Treatment for solid tumors

Abstract

Methods of treating cancers are provided, the methods comprise administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with a cancer. In another aspect, methods of treating glioblastoma are provided, those methods comprise administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with glioblastoma.

Description

TREATMENT FOR SOLID TUMORS1. BACKGROUND OF THE INVENTION

[0001] Cancer is one of the leading causes of death in developed nations. In the United States, cancer is the second most common cause of death, behind heart disease. In 2024, 2,001,140 new cancer cases and 611,720 cancer deaths are projected to occur in the United States. More specifically, pancreatic cancer is a lethal condition and a major cause of cancer- related deaths. At time of writing, pancreatic cancer is the third-leading cause of cancer related deaths in the United States and is projected to become the second leading cause by 2030. This cancer is characterized by high mortality. Due to non-specific symptoms, pancreatic cancer is mostly diagnosed at an advanced stage of the disease when patients typically present with locally advanced or metastatic, unresectable disease. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents, and because it metastasizes microscopically early in the disease course therapies such as radiation are limited in their effect. Only about 4% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) are expected to survive beyond 5 years, ranking PDAC firmly last amongst all cancers in terms of prognostic outcomes for patients. There is therefore an urgent need for improved therapies effective in the treatment of cancer, specifically PDAC that can prolong the survival of patients.2. SUMMARY OF THE INVENTION

[0002] As described herein, experiments were performed to assess the survival benefit of adding azeliragon administration to radiation therapy in treatment of pancreatic cancer, as compared to radiation therapy alone and azeliragon alone using homozygous nu / nu immunodeficient nude mouse models. Azeliragon is an orally bioavailable inhibitor of the receptor for advanced glycation end-products (RAGE). Results using human pancreatic cell line grown subcutaneously in our chosen mouse model demonstrated a significant improvement in survival when azeliragon was added to RT, as compared to administration of RT alone and azeliragon alone.

[0003] Accordingly, in a first aspect, methods of treating cancer are provided. The method comprises administering a therapeutically effective amount of azeliragon, or apharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with a cancer.

[0004] In a second aspect, methods of treating a cancer other than glioblastoma and highgrade glioma are provided. The method comprises administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with a cancer other than glioblastoma and high-grade glioma.3. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0005] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0006] FIG. 1 schematizes the experimental protocol used in Example 1 to assess the survival benefit of adding azeliragon administration to radiation therapy in treatment of glioblastoma, as compared to azeliragon administration alone and to radiation therapy alone, in immune-competent murine orthotopic glioblastoma multiforme (GBM) tumor models.

[0007] FIG. 2 presents Kaplan-Meier survival curves in four groups of C57 albino mice following GL261 cell implantation: control mice receiving no active treatment (“Tumor”), mice treated with azeliragon alone (“Azeliragon”), mice treated with radiation therapy alone (“RT”), and mice receiving both azeliragon and radiation therapy (“RT+Azeliragon”). The data show a significant improvement in survival with the combination therapy.

[0008] FIG. 3 presents Kaplan-Meier survival curves in four groups of C57 albino mice following CT2A cell implantation: control mice receiving no active treatment (“Tumor”), mice treated with azeliragon alone (“Azeliragon”), mice treated with radiation therapy alone (“RT”), and mice receiving both azeliragon and radiation therapy (“RT + Azeliragon”). The data show a significant improvement in survival with the combination therapy.

[0009] FIG. 4 presents a line graph depicting tumor volume progression in four groups of nude mice following Panel cell implantation: control mice receiving no active treatment (“control”), mice treated with radiation therapy alone (“RT”), mice treated with azeliragon alone (“AZ”), and mice receiving both radiation therapy and azeliragon (“RT+AZ”). Thedata show a significant reduction in tumor volume and maintenance of reduced tumor volume with the combination therapy versus radiation therapy alone and treatment with azeliragon alone.4. DETAILED DESCRIPTION OF THE INVENTION4.1 Definitions

[0010] Unless otherwise defined herein, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains.

[0011] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.

[0012] As used herein, the term “patient” refers to a human “subject.”

[0013] The terms "treat", "treated", "treating", or “treatment” as used herein have the meanings commonly understood in the medical arts, and therefore do not require cure or complete remission, and therefore include any beneficial or desired clinical results. A “therapeutically effective amount” of a compound, composition, or radiation is an amount effective to treat.

[0014] The term “pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions that are approvable by health regulators for inclusion in a drug substance. Suitable salts include those described in Stahl and Wermuth (Eds.), Pharmaceutical Salts: Properties, Selection, and Use, 2ndrevised edition, 2011.

[0015] The terms “co-administer” and “co-administering” refer to treatment regimens in which a plurality of different therapeutic compounds, or at least one therapeutic compound and radiation therapy (RT), are administered to a subject in sufficient temporal proximity to one another as to provide clinical benefit greater than administration of either, or any one, alone. Co-administration may involve separate simultaneous, or sequential, administration of a plurality of different therapeutic compounds, or of at least one therapeutic compound and radiation therapy (RT).4.2 Methods of treating cancer

[0016] In a first aspect, methods of treating cancer are provided. The method comprises administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with a cancer. The first aspect can alternatively be worded as azeliragon, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, comprising: administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with a cancer.

[0017] In a second aspect, methods of treating cancer other than glioblastoma and high-grade glioma are provided. The method comprises administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with a cancer other than glioblastoma and high-grade glioma. The second aspect can alternatively be worded as azeliragon, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer other than glioblastoma and high-grade glioma, comprising: administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a patient who has been diagnosed with a cancer other than glioblastoma and high-grade glioma.4.2.1. Patient selection

[0018] In typical embodiments, the patient has been diagnosed a cancer.

[0019] In some embodiments, the cancer is one other than glioblastoma and high-grade glioma.

[0020] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a sarcoma or carcinoma. In some embodiments, the cancer is a mixed-type cancer. In some embodiments, the cancer is adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma, or teratocarcinoma.

[0021] In further embodiments, the cancer is lung cancer, breast cancer, ovarian cancer, lymphoid cancer, gastrointestinal cancer, anal cancer, genital or genitourinary tract cancer, pharynx cancer, CNS cancer, head and neck cancer, skin cancer, pancreatic cancer, coloncancer, rectal cancer, renal-cell carcinoma, liver cancer, lung cancer, or esophageal cancer. In some embodiments, the cancer is pancreatic ductal carcinoma (PDAC).

[0022] In typical embodiments, the subject is human. In some embodiments, the subject is an adult. In various embodiments, the subject is at least 18 years old, 21 years old, 30 years old, 40 years old, 50 years old, 60 years old, 70 years old, 75 years old, or 80 years old.

[0023] In some embodiments, the subject is an infant or child. In various embodiments, the subject is no more than 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old or 10 years old. In various embodiments, the subject is no more than 15 years old, 16 years old, or 17 years old.

[0024] In another aspect, the subject diagnosed with a cancer has stage I, stage II, stage III, or stage IV cancer.

[0025] In some embodiments, the subject has been diagnosed with grade I, grade II, grade III, or grade IV tumor.4.2.2. Azeliragon drug substance and drug product

[0026] “Azeliragon”, also known as “TTP448” and “PF-04494700”, CAS RegistryNo. 603148-36-3, is an orally bioavailable inhibitor of the receptor for advanced glycation endproducts (RAGE) having the structure of Formula IAzeliragon’s IUPAC chemical name is 3-[4-[2-butyl-l-[4-(4- chlorophenoxy)phenyl]imidazol-4-yl]phenoxy]-7V,7V-diethylpropan- 1 -amine. An alternative chemical name is N-[3-[4-[2-butyl-l-[4-(4-chlorophenoxy)phenyl]-lH-imidazol-4-yl]phenoxy]propyl]-N,N-diethylamine. U.S. Patent Nos. 7,361,678, 7,884,219, and 8,372,988, the disclosures of which are hereby incorporated by reference in their entireties, describe azeliragon and methods of synthesizing azeliragon.

[0027] In some embodiments, azeliragon is administered in a crystalline form. In various embodiments, azeliragon is administered in a crystalline form described in any one of U.S. Pat Nos. 7,884,219; 8,372,988; and US pre-grant publication no. US 2021 / 0070714, the disclosures of which are hereby incorporated by reference in their entireties.

[0028] In certain embodiments, azeliragon is administered as crystalline Form I, characterized as having a solid state13C NMR spectrum comprising peaks at 149.7 and 141.0 ppm; having X-ray powder diffraction peaks expressed in degrees 29 at 16.5° and 26.8°; and / or having a Raman spectrum comprising peaks at 335 and 798 cm as described in U.S. Patent No. 7,884,219, herein incorporated by reference.

[0029] In certain embodiments, azeliragon is administered as crystalline Form II, characterized as having a solid state13C NMR spectrum comprising peaks at 153.6, 140.1 and 119.9 ppm; having X-ray powder diffraction peaks expressed in degrees 29 at 18.8° and 20.1°; and / or having a Raman spectrum comprising peaks at 300 and 1180 cm ’, as described in U.S. Patent No. 7,884,219 and incorporated herein by reference.

[0030] In certain embodiments, azeliragon is administered as crystalline Form III, characterized as having an XRPD pattern comprising peaks at 29 angles of 5.4°, 21.5°, and 22.0°±0.2°; and / oor an XRPD pattern characterized in FIG. 1 of US PreGrant publication 2021 / 0070714, incorporated herein by reference.

[0031] In some embodiments, azeliragon is administered as crystalline Form IV, characterized as having an XRPD pattern comprising peaks at 29 angles of 19.7°, 22.0°, and 30.2°±0.2°, as described in US PreGrant publication 2021 / 0070714, incorporated herein by reference.

[0032] In some embodiments, azeliragon is amorphous.

[0033] In some embodiments, azeliragon is administered as the free base.

[0034] In some embodiments, azeliragon is administered in the form of a pharmaceutically acceptable salt. In various embodiments, the azeliragon salt is a salt described in US pregrant publication no. 2021 / 0059988, the disclosure of which is incorporated herein by reference in its entirety. In particular embodiments, azeliragon is administered in the form of a pharmaceutically acceptable salt selected from the group consisting of 4-aminosalicylic acid, fumaric acid, galactaric acid, gentisic acid, hippuric acid, hydrobromic acid, hydrochloric acid, maleic acid, L-malic acid, methane sulfonic acid, oxalic acid, phosphoric acid, saccharin, L-tartaric acid, and vanillic acid.

[0035] In some embodiments, azeliragon is administered in a liquid formulation.

[0036] In some embodiments, azeliragon is administered in a solid dosage form.

[0037] In some embodiments, azeliragon is administered in orally. In some particular embodiments, it is administered as a tablet. In particular embodiments, it is administered as a capsule.

[0038] In various embodiments, the solid dosage form is crystalline azeliragon. In various embodiments, the crystalline azeliragon is Form II.4.2.3. Azeliragon dose regimen

[0039] In typical embodiments, azeliragon is administered orally. In various embodiments, azeliragon is administered without regard to food.

[0040] In some embodiments, azeliragon is administered daily for a first plurality of days at a loading dose, followed by daily administration thereafter for a second plurality of days at a maintenance dose.

[0041] In various embodiments, the loading dose is administered daily for at least 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In various embodiments, the loading dose is administered daily for 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In certain embodiments, the first loading dose is administered at least 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days,12 days, 13 days, or 14 days before commencing RT. In certain embodiments, the first loading dose is administered 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,13 days, or 14 days before commencing RT.

[0042] In some embodiments, the loading dose is 200 mg per day, 199 mg per day, 198 mg per day, 197 mg per day, 196 mg per day, 195 mg per day, 194 mg per day, 193 mg per day, 192 mg per day, 191 mg per day, 190 mg per day, 189 mg per day, 188 mg per day, 187 mg per day, 186 mg per day, 185 mg per day, 184 mg per day, 183 mg per day, 182 mg per day, 181 mg per day, 180 mg per day, 179 mg per day, 178 mg per day, 177 mg per day, 176 mg per day, 175 mg per day, 174 mg per day, 173 mg per day, 172 mg per day, 171 mg per day, 170 mg per day, 169 mg per day, 168 mg per day, 167 mg per day, 166 mg per day, 165 mg per day, 164 mg per day, 163 mg per day, 162 mg per day, 161 mg per day, 160 mg per day, 159 mg per day, 158 mg per day, 157 mg per day, 156 mg per day, 155 mg per day, 154 mg per day, 153 mg per day, 152 mg per day, 151 mg per day, 150 mg per day, 149 mg per day, 148 mg per day, 147 mg per day, 146 mg per day, 145 mg per day, 144 mg per day, 143 mg per day, 142 mg per day, 141 mg per day, 140 mg per day, 139 mg per day, 138 mg per day, 137 mg per day, 136 mg per day, 135 mg per day, 134 mg per day, 133 mg per day, 132 mg per day, 131 mg per day, 130 mg per day, 129 mg per day, 128 mg per day, 127 mg per day, 126 mg per day, 125 mg per day, 124 mg per day, 123 mg per day, 122 mg per day, 121 mg per day, 120 mg per day, 119 mg per day, 118 mg per day, 117 mg per day, 116 mg per day, 115 mg per day, 114 mg per day, 113 mg per day, 112 mg per day, 111 mg per day, 110 mg per day, 109 mg per day, 108 mg per day, 107 mg per day, 106 mg per day, 105 mg per day, 104 mg per day, 103 mg per day, 102 mg per day, 101 mg per day, 100 mg per day, 99 mg per day, 98 mg per day, 97 mg per day, 96 mg per day, 95 mg per day, 94 mg per day, 93 mg per day, 92 mg per day, 91 mg per day, 90 mg per day, 89 mg per day, 88 mg per day, 87 mg per day, 86 mg per day, 85 mg per day, 84 mg per day, 83 mg per day, 82 mg per day, 81 mg per day, 80 mg per day, 79 mg per day, 78 mg per day, 77 mg per day, 76 mg per day, 75 mg per day, 74 mg per day, 73 mg per day, 72 mg per day, 71 mg per day, 70 mg per day, 69 mg per day, 68 mg per day, 67 mg per day, 66 mg per day, 65 mg per day, 64 mg per day, 63 mg per day, 62 mg per day, 61 mg per day, 60 mg per day, 59 mg per day, 58 mg per day, 57 mg per day, 56 mg per day, 55 mg per day, 54 mg per day, 53 mg per day, 52 mg per day, 51 mg per day, 50 mg per day, 49 mg per day, 48 mg per day, 47 mg per day, 46 mg per day, 45 mg per day, 44 mg per day, 43 mg per day, 42 mg per day, 41 mg per day, 40 mg per day, 39 mg per day, 38 mg per day, 37 mg per day, 36 mg per day, 35 mg per day, 34 mg per day, 33 mg per day, 32 mg per day, 31 mg per day, 30 mg per day, 29 mg per day, 28 mg per day, 27 mg per day, 26 mg per day, 25 mg per day, 24 mg per day, 23 mg per day, 22 mg per day, 21 mgper day, 20 mg per day, 19 mg per day, 18 mg per day, 17 mg per day, 16 mg per day, or 15 mg per day.

[0043] In some embodiments, the maintenance dose is 100 mg per day, 99 mg per day, 98 mg per day, 97 mg per day, 96 mg per day, 95 mg per day, 94 mg per day, 93 mg per day, 92 mg per day, 91 mg per day, 90 mg per day, 89 mg per day, 88 mg per day, 87 mg per day, 86 mg per day, 85 mg per day, 84 mg per day, 83 mg per day, 82 mg per day, 81 mg per day, 80 mg per day, 79 mg per day, 78 mg per day, 77 mg per day, 76 mg per day, 75 mg per day, 74 mg per day, 73 mg per day, 72 mg per day, 71 mg per day, 70 mg per day, 69 mg per day, 68 mg per day, 67 mg per day, 66 mg per day, 65 mg per day, 64 mg per day, 63 mg per day, 62 mg per day, 61 mg per day, 60 mg per day, 59 mg per day, 58 mg per day, 57 mg per day, 56 mg per day, 55 mg per day, 54 mg per day, 53 mg per day, 52 mg per day, 51 mg per day, 50 mg per day, 49 mg per day, 48 mg per day, 47 mg per day, 46 mg per day, 45 mg per day, 44 mg per day, 43 mg per day, 42 mg per day, 41 mg per day, 40 mg per day, 39 mg per day, 38 mg per day, 37 mg per day, 36 mg per day, 35 mg per day, 34 mg per day, 33 mg per day, 32 mg per day, 31 mg per day, 30 mg per day, 29 mg per day, 28 mg per day, 27 mg per day, 26 mg per day, 25 mg per day, 24 mg per day, 23 mg per day, 22 mg per day, 21 mg per day, 20 mg per day, 19 mg per day, 18 mg per day, 17 mg per day, 16 mg per day, 15 mg per day, 14 mg per day, 13 mg per day, 12 mg per day, 11 mg per day, 10 mg per day, 9 mg per day, 8 mg per day, 7 mg per day, 6 mg per day, or 5 mg per day.

[0044] In some embodiments, the daily loading dose and / or daily maintenance dose can be administered as a single daily dose or as a plurality of split doses administered multiple times per day, such as twice per day or three times per day. In various embodiments the split doses can be equal or unequal doses.

[0045] In certain embodiments, the loading dose is 60 mg twice daily (120 mg daily dose) and the maintenance dose is 40 mg once daily. In specific embodiments, the loading dose is 60 mg twice daily for 6 days and the maintenance dose is 40 mg once daily for at least 3 months, 6 months, 9months, or 12 months. In certain embodiments, the loading dose is 30 mg twice daily (60 mg daily dose) and the maintenance dose is 20 mg once daily. In specific embodiments, the loading dose is 30 mg twice daily for 6 days and the maintenance dose is 20 mg once daily for at least 3 months, 6 months, 9months, or 12 months. In certain embodiments, the loading dose is 15 mg twice daily (30 mg daily dose) and the maintenancedose is 10 mg once daily. In specific embodiments, the loading dose is 15 mg twice daily for 6 days and the maintenance dose is 10 mg once daily for at least 3 months, 6 months, 9 months, or 12 months. In certain embodiments, the loading dose is 15 mg once daily and the maintenance dose is 5 mg once daily. In specific embodiments, the loading dose is 15 mg once daily for 6 days and the maintenance dose is 5 mg once daily for at least 3 months, 6 months, 9 months, or 12 months.

[0046] In certain embodiments, the first maintenance dose is administered before commencing RT. In certain embodiments, the first maintenance dose is administered on the same day that RT commences. In certain embodiments, the first maintenance dose follows commencement of RT. In some embodiments, azeliragon is administered at the maintenance dose daily for at least 3 months, 6 months, 9 months, or 12 months.

[0047] In some embodiments, azeliragon is administered at the maintenance dose daily for 3 months, 6 months, 9 months, or 12 months. In some embodiments, azeliragon is administered at the maintenance dose daily for at least 15 months, 18 months, 21 months, or 24 months. In some embodiments, azeliragon is administered at the maintenance dose daily for 15 months, 18 months, 21 months, or 24 months. In some embodiments, azeliragon is administered at the maintenance dose daily for at least 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. In some embodiments, azeliragon is administered at the maintenance dose daily for 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. In some embodiments, azeliragon is administered at the maintenance dose for the rest of the patient’s life.

[0048] In various embodiments, azeliragon is administered daily following during administration of RT. In various embodiments, azeliragon is administered daily prior to administration of RT. In various embodiments, azeliragon is administered daily following administration of RT.4.2.4. Radiation therapy (RT)

[0049] In typical embodiments, radiation therapy is fractionated radiotherapy. In certain embodiments, RT is fractionated conformal radiotherapy. In certain embodiments, RT is fractionated focal irradiation. In certain embodiments, RT is intensity-modulatedradiotherapy (IMRT). In certain embodiments, RT is image-guided radiation therapy. In certain embodiments, RT is stereotactic body RT.

[0050] In certain embodiments, RT is administered in a plurality of fractionated doses. In certain embodiments, RT is administered at a daily dose of 2 gray (Gy). In certain embodiments, RT is administered at a daily dose of 2 Gy for 5 days a week for 6 weeks, for a total dose of up to 60 Gy. In some embodiments, the RT is administered at a daily dose of 2 Gy for 5 days a week. In some embodiments the RT is administered at a daily dose of 2 Gy not exceeding 68 Gy.

[0051] In some conformal embodiments where the cancer is glioblastoma, RT is delivered to an initial volume consisting of the area of enhancement, the postoperative cavity, plus surrounding edema (or other abnormality as seen on fluid attenuated inversion recovery [FLAIR] images on MRI), and a 2-cm margin. In certain embodiments, the total dose is 46 Gy in 23 fractions, followed by a boost of 14 Gy in 7 fractions to the area of enhancement plus the cavity and a 2.5-cm margin.

[0052] In some embodiments, the RT is proton therapy.

[0053] In some embodiments, the RT dose is administered after azeliragon has been administered daily at the loading dose for 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In some embodiments, the first RT dose is administered after azeliragon has been administered daily at the loading dose for 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days and azeliragon has thereafter been administered daily at the maintenance dose for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

[0054] In some embodiments, the first RT dose is administered after azeliragon has been administered at the loading dose for 6 days or 7 days. In some embodiments, RT begins on the same day as the first administration of the azeliragon maintenance dose.4.2.5. Surgery

[0055] In some embodiments, the subject’s tumor has been surgically resected from the subject prior to initiation of administration of azeliragon. In some embodiments, the subject’s tumor has been surgically resected from the subject prior to initiation of administration ofRT. In some embodiments, the subject’s tumor has been surgically resected from the subject prior to initiation of administration of azeliragon and co-administration of RT.

[0056] In various embodiments, the subject’s tumor could not be surgically resected from the subject prior to initiation of administration of azeliragon. In various embodiments, the subject’s tumor could not be surgically resected from the subject prior to initiation of administration of RT. In various embodiments, the subject’s tumor could not be surgically resected from the subject prior to initiation of administration of azeliragon and coadministration of RT.4.2.6. Optional anti-cancer agent

[0057] In some embodiments, the method optionally further comprises administering additional anti-cancer agents in addition to azeliragon. In some embodiments, the anti-cancer agent is administered concurrently with RT and azeliragon. In certain embodiments, the maintenance anti-cancer agent dose is further administered for a plurality of days following administration of the last dose of RT. In certain embodiments, the anti-cancer agent administration is terminated after completion of radiotherapy.

[0058] In certain embodiments, the anti-cancer agent is administered orally at a daily dose of 75 mg per square meter of body surface. In certain embodiments, the anti-cancer agent is administered orally at a daily dose of 75 mg / m2for 42 days concomitant with focal radiotherapy, at 60 Gy administered in 30 fractions of 2 Gy each. In certain embodiments the focal radiotherapy is administered at 2 Gy each up to 68 Gy.

[0059] In some embodiments, the anti-cancer agent is temozolomide (TMZ), gemcitabine, nab-paclitaxel, 5-Fluorouracil, irinotecan, liposomal irinotecan, leucovorin, oxaliplatin or capecitabine.4.2.7. Clinical benefit

[0060] In some embodiments, administration of azeliragon or pharmaceutically acceptable salt thereof is effect to stabilize the subject’s ECOG status.

[0061] In some embodiments, the treatment is effective to stabilize or improve quality of life, as indicated by the ECOG performance scale, which is widely used to assess a subject’s functional status, ability to respond to treatment, and the subject’s overall prognosis. In someembodiments, the stabilization of the ECOG performance status following initial treatment with azeliragon has a duration of at least 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7, weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks.

[0062] In various embodiments, the treatment is effective to slow progression of PDAC. In various embodiments, the treatment is effective to cause remission of PDAC. In various embodiments, the treatment is effective to reduce pain associated with PDAC. In various embodiments, the treatment is effective to reduce muscle wasting, also known as cachexia, associated with PDAC.

[0063] In some embodiments, cachexia associated with cancer is weight loss in excess of 5% over the preceding 6 months, 5 months, 4 months, 3 months, 2 months, or 1 month.

[0064] In some embodiments, cachexia associated with cancer is a body mass index (BMI) < 20 kg / m2with ongoing > 2% weight loss. In some embodiments “ongoing” is at least 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

[0065] In some embodiments, cachexia associated with cancer is depletion of muscle mass and > 2% weight loss.

[0066] In various embodiments, the treatment is effective to reduce cachexia associated with cancer. In various embodiments, the cancer is PDAC.

[0067] In various embodiments, the treatment is effective to inhibit the progression of cachexia associated with cancer. In various embodiments, the cancer is PDAC.

[0068] In various embodiments, the treatment is effective to extend survival of a subject patient with PDAC.

[0069] In certain embodiments, the treatment is effective to reduce tumor volume. In certain embodiments, the treatment is effective to reduce tumor volume by 80%, 79%, 78%, 77%,76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, or 10% as measured prior to treatment.

[0070] In certain embodiments, the treatment is effective to reduce tumor volume by at least 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%,64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, 50%, 49%,48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%,32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%,16%, 15%, 14%, 13%, 12%, 11%, or 10% as measured prior to treatment.

[0071] In various embodiments, the treatment is effective to maintain tumor volume. In various embodiments, the treatment is effective to maintain tumor volume within 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the tumor volume measured prior to treatment.

[0072] In some embodiments, the treatment is effective to provide a median overall survival of at least 12 months, 13 months, 14, months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, 37 months, 38 months, 39 months, 40 months, 41 months, 42 months, 43 months, 44 months, 45 months, 46 months, 47 months, or 48 months in the cancer population treated according to the methods described herein.

[0073] In some embodiments, the treatment is effective to provide a 2-year overall survival of at least 30%, 40%, 50%, or 60% in the cancer population treated according to the methods described herein.4.3. Examples

[0074] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.4.3.1. Example 1 : Adding azeliragon administration to radiation therapy (RT) significantly improves survival in orthotopic glioblastoma multiforme (GBM) tumor models

[0075] Standard immunocompetent murine glioblastoma models were used. See, e.g., Oh et al., “Immunocompetent murine models for the study of glioblastoma immunotherapy,” J. Transl. Med. 12: 107 (2014). Murine cell lines GL261 and CT2A were separately implanted into the brain of immune competent C57 albino mice. For each tumor cell line, mice were assigned to one of four treatment groups, with 8 evaluable mice per group (10 mice were injected per group to ensure that at least 8 mice had adequate tumor engraftment): (z) control (tumor implantation without active treatment); (zz) azeliragon; (zzz) radiation therapy (RT); and (iv) azeliragon + RT. Azeliragon was administered at a dose of 100 pg / mouse / day by intraperitoneal injection (i.p.). RT was administered at a dose of 2 Gy for 5 consecutive days. The experimental protocol with treatment timings is schematized in FIG. 1.

[0076] FIG. 2 presents Kaplan-Meier survival curves for the GL261 tumor experiment. Azeliragon alone and radiation therapy (RT) alone provided a measurable survival benefit as compared to the control group. The combination of azeliragon and radiation therapy provided significantly longer survival than azeliragon alone or RT alone, with 40% of mice surviving to the prespecified end of study day 60.

[0077] FIG. 3 presents Kaplan-Meier survival curves for the CT2A tumor experiment. Azeliragon alone provided no significant benefit, whereas radiation therapy alone increased survival. The combination of azeliragon and RT provided significantly longer survival than azeliragon alone or RT alone.4.3.2. Example 2: Adding azeliragon administration to radiation therapy (RT) significantly inhibits tumor volume growth in pancreatic cancer cell lines in vivo

[0078] Nude mice were used to determine the ability of azeliragon to enhance radiation response in pancreatic cell lines in vivo. The nu / nu mice display an immunodeficient deficient phenotype and are a standard tool in cancer research. See, e.g., Marincola et al., “The nude mouse as a model for the study of human pancreatic cancer,” J. Surg. Res. 47, 520-529 (1989). Human PANCI cells were implanted subcutaneously into nu / nu mice to generate PANCI tumor xenografts. Mice with subcutaneous Panel tumor xenografts were assigned to one of four treatment groups: (i) control group (represented tumor implantation withoutactive treatment); (zz) radiation therapy (RT); (zzz) azeliragon (AZ); and (iv) RT + AZ. Azeliragon was administered at a dose of 100 pg / mouse / day by intraperitoneal injection (i.p.) for 10 days. RT was administered at a dose of 2 Gy for 5 consecutive days. Tumor volume (mm3) was measured over the course of 30 days.

[0079] FIG. 4 presents a line graph depicting tumor volume progression in four groups of nude mice following Panel cell implantation: control mice receiving no active treatment (“control”), mice treated with radiation therapy alone (“RT”), mice treated with azeliragon alone (“AZ”), and mice receiving both radiation therapy and azeliragon (“RT+AZ”). The data show a significant reduction in tumor volume and maintenance of reduced tumor volume with the combination therapy compared to treatment with radiation therapy alone or treatment with azeliragon alone.5. EQUIVALENTS, EMBODIMENTS AND INCORPORATION BY REFERENCE

[0080] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention. It is to be understood that any and all embodiments described herein can be combined with any other embodiment described herein.

[0081] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method of treating cancer, comprising: administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a subject who has been diagnosed with a cancer.

2. The method according to claim 1, wherein the cancer is a solid tumor.

3. The method according to claim 1 or 2, wherein the cancer is a sarcoma or carcinoma.

4. The method according to any one of claims 1-3, wherein the cancer is a mixed-type cancer.

5. The method according to claim 4, wherein the cancer is adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma, or teratocarcinoma.

6. The method according to any one of claims 1-5, wherein the cancer comprises lung cancer, breast cancer, ovarian cancer, lymphoid cancer, gastrointestinal cancer, anal cancer, genital or genitourinary tract cancer, pharynx cancer, CNS cancer, head and neck cancer, skin cancer, pancreatic cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, lung cancer, or esophageal cancer.

7. The method according to claim 1, wherein the cancer is pancreatic ductal carcinoma (PDAC).

8. The method according to claim 7, wherein the treatment is effective to stabilize the subject’s ECOG status.

9. The method according to claim 7 or claim 8, wherein the treatment is effective to slow progression of PDAC.

10. The method according to any one of claims 7-9, wherein the treatment is effective to cause remission of PDAC.

11. The method according to any one of claims 7-10, wherein the treatment is effective to reduce pain associated with PDAC.

12. The method according to any one of claims 7-11, wherein the treatment is effective to inhibit the progression of cachexia associated with PDAC.

13. The method according to any one of claims 7-11, wherein the treatment is effective to reduce cachexia associated with PDAC.

14. The method according to any one of claims 7-13, wherein the administration is effective to provide a median overall survival of at least 6 months among treated subjects with PDAC.

15. The method according to any one of claims 1-14, wherein the subject is human.

16. The method according to any one of claims 1-15, wherein azeliragon is administered orally.

17. The method according to claim 16, wherein azeliragon is administered in a solid oral dosage form.

18. The method according to claim 17, wherein the solid dosage form comprises crystalline azeliragon.

19. The method according to claim 18, wherein the crystalline azeliragon is Form II.

20. The method according to any one of claims 1-19, wherein azeliragon is administered daily for a plurality of days at a loading dose followed thereafter by daily administration for a plurality of days at a maintenance dose.

21. The method according to claim 20, wherein the loading dose of azeliragon is administered daily for at least 5 days.

22. The method according to claim 20 or 21, wherein the loading dose is 60 mg per day.

23. The method according to claim 20 or 21, wherein the loading dose is 30 mg per day.

24. The method according to claim 20 or 21, wherein the loading dose is 15 mg per day.

25. The method according to claim 20 or 21, wherein the maintenance dose is administered daily for at least 6 months.

26. The method according to any one of claims 20-25, wherein the maintenance dose is 100 mg.

27. The method according to any one of claims 20-25, wherein the maintenance dose is 50 mg.

28. The method according to any one of claims 20-25, wherein the maintenance dose is 30 mg.

29. The method according to any one of claims 20-25, wherein the maintenance dose is 20 mg per day.

30. The method according to any one of claims 20-25, wherein the maintenance dose is 10 mg per day.

31. The method according to any one of claims 20-25, wherein the maintenance dose is 5 mg per day.

32. The method according to any one of claims 1-31, wherein the co-administered RT is administered in a plurality of fractionated doses.

33. The method according to claim 32, wherein RT is fractionated into 2 Gy daily doses.

34. The method according to claim 33, wherein RT is administered at a daily dose of 2 Gy for 5 days a week for 6 weeks, for a total dose of 60 Gy.

35. The method according to claim 32, wherein the total radiation administered does not exceed 68 Gy.

36. The method according to any one of claims 1-35, wherein azeliragon is administered daily during administration of RT.

37. The method according to any one of claims 1-35, wherein azeliragon is administered daily prior to administration of RT.

38. The method according to any one of claims 1-35, wherein azeliragon is administered daily following administration of RT.

39. The method according to any one of claims 1-38, wherein RT is administered by stereotactic body radiation (SBRT).

40. The method according to any one of claims 2-39, wherein the tumor was surgically resected from the subject prior to initiation of azeliragon administration.

41. The method according to any one of claims 2-39, wherein the tumor was not surgically resected from the subject prior to initiation of azeliragon administration.

42. The method according to any one of claims 1-41, further comprising administering a therapeutically effective amount of a second additional anti-cancer agent.

43. The method according to any one of claims 2-42, wherein the treatment is effective to maintain tumor volume.

44. The method according to any one of claims 2-43 wherein the treatment is effective to reduce tumor volume.

45. The method according to any one of the preceding claims, wherein the treatment is effective to provide a median overall survival of at least 12 months among treated patients.

46. The method according to any one of the preceding claims, wherein the treatment is effective to provide a median overall survival of at least 18 months among treated patients.

47. The method according to any one of the preceding claims, wherein the treatment is effective to provide a median overall survival of at least 24 months among treated patients.

48. The method according to any one of the preceding claims, wherein the treatment is effective to provide a median overall survival of at least 30 months among treated patients.

49. The method according to any one of the preceding claims, wherein the treatment is effective to provide a median overall survival of at least 36 months among treated patients.

50. The method according to any one of the preceding claims, wherein the treatment is effective to provide a median overall survival of at least 42 months among treated patients.

51. The method according to any one of the preceding claims, wherein the treatment is effective to provide a median overall survival of at least 48 months among treated patients.

52. The method according to any one of the preceding claims, wherein the treatment is effective to provide a 2-year overall survival of at least 30% among treated patients.

53. The method according to any one of the preceding claims, wherein the treatment is effective to provide a 2-year overall survival of at least 40% among treated patients.

54. The method according to any one of the preceding claims, wherein the treatment is effective to provide a 2-year overall survival of at least 50% among treated patients.

55. A method of treating cancer except glioblastoma and high-grade glioma, comprising: administering a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT), to a subject who has been diagnosed with a cancer.

56. The method according to claim 55, wherein the cancer is a solid tumor.

57. The method according to claim 55 or 56, wherein the cancer is a sarcoma or carcinoma.

58. The method according to any one of claims 55-57, wherein the cancer is a mixed-type cancer.

59. The method according to claim 58, wherein the cancer is adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma, or teratocarcinoma.

60. The method according to any one of claims 55-59, wherein the cancer comprises lung cancer, breast cancer, ovarian cancer, lymphoid cancer, gastrointestinal cancer, anal cancer, genital or genitourinary tract cancer, pharynx cancer, CNS cancer, head and neck cancer, skin cancer, pancreatic cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, lung cancer, or esophageal cancer.

61. The method according to claim 55, wherein the cancer is pancreatic ductal carcinoma (PDAC).

62. The method according to claim 61, wherein the administering of a therapeutically effective amount of azeliragon, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of radiation therapy (RT) is effective to stabilize the subject’s ECOG status.

63. The method according to claim 61 or claim 62, wherein the administration is effective to slow progression of PDAC.

64. The method according to any one of claims 55-63, wherein the subject is human.

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