WO2023049257A1 - Methods for treating triple-negative breast cancer in pre-selected patient populations with a combination of a bet bromodomain inhibitor and a parp inhibitor - Google Patents
Methods for treating triple-negative breast cancer in pre-selected patient populations with a combination of a bet bromodomain inhibitor and a parp inhibitor Download PDFInfo
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- WO2023049257A1 WO2023049257A1 PCT/US2022/044375 US2022044375W WO2023049257A1 WO 2023049257 A1 WO2023049257 A1 WO 2023049257A1 US 2022044375 W US2022044375 W US 2022044375W WO 2023049257 A1 WO2023049257 A1 WO 2023049257A1
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- inhibitor
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- breast cancer
- bet bromodomain
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Classifications
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- 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
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present disclosure relates to the treatment of triple-negative breast cancer in select patient populations with a combination of a poly (ADP-ribose) polymerase (PARP) inhibitor and BET bromodomain inhibitor, such as for example a compound of Formula la or Formula lb or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof.
- a poly (ADP-ribose) polymerase (PARP) inhibitor such as for example a compound of Formula la or Formula lb or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof.
- TNBC Triple-negative breast cancer
- ER estrogen receptor
- PR progesterone receptor
- HER2 human epidermal growth factor receptor 2
- TNBC patients have overall worse prognosis compared with other types of breast cancer with increased likelihood of early distance recurrences and death (Bauer et al. 2007).
- Metastatic disease is marked by a high rate of visceral and central nervous metastases with a median survival of approximately 1 year (Kassam et al. 2009). Novel therapeutic strategies are therefore highly needed. In particular, it is important to identify patient sub-populations that respond significantly better to specific treatments, compared to the response of the overall TNBC patient population.
- TNBC patients with germline BRCA1 and BRCA2 mutations derive benefit from treatment with a class of targeted agents called poly (ADP-ribose) polymerase (PARP) inhibitors that target base-excision repair (a mechanism of DNA repair) and that cause synthetic lethality in tumors with a deficit in a DNA repair mechanism, such as homologous recombination.
- PARP poly (ADP-ribose) polymerase
- FDA Food and Drug Administration
- mTNBC metastatic triple-negative breast cancer
- Table 2 Comparison of data for all TNBC patients with or without a PIK3CA mutation.
- PIK3CA activating mutations are defined as activating mutations in the linker, helical, and kinase domains of PIK3CA or PIK3CG. This effect is even more pronounced in patients that were initially diagnosed with TNBC (Table 3).
- Table 3 Comparing data for patients with TNBC at diagnosis and either with or without a
- Table 4 Patients with TNBC at diagnosis, having an activating RAS/MAPK signaling mutation.
- the present disclosure describes methods of treating specific sub-populations of triple-negative breast cancer patients by co-administration of a BET bromodomain inhibitor and a PARP inhibitor to the patients.
- the present disclosure describes methods of treating specific sub-populations of triple-negative breast cancer patients by coadministration of a BET bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or co-crystal, or hydrate thereof, and a PARP inhibitor to the patients.
- the BET bromodomain inhibitor is administered simultaneously with the PARP inhibitor. In some embodiments, the BET bromodomain inhibitor is administered sequentially with the PARP inhibitor. In some embodiments, the BET bromodomain inhibitor is administered in a single pharmaceutical composition with the PARP inhibitor. In some embodiments, the BET bromodomain inhibitor and the PARP inhibitor are administered in separate compositions.
- the BET bromodomain inhibitor used in the combination therapies of the present disclosure may be a compound of Formula la or Formula lb (Formula la) (Formula lb) or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, wherein: Ring A and Ring B may be optionally substituted with groups independently selected from deuterium, -NH2, amino, heterocycle(C4-Cg), carbocycle(C4-Ce), halogen, -CN, -OH, -CF3, alkyl (Ci-Cg), thioalkyl (Ci-Cg), alkenyl (Ci-Cg), and alkoxy (Ci-Cg);
- X is selected from -NH-, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 O-, -CH 2 CH 2 NH-, -CH 2 CH 2 S-, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -CH 2 C(O)-, -CH 2 CH 2 C(O)-, -C(O)NH-, -C(O)O-, -C(O)S-, -C(O)NHCH 2 -, -C(O)OCH 2 -, and -C(O)SCH 2 -, wherein one or more hydrogen may independently be replaced with deuterium, hydroxyl, methyl, halogen, -CF3, or ketone, and wherein S may be oxidized to sulfoxide or sulfone;
- R4 is selected from optionally substituted 3-7 membered carbocycles and heterocycles.
- Di is selected from the following 5-membered monocyclic heterocycles: which are optionally substituted with deuterium, alkyl (C1-C4), alkoxy (C1-C4), amino, halogen, amide, -CF 3 , -CN, -N 3 , ketone (C1-C4), -S(O)Alkyl(Ci-C 4 ), -SO 2 alkyl(Ci-C 4 ),
- -thioalkyl(Ci-C4), -COOH, and/or ester each of which may be optionally substituted with F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo, and/or thio-oxo.
- the BET bromodomain inhibitor used in the combination therapies of the present disclosure may also be any clinically relevant BET bromodomain inhibitor, including PLX2853, FT-1101, CPI-0610, Molibresib, BMS-986378, BMS-986158, AZD5153/SRA515, INCB057643, BI894999, ABBV-744, and NUV-868.
- the BET bromodomain inhibitor for use in the combination therapies of the present disclosure is a compound of Formula la.
- the compound of Formula la is l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl- lH-imidazo[4,5-b]pyridine-2-amine ("Compound I”), which has the following formula:
- the BET bromodomain inhibitor of Formula la is 1-benzyl- 6-(3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2-amine.
- the BET bromodomain inhibitor of Formula la is a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate of Compound I.
- the BET bromodomain inhibitor of Formula la is a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate of l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2- amine.
- the BET bromodomain inhibitor is a mesylate salt/co-crystal of Compound I in crystalline form I, as described in PCT International Patent Publication WO 2020/053660, which is incorporated herein by reference as related to Compound I Form I.
- the BET bromodomain inhibitor is a mesylate salt/co-crystal of l-benzyl-6- (3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2-amine in crystalline form.
- the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising peak, in terms of 2-theta, at about 16.9 ⁇ 2.0 degrees, as determined on a diffractometer using Cu-Ka radiation tube.
- XRPD X-ray powder diffractogram
- mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising one or more peaks, in terms of 2-theta, at 8.4 ⁇ 0.2,
- the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising of three or more peaks, in terms of 2-theta, at 8.4 ⁇ 0.2, 10.6 ⁇ 0.2, 11.7 ⁇ 0.2, 14.5 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 18.2 ⁇ 0.2, 19.0 ⁇ 0.2, 19.9 ⁇ 0.2, 20.5 ⁇ 0.2, 22.6 ⁇ 0.2, 23.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 27.6 ⁇ 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube.
- XRPD X-ray powder diffractogram
- the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising of six or more peaks, in terms of 2-theta, at 8.4 ⁇ 0.2, 10.6 ⁇ 0.2,
- XRPD X-ray powder diffractogram
- the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising of nine or more peaks, in terms of 2-theta, at 8.4 ⁇ 0.2, 10.6 ⁇ 0.2, 11.7 ⁇ 0.2, 14.5 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 18.2 ⁇ 0.2, 19.0 ⁇ 0.2, 19.9 ⁇ 0.2, 20.5 ⁇ 0.2, 22.6 ⁇ 0.2, 23.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 27.6 ⁇ 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube.
- XRPD X-ray powder diffractogram
- the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising peaks, in terms of 2- theta, at 8.4 ⁇ 0.2, 10.6 ⁇ 0.2, 11.7 ⁇ 0.2, 14.5 ⁇ 0.2, 15.3 ⁇ 0.2, 16.9 ⁇ 0.2, 18.2 ⁇ 0.2, 19.0 ⁇ 0.2, 19.9 ⁇ 0.2, 20.5 ⁇ 0.2, 22.6 ⁇ 0.2, 23.8 ⁇ 0.2, 24.5 ⁇ 0.2, and 27.6 ⁇ 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube.
- XRPD X-ray powder diffractogram
- the mesylate salt/co-crystal of Compound I Form I is characterized by a differential scanning calorimetry (DSC) thermogram pattern with an endothermic peak at a temperature of about 207 ⁇ 0.2 °C.
- DSC differential scanning calorimetry
- the mesylate salt/co-crystal of Compound I Form I is characterized by having been formed using a solvent or mixture of solvents selected from: Ethanol, water, acetone, acetonitrile, 1-butanol, ethyl acetate, isopropyl acetate, 1,4-dioxane, isopropyl alcohol (IPA), methyl ethyl ketone (MEK), methyl iso-butyl ketone (MIBK), n-heptane, methyl tert-butyl ether (MTBE), and dimethylformamide (DMF), using slurries, evaporation, cooling, and precipitation with anti-solvents.
- IPA isopropyl alcohol
- MEK methyl ethyl ketone
- MIBK methyl iso-butyl ketone
- MTBE tert-butyl ether
- DMF dimethylformamide
- FIG. 1 shows a comparison of Progression-Free Survival (PFS) data for patients with TNBC at diagnosis versus patients with a history of hormone receptor positivity.
- PFS Progression-Free Survival
- treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
- treatment refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient.
- treatment or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, or physiologically, e.g., stabilization of a physiological parameter, or both.
- treatment or “treating” refers to delaying the onset of a disease or disorder.
- alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-Cs)alkenyl.
- alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.
- alkoxy refers to an alkyl group attached to an oxygen (-O-alkyl-).
- Alkoxy also include, but are not limited to, an alkenyl group attached to an oxygen (“alkenyloxy”) or an alkynyl group attached to an oxygen (“alkynyloxy”).
- alkenyloxy an alkenyl group attached to an oxygen
- alkynyloxy an alkynyl group attached to an oxygen
- Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl, or alkynyl group of 1-8 carbon atoms, referred to herein as (Ci-Cs)alkoxy.
- Exemplary alkoxy groups include, but are not limited to methoxy and ethoxy.
- alkyl refers to a saturated, straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as (Ci-Cs)al ky I.
- Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl- 3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l- butyl, 2-ethyl-l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
- amide refers to the form -NR a C(O)(R
- the amide can be attached to another group through the carbon, the nitrogen, R
- the amide also may be cyclic, for example, R ⁇ and R c may be joined to form a 3- to 8- membered ring, such as 5- or 6-membered ring.
- amide encompasses groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof.
- amide also encompasses an amide group attached to a carboxy group, e.g., -amide-COOH or salts such as -amide-COONa, or an amino group attached to a carboxy group (e.g., -amino- COOH or salts such as -amino-COONa).
- amine or “amino” as used herein refer to the form -NR ⁇ Rg or -NfRgiJRg-, where R ⁇ and R e are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen.
- the amino can be attached to the parent molecular group through the nitrogen.
- the amino also may be cyclic, for example, any two of R ⁇ and R e may be joined together or with the N to form a 3- to 12-membered ring (e.g., morpholino or piperidinyl).
- amino also includes, but is not limited to, the corresponding quaternary ammonium salt of any amino group.
- exemplary amino groups include, but are not limited to, alkylamino groups, wherein at least one of Rj or R e is an alkyl group.
- Rd and R e each may be optionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.
- aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system.
- the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls.
- the aryl groups of this present disclosure can be substituted with one or more groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
- Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
- Exemplary aryl groups also include, but are not limited to, a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Cgjaryl.”
- arylalkyl refers to an alkyl group having at least one aryl substituent (e.g., -a ryl-al kyl-).
- exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Cg)a ryla I kyl.”
- carbamate refers to the form -RgOC(O)N(Rh)-, -RgOC(O)N(Rh)Rj-, or -OC(O)NR
- Exemplary carbamates include, but are not limited to, arylcarbamates and heteroaryl carbamates (e.g., wherein at least one of Rg, R ⁇ , and Rj are
- -ID- independently selected from aryl and heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).
- carrier refers to an aryl or cycloalkyl group.
- carboxy refers to -COOH or its corresponding carboxylate salts (e.g., -COONa).
- carboxy also includes, but is not limited to, "carboxycarbonyl,” e.g., a carboxy group attached to a carbonyl group, e.g., -C(O)-COOH or salts, such as -C(O)-COONa.
- cycloalkoxy refers to a cycloalkyl group attached to an oxygen.
- cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, referred to herein as "(C3-Cs)cycloalkyl,” derived from a cycloalkane.
- exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
- Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups can be fused to other cycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.
- dicarboxylic acid refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof.
- Exemplary dicarboxylic acids include, but are not limited to, alkyl dicarboxylic acids.
- Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
- Dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid, and terephthalic acid.
- Dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, and hydrazides (for example, succinic anhydride and succinimide).
- esters refers to the structure -C(O)O-, -C(O)O-Rj-, -R ⁇ CfOjO-Rj-, or -R ⁇ CfOjO-, wherein O is not bound to hydrogen, and Rj can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl. can be a hydrogen, but Rj cannot be hydrogen.
- the ester may be cyclic, for example, the carbon atom and Rj, the oxygen atom and R ⁇ , or Rj and R ⁇ may be joined to form a 3- to 12-membered ring.
- Exemplary esters include, but are not limited to, alkyl esters, wherein at least one of Rj or Rk is alkyl, such as -O-C(O)-alkyl-, -C(O)-O-alkyl-, and -a I ky l-C(O)-O-a Ikyl-.
- Exemplary esters also include, but are not limited to, aryl or heteoraryl esters, e.g.
- Rj or Rk is a heteroaryl group, such as, e.g., pyridine, pyridazine, pyrimidine, or pyrazine, such as a nicotinate ester.
- exemplary esters also include, but are not limited to, reverse esters having the structure -RkC(O)O-, where the oxygen is bound to the parent molecule.
- exemplary reverse esters include, but are not limited to, succinate, D-argininate, L-argininate, L-lysinate, and D-lysinate.
- Esters also include, but are not limited to, carboxylic acid anhydrides and acid halides.
- halo or halogen as used herein refer to F, Cl, Br, or I.
- haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
- Haloalkyls also encompass, but are not limited to, alkenyl or alkynyl groups substituted with one or more halogen atoms.
- heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example, 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur.
- Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heteroaryls can also be fused to non-aromatic rings.
- heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
- Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2-Cs)heteroaryl.”
- heterocycle refers to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
- Heterocycles can be aromatic (heteroaryls) or non-aromatic.
- Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
- substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycl
- Heterocycles also include, but are not limited to, bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
- heterocycles include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl
- hydroxyalkyl refers to a hydroxy attached to an alkyl group.
- hydroxyaryl refers to a hydroxy attached to an aryl group.
- ketone refers to the structure -C(O)-R n (such as acetyl, -C(O)CH3) or -R n _C(O)-R o _.
- the ketone can be attached to another group through R n or R o , R n or R o can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl; or R n or R o can be joined to form a 3- to 12-membered ring.
- phenyl refers to a 6-membered carbocyclic aromatic ring.
- the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
- Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
- thioalkyl refers to an alkyl group attached to a sulfur (-S)
- alkyl/' "alkenyl/' "alkynyl,” “alkoxy/' “amino/' and “amide” groups can be optionally substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N.
- the substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.
- a suitable substitution on an optionally substituted substituent refers to a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the present disclosure or the intermediates useful for preparing them.
- suitable substitutions include, but are not limited to: Ci-s alkyl, alkenyl, or alkynyl; Ci-e aryl; C2-5 heteroaryl; C3-7 cycloalkyl; C1-8 alkoxy; Cg aryloxy; -CN; -OH; oxo; halo; carboxy; amino, such as -N H(CI-8 alkyl), -N(Ci-s alkyl)?, -NH((Cg)aryl), or -N((Cg)aryl)2; formyl; ketones, such as -CO2(Ci- s alkyl) and -CO2(Cgaryl) esters, such as -CO2(Ci-s alkyl) and -CO
- composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
- compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
- TNBC triple negative breast cancer
- HR hormone receptor
- PIK3CA pathway activating mutations are defined as activating mutations in
- PIK3CA PIK3CG.
- Activating mutations of the PI3K pathway could include one or more of the following:
- PIK3CA R38C/H, E81K, R88Q, R93Q/W/L, P104L/R, G106V/R/_R108del/C/_N107delinsVS, R108H/L/S/_lll2delinsV, E110del/09K/10_Kllldup, KlllE/N/del/Q/J 112del, R115L/P/Q, G118D, L436_P449dup, V344G/M, N345K/l/Y/T/D/H_V346delinsKG,D350G/N/V, E365K, H419_C420del/L422del, C420R, P447_E453K/Q/_D454del/_T462del, L455del, L452_P458del, E726K, E542K/A/Q/V, E545K/G/Q/
- PIK3CG R26H/C, G92E/K/V, V162I/A, V165I, R184S/C, E279D/Q, R477H, E511D/G, A676T/S, P810A/T/S, R839C/L, R849Q, E880K;
- Activating mutations of the PI3K pathway of interest include C420R, E542K, E545K/A/D/G, Q546R/E, and H1047R/L/Y.
- RAS/MAPK activating mutations are defined as an activating mutation or amplification in either KRAS, HRAS, NRAS (codons 12, 13, 61, etc.) or BRAF, inactivation of NF1, loss of DUSP2 or DUSP4, amplification or overexpression of EGFR, FGFR2, FGFR3, c-KIT, c-MET, PDGFRA, or PDGFRB, increased phosphorylation of ERK1 and/or ERK2 at amino acid residues Thr202/Tyr204 (ERK1) and Thrl85/Tyrl87 (ERK2), increased phosphorylation of MEK1 and/or MEK2 at residues Ser217/Ser221 (MEK1/2) or Ser298 (MEK1).
- KRAS G12D/V/C/A/R/S/F/I/L, G13D/C/V/E/R, Q61H/R/L/K/A/P, K117N/I/R, A146T/V/P;
- NRAS G12D/C/S/V/A/R, G13R/D/S/C/F, Q61R/K/L/H/P;
- GNA11 Q209L/P
- GNAQ R183Q/P, Q209P/L/H;
- GNAS R160C/P, R201H/C/S, Q227K/L/H/E;
- MAP2K1 F53L/C/V, Q56P, K57N/E/T, l99_K104del/X98_splice, E102_ll03del, N109_R113del, C121S, P124L/M/R/S, G128D/V, Y130C/H/N, E203K, S231L;
- MAP2K2 V35M, L46F, R92G/I, R112Q/W, C125S, N126D, E167K, R231C/H, R388Q/W;
- PTPN11 D61Y, E69K/D, A72V/T/G, E76K/G/Q, E123D, V428M, S502L/P;
- RAFI S257L, S259F/P/C, P261R, R282Q;
- ARAF1 S214P/A/F/Y, P216R/L, R255Gfs*37, R297Q/W;
- Fusions and/or overexpression that results in activation of RAS/MAPK signaling EGFR, FGFR2, FGFR3, c-KIT, c-MET, NTRK1, PDGFRA, PDGFRB;
- Proteomics readouts of RAS/MAPK activation phosphorylation of MEK1/2 and/or ERK1/2.
- the present disclosure provides methods of treating TNBC with a combination therapy that includes administration of a BET bromodomain inhibitor and a PARP inhibitor to a subject in need thereof.
- the disclosure provides methods of treating TNBC with a combination therapy that includes administration of a BET bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, and a PARP inhibitor to a subject in need thereof.
- the present disclosure provides a combination therapy comprising a BET bromodomain inhibitor and a PARP inhibitor.
- the present disclosure provides a combination for use in a method for the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET bromodomain inhibitor and a PARP inhibitor.
- the present disclosure provides a combination for use in the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, and a PARP inhibitor.
- the present disclosure provides for the use a combination therapy in a method for the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET bromodomain inhibitor and a PARP inhibitor.
- the present disclosure provides for the use a combination in the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, and a PARP inhibitor.
- the present disclosure provides for the use a BET bromodomain inhibitor and a PARP inhibitor in the manufacture of a combination therapy or a medicament for the treatment of TNBC in a subject in need thereof.
- the present disclosure provides for the use a BET bromodomain inhibitor and a PARP inhibitor in the manufacture of a combination therapy or a medicament for the treatment of TNBC in a subject in need thereof, wherein the BET bromodomain inhibitor is a compound of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof.
- the disclosure provides a method for treating TNBC comprising administrating a BET bromodomain inhibitor of Formula la or Formula lb (Formula la) (Formula lb) or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, together with a second therapeutic agent, wherein:
- Ring A and Ring B may be optionally substituted with groups independently selected from deuterium, -NH2, amino, heterocycle(C4-Cg), carbocycle(C4-Cg), halogen, -CN, -OH, -CF3, alkyl (Ci-Cg), thioalkyl (Ci-Cg), alkenyl (Ci-Cg), and alkoxy (Ci-Cg);
- X is selected from -NH-, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 O-, -CH 2 CH 2 NH-, -CH 2 CH 2 S-, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, -CH 2 C(O)-, -CH 2 CH 2 C(O)-, -C(O)NH-, -C(O)O-, -C(O)S-, -C(O)NHCH 2 -, -C(O)OCH 2 -, and -C(O)SCH 2 -, wherein one or more hydrogen may independently be replaced with deuterium, hydroxyl, methyl, halogen, -CF3, or ketone, and wherein S may be oxidized to sulfoxide or sulfone;
- R4 is selected from optionally substituted 3-7 membered carbocycles and heterocycles.
- Di is selected from the following 5-membered monocyclic heterocycles: which are optionally substituted with deuterium, alkyl (C1-C4), alkoxy (C1-C4), amino, halogen, amide, -CF3, -CN, -N3, ketone (C1-C4), -S(O)Alkyl(Ci-C4), -SO2alkyl(Ci-C4), -thioalkyl(Ci-C4), - COOH, and/or ester, each of which may be optionally substituted with F, Cl, Br, -OH, -NH2, -NHMe, -OMe, -SMe, oxo, and/or thio-oxo.
- the BET bromodomain inhibitor of Formula la or Formula lb is selected from: l-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-lH-imidazo[4,5-b]pyridin-2-amine; l-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-lH-imidazo[4,5-b]pyridin-2-amine;
- the disclosure provides a method for treating triplenegative breast cancer (TNBC) comprising administrating to a subject in need thereof a BET bromodomain inhibitor selected from l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-lH- imidazo[4,5-b]pyridin-2-amine (Compound I), l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-lH- imidazo[4,5-b]pyridin-2-amine, and stereoisomers, tautomers, pharmaceutically acceptable salts, co-crystals, and hydrates thereof, with a PARP inhibitor.
- TNBC triplenegative breast cancer
- the disclosure provides a method for treating triplenegative breast cancer (TNBC) comprising administrating a subject in need thereof a BET bromodomain inhibitor selected from PLX2853, FT-1101, CPI-0610, Molibresib, BMS-986378, BMS-986158, AZD5153/SRA515, INCB057643, BI894999, ABBV-744, and NUV-868 with a PARP inhibitor.
- TNBC triplenegative breast cancer
- the subject does not harbor germline mutations in BRCA1 or BRCA2. In some embodiments, the subject does not harbor germline mutations in one of BRCA1 orBRCA2. In some embodiments, the subject does not harbor germline mutations in BRCA1 andBRCA2.
- the subject was initially diagnosed (i.e., first diagnosed primary breast cancer) with TNBC.
- the subject was initially diagnosed with TNBC and does not have a history of hormone receptor positivity (HR+) (i.e., positive for estrogen receptors (ER+), progesterone receptors (PR+) or both (ER/PR+).
- HR+ hormone receptor positivity
- the subject was initially diagnosed with TNBC and does not have a history of hormone receptor positivity (HR+) that subsequently converted to TNBC.
- the subject does not have any PIK3CA activating mutations.
- the subject has an activating RAS/MAPK signaling mutation.
- the subject was either initially diagnosed with TNBC or did not have a history of hormone receptor positivity (HR+) and lack of a PI3K mutation.
- the PARP inhibitor is talazoparib.
- the BET inhibitor is administered at a dose of 25 mg/day to 200 mg/day. In some embodiments, the BET inhibitor is administered at a dose of 36 mg/day to 144 mg/day. In some embodiments, the BET inhibitor is administered at a dose of 48 mg/day to 96 mg/day. In some embodiments, the BET inhibitor is administered at a dose of 48 mg/day, 60 mg/day, 72 mg/day, or 96 mg/day.
- the BET inhibitor is administered at a dosage level providing an exposure in humans similar to an amount of 25 mg/day to 200 mg/day of the corresponding free base. In some embodiments, the BET inhibitor is administered at a dosage level providing an exposure in humans similar to an amount of 36 mg/day to 144 mg/day of the corresponding free base. In some embodiments, the BET inhibitor is administered at a dosage level providing an exposure in humans similar to an amount of 48 mg/day to 96 mg/day of the corresponding free base.
- the BET inhibitor e.g., Compound I
- the BET inhibitor is administered in combination with 0.25 mg to 1 mg of the PARP inhibitor (e.g., talazoparib).
- the BET inhibitor e.g., Compound I
- the BET inhibitor is administered in combination with 0.50 mg of the PARP inhibitor (e.g., talazoparib).
- the BET inhibitor is administered in combination with 0.75 mg of the PARP inhibitor (e.g., talazoparib).
- 36 to 144 mg of the BET inhibitor is administered in combination with 0.25 mg to 1 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, 36 mg to 144 mg of the BET inhibitor (e.g., Compound I) is administered in combination with 0.50 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, 36 mg to 144 mg of the BET inhibitor (e.g., Compound I) is administered in combination with 0.75 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, 48 mg of the BET inhibitor (e.g., Compound I) is administered in combination with 0.75 mg of the PARP inhibitor (e.g., talazoparib).
- the subject was previously treated with a breast cancer therapy.
- the breast cancer therapy was chemotherapy.
- the breast cancer therapy was immunotherapy.
- the cancer therapy comprises mechanistic target or rapamycin (mTOR) or CDK4/6 inhibitors.
- the cancer therapy comprises immune-oncology agents.
- the cancer therapy comprises tyrosine kinase inhibitors.
- the cancer therapy comprises monoclonal antibodies against CTL4 or VEGF.
- the subject was not a candidate for endocrine based therapy. In some embodiments, the subject has progressed on at least 2 prior endocrine based therapies in the locally advanced or metastatic setting.
- the subject is a human. In some embodiments, the subject is a male or female 18 years or older.
- the PARP inhibitor is selected from olaparib, talazoparib, rucaparib, veliparib, pamiparib, and niraparib.
- the PARP inhibitor is olaparib.
- the subject was previously treated with sacituzumab govitecan.
- the subject has progressed on at least one prior cytotoxic chemotherapy. In some embodiments, the subject has progressed on no more than 3 prior chemotherapy-inclusive regimens for locally advanced or metastatic disease.
- the BET bromodomain inhibitor is Compound I.
- the subject with breast cancer does not carry germline mutations to BRCA1 or BRCA2. In some embodiments, the subject does not harbor germline mutations in BRCA1. In some embodiments, the subject does not harbor germline mutations in BRCA2. In some embodiments, the subject does not harbor germline mutations in BRCA1 andBRCA2.
- the BET bromodomain inhibitor as described herein may be administered concomitantly with the other therapeutic agent.
- Concomitantly means that the BET bromodomain inhibitor as described herein and the other therapeutic agent are administered with a time separation of a few seconds (for example ,15 sec., 30 sec., 45 sec., 60 sec. or less), several minutes (for example, 1 min., 2 min., 5 min. or less, 10 min. or less, 15 min. or less), or 1-12 hours.
- the BET bromodomain inhibitor and the other therapeutic agent may be administered in two or more administrations, and contained in separate compositions or dosage forms, which may be contained in the same or different package or packages.
- a Phase lb/2 study of a BET inhibitor (Compound I) + a PARP inhibitor (talazoparib) in wildtype gBRCAl/2 TNBC patients is ongoing with 51 patients dosed to date (Clinicaltrials.gov: NCT03901469).
- CBR clinical benefit rate + stable disease > 4 months
- TNBC patients enrolled in this study had a median of 3 prior lines of therapy (range 1- 8) including a median of 1 line of therapy in the metastatic setting (range 0-4). Median duration of the immediate last therapy in the metastatic setting was 18.3 weeks (3 - 384 weeks), suggesting rapidly progressing disease upon study entry.
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Abstract
The present disclosure provides methods for treating triple negative breast cancer in a subtype of subjects in need thereof, comprising adminstering to the subjects a BET bromodomain inhibitor in combination with a PARP inhibitor.
Description
METHODS FOR TREATING TRIPLE-NEGATIVE BREAST CANCER IN PRE-SELECTED PATIENT POPULATIONS WITH A COMBINATION OF A BET BROMODOMAIN INHIBITOR AND A PARP INHIBITOR
RELATED APPLICATIONS
[001] This application claims the benefit of: U.S. Provisional Patent Application No. 63/261,527, filed September 23, 2021, entitled "Methods for treating triple-negative breast cancer in pre-selected patient populations with a combination of a BET bromodomain inhibitor and a PARP inhibitor"; and U.S. Provisional Patent Application No. 63/330,034, filed April 12, 2022, entitled "Methods for treating triple-negative breast cancer in pre-selected patient populations with a combination of a BET bromodomain inhibitor and a PARP inhibitor"; the contents of which are each incorporated herein by reference in their entirety.
DISCLOSURE
[002] The present disclosure relates to the treatment of triple-negative breast cancer in select patient populations with a combination of a poly (ADP-ribose) polymerase (PARP) inhibitor and BET bromodomain inhibitor, such as for example a compound of Formula la or Formula lb or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof.
[003] Triple-negative breast cancer (TNBC), generally defined by the lack of expression of estrogen receptor ("ER") and progesterone receptor ("PR"), and the absence of human epidermal growth factor receptor 2 ("HER2") overexpression and amplification, represents about 10-20% of all breast cancers. TNBC patients have overall worse prognosis compared with other types of breast cancer with increased likelihood of early distance recurrences and death (Bauer et al. 2007). Metastatic disease is marked by a high rate of visceral and central nervous metastases with a median survival of approximately 1 year (Kassam et al. 2009). Novel therapeutic strategies are therefore highly needed. In particular, it is important to identify patient sub-populations that respond significantly better to specific treatments, compared to the response of the overall TNBC patient population.
[004] Recent advances in the biology of the disease might offer opportunities to classify this heterogeneous entity into molecular subtypes with distinct drivers (Bareche et al. 2018). In particular, TNBC patients with germline BRCA1 and BRCA2 mutations derive benefit
from treatment with a class of targeted agents called poly (ADP-ribose) polymerase (PARP) inhibitors that target base-excision repair (a mechanism of DNA repair) and that cause synthetic lethality in tumors with a deficit in a DNA repair mechanism, such as homologous recombination. Specifically, two Phase 3 trials that enrolled metastatic breast cancer patients with germline BRCA1 or BRCA2 mutations have reported positive results with PARP inhibitors Olaparib (Robson et al. 2017) and Talazoparib (Litton et al. 2017) versus standard chemotherapy.
[005] Even though the prevalence of BRCA1 and BRCA2 mutations is higher in TNBC patients (up to 24% in some cohorts) (Copson et al. 2018), the majority of patients with TNBC do not carry germline BRCA1 or BRCA2 mutations and would therefore not derive benefit from treatment with a PARP inhibitor (O'Shaughnessy et al. 2014). These patients have limited nonchemotherapy options, and poor prognosis upon progression with a PD-1 immune checkpoint therapy plus chemotherapy regimen. Chemotherapy administered for late line metastatic disease has limited efficacy with an overall response rate (ORR) < 5% and progression free survival (PFS) < 2 months (Bardia et al., 2019). Recently, the U.S. Food and Drug Administration (FDA) approved sacituzumab govitecan for patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease, but this is associated with chemotherapylike adverse events such as significant neutropenia and diarrhea. Regardless, post antibody drug conjugates, there are no current available therapies except chemotherapy and there is a significant need for therapies without cytotoxic side effects.
[006] In an ongoing clinical trial (Clinicaltrials.gov: NCT03901469), TNBC patients whose tumors do not harbor germline mutations in BRCA1/2 were treated with a combination of the BET bromodomain inhibitor (BETi) Compound I and the PARP inhibitor (PARPi) Talazoparib. Although this patient population does not respond to the two therapies as single agents, the clinical data to date from NCT03901469 has shown that the combination of the two therapies is significantly active with an Overall Response Rate (ORR) of 22% and a Clinical Benefit Rate (CBR) of 35% (n=50 evaluated patients) (Table 1).
Table 1: Comparison of all TNBC patients versus patients with TNBC at diagnosis and patients with a prior history of hormone receptor positivity.
*Overall response rates (ORR= complete + partial responses) and Clinical Benefit Rates (CBR = complete + partial responses + stable disease) does not include unconfirmed partial responses. HR- = TNBC at diagnosis; HR+ to TNBC= Patients with a prior history of hormone receptor positivity.
[007] The TNBC patients (HR status <10%) evaluated consisted of both patients that were initially diagnosed with TNBC (HR-) and TNBC patients with a history of hormone receptor positivity (HR+). Surprisingly, patients that were initially diagnosed with TNBC had a significantly higher ORR of 32% and CBR of 44% compared to ORR of 0% and CBR of 18% for patients whose tumors had converted from HR+ breast cancer to TNBC (Table 1). All the confirmed responses were from patients who had TNBC at the time of initial diagnosis and had significantly higher PFS of 17 weeks compared to 10 weeks for HR+ to TNBC patients (HR=0.52; 95% Cl, 0.244-1.109; p=0.1) (FIG. 1).
[008] Further analysis revealed that patients whose tumors do not have PIK3CA activating mutations responded better to the combination therapy compared to patients with PIK3CA activating mutation, as defined by overall response rates, clinical benefit rates, and time on treatment (Table 2).
*Overall response rates (ORR= complete + partial responses) and Clinica Benefit Rates
(CBR = complete + partial responses + stable disease) does not include unconfirmed partial responses.
[009] PIK3CA activating mutations are defined as activating mutations in the linker, helical, and kinase domains of PIK3CA or PIK3CG. This effect is even more pronounced in patients that were initially diagnosed with TNBC (Table 3).
Table 3: Comparing data for patients with TNBC at diagnosis and either with or without a
*Overall response rates (ORR= complete + partial responses) and Clinical Benefit Rates
(CBR = complete + partial responses + stable disease > 4 months) does not include unconfirmed partial responses
[0010] Also, patients initially diagnosed with TNBC and having an activating RAS/MAPK signaling mutation responded well to treatment with the combination therapy in both the group without a PIK3CA mutation and the group with a PIK3CA mutation (Table 4).
*This patient was HR+ at diagnosis. cPR = confirmed partial response, cSD = confirmed stable disease, ncPR = non-confirmed partial response.
[0011] The present disclosure describes methods of treating specific sub-populations of triple-negative breast cancer patients by co-administration of a BET bromodomain inhibitor and a PARP inhibitor to the patients. In some embodiments, the present disclosure describes methods of treating specific sub-populations of triple-negative breast cancer patients by coadministration of a BET bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or co-crystal, or hydrate thereof, and a PARP inhibitor to the patients.
[0012] In some embodiments, the BET bromodomain inhibitor is administered simultaneously with the PARP inhibitor. In some embodiments, the BET bromodomain inhibitor is administered sequentially with the PARP inhibitor. In some embodiments, the BET bromodomain inhibitor is administered in a single pharmaceutical composition with the PARP inhibitor. In some embodiments, the BET bromodomain inhibitor and the PARP inhibitor are administered in separate compositions.
[0013] The BET bromodomain inhibitor used in the combination therapies of the present disclosure may be a compound of Formula la or Formula lb
(Formula la)
(Formula lb) or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, wherein:
Ring A and Ring B may be optionally substituted with groups independently selected from deuterium, -NH2, amino, heterocycle(C4-Cg), carbocycle(C4-Ce), halogen, -CN, -OH, -CF3, alkyl (Ci-Cg), thioalkyl (Ci-Cg), alkenyl (Ci-Cg), and alkoxy (Ci-Cg);
X is selected from -NH-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2NH-, -CH2CH2S-, -C(O)-, -C(O)CH2-, -C(O)CH2CH2-, -CH2C(O)-, -CH2CH2C(O)-, -C(O)NH-, -C(O)O-, -C(O)S-, -C(O)NHCH2-, -C(O)OCH2-, and -C(O)SCH2-, wherein one or more hydrogen may independently be replaced with deuterium, hydroxyl, methyl, halogen, -CF3, or ketone, and wherein S may be oxidized to sulfoxide or sulfone;
R4 is selected from optionally substituted 3-7 membered carbocycles and heterocycles; and
Di is selected from the following 5-membered monocyclic heterocycles:
which are optionally substituted with deuterium, alkyl (C1-C4), alkoxy (C1-C4), amino, halogen, amide, -CF3, -CN, -N3, ketone (C1-C4), -S(O)Alkyl(Ci-C4), -SO2alkyl(Ci-C4),
-thioalkyl(Ci-C4), -COOH, and/or ester, each of which may be optionally substituted with F, Cl, Br, -OH, -NH2, -NHMe, -OMe, -SMe, oxo, and/or thio-oxo.
[0014] The BET bromodomain inhibitor used in the combination therapies of the present disclosure may also be any clinically relevant BET bromodomain inhibitor, including PLX2853, FT-1101, CPI-0610, Molibresib, BMS-986378, BMS-986158, AZD5153/SRA515, INCB057643, BI894999, ABBV-744, and NUV-868.
[0015] In some embodiments, the BET bromodomain inhibitor for use in the combination therapies of the present disclosure is a compound of Formula la. In some embodiments, the compound of Formula la is l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl- lH-imidazo[4,5-b]pyridine-2-amine ("Compound I"), which has the following formula:
[0016] In some embodiment, the BET bromodomain inhibitor of Formula la is 1-benzyl- 6-(3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2-amine. In some embodiments, the
BET bromodomain inhibitor of Formula la is a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate of Compound I. In some embodiments, the BET bromodomain inhibitor of Formula la is a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate of l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2- amine. In some embodiments, the BET bromodomain inhibitor is a mesylate salt/co-crystal of Compound I in crystalline form I, as described in PCT International Patent Publication WO 2020/053660, which is incorporated herein by reference as related to Compound I Form I. In some embodiments, the BET bromodomain inhibitor is a mesylate salt/co-crystal of l-benzyl-6- (3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2-amine in crystalline form.
[0017] In some embodiments, the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising peak, in terms of 2-theta, at about 16.9 ± 2.0 degrees, as determined on a diffractometer using Cu-Ka radiation tube. In some embodiments, mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising one or more peaks, in terms of 2-theta, at 8.4 ± 0.2,
10.6 ± 0.2, 11.7 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 22.6 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, and 27.6 ± 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube. In some embodiments, the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising of three or more peaks, in terms of 2-theta, at 8.4 ± 0.2, 10.6 ± 0.2, 11.7 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 22.6 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, and 27.6 ± 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube. In some embodiments, the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising of six or more peaks, in terms of 2-theta, at 8.4 ± 0.2, 10.6 ± 0.2,
11.7 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 22.6 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, and 27.6 ± 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube. In some embodiments, the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising of nine or more peaks, in terms of 2-theta, at 8.4 ± 0.2, 10.6 ± 0.2, 11.7 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 22.6 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, and 27.6 ± 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube. In some embodiments, the mesylate salt/co-crystal of Compound I Form I is characterized by an X-ray powder diffractogram (XRPD) comprising peaks, in terms of 2- theta, at 8.4 ± 0.2, 10.6 ± 0.2, 11.7 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2,
16.9 ± 0.2, 18.2 ± 0.2, 19.0 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 22.6 ± 0.2, 23.8 ± 0.2, 24.5 ± 0.2, and 27.6 ± 0.2 degrees, as determined on a diffractometer using Cu-Ka radiation tube. In some embodiments, the mesylate salt/co-crystal of Compound I Form I is characterized by a differential scanning calorimetry (DSC) thermogram pattern with an endothermic peak at a temperature of about 207 ± 0.2 °C.
[0018] In some embodiments, the mesylate salt/co-crystal of Compound I Form I is characterized by having been formed using a solvent or mixture of solvents selected from: Ethanol, water, acetone, acetonitrile, 1-butanol, ethyl acetate, isopropyl acetate, 1,4-dioxane, isopropyl alcohol (IPA), methyl ethyl ketone (MEK), methyl iso-butyl ketone (MIBK), n-heptane, methyl tert-butyl ether (MTBE), and dimethylformamide (DMF), using slurries, evaporation, cooling, and precipitation with anti-solvents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 shows a comparison of Progression-Free Survival (PFS) data for patients with TNBC at diagnosis versus patients with a history of hormone receptor positivity.
DEFINITIONS
[0020] The terms "treatment" or "treating" as used herein refer to an amelioration of a disease or disorder, or at least one discernible symptom thereof. In another embodiment, "treatment" or "treating" refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient. In yet another embodiment, "treatment" or "treating" refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, or physiologically, e.g., stabilization of a physiological parameter, or both. In yet another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder.
[0021] The terms "optional" or "optionally," as used herein mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable.
[0022] The term "hydrate" as used herein refers to a crystal form with either a stoichiometric or non-stoichiometric amount of water incorporated into the crystal structure.
[0023] The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-Cs)alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.
[0024] The term "alkoxy" as used herein refers to an alkyl group attached to an oxygen (-O-alkyl-). "Alkoxy" groups also include, but are not limited to, an alkenyl group attached to an oxygen ("alkenyloxy") or an alkynyl group attached to an oxygen ("alkynyloxy"). Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl, or alkynyl group of 1-8 carbon atoms, referred to herein as (Ci-Cs)alkoxy. Exemplary alkoxy groups include, but are not limited to methoxy and ethoxy.
[0025] The term "alkyl" as used herein refers to a saturated, straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as (Ci-Cs)al ky I. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl- 3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l- butyl, 2-ethyl-l-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
[0026] The term "amide" as used herein refers to the form -NRaC(O)(R|j)- or -CfOjNRijRj-, wherein Ra, R|j, and Rc are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amide can be attached to another group through the carbon, the nitrogen, R|j, or Rc. The amide also may be cyclic, for example, R^ and Rc may be joined to form a 3- to 8- membered ring, such as 5- or 6-membered ring. The term "amide" encompasses groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof. The term "amide" also encompasses an amide group attached to a carboxy group, e.g., -amide-COOH or salts such as -amide-COONa, or an amino group attached to a carboxy group (e.g., -amino- COOH or salts such as -amino-COONa).
10027] The terms "amine" or "amino" as used herein refer to the form -NR^Rg or -NfRgiJRg-, where R^ and Re are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen. The amino can be attached to the parent molecular group through the nitrogen. The amino also may be cyclic, for example, any two of R^ and Re may be joined together or with the N to form a 3- to 12-membered ring (e.g., morpholino or piperidinyl). The term amino also includes, but is not limited to, the corresponding quaternary ammonium salt of any amino group. Exemplary amino groups include, but are not limited to, alkylamino groups, wherein at least one of Rj or Re is an alkyl group. In some embodiments, Rd and Re each may be optionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.
[0028] The term "aryl" as used herein refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system. The aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls. The aryl groups of this present disclosure can be substituted with one or more groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Cgjaryl."
[0029] The term "arylalkyl" as used herein refers to an alkyl group having at least one aryl substituent (e.g., -a ryl-al kyl-). Exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Cg)a ryla I kyl."
[0030] The term "carbamate" as used herein refers to the form -RgOC(O)N(Rh)-, -RgOC(O)N(Rh)Rj-, or -OC(O)NR|-|Rj, wherein Rg, R^, and Rj are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates and heteroaryl carbamates (e.g., wherein at least one of Rg, R^, and Rj are
-ID-
independently selected from aryl and heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).
[0031] The term "carbocycle" as used herein refers to an aryl or cycloalkyl group.
[0032] The term "carboxy" as used herein refers to -COOH or its corresponding carboxylate salts (e.g., -COONa). The term carboxy also includes, but is not limited to, "carboxycarbonyl," e.g., a carboxy group attached to a carbonyl group, e.g., -C(O)-COOH or salts, such as -C(O)-COONa.
[0033] The term "cycloalkoxy" as used herein refers to a cycloalkyl group attached to an oxygen.
[0034] The term "cycloalkyl" as used herein refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, referred to herein as "(C3-Cs)cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups can be fused to other cycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.
[0035] The term "dicarboxylic acid" as used herein refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylic acids include, but are not limited to, alkyl dicarboxylic acids. Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid, and terephthalic acid. Dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, and hydrazides (for example, succinic anhydride and succinimide).
[0036] The term "ester" as used herein refers to the structure -C(O)O-, -C(O)O-Rj-, -R^CfOjO-Rj-, or -R^CfOjO-, wherein O is not bound to hydrogen, and Rj
can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl.
can be a hydrogen, but Rj cannot be hydrogen. The ester may be cyclic, for example, the carbon atom and Rj, the oxygen atom and R^, or Rj and R^ may be joined to form a 3- to 12-membered ring. Exemplary esters include, but are not limited to, alkyl esters, wherein at least one of Rj or Rk is alkyl, such as -O-C(O)-alkyl-, -C(O)-O-alkyl-, and -a I ky l-C(O)-O-a Ikyl-. Exemplary esters also include, but are not limited to, aryl or heteoraryl esters, e.g. wherein at least one of Rj or Rk is a heteroaryl group, such as, e.g., pyridine, pyridazine, pyrimidine, or pyrazine, such as a nicotinate ester. Exemplary esters also include, but are not limited to, reverse esters having the structure -RkC(O)O-, where the oxygen is bound to the parent molecule. Exemplary reverse esters include, but are not limited to, succinate, D-argininate, L-argininate, L-lysinate, and D-lysinate. Esters also include, but are not limited to, carboxylic acid anhydrides and acid halides.
[0037] The terms "halo" or "halogen" as used herein refer to F, Cl, Br, or I.
[0038] The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms. "Haloalkyls" also encompass, but are not limited to, alkenyl or alkynyl groups substituted with one or more halogen atoms.
[0039] The term "heteroaryl" as used herein refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example, 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heteroaryls can also be fused to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2-Cs)heteroaryl."
[0040] The terms "heterocycle," "heterocyclyl," or "heterocyclic" as used herein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heterocycles can be
aromatic (heteroaryls) or non-aromatic. Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Heterocycles also include, but are not limited to, bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles. Exemplary heterocycles include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.
[0041] The terms "hydroxy" and "hydroxyl" as used herein refer to -OH.
[0042] The term "hydroxyalkyl" as used herein refers to a hydroxy attached to an alkyl group.
[0043] The term "hydroxyaryl" as used herein refers to a hydroxy attached to an aryl group.
[0044] The term "ketone" as used herein refers to the structure -C(O)-Rn (such as acetyl, -C(O)CH3) or -Rn_C(O)-Ro_. The ketone can be attached to another group through Rn or Ro, Rn or Ro can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl; or Rn or Ro can be joined to form a 3- to 12-membered ring.
[0045] The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. The phenyl group can also be fused to a cyclohexane or cyclopentane ring. Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
[0046] The term "thioalkyl" as used herein refers to an alkyl group attached to a sulfur (-S-alkyl-).
[0047] "Alkyl/' "alkenyl/' "alkynyl," "alkoxy/' "amino/' and "amide" groups can be optionally substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N. The substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.
[0048] As used herein, a suitable substitution on an optionally substituted substituent refers to a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the present disclosure or the intermediates useful for preparing them. Examples of suitable substitutions include, but are not limited to: Ci-s alkyl, alkenyl, or alkynyl; Ci-e aryl; C2-5 heteroaryl; C3-7 cycloalkyl; C1-8 alkoxy; Cg aryloxy; -CN; -OH; oxo; halo; carboxy; amino, such as -N H(CI-8 alkyl), -N(Ci-s alkyl)?, -NH((Cg)aryl), or -N((Cg)aryl)2; formyl; ketones, such as -CO2(Ci- s alkyl) and -CO2(Cgaryl) esters, such as -CO2(Ci-s alkyl) and -CO2(Cgaryl). One of skill in art can readily choose a suitable substitution based on the stability and pharmacological and synthetic activity of the compounds of the present disclosure.
[0049] The term "pharmaceutically acceptable composition" as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
[0050] The term "pharmaceutically acceptable carrier" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
[0051] The term "triple negative breast cancer" or "TNBC" is used herein to refer to breast cancer that is characterized by the lack of both estrogen and progesterone receptors and is not characterized by overexpression or gene amplification of HER2 (Dawood 2010). For TNBC the hormone receptor (HR) positivity status is <1% (Allison et al. 2020).
[0052] PIK3CA pathway activating mutations are defined as activating mutations in
PIK3CA or PIK3CG. Activating mutations of the PI3K pathway could include one or more of the following:
PIK3CA: R38C/H, E81K, R88Q, R93Q/W/L, P104L/R, G106V/R/_R108del/C/_N107delinsVS, R108H/L/S/_lll2delinsV, E110del/09K/10_Kllldup, KlllE/N/del/Q/J 112del, R115L/P/Q, G118D, L436_P449dup, V344G/M, N345K/l/Y/T/D/H_V346delinsKG,D350G/N/V, E365K, H419_C420del/L422del, C420R, P447_E453K/Q/_D454del/_T462del, L455del, L452_P458del, E726K, E542K/A/Q/V, E545K/G/Q/A/D, Q546K/P/R/H/E_Q546delinsDK, E726K, K733R, C901F, E970K, M1004I, G1007R/D, Y1021C/H, M1043I/V/L/T, N1044K, H1047R/L/Y/Q, H1048delinsRR, G1049R/A, H1065Y;
PIK3CG: R26H/C, G92E/K/V, V162I/A, V165I, R184S/C, E279D/Q, R477H, E511D/G, A676T/S, P810A/T/S, R839C/L, R849Q, E880K;
[0053] Activating mutations of the PI3K pathway of interest include C420R, E542K, E545K/A/D/G, Q546R/E, and H1047R/L/Y.
[0054] RAS/MAPK activating mutations are defined as an activating mutation or amplification in either KRAS, HRAS, NRAS (codons 12, 13, 61, etc.) or BRAF, inactivation of NF1, loss of DUSP2 or DUSP4, amplification or overexpression of EGFR, FGFR2, FGFR3, c-KIT, c-MET, PDGFRA, or PDGFRB, increased phosphorylation of ERK1 and/or ERK2 at amino acid residues Thr202/Tyr204 (ERK1) and Thrl85/Tyrl87 (ERK2), increased phosphorylation of MEK1 and/or MEK2 at residues Ser217/Ser221 (MEK1/2) or Ser298 (MEK1).
[0055] Examples of mutations that can activate the RAS/MAPK pathway:
KRAS: G12D/V/C/A/R/S/F/I/L, G13D/C/V/E/R, Q61H/R/L/K/A/P, K117N/I/R, A146T/V/P;
HRAS: G12D/S/V/N, G13R/V/D/C/N/S, Q61R/K/L;
NRAS: G12D/C/S/V/A/R, G13R/D/S/C/F, Q61R/K/L/H/P;
BRAF: G464V/E/R, G466E/V/A, G469A/R/V/E/S, N581S/N581l/X581_splice/N581D/N581Y, D594N/G/V/E/Y, V600E/K/R/_K601delinsE, K601E/N/_S602delinsNT;
GNA11: Q209L/P;
GNAQ: R183Q/P, Q209P/L/H;
GNAS: R160C/P, R201H/C/S, Q227K/L/H/E;
MAP2K1: F53L/C/V, Q56P, K57N/E/T, l99_K104del/X98_splice, E102_ll03del, N109_R113del, C121S, P124L/M/R/S, G128D/V, Y130C/H/N, E203K, S231L;
MAP2K2: V35M, L46F, R92G/I, R112Q/W, C125S, N126D, E167K, R231C/H, R388Q/W;
PTPN11: D61Y, E69K/D, A72V/T/G, E76K/G/Q, E123D, V428M, S502L/P;
RAFI: S257L, S259F/P/C, P261R, R282Q;
ARAF1: S214P/A/F/Y, P216R/L, R255Gfs*37, R297Q/W;
DUSP2, DUSP4, GNA11, GNAQ, GNAS, KDM6A, MAP2K4, NF1, RASA1, SMAD4, SPRED1, SPRED2: mutations and/or genomic alterations that are predicted to result in their loss of function;
Fusions and/or overexpression that results in activation of RAS/MAPK signaling: EGFR, FGFR2, FGFR3, c-KIT, c-MET, NTRK1, PDGFRA, PDGFRB;
Proteomics readouts of RAS/MAPK activation: phosphorylation of MEK1/2 and/or ERK1/2.
EXEMPLARY EMBODIMENTS
[0056] As summarized above, the present disclosure provides methods of treating TNBC with a combination therapy that includes administration of a BET bromodomain inhibitor and a PARP inhibitor to a subject in need thereof.
[0057] In some embodiments, the disclosure provides methods of treating TNBC with a combination therapy that includes administration of a BET bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, and a PARP inhibitor to a subject in need thereof.
[0058] In some embodiments, the present disclosure provides a combination therapy comprising a BET bromodomain inhibitor and a PARP inhibitor. In some embodiments, the present disclosure provides a combination for use in a method for the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET bromodomain inhibitor and a PARP inhibitor. In some embodiments, the present disclosure provides a combination for use in the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, and a PARP inhibitor.
[0059] In some embodiments, the present disclosure provides for the use a combination therapy in a method for the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET bromodomain inhibitor and a PARP inhibitor. In some embodiments, the present disclosure provides for the use a combination in the treatment of TNBC in a subject in need thereof, wherein the combination comprises a BET
bromodomain inhibitor of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, and a PARP inhibitor.
[0060] In some embodiments, the present disclosure provides for the use a BET bromodomain inhibitor and a PARP inhibitor in the manufacture of a combination therapy or a medicament for the treatment of TNBC in a subject in need thereof. In some embodiments, the present disclosure provides for the use a BET bromodomain inhibitor and a PARP inhibitor in the manufacture of a combination therapy or a medicament for the treatment of TNBC in a subject in need thereof, wherein the BET bromodomain inhibitor is a compound of Formula la or Formula lb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof.
[0061] In some embodiments, the disclosure provides a method for treating TNBC comprising administrating a BET bromodomain inhibitor of Formula la or Formula lb
(Formula la)
(Formula lb) or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof, together with a second therapeutic agent, wherein:
Ring A and Ring B may be optionally substituted with groups independently selected from deuterium, -NH2, amino, heterocycle(C4-Cg), carbocycle(C4-Cg), halogen, -CN, -OH, -CF3, alkyl (Ci-Cg), thioalkyl (Ci-Cg), alkenyl (Ci-Cg), and alkoxy (Ci-Cg);
X is selected from -NH-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2O-, -CH2CH2NH-, -CH2CH2S-, -C(O)-, -C(O)CH2-, -C(O)CH2CH2-, -CH2C(O)-, -CH2CH2C(O)-, -C(O)NH-, -C(O)O-, -C(O)S-, -C(O)NHCH2-, -C(O)OCH2-, and -C(O)SCH2-, wherein one or more hydrogen may independently be replaced with deuterium, hydroxyl, methyl, halogen, -CF3, or ketone, and wherein S may be oxidized to sulfoxide or sulfone;
R4 is selected from optionally substituted 3-7 membered carbocycles and heterocycles; and
Di is selected from the following 5-membered monocyclic heterocycles:
which are optionally substituted with deuterium, alkyl (C1-C4), alkoxy (C1-C4), amino, halogen, amide, -CF3, -CN, -N3, ketone (C1-C4), -S(O)Alkyl(Ci-C4), -SO2alkyl(Ci-C4), -thioalkyl(Ci-C4), - COOH, and/or ester, each of which may be optionally substituted with F, Cl, Br, -OH, -NH2, -NHMe, -OMe, -SMe, oxo, and/or thio-oxo.
[0062] Compounds of Formula la and lb, including Compound I, have been previously described in PCT International Patent Publication WO 2015/002754, which is incorporated herein by reference in its entirety, including its description of the compounds of Formula la and Formula lb, such as Compound I, their syntheses, and the demonstration of their BET bromodomain inhibitor activity.
[0063] In some embodiments, the BET bromodomain inhibitor of Formula la or Formula lb is selected from: l-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-lH-imidazo[4,5-b]pyridin-2-amine; l-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-lH-imidazo[4,5-b]pyridin-2-amine;
N,l-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b] pyridin-2-amine; l-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)-lH-imidazo[4,5-b]pyridin- 2-amine;
4-(l-Benzyl-2-(pyrrolidin-l-yl)-lH-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;
4-(2-(Azetidin-l-yl)-l-(cyclopentylmethyl)-lH-imidazo[4,5-b] pyridin-6-yl)-3,5- dimethylisoxazole; l-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2-amine; l-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-lH- imidazo[4,5-b] pyridin-2-amine;
4-Amino-l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-lH-benzo[d]imidazol-2(3H)-one;
4-Amino-6-(3,5-dimethylisoxazol-4-yl)-l-(4-methoxybenzyl)-lH-benzo[d]imidazol-2(3H)- one;
4-Amino-6-(3,5-dimethylisoxazol-4-yl)-l-(l-phenylethyl)-lH-benzo[d]imidazol-2(3H)- one; and
4-Amino-l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-lH-benzo[d]imidazol-2(3H)- one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, co-crystal, or hydrate thereof.
[0064] In some embodiments, the disclosure provides a method for treating triplenegative breast cancer (TNBC) comprising administrating to a subject in need thereof a BET bromodomain inhibitor selected from l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-lH- imidazo[4,5-b]pyridin-2-amine (Compound I), l-benzyl-6-(3,5-dimethylisoxazol-4-yl)-lH- imidazo[4,5-b]pyridin-2-amine, and stereoisomers, tautomers, pharmaceutically acceptable salts, co-crystals, and hydrates thereof, with a PARP inhibitor.
[0065] In some embodiments, the disclosure provides a method for treating triplenegative breast cancer (TNBC) comprising administrating a subject in need thereof a BET bromodomain inhibitor selected from PLX2853, FT-1101, CPI-0610, Molibresib, BMS-986378, BMS-986158, AZD5153/SRA515, INCB057643, BI894999, ABBV-744, and NUV-868 with a PARP inhibitor.
[0066] In some embodiments, the subject does not harbor germline mutations in BRCA1 or BRCA2. In some embodiments, the subject does not harbor germline mutations in one of BRCA1 orBRCA2. In some embodiments, the subject does not harbor germline mutations in BRCA1 andBRCA2.
[0067] In some embodiments, the subject was initially diagnosed (i.e., first diagnosed primary breast cancer) with TNBC.
[0068] In some embodiments, the subject was initially diagnosed with TNBC and does not have a history of hormone receptor positivity (HR+) (i.e., positive for estrogen receptors (ER+), progesterone receptors (PR+) or both (ER/PR+). In some embodiments, the subject was initially diagnosed with TNBC and does not have a history of hormone receptor positivity (HR+) that subsequently converted to TNBC.
[0069] In some embodiments, the subject does not have any PIK3CA activating mutations.
[0070] In some embodiments, the subject has an activating RAS/MAPK signaling mutation.
[0071] In some embodiments, the subject was either initially diagnosed with TNBC or did not have a history of hormone receptor positivity (HR+) and lack of a PI3K mutation.
[0072] In some embodiments, the PARP inhibitor is talazoparib.
[0073] In some embodiments, the BET inhibitor is administered at a dose of 25 mg/day to 200 mg/day. In some embodiments, the BET inhibitor is administered at a dose of 36 mg/day to 144 mg/day. In some embodiments, the BET inhibitor is administered at a dose of 48 mg/day to 96 mg/day. In some embodiments, the BET inhibitor is administered at a dose of 48 mg/day, 60 mg/day, 72 mg/day, or 96 mg/day.
[0074] In some embodiments, the BET inhibitor is administered at a dosage level providing an exposure in humans similar to an amount of 25 mg/day to 200 mg/day of the corresponding free base. In some embodiments, the BET inhibitor is administered at a dosage level providing an exposure in humans similar to an amount of 36 mg/day to 144 mg/day of the corresponding free base. In some embodiments, the BET inhibitor is administered at a dosage level providing an exposure in humans similar to an amount of 48 mg/day to 96 mg/day of the corresponding free base.
[0075] In some embodiments, the BET inhibitor (e.g., Compound I) is administered in combination with 0.25 mg to 1 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, the BET inhibitor (e.g., Compound I) is administered in combination with 0.50 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, the BET inhibitor (e.g., Compound I) is administered in combination with 0.75 mg of the PARP inhibitor (e.g., talazoparib).
[0076] In some embodiments, 36 to 144 mg of the BET inhibitor (e.g., Compound I) is administered in combination with 0.25 mg to 1 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, 36 mg to 144 mg of the BET inhibitor (e.g., Compound I) is administered in combination with 0.50 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, 36 mg to 144 mg of the BET inhibitor (e.g., Compound I) is administered in combination with 0.75 mg of the PARP inhibitor (e.g., talazoparib). In some embodiments, 48 mg of the BET inhibitor (e.g., Compound I) is administered in combination with 0.75 mg of the PARP inhibitor (e.g., talazoparib).
[0077] In some embodiments, the subject was previously treated with a breast cancer therapy.
[0078] In some embodiments, the breast cancer therapy was chemotherapy.
[0079] In some embodiments, the breast cancer therapy was immunotherapy.
[0080] In some embodiments, the cancer therapy comprises mechanistic target or rapamycin (mTOR) or CDK4/6 inhibitors. In some embodiments, the cancer therapy comprises immune-oncology agents. In some embodiments, the cancer therapy comprises tyrosine kinase inhibitors. In some embodiments, the cancer therapy comprises monoclonal antibodies against CTL4 or VEGF.
[0081] In some embodiments, the subject was not a candidate for endocrine based therapy. In some embodiments, the subject has progressed on at least 2 prior endocrine based therapies in the locally advanced or metastatic setting.
[0082] In some embodiments, the subject is a human. In some embodiments, the subject is a male or female 18 years or older.
[0083] In some embodiments, the PARP inhibitor is selected from olaparib, talazoparib, rucaparib, veliparib, pamiparib, and niraparib.
[0084] In some embodiments, the PARP inhibitor is olaparib.
[0085] In some embodiments, the subject was previously treated with sacituzumab govitecan.
[0086] In some embodiments, the subject has progressed on at least one prior cytotoxic chemotherapy. In some embodiments, the subject has progressed on no more than 3 prior chemotherapy-inclusive regimens for locally advanced or metastatic disease.
[0087] In some embodiments, the BET bromodomain inhibitor is Compound I.
[0088] In some embodiments, the subject with breast cancer does not carry germline mutations to BRCA1 or BRCA2. In some embodiments, the subject does not harbor germline mutations in BRCA1. In some embodiments, the subject does not harbor germline mutations in BRCA2. In some embodiments, the subject does not harbor germline mutations in BRCA1 andBRCA2.
[0089] In some embodiments, the BET bromodomain inhibitor as described herein may be administered concomitantly with the other therapeutic agent. Concomitantly means that the BET bromodomain inhibitor as described herein and the other therapeutic agent are administered with a time separation of a few seconds (for example ,15 sec., 30 sec., 45 sec., 60 sec. or less), several minutes (for example, 1 min., 2 min., 5 min. or less, 10 min. or less, 15 min. or less), or 1-12 hours. When administered concomitantly, the BET bromodomain inhibitor and the other therapeutic agent may be administered in two or more administrations, and contained
in separate compositions or dosage forms, which may be contained in the same or different package or packages.
REFERENCES
Allison, K. H. et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38, 1346-1366, doi:10.1200/jco,19.02309 (2020).
Bardia, A. et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. New England Journal of Medicine 384, 1529-1541, doi:10.1056/NEJMoa2028485 (2021).
Bareche Y, Venet D, Ignatiadis M, Aftimos P, Piccart M, Rothe F, Sotiriou C. Unravelling triplenegative breast cancer molecular heterogeneity using an integrative multiomic analysis. Ann Oncol. 2018 Jan 22
Bauer, KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER) negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007 May l;109(9):1721-8
Copson ER, Maishman TC, Tapper WJ, Cutress Rl, Greville-Heygate S, Altman DG, Eccles B, Gerty S, Durcan LT, Jones L, Evans DG, Thompson AM, Pharoah P, Easton DF, Dunning AM, Hanby A, Lakhani S, Eeles R, Gilbert FJ, Hamed H, Hodgson S, Simmonds P, Stanton L, Eccles DM. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018 Feb;19(2):169-180. doi: 10.1016/51470-2045(17)30891-4
Kassam F, Enright K, Dent R, Dranitsaris G, Myers J, Flynn C, Fralick M, Kumar R, Clemons M. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009 Feb;9(l):29-33
Litton J, Rugo HS, Ettl J, Hurvitz S, Gongalves A, Lee K-H, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roche H, Im Y-H, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018: 379:753-763
O'Shaughnessy J, Schwa rtzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E,
Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec l;32(34):3840-7
Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017 Aug 10;377(6):523-533
EXAMPLES
[0090] Synthesis of Compound I and salts thereof are described in US Patent Publication No. US 20220048905 Al, which is incorporated herein in its entirety as related to the synthesis of Compound I and salts thereof.
Example 1: Clinical Development
[0091] A Phase lb/2 study of a BET inhibitor (Compound I) + a PARP inhibitor (talazoparib) in wildtype gBRCAl/2 TNBC patients is ongoing with 51 patients dosed to date (Clinicaltrials.gov: NCT03901469). The Phase lb (n=15) portion of the trial (Part 1) was a 3+3 dose escalation design, where a dose of 48 mg Compound I + 0.75 mg talazoparib once daily was selected for the Phase 2 portion of the trial (Part 2 Simon 2-Stage). The Phase 2 study was designed to have a type I error rate of 0.1 when the true clinical benefit rate (CBR = objective response rate + stable disease > 4 months) is 20% and a power of 90% when the true CBR is 40%. The first stage the Phase 2 trial (n=17) has been completed and met the CBR threshold to progress to the second stage, which is currently enrolling (n=20).
[0092] The clinical data to date has shown that the combination therapy is significantly active with an ORR of 22% and a CBR of 35% (n=51 evaluable patients). Patients that were initially diagnosed with TNBC had a significantly higher ORR of 32% and CBR of 44% compared to ORR of 0% and CBR of 18% for patients whose tumors had converted from HR+ breast cancer to TNBC. All the confirmed responses were in patients who had TNBC at the time of initial diagnosis, and among all patients, TNBC at diagnosis patients had a higher PFS of 17 weeks compared to 10 weeks for HR+ to TNBC patients(HR=0.52; 95% Cl, 0.244-1.109; p=0.1). The median confirmed DOR is 24 weeks with one patient in complete responses (CR) ongoing. Genomic analysis showed that a very high percentage of patients with an original diagnosis of HR+ who had converted to TNBC had activating PIK3CA mutations while a very small percentage of TNBC patients at initial diagnosis had PIK3CA mutations. In the responding
population, only one patient had a somatic pathogenic BRCA1/2 mutation and one had a germline PALB2 mutation, suggesting that efficacy is due to the combination of the two agents. TNBC patients enrolled in this study had a median of 3 prior lines of therapy (range 1- 8) including a median of 1 line of therapy in the metastatic setting (range 0-4). Median duration of the immediate last therapy in the metastatic setting was 18.3 weeks (3 - 384 weeks), suggesting rapidly progressing disease upon study entry.
Claims
1. A method for treating triple-negative breast cancer (TNBC) comprising administrating to a subject in need thereof a BET bromodomain inhibitor with a PARP inhibitor, wherein the subject was initially diagnosed with TNBC and did not have a history of hormone receptor positivity (HR+) that subsequently converted to TNBC.
2. The method according to claim 1, wherein the BET bromodomain inhibitor is selected from PLX2853, FT-1101, CPI-0610, Molibresib, BMS-986378, BMS-986158, AZD5153/SRA515, INCB057643, BI894999, ABBV-744, and NUV-868.
3. A method for treating triple-negative breast cancer (TNBC) comprising administrating to a subject in need thereof a BET bromodomain inhibitor selected from l-benzyl-6-(3,5- dimethylisoxazol-4-yl)-N-methyl-lH-imidazo[4,5-b]pyridin-2-amine (Compound I), l-benzyl-6- (3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2-amine, and stereoisomers, tautomers, pharmaceutically acceptable salts, co-crystals, and hydrates thereof, with a PARP inhibitor, wherein the subject was initially diagnosed with TNBC and did not have a history of hormone receptor positivity (HR+) that subsequently converted to TNBC.
4. The method according to any one of claims 1-3, wherein the subject does not have PIK3CA activating mutations.
5. The method according to any one of claims 1-4, wherein the subject has an activating RAS/MAPK signaling mutation.
6. A method for treating triple-negative breast cancer (TNBC) comprising administrating to a subject in need thereof a BET bromodomain inhibitor with a PARP inhibitor, wherein the subject did not have a history of hormone receptor positivity (HR+) and does not have PIK3CA activating mutations.
7. The method according to claim 6, wherein the BET bromodomain inhibitor is selected from PLX2853, FT-1101, CPI-0610, Molibresib, BMS-986378, BMS-986158, AZD5153/SRA515, INCB057643, BI894999, ABBV-744, and NUV-868.
-25-
8. A method for treating triple-negative breast cancer (TNBC) comprising administrating to a subject in need thereof a BET bromodomain inhibitor selected from l-benzyl-6-(3,5- dimethylisoxazol-4-yl)-N-methyl-lH-imidazo[4,5-b]pyridin-2-amine (Compound I), l-benzyl-6- (3,5-dimethylisoxazol-4-yl)-lH-imidazo[4,5-b]pyridin-2-amine, and stereoisomers, tautomers, pharmaceutically acceptable salts, co-crystals, and hydrates thereof, with a PARP inhibitor, wherein the subject did not have a history of hormone receptor positivity (HR+) and does not have PIK3CA activating mutations.
9. The method according to any one of claims 1-8, wherein the subject does not harbor germline mutations in BRCA1 or BRCA2.
10. The method according to any one of claims 1-9, wherein the PARP inhibitor is talazoparib.
11. The method according to claim 10, wherein the subject is treated with a once daily dose of the BET bromodomain inhibitor and a once daily dose of talazoparib.
12. The method according to any one of claims 1, 3, 6, or 8 , wherein the once daily dose of the BET bromodomain inhibitor is 48 mg per day, and the once daily dose of talazoparib is 0.75 mg per day.
13. The method according to any one of claims 1-12, wherein the subject was previously treated with a breast cancer therapy.
14. The method according to claim 13, wherein the breast cancer therapy is chemotherapy.
15. The method according to claim 13, wherein the breast cancer therapy is immunotherapy.
16. The method according to any one of claims 1-15, wherein the subject is a human.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015002754A2 (en) | 2013-06-21 | 2015-01-08 | Zenith Epigenetics Corp. | Novel bicyclic bromodomain inhibitors |
WO2020053660A1 (en) | 2018-09-13 | 2020-03-19 | Zenith Epigenetics Ltd. | Solid forms of a bet inhibitor |
WO2020053655A1 (en) * | 2018-09-13 | 2020-03-19 | Zenith Epigenetics Ltd. | Combination therapy for the treatment of triple-negative breast cancer |
US20220048905A1 (en) | 2018-09-13 | 2022-02-17 | Zenith Epigenetics Ltd. | Method of manufacturing a solid form of a bet bromodomain inhibitor |
-
2022
- 2022-09-21 TW TW111135751A patent/TW202327594A/en unknown
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015002754A2 (en) | 2013-06-21 | 2015-01-08 | Zenith Epigenetics Corp. | Novel bicyclic bromodomain inhibitors |
WO2020053660A1 (en) | 2018-09-13 | 2020-03-19 | Zenith Epigenetics Ltd. | Solid forms of a bet inhibitor |
WO2020053655A1 (en) * | 2018-09-13 | 2020-03-19 | Zenith Epigenetics Ltd. | Combination therapy for the treatment of triple-negative breast cancer |
US20220048905A1 (en) | 2018-09-13 | 2022-02-17 | Zenith Epigenetics Ltd. | Method of manufacturing a solid form of a bet bromodomain inhibitor |
Non-Patent Citations (13)
Title |
---|
AFTIMOS PHILIPPE ET AL: "Abstract PS11-10: A Phase 1b/2 Study of the BET inhibitor ZEN003694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations", CANCER RESEARCH, 9 December 2020 (2020-12-09), US, XP093007822, ISSN: 0008-5472 * |
AFTIMOS PHILIPPE GEORGES ET AL: "A phase 1b/2 study of the BET inhibitor ZEN-3694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations", JOURNAL OF CLINICAL ONCOLOGY, vol. 40, no. 16_suppl, June 2022 (2022-06-01), pages 1023 - 1023, XP093007835 * |
AGOSTINETTO ELISA ET AL: "Emerging Therapeutics for Patients with Triple-Negative Breast Cancer", CURRENT ONCOLOGY REPORTS, CURRENT SCIENCE, GB, vol. 23, no. 5, 24 March 2021 (2021-03-24), XP037426455, ISSN: 1523-3790, [retrieved on 20210324], DOI: 10.1007/S11912-021-01038-6 * |
ALLISON, K. H. ET AL.: "Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update", JOURNAL OF CLINICAL ONCOLOGY: OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY, vol. 38, 2020, pages 1346 - 1366 |
BARDIA, A ET AL.: "Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer", NEW ENGLAND JOURNAL OF MEDICINE, vol. 384, 2021, pages 1529 - 1541, XP055958141, DOI: 10.1056/NEJMoa2028485 |
BARECHE YVENET DIGNATIADIS MAFTIMOS PPICCART MROTHE FSOTIRIOU C: "Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis", ANN ONCOL, 22 January 2018 (2018-01-22) |
BAUER, KRBROWN MCRESS RDPARISE CACAGGIANO V: "Descriptive analysis of estrogen receptor (ER) negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry", CANCER, vol. 109, no. 9, 1 May 2007 (2007-05-01), pages 1721 - 8 |
CATIA MIO ET AL: "BET proteins regulate homologous recombination-mediated DNA repair: BRCAness and implications for cancer therapy", INTERNATIONAL JOURNAL OF CANCER, JOHN WILEY & SONS, INC, US, vol. 144, no. 4, 4 December 2018 (2018-12-04), pages 755 - 766, XP071291053, ISSN: 0020-7136, DOI: 10.1002/IJC.31898 * |
COPSON ERMAISHMAN TCTAPPER WJCUTRESS RIGREVILLE-HEYGATE SALTMAN DGECCLES BGERTY SDURCAN LTJONES L: "Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study", LANCET ONCOL, vol. 19, no. 2, February 2018 (2018-02-01), pages 169 - 180 |
KASSAM FENRIGHT KDENT RDRANITSARIS GMYERS JFLYNN CFRALICK MKUMAR RCLEMONS M: "Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design", CLIN BREAST CANCER, vol. 9, no. 1, February 2009 (2009-02-01), pages 29 - 33 |
LITTON J, RUGO HS, ETTL J, HURVITZ S, GONGALVES A, LEE K-H, FEHRENBACHER L, YERUSHALMI R, MINA LA, MARTIN M, ROCHE H, IM Y-H, QUEK: "Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation", N ENGL J MED., vol. 379, 2018, pages 753 - 763, XP055828150, DOI: 10.1056/NEJMoa1802905 |
O'SHAUGHNESSY JSCHWARTZBERG LDANSO MAMILLER KDRUGO HSNEUBAUER MROBERT NHELLERSTEDT BSALEH MRICHARDS P: "Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer", J CLIN ONCOL, vol. 32, no. 34, 1 December 2014 (2014-12-01), pages 3840 - 7 |
ROBSON MIM SASENKUS EXU BDOMCHEK SMMASUDA NDELALOGE SLI WTUNG NARMSTRONG A: "Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation", N ENGL J MED, vol. 377, no. 6, 10 August 2017 (2017-08-10), pages 523 - 533, XP055828125, DOI: 10.1056/NEJMoa1706450 |
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