Combinations containing everolimus and amsenestrant

Abstract

Provided herein are combinations of everolimus and amsenestrant, or pharma- ceutically acceptable salts thereof, pharmaceutical compositions containing such combinations, and therapeutic uses thereof, particularly for the treatment of cancer, including breast cancer.

Description

[Technical field]

[0001] Provided herein are combinations of everolimus and amsenestrant, pharmaceutical compositions containing such combinations, and therapeutic uses of such combinations and pharmaceutical compositions, particularly for the treatment of cancer. [Background technology]

[0002] Estrogen receptor alpha (ESR1) is expressed in many breast tumors, enabling them to respond to the mitogenic effects of estrogen.

[0003] Amcenestrant, the INN name for the compound 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (also known by its laboratory code SAR439859), is an estrogen receptor antagonist and a selective estrogen receptor degrader (SERD) that promotes proteasomal degradation of the estrogen receptor. This compound: [ka] is disclosed in (Patent Document 1).

[0004] Everolimus (INN name) is an inhibitor of the mammalian target of rapamycin (mTOR). It has the following formula: [ka] has.

[0005] Everolimus is a marketed drug with AFINITOR® as one of its trade names. It is indicated in several oncological settings. In breast cancer, everolimus is indicated in combination with exemestane for the treatment of postmenopausal women with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer after failure of treatment with letrozole or anastrozole (FDA labeled). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent application WO 2017 / 140669 Summary of the Invention [Problem to be solved by the invention]

[0007] There is a constant need to find new antitumor treatments. It is now shown herein that the combination of amsenestrant with everolimus exhibits significant antitumor efficacy and induces tumor regression in a synergistic manner compared to each of the active ingredients alone. [Means for solving the problem]

[0008] Provided herein is a combination comprising amsenestrant and everolimus.

[0009] In the combinations provided herein, amsenestrant can exist not only in the form of a zwitterion (i.e., a generally neutral molecule having an acidic group and a basic group), but also in the form of an addition salt with an acid or base. Such addition salts can be used in the above combinations. Thus, a combination comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus is provided herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In one embodiment, the combination of amsenestrant, or a pharma- ceutically acceptable salt thereof, with everolimus exhibits therapeutic synergy. A combination exhibits therapeutic synergy if the therapeutic effect is superior to the cumulative effect of either active agent of the combination alone.

[0011] In another embodiment, the amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus are administered orally.

[0012] Also provided herein is a combination of amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus, for its use as a pharmaceutical.

[0013] Also provided herein is a pharmaceutical composition comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus, and at least one pharma- ceutically acceptable excipient.

[0014] The excipients are selected from the usual excipients known to those skilled in the art, more particularly from those useful for oral administration in any form (liquid solutions, dispersions or suspensions, tablets, capsules, etc.).

[0015] In another embodiment, amsenestrant, or its pharma- ceutically acceptable salt, and everolimus are administered simultaneously, separately, or at a certain interval (sequential administration).Therefore, the combinations and pharmaceutical compositions provided herein are not limited to those obtained by the physical association of the constituents in a single unit dosage form, but also limited to those that allow for separate administration, which may be simultaneously or sequentially at a certain interval (also called "at an interval" or "extended").

[0016] (i) a first pharmaceutical composition comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient; (ii) a second pharmaceutical composition comprising everolimus, and at least one pharma- ceutically acceptable excipient; A pharmaceutical kit comprising: Also provided herein are pharmaceutical kits, in which the first pharmaceutical composition and the second pharmaceutical composition are in separate compartments and each is intended to be administered independently, with administration of each being simultaneous or spaced apart (sequential) with respect to the other.

[0017] In the above combination, pharmaceutical composition and pharmaceutical kit, amsenestrant or its pharmaceutically acceptable salt and everolimus are advantageously present in effective amounts adapted taking into account the pathology to be treated and the condition of the patient to whom the combination is administered.In particular, for everolimus, the recommended dosage for adult patients is 10 mg taken orally once a day.

[0018] Also provided herein are combinations comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus, for use in treating cancer, as well as pharmaceutical compositions and kits as described above.

[0019] Also provided herein is amsenestrant, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer by co-administration with everolimus.

[0020] Also provided herein is everolimus for use in the treatment of cancer by co-administration with amsenestrant, or a pharma- ceutically acceptable salt thereof.

[0021] Concomitant administration is understood herein as the administration of active ingredients to a patient in need thereof, which may be separately, simultaneously or with some interval (sequential) with respect to each active ingredient.

[0022] In some embodiments, amsenestrant or its pharma- ceutically acceptable salt and everolimus are administered in a therapeutically effective amount. "Therapeutically effective amount" refers to the amount of active ingredient or combination of active ingredients that, when administered to a patient for treating a disease, is sufficient to affect such treatment against the disease. "Therapeutically effective amount" will vary depending on the disease and its severity and the age, weight, etc., of the subject to be treated.

[0023] In some embodiments, the amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus are administered in amounts that exhibit therapeutic synergy.

[0024] In another embodiment, the cancer is a hormone-dependent cancer.

[0025] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular the cancer is an estrogen receptor alpha dependent cancer.

[0026] Also provided herein is a method for treating the above-noted pathological conditions, particularly breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of amsenestrant, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of everolimus.

[0027] Also provided herein is a method of treating the above indicated pathological conditions, particularly breast cancer, comprising administering to a subject in need thereof the above-mentioned pharmaceutical composition or pharmaceutical kit.

[0028] Also provided herein is a method of treating the above indicated pathological conditions, in particular breast cancer, comprising administering to a subject in need thereof the above combination.

[0029] Also provided herein is a method for treating the above-mentioned pathological conditions, particularly breast cancer, comprising administering amsenestrant or its pharmaceutically acceptable salt and everolimus to a subject in need thereof.In said method, amsenestrant or its pharmaceutically acceptable salt is administered separately, simultaneously or at a certain interval together with everolimus.

[0030] Also provided herein is a method for treating the above-mentioned pathological conditions, particularly breast cancer, comprising co-administering everolimus and amsenestrant, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein everolimus is administered separately, simultaneously or at an interval with amsenestrant, or a pharmaceutically acceptable salt thereof.

[0031] Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of amsenestrant, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of everolimus.

[0032] Also provided herein is a method of treating cancer in a patient undergoing treatment with the compound amsenestrant, or a pharma- ceutically acceptable salt thereof, comprising administering to the patient an effective amount of everolimus.

[0033] Also provided herein is a method of treating cancer in a patient receiving stable treatment with the compound amsenestrant, or a pharma- ceutically acceptable salt thereof, comprising administering to the patient a therapeutically effective amount of everolimus.

[0034] Also provided herein is a method of treating cancer comprising administering a therapeutically effective amount of the compound everolimus to a patient in need thereof, wherein the patient is also receiving treatment with amsenestrant or a pharmaceutically acceptable salt thereof.

[0035] In an embodiment of the above method, the subject is a mammal. In another embodiment, the subject is a human.

[0036] Also provided herein is a combination comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus for the manufacture of a medicament useful for treating the above indicated pathological conditions, in particular breast cancer.

[0037] There is also provided herein the use of amsenestrant, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament useful for treating the above indicated pathological conditions, particularly breast cancer, by co-administration with everolimus.

[0038] There is also provided herein the use of everolimus in the manufacture of a medicament useful for treating the above indicated pathological conditions, particularly breast cancer, by co-administration with amsenestrant or a pharma- ceutically acceptable salt thereof.

[0039] -Packaging materials; a combination, a pharmaceutical composition or a pharmaceutical kit as defined above; and - a label or package insert contained within said packaging material indicating that said combination, pharmaceutical composition or pharmaceutical kit is administered to a patient for the treatment of cancer. Also provided herein is an article of manufacture, package, or dosage unit comprising:

[0040] The following examples show the pharmacological results obtained with amsenestrant, everolimus and their combination against breast cancer cell line xenografts in NOD / SCID (non-obese diabetic / severe combined immunodeficiency) mice. EXAMPLES

[0041] Evaluation of the efficacy of amsenestrant in combination with everolimus against subcutaneous breast cancer cell line xenografts in female NOD / SCID mice In this study, the antitumor efficacy of amsenestrant in combination with everolimus was investigated after 28 days of treatment against orthotopic MCF7 human breast cancer cell line xenografts in female NOD / SCID mice.

[0042] Treatment groups included amsenestrant 10 mg / kg alone, everolimus 10 mg / kg alone, and a combination of amsenestrant and everolimus at the same doses and regimens.

[0043] Amsenestrant was administered orally twice daily (BID) and everolimus was administered orally twice weekly (BIW) for 28 days. Antitumor efficacy was assessed by tumor volumetric measurements.

[0044] 1: Experimental procedure 1-1: Animals, cell lines, compounds Female NOD / SCID mice were obtained from GemPharmatech Co.,Ltd (Nanjing University National Resource Center for Mutant Mice, Model Animal Research Center), Nanjing, China. Animals were allowed to acclimate for at least 4 days prior to study enrollment. Mice were 7-8 weeks old and weighed between 22.5 and 28.4 grams at the start of treatment. The animals were housed under conditions outlined in guidelines approved by CrownBio's Institutional Animal Care and Use Committee (IACUC) in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) guidance.

[0045] MCF7 cells were obtained from the American Type Culture Collection (ATCC® HTB-22™). MCF7 tumor cells were maintained in vitro at 37° C. in an atmosphere of 5% CO2 in air using MEM medium supplemented with 10% fetal bovine serum, 0.01 mM non-essential amino acids, 0.01 mg / ml bovine insulin, and 2 mM L-glutamine. Cells in logarithmic growth phase were harvested prior to tumor inoculation and quantified by cell counter.

[0046] One day before tumor inoculation, mice were subcutaneously implanted with estrogen pellets (0.18 mg / pellet, 17β-estradiol, Innovative Research of America, Sarasota, FL, USA), hereafter referred to as “E2 supplement,” on the right flank. For tumor development, 0.25 ml of a PBS / Matrigel (1:1) mixture of MCF-7 tumor cells (2 × 10e7) was inoculated into the right mammary fat pad of each mouse.

[0047] Everolimus (Manufacturer: Selleck; Lot Number: S1120) was formulated in 30% propylene glycol (dissolved first): 5% Tween 80: 65% ddH2O (double distilled water).

[0048] Dosage volume of amsenestrant and everolimus for oral administration: 10 ml / kg.

[0049] Dose: Amsenestrant 10 mg / kg and everolimus 10 mg / kg in the above volumes.

[0050] 1-2: Research design and evaluation items The animals required for the experiment (plus spares) were pooled and implanted with MCF7 cells. On day 0 (12 days after implantation), the mice were pooled and randomly distributed into treatment and control groups (10 mice per group), where the median tumor volume for each group was 119 mm. 3Amsenestrant and everolimus treatment was initiated on day 1. Amsenestrant was administered orally at 10 mg / kg BID (every 8 hours) and everolimus was administered orally at 10 mg / kg BIW for 28 days. Animal body weights were assessed daily.

[0051] Dosages were expressed in mg / kg and were based on daily body weight per animal. Vehicle-treated animals served as controls. Mice were checked daily for adverse clinical reactions. Individual mice were weighed daily until the end of the experiment. Mice were euthanized if lesions or body weight loss ≥ 20% were observed. Tumors were measured twice weekly with calipers until terminal sacrifice. Tumors were measured twice weekly with calipers until tumor size reached approximately 3000 mm 3 When the tumor volume reached 100 μg / kg / day or when the animal had health problems (ulceration of 40% of the tumor area), the animal was euthanized and the date of death was recorded. Solid tumor volume was estimated from bidimensional tumor measurements and calculated using the following equation:

number

[0052] Toxicity endpoints: Doses that resulted in either 15% weight loss for three consecutive days, 20% weight loss for one day, or 10% or more drug-related death for individual mice were considered excessively toxic doses, unless the weight loss or animal death could be considered non-drug related under certain circumstances. Examples include weight loss and painful urination associated with E2 supplements, animal handling issues such as forced dosing errors, tumor model related issues such as tumor-induced cachexia resulting in observable weight loss in control or vehicle-treated groups, and excessive tumor ulceration. Mice with non-drug related deaths or severe weight loss were not considered toxic and were excluded from statistical analysis. Animal weights included tumor weights.

[0053] Efficacy endpoints: Primary efficacy endpoints included tumor volume change from baseline summarized by the ratio of median tumor volume change from baseline between treatment and control groups (ΔT / ΔC). Tumor volume change for each treatment (T) and control (C) group was calculated for each day by subtracting the tumor volume on the day of first treatment (diagnosis day) from the tumor volume on the specific observation day for each animal. Median ΔT was calculated for treatment groups and median ΔC was calculated for control groups. Ratio ΔT / ΔC:

number

[0054] ΔT / ΔC≦40% was considered therapeutically active, ΔT / ΔC=0% was considered tumor stasis, ΔT / ΔC<0% was considered tumor regression (highly active), and ΔT / ΔC>40% was considered therapeutically inactive.

[0055] Percentage tumor regression was defined as the % (percentage value) of tumor volume reduction in a treatment group on a particular observation date compared to its volume when the study began. At a particular time point (t) and for each animal, the percent regression value was calculated using the following formula:

number

[0056] The median percent regression for a group on a given day was then calculated by taking the median of the individual % regression values ​​calculated for each animal in that group. The day of calculation was determined by the day on which ΔT / ΔC was calculated unless the median percent regression was not representative of the activity of the group. In this case, the day was determined by the first day on which the median percent regression was greatest.

[0057] 1-3: Statistical analysis A two-way analysis of variance (ANOVA) with factors of treatment and day (repeated) was performed on the change in tumor volume from baseline, followed by contrast analyses with Bonferroni-Holm correction for multiplicity to compare all treatment groups to the control group and to compare the combination to each single agent at the dose included in the combination on each day from days 4 to 28.

[0058] In the figures, the median and median absolute deviation (MAD) for each group are presented for each measurement day.

[0059] The table shows the median and normalized MAD (nMAD=1.4826) for each group. * MAD) was reported for each measurement date.

[0060] Tumor volume change from baseline was calculated for each animal each day by subtracting the tumor volume on the first treatment day (day 0) from the tumor volume on a particular observation day.

[0061] All statistical analyses were performed using SAS version 9.2 software. A probability of less than 5% (p<0.05) was considered significant.

[0062] 2:Result Amsenestrant at 10 mg / kg BID for 28 days, everolimus 10 mg / kg BIW and the combination of amsenestrant and everolimus at this dose and regimen were well tolerated in this study and no drug-related weight loss / animal deaths were observed. However, significant weight loss or deaths associated with E2 supplementation were observed and were excluded from the data statistical analysis.

[0063] Amsenestrant at a dose of 10 mg / kg BID for 28 days had a statistically significant antitumor efficacy with a ΔT / ΔC value of -13% (p<0.0001) at day 28. Everolimus at a dose of 10 mg / kg BIW for 28 days induced a statistically significant antitumor efficacy with a ΔT / ΔC value of -17% (p<0.0001) at day 28. When amsenestrant 10 mg / kg was combined with everolimus 10 mg / kg at the same dosing schedule BID for amsenestrant and BIW for everolimus, the combined treatment showed a statistically significant antitumor efficacy (tumor regression) with a ΔT / ΔC value of -31% (p<0.0001) at day 28. Statistical analysis showed that the combination effect was significantly different when compared with either amsenestrant alone or everolimus alone at day 28 (p<0.0001).

[0064] Detailed results are shown in Tables 1 to 3 below and in Figures 1 and 2. [Brief description of the drawings]

[0065] [Figure 1] Figure 1 shows the antitumor activity of amsenestrant in combination with everolimus against orthotopic human breast cancer cell line MCF7 xenografts in NOD / SCID mice: Tumor volume evolution. Curves represent the median + or - MAD (median absolute deviation) for each group on each day. [Diagram 2] Figure 1 shows antitumor activity of amsenestrant in combination with everolimus against orthotopic human breast cancer cell line MCF7 xenografts in NOD / SCID mice: Tumor volume change from baseline at day 28. Points represent individual tumor volume change from baseline at day 28, bars represent median values.

[0066] From this study it was concluded that amsenestrant at 10 mg / kg twice daily in combination with the mTOR inhibitor everolimus at 10 mg / kg twice weekly induced significant antitumor efficacy superior to either agent alone in an MCF7 human breast cancer cell line xenograft model in NOD / SCID mice, and induced tumor growth inhibition and tumor regression.

[0067] [Table 1]

[0068] [Table 2]

[0069] [Table 3]

Claims

1. A combination comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus.

2. 2. The combination of claim 1 which exhibits therapeutic synergy.

3. The combination according to claim 1 for treating cancer.

4. The combination for treating cancer according to claim 3, wherein the cancer is breast cancer.

5. The combination according to any one of claims 1 to 4, wherein amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus are administered separately, simultaneously or at a fixed interval.

6. A pharmaceutical composition comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and everolimus, and at least one pharma- ceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6 for treating cancer.

8. The pharmaceutical composition for treating cancer according to claim 7, wherein the cancer is breast cancer.

9. Amsenestrant or a pharma- ceutically acceptable salt thereof for the treatment of cancer, comprising administering amsenestrant or a pharma- ceutically acceptable salt thereof in combination with everolimus for the treatment of cancer.

10. The compound for treating cancer according to claim 9, which is administered together with everolimus separately, simultaneously or at an interval.

11. Everolimus for treating cancer, by co-administration with amsenestrant or a pharma- ceutically acceptable salt thereof.

12. Everolimus for treating cancer according to claim 11, administered together with amsenestrant or a pharma- ceutically acceptable salt thereof, separately, simultaneously or at an interval.

13. (i) a first pharmaceutical composition comprising amsenestrant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient; (ii) a second pharmaceutical composition comprising everolimus, and at least one pharma- ceutically acceptable excipient; A pharmaceutical kit comprising: A pharmaceutical kit, wherein said first pharmaceutical composition and said second pharmaceutical composition are in separate compartments and each are intended to be administered independently, with administration of each being simultaneous or at an interval with respect to the other.

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