WO2015127172A1 - Composés thérapeutiquement actifs et leurs procédés d'utilisation - Google Patents
Composés thérapeutiquement actifs et leurs procédés d'utilisation Download PDFInfo
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- WO2015127172A1 WO2015127172A1 PCT/US2015/016766 US2015016766W WO2015127172A1 WO 2015127172 A1 WO2015127172 A1 WO 2015127172A1 US 2015016766 W US2015016766 W US 2015016766W WO 2015127172 A1 WO2015127172 A1 WO 2015127172A1
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- 229940116269 uric acid Drugs 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57426—Specifically defined cancers leukemia
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Definitions
- Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., a-ketoglutarate). These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+).
- NAD(+) the electron acceptor
- NADP(+)-dependent isocitrate dehydrogenases Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP(+)-dependent isozyme is a homodimer.
- IDH1 isocitrate dehydrogenase 1 (NADP+), cytosolic
- IDP isocitrate dehydrogenase 1
- IDCD isocitrate dehydrogenase 1
- PICD PICD
- the protein encoded by this gene is the NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2, 4-dienoyl- CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid.
- the cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.
- the human IDH1 gene encodes a protein of 414 amino acids.
- the nucleotide and amino acid sequences for human IDH1 can be found as GenBank entries NM_005896.2 and
- NP_005887.2 respectively.
- the nucleotide and amino acid sequences for IDH1 are also described in, e.g., Nekrutenko et al., Mol. Biol. Evol. 15: 1674-1684(1998); Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999); Wiemann et al, Genome Res. 11:422-435(2001); The MGC Project Team, Genome Res.
- Non-mutant e.g., wild type, IDHl catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate thereby reducing NAD + (NADP + ) to NADH (NADPH), e.g., in the forward reaction:
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MDS myeloproliferative neoplasms
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B-a
- the advanced hematologic malignancies are characterized by a mutant allele of IDHl, wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of ⁇ -ketoglutarate to R(-)-2-hydroxyglutarate (2HG) in a patient.
- the mutant IDHl has an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
- the R132X mutation is R132H or R132C.
- the R132X mutation is R132H.
- the advanced hematologic malignancies harbor a co- mutation, e.g. , a co-mutation selected from NPMl, FLT3, TET2, CEBPA, DNMT3A, and MLL.
- the present invention provides a method of evaluating a subject, the method comprising: acquiring, e.g., directly acquiring, a value for the level of a compound (S)- N-((S)-l-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)- l-(4-cyanopyridin-2- yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1), or a compound (S)- N-((S)-l-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)- l-(4-cyanopyridin-2- yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carbox
- the present invention provides a method of evaluating a subject, the method comprising: administering to the subject in need thereof a compound (S)-N-((S)- l-(2- chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)- l-(4-cyanopyridin-2-yl)-N-(5- fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof; and acquiring a value for the level of Compound 1 or the level of an alpha hydroxy neoactivity product, e.g. , 2HG, e.g., R-2HG (2HG), in the subject, to thereby evaluate the subject.
- Compound 1 or the level of an alpha hydroxy neoactivity product, e.g. , 2HG, e.g., R-2HG (2HG)
- acquiring comprises receiving a sample from the subject. In some embodiments, acquiring comprises transmitting the value to another party, e.g., the party that administered Compound 1.
- the value for the level of Compound 1 is acquired by analyzing the concentration of Compound 1 in a bodily fluid, e.g., blood, plasma or urine. In some embodiments, the value for the level of Compound 1 is acquired by analyzing the level of Compound 1 in bone marrow, e.g., analyzing a sample from a bone marrow biopsy and/or aspirate for the level of Compound 1.
- a bodily fluid e.g., blood, plasma or urine.
- the value for the level of Compound 1 is acquired by analyzing the level of Compound 1 in bone marrow, e.g., analyzing a sample from a bone marrow biopsy and/or aspirate for the level of Compound 1.
- the value for the level of 2HG is acquired by analyzing the concentration of 2HG in a bodily fluid, e.g. , blood, plasma or urine. In some embodiments, the value for the level of 2HG is acquired by analyzing the level of 2HG in bone marrow, e.g. , analyzing a sample from a bone marrow biopsy and/or aspirate for the level of 2HG.
- a bodily fluid e.g. , blood, plasma or urine.
- the value for the level of 2HG is acquired by analyzing the level of 2HG in bone marrow, e.g. , analyzing a sample from a bone marrow biopsy and/or aspirate for the level of 2HG.
- the analysis is performed by sample analysis of bodily fluid, such as blood, plasma or urine, by e.g. , a chromatographic method, e.g., mass spectroscopy, e.g. LC- MS.
- a chromatographic method e.g., mass spectroscopy, e.g. LC- MS.
- the analysis is performed by spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS measurement.
- the subject has been administered Compound 1 less than about 30 days prior to the evaluation, e.g. , less than about 29 days, e.g. , less than about 28 days, e.g. , less than about 27 days, e.g. , less than about 26 days, e.g., less than about 25 days, less than about 24 days, e.g., less than about 23 days, e.g., less than about 22 days, e.g., less than about 21 days, e.g. , less than about 20 days, e.g. , less than about 19 days, e.g. , less than about 18 days, e.g. , less than about 17 days, e.g.
- less than about 16 days e.g., less than about 15 days, e.g. , less than about 14 days, e.g., about 7 days, less than about 6 days, less than about 5 days, less than about 4 days, less than about 3 days, or less than 72 hours prior to the evaluation, e.g. , less than 48 hours, less than 24 hours, less than 12 hours, less than 10 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 15 minutes, prior to the evaluation.
- the subject has been administered, e.g., orally, Compound 1 at a dose of about 10 mg to about 3000 mg, e.g. , once or twice daily, (e.g. , about every 8-16 hours, e.g. , about every 12 hours), or (e.g. , about every 12-36 hours, e.g. , about every 24 hours), e.g.
- the subject has or is diagnosed as having a disorder.
- the disorder is an advanced hematologic malignancy, e.g. , an advanced
- the advanced hematologic malignancy is characterized by a mutant allele of IDHl, wherein the IDHl mutation results in a new ability of the enzyme to catalyze the
- the mutant IDHl has an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
- the R132X mutation is R132H or R132C.
- the R132X mutation is R132H.
- the advanced hematologic malignancy harbors a co- mutation, e.g. , a co-mutation selected from NPMl, FLT3, TET2, CEBPA, DNMT3A, and MLL.
- the disorder is selected from acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B- acute lymphoblastic leukemias (B-ALL), B-acute lymphoblastic leukemias (B-ALL), and lymphoma ⁇ e.g. , T-cell lymphoma), wherein each is characterized by the presence of a mutant allele of IDH1.
- the disorder is selected from advanced IDH1 mutation-positive relapsed and/or refractory AML (R/R AML), untreated AML, and MDS.
- the subject has been previously treated with one or more chemotherapeutic agent(s).
- the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacytidine, decitabine, SGN33A, sargramostim, WT- 1 analog peptide vaccine, tipifarnib, MK-8242, campath, and 6 Mercaptopurine (6MP).
- the present invention provides a method of evaluating a subject, the method comprising: acquiring, e.g., directly acquiring, a value for the level of blast cells, e.g., leukemic blast cells, e.g.
- the present invention provides a method of evaluating a subject, the method comprising: administering to the subject in need thereof a compound (S)-N-((S)- l-(2- chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)- l-(4-cyanopyridin-2-yl)-N-(5- fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof; and acquiring a value for the level of blast cells, e.g. , leukemic blast cells, e.g., myeloblasts or myeloid blasts, in the subject, to thereby evaluate the subject.
- a compound e.g. , leukemic blast cells, e.g., myeloblasts or myeloid blasts
- acquiring comprises receiving a sample from the subject. In some embodiments, acquiring comprises transmitting the value to another party, e.g., the party that administered Compound 1. In some embodiments, the evaluation comprises acquiring a value for the level of blast cells, e.g., leukemic blast cells, e.g. , myeloblasts or myeloid blasts, e.g., a blast cell count, in a sample from the subject, and comparing the value to a reference standard. In some
- the reference standard is the total number of cells in the sample.
- the sample comprises blast cells, myelocytes, neutrophils, promyelocytes, metamyelocytes, and monocytes.
- the value for the level of blast cells is acquired by analyzing the bone marrow, e.g., by analyzing blast counts in bone marrow aspirates.
- the bone marrow is analyzed, e.g., about every two weeks, e.g. , (between days 12- 18, e.g, on day 15), (between days 26-32, e.g., on day 29), (between days 54-60, e.g. , on day 57), and then about every 50-60 days thereafter, e.g., every 56 days thereafter, e.g. , on days 15, 29 and 57, and then every 56 days thereafter.
- the subject has been administered Compound 1 less than about 30 days prior to the evaluation, e.g. , less than about 29 days, e.g. , less than about 28 days, e.g. , less than about 27 days, e.g. , less than about 26 days, e.g., less than about 25 days, less than about 24 days, e.g. , less than about 23 days, e.g., less than about 22 days, e.g., less than about 21 days, e.g. , less than about 20 days, e.g. , less than about 19 days, e.g. , less than about 18 days, e.g. , less than about 17 days, e.g.
- less than about 16 days e.g., less than about 15 days, e.g. , less than about 14 days, e.g., about 7 days, less than about 6 days, less than about 5 days, less than about 4 days, less than about 3 days, or less than 72 hours prior to the evaluation, e.g. , less than 48 hours, less than 24 hours, less than 12 hours, less than 10 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, or less than 15 minutes, prior to the evaluation.
- the subject has been administered, e.g., orally, Compound 1 at a dose of about 10 mg to about 3000 mg, e.g. , once or twice daily, (e.g. , about every 8-16 hours, e.g. , about every 12 hours), or (e.g. , about every 12-36 hours, e.g. , about every 24 hours), e.g.
- the subject has or is diagnosed as having a disorder.
- the disorder is an advanced hematologic malignancy, e.g. , an advanced
- the advanced hematologic malignancy is characterized by a mutant allele of IDHl, wherein the IDHl mutation results in a new ability of the enzyme to catalyze the
- the mutant IDHl has an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
- the R132X mutation is R132H or R132C.
- the R132X mutation is R132H.
- the advanced hematologic malignancy is characterized by a co- mutation, e.g. , a co-mutation selected from NPM1, FLT3, TET2, CEBPA, DNMT3A, and MLL.
- the disorder is selected from acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B- acute lymphoblastic leukemias (B-ALL), B-acute lymphoblastic leukemias (B-ALL), and lymphoma (e.g. , T-cell lymphoma), wherein each is characterized by the presence of a mutant allele of IDHl .
- the disorder is selected from advanced IDHl mutation-positive relapsed and/or refractory AML (R/R AML), untreated AML, and MDS.
- the subject has been previously treated with one or more chemotherapeutic agent(s).
- the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacytidine, decitabine, SGN33A, sargramostim, WT- 1 analog peptide vaccine, tipifarnib, MK-8242, campath, and 6 Mercaptopurine (6MP).
- the present invention provides a method of treating a disorder in a subject, the method comprising: administering to the subject in need thereof a compound (S)-N- ((S)- l-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-l-(4-cyanopyridin-2-yl)- N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof, in an amount sufficient to provide a reduction in blast cells, e.g., leukemic blast cells, e.g.
- the disorder is an advanced hematologic malignancy, e.g., an advanced hematologic malignancy characterized by the presence of a mutant allele of IDH1.
- the advanced hematologic malignancy is characterized by a mutant allele of IDH1, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the
- the mutant IDH1 has an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
- the R132X mutation is R132H or R132C.
- the R132X mutation is R132H.
- the disorder is selected from acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B- acute lymphoblastic leukemias (B-ALL), B-acute lymphoblastic leukemias (B-ALL), and lymphoma (e.g. , T-cell lymphoma), wherein each is characterized by the presence of a mutant allele of IDH1.
- the disorder is selected from advanced IDH1 mutation-positive relapsed and/or refractory AML (R/R AML), untreated AML, and MDS.
- the subject has been previously treated with one or more chemotherapeutic agent(s).
- the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacytidine, decitabine, SGN33A, sargramostim, WT- 1 analog peptide vaccine, tipifarnib, MK-8242, campath, and 6 Mercaptopurine (6MP).
- the reduction in blast cells is by about at least a factor of 10, e.g. , relative to a reference standard, e.g. , by about at least a factor of 11, e.g. , by about at least a factor of 12, e.g. , by about at least a factor of 13, e.g. , by about at least a factor of 14, e.g., by about at least a factor of 15, e.g. , by about at least a factor of 16, e.g., by about at least a factor of 17, e.g. , by about at least a factor of 18, e.g. , by about at least a factor of 19, e.g. , by about at least a factor of 20, relative to a reference standard.
- the blast cells e.g., leukemic blast cells, e.g., myeloblasts or myeloid blasts
- a reference standard e.g., to a level that is less than about 10%, e.g., less than about 9%, e.g. , less than about 8%, e.g., less than about 7%, e.g. , less than about 6%, e.g. , less than about 5%, e.g., less than about 4%, e.g. , less than about 3%, e.g., less than about 2%, e.g., complete remission (CR), relative to a reference standard.
- a reference standard e.g., to a level that is less than about 10%, e.g., less than about 9%, e.g. , less than about 8%, e.g., less than about 7%, e.g. , less than about 6%, e.g.
- the reference standard is the level of blast cells, e.g., leukemic blast cells, e.g., myeloblasts or myeloid blasts, in the subject prior to administration of
- Compound 1 e.g. , in an untreated subject, e.g. , in a subject not previously treated with
- the subject has been previously treated with one or more chemotherapeutic agent(s).
- the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacytidine, decitabine, SGN33A, sargramostim, WT- 1 analog peptide vaccine, tipifarnib, MK-8242, campath, and 6 Mercaptopurine (6MP).
- the reference standard is the total number of cells in the sample.
- the sample comprises blast cells, myelocytes, neutrophils, promyelocytes, metamyelocytes, and monocytes.
- the subject is monitored for an adverse event. In some embodiments, the subject is monitored for an adverse event.
- the adverse event includes without limitation, febrile neutropenia, dyspnea, hypotension, mental status changes, neutropenia, increase in the level of blood uric acid, bronchopulmonary aspergillosis, dizziness, prolonged electrocardiogram QT, fatigue, intracranial hemorrhage, hypoxia, leukocytosis, leukostasis, lung infection, metabolic acidosis, nausea, organ failure, pericardial effusion, fungal pneumonia, pyrexia, renal impairment, retinoic acid syndrome, septic shock, systemic Candida, tachycardia, and vertigo.
- the adverse event is differentiation syndrome wherein symptoms comprise fever and/or dyspnea.
- the subject is monitored for
- differentiation syndrome and if the subject experiences differentiation syndrome is treated with steroids.
- the subject is monitored for an adverse event, e.g. , a serious adverse event (SAE), and if an adverse event, e.g., SAE, is experienced by the patient, then treatment is modified or discontinued.
- SAE serious adverse event
- Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with Compound 1.
- the method prior to and/or after treatment with Compound 1, the method further comprises the step of evaluating PK and PD parameters (e.g., tissue, blood, plasma and/or urine concentration(s) of Compound 1 or 2HG).
- PK and PD parameters e.g., tissue, blood, plasma and/or urine concentration(s) of Compound 1 or 2HG.
- This evaluation may be achieved by sample analysis of bodily tissue or bodily fluid, such as blood, plasma or urine by e.g., mass spectroscopy, e.g. LC-MS.
- Figure 1A depicts a line graph showing reduction in 2HG following a single dose (50 mg/kg) of a compound (S)-N-((S)-l-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2- oxoethyl)-l-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1) in an IDH1 mutant R132H xenograft model.
- Figure IB depicts a bar graph showing Compound 1 (at 0.5 uM, 1 uM and 5 uM concentrations) reduced intracellular 2HG in primary human IDH-mutated blast cells (ex vivo).
- Figure 2A depicts a bar graph showing the PK profile following oral administration of Compound 1 in patients treated at day -3 with a single dose, at day 15 of cycle 1, and at day 1 of cycle 2, each at doses of 100 mg BID, 300 mg QD or 500 mg QD.
- Figure 2B depicts a bar graph showing that plasma concentrations of 2HG were reduced to normal ranges at day -3 with a single dose, at day 15 of cycle 1, and at day 1 of cycle 2, each at doses of 100 mg BID, 300 mg QD or 500 mg QD.
- Figure 3A, 3B and 3C depict images of bone marrow aspirate showing blasts
- the term “elevated levels of 2HG” means 10%, 20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG than is present in a subject that does not carry a mutant IDH1 allele.
- the term “elevated levels of 2HG” may refer to the amount of 2HG within a cell, within a tumor, within an organ comprising a tumor, or within a bodily fluid.
- the term "acquire” or “acquiring” refers to obtaining possession of a physical entity (e.g. , a sample, e.g., blood sample or blood plasma sample), or a value, e.g. , a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value.
- a physical entity e.g. , a sample, e.g., blood sample or blood plasma sample
- a value e.g., a numerical value
- Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample, performing an analytical method, e.g. , a method as described herein, e.g. , by sample analysis of bodily fluid, such as blood or plasma by, e.g. , mass spectroscopy, e.g. LC-MS.
- an analytical method e.g. , a method as described herein, e.g. , by sample analysis of bodily fluid, such as blood or plasma by, e.g. , mass spectroscopy, e.g. LC-MS.
- the term "bodily fluid” includes one or more of amniotic fluid surrounding a fetus, aqueous humour, blood (e.g., blood plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's fluid, female ejaculate, interstitial fluid, lymph, breast milk, mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretion, or vomit.
- blood e.g., blood plasma
- serum Cerebrospinal fluid
- cerumen cerumen
- chyme chyme
- Cowper's fluid female ejaculate
- interstitial fluid lymph
- breast milk mucus (e.g., nasal drainage or phlegm)
- mucus e.g., nasal drainage or phlegm
- pleural fluid pus, saliva, sebum, semen, serum
- inhibitor or “prevent” include both complete and partial inhibition and prevention.
- An inhibitor may completely or partially inhibit the intended target.
- treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease/disorder (i.e., an advanced hematologic malignancy such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS),
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- myeloproliferative neoplasms MPN
- chronic myelomonocytic leukemia CMML
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- MDS myelodysplasia syndrome
- MPN myeloproliferative neoplasms
- myelomonocytic leukemia CMML
- B-acute lymphoblastic leukemias B-ALL
- lymphoma e.g., T-cell lymphoma
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- an amount of a compound effective to treat a disorder or a
- terapéuticaally effective amount refers to an amount of the compound, which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.
- the term "subject" is intended to mean human.
- exemplary human subjects include a human patient (referred to as a patient) having a disorder, e.g., a disorder described herein or a normal subject.
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g.
- T-cell lymphoma each characterized by the presence of a mutant allele of IDHl, comprising administering to a subject in need thereof a compound (S)-N-((S)-l-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-l-(4- cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1), or a pharmaceutically acceptable salt thereof.
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MMPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g
- Compound 1, or a pharmaceutically acceptable salt thereof, utilized in the methods described herein may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to being administered to a subject.
- pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a subject, together with a compound, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
- pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a- tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene
- Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
- the pharmaceutical compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
- the pharmaceutical compositions of one aspect of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound, or its delivery form.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of
- pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
- Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- the pharmaceutical compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
- carriers which are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
- the pharmaceutical compositions may also be administered in the form of suppositories for rectal administration.
- These compositions can be prepared by mixing Compound 1, or a pharmaceutically acceptable salt thereof, with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
- suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
- topical administration of the pharmaceutical compositions is useful when the desired treatment involves areas or organs readily accessible by topical application.
- the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
- Carriers for topical administration of Compound 1, or a pharmaceutically acceptable salt thereof include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound, suspended or dissolved in a carrier with suitable emulsifying agents.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the pharmaceutical compositions of one aspect of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in one aspect of this invention.
- the pharmaceutical compositions may be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
- the compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
- the methods herein contemplate administration of an effective amount of compound, or compound composition to achieve the desired or stated effect.
- the pharmaceutical compositions of one aspect of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
- administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% w/w active compound.
- such preparations contain from about 20% to about 80% active compound.
- a subject may be administered a dose of Compound 1, or a pharmaceutically acceptable salt thereof, as described in Example 2. Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound, employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug
- a maintenance dose of a compound, composition or combination of one aspect of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- Some embodiments of the invention are directed toward a tablet comprising at least one pharmaceutically acceptable carrier or diluent, and Compound 1, or a pharmaceutically acceptable salt thereof.
- IDH1 mutants e.g. , IDH1R132H or IDH1R132C
- IDH1 mutants e.g. , IDH1R132H or IDH1R132C
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MDS myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g. , T-cell lymphoma
- the advanced hematologic malignancy such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B- acute lymphoblastic leukemias (B-ALL), or lymphoma (e.g., T-cell lymphoma)
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- the mutant IDHl has an R132X mutation.
- the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.
- the R132X mutation is R132H or R132C.
- the R132X mutation is R132H.
- Advanced hematologic malignancies such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), chronic
- CMML myelomonocytic leukemia
- B-ALL B-acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- mutant alleles of IDHl wherein the IDHl mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of a-ketoglutarate to R(-)-2-hydroxyglutarate, and in particular R132H mutations of IDHl, characterize a subset of all types of cancers, without regard to their cellular nature or location in the body.
- advanced hematologic malignancies such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), chronic
- CMML myelomonocytic leukemia
- B-ALL B-acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- the efficacy of treatment of advanced hematologic malignancies such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS),
- myeloproliferative neoplasms MPN
- chronic myelomonocytic leukemia CMML
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- levels of 2HG are measured prior to treatment, wherein an elevated level is indicated for the use of Compound 1, or a pharmaceutically acceptable salt thereof, to treat the advanced hematologic malignancies, such as acute myelogenous leukemia (AML),
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MPN myeloproliferative neoplasms
- CMML myelomonocytic leukemia
- B-ALL B-acute lymphoblastic leukemias
- lymphoma e.g., T-cell lymphoma
- the these 2HG measurements will be utilized together with other well-known determinations of efficacy of cancer treatment, such as reduction in number and size of tumors and/or other cancer-associated lesions, evaluation of bone marrow biopsies and/or aspirates, complete blood counts and examination of peripheral blood films, improvement in the general health of the subject, and alterations in other biomarkers that are associated with cancer treatment efficacy.
- Embodiments of the method comprise evaluation of one or more parameters related to IDH1, an alpha hydroxy neoactivity, e.g., 2HG neoactivity, e.g., to evaluate the IDH1 2HG neoactivity genotype or phenotype.
- the evaluation can be performed, e.g. , to select, diagnose or prognose the subject, to select a therapeutic agent, e.g., an inhibitor, or to evaluate response to the treatment or progression of disease.
- the evaluation which can be performed before and/or after treatment has begun, is based, at least in part, on analysis of a tumor sample, cancer cell sample, or precancerous cell sample, from the subject.
- a sample from the patient can be analyzed for the presence or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, by evaluating a parameter correlated to the presence or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG.
- An alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, in the sample can be determined by a chromatographic method, e.g., by LC-MS analysis.
- a specific binding agent e.g., an antibody, which binds the alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, and allows detection.
- the sample is analyzed for the level of neoactivity, e.g., an alpha hydroxy neoactivity, e.g., 2HG neoactivity.
- the sample is analyzed for the presence of a mutant IDH1, protein having an alpha hydroxy neoactivity, e.g. , 2HG neoactivity (or a corresponding RNA).
- a mutant protein specific reagent e.g., an antibody that specifically binds an IDH1 mutant protein, e.g., an antibody that specifically binds an IDH1- R132H mutant protein
- a nucleic acid from the sample is sequenced to determine if a selected allele or mutation of IDH1 disclosed herein is present.
- the analysis is other than directly determining the presence of a mutant IDH1 protein (or corresponding RNA) or sequencing of an IDH1 gene.
- the analysis is other than directly determining, e.g., it is other than sequencing genomic DNA or cDNA, the presence of a mutation at residue 132 of IDH1.
- the analysis can be the detection of an alpha hydroxy neoactivity product, e.g. , 2HG, e.g., R-2HG, or the measurement of the mutation's an alpha hydroxy neoactivity, e.g. , 2HG neoactivity.
- the sample is removed from the patient and analyzed.
- the evaluation can include one or more of performing the analysis of the sample, requesting analysis of the sample, requesting results from analysis of the sample, or receiving the results from analysis of the sample.
- analysis can include one or both of performing the underlying method or receiving data from another who has performed the underlying method.
- the evaluation which can be performed before and/or after treatment has begun, is based, at least in part, on analysis of a tissue (e.g., a tissue other than a tumor sample), or bodily fluid, or bodily product.
- tissue e.g., a tissue other than a tumor sample
- bodily fluid e.g., a tissue other than a tumor sample
- bodily fluids include blood, plasma, urine, lymph, tears, sweat, saliva, semen, and cerebrospinal fluid.
- Exemplary bodily products include exhaled breath.
- the tissue, fluid or product can be analyzed for the presence or level of an alpha hydroxy neoactivity product, e.g.
- an alpha hydroxy neoactivity product e.g. , 2HG, e.g., R-2HG
- An alpha hydroxy neoactivity product, e.g. , 2HG, e.g., R-2HG, in the sample can be determined by a
- chromatographic method e.g., by LC-MS analysis. It can also be determined by contact with a specific binding agent, e.g., an antibody, which binds the alpha hydroxy neoactivity product, e.g. , 2HG, e.g., R-2HG, and allows detection.
- a specific binding agent e.g., an antibody
- the tissue, fluid or product can be analyzed for the level of neoactivity, e.g., an alpha hydroxy neoactivity, e.g. , the 2HG neoactivity.
- the sample is analysed for the presence of a mutant IDH1 protein having an alpha hydroxy neoactivity, e.g., 2HG neoactivity (or a corresponding RNA).
- a mutant protein specific reagent e.g. , an antibody that specifically binds an IDH mutant protein, e.g. , an antibody that specifically binds an IDH1-R132H mutant protein can be used to detect neoactive mutant enzyme.
- a nucleic acid from the sample is sequenced to determine if a selected allele or mutation of IDH1 disclosed herein is present.
- the analysis is other than directly determining the presence of a mutant IDH1 protein (or corresponding RNA) or sequencing of an IDH1 gene.
- the analysis can be the detection of an alpha hydroxy neoactivity product, e.g. , 2HG, e.g., R-2HG, or the measurement of 2HG neoactivity.
- the tissue, fluid or product is removed from the patient and analyzed.
- the evaluation can include one or more of performing the analysis of the tissue, fluid or product, requesting analysis of the tissue, fluid or product, requesting results from analysis of the tissue, fluid or product, or receiving the results from analysis of the tissue, fluid or product.
- the evaluation which can be performed before and/or after treatment has begun, is based, at least in part, on alpha hydroxy neoactivity product, e.g., 2HG, e.g., R- 2HG, imaging of the subject.
- alpha hydroxy neoactivity product e.g., 2HG, e.g., R- 2HG
- magnetic resonance methods are is used to evaluate the presence, distribution, or level of an alpha hydroxy neoactivity product, e.g. , 2HG, e.g., R-2HG, in the subject.
- the subject is subjected to imaging and/or spectroscopic analysis, e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS e.g., analysis, and optionally an image corresponding to the presence, distribution, or level of an alpha hydroxy neoactivity product, e.g., 2HG, e.g., R-2HG, or of the tumor, is formed.
- imaging and/or spectroscopic analysis e.g., magnetic resonance-based analysis, e.g., MRI and/or MRS e.g., analysis
- an image corresponding to the presence, distribution, or level of an alpha hydroxy neoactivity product e.g., 2HG, e.g., R-2HG
- the image or a value related to the image is stored in a tangible medium and/or transmitted to a second site.
- the evaluation can include one or more of performing imaging analysis, requesting imaging analysis, requesting results from imaging analysis, or receiving the results from imaging analysis
- 2HG is directly evaluated.
- a derivative of 2HG formed in process of performing the analytic method is evaluated.
- a derivative can be a derivative formed in MS analysis.
- Derivatives can include a salt adduct, e.g., a Na adduct, a hydration variant, or a hydration variant which is also a salt adduct, e.g., a Na adduct, e.g., as formed in MS analysis.
- a metabolic derivative of 2HG is evaluated.
- examples include species that build up or are elevated, or reduced, as a result of the presence of 2HG, such as glutarate or glutamate that will be correlated to 2HG, e.g., R-2HG.
- Exemplary 2HG derivatives include dehydrated derivatives such as the compounds provided below or a salt adduct thereof:
- the advanced hematologic malignancy such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), or lymphoma (e.g., T-cell lymphoma) is a tumor wherein at least 30, 40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDHl mutation, and in particular an IDHl R132H or R132C mutation, at the time of diagnosis or treatment.
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MMPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B-acute lymphoblastic leukemias
- lymphoma e.g., T
- the advanced hematologic malignancy to be treated is AML, characterized by the presence of a mutant allele of IDHl .
- the AML is relapsed and/or primary refractory.
- the AML is relapsed.
- the AML is primary refractory.
- the AML is untreated.
- the advanced hematologic malignancy to be treated is MDS, characterized by the presence of a mutant allele of IDHl.
- the advanced hematologic malignancy to be treated is MDS with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2).
- the MDS is considered high-risk by the IPSS-R (Greenberg et al. Blood. 2012;120(12):2454-65).
- the MDS is recurrent.
- the MDS is refractory.
- the subject having MDS is intolerant to established therapy known to provide clinical benefit for their conditions, according to the treating physician.
- the advanced hematologic malignancy to be treated is CMML, characterized by the presence of a mutant allele of IDHl.
- the CMML is relapsed and/or primary refractory.
- the CMML is relapsed.
- the CMML is primary refractory.
- Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with Compound 1, or a pharmaceutically acceptable salt thereof.
- the method further comprises evaluating the growth, size, weight, invasiveness, stage and/or other phenotype of the advanced hematologic malignancies, such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B- acute lymphoblastic leukemias (B-ALL), or lymphoma ⁇ e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDHl.
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B- acute lymphoblastic leukemias
- lymphoma ⁇ e.g., T-cell lymphoma
- the method further comprises evaluating the IDHl genotype of the advanced hematologic malignancies, such as acute myelogenous leukemia (AML), myelodysplasia syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-acute lymphoblastic leukemias (B-ALL), or lymphoma ⁇ e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDHl.
- AML acute myelogenous leukemia
- MDS myelodysplasia syndrome
- MPN myeloproliferative neoplasms
- CMML chronic myelomonocytic leukemia
- B-ALL B-acute lymphoblastic leukemias
- lymphoma ⁇ e.g., T-cell lymphoma
- the method further comprises determining the 2HG level in the subject. This may be achieved by spectroscopic analysis, e.g., magnetic
- resonance-based analysis e.g., MRI and/or MRS measurement
- sample analysis of bodily fluid such as blood, plasma, urine, or spinal cord fluid analysis
- analysis of surgical material e.g., by mass-spectroscopy (e.g. LC-MS, GC-MS), or any of the methods described herein.
- Example 1 Compound 1 Induces Myeloid Differentiation in Primary IDH1 (R132C) Samples from Patients with AML
- Bone marrow aspirates are obtained from patients at the time of diagnosis of their malignancy.
- the diagnosis of AML may be morphologically confirmed according to the French- American-British classification or World Health Organization criteria, and a description of the karyotypes follows the International System for Human Cytogenetic Nomenclature (Mitelman International System for Cytogenetic Nomenclature. Guidelines for Cancer Cytogenetics.
- the bone marrow blasts or blood blasts of primary samples from each patient are analyzed for morphology and differentiation status by cytology.
- Treatment with Compound 1, or a pharmaceutically acceptable salt thereof, (0.5, 1 and 5 ⁇ ) reduces the level of intracellular 2HG levels by 99% relative to DMSO control at the highest dose in patient samples harboring IDHl mutations, and induces differentiation of IDHl mutant (R132H or R132C) patient myeloblast cells as measured by cytology and FACS analysis. No 2HG is measurable in wild-type patient samples.
- the clinical study is a Phase 1, multicenter, open-label, dose-escalation, safety, PK/PD, and clinical activity evaluation of orally administered Compound 1, or a pharmaceutically acceptable salt thereof in subjects with advanced hematologic malignancies, such as AML, MDS, MPN, or CMML), that harbor an IDHl mutation.
- Primary study objectives include 1) assessment of the safety and tolerability of treatment with Compound 1, or a pharmaceutically acceptable salt thereof when administered continuously as a single agent dosed orally twice daily (approximately every 12 hours) on Days 1 to 28 of a 28-day cycle, and 2) determination of the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose of Compound 1, or a pharmaceutically acceptable salt thereof in subjects.
- MTD maximum tolerated dose
- PK pharmacokinetics
- hematologic malignancies such as AML, MDS, MPN, or CMML, that harbor an IDHl mutation.
- Exploratory study objectives include 1) evaluation of changes in Ki67 levels in tumor samples, 2) characterization of the PD effects of Compound 1, or a pharmaceutically acceptable salt thereof, in subjects with advanced hematologic malignancies, such as AML, MDS, MPN, or CMML, that harbor an IDHl mutation by the assessment of changes in the patterns of cellular differentiation of isocitrate dehydrogenase- 1 (IDHl)-mutated tumor cells and changes in histone and deoxyribonucleic acid (DNA) methylation profiles in IDHl -mutated tumor cells, 3) evaluation of gene mutation status, global gene expression profiles, and other potential prognostic markers (cytogenetics) in IDHl -mutated tumor cells, as well as subclonal populations of non-IDHl mutated tumor cells, to explore predictors of anti-tumor activity and/or resistance, and 4) monitoring plasma cholesterol and 4p-OH-cholesterol levels as a potential CYP3A4 induction marker.
- IDHl i
- Compound 1 will be administered orally twice daily (approximately every 12 hours) on Days 1 to 28 in 28-day cycles. If warranted based on the emerging data, an alternative dosing schedule (e.g., once daily or three times daily), including administration of the same total daily dose using different dosing schedules in concurrent cohorts, may be explored.
- Subjects will be dispensed the appropriate number of tablets for 28 days of dosing (plus an additional 2-day supply to allow for scheduling of visits) on Day 1 of each cycle.
- Subjects are to return all unused tablets (or the empty bottles) on Day 1 of each treatment cycle. Subjects will be given a dosing diary for each treatment cycle. They should record relevant information regarding their study drug in the diary (e.g., confirmation that each daily dose was taken, reasons for missed doses). Treatment compliance will be assessed based on return of unused drug and the dosing diary.
- Subjects should be instructed to take their daily dose at approximately the same time each day. Each dose should be taken with a glass of water and consumed over as short a time as possible. Subjects should be instructed to swallow tablets whole and to not chew the tablets. Subjects may take Compound 1, or a pharmaceutically acceptable salt thereof with or without food. If the subject forgets to take the daily morning (or evening) dose, then they should take Compound 1, or a pharmaceutically acceptable salt thereof within 6 hours after the missed dose. If more than 6 hours have elapsed, then that dose should be omitted, and the subject should resume treatment with the next scheduled dose.
- the study includes a dose escalation phase to determine MTD followed by
- the dose escalation phase will utilize a standard "3 + 3" design.
- consented eligible subjects will be enrolled into sequential cohorts of increasing doses of Compound 1, or a pharmaceutically acceptable salt thereof.
- Each dose cohort will plan to enroll a minimum of 3 subjects.
- the first 3 subjects enrolled in each dosing cohort during the dose escalation phase of the study will initially receive a single dose of study drug on Day -3 (i.e., 3 days prior to the start of daily dosing) and undergo PK/PD assessments over 72 hours to evaluate drug concentrations and 2HG levels.
- the next dose of study drug will be on Cycle 1 Day 1 (C1D1) at which time daily dosing will begin.
- the initial dosing regimen will be twice daily (approximately every 12 hours).
- an alternative dosing schedule e.g. , once daily or three times daily, including administration of the same total daily dose using different dosing schedules in concurrent cohorts, may be explored. If there are multiple subjects in the screening process at the time the third subject within a cohort begins treatment, up to 2 additional subjects may be enrolled with approval of the Medical Monitor. For these additional subjects, the Day -3 through Day 1 PK/PD assessments are optional following discussion with the Medical Monitor.
- the planned dose escalation scheme is illustrated in Table 1.
- Compound 1, or a pharmaceutically acceptable salt thereof may be administered twice daily (approximately every 12 hours). If warranted based on the emerging data, an alternative dosing schedule (e.g. , once daily or three times daily), including administration of the same total daily dose using different dosing schedules in concurrent cohorts, may be explored.
- an alternative dosing schedule e.g. , once daily or three times daily, including administration of the same total daily dose using different dosing schedules in concurrent cohorts, may be explored.
- Toxicity severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
- the study will proceed with dose escalation to the next cohort following safety review by the Clinical Study Team. If 1 of 3 subjects experiences a DLT during the first cycle, 3 additional subjects will be enrolled in that cohort. If none of the additional 3 subjects experience a DLT, dose escalation may continue to the next cohort following safety review. If 2 or more subjects in a cohort experience DLTs during the first cycle, dose escalation will be halted and the next lower dose level will be declared the MTD.
- a dose level intermediate between the dose level exceeding MTD and the previous does level may be explored and declared MTD if ⁇ 2 out of 6 patients experience a DLT at that dose. If the MTD cohort includes only 3 subjects, an additional 3 subjects will be enrolled at that dose level to confirm that ⁇ 2 of 6 subjects experience a DLT at that dose.
- Increases in the dose of Compound 1, or a pharmaceutically acceptable salt thereof, for each dose cohort will be guided by an accelerated titration design, where the dose will be doubled (100% increase) from one cohort to the next until Compound 1 -related NCI CTCAE version 4.03 Grade 2 or greater toxicity is observed in any subject within the cohort. Subsequent increases in dose will be guided by the observed toxicity, and potentially PK and PK/PD data, until the MTD is determined. The absolute percent increase in the daily dose will be determined predicated on the type and severity of any toxicity seen in the prior dose cohorts (but will never exceed 100%). If warranted based on the emerging data, an alternative dosing schedule (e.g. , once daily or three times daily) may be explored, including administration of the same total daily dose using different dosing schedules in concurrent cohorts.
- the MTD is the highest dose that causes DLTs in ⁇ 2 of 6 subjects.
- dose escalation may continue for 2 dose levels above the projected maximum biologically effective dose, as determined by an ongoing assessment of PK/PD and any observed clinical activity, to determine the recommended Phase 2 dose.
- intra- subject dose escalation will be permitted.
- 3 or more expansion cohorts (with AML, MDS, MPN, or CMML) of approximately 12 subjects each will be treated at that dose.
- the purpose of the expansion cohorts is to evaluate and confirm the safety and tolerability of the recommended Phase 2 dose in specific disease indications.
- Subjects enrolled in these cohorts will undergo the same procedures as subjects in the dose escalation cohorts with the exception that the Day -3 through Day 1 PK/PD assessments will be optional.
- Screening procedures include medical, surgical, and medication history, confirmation of IDH1 mutation via tumor biopsies or leukemic blasts (if not documented previously), physical examination, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status (PS), 12-lead electrocardiogram (ECG), evaluation of left ventricular ejection fraction (LVEF), clinical laboratory assessments (hematology, chemistry, coagulation, urinalysis, and serum pregnancy test), bone marrow biopsy and aspirate, and blood and urine samples for 2HG measurement; and blood samples for determination of plasma cholesterol and 4p-OH-cholesterol levels.
- ECOG Eastern Cooperative Oncology Group
- PS 12-lead electrocardiogram
- LVEF left ventricular ejection fraction
- clinical laboratory assessments hematology, chemistry, coagulation, urinalysis, and serum pregnancy test
- bone marrow biopsy and aspirate and blood and urine samples for 2HG measurement
- blood samples for determination of plasma cholesterol and 4p-OH-cholesterol levels.
- the first 3 subjects enrolled in each cohort in the dose escalation phase will receive a single dose of Compound 1, or a pharmaceutically acceptable salt thereof in clinic and have serial blood and urine samples obtained for determination of blood and urine concentrations of Compound 1, or a pharmaceutically acceptable salt thereof, its metabolite, and 2HG.
- a full 72-hour PK/PD profile will be conducted: subjects will be required to remain at the study site for 10 hours on Day -3 and return on Days -2, -1, and 1 for 24, 48, and 72 hour samples, respectively.
- Subjects will undergo radiographic evaluations (CT/MRI), and assessment of bone marrow aspirates and biopsies and peripheral blood to assess the extent of disease, at screening, on Day 15, Day 29 and Day 57, and every 56 days thereafter while on study drug treatment, independent of dose delays and/or dose interruptions, and/or at any time when progression of disease is suspected.
- CT/MRI radiographic evaluations
- Two core tumor biopsies will be obtained at screening, at the time of the first assessment of response, and at the time of disease progression within a window of +3 days around the planned assessment time point.
- response to treatment will be determined by the Investigators based on modified International Working Group (r G) response criteria.
- Subjects may continue treatment with Compound 1, or a pharmaceutically acceptable salt thereof until disease progression, occurrence of a DLT, or development of other unacceptable toxicity. All subjects are to undergo an end of treatment assessment (within approximately 5 days of the last dose of study drug); in addition, a follow-up assessment is to be scheduled 28 days after the last dose.
- a patient must meet all of the following inclusion criteria to be enrolled in the clinical study. 1) Subject must be >18 years of age; 2) Subjects must have a) an advanced hematologic malignancy including: i) Relapsed and/or primary refractory AML as defined by World Health Organization (WHO) criteria, ii) untreated AML, >60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor, iii) Myelodysplastic syndrome with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R) (Greenberg et al. Blood.
- WHO World Health Organization
- a pretreatment tumor sample (from blood and/or bone marrow) will be required for all screened subjects for central laboratory biomarker analysis.
- Gene mutation analysis of a tumor sample (from blood or bone marrow) is to be repeated at the End of Treatment visit and submitted to the central laboratory for biomarker analysis; 4) Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study. (The diagnosis and evaluation of AML or MDS can be made by bone marrow aspiration when a core biopsy is unobtainable and/or is not a part of the standard of care.
- a bone marrow biopsy is required in case of dry tap or failure (mainly dilution) with the aspiration.); 5) Subjects or their legal representatives must be able to understand and sign an informed consent; 6) subjects must have ECOG PS of 0 to 2; 7) subjects must have a platelet count >20,000/ ⁇ (Transfusions to achieve this level are allowed.) Subjects with a baseline platelet count of ⁇ 20,000/ ⁇ due to underlying malignancy are eligible with Medical Monitor approval; 8) Subjects must have adequate hepatic function as evidenced by: a) Serum total bilirubin ⁇ 1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic organ involvement, and b) Aspartate aminotransferase, ALT, and alkaline phosphatase (ALP) ⁇ 3.0 x ULN, unless considered due to leukemic organ involvement; 9) Subjects must have adequate renal function as evidenced by a serum creatinine ⁇ 2.0 x
- Subjects with residual Grade 1 toxicity for example Grade 1 peripheral neuropathy or residual alopecia, are allowed with approval of the Medical Monitor.
- Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy.
- Subjects with reproductive potential are defined as one who is biologically capable of becoming pregnant. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of Compound 1, or a pharmaceutically acceptable salt thereof.
- Compound 1, or a pharmaceutically acceptable salt thereof will be provided as 50 and 200 mg strength tablets to be administered orally, twice daily or once daily.
- the first 3 subjects in each cohort in the dose escalation portion of the study will receive a single dose of study drug on Day -3; their next dose of study drug will be administered on ClDl at which time subjects will start dosing twice daily (approximately every 12 hours) on Days 1 to 28 in 28-day cycles. Starting with ClDl, dosing is continuous; there are no inter-cycle rest periods. Subjects who are not required to undergo the Day -3 PK/PD assessments will initiate twice daily dosing (approximately every 12 hours) with Compound 1, or a
- the dose of Compound 1, or a pharmaceutically acceptable salt thereof administered to a subject will be dependent upon which dose cohort is open for enrollment when the subject qualifies for the study.
- the starting dose of Compound 1, or a pharmaceutically acceptable salt thereof to be administered to the first cohort of subjects is 100 mg strength administered orally twice a day (200 mg/day).
- Subjects may continue treatment with Compound 1, or a pharmaceutically acceptable salt thereof until disease progression, occurrence of a DLT, or development of other unacceptable toxicity.
- AEs including determination of DLTs, serious adverse events (SAEs), and AEs leading to discontinuation; safety laboratory parameters; physical examination findings; vital signs; 12-lead ECGs; LVEF; and ECOG PS will be monitored during the clinical study.
- SAEs serious adverse events
- AEs leading to discontinuation safety laboratory parameters
- physical examination findings vital signs
- 12-lead ECGs vital signs
- 12-lead ECGs vital signs
- LVEF LVEF
- ECOG PS ECOG PS
- Compound 1, or a pharmaceutically acceptable salt thereof may cause sensitivity to direct and indirect sunlight.
- the subjects should be warned to avoid direct sun exposure.
- the subject should be instructed to apply factor 30 or higher sunscreen to exposed areas and wear protective clothing and
- Serial blood samples will be evaluated for determination of concentration-time profiles of Compound 1, or a pharmaceutically acceptable salt thereof.
- Urine samples will be evaluated for determination of urinary excretion of Compound 1, or a pharmaceutically acceptable salt thereof.
- Blood, bone marrow, and urine samples will be evaluated for determination of 2HG levels.
- Tumor biopsies will be taken for evaluation of 2HG and Compound 1, or a pharmaceutically acceptable salt thereof.
- Serial blood samples will be drawn before and after dosing with Compound 1, or a pharmaceutically acceptable salt thereof in order to determine circulating plasma concentrations of Compound 1, or a pharmaceutically acceptable salt thereof.
- the blood samples will also be used for the determination of 2HG concentrations and for evaluation of cholesterol and 4 ⁇ - ⁇ - cholesterol levels.
- a single dose of Compound 1, or a pharmaceutically acceptable salt thereof will be administered on Day -3 (i.e., 3 days prior to their scheduled C1D1 dose). Blood samples will be drawn prior to the single-dose administration of Compound 1, or a pharmaceutically acceptable salt thereof and at the following time points after administration: 30 minutes and 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours. After 72 hours of blood sample collection, subjects will begin oral twice daily dosing of Compound 1, or a pharmaceutically acceptable salt thereof (i.e., C1D1).
- the PK/PD profile from Day -3 through Day 1 is optional for additional subjects enrolled in the dose escalation phase (i.e., for any subjects beyond the 3 initial subjects enrolled in a cohort) and is not required for subjects enrolled in the expansion cohorts.
- All subjects will undergo 10-hour PK/PD sampling on C1D15 and C2D1 (i.e., on Days 15 and 29 of twice daily dosing).
- one blood sample will be drawn immediately prior to that day's first dose of Compound 1, or a pharmaceutically acceptable salt thereof (i.e., dosing with Compound 1, or a pharmaceutically acceptable salt thereof will occur at the clinical site); subsequent blood samples will be drawn at the following time points after dosing: 30 minutes, and 1, 2, 3, 4, 6, 8, and 10 hours. Blood samples also will be drawn on Days 8 and 22 of Cycle 1, Day 15 of Cycle 2, Days 1 and 15 of Cycle 3, and Day 1 of each cycle thereafter; all samples will be obtained prior to dosing. Additionally, one blood sample will be drawn at the End of Treatment Visit.
- the timing of blood samples drawn for Compound 1, or a pharmaceutically acceptable salt thereof concentration determination may be changed if the emerging data indicates that an alteration in the sampling scheme is needed to better characterize the PK profile of Compound 1, or a pharmaceutically acceptable salt thereof.
- Serial blood samples will be drawn before and after dosing with Compound 1, or a pharmaceutically acceptable salt thereof in order to determine circulating concentrations of 2HG.
- Samples collected for PK assessments also will be used to assess 2HG levels.
- subjects will have blood drawn for determination of 2HG levels at the screening assessment.
- the timing of blood samples drawn for 2HG concentration determination may be changed if the emerging data indicate that an alteration in the sampling scheme is needed to better characterize the 2HG response to Compound 1, or a pharmaceutically acceptable salt thereof, treatment.
- Urine will be collected for the determination of concentrations of 2HG levels at the screening assessment and prior to dosing on Day 15 of Cycle 1 and on Day 1 of Cycle 2 and every cycle thereafter. At least 20 mL of urine will be collected for each sample.
- the volume of each collection will be measured and recorded and sent to a central laboratory for determination of urinary 2HG concentration. An aliquot from each collection will be analyzed for urinary creatinine concentration.
- Tumor biopsy specimens will be collected and assessed for 2HG levels, at the screening assessment, at the time of the first disease assessment, and at any time disease progression is suspected. A window of +3 days around the planned assessment time point is acceptable for all biopsy samples. Tumor biopsies are to be evaluated for morphology and for cellular
- Tumor samples may also be evaluated for 2HG levels, Ki67 levels, and, if feasible, intra- tumoral Compound 1, or a pharmaceutically acceptable salt thereof, levels.
- Serial blood samples will be drawn to obtain plasma cholesterol and 4p-OH-cholesterol levels as a potential CYP3A4 induction marker. Samples are obtained on Day -3 (within 30 minutes), at 24, 48, and 72 hours (+1 hour), and on Days 8, 15 and 22 of Cycle 1, Days 1 and 15 of Cycles 2 and 3, and Day 1 of every cycle thereafter.
- Serial blood and bone marrow biopsies will be evaluated during the clinical study to determine response to Compound 1, or a pharmaceutically acceptable salt thereof treatment according to the 2006 modified IWG criteria for hematologic malignancies, such as MDS, MDS, MPN or AML (Cheson BD, et al. Blood. 2006;108(2):419-25).
- hematologic malignancies such as MDS, MDS, MPN or AML (Cheson BD, et al. Blood. 2006;108(2):419-25).
- Disease response to treatment will be assessed through the evaluation of bone marrow biopsies and/or aspirates, along with complete blood counts and examination of peripheral blood films. Subjects will have the extent of their disease assessed and recorded at screening, on Days 15, 29, and 57, every 56 days thereafter while on study drug treatment, independent of dose- delays and/or dose interruptions, and/or at any time when progression of disease is suspected. An assessment also will be conducted at the End of Treatment visit for subjects who discontinue the study due to reasons other than disease progression.
- Statistical analyses will be primarily descriptive in nature since the goal of the study is to determine the MTD of Compound 1, or a pharmaceutically acceptable salt thereof. Tabulations will be produced for appropriate disposition, demographic, baseline, safety, PK, PD, and clinical activity parameters and will be presented by dose level and overall. Categorical variables will be summarized by frequency distributions (number and percentages of subjects) and continuous variables will be summarized by descriptive statistics (mean, standard deviation, median, minimum, and maximum).
- Adverse events will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Separate tabulations will be produced for all treatment- emergent AEs (TEAEs), treatment-related AEs (those considered by the Investigator as at least possibly drug related), SAEs, discontinuations due to AEs, and AEs of at least Grade 3 severity. By-subject listings will be provided for deaths, SAEs, DLTs, and AEs leading to discontinuation of treatment.
- TEAEs treatment- emergent AEs
- SAEs discontinuations due to AEs
- AEs of at least Grade 3 severity.
- Descriptive statistics will be provided for clinical laboratory, ECG interval, LVEF, and vital signs data, presented as both actual values and changes from baseline relative to each on- study evaluation and to the last evaluation on study. Shift analyses will be conducted for laboratory parameters and ECOG PS.
- Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population.
- the potential relationship between plasma levels of Compound 1, or a pharmaceutically acceptable salt thereof and blood, plasma or urine 2HG levels will be explored with descriptive and graphical methods.
- Descriptive statistics will be used to summarize Ki67 levels from tumor biopsies.
- Compound 1 had a cellular IC 50 value of 8-20 nM. Reduction in 2HG was observed following a single dose of Compound 1 in an IDHl mutant R132H xenograft model ( Figure 1A). In addition, Compound 1 reduced intracellular 2HG in primary human IDH-mutated blast cells ex vivo ( Figure IB).
- DLT dose limiting toxicity
- AEs include: hypotension 2 (12%), mental status changes 2 (12%), neutropenia 2 (12%). AEs appear typical for this patient population.
- R BBB right bundle branch block
- Figures 2A and 2B shows the PK profile of Compound 1 following oral administration.
- Compound 1 showed high plasma exposure, drug accumulation and half-life of 182 hours.
- the plasma levels of 2HG were reduced to a normal range at all dose levels (up tp 98% inhibition).
- the 2HG baseline was taken at Day -3 pre-treatment 2HG inhibition estimated based on 2HG pre-treatment level and AUCo io hr post treatment.
- 100 mg BID and 300 mg QD Cohorts 3 to 4 patients were measured per time point and for the 500 mg QD Cohort, 1 to 3 patients were measured per time point.
- Marrow CR ⁇ 5% blasts in BM; no hematological recovery
- ORR CR, Marrow CR and PR
- Figures 3A-3C are images of aspirate from a 74 year old female patient who was refractory to induction with 7+3.
- her bone marrow displayed monotonous cellularity, from the preponderance of blast cells.
- the inset shows the appearance of the blast cells on the aspirate.
- the core biopsy showed ongoing hypercellularity, but clear evidence of maturation, as determined by the cells that have varied sizes and shapes, approximating the "field of flowers" appearance of a normal marrow.
- the aspirate no longer shows blast cells, but instead mostly myelocytes, which is evidence of differentiation.
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Abstract
L'invention concerne des composés utiles pour traiter un cancer, et des méthodes de traitement du cancer comprenant l'administration, à un sujet en ayant besoin, d'un composé décrit dans l'invention. La présente invention concerne des méthodes de traitement de tumeurs malignes hématologiques avancées, caractérisées par la présence d'un allèle mutant de IDH1. Dans un mode de réalisation, le mutant IDHI présente une mutation R132X. Dans un mode de réalisation, la mutation R132X est choisie parmi R132H, R132C, R132L, R132V, R132S et R132G. Dans certains modes de réalisation, les tumeurs malignes hématologiques avancées abritent une co-mutation, par exemple une co-mutation choisie parmi NPM1, FLT3, TET2, CEBPA, DNMT3A et MLL. Dans un aspect, la présente invention concerne un procédé d'évaluation d'un sujet, le procédé comprenant : acquérir une valeur pour le taux d'un composé (S)-N-((S)-1-(2-chlorophényl)-2-((3,3<lifluorocyclobutyl)am 5HDXopyrrolidine-2-carboxamide (Composé 1), ou le taux d'un produit de néoactivité alpha-hydroxy, par exemple 2HG, par exemple R-2HG (2HG), chez le sujet.
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US10449184B2 (en) | 2014-03-14 | 2019-10-22 | Agios Pharmaceuticals, Inc. | Pharmaceutical compositions of therapeutically active compounds |
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US10449184B2 (en) | 2014-03-14 | 2019-10-22 | Agios Pharmaceuticals, Inc. | Pharmaceutical compositions of therapeutically active compounds |
US11419859B2 (en) | 2015-10-15 | 2022-08-23 | Servier Pharmaceuticals Llc | Combination therapy for treating malignancies |
US10653710B2 (en) | 2015-10-15 | 2020-05-19 | Agios Pharmaceuticals, Inc. | Combination therapy for treating malignancies |
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US10980788B2 (en) | 2018-06-08 | 2021-04-20 | Agios Pharmaceuticals, Inc. | Therapy for treating malignancies |
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