  • Other treatments include a combination treatment with anti- CTLA-4 antibody (ref: BE0131, Bioxcell; clone: 9H10; reactivity: mouse; isotype: Hamster IgGl; storage conditions: +4°C).
  • CA4P and anti-CTLA-4 antibodies were prepared in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • CA4P was injected at the dose of 100 mg/kg.
  • the anti-CTLA-4 antibody was injected at the dose of 10 mg/kg.
  • the tested items were injected into the peritoneal cavity of mice (e.g.
  • IP intraperitoneally, IP.
  • the administration volume was 10 mL/kg (200 ⁇ / ⁇ ⁇ of 20 g) adjusted to the most recent individual body weight of the mice.
  • EMT-6 cell line having an ATCC origin and a culture medium was used.
  • the EMT-6 cell line was established from a transplantable murine mammary carcinoma that arose in a BALB/cCRGL mouse after implantation of a hyperplastic mammary alveolar nodule.
  • EMT-6 tumor cells were grown as a monolayer at 37°C in a humidified atmosphere (5% C0 2 , 95% air).
  • the culture medium was RPMI 1640 containing 2 mM L-glutamine (ref: BE12-702F, Lonza,
  • mice Healthy female Balb/C mice, 6-8 weeks old at reception, were used in the study.
  • the treatment started when the tumors reached a mean volume of approximately 75-150 mm 3 .
  • the mice were randomized according to their individual tumor volume into groups of 8 animals each using Vivo manager ® software (Biosystemes, Couternon, France).
  • Vivo manager ® software Biosystemes, Couternon, France.
  • a statistical test analysis of variance
  • TWx2 refers to one injection twice weekly for two consecutive weeks. CA4P were administered 24 hours prior to each dose of the antibody.
  • FIGS. 1-2 Results for the tumor volume versus time and the body weight versus time for the mice in the study are illustrated in FIGS. 1-2, respectively. Once more than 20% of the mice were dead in a given group then the study was discontinued for the given group.
  • FIG. 1 shows that the average tumor size decreased significantly for the mice that received both CA4P and anti-CTLA-4 antibody in contrast to the control group, CA4P only group, and the anti-CTLA-4 antibody only groups where tumor sizes steadily increased on average.
  • Two of the eight mice receiving anti-CTLA-4 antibody only showed tumor regression with the treatment.
  • One of the eight mice receiving CA4P only showed tumor regression. Unexpectedly, seven of the eight mice receiving both CA4P and anti-CTLA-4 antibody showed complete tumor regression.
  • mice receiving both CA4P and anti-CTLA-4 antibody were still alive at the 41 day mark of the study.
  • the combination treatment with both CA4P and anti-CTLA-4 antibody resulted in a synergistic effect against the tumors in the mice exemplified by the
  • FIGS. 3A-5 Larger tumors were studied in the results illustrated in FIGS. 3A-5 with initial tumor sizes around 200 mm 3 -250 mm 3 in comparison to the mean tumor size of 35-45 mm 3 studied in FIGS. 1-2.
  • the data from FIGS. 3A-3B were obtained using the following experimental conditions.
  • the tumor model used was an EMT-6 mouse mammary carcinoma implanted in the mammary fatpad.
  • CA4P was provided intraperitoneally at 100 mg/kg.
  • the PD-1 and PD-Ll antibodies were provided to the mice all at 10 mg/kg intraperitoneally.
  • CA4P was delivered intraperitoneally on days 0, 3, 7, and 10 with antibodies delivered intraperitoneally on days 1, 4,
  • the initial tumor volume provided to the mice was about 250 mm 3 .
  • the treatment endpoints was based on the tumor volume reaching about 1000 mm 3 .
  • FIG. 3A is a graph illustrating median tumor growth versus time in mice receiving treatment with a PD-1 antibody alone and a PD-1 antibody with CA4P.
  • FIG. 3 A shows that the mice receiving both the PD-1 antibody and CA4P had a much slower tumor growth and lived longer before reaching the study end point versus mice receiving only PD-1.
  • FIG. 3 A also illustrates the survival rate for mice versus time for mice receiving treatment with a PD-1 antibody alone and a PD-1 antibody with CA4P. The survival rate was longer for mice receiving the PD-1 antibody with CA4P versus those receiving the PD-1 antibody alone.
  • FIG. 3B is a graph illustrating median tumor growth versus time in mice receiving treatment with a PD-Ll antibody alone and a PD-Ll antibody with CA4P.
  • FIG. 3B shows that the mice receiving both the PD-Ll antibody and CA4P had a much slower tumor growth and lived longer before reaching the study end point versus mice receiving only PD-Ll.
  • FIG. 3B also illustrates the survival rate for mice versus time for mice receiving treatment with a PD-Ll antibody alone and a PD-1 antibody with CA4P.
  • mice with EMT-6 mammary tumors that showed further evidence of improvement in anti-tumor effects.
  • the test conditions were the same as the EMT-6 test conditions described in the above example but larger tumors were treated.
  • the tumors studied had an average size of about 125 mg. .
  • the following table illustrates data for the EMT-6 study at the completion of the study, which corresponded to 34 days after the treatment was initiated.
  • the survival rates at the end of the study showed a survival rate of 0/8 for the vehicle and 0/8 for the anti-PDl only treatments.
  • Treatment with CA4P alone resulted in a survival rate of 1/8.
  • the combined treatment of CA4P and anti-PD-1 resulted in a survival rate of 2/8.
  • the EMT-6 study data supports the synergistic combination of the CA4P and anti-PD-1 treatments through the decreased tumor growth rates and increased survival rates over the treatments alone. Number of Animals that are
  • the data from FIGS. 4-5 was obtained using the following experimental conditions.
  • the tumor and mouse models used were C3H mammary carcinoma in male CDF1 mice.
  • CA4P was provided intraperitoneally at 100 mg/kg.
  • the anti-PD-l/PD-Ll/CTLA-4 antibodies were provided to the mice all at 10 mg/kg intraperitoneally.
  • CA4P was delivered intraperitoneally on days 0, 3, 7, and 10 with antibodies delivered intraperitoneally on days 1, 4, 8, and 11.
  • the treatment endpoints were either based on body weight change or time to 3 times the treatment volume of 200 mm 3 (TGT3).
  • the initial tumor volume at treatment initiation was about 200 mm 3 .
  • FIG. 4 is a graph illustrating tumor volume versus time for mice receiving various treatments. Mice with 200 mm 3 tumors received the PBS control, anti-PD-1 antibody, anti-PD- Ll antibody, anti-CTLA-4 antibody, combretastatin alone, CA4P plus anti-PD-1 antibody, CA4P plus anti-PD-Ll antibody, and CA4P plus anti-CTLA-4 antibody. The tumor volume versus time is shown in FIG. 4. FIG. 4 shows similar tumor growth rates and endpoints for the PBS control, anti-PD-1 antibody, anti-PD-Ll antibody, and anti-CTLA-4 antibody. The combretastatin treatment alone slowed the tumor growth rate and extended the endpoint in comparison to the antibody alone and control treatments.
  • the combination of CA4P and each of the anti-PD-1 antibody, anti-PD-Ll antibody, and anti-CTLA-4 antibody showed extended mouse lifespan before reaching the study endpoints along with slowed tumor growth.
  • the combination of CA4P and anti-PD-Ll antibodies had the longest time until the endpoint was reached and slowest tumor growth rate, followed by CA4P and anti- CTLA-4 antibody and CA4P plus anti-PD-1 antibody.
  • FIG. 5 illustrates the number of days until the chosen endpoint i.e. time to reach three times the tumor volume at start of treatment (TGT3) of the study for mice receiving various treatments along with error bars.
  • FIG. 5 shows similar endpoints for the PBS control, anti-PD-1 antibody, anti-PD-Ll antibody, and anti-CTLA-4 antibody of around 5 days.
  • the combretastatin treatment alone extended the endpoint to about 6 days.
  • the combination of CA4P and each of the anti-PD-1 antibody, anti-PD-Ll antibody, and anti-CTLA-4 antibody showed extended mouse lifespan before reaching the study endpoints.
  • the combination of CA4P plus anti-PD-1 antibody had a TGT3 endpoint slightly above 6 days.
  • the combination of CA4P plus anti-PD-Ll antibody and CA4P plus anti-CTLA-4 antibody each had a TGT3 endpoint of about 6.5 days.
  • CA4P and anti-PD-Ll antibodies had the longest time until the endpoint was reached at nearly 8 days.
  • FIGS. 6-7 are graphs illustrating tumor volume versus time for mice with large CT-26 colon tumors receiving various treatments.
  • FIG. 6 illustrates the tumor data for the first 14 days of treatment.
  • FIG. 7 illustrates the tumor data for up to 34 days.
  • CA4P was administered at the dose 100 mg/kg.
  • Anti-CTLA-4 antibody was administered at the dose 10 mg/kg.
  • Anti-PD-1 antibody was administered at the dose 10 mg/kg.
  • the treatment schedule is summarized below:
  • TWx2 One injection twice weekly for two consecutive weeks.
  • FIG. 6 shows the data for the first 14 days of treatment. Following 14 days of treatment, tumors in the control group grew to an average size of 2005 mm 3 , while those treated with the combination of CA4P and an anti-CTLA antibody grew to only 229 mm 3 .
  • the tumors in the anti-CTLA-4 monotherapy group grew to 1016 mm 3 and the tumors in the CA4P monotherapy group grew to 1265 mm 3 .
  • 8 of 8 mice receiving the CA4P and anti-CTLA-4 combination survived to Day 14, compared to 4 of 8 in the anti-CTLA-4 antibody monotherapy group, 2 of 8 in the CA4P monotherapy group and 0 of 8 in the control group.
  • CA4P increases the effects of checkpoint inhibitors because it rapidly causes tumor cell death, which likely increases tumor antigen presentation and T-cell activation and the overall immunologic response. Key statistics from Day 14 results are below:
  • CA4P in combination with anti-CTLA-4 antibodies resulted in 77% reduction in tumor size compared to anti-CTLA-4 antibodies alone and 88% compared to the control.
  • a clear survival benefit was shown for animals receiving the combination therapy.
  • the animals in the combination CA4P and anti-CTLA-4 antibody treatment group continue to show declines in tumor volume beyond Day 14 as shown in FIG. 7. Note that day 0 on Figure 6 corresponds to Day 13 on FIG. 7.
  • the animals in the combination CA4P and anti- CTLA-4 antibody treatment group also show significantly improved survival rates over the other groups as shown in FIG. 7.
  • FIGS. 8A-8B are graphs illustrating the MC38 tumor volume versus time for various treatments, including the vehicle, anti-PD-1, CA4P, and a combination of CA4P and anti-PD-1.
  • the mice were inoculated with tumors on day 0 and the treatment commenced on study day 15.
  • FIGS. 8A-8B show that the combination treatment of CA4P and anti-PD-1 antibodies resulted in mice with decreased tumor growth and volumes as compared to the control and individual treatments.
  • the following table illustrates data for the MC38 study counting the number of mice with tumors having a volume of less than 1000 mm 3 at the completion of the study, which corresponded to study day 33.
  • FIGS. 9A-9D illustrate tumor volume versus study day for mice with MC38 tumors receiving different treatments.
  • FIG. 9A is a graph showing the tumor volume versus study day for a variety of animals receiving the vehicle treatment.
  • FIG. 9B is a graph showing the tumor volume versus study day for a variety of animals receiving the anti-PD-1 treatment alone.
  • FIG. 9C is a graph showing the tumor volume versus study day for a variety of animals receiving the CA4P treatment alone.
  • FIG. 9D is a graph showing the tumor volume versus study day for a variety of animals receiving the combination treatment of CA4P and anti-PD-1.
  • the tumors were inoculated on Study Day 0 and treatment commenced Study Day 15.
  • FIGS. 9A- 9D the tumors were inoculated on Study Day 0 and treatment commenced Study Day 15.
  • FIGS. 9A- 9D the tumors were inoculated on Study Day 0 and treatment commenced Study Day 15.
  • FIGS. 9A- 9D the tumors were
  • 9A-9D include animals with tumors that had volumes of greater than 3000 mm 3 and were euthanized. As shown in FIGS. 9A-9D, the tumor growth rates were highest with the vehicle treatment. The C A4P alone and anti-PD- 1 treatments showed some decreased tumor growth rates and progression in comparison to the vehicle treatment. The combination treatment of CA4P and anti-PD-1 showed lower tumor progression and decrease tumor sizes in comparison to the single treatments.
  • FIG. 10A is a table illustrating a preliminary study examining the combination therapy of CA4P and anti-CTLA-4 in a mouse model of colon cancer. Previous tests with this model indicated that reductions in tumor volume after treatment with CA4P and anti-CTLA-4 combination therapy; as shown in FIG. 10A, the combination therapies described herein may also be associated with an enhanced immune response.
  • the combination therapy of CA4P and anti-CTLA-4 shows increases in the median number of tumor-associated white blood cells (WBC's) (69.2K vs. 39.0K vs. 16.7K for CA4P plus anti-CTLA-4, anti-CTLA-4 alone and vehicle control, respectively), T cells (5.2K vs. 1.6K vs.
  • WBC's tumor-associated white blood cells
  • WBC was shown by CD45+ cell count (see, e.g., FIG. 10B).
  • T cells were shown by CD3+ cells among CD45+ cells (see, e.g., FIG. IOC).
  • Effector cytotoxic CD8+ T Cells were shown by CD8+ cells among CD3+ cells (Treff, see, e.g., FIG. 10D).
  • treatment with both CA4P and anti-CTLA-4 generally maintains an elevated tumor-associated median effector T cell/regulatory T cell ratio, which also indicates a heightened immune response.
  • the VDA e.g., combretastatin agent CA4P
  • the VDA induces immediate, rapid and extensive tumor cell necrosis which can stimulate the immune system
  • antibodies to CTLA-4 stimulate the immune system through a different mechanism, by blocking immunosuppression (similar to the approved drug marketed under the trade name Yervoy).
  • the combination of these two drugs is surprisingly more effective than either alone.
  • numeric value may have a value that is +/- 0.1% of the stated value (or range of values), +/- 1% of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.
  • any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and/or steps may alternatively be exclusive, and may be expressed as “consisting of or alternatively “consisting essentially of the various components, steps, sub-components or sub-steps.
  • any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative alternative
  • one or more method steps may be skipped altogether.
  • Optional features of various device and system embodiments may be included in some embodiments and not in others.
  • inventive subject matter may be referred to herein individually or collectively by the term "invention" merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed.
  • inventive concept any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown.
  • This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

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Abstract

L'invention concerne des méthodes destinées à produire un effet antitumoral chez un individu atteint d'un cancer ou d'une tumeur. Les méthodes selon l'invention consistent à administrer au patient un agent vasculoclastique (VDA) tel qu'un agent de combrétastatine et au moins un anticorps sélectionné dans le groupe constitué par : un anticorps anti-CTLA-4, un anticorps anti-PD-1, un anticorps anti-PD-L1 et un anticorps anti-PD-L2, dans des quantités efficaces. Des exemples de combrétastatine comprennent CA1P, CA4P, ainsi que leurs sels et promédicaments correspondants. La combinaison du VDA et d'au moins un des anticorps produit un effet antitumoral synergique.
PCT/US2018/017639 2017-02-09 2018-02-09 Utilisation d'agents vasculoclastiques (vda) pour améliorer des traitements immunomodulateurs contre des tumeurs Ceased WO2018148555A1 (fr)

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