OA18036A - Crenolanib for treating FLT3 mutated proliferative disorders. - Google Patents

Abstract

The present invention relates to the use of crenolanib, in a pharmaceutically acceptable salt form for the treatment of FLT3 mutated proliferative disorders driven by constitutively activated mutant FLT3, and to a method of treatment of warm-blooded animals, preferably humans, in which a therapeutically effective dose of crenolanib is administered to an animal suffering from said disease or condition.

Description

[0001] This application daims priority to U.S. Provisional Application Serial No. 61/749,695, filed January 7,2013, the entire content of which is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION [0002] The présent invention relates to the use of crenolanib, in a pharmaceutically acceptable sait form for the treatment of FLT3 mutated proliférative disorder(s) driven by constitutively activated mutant FLT3, and to a method of treatment of warm-blooded animais, preferably humans, in which a therapeutically effective dose of crenolanib is administered to a subject suffering from said disease or condition.

STATEMENT OF FEDERALLY FUNDED RESEARCH [0003] None.

INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC [0004] None.

BACKGROUND OF THE INVENTION [0005] Without limiting the scope of the invention, its background is described in connection with FLT3 tyrosine kinase.

[0006] The FMS-like tyrosine kinase 3 (FLT3) gene encodes a membrane bound receptor tyrosine kinase that affects hematopoiesis leading to hematological disorders and malignancies.

See Drexler, HG et al. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia. 1996; 10:588-599; Gilliland, DG and JD Griffîn. The rôles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532-1542; Stirewalt, DL and JP Radich. The rôle of FLT3 in hematopoietic malignancies. Nat Rev Cancer. 2003;3:650-665. Activation of FLT3 receptor tyrosine kinases is initiated through the binding of the FLT3 ligand (FLT3-L) to the FLT3 receptor, also known as Stem cell tyrosine kinase-1 (STK-1) and fêtai liver kinase-2 (flk2), which is expressed on hematopoietic progenitor and stem cells.

[0007] FLT3 is one of the most frequently mutated genes in hematological malignancies, présent in approximately 30% of adult acute myeloid leukemias (AML). See Nakao M, S Yokota and T

AROG:1002

Iwai. Internai tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911-1918; H Kiyoi, M Towatari and S Yokota. Internai Tandem duplication of the FLT3 gene is a novel modality of élongation mutation, which causes constitutive activation of the product. Leukemia. 1998;12:1333-1337; PD Kottaridis, RE Gale, et al. The presence of a 5 FLT3 internai tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1742-1759; Yamamoto Y, Kiyoi H, Nakano Y. Activating mutation of D835 within the activation loop of FLT3 in human hématologie malignancies.

Blood. 2001;97:2434-2439; Thiede C, C Steudel, Mohr B. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326-4335.

[0008] The most common FLT3 mutations are internai tandem duplications (ITDs) that lead to in-frame insertions within the juxtamembrane domain of the FLT3 receptor. FLT3-ITD 15 mutations hâve been reported in 15-35% of adult AML patients. See Nakao M, S Yokota and T

Iwai. Internai tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911-1918; H Kiyoi, M Towatari and S Yokota. Internai Tandem duplication of the FLT3 gene is a novel modality of élongation mutation, which causes constitutive activation of the product. Leukemia. 1998;12:1333-1337; H Kiyoi, T Naoe and S Yokota. Internai tandem 20 duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia. 1997;11:1447-1452;

S Schnittgcr, C Schoch and M Duga. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: corrélation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the détection of minimal residual disease. Blood.

2002; 100:59-66. A FLT3-ITD mutation is an independent predictor of poor patient prognosis and is associated with increased relapse risk after standard chemotherapy, and decreased disease free and overall survival. See FM Abu-Duhier, Goodeve AC, Wilson GA, et al. FLT3 internai tandem duplication mutations in adult acute myeloid leukemia define a high risk group. British Journal of Haematology. 2000; 111:190-195 ; H Kiyoi, T Naoe, Y Nakano, et al. Prognostic implication of

FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074-3080.

AROG:1002 [0009] Less frequent are FLT3 point mutations that arise in the activation loop of the FLT3 receptor. The most commonly affected codon is aspartate 835 (D835). Nucléotide substitutions of the D835 residue occur in approximately 5-10% of adult AML patients. See DL Stirewalt and JP Radich. The rôle of FLT3 in haematopoietic malignancies. Nature Reviews Cancer. 2003;3:650-665;Y Yamamoto, H Kiyoi and Y Nakano, et al. Activating mutation of D835 within the activation loop of FLT3 in human hématologie malignancies. Blood. 2001;97:2434-2439; C Thiede, Steudal C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326-4335;U Bâcher, Haferlach C, W Kern, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters-an analysis of 3082 patients. Blood. 2008;111:2527-2537.

[0010] The heightened frequency of constitutively activated mutant FLT3 in adult AML has made the FLT3 gene a highly attractive drug target in this tumor type. Several FLT3 inhibitors with varying degrees of potency and selectivity for the target hâve been or are currently being investigated and examined in AML patients. See T Kindler, Lipka DB, and Fischer T. FLT3 as a therapeutic target in AML: still challenging after ail these years. Blood.2010;l 16:5089-102.

[0011] FLT3 inhibitors known in the art include Lcstaurtinib (also known as CEP 701, formerly KT-555, Kyowa Hakko, licensed to Cephalon); CHIR-258 (Chiron Corp.); EB10 and IMC-EB10 (ImClone Systems Inc.); Midostaurin (also known as PKC412, Novartis AG); Tandutinib (also known as MLN-518, formerly CT53518, COR Therapeutics Inc., licensed to Millennium Pharmaceuticals Inc.); Sunitinib (also known as SU11248, Pfizer USA); Quizartinib (also known as AC220, Ambit Bioscicnccs); XL 999 (Exclixis USA, licensed to Symphony Evolution, Inc.); GTP 14564 (Merck Biosciences UK); AG1295 and AG1296; CEP-5214 and CEP-7055 (Cephalon). The following PCT International Applications and U.S. patent applications disclose additional kinase modulators, including modulators of FLT3: WO 2002032861, WO 2002092599, WO 2003035009, WO 2003024931, WO 2003037347, WO 2003057690, WO 2003099771, WO 2004005281, WO 2004016597, WO 2004018419, WO 2004039782, WO 2004043389, WO 2004046120, WO 2004058749, WO 2004058749, WO 2003024969 and U.S Patent Application No, 20040049032. See also Levis M, KF Tse, et al. 2001 “A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internai tandem duplication mutations.” Blood 98(3): 885-887; Tse K F, et al., Inhibition of FLT318036

AROG:1002 mediated transformation by use of a tyrosine kinase inhîbitor. Leukemia. July 2001; 15 (7): 1001-1010; Smith, B. Douglas et al., Single agent CEP-701, a novel FLT3 inhîbitor, shows biologie and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 2004; 103: 3669-3676; Griswold, Ian J. et al., Effects of MLN518, A Dual FLT3 and KIT Inhîbitor, on Normal and Malignant Hematopoiesis. Blood, Nov 2004; 104 (9): 2912-2918 [Epub ahead of print Jul 8]; Yee, Kevin W.H. et al., SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood, Oct 2002; 100(8): 2941-2949. O’Farrell, Anne-Marie et al., SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, May 2003; 101(9): 3597-3605; Stone, R. M et al., PKC-412 FLT3 inhibitor therapy in AML: résulte of a phase II trials. Ann. Hematol. 2004; 83 Suppl 1 :S8990; and Murata, K. et al., Sélective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol Chem. Aug. 29, 2003; 278 (35): 32892-32898 [Epub 2003 Jun 18]; Levis, Mark et al., Small Molécule FLT3 Tyrosine Kinase Inhibitors. Current Pharmaceutical Design, 2004, 10, 1183-1193.

[0012] The aforementioned inhibitors hâve either been or are currently being investi gated in the prcclinical setting, or phase I and II trials as monotherapy in relapsed AML, or in phase III combination studies in relapsed AML. Despite reports of successful inhibition of FLT3 with these compounds in preclinical studies, complété remissions hâve rarely been achieved in FLT3 mutant AML patients in the clinical setting. In the majority of patients, the clinical response is short-lived. Response criteria for AML clinical trials are adapted from the International Working Group for AML. Scc Chcson et al. Rcviscd Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003; 21: 46424649. Responders are patients who obtain a Complété Response (CR), Complété Response with incomplète blood count recovery (CRi), or Partial Remission (PR). Briefly, criteria are as follows:

1. Complété Remission (CR) :

a. Peripheral blood counts:

i. No circulating blasts ii. Neutrophil count > 1.0 x 10⁹/L

AROG:1002 iii. Platelet count > 100 x 10⁹/L b. Bone marrow aspirate and biopsy:

i. <5% blasts ii. No Auer Rods

2.

3.

iii. No extramedullary leukemia

Complété remission with incomplète blood count recovery (CRi):

a. Peripheral blood counts:

i. No circulating blasts ii. Neutroph.il count <1.0 x 10⁹/L, or iii. Platelet count <100 x 10⁹/L

b. Bone marrow aspirate and biopsy

i. < 5 % blasts ii. NoAuerRods iii. No extramedullary leukemia

Partial remission:

a. Ail CR criteria if abnormal before treatment except:

b. >50% réduction in bonc marrow blast but still >5% [0013] To date, clinical rcsponscs to FLT3 inhibitors hâve been primarily limitcd to clearance of peripheral blood (PB) blasts, which frequently return within a matter of weeks, while bone marrow (BM) blasts remain largely unaffected. For example, treatment with sorafenib, the prior mentioned multi-kinase inhibitor with activity against mutant FLT3, while effective in clearing PB blasts, has resulted in only modest BM blast réductions. See G Borthakur et al. Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Haematologica. Jan 2011; 96: 62-8. BM blast percentage plays a central rôle in the diagnosis and classification of AML. The presence of a heightened percentage of blasts in BM is associated with significantly shorter overall survival. See Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ Program. 2006: 178-84; HM Amin et al. Having a higher blast percentage in circulation than bone marrow: clinical implications in myelodysplastic syndrome and acute lymphoid and myeloid leukemias. Leukemia. 2005; 19: 1567-72. To effectively treat FLT3 mutated AML patients and overcome the significant unmet need in this patient population, an inhibitor that significantly depletes both PB and BM blasts, bridge high risk and heavily

AROG:1002 pretreated patients to stem cell transplant, and can help to decrease relapse rates and increase overall survival in early stage disease patients. The current invention seeks to overcome disadvantages of the prior art.

SUMMARY OF THE INVENTION [0014] In one embodiment, the présent invention includes a method for treating a FLT3 mutated proliférative disorder in a patient which comprises administering to the patient a therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof. In one aspect, the method may also include identifying a patient with a proliférative disorder selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy. In another aspect, the therapeutically effective amounts of crenolanib or a pharmaceutically acceptable sait thereof arc from about 50 to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is administered at least one of continuously, intenmttently, systemically, or locally. In another aspect, the mutated FLT3 is defined further as a constitutively active FLT3 mutant. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is administered orally, intravenously, or intraperitoneally. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is crenolanib besylate, crenolanib phosphate, crenolanib lactate, crenolanib hydrochloride, crenolanib citrate, crenolanib acetate, crenolanib toluenesulphonate and crenolanib succinate. In another aspect, the FLT3 is at least one of FLT3-ITD or FLT3-TKD. In another aspect, the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof is administered up to three rimes or more a day for as long as the subject is in need of treatment for the proliférative disorder. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed proliférative disorder patient, to maintain remission of an existing patient, or a relapsed/refractory proliférative disease patient. In another aspect, the crenolanib or a

AROG:1002 pharmaceutically acceptable sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a patient with a newly diagnosed proliférative disorder, to maintain remission, or a relapsed/refractory proliférative disease patient. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disorder pédiatrie patient, to maintain remission, or a relapsed/refractory proliférative disorder pédiatrie patient. In another aspect, the patient is relapsed/refractory to other FLT3 tyrosine kinase inhibitors.

[0015] Another embodiment of the présent invention includes a method for treating a patient suffering from a proliférative disease comprising: identifying the patient in need of therapy for the proliférative disease; and administering to the patient in need of such treatment a therapeutically effective amount of Crenolanib or a sait thereof, wherein the cell proliférative disorder is characterized by deregulated FLT3 receptor tyrosine kinase activity, wherein the proliférative disease is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and ncck cancer, liver cancer, lung cancer, nasopharyngcal cancer, ncurocndocrinc cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy. In one aspect, the crenolanib or a pharmaceutically acceptable sait thereof is administered orally, intravenously, or intraperitoneally. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is at least onc of Crenolanib Bcsylatc, Crenolanib Phosphate, Crenolanib Lactate, Crenolanib Hydrochloride, Crenolanib Citrate, Crenolanib Acetate, Crenolanib Touluenesulphonate and Crenolanib Succinate Crenolanib Besylate. In another aspect, the FLT3 is at least one of FLT3-ITD or FLT3-TKD. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is provided at least one of sequentially or concomitantly, with another chemotherapeutic agent in a newly diagnosed proliférative disease, to maintain remission, or a relapsed/refractory proliférative disease. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is provided as a single agent or in combination with another chemotherapeutic agent for treatment of pédiatrie patient with the proliférative disease. In another aspect, the crenolanib or a pharmaceutically

AROG:1002 acceptable sait thereof is provided as a single agent to at least one of post standard induction therapy, or high dose induction therapy, in newly diagnosed proliférative disease. In another aspect, the crenolanib or a pharmaceutically acceptable sait thereof is provided as a single agent in treatment of patients with the proliférative disease that is either refractory to, or has relapsed after prior treatment with a chemotherapeutic agent. In another aspect, the patient is refractory to at least one other tyrosine kinase inhibitor.

[0016] Yet another embodiment of the présent invention includes a method for treating a patient suffering from leukemia comprising: obtaining a sample from the patient suspected of having a leukemia; determining from the patient sample that the patient has a deregulated FLT3 receptor tyrosine kinase; and administering to the patient in need of such treatment a therapeutically effective amount of Crenolanib or a saLt thereof, wherein the leukemia is characterized by deregulated FLT3 receptor tyrosine kinase activity. In one aspect, the leukemia is selected from Hodgkin’s disease, and myeloma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilie leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvénile myclomonocytic leukemia (JMML), adult T-ccll ALL, AML, with trilincagc myclodysplasia (AMLITMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM).

[0017] Yet another embodiment of the présent invention includes a method for specifïcally inhibiting a deregulated receptor tyrosine kinase comprising: obtaining a patient sample and determining which receptor tyrosine kinases arc deregulated; and administering to a mammal in need of such treatment a therapeutically effective amount of crenolanib or a sait thereof, wherein the deregulated receptor tyrosine kinase is a FLT3 receptor tyrosine kinase. In one aspect, the therapeutically effective amount of crenolanib or a sait thereof is provided in an amount that decreases patient circulating peripheral blood blast count. In another aspect, the therapeutically effective amount of crenolanib or a sait thereof is provided in an amount that decreases a patient bone marrow blast count. In another aspect, the proliférative disease is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer,

AROG:1002 nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy. In another aspect, the therapeutically effective amount can also be a prophylactically effective amount of crenolanib or a sait thereof and are from about 50 to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day. In another aspect, the crenolanib or a sait thereof is administered at least one of continuously, intermittently, systemically, or locally. In another aspect, the deregulated FLT3 is defined further as a mutated FLT3 is constitutively active. In another aspect, the crenolanib or a sait thereof is administered orally, intravenously, or intraperitoneally. In another aspect, the crenolanib or a sait thereof is at least one of Crenolanib Besylate, Crenolanib Phosphate, Crenolanib Lactate, Crenolanib Hydrochloride, Crenolanib Citrate, Crenolanib Acétate, Crenolanib Touluenesulphonate and Crenolanib Succinate Crenolanib Besylate. In another aspect, the FLT3 is at least one of FLT3-ITD or FLT3-TKD. In another aspect, the therapeutically effective amount of the crenolanib or a sait thereof is administered up to three fîmes or more a day for as long as the subject is in need of treatment for the proliférative disease. In another aspect, the patient is provided treatment, and the method further comprises the steps of: obtaining one or more patient samples to détermine the effect of the treatment, and continuing treatment until the proliférative disease is reduced or eliminated. In another aspect, the crenolanib or a sait thereof is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed proliférative disease patient, to maintain rémission, or a rclapscd/rcfractory proliférative disease patient. In another aspect, the crenolanib or a sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disease patient, to maintain remission, or a relapsed/refractory proliférative disease patient. In another aspect, the crenolanib or a sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disease pédiatrie patient, to maintain remission, or a relapsed/refractory proliférative disease pédiatrie patient. In another aspect, the patient is relapsed/refractory to a prior tyrosine kinase inhibitor. Non-limiting examples of other FLT3 inhibitors to which the proliférative disease or disorder is résistant includes, e.g., Lestaurtinib (also known as CEP 701, Cephalon); CHIR-258 (Chiron Corp.); EB10 and IMC-EB10 (ImClone Systems Inc.); Midostaurin (also

AROG:1002 known as PKC412, Novartis AG); Tandutinib (also known as MLN-518, Millennium Pharmaceuticals Inc.); Sunitinib (also known as SU11248, Pfîzer USA); Quizartinib (also known as AC220, Ambit Biosciences); XL 999 (Symphony Evolution, Inc.); GTP 14564 (Merck Biosciences UK); AG1295 and AG1296; and CEP-5214 and CEP-7055 (Cephalon).

[0018] Yet another embodiment of the présent invention includes a method for treating a patient with a proliférative disease comprising: obtaining a sample from the patient; determining if the patient that has become résistant to prior tyrosine kinase inhibitors; and administering a therapeutically effective amount of Crenolanib or a sait thereof to overcome the résistance to the prior protein tyrosine kinase inhibitors. This summary of the invention does not necessarily describe ail necessary features of the invention.

DETAILED DESCRIPTION OF THE INVENTION [0019] While the making and using of various embodiments of the présent invention are discussed in detail below, it should be appreciated that the présent invention provides many applicable inventive concepts that can be embodied in a wide variety of spécifie contexts. The spécifie embodiments discussed herein are merely illustrative of spécifie ways to make and use the invention and do not delimit the scopc of the invention.

[0020] To facilitate the understanding of this invention, a number of terms are defined below. Ternis defined herein hâve meanings as commonly understood by a person of ordinary skill in the areas relevant to the présent invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a spécifie example may be used for illustration. The terminology herein is used to describe spécifie embodiments of the invention, but their usage does not delimit the invention, except as outlined in the daims.

[0021] The présent invention comprises the use of the compounds of the présent invention to treat disorders related to FLT3 kinase activity or expression in a subject, e.g., deregulated FLT3 tyrosine kinase activity.

[0022] The compound is Crenolanib (4-Piperidinamine, l-[2-[5-[(3-methyl-3-oxetanyl) methoxy]-lH-benzimidazol-l-yl]-8-quinolinyl]) and its pharmaceutically acceptable salts, which are protein tyrosine kinase inhibitors sélective for constitutively active FLT3 mutations, including FLT3 ITD and FLT3 TKD mutations. Unlike prior FLT3 inhibitors in the art, the besylate sait form of crenolanib has shown to be remarkably effective in depleting absolute r

AROG:1002 circulating peripheral blood blasts and bone marrow blast percentages in heavily pretreated FLT3 mutant AML patients.

[0023] In one embodiment to this aspect, the présent invention provides amethod forreducing or inhibiting the kinase activity of FLT3 in a subject comprising the step of administering a compound of the présent invention to the subject.

[0024] As used herein, the term “subject” refers to an animal, such as a mammal or a human, who has been the object of treatment, observation or experiment.

[0025] In other embodiments, the présent invention provides therapeutic methods for treating a subject with a cell proliférative disorder driven by aberrant kinase activity of mutant FLT3. In one example, the invention provides methods for treating a cell proliférative disorder related to mutant FLT3, comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising a compound of the présent invention in a subject. Administration of the therapeutic agent can occur upon manifestation of symptoms characteristic of the FLT3 driven cell proliférative disorder, such that a disease or disorder treated.

[0026] As used herein, the term “therapeutically effective amount”, refers to an amount of active compound or pharmaceutical sait that elicits the biological or médicinal response in a subject that is being sought by a rcscarchcr, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. Methods for determining therapeutically effective doses for pharmaceutical compositions comprising a compound of the présent invention are known in the art. Techniques and compositions for making useful dosage forms using the présent invention are described in one or more of the following rcfcrcnccs: Anderson, Philip O.; Knobcn, James E.; Troutman, William G, cds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); relevant portions incorporated herein by reference.

[0027] As used herein, the term “composition” refers to a product comprising the specified ingrédients in the specified amounts, as well as any product, which résulte, directly or

AROG-.1002 indirectly, from combinations of the specifîed ingrédients in the specified amounts. In one example, the composition includes crenolanib or a pharmaceutically acceptable sait thereof in an amount suffïcient for the treatment of a disease.

[0028] As used herein, the terms “FLT3 mutated proliférative disorder(s)”, “disorder related to FLT3,” or “disorders related to FLT3 receptor,” or “disorders related to FLT3 receptor tyrosine kinase,” “a deregulated FLT3 receptor tyrosine kinase disease” or “FLT3 driven cell proliférative disorder” includes diseases associated with or implicating FLT3 activity, for example, mutations leading to constitutive activation of FLT3. Examples of “FLT3 mutated proliférative disorder(s)” include disorders resulting from over stimulation of FLT3 due to mutations in FLT3, or disorders resulting from abnormally high amount of FLT3 activity due to abnormally high amount of mutations in FLT3. It is known that over-activity of FLT3 has been implicated in the pathogenesis of many diseases, including the following listed cell proliférative disorders, neoplastic disorders and cancers. Non-limiting examples of proliférative disorders for treatment with the présent invention include leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngcal cancer, ncurocndocrinc cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy.

[0029] As used herein, the terms “proliférative disorder(s)” and “cell proliférative disorder(s)” refer to cxccss ccll prolifération of one or more subset of colis in a multiccllular organism resulting in harm (i.e. discomfort or decreased life expectancy) to the multicellular organism. Cell proliférative disorders can occur in different types of animais and humans. As used herein, “cell proliférative disorders” include neoplastic disorders.

[0030] As used herein, the term “neoplastic disorder” refers to a tumor resulting from abnormal or uncontrolled cellular growth. Examples of neoplastic disorders include, but are not limited to the following disorders, for instance: the myeloproliferative disorders, such as thrombocytopenia, essential thrombocytosis (ET), agnogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (UIMF), and polycythemia vera (PV), the cytopenias, and pre-malignant myelodysplastic syndromes;

AROG:1002 cancers such as glioma cancers, lung cancers, breast cancers, colorectal cancers, prostate cancers, gastric cancers, esophageal cancers, colon cancers, pancreatic cancers, ovarian cancers, and hematological malignancies, including myelodysplasia, multiple myeloma, leukemias, and lymphomas. Examples of hematological malignancies include, for instance, leukemias, 5 lymphomas, Hodgkin’s disease, and myeloma. Also, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilie leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvénile myelomonocytic leukemia (JMML), adult T-cell ALL, AML, with 10 trilineage myelodysplasia (AMLITMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM). In certain embodiments, the présent invention is directed at the use of crenolanib or a pharmaceutically acceptable sait thereof in an amount sufficient for the treatment of a neoplastic disorder.

[0031] In one embodiment of the présent invention, the crenolanib or a pharmaceutically acceptable sait thereof is provided at least one of sequentially or concomitantly, with another chcmothcrapcutic agent in a ncwly diagnoscd proliférative disease, to maintain rémission, or a relapsed/refractory proliférative disease. The crenolanib or a pharmaceutically acceptable sait thereof may be provided as a single agent or in combination with another chemotherapeutic agent 20 for treatment of pédiatrie patient with the proliférative disease. The crenolanib or a pharmaceutically acceptable sait thereof may also be provided as a single agent to at least one of post standard induction therapy, or high dose induction therapy, in ncwly diagnoscd proliférative disease. The crenolanib or a pharmaceutically acceptable sait thereof may also be provided as a single agent in treatment of patients with the proliférative disease that is either reffactory to, or 25 has relapsed after prior treatment with a chemotherapeutic agent. Finally, the patient may be refractory to at least one other tyrosine kinase inhibitor prior to treatment.

[0032] In a further embodiment, the présent invention can be combined with another therapy as a combination therapy for treating or inhibiting the onset of a cell proliférative disorder related to FLT3 in a subject. The combination therapy comprises the administration of a therapeutically 30 effective amount of a compound of the présent invention and one or more other anti-cell prolifération thérapies including, but not limited to, chemotherapy and radiation therapy.

AROG:1002 [0033] In an embodiment of the présent invention, a compound of the présent invention may be administered in combination with chemotherapy. Used herein, chemotherapy refers to a therapy involving a chemotherapeutic agent. A variety of chemotherapeutic agents may be used in combination with the présent invention. By way of example only, taxane compounds, specifîcally docetaxel, is safely administered in combination with a compound of the présent invention in a dosage of 75 mg per square meter (mg/m²) of body surface area.

[0034] Chemotherapy is known to those skilled in the art. The appropriate dosage and scheme for chemotherapy will be similar to those already employed in clinical thérapies wherein the chemotherapy is delivered in combination with other thérapies or used alone.

[0035] In another embodiment of the présent invention, compounds of the présent invention may be administered in combination with radiation therapy. Used herein, “radiation therapy” refers to a therapy that comprises the exposure of a subject in need to radiation. Radiation therapy is known to those skilled in the art. The appropriate dosage and scheme for radiation therapy will be similar to those already employed in clinical thérapies wherein the radiation therapy is delivered in combination with other thérapies or used alone.

[0036] In another embodiment of the présent invention, the compounds of the présent invention may be administered in combination with a targeted therapy. As used herein, “targeted therapy” refers to a therapy targeting a particular class of proteins involved in tumor development or oncogenic signaling. For example, tyrosine kinase inhibitors against vascular endothélial growth factor hâve been used in treating cancers.

[0037] The présent invention also includes methods that include the use of a second pharmaccutical agent in addition to compounds of the présent invention, the two may be administered simultaneously or sequentially (in either order).

[0038] In one embodiment, the présent invention is of the compound having formula I:

AROG:1002

[0039] or a pharmaceutically acceptable sait or solvaté thereof, in a therapeutically or prophylactically effective amount against a proliférative disease is selected from. at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy. Pharmaceutically acceptable salts including hydrochloride, phosphate and lactate are prepared in a manner similar to the benzenesulfonate sait and are well known to those of moderate skill in the art.

[0040] Compounds of the présent invention may be administered to a subject systemically, for example, orally, intravenously, subcutaneously, intramuscular, intradermal or parenterally. The compounds of the présent invention can also be administered to a subject locally.

[0041] Compounds of the présent invention may be formulated for slow-release or fast-release with the objective of maintaining contact of compounds of the présent invention with targeted tissucs for a desired range of time.

[0042] Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules, granules, and powders, liquid forms, such as solutions, émulsions, and suspensions. Forms useful for parentéral administration include stérile solutions, émulsions and suspensions.

[0043] The daily dosage of the compounds of the présent invention may be varied over a widc range from 50 to 500 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 20 and 100 milligrams. The compounds of

AROG:1002 the présent invention may be administered on a regimen up to three times or more per day. Preferably three times per day. Optimal doses to be administered may be determined by those skilled in the art, and will vary with the compound of the présent invention used, the mode of administration, the time of administration, the strength of the préparation, and the details of the 5 disease condition. Factors associated with patient characteristics, such as âge, weight, and diet will call for dosage adjustments.

[0044] Préparation of the compounds of the présent invention. General synthetic methods, which may be referred to for preparing the compounds of formula I are provided in U.S. Pat. No. 5,990,146 (issued Nov. 23, 1999) (Wamer-Lambert Co.) and PCT published application numbers 10 WO 99/16755 (published Apr. 8, 1999) (Merck & Co.) WO 01/40217 (published Jul. 7, 2001) (Pfizer, Inc.), US Patent Application No. US 2005/0124599 (Pfizer, Inc.) and U.S. Patent No. 7,183,414 (Pfizer, Inc.), relevant portions incorporated hereinby reference.

[0045] Pharmaceutically acceptable salts such as hydrochloride, phosphate and lactate are prepared in a manner similar to the benzenesulfonate sait and are well known to those of 15 moderate skill in the art. The following représentative compounds of the présent invention are for exemplary purposes only and are in no way meant to limit the invention, including Crcnolanib as Crcnolanib Bcsylatc, Crcnolanib Phosphate, Crcnolanib Lactate, Crcnolanib Hydrochloride, Crenolanib Citrate, Crenolanib Acetate, Crenolanib Toluenesulphonate and Crenolanib Succinate.

[0046] Summary of Examples [0047] Example 1. Patient harbored a de novo FLT3-ITD mutation and an acquired FLT3-D835 TKD mutation. Following progression on another FLT3 inhîbitor, the patient achieved a hématologie benefit categorized as a CR on crenolanib besylate therapy, and was bridged to a curative allogeneic stem cell transplant.

[0048] Example 2. Patient harbored a de novo FLT3-ITD mutation and an acquired FLT3-D835

TKD mutation. Following progression on another FLT3 inhibitor, the patient achieved hématologie benefit categorized as a CRi on crenolanib besylate therapy, and was bridged to a curative allogeneic stem cell transplant.

[0049] Example 3. Patient harbored acquired FLT-ITD and FLT3-D835 TKD mutations. 30 Following progression on cytotoxic chemotherapy and an autologous stem cell transplant, the

AROG:1002 patient achieved hematological benefit categorized as CRi on crenolanib besylate therapy, and was bridged to a curative allogeneic stem cell transplant.

[0050] Example 4. Patient harbored an acquired FLT3-ITD mutation. Following progression on cytotoxic chemotherapy, the patient achieved hematological benefit characterized as CRi on crenolanib besylate therapy, and was bridged to a curative allogeneic stem cell transplant.

[0051] Example 1 [0052] Effect of Crenolanib Besylate Therapy in a Relapsed/Refractory AML Patient with a de novo FLT3-ITD Mutation and Acquired FLT3-D835 TKD Mutation: CR and Bridge to Transplant.

[0053] A 34 year old, 82.28 kg male diagnosed with AML in July 2012. At initial diagnosis, laboratory testing revealed elevated peripheral blood and bone marrow blasts. The patient was positive for a de novo FLT3-ITD mutation, categorizing him as a high risk AML patient, which is associated with poor prognosis, increased cumulative incidence of relapse and shortened overall survival.

[0054] The patient was initially treated with induction chemotherapy including a standard dose of cytarabinc givcn as a continuous infusion for 7 days and 3 days of daunorubicin dclivcrcd intravenously. Following 1 cycle of induction therapy, the patient’s bone marrow showed no evidence of AML and remission was confïrmed. To maintain the clinical remission, two cycles of consolidation therapy with high dose cytarabine were completed. Approximately 1 month later, a bone marrow biopsy showed that the patient had relapsed. With no other approved standard treatment options available, the patient was enrolled on a phase I clinical trial for relapsed and refractory AML patients, where he was treated twice daily with an oral investigational FLT3 tyrosine kinase inhibitor, FLT3 tyrosine kinase inhibitor Y. Following approximately 3 months of FLT3 tyrosine kinase inhibitor Y treatment, the patient’s disease progressed and he was withdrawn from the investigational study.

[0055] Further analysis showed that the patient had acquired a FLT3-TKD mutation in addition to the FLT3-ITD mutation that was présent upon initial treatment. Presence of both the FLT3 ITD and FLT3-TKD mutations placed the patient in an even higher risk group. Due to the increased aggressive nature of the patient’s disease, he was treated with salvage high dose cytarabine chemotherapy and hydroxyurea. Despite administration of the salvage cytotoxic

AROG:1002 regimens, there was no significant decrease in the patient’s bone marrow blast counts. The patient discontinued both thérapies.

[0056] To overcome résistance to prior therapy, the patient was provided single agent oral crenolanib besylate on a clinical trial for relapsed or refractory AML patients with a FLT3-D835 TKD mutation (NCT01522469). At baseline, the patient presented with 75% bone marrow blasts. The patient began treatment with 100 mg of oral crenolanib three times daily. Despite decreasing the crenolanib dose to 80 mg three times daily, after 29 days of therapy a bone marrow biopsy revealed that crenolanib overcame prior FLT3 tyrosine kinase inhibitor résistance and the patient achieved complété remission (CR). The sustained clearance of bone marrow blasts made the patient eligible for stem cell transplant (see Table 1). The patient discontinued crenolanib therapy and underwent allogeneic stem cell transplant.

[0057] Table 1 illustrâtes the ability of crenolanib to clear malignant leukemia in the bone marrow of Example 1, a relapsed/refractory AML patient with a de novo FLT3-ITD mutation and acquired FLT3-D835 TKD mutation, after only 29 days of therapy

Days on Study Drug	Bone Marrow Blast (%)
0	75
29	0
57	1

[0058] Example 2 [0059] Effect of Crenolanib Besylate Therapy in a Relapsed/Refractory AML Patient with a de novo FLT3 ITD Mutation and Acquired FLT3-D835 TKD Mutation: CRi and Bridge to Transplant.

[0060] A 45 year old, 49.7 kg female diagnosed with AML in February 2012. At initial diagnosis, laboratory testing revealed an elevated bone marrow blast percentage of 65%. The patient was positive for a de novo FLT3-ITD mutation, categorizing her as a high risk AML patient, which is associated with poor prognosis, increased cumulative incidence of relapse and shortened overall survival.

[0061] The patient was initially treated with induction chemotherapy including a standard dose of cytarabine given as a continuous infusion for 5 days and 3 days of idaurubicin given intravenously. Following 1 cycle of induction therapy, the patient achieved a clinical complété remission. Laboratory tests showed a decrease in bone marrow blast percentage to 1% at week 5.

AROG:1002

To maintain the clinical remission, consolidation therapy with high dose cytarabine at 3 g/m² every 12 hours on days 1,3, and 5 was initiated for one cycle. In préparation for a stem cell transplant, the patient underwent an observational bone marrow biopsy. At week 12 the bone marrow biopsy showed that the patient had relapsed, with a bone marrow blast percentage 5 increase to 57%. In an effort to achieve a second remission, the patient was treated with salvage chemotherapy consisting of a combination of mitoxantrone, etoposide and cytarabine. At week 16, a bone marrow biopsy revealed that the patient had achieved a second complété rémission with 3% bone marrow blasts. In préparation for a stem cell transplant, the patient underwent an observational bone marrow biopsy at week 20. The biopsy results indicated that the patient 10 experienced a second relapse, with a bone marrow blast percentage of 30%. With no other approved standard treatment options available, the patient was enrolled on a clinical trial for relapsed and refractory AML patients, where she was treated daily with an oral investigational FLT3 tyrosine kinase inhibitor, FLT3 tyrosine kinase inhibitor X, at dose level 1. Following one treatment cycle of FLT3 tyrosine kinase inhibitor X, the patient presented with an elevated bone 15 marrow blast percentage of 38%. Further analysis showed that the patient had acquired a FLT3TKD mutation in addition to the FLT3-1TD mutation that was présent upon initial treatment. Présence of both the FLT3-ITD and FLT3-TKD mutations placcd the patient in an even higher risk group. Due to the increased aggressive nature of the patient’s disease, the daily dose of FLT3 tyrosine kinase inhibitor X was increased by 100% to dose level 2. Despite the increased dose of 20 FLT3 tyrosine kinase inhibitor X, the patient experienced an increase in bone marrow blasts to 60%. The patient discontinued the FLT3 tyrosine kinase inhibitor X investigational study.

[0062] To ovcrcomc résistance to prior therapy with FLT3 tyrosine kinase inhibitor X, the patient was provided single agent oral crenolanib besylate on a clinical trial for relapsed or refractory AML patients with a FLT3-D835 mutation (NCT01522469). At baseline, the patient 25 presented with 91% bone marrow blasts and 4800 units/uL of absolute circulating peripheral blood blasts. The patient began treatment with 80 mg of oral crenolanib three times daily. After only 14 days of crenolanib therapy, the patient achieved complété clearance of malignant leukemic blasts in her peripheral blood. Over the course of 65 days of therapy, a bone marrow biopsy revealed that crenolanib overcame prior FLT3 tyrosine kinase inhibitor résistance and the 30 patient achieved complété remission with incomplète blood count recovery (CRi). A decrease in

AROG:1002 bone marrow blasts to 4-5% made the patient eligible for stem cell transplant (see Tables 1 and 2). The patient discontinued crenolanib therapy and underwent allogeneic stem cell transplant.

[0063] Table 1 illustrâtes the ability of crenolanib to clear malignant leukemia in the peripheral blood of Example 2, a relapsed/refractory AML patient with a de novo FLT3-ITD mutation and 5 acquired FLT3-D835 TKD mutation, after only 14 days of therapy;

Days on Study Drug	Absolute Peripheral Blast Count (units/uL)
1	4800
3	2747
4	250
7	49
9	35
14	0
21	0
28	0
37	0
38	0
39	0
40	0
41	0
42	0
43	0
45	0
46	0
47	0
48	0
49	0
50	0
51	0
52	0
69	0

[0064] Table 2 illustrâtes the ability of crenolanib to clear malignant leukemia in the bone marrow of Example 2, a relapsed/refractory AML patient with a de novo FLT3-1TD mutation

AROG:1002 and acquired FLT3-D835 TKD mutation, for a sustained period of 65 days following immédiate relapse on another investigational FLT3 inhibitor;

FLT3 Inhibitor	Days on Study Drug	Bone Marrow Blast ( %)
FLT3 Inhibitor X	0	30
28	38
42	60
Crenolanib	0	91
21	32
35	2
65	4-5

[0065] Example 3 [0066] Effect of Crenolanib Besylate Therapy in a Relapsed/Refractory AML Patient with acquired FLT3-ITD and FLT3-D835 TKD Mutations: CRi and Bridge to Transplant.

[0067] A 44 year old, 59.2 kg female diagnosed with AML December 2011. Following initial diagnosis the patient was treated with 7 + 3 induction chemotherapy, followed by consolidation therapy with 1 cycle of high dose cytarabine. Five months later the patient underwent autologous stem cell transplantation with etoposide and busulfan conditioning. There was no evidence of clinical response following transplant. Laboratory testing revealed that the patient’s circulating peripheral blood blast were elevated two months later and her bone marrow blast percentage was 42% three months later. Additionally, it was discovered that the patient had acquired both a FLT3-ITD and FLT3-D835 TKD mutation. Given the in vitro FLT3 target specificity of crenolanib for both of the constitutively active mutations, the patient was initiated on the phase 11 crenolanib monotherapy clinical trial (NCT01522469). At baseline (Day 0), before administration of crenolanib besylate, the patient had absolute circulating peripheral blood blasts of 196 units/uL and 60-70% bone marrow blasts. The patient was treated with 100 mg of crenolanib besylate three times daily. After only 15 days of crenolanib therapy, the patient achieved complété clearance of malignant leukemic blasts in her peripheral blood. After 33 days of therapy, a bone marrow biopsy revealed that while on crenolanib therapy the patient achieved a complété remission with incomplète blood count recovery (CRi). A decrease in bone marrow blasts to 5% made the patient eligible for stem cell transplant. The patient discontinued

AROG:1002 crenolanib therapy to undergo allogeneic stem cell transplantation conditioning. The patient discontinued crenolanib therapy and underwent allogeneic stem cell transplant.

[0068] Table 3 illustrâtes the ability of crenolanib to clear malignant leukemia in the peripheral blood of Example 3, a heavily pretreated relapsed/refractory AML patient with acquired FLT3 5 ITD and FLT3-D835 TKD mutations, after only 15 days of therapy;

Days on Study Drug	Absolute Peripheral Blast Count (units/uL)
0	196
14	14
15	0
16	0
17	0
18	0
28	0
29	0
31	0
32	0
33	0
39	0
42	0
44	0
45	0
46	0
47	0
48	0
49	0
50	0
51	0
52	0

AROG:1002 [0069] Table 4 illustrâtes the ability of crenolanib to clear malignant leukemia in the bone marrow of Example 3, a heavily pretreated relapsed/refractory AML patient with acquired FLT3ITD and FLT3-D835 TKD mutations, for a sustained period of 33 days.

Days on Study Drug	Bone Marrow Blast (%)
0	60-70
27	10
33	5

[0070] Example 4 [0071] Effect of Crenolanib Besylate Therapy in a Relapsed/Refractory AML Patient with an acquired FLT3-ITD Mutation: CRi and Bridge to Transplant.

[0072] A 51 year old, 60.6 kg female diagnosed with FLT3-negative AML January 2012. Following initial diagnosis the patient was treated with standard 7 + 3 induction chemotherapy to which complété remission was achieved. The patient was then treated with 4 cycles of high dose cytarabine consolidation therapy. Laboratory testing revealed that the patient progressed on consolidation therapy. An acquired FLT3-ITD mutation was noted upon relapse and the patient was enrolled on the phase IT crenolanib besylate monotherapy clinical trial (NCT01522469). At baseline (Day 0), bcforc administration of crenolanib besylate, the patient had absolutc circulating peripheral blood blasts of 198 units/uL and 76% bone marrow blasts. The patient was treated with 100 mg of crenolanib besylate three times daily. After only 15 days of crenolanib therapy, the patient achieved complété clearance of malignant leukemic blasts in her peripheral blood. After 29 days of therapy, a bone marrow biopsy revealed that while on crenolanib therapy the patient achieved a complété remission with incomplète blood count recovery (CRi). A sustained level of bone marrow leukemic blasts at 1% qualifîed the patient for a stem cell transplant. The patient discontinued crenolanib therapy and underwent allogeneic stem cell transplant.

AROG:1002 [0073] Table 3 illustrâtes the ability of crenolanib to clear malignant leukemia in the peripheral blood of Example 4, a relapsed/refractory AML patient with an acquired FLT3-ITD mutation, after only 15 days of therapy;

Days on Study Drug	Absolute Peripheral Blast Count (cells/uL)
0	198
1	130
8	19
15	0
22	0
29	0
58	0

[0074] Table 4 illustrâtes the ability of crenolanib to clear malignant leukemia in the bone marrow of Example 4, a relapsed/refractory AML patient with an acquired FLT3-ITD mutation, after only 29 days of therapy.

Days on Study Drug	Bone Marrow Blast (%)
0	76
29	1
58	1

[0075] It is contemplated that any embodiment discussed in this spécification can be 10 implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.

[0076] It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be 15 employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine

AROG:1002 expérimentation, numerous équivalents to the spécifie procedures described herein. Such équivalents are considered to be within the scope of this invention and are covered by the daims. [0077] Ail publications and patent applications mentioned in the spécification are indicative of the level of skill of those skilled in the art to which this invention pertains. AU publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0078] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the daims and/or the spécification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the daims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a définition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inhérent variation of error for the device, the method being employed to détermine the value, or the variation that exists among the study subjects.

[0079] As used in this spécification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “hâve” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited éléments or method steps.

[0080] The term “or combinations thereof’ as used herein refers to ail permutations and combinations of the listcd items preceding the term. For cxamplc, “A, B, C, or combinations thereof’ is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0081] As used herein, words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill

AROG:1002 in the art to warrant designating the condition as being présent. The extent to which the description may vary will dépend on how great a change can be instituted and still hâve one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodifïed feature. In general, but subject to the preceding 5 discussion, a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7,10,12 or 15%.

[0082] Ail of the compositions and/or methods disclosed and claimed herein can be made and executed without undue expérimentation in light of the présent disclosure. While the compositions and methods of this invention hâve been described in terme of preferred 10 embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. Ail such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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[0109] J Cortès et al. AC220, a potent, sélective, second génération FLT3 receptor tyrosine kinase (RTK) inhibitor, in a fîrst-in-human (FIH) phase I AML study. Blood (ASH Annual Meeting Abstracts) 2009 Nov.

[0110] J Cortès et al. A phase II open-label, AC220 monotherapy efficacy study in patients with refractory/relapsed FLT3-ITD positive acute myeloid leukemia: updated intérim results. Blood (ASH Annual Meeting Abstracts) 2011 Dec.

[0111] N Lewis et al., J Clin Oncol. 2009; 27: p5262-5269.

[0112] A Mead et al. FLT3 tyrosine kinase domain mutations are biologically distinct from and hâve a sïgnifïcantly more favorable prognosis than FLT3 internai tandem duplications in patients

AROG:1002 with acute myeloid leukemia. Blood. 2007; 110: 1262; R Schlenk et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia. NEJM. 2008; 358: 1909.

[0113] Cheson et al. Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards 5 for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003; 21: 4642-4649.

AROG:1002

Claims (41)

1. A method for treating a FLT3 mutated proliférative disorder in a patient that comprises administering to the patient a therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof.

2. The method of claim 1, wherein the proliférative disorder is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy.

3. The method of claim 1, wherein the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof are from about 50 to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day.

4. The method of claim 1, wherein the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof is administered at least one of continuously, intennittently, systemically, or locally.

5. The method of claim 1, wherein the mutated. FLT3 is defined further as a constitutively active FLT3 mutant.

6. The method of claim 1, wherein the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof is administered orally, intravenously, or intraperitoneally.

7. The method according to claim 1, wherein the crenolanib is crenolanib besylate, crenolanib phosphate, crenolanib lactate, crenolanib hydrochloride, crenolanib citrate, crenolanib acetate, crenolanib toluenesulphonate and crenolanib succinate.

8. The method of claim 1, wherein the FLT3 is at least one of FLT3-ITD or FLT-TKD.

9. The method of claim 1, wherein the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof is administered up to three rimes or more a day for as long as the subject is in need of treatment for the proliférative disorder.

AROG:1002

10. The method of claim 1, wherein the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed proliférative disorder patient, to maintain rémission of an existing patient, or a relapsed/refractory proliférative disease patient.

11. The method of claim 1, wherein the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a patient with a newly diagnosed proliférative disorder, to maintain remission, or a relapsed/refractory proliférative disease patient.

12. The method of claim 1, wherein the therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disorder pédiatrie patient, to maintain remission, or a relapsed/refractory proliférative disorder pédiatrie patient.

13. The method of claim 1, wherein the patient is relapsed/refractory to other FLT3 tyrosine kinase inhibitors or another chemotherapy.

14. A method for treating a patient suffering from a proliférative disease comprising: identifying the patient in need of therapy for the proliférative disease; and administering to the patient in need of such treatment a therapeutically effective amount of Crenolanib or a sait thereof, wherein the cell proliférative disorder is characterized by deregulated FLT3 receptor tyrosine kinase activity, wherein the proliférative disease is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, csophagcal cancer, head and ncck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy.

15. The method of claim 14, wherein the Crenolanib or a sait thereof is administered orally, intravenously, or intraperitoneally.

16. The method of claim 14, wherein the Crenolanib or a sait thereof is at least one of Crenolanib Besylate, Crenolanib Phosphate, Crenolanib Lactate, Crenolanib Hydrochloride, Crenolanib Citrate, Crenolanib Acetate, Crenolanib Touluenesulphonate and Crenolanib Succinate Crenolanib Besylate.

AROG:1002

17. The method of claim 14, wherein the FLT3 is at least one of FLT3-ITD or FLT3-TKD.

18. The method of claim 14, wherein the Crenolanib or a sait thereof is provided at least one of sequentially or concomitantly, with another chemotherapeutic agent in a newly diagnosed proliférative disease, to maintain remission, or a relapsed/refractory proliférative disease.

19. The method of claim 14, wherein the Crenolanib or a sait thereof is provided as a single agent or in combination with another chemotherapeutic agent for treatment of pédiatrie patient with the proliférative disease.

20. The method of claim 14, wherein the Crenolanib or a sait thereof is provided as a single agent to at least one of post standard induction therapy, or high dose induction therapy, in newly diagnosed proliférative disease.

21. The method of claim 14, wherein the Crenolanib or a sait thereof is provided as a single agent in treatment of patients with the proliférative disease that is either reffactory to, or has relapsed after prior treatment with a chemotherapeutic agent.

22. The method of claim 14, wherein the patient is refractory to at least one other tyrosine kinase inhibitor or another chemotherapy.

23. A method for treating a patient suffering from leukemia comprising: obtaining a samplc from the patient suspcctcd of having leukemia;

determining from the patient sample that the patient has a deregulated FLT3 receptor tyrosine kinase; and administering to the patient in need of such treatment a therapeutically effective amount of Crenolanib or a sait thereof, wherein the leukemia is characterized by deregulated FLT3 receptor tyrosine kinase activity.

24. The method of claim 23, wherein the leukemia is selected from Hodgkin’s disease, and myeloma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilie leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvénile myelomonocytic leukemia (JMML), adult T-cell ALL, AML, with trilineage myelodysplasia (AMLITMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM).

25. A method for specifically inhibiting a deregulated receptor tyrosine kinase comprising:

AROG:1002 obtaining a patient sample;

determining which. receptor tyrosine kinases are deregulated; and administering to a mammal in need of such treatment a therapeutically effective amount of crenolanib or a sait thereof, wherein the deregulated receptor tyrosine kinase is a FLT3 receptor tyrosine kinase.

26. The method of claim 25, wherein the therapeutically effective amount of crenolanib or a sait thereof is provided in an amount that decreases patient circulating peripheral blood blast count.

27. The method of claim 25, wherein the therapeutically effective amount of crenolanib or a sait thereof is provided in. an amount that decreases a patient bone marrow blast count.

28. The method of claim 25, wherein the proliférative disease is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, tcsticular cancer, thyroid cancer, utérine cancer, and hématologie malignancy.

29. The method of claim 25, wherein the therapeutically effective amount of crenolanib or a sait thereof is also provided prophylactically at effective amounts are from about 50 to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day.

30. The method of claim 25, wherein therapeutically effective amount of crenolanib or a sait thereof is administered at least one of continuously, intermittently, systemically, or locally.

31. The method of claim 25, wherein the deregulated FLT3 is defined further as a mutated FLT3 is constitutively active.

32. The method of claim 25, wherein therapeutically effective amount of crenolanib or a sait thereof is administered orally, intravenously, or intraperitoneally.

33. The method of claim 25, wherein the Crenolanib is at least one of Crenolanib Besylate, Crenolanib Phosphate, Crenolanib Lactate, Crenolanib Hydrochloride, Crenolanib Citrate, Crenolanib Acetate, Crenolanib Touluenesulphonate and Crenolanib Succinate Crenolanib Besylate.

AROG:1002

34. The method of claim 25, wherein the FLT3 is at least one of FLT3-ITD or FLT3-TKD.

35. The method of claim 25, wherein therapeutically effective amount of crenolanib or a sait thereof is administered up to three times or more a day for as long as the subject is in need of treatment for the proliférative disease.

36. The method of claim 25, wherein the patient is provided treatment, and the method further comprises the steps of obtaining one or more patient samples to détermine the effect of the treatment, and continuing treatment until the proliférative disease is reduced or eliminated.

37. The method of claim 25, wherein therapeutically effective amount of crenolanib or a sait thereof is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed proliférative disease patient, to maintain remission, or a relapsed/refractory proliférative disease patient.

38. The method of claim 25, wherein therapeutically effective amount of crenolanib or a sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disease patient, to maintain remission, or a relapsed/refractory proliférative disease patient.

39. The method of claim 25, wherein therapeutically effective amount of crenolanib or a sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disease pédiatrie patient, to maintain remission, or a relapsed/refractory proliférative disease pédiatrie patient.

40. The method of claim 25, wherein the patient is relapsed/refractory to a prior tyrosine kinase inhibitor or another chemotherapy.

41. A method for treating a patient with a proliférative disease comprising:

obtaining a sample from the patient;

determining if the patient that has become résistant to prior tyrosine kinase inhibitors or chemotherapy; and administering a therapeutically effective amount of Crenolanib or a sait thereof to overcome the résistance to the prior protein tyrosine kinase inhibitors.