US 20170224730A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0224730 A1 BERENSON (43) Pub. Date: Aug. 10, 2017 (54) ANT-CANCER EFFECTS OF PROTEASOME Publication Classification INHIBITORS IN COMBINATION WITH (51) Int. Cl. GLUCOCORTICOIDS, ARSENIC A633/36 (2006.01) CONTAINING COMPOUNDS, AND A6IR 9/00 (2006.01) ASCORBC ACID A 6LX 3L/375 (2006.01) (71) Applicant: Institute for Myeloma & Bone Cancer A638/07 (2006.01) Research, West Hollywood, CA (US) A 6LX 3/573 (2006.01) (52) U.S. Cl. (72) Inventor: James R. BERENSON, West CPC .............. A61K 33/36 (2013.01); A61K 38/07 Hollywood, CA (US) (2013.01); A61 K3I/573 (2013.01); A61 K 31/375 (2013.01); A61K 9/0019 (2013.01); (73) Assignee: Institute for Myeloma & Bone Cancer A61K 9/0053 (2013.01) Research, West Hollywood, CA (US) (21) Appl. No.: 15/317,690 (57) ABSTRACT PCT Fed: Jun. 10, 2015 The present invention provides methods of treatment for (22) hematological malignancies involving synergistic combina (86) PCT No.: PCT/US2O15/035O23 tion of a proteasome inhibitor, a glucocorticoid, an arsenic containing compound, and ascorbic acid or a derivative S 371 (c)(1), thereof provide an unexpected efficacy in the treatment for (2) Date: Dec. 9, 2016 hematological disorders. The hematological disorders treated by the current invention include multiple myeloma, Related U.S. Application Data and may also include hematological disorders that are (60) Provisional application No. 62/010.391, filed on Jun. refractory to prior cancer treatments, or relapsed hemato 10, 2014. logic disorders. US 2017/0224730 A1 Aug. 10, 2017 ANT-CANCER EFFECTS OF PROTEASOME cortisone, desoxycorticosterone, fludrocortisone, betame INHIBITORS IN COMBINATION WITH thasome, dexamethasone, prednisolone, prednisone, meth GLUCOCORTICOIDS, ARSENIC ylprednisolone, methylprednisone, paramethasone, triamci CONTAINING COMPOUNDS, AND nolone, flumethasone, fluocinolone, fluocinonide, ASCORBIC ACID fluprednisolone, halcinonide, flurandrenolide, mepred nisone, and medrysone. CROSS REFERENCE TO RELATED 0012. In particular embodiments, the glucocorticoid is APPLICATIONS dexamethasone. 0001. This application claims the benefit under 35 U.S.C. 0013. In certain embodiments, the arsenic-containing S119(e) of U.S. Provisional Application No. 62/010,391, compound is selected from the group consisting of arsenic filed Jun. 10, 2014, which is incorporated by reference trioxide (As2O3), arsenic pentoxide (As2O5), arsenic herein in its entirety. hexoxide AS4O6), arsenic triselenide (As2Se3), arsenic dis ulfide (As2S2), arsenic trisulfide (As2S3), arsenic pentasul BACKGROUND fide (As2O5), arsenic tritelluride (As2Te3), sodium arsenate (Na2HAsO4), potassium arsenate (KH2AsO4), and sodium Technical Field arsenyl tartrate (NaC4H4AsO6). 0002 The invention generally relates to novel methods of 0014. In further embodiments, the arsenic-containing treating hematological malignancies, including multiple compound is arsenic trioxide. 0015. In additional embodiments, the ascorbic acid or myeloma. More particularly the invention relates to methods derivative thereof is selected from the group consisting of of treating hematological malignancies with a proteasome ascorbic acid, L-ascorbic acid-2-pyrophosphate esters, inhibitor, glucocorticoid, arsenic containing compound, and L-ascorbic acid-2-triphosphate esters, L-ascorbic acid-2- ascorbic acid or a derivative thereof. polyphosphate esters, sodium L-ascorbic acid-2-phosphate 0003. Description of the Related Art 6-palmitate, L-ascorbic acid-2-phosphate-6-palmitate, 0004 Multiple myeloma is a malignancy characterized L-ascorbic acid-2-phosphate-6-stearate, L-ascorbic acid-2- by the expansion of plasma cells that produce monoclonal phosphate-6-oleate and L-ascorbic acid-2-phosphate-6- immunoglobulin (IgG, IgA, Ig), IgE, or free W or K light arachidonate, 5,6-O-isoalkylidene ascorbic acid, 5,6-O-iso chains). The overall survival of patients with multiple propylidine ascorbic acid, and L-ascorbate 2-Sulphate. myeloma varies greatly from a few months to many years; 0016. In particular embodiments, the ascorbic acid or the mean is approximately five years. Anemia, hypercalce derivative thereof is ascorbic acid. mia and bone lesions correlate directly with total mass of myeloma cells and have important prognostic significance. 0017. In further embodiments, the methods comprise Other prognostic factors include age, the plasma cell label administering carfilzomib, arsenic trioxide, dexamethasone, ing index, serum albumin, B2-microglobulin, C-reactive and ascorbic acid. protein, thymidine kinase, and soluble interleukin 6 receptor. 0018. In certain embodiments, the methods comprise Major complications, such as infection and renal insuffi administering carfilzomib intravenously. ciency, are the main causes of death for myeloma patients. 0019. In particular embodiments, the methods comprise 0005. Current therapies for multiple myeloma fail to cure administering carfilzomib at a dose of 1-100 mg/m. the disease and nearly all patients eventually develop resis 0020. In some embodiments, the methods comprise tance to these therapies. Moreover, there are a paucity of administering arsenic trioxide intravenously. multiple myeloma targets and a lack of therapeutic options 0021. In additional embodiments, the methods comprise that are effective in overcoming drug resistance. administering arsenic trioxide at a dose of 0-5 mg/kg. 0022. In particular embodiments, the methods comprise BRIEF SUMMARY administering dexamethasone orally. 0006. The present invention generally provides novel and 0023. In further embodiments, the methods comprise synergistic treatments for multiple myeloma and related B administering dexamethasone intravenously. cell disorders. 0024. In particular embodiments, the methods comprise 0007. In various embodiments, a method of treating or administering dexamethasone at a dose of 1-100 mg. preventing a hematological malignancy in a subject com 0025. In certain embodiments, the methods comprise prising administering to the Subject a proteasome inhibitor, administering ascorbic acid orally. a glucocorticoid, an arsenic-containing compound, and 0026. In further embodiments, the methods comprise ascorbic acid or a derivative thereof is provided. administering ascorbic acid orally at a dose of 100-2000 mg. 0008. In particular embodiments, the hematological 0027. In some embodiments, the methods comprise malignancy is selected from the group consisting of mul administering ascorbic acid intravenously. tiple myeloma, chronic lymphocytic leukemia, or B-cell 0028. In particular embodiments, the methods comprise non-Hodgkin lymphoma. administering ascorbic acid intravenously at a dose of 1-50 0009. In additional embodiments, the proteasome inhibi ng. tor is selected from the group consisting of bortezomib, 0029. In various embodiments, a method of treating or carfilzomib, oprozomib, ixazomib citrate, marizomib, delan preventing multiple myeloma in a subject comprising Zomib, and Syringolin A. administering to the Subject a proteasome inhibitor, arsenic 0010. In some embodiments, the proteasome inhibitor is trioxide, a glucocorticoid, and ascorbic acid is provided. carfilzomib. 0030. In certain embodiments, the proteasome inhibitor is 0011. In particular embodiments, the glucocorticoid is selected from the group consisting of wherein the protea selected from the group consisting of hydroxycortisone, Some inhibitor is selected from the group consisting of US 2017/0224730 A1 Aug. 10, 2017 bortezomib, carfilzomib, oproZomib, ixazomib citrate, mari 0050. In various embodiments, a method of treating or Zomib, delanzomib, and Syringolin A. preventing a relapsed hematological malignancy in a subject 0031. In some embodiments, the proteasome inhibitor is comprising administering to the Subject, a glucocorticoid, an carfilzomib. arsenic-containing compound, and ascorbic acid or a deriva 0032. In some embodiments, the glucocorticoid is tive thereof is provided. selected from the group consisting of hydroxycortisone, 0051. In various other embodiments, a method of treating cortisone, desoxycorticosterone, fludrocortisone, betame or preventing hematological malignancy that is refractory to thasome, dexamethasone, prednisolone, prednisone, meth a prior treatment or treatments for cancer in a subject ylprednisolone, methylprednisone, paramethasone, triamci comprising administering to the Subject a proteasome inhibi nolone, flumethasone, fluocinolone, fluocinonide, tor, a glucocorticoid, an arsenic-containing compound, and fluprednisolone, halcinonide, flurandrenolide, mepred ascorbic acid or a derivative thereof is provided. nisone, and medrysone. 0052. In further embodiments, the hematological malig 0033. In particular embodiments, the glucocorticoid is nancy is selected from the group consisting of multiple dexamethasone. myeloma, chronic lymphocytic leukemia, or B-cell non 0034. In additional embodiments, the arsenic-containing Hodgkin lymphoma. compound is selected from the group consisting of arsenic 0053. In particular embodiments, the subject was previ trioxide (As2O3), arsenic pentoxide (As2O5), arsenic ously treated with a proteasome inhibitor. hexoxide AS4O6), arsenic triselenide (As2Se3), arsenic dis 0054. In additional embodiments, the subject was previ ulfide (As2S2), arsenic trisulfide (As2S3), arsenic pentasul ously treated with carfilzomib. fide (As2O5), arsenic tritelluride (As2Te3), sodium arsenate 0055. In additional embodiments, the subject was previ (Na2HAsO4), potassium