WO2019062919A1 - Méthode de traitement de la leucémie - Google Patents

Méthode de traitement de la leucémie Download PDF

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WO2019062919A1
WO2019062919A1 PCT/CN2018/108649 CN2018108649W WO2019062919A1 WO 2019062919 A1 WO2019062919 A1 WO 2019062919A1 CN 2018108649 W CN2018108649 W CN 2018108649W WO 2019062919 A1 WO2019062919 A1 WO 2019062919A1
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compound
acute lymphoblastic
lymphoblastic leukemia
pharmaceutical composition
agents
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Richard Bryan LOCK
Jian-Xin Duan
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Childrens Cancer Institute Australia for Medical Research
Ascentawits Pharmaceuticals Ltd
OBI Pharma Inc
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Childrens Cancer Institute Australia for Medical Research
Ascentawits Pharmaceuticals Ltd
OBI Pharma Inc
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    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids

Definitions

  • the present disclosure relates a method for treating Leukemia; particularly for treating Acute Lymphoblastic Leukemia.
  • Aldo-keto reductases are a superfamily of NADPH-dependent oxidoreductases that primarily catalyze the reduction of aldehydes and ketones to their corresponding alcohols (Penning TM and Drury JE. Arch Biochem Biophys. 2007; 464 (2) : 241-250) .
  • AKR family I member C3 (AKR1C3) , is a hydroxysteroid dehydrogenase involved in the synthesis of steroid hormones and prostaglandins (Penning TM. Chem Biol Interact. 2015; 234: 236-246) and is widely expressed in normal human tissues (Penning TM et al. Biochem J.
  • AKR1C3 is also expressed in pediatric and adult ALL, with significantly higher mRNA levels detected in T-ALL than B-ALL (Jamieson SM et al. Biochem Pharmacol. 2014; 88 (1) : 36-45) . Recently, elevated expression and activity of AKR1C3 and other subfamily members were shown in diagnostic samples from pediatric T-ALL patients who went on to respond poorly to treatment when compared to treatment responders, suggesting a relationship between AKR1C3 expression and sensitivity of T-ALL cells to conventional drugs including daunorubicin, vincristine, and L-asparaginase.
  • AKR1C3 activity of AKR1C3 and its subfamily members affects the in vitro sensitivity of primary T-ALL cells and cell lines to vincristine (Bortolozzi R et al. Br J Cancer. 2018; 118 (7) : 985-994) . Therefore, AKR1C3 overexpression in pediatric T-ALL is a potential therapeutic target as well as a possible biomarker for treatment resistance.
  • Leukemia is a kind of cancer resulting from carcinogenesis in bone marrow. Patients bearing leukemia have abnormal white blood cells that are immaturely developed and lack normal functions. Common symptoms of leukemia include bleeding and bruising problems, feeling tired, fever, and an increased risk of infections. Clinically available treatments include chemotherapy, radiation therapy, targeted therapy, and bone marrow transplant. The average five-year survival rate is about 57%in the United States.
  • Acute Lymphoblastic Leukemia also known as Acute Lymphocytic Leukemia, is a rare blood cancer affecting the maturation of B-cell and T-cell lymphoblasts from progenitor cells.
  • Acute Lymphoblastic Leukemia arises from the malignant transformation of B cell progenitors and T cell progenitors are named B-ALL and T-ALL respectively.
  • Subtypes of B-ALL include early pre-B-ALL, common B-ALL (constitutes about 50%of the population) , pre-B-ALL, and mature B-ALL.
  • Subtypes of T-ALL include pre-T-ALL and mature T-ALL. Generally, T-ALL has a better prognosis compared to mature B-ALL. Other types of B-ALL have prognosis that falls in between.
  • ALL The current prevalence of ALL in the US is around 86, 462 cases in 2018. The disease affects primarily children, with 60%of cases occurring at age ⁇ 20 years. The remission rate for pediatric ALL has been high at around 90%, with overall survival at around 60-70%in recent years. However, current treatments for ALL have been less successful for patients with recurrent disease as well as infant and adult patients, leading to an unmet medical need for new treatments.
  • the present disclosure provides a method for treating leukemia.
  • Said method comprises administering a subject in need with an effective amount of a compound having the following Formula I or Formula II:
  • the present disclosure provides pharmaceutical composition for treating leukemia.
  • Said pharmaceutical composition comprises a compound of Formula I, Formula II, or a salt, an isotopic variant, a solvate, or a hydrate of each thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • Figure 1 shows the results of the tolerability study.
  • A The curve of weight of the mice during experiment period.
  • B The median percentage change in weight during experiment period.
  • the arrows indicate OBI-3424 administration.
  • Figure 2 shows the results of the efficacy study of ALL-8 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 3 shows the results of the efficacy study of ALL-27 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 4 shows the results of the efficacy study of ALL-29 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 5 shows the results of the efficacy study of ALL-30 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 6 shows the results of the efficacy study of ALL-31 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 7 shows the results of the efficacy study of ALL-32 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 8 shows the results of the efficacy study of ALL-11/EV PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 9 shows the results of the efficacy study of ALL-11/AKR1C3 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 10 shows the results of the efficacy study of ALL-28 PDX.
  • A The change of the percentage of human CD45 + during experiment period. The arrows indicate OBI-3424 administration.
  • B Percentage of survival during experiment period.
  • Figure 11 shows the results of the organ infiltration study.
  • EV Empty vector
  • AKR1C3 aldo-keto reductase family 1 member C3
  • ALL acute lymphoblastic leukemia.
  • PB peripheral blood
  • SPL spleen
  • Right graphs are samples taken from central (C) and endosteal (E) regions of bone marrow (BM) taken from left (L) and right (R) sides.
  • ALL-8 ALL-27
  • C ALL-29.
  • Figure 12 shows the results of the organ infiltration study.
  • EV Empty vector
  • AKR1C3 aldo-keto reductase family 1 member C3
  • ALL acute lymphoblastic leukemia.
  • Left graphs are samples taken from peripheral blood (PB) , spleen (SPL) .
  • Right graphs are from samples taken from central (C) and endosteal (E) regions of bone marrow (BM) taken from left (L) and right (R) sides.
  • ALL-30 ALL-30
  • ALL-31 ALL-32.
  • Figure 13 shows the results of the organ infiltration study.
  • EV Empty vector
  • AKR1C3 aldo-keto reductase family 1 member C3
  • ALL acute lymphoblastic leukemia.
  • Left graphs are samples taken from peripheral blood (PB) , spleen (SPL) .
  • Right graphs are from samples taken from central (C) and endosteal (E) regions of bone marrow (BM) taken from left (L) and right (R) sides.
  • ALL-28 ALL-11/EV
  • Figure 14 shows the tumor burden growth curve.
  • AST-106 OBI-3424.
  • mpk mg/kg. Arrows represent the time a dose is administered. “ ⁇ ” indicates only dosing for Group 1 and Group 2.
  • Figure 15 shows the anti-tumor efficacy in blood, spleen and bone marrow samples.
  • AST-106 OBI-3424.
  • mpk mg/kg. *P ⁇ 0.05, ***P ⁇ 0.001.
  • Figure 16 shows the in vivo results of the dosage evaluation.
  • ALL-8 ALL-8
  • ALL-31 Left panels show engraftment of each PDX as the %huCD45 + over time.
  • Middle panels show the mouse EFS and right panels show the %huCD45 + of murine bone marrow.
  • BM L left bone marrow
  • BM R right bone marrow. ****P ⁇ 0.0001 comparing OBI-3424 treated and control mice.
  • Figure 17 shows the in vivo results in combination with nelarabine treatment.
  • ALL-8 ALL-8
  • ALL-31 **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001 comparing OBI-3424 treated and control mice.
  • Left panels show engraftment of each PDX as the %huCD45 + over time.
  • Middle panels show the mouse EFS and right panels show the %huCD45 + of murine bone marrow.
  • AKR family I member C3 (AKR1C3) is a hydroxysteroid dehydrogenase involved in the synthesis of steroid hormones and prostaglandins 8 and is over expressed in pediatric and adult ALL.
  • a potential novel therapeutic approach is to exploit the enzymatic activity of AKR1C3 to activate novel prodrugs.
  • OBI-3424 (the Formula I and Formula II compound of the present disclosure) , is a prodrug that is selectively activated by AKR1C3 to a potent DNA alkylating agent.
  • compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the composition or method.
  • Consisting of shall mean excluding more than trace elements of other ingredients for claimed compositions and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention. Accordingly, it is intended that the methods and compositions can include additional steps and components (comprising) or alternatively including steps and compositions of no significance (consisting essentially of) or alternatively, intending only the stated method steps or compositions (consisting of) .
  • optically active and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 10%, no less than about 20%, no less than about 30%, no less than about 40%, no less than about 50%, no less than about 60%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, no less than about 99.8%, or no less than about 99.9%.
  • the enantiomeric excess for an optically or enantiomerically active compound is no less than about 90%, no less than about 95%, no less than about 98%, or no less than about 99%.
  • the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • optically pure and “enantiomerically pure” refer to a collection of molecules, which has an enantiomeric excess (ee) of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, no less than about 99.8%, or no less than about 99.9%.
  • ee enantiomeric excess
  • the enantiomeric excess for an optically or enantiomerically pure compound is no less than about 90%, no less than about 95%, no less than about 98%, or no less than about 99%.
  • An enantiomeric excess of a compound can be determined by any standard methods used by one of ordinary skill in the art, including, but not limited to, chiroptical chromatography (gas chromatography, high-performance liquid chromatography, and thin-layer chromatography) using an optically active stationary phase, isotopic dilution, electrophoresis, calorimetry, polarimetry, NMR resolution methods with chiral derivatization, and NMR methods with a chiral solvating agent or chiral shift reagent.
  • substantially pure and substantially homogeneous mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC) , gel electrophoresis, high performance liquid chromatography (HPLC) , gas chromatography (GC) , nuclear magnetic resonance (NMR) , and mass spectrometry (MS) ; or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • substantially pure or substantially homogeneous refers to a collection of molecules, wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5%by weight of the molecules are a single stereoisomer of a compound, as determined by standard analytical methods.
  • isotopic variant refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such compounds.
  • an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H) , deuterium ( 2 H) , tritium ( 3 H) , carbon-11 ( 11 C) carbon-12 ( 12 C) , carbon-13 ( 13 C) , carbon-14 ( 14 C) , nitrogen-13 ( 13 N) , nitrogen-14 ( 14 N) , nitrogen-15 ( 15 N) , oxygen-14 ( 14 O) , oxygen-15 ( 15 O) , oxygen-16 ( 16 O) , oxygen-17 ( 17 O) , oxygen-18 ( 18 O) , fluorine-17 ( 17 F) , fluorine-18 ( 18 F) , phosphorus-31 ( 31 P) , phosphorus-32 ( 32 P) , phosphorus-33 ( 33 P) , sulfur-32 ( 32 P) , phospho
  • an "isotopic variant" of a compound is in a stable form, that is, non-radioactive.
  • an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H) , deuterium ( 2 H) , carbon-12 ( 12 C) , carbon-13 ( 13 C) , nitrogen-14 ( 14 N) , nitrogen-15 ( 15 N) , oxygen-16 ( 16 O) , oxygen-17 ( 17 O) , oxygen-18 ( 18 O) , fluorine-17 ( 17 F) , phosphorus-31 ( 31 P) , sulfur-32 ( 32 S) , sulfur-33 ( 33 S) , sulfur-34 ( 34 S) , sulfur-36 ( 36 S) , chlorine-35 ( 35 Cl) , chlorine-37 ( 37 Cl) , bromine-79 ( 79 Br) , bromine-81 ( 81 Br) , and iodine-127 ( 127 I) .
  • an "isotopic variant" of a compound is in an unstable form, that is, radioactive.
  • an "isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H) , carbon-11 ( 11 C) , carbon-14 ( 14 C) , nitrogen-13 ( 13 N) , oxygen-14 ( 14 O) , oxygen-15 ( 15 O) , fluorine-18 ( 18 F) , phosphorus-32 ( 32 P) , phosphorus-33 ( 33 P) , sulfur-35 ( 35 S) , chlorine-36 ( 36 Cl) , iodine-123 ( 123 I) , iodine-125 ( 125 I) , iodine-129 ( 129 I) , and iodine-131 ( 131 I) .
  • any hydrogen can be 2 H, for example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, and any oxygen can be 18 O, where feasible according to the judgment of one of skill.
  • an "isotopic variant" of a compound contains unnatural proportions of deuterium.
  • phase “or a salt, an isotopic variant, a solvate, or a hydrate of each thereof” has the same meaning as the phrase “or a salt of the compound referenced therein, an isotopic variant of the compound referenced therein, a solvate of the compound referenced therein, or a hydrate of the compound referenced therein” .
  • administering or “administration of” a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self-administration, and/or indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
  • “Patient, ” “subject, ” and “subject in need” are used interchangeably to refer to a mammal in need of treatment for cancer, particularly leukemia, more particularly T-cell acute lymphoblastic leukemia.
  • the patient is a human.
  • the patient is a human diagnosed with cancer.
  • a “patient, ” “subject, ” or “subject in need” may refer to a non-human mammal used in screening, characterizing, and evaluating drugs and therapies, such as a non-human primate, a dog, cat, rabbit, pig, mouse, or rat.
  • Effective amount used herein is referred to the amount of each active agent required to confer the desired effect on the subject, either alone or in combination with one or more other active agents.
  • An effective amount varies, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any) , the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment.
  • the effective amount is about 0.10 ⁇ g/kg to about 100 mg/kg.
  • Treating, ” “treatment of, ” or “therapy of” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms of cancer; diminishment of extent of disease; delay or slowing of disease progression; amelioration, palliation, or stabilization of the disease state; or other beneficial results.
  • Treatment of cancer may, in some cases, results in partial response or stable disease.
  • “Pharmaceutically acceptable” component means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • Carrier means a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and characteristics of a given compound.
  • Excipient means an inert substance added into a pharmaceutical composition to facilitate administration of a compound.
  • PNA Purine nucleoside analog
  • CAFdA clofarabine
  • nelarabine nelarabine
  • immucillin H BCX-1777, forodesine
  • 8-chloroadenosine 8-Cl-Ado
  • a “combination” refers to combination therapy having an amount of OBI-3424 and/or an amount of other medicines administered together (either as co-administration and/or co-formulation) , either sequentially or simultaneously, on the same or different days during a treatment cycle, has a synergistic effect that is therapeutically effective and more than therapeutically additive.
  • a usable pharmaceutically acceptable carrier, or excipient are disclosed in various references including Handbook of Pharmaceuticals Excipients edited by Raymond C Rowe, Paul J Sheskey, and Marian E Quinn.
  • said pharmaceutically acceptable carrier, or excipient can be selected from the group consisting of inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Said compositions optionally further comprises at least one additional biologically active compound or agent.
  • the pharmaceutical composition might comprise but not limited to a single unit dose of the active ingredient (for instance, the compound of the present disclosure) .
  • a dose unit can be in the form of a discrete article such as but not limited to a tablet or capsule, or can be a measurable volume of a solution, suspension or the like containing a unit dose of the active ingredient.
  • unit dose herein refers to an amount of active ingredient intended for a single but not limited to oral, intravenous, intramuscular, cutaneous, subcutaneous, intrathecal, transdermal, implantation, sublingual, buccal, rectal, vaginal, ocular, otic, nasal, inhalation, or nebulization administration to a subject for treatment such as but not limited to alcohol dependence, opioid dependence, pain relief, or other diseases.
  • the treatment may require periodic administration of unit doses of the compound of the present disclosure, for example one unit dose two or more times a day, one unit dose with each meal, one unit dose every four hours or other interval, or only one unit dose per day.
  • the first aspect of the present disclosure provides a method for treating leukemia comprising administering a subject in need with an effective amount of a compound having the following Formula I or Formula II:
  • said compound has an enantiomeric excess of no less than 80%, no less than 90%, or no less than 95%.
  • said compound is substantially pure.
  • said compound has a purity of at least 50%or at least 90%.
  • said leukemia is acute lymphoblastic leukemia.
  • said acute lymphoblastic leukemia is T-cell acute lymphoblastic leukemia.
  • the method further comprises administering the subject an anti-cancer medicine.
  • the anti-cancer medicine includes but not limited to nelarabine, clofarabine, fludarabine, cladribine, pentostatin, forodesine, 8-chloroadenosine, azathioprine or a combination thereof.
  • administration of OBI-3424 and administration of the anti-cancer medicine can be conducted at any time interval.
  • the time interval is 1 minute, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3weeks, or 1 month.
  • said acute lymphoblastic leukemia is B-cell acute lymphoblastic leukemia.
  • the second aspect of the present disclosure provides a pharmaceutical composition for treating leukemia.
  • Said pharmaceutical composition comprises a compound of above Formula I or Formula II and at least one pharmaceutically acceptable carrier or excipient.
  • said leukemia is acute lymphoblastic leukemia.
  • said acute lymphoblastic leukemia is T-cell acute lymphoblastic leukemia.
  • said acute lymphoblastic leukemia is B-cell acute lymphoblastic leukemia.
  • said pharmaceutical composition is formulated to be administered through oral, intravenous, intramuscular, cutaneous, subcutaneous, intrathecal, transdermal, implantation, sublingual, buccal, rectal, vaginal, ocular, otic, nasal, inhalation, or nebulization administration route.
  • the pharmaceutical composition further comprises an anti-cancer medicine.
  • the anti-cancer medicine includes but not limited to nelarabine, clofarabine, fludarabine, cladribine, pentostatin, forodesine, 8-chloroadenosine, azathioprine or a combination thereof.
  • Another aspect provides a pharmaceutical combination comprising a Formula I or II compound and a second compound having anti-cancer properties or other therapeutic effects.
  • In-vitro cytotoxicity of AKR1C3-associated OBI-3424 was investigated in eleven T-ALL cell lines, one B-ALL cell line transfected with granulocyte-colony stimulating factor, and one BCP-ALL cell line. Expression levels of AKR1C3 protein were determined using western blot analysis. The in vitro cytotoxicity, calculated as 50%maximal inhibitory concentration (IC 50 ) of OBI-3424, was determined using a CellTiter-Glo assay. The properties of OBI-3424 were listed as Table 1.
  • Table 1 The properties of OBI-3424.
  • OBI-3424 displayed in vitro cytotoxicity with an IC 50 range of around 3.0–30.0 nM in six cell lines expressing high (strong) levels of AKR1C3.
  • the IC 50 range was 3.0–84.0 nM (Table 2) .
  • ALL patient-derived xenografts was conducted.
  • the experiment included four B-ALL PDX cell lines, seven T-ALL cell lines, and six ETP-ALL (Early T-cell Precursor Acute Lymphoblastic Leukemia) cell lines.
  • ALL PDX cells were cultured in QBSF medium (Quality Biological Inc., Gaithersburg MD, USA) supplemented with Flt-3 ligand (Bionovus Life Sciences, Cherrybrook, NSW, Australia) or IL-7 (Jomar Life Research, Melbourne, VIC Australia) . Cells were plated according to optimal cell density and incubated for 3 h or overnight (37 °C, 5%CO 2 ) .
  • PDX cells were treated with OBI-3424 or vehicle control for 48 h or 72 h, respectively. Viability was determined using Alamar Blue reduction assay, or Cell Titer-Glo Luminescent Cell Viability Assay (Promega, Madison, WI) . The half-maximal inhibitory concentration (IC 50 ) was calculated by interpolation of non-linear regression curves calculated by Graphpad Prism 7 software.
  • mice were weighed and bled (for biochemistry &hematology markers) weekly to monitor drug toxicity.
  • the mice were treated intraperitoneally once weekly with OBI-3424 at various dosage (0.625, 1.25, 1.875, and 2.5 mg/kg) for 3 weeks.
  • the weight of mice was measured and recorded; the changes in weight were calculated.
  • the results ( Figure 1) showed that the treatment has minimal impact on mouse weight.
  • OBI-3424 was well tolerated, with a toxicity rate of only 2.8%in the drug-treated groups.
  • ALL patient-derived xenografts grew in an orthotopic manner following intravenous inoculation into NSG mice. See Table 5.
  • Mice were bled (IV) weekly to determine %human CD45 + (%huCD45 + ) in the peripheral blood (PB) .
  • Treatment of OBI-3424 (2.5 mg/kg by the intraperitoneal route once weekly for 3 weeks) or vehicle commenced when the %huCD45 + exceeded a median of 1%.
  • An event was defined as the %huCD45 + exceeding 25%or leukemia-related morbidity.
  • Leukemia growth delay (LGD) was calculated as the median EFS of treated mice minus that of control.
  • EFS event free survival
  • the Kaplan-Meier method was used to compare event-free survival (EFS) between treatment (T) and control (C) groups.
  • Stringent objective response measures (ORM) were assigned to each mouse and reported as group medians (Houghton et al, Pediatr Blood Cancer, 2007; 49: 928-40) .
  • the Objective Response categories were progressive disease (PD, which was subdivided into progressive disease without and with growth delay, PD1 and PD2 respectively, defined only for mice in treatment groups) , stable disease (PD) , partial response (PR) , complete response (CR) , and maintained complete response (MCR) . Detailed description thereof was set forth in Table 7.
  • Table 5 ALL patient-derived xenografts (PDXs) mouse model.
  • PDX patient derived xenograft
  • ALL Acute lymphoblastic leukemia
  • T-ALL T-Cell Acute Lymphoblastic Leukemia
  • CR2 Second complete remission
  • CR1 First complete remission
  • BCP-ALL B-Cell Precursor Acute Lymphoblastic Leukemia
  • EV empty vector
  • AKR1C3 Aldo-keto reductase family 1 member C3
  • PDX patient-derived xenograft
  • ALL acute lymphoblastic leukemia
  • T-ALL T-cell acute lymphoblastic leukemia
  • BCP-ALL B-cell precursor acute lymphoblastic leukemia
  • EV empty vector
  • AKR1C3 Aldo-keto reductase family 1 member C3
  • N total number of mice
  • an event was defined as %HuCD45 cells exceeding 25%in PB.
  • Treatment groups with PR, CR, or MCR were considered to have an objective response. Agents inducing objective responses were considered highly active against the tested line, while agents inducing SD or PD2 were considered to have intermediate activity, and agents producing PD1 were considered to have low level of activity against the tested line.
  • T-C Leukemia progression delay
  • EFS T/C EFS tumor growth inhibition rate
  • the BCP-ALL PDX panel which had a lower expression of AKR1C3, had T-C values ranging from 21.2 days to 58.2 days (p ⁇ 0.001) , and EFS T/C values of around 2.5% (p ⁇ 0.001; Table 6) .
  • Each mouse was assigned an ORM as per the PPTC criteria (Tables 7-8) , from which the median was calculated.
  • T-ALL PDXs 5/6 showed objective responses, with 1/6 showing a CR, 4/6 showing a MCR, and 1/6 showing SD.
  • the ALL-27 T-ALL PDX model was contaminated with a mouse-origin lymphoma, so only four mice in this group were used for EFS analyses (Table 8) .
  • BCP-ALL PDXs 1/3 showed CR and 2/3 showed MCR.
  • Table 8 The Objective Response of Nine PDXs mice.
  • Organ infiltration was determined by flow cytometry, and dead cells were excluded using a fixable viability dye. Data were analysed by a Two-way ANOVA coupled with a Tukey’s multiple comparison test. Data are expressed as individual values, with a line indicating the median.
  • 4/6 showed significantly decreased leukemic infiltration of PB, CP, SPL, and BM samples taken from central and endosteal regions of both femurs in mice treated with OBI-3424 compared to the mice treated with the vehicle control.
  • ALL-27 showed significant decreases in leukemic infiltration in PB, CP, and SPL, but no decrease in bone regions.
  • ALL-32 showed no significant decrease in leukemic infiltration.
  • ALL-11/AKR1C3 showed infiltration levels similar to those seen in the T-ALL PDX models.
  • ALL-11/EV only showed significant decreases in infiltration in PB and CP.
  • mice Forty female NOD/SCID mice, impaired T-cell, B-cell, and natural killer cell lymphocyte development, were inoculated via IV injection with 100 ⁇ L saline containing 2 ⁇ 10 6 prepared ALL model AL7473 cells.
  • Mice were divided into 4 treatment groups of 10 mice each one week after tumor inoculation. Groups were treated intravenously with either dextrose 5%in water (D5W) solution as vehicle control (Group 1) , OBI-3424 (coded as AST-106) at 0.5 mg/kg (Group 2) , 1.5 mg/kg (Group 3) , or 4.5 mg/kg (Group 4) weekly for 4 weeks. All mice were sacrificed 6 days after the fourth treatment dose. PB, SPL, and BM were collected and analyzed using HuCD45 + fluorescent-activated cell sorting (FACS) detection.
  • FACS HuCD45 + fluorescent-activated cell sorting
  • OBI-3424 (or vehicle control) was administered at 2.5 mg/kg, 1 mg/kg or 0.5 mg/kg via intraperitoneal (IP) injection once weekly for three weeks.
  • OBI-3424 The single-agent efficacy of OBI-3424 was consistent with that reported above, and OBI-3424 combined with nelarabine significantly enhanced the effects of each single agent alone ( Figure 17A and B left and middle panels) .
  • the criterion for Therapeutic Enhancement (P ⁇ 0.01) of the OBI-3424/nelarabine combination was achieved in ALL-8.
  • the OBI-3424/nelarabine combination also profoundly decreased organ infiltration at Day 28 compared to nelarabine alone or vehicle control ( Figure 17A and B, right panels) .

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Abstract

L'invention concerne une méthode et une composition pour le traitement de la leucémie. La méthode comprend l'administration, à un sujet en ayant besoin, d'une quantité efficace d'un composé nommé OBI-3424 ou OBI-3423. Cette méthode présente une efficacité particulière dans le traitement de la leucémie lymphoblastique aiguë (ALL), y compris la T-ALL et la B-ALL.
PCT/CN2018/108649 2017-09-29 2018-09-29 Méthode de traitement de la leucémie Ceased WO2019062919A1 (fr)

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CN112004799A (zh) * 2019-07-01 2020-11-27 深圳艾欣达伟医药科技有限公司 Akr1c3抑制剂及医药用途
WO2021000862A1 (fr) * 2019-07-01 2021-01-07 深圳艾欣达伟医药科技有限公司 Inhibiteur akr1c3 et utilisation médicale
WO2021008520A1 (fr) * 2019-07-15 2021-01-21 深圳艾欣达伟医药科技有限公司 Préparation d'injection d'ast-3424 stable et procédé de préparation
WO2021083315A1 (fr) * 2019-11-01 2021-05-06 深圳艾欣达伟医药科技有限公司 Médicament sous forme pharmaceutique solide administré par voie orale
WO2021120717A1 (fr) * 2019-12-20 2021-06-24 深圳艾欣达伟医药科技有限公司 Composé anticancéreux et son utilisation médicale
CN113853379A (zh) * 2019-05-13 2021-12-28 深圳艾欣达伟医药科技有限公司 含氟化合物及抗癌医药用途
EP3821884A4 (fr) * 2018-07-09 2022-04-20 Ascentawits Pharmaceuticals, Ltd. Utilisation d'un composé dans un médicament servant à prévenir, à traiter ou à soulager la douleur
WO2022178821A1 (fr) * 2021-02-26 2022-09-01 Ascentawits Pharmaceuticals, Ltd. Utilisation d'un composé activé par akr1c3
WO2022183483A1 (fr) 2021-03-05 2022-09-09 深圳艾欣达伟医药科技有限公司 Composition d'amorce-sonde, kit et procédé de détection
WO2022231580A1 (fr) * 2021-04-28 2022-11-03 Obi Pharma, Inc. Polythérapie faisant appel à un composé activé par akr1c3 avec un inhibiteur de point de contrôle immunitaire
WO2023046060A1 (fr) 2021-09-26 2023-03-30 深圳艾欣达伟医药科技有限公司 Traitement de patients atteints d'un cancer présentant des mutations de kras
CN116249698A (zh) * 2020-09-18 2023-06-09 深圳扬厉医药技术有限公司 异色满类化合物
WO2023174319A1 (fr) 2022-03-15 2023-09-21 深圳艾欣达伟医药科技有限公司 Méthode de traitement d'un patient atteint d'un cancer à mutation de brca
WO2023237080A1 (fr) 2022-06-10 2023-12-14 深圳艾欣达伟医药科技有限公司 Méthode de traitement d'un patient atteint d'un cancer avec promédicament activé par enzyme akr1c3
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WO2024078568A1 (fr) * 2022-10-12 2024-04-18 深圳艾欣达伟医药科技有限公司 Association d'un composé promédicament anticancéreux activé par akr1c3 et d'un médicament analgésique pour le traitement de patients cancéreux présentant une douleur
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WO2022231580A1 (fr) * 2021-04-28 2022-11-03 Obi Pharma, Inc. Polythérapie faisant appel à un composé activé par akr1c3 avec un inhibiteur de point de contrôle immunitaire
WO2023046060A1 (fr) 2021-09-26 2023-03-30 深圳艾欣达伟医药科技有限公司 Traitement de patients atteints d'un cancer présentant des mutations de kras
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WO2023237080A1 (fr) 2022-06-10 2023-12-14 深圳艾欣达伟医药科技有限公司 Méthode de traitement d'un patient atteint d'un cancer avec promédicament activé par enzyme akr1c3
WO2024051792A1 (fr) * 2022-09-09 2024-03-14 深圳艾欣达伟医药科技有限公司 Combinaison ast-3424 pour le traitement de la leucémie et du lymphome
WO2024078568A1 (fr) * 2022-10-12 2024-04-18 深圳艾欣达伟医药科技有限公司 Association d'un composé promédicament anticancéreux activé par akr1c3 et d'un médicament analgésique pour le traitement de patients cancéreux présentant une douleur
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