# US 11,078,541 B2 · Crenolanib for treating FLT3 mutated proliferative disorders associated mutations

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- Number: US 11,078,541 B2
- Document ID: US11078541B2
- Status: Granted
- Kind: B2
- Application number: 15/799,684
- Filed: 2017-10-31
- Published: 2018-05-03
- Granted: 2021-08-03
- Earliest claimed: 2016-11-02
- Assignees: Arog Pharmaceuticals, Inc.
- Applicants: Arog Pharmaceuticals, Inc.
- Inventors: Vinay K. Jain
- Web page: https://patentgrep.com/patent/US11078541B2

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/156: Polymorphic or mutational markers
- G01N 2333/912: transferring phosphorus containing groups, e.g. kinases (2.7)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention includes methods for treating a FLT3 mutated proliferative disorder comprising: measuring expression of a mutated FLT3 and one or more genetic abnormalities in a sample obtained from a tumor sample obtained from the patient, wherein the presence of the one or more genetic abnormalities indicates that the patient has a poor prognosis; and administering to the patient a therapeutically effective amount of crenolanib or a pharmaceutically acceptable salt thereof, wherein the crenolanib increases a chance of survival of the patient having both the mutated FLT3 and the one or more genetic abnormalities, wherein the crenolanib, as shown below, is administered to a subject suffering from said disorder:

## Claims

### Claim 1

A method for treating a human patient with Crenolanib, wherein the human patient is suffering from FLT3 mutated leukemia, the method comprising:
determining that the human patient has a poor prognosis for the FLT3 mutated leukemia by:
obtaining or having obtained a leukemia biological sample from the human patient; and
performing or having performed a genotyping assay on the biological sample to determine that the human patient has both a mutated FLT3 or a constitutively active FLT3 mutant and one or more driver mutations in DNMT3A, wherein the presence of both the mutated FLT3 and the one or more driver mutations in DNMT3A indicates that the patient has a poor prognosis; and
administering to the patient determined to have the poor prognosis a therapeutically effective amount of crenolanib or a pharmaceutically acceptable salt thereof, to treat the leukemia.

### Claim 2 (depends on 1)

The method of claim 1, further comprising detecting a mutation of at least one of NPM1, NRAS, KRAS, JAK2, PTPN11, TET2, IDH1, IDH2, WT1, RUNX1, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1A, TUSC3, BRP1, CD36, TYK2, or MUTYH.

### Claim 3 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of crenolanib or the pharmaceutically acceptable salt 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; or
the therapeutically effective amount of crenolanib or the pharmaceutically acceptable salt thereof is administered at least one of continuously, intermittently, systemically, or locally; or
the therapeutically effective amount of crenolanib or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or intraperitoneally.

### Claim 4 (depends on 1)

The method of claim 1, wherein the crenolanib or the pharmaceutically acceptable salt thereof is crenolanib besylate, crenolanib phosphate, crenolanib lactate, crenolanib hydrochloride, crenolanib citrate, crenolanib acetate, crenolanib toluenesulphonate, and crenolanib succinate.

### Claim 5 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of crenolanib or the pharmaceutically acceptable salt thereof is:
administered up to three times or more a day for as long as the human patient is in need of treatment for the leukemia; or
provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed leukemia human patient, to maintain remission of an existing human leukemia patient, or in a relapsed/refractory human leukemia patient; or
provided as a single agent or in combination with another pharmaceutical agent in a patient with a newly diagnosed leukemia, to maintain remission, or in a relapsed/refractory human leukemia patient; or
provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed human leukemia pediatric patient, to maintain remission, or in a relapsed/refractory human leukemia pediatric patient.

### Claim 6 (depends on 1)

The method of claim 1, wherein the human patient is relapsed/refractory to another tyrosine kinase inhibitor or chemotherapy.

### Claim 7

A method for treating a human patient suffering from a leukemia comprising:
identifying the human patient in need of therapy for leukemia, by determining that the leukemia comprises both a deregulated FLT3 receptor tyrosine kinase and one or more driver mutations in DNMT3A from testing performed on a sample of the leukemia obtained from the human patient, and wherein the leukemia is characterized as having a poor prognosis from the presence of both the deregulated FLT3 receptor tyrosine kinase and the driver mutation in DNMT3A; and
administering to the patient identified as having leukemia with both a deregulated FLT3 receptor tyrosine kinase and a loss of function mutation in DNMT3A a therapeutically effective amount of crenolanib or a salt thereof sufficient to treat the leukemia.

### Claim 8 (depends on 7)

The method of claim 7, wherein the FLT3 mutation is selected from at least one of FLT3-ITD or FLT3-TKD.

### Claim 9 (depends on 7)

The method of claim 7, further comprising detecting a genetic abnormality of NPM1, NRAS, KRAS, JAK2, PTPN11, TET2, IDH1, IDH2, WT1, RUNX1, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1A, TUSC3, BRP1, CD36, TYK2, or MUTYH.

### Claim 10 (depends on 7)

The method of claim 7, wherein the therapeutically effective amount of crenolanib or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or intraperitoneally.

### Claim 11 (depends on 7)

The method of claim 7, wherein the therapeutically effective amount of crenolanib or the pharmaceutically acceptable salt thereof is:
at least one of crenolanib besylate, crenolanib phosphate, crenolanib lactate, crenolanib hydrochloride, crenolanib citrate, crenolanib acetate, crenolanib touluenesulphonate and crenolanib succinate; or
is provided at least one of sequentially or concomitantly, with a chemotherapeutic agent in a newly diagnosed leukemia, to maintain remission, or a relapsed/refractory leukemia; or
is provided as a single agent or in combination with a chemotherapeutic agent for treatment of pediatric patient with the leukemia; or
is provided at least one of sequentially or concomitantly to at least one of post standard induction therapy, or high dose induction therapy, in newly diagnosed leukemia; or
is provided as a single agent in treatment of patients with the leukemia that is either refractory to, or has relapsed after prior treatment with a chemotherapeutic agent.

### Claim 12 (depends on 7)

The method of claim 7, wherein the patient is refractory to at least one other tyrosine kinase inhibitor or a chemotherapy.

### Claim 13

A method for treating a human patient suffering from acute myelogenous leukemia (AML) comprising:
obtaining a biological sample from the human patient;
determining from the sample that the human patient has AML with a deregulated FLT3 receptor or a constitutively active FLT3 receptor;
determining that the AML has one or more driver mutations in a DNMT3A gene; and
administering to the human patient in need of such treatment for AML determined to have both the deregulated FLT3 receptor or a constitutively active FLT3 receptor and the one or more driver mutations in the DNMT3 A gene a therapeutically effective amount of crenolanib or a salt thereof, thereby treating the AML.

### Claim 14 (depends on 13)

The method of claim 13, further comprising detecting one or more genetic abnormalities selected from at least one of NPM1, NRAS, KRAS, JAK2, PTPN11, TET2, IDH1, IDH2, WT1, RUNX1, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1A, TUSC3, BRP1, CD36, TYK2, or MUTYH.

### Claim 15

A method for specifically inhibiting a deregulated or constitutively active FLT3 receptor tyrosine kinase, comprising:
obtaining a sample from a human patient having acute myelogenous leukemia (AML);
determining that the AML has a FLT3 receptor tyrosine kinase that is deregulated or constitutively active and one or more driver mutations in a DNMT3A gene by performing or having performed genetic testing on the sample from the patient;
wherein the AML with both the deregulated or constitutively active FLT3 receptor tyrosine kinase and the one or more driver mutations in a DNMT3A gene cause a poor prognosis from the presence of both the deregulated FLT3 receptor tyrosine kinase and the driver mutation in DNMT3A; and
administering to the human patient in need of such treatment for AML determined to have both the deregulated or constitutively active FLT3 receptor tyrosine kinase and the one or more driver mutations in a DNMT3 A gene a therapeutically effective amount of crenolanib or a salt thereof, sufficient to reduce or eliminate the AML.

### Claim 16 (depends on 15)

The method of claim 15, wherein the deregulated FLT3 receptor is selected from at least one of FLT3-ITD or FLT3-TKD.

### Claim 17 (depends on 15)

The method of claim 15, wherein the therapeutically effective amount of crenolanib or the salt thereof is provided:
in an amount that decreases the human patient's circulating peripheral blood blast count; or
in an amount that decreases the human patient's bone marrow blast count; or
in an amount 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; or
in an amount that is delivered at least one of continuously, intermittently, systemically, or locally.

### Claim 18 (depends on 15)

The method of claim 15, wherein the therapeutically effective amount of crenolanib or the salt thereof is administered orally, intravenously, or intraperitoneally.

### Claim 19 (depends on 15)

The method of claim 15, wherein the crenolanib or the salt thereof is at least one of crenolanib besylate, crenolanib phosphate, crenolanib lactate, crenolanib hydrochloride, crenolanib citrate, crenolanib acetate, crenolanib touluenesulphonate and crenolanib succinate.

### Claim 20 (depends on 15)

The method of claim 15, wherein the therapeutically effective amount of crenolanib or the salt thereof is at least one of:
administered up to three times or more a day for as long as the human patient is in need of treatment; or
is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed AML, to maintain remission, or in a relapsed/refractory leukemia; or
the crenolanib or the salt thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed AML, to maintain remission, or in a relapsed/refractory AML; or
the therapeutically effective amount of crenolanib or the salt thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed AML pediatric patient, to maintain remission, or in a relapsed/refractory AML pediatric patient.

### Claim 21 (depends on 15)

The method of claim 15, wherein the patient is relapsed/refractory to a prior tyrosine kinase inhibitor.