Classifications

• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the estrogen receptor a (ESR1) is expressed in the majority of breast tumors, enabling them to respond to the mitogenic actions of estrogens.
• Compound (1) 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9- dihydro-7H-benzo[7]annulene-2-carboxylic acid, hereafter designated as “compound (1)”, is a selective estrogen receptor degrader (SERD) which is an estrogen receptor antagonist and accelerates the proteasomal degradation of the estrogen receptor.
• SESD selective estrogen receptor degrader
• Alpelisib also known as (2S)-N 1 - ⁇ 4-methyl-5-[1-(1,1,1-trifluoro-2-methylpropan-2- yl)pyridin4-yl]-1,3-thiazol-2-yl ⁇ pyrrolidine-1, 2-dicarboxamide, is an alpha-specific PI3K inhibitor, with the following formula:
• Alpelisib is marketed under the tradename PIQRAY ® and is indicated, in combination with the endocrine therapy fulvestrant, for the treatment of breast cancer in postmenopausal women, and in men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen (FDA label).
• HR hormone receptor
• HER2 human epidermal growth factor receptor 2
• FDA label endocrine-based regimen
• compound (1) may exist not only in the form of a zwitterion (i.e. a globally neutral molecule having an acid group and a basic group), but also in the form of addition salts with acids or bases. Such addition salts may be used in the above combination.
• a combination comprising compound (1), or a pharmaceutically acceptable salt thereof, and alpelisib.
• the combination of compound (1), or a pharmaceutically acceptable salt thereof, with alpelisib shows therapeutic synergy.
• a combination demonstrates therapeutic synergy if its therapeutic effect is superior compared to the cumulative effect of either active agent of the combination alone.
• compound (1), or a pharmaceutically acceptable salt thereof, and alpelisib are administered by the oral route.
• composition comprising compound (1), or a pharmaceutically acceptable salt thereof, and alpelisib, as well as at least one pharmaceutically acceptable excipient.
• excipients are selected from the customary excipients which are known to a person skilled in the art. More particularly, the excipients are selected from those useful for oral administration in whatever form (liquid solution, dispersion or suspension, tablets, capsules or the like).
• compound (1), or a pharmaceutically acceptable salt thereof, and alpelisib may be administered simultaneously, separately, or spaced out over a period of time (sequential administration). Therefore, the combination and pharmaceutical composition provided herein are not exclusively limited to the ones which are obtained by physical association of the constituents in a single unit dosage, but also to those which allow a separate administration, which can be simultaneous or sequential (also called “spaced out”, or “spread out”) over a period of time.
• a pharmaceutical kit which comprises:
• a second pharmaceutical composition comprising alpelisib, and at least one pharmaceutically acceptable excipient; wherein the first pharmaceutical composition and the second pharmaceutical composition are in separate compartments and are intended to be independently administered, each administration with regards to the other one being simultaneous or spaced out (sequential) over time.
• the compound (1) or pharmaceutically acceptable salt thereof and alpelisib are advantageously present at effective doses, adapted considering the treated pathology and the condition of the patient to which it is administered.
• the recommended dose for cancer treatment for adult patients is 300 mg (two 150 mg tablets) taken orally once daily, with food.
• compound (1) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer by co-administration with alpelisib.
• alpelisib for use in the treatment of cancer by co-administration with compound (1) or a pharmaceutically acceptable salt thereof.
• Co-administration is understood herein as an administration of the active ingredients to a patient in need thereof, which is separated, simultaneous or spaced out (sequential) over time, in respect of each of the active ingredient.
• compound (1) ora pharmaceutically acceptable salt thereof and alpelisib are administered in a therapeutically effective amount.
• a “therapeutically effective amount” means the amount of an active ingredient or combination of active ingredients that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease.
• the “therapeutically effective amount” will vary depending on the disease and its severity and the age, weight, etc ... , of the mammal to be treated.
• compound (1) or a pharmaceutically acceptable salt thereof and alpelisib are administered in an amount to show therapeutic synergy.
• the cancer is a hormone dependent cancer.
• the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.
• the cancer is resistant to anti-hormonal treatment.
• the cancer is a cancer with wild type estrogen receptors.
• the cancer is a cancer with deregulated function of estrogen receptors related to, but not limited to, at least one epigenetic and genetic alteration of estrogen receptors such as mutation, amplification, splice variant.
• the cancer is a cancer with mutated estrogen receptors.
• the mutations of estrogen receptors can include, but not limited to, new or known mutations such as Leu536Arg, Tyr537Ser, Tyr537Asn, or Asp538Gly.
• the cancer is an estrogen-sensitive cancer.
• the cancer is breast cancer, more particularly an estrogen receptor positive breast cancer (ERa positive breast cancer), or a metastasis thereof, such as a cerebral metastasis.
• ERa positive breast cancer estrogen receptor positive breast cancer
• metastasis thereof such as a cerebral metastasis.
• a method of treating the pathological conditions indicated above, particularly breast cancer comprising administering to a subject in need thereof a therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of alpelisib.
• a method of treating the pathological conditions indicated above, particularly breast cancer comprising administering to a subject in need thereof a pharmaceutical composition or a pharmaceutical kit as described above.
• a method of treating the pathological conditions indicated above, particularly breast cancer comprising administering to a subject in need thereof a combination as described above.
• a method of treating the pathological conditions indicated above, particularly breast cancer comprising co-administering to a subject in need thereof compound (1) or a pharmaceutically acceptable salt thereof and alpelisib.
• compound (1) or a pharmaceutically acceptable salt thereof is administered with alpelisib either simultaneously or spaced out over time.
• alpelisib is administered with compound (1), or a pharmaceutically acceptable salt thereof, either simultaneously or spaced out over time.
• the subject is a human.
• a combination comprising compound (1), or a pharmaceutically acceptable salt thereof, and alpelisib for the manufacture of a medicament useful in treating the pathological conditions indicated above, particularly breast cancer.
• compound (1) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament useful in treating the pathological conditions indicated above, particularly breast cancer, by co-administration with alpelisib.
• alpelisib in the manufacture of a medicament useful in treating the pathological conditions indicated above, particularly breast cancer, by co administration with compound (1) or a pharmaceutically acceptable salt thereof.
• an article of manufacture comprising:
• the treated groups included compound (1) at 20 mg/kg alone, alpelisib at 25 mg/kg alone, and the combination of compound (1) and alpelisib at the same dose and regime.
• Compound (1) was orally dosed twice a day (BID) and alpelisib was orally dosed once a day (QD) for 22 days.
• Anti-tumor efficacy was evaluated by tumor volume measurement.
• mice Female BALB/c nude mice were obtained from Shanghai Sino-British SIPPR/BK Laboratory Animal Co., LTD (Shanghai, CHINA). Animals were allowed to acclimate for at least four days before the study enrollment. Mice were 6 to 8 weeks old and weighed between 18 and 24 grams at the beginning of the treatments. These animals were housed under conditions outlined in the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).
• IACUC Institutional Animal Care and Use Committee
• MCF7-Y537S (ESR1) cell line was MCF7 cells expressing the ER.Y537S variant that was generated by Sanofi Biology Discovery Group.
• ESR1 construct was introduced in ESR1 construct (GenBank NM_000125.3) by site directed mutagenesis (Toy W. eta!., Cancer Discovery, 2017, 7, 277-287). The construct was transfected in MCF7 cells which were selected for their growth in absence of estradiol.
• MCF-Y537S is an ESR1 mutation that confers estrogen-independent activity to ERa (Estrogen Receptor alpha) and contributes to endocrine resistant disease (Robinson D.R. etal., Nat Genet., 2013, 45 (12), 1446-1451).
• the cells were grown in Eagle's Minimum Essential Medium (EMEM) supplemented with 10% fetal bovine serum (FBS), human Insulin, in 5% CO2 at 37°C.
• the cells were harvested in 0.25% Trypsin EDTA and washed by Phosphate Buffered Saline (PBS) and re-suspended in PBS with 75% Matrigel.
• the cells (20 c 10 6 cells/per mouse) were subcutaneously (SC) implanted into the right flank of female nude mice.
• the tumors were reserved as tumor stocks for fragment implantation.
• the tumors were serially propagated through fragment tissue transplantation subcutaneously.
• the fragment tumor tissues were subcutaneously implanted into the right flank of female nude mice. 28 mice were assigned in this experiment.
• Alpelisib (commercially available, marketed under the tradename PIQRAY ® ) was formulated in 100% of HPMC (hydroxypropyl-methylcellulose)/TWEEN80 0.5/0.1% in water.
• Compound (1) was prepared in 5% Solutol HS15 (purchased from Sigma) at pH 3.0.
• Dose volume for compound (1) and alpelisib for oral administration 10 ml/kg by oral gavage.
• Doses compound (1) at 20 mg/kg and alpelisib at 25 mg/kg in the above volume.
• mice were pooled and randomly distributed to the treatment and control groups (7 mice per group), where median tumor volumes for each group was 173 mm 3 .
• Treatments of compound (1) and alpelisib were initiated on day 0.
• Compound (1) was orally administered at 20 mg/kg BID (8 hours apart) and alpelisib was orally administered at 25 mg/kg QD, for 22 days. Animal body weight was assessed daily.
• the dosages are expressed in mg/kg and based on daily body weight per animal. Vehicle treated animals were used as controls. Mice were checked daily for adverse clinical reactions. Individual mice were weighed daily until the end of the experiment. Mice would be euthanized when morbid or weight loss 320% was observed. Tumors were measured with a caliper twice weekly until final sacrifice. When a tumor size reached approximately 2000 mm 3 or when there are animal health issues (40% area of a tumor ulcerated), animals would be euthanized, and date of death recorded. Solid tumor volumes were estimated from two-dimensional tumor measurements and calculated according to the following equation: length ⁇ mm) x width 2 ⁇ mm 2 )
• Examples include animal handling issues such as misgavage, tumor model related issues such as tumor induced cachexia leading to body weight loss that can be observed in control or vehicle treated groups and excessive tumor ulceration. Mice that have non-drug related death or significant bodyweight loss will not be considered toxic and will be excluded from statistical analysis. Animal body weight included the tumor weight.
• the primary efficacy end points include tumor volume changes from baseline summarized by the ratio of medians of tumor volume changes from baseline between the treated and control groups (AT/AC). Changes in tumor volume for each treated (T) and control (C) group are calculated for each animal on each day by subtracting the tumor volume on the day of first treatment (staging day) from the tumor volume on the specified observation day. The median DT is calculated for the treated group and the median AC is calculated for the control group. The ratio DT/DO is calculated and expressed as percentage: 100
• Percent tumor regression is defined as % (percentage) of tumor volume decrease in the treated group on a specified observation day compared to its volume when the study was initiated. At a specific timepoint (t) and for each animal, the regression percentage is calculated using the following formula: volume t0 - volume t
• the median percent regression for a group on a given day is then calculated by taking the median of individual % regression values calculated for each animal in the group.
• the day of calculation is determined by the day when DT/DO is calculated, except if median percent regression is not representative of the activity of the group. In this case, the day is determined by the first day when the median percent regression is maximal.
• a two-way analysis of variance (ANOVA) with factors treatment and day (repeated) is performed on tumor volume changes from baseline. It is followed by contrast analyses with Bonferroni-Holm correction for multiplicity to compare all treated groups to the control group and to compare the combination versus each single agent at the dose involved in the combination at each day from day 0 to 22.
• Tumor volume changes from baseline are calculated for each animal and each day by subtracting the tumor volume on the day of first treatment (day 0) from the tumor volume on the specified observation day.
• Table 2 Efficacy of compound (1) combined with alpelisib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice, according to experiment 1. Comparison of each group to the control group at each day.
• Table 3 Efficacy of compound (1) combined with alpelisib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice, according to experiment 1. Comparison of compound (1) 20 mg/kg and alpelisib 25 mg/kg as single agents versus the combination at each day. 2: Experiment 2
• mice were inoculated subcutaneously in the right flank region with MCF7-Sanofi tumor cells (2 x 10 7 ) in 0.25 ml of PBS/Matrigel (1 :1) mixture for tumor development. 32 mice were assigned in this experiment.
• Compound (1) was prepared in 20% Solutol HS15 (purchased from Sigma) at pH 3.5.
• mice Female BALB/c nude mice were obtained from Vital River Laboratories Research Models and Services (Beijing, China). These animals were housed under conditions outlined in the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Crown Bioscience Inc. (Beijing) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).
• IACUC Institutional Animal Care and Use Committee
• mice were pooled and implanted with MCF7-Y537S tumor cells. On day 0 (40 days post implantation), the mice were pooled and randomly distributed to the treatment and control groups (8 mice per group), where median tumor volumes for each group was 201 mm 3 .
• Compound (1) was orally administered at 10 mg/kg BID (8 hours apart) and alpelisib was orally administered at 25 mg/kg QD, for 28 days. Animal body weight was assessed daily.
• Alpelisib at a dose of 25 mg/kg QD for 28 days induced statistically significant anti-tumor efficacy with AT/AC value of 66% (p 0.0271) on day 28.
• the combination treatment demonstrated statistically significant anti-tumor efficacy (tumor regression) with AT/AC value of -16% (p ⁇ 0.0001) on day 28.
• Figure 3 Antitumor activity of compound (1) combined with alpelisib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft in nude mice according to experiment 2: tumor volume evolution. The curves represent medians + or - MAD (Median Absolute Deviation) at each day for each group.
• MAD Median Absolute Deviation
• Figure 4 Antitumor activity of compound (1) combined with alpelisib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft in nude mice according to experiment 2: tumor volume changes from baseline on day 28. Points represent individual tumor volume changes from baseline on day 28, bars correspond to medians.
• Table 5 Efficacy of compound (1) combined with alpelisib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice, according to experiment 2. Comparison of each group to the control group at each day.
• Table 6 Efficacy of compound (1) combined with alpelisib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice, according to experiment 2. Comparison of compound (1) 10 mg/kg and alpelisib 25 mg/kg as single agents versus the combination at each day.

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