Combination Therapies for Cancer Treatment

Abstract

The present disclosure relates to the treatment of cancer using a combination therapy comprising Compound 1 and / or a tautomer thereof, or a pharma- ceutically acceptable salt or hydrate thereof, and one or more PARP inhibitors. [Formula 1] JPEG2024506314000020.jpg46158

Description

[Technical field]

[0001] The present disclosure relates to (i) Compound 1

[0002] [ka]

[0003] and / or a tautomer thereof, or a pharma- ceutically acceptable salt or hydrate thereof, and (ii) the treatment of cancer using a combination therapy comprising one or more PARP inhibitors. [Background technology]

[0004] CDC7 is a serine / threonine kinase that contributes to the initiation of DNA replication by phosphorylating MCM2. The kinase activity of CDC7 is regulated by its binding protein Dbf4 in a cell cycle-dependent manner. Recent studies have revealed that CDC7 is involved in DNA replication as well as DNA damage response (DDR), suggesting that CDC7 plays an important role in both cell proliferation during S phase and genomic stability in the DDR. Furthermore, elevated CDC7 expression has been reported in various cancers and correlates with poor prognosis, such as in diffuse large B-cell lymphoma, oral squamous cell carcinoma, breast tumors, colon tumors, ovarian tumors, and lung tumors.

[0005] If CDC7 is involved in two important functions, DNA replication and DDR, it is believed that CDC7 is an important gene for the proliferation and survival of cancer cells, and inhibition of CDC7 is expected to induce anti-proliferation and apoptosis in a wide range of cancers, not limited to specific organ types. Novel cancer therapies, such as combination therapies containing CDC7 inhibitors, are needed. Summary of the Invention

[0006] In one aspect, the disclosure provides a method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1.

[0007] [ka]

[0008] and / or a tautomer thereof, or a pharma- ceutically acceptable salt or hydrate thereof; and one or more PARP inhibitors.

[0009] In some embodiments, the PARP inhibitor is niraparib.

[0010] In some embodiments, the PARP inhibitor is olaparib.

[0011] In some embodiments, the cancer is ovarian cancer.

[0012] In some embodiments, the cancer is breast cancer.

[0013] Another aspect of the present disclosure is compound 1

[0014] [ka]

[0015] and / or a tautomer thereof, or a pharma- ceutically acceptable salt or hydrate thereof; and one or more PARP inhibitors.

[0016] In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient.

[0017] Another aspect of the disclosure relates to compound 1 for use in combination with one or more PARP inhibitors for the treatment of cancer.

[0018] [ka]

[0019] and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof.

[0020] Another aspect of the disclosure is the use of compound 1 in combination with one or more PARP inhibitors for the treatment of cancer.

[0021] [ka]

[0022] and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof. [Brief description of the drawings]

[0023] [Figure 1] 1 shows that compound 1 in combination with niraparib exhibits potent antitumor activity against PHTXS-13O human primary ovarian cancer xenografts compared to either treatment alone. [Diagram 2] 1 shows that compound 1 in combination with olaparib exhibits potent antitumor activity against PHTXS-13O human primary ovarian cancer xenografts compared to either treatment alone. [Diagram 3] 1 shows the combined antitumor activity of Compound 1 and Niraparib in BALB / c nude mice bearing PHTXS-13O human primary ovarian cancer xenografts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Thus, the following terms are intended to have the following meanings:

[0025] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0026] As used herein, "administration" of the disclosed compounds includes delivering to a subject a compound described herein, or a prodrug or other pharma- ceutically acceptable derivative thereof, using, for example, any suitable formulation or route of administration described herein.

[0027] As used herein, "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended use, including but not limited to the treatment of a disease, as set forth below. In some embodiments, it is an amount effective to kill or inhibit the growth or spread of detectable cancer cells, the size or number of tumors, or other measures of the level, stage, progression, or severity of cancer. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the method of administration, etc., and the amount can be easily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, such as a decrease in cell migration. A particular dose will vary, for example, depending on the particular compound selected, the species of subjects and their age / existing health conditions or risk of health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is delivered.

[0028] As used herein, "treatment" and "treating" refer to an approach to obtain beneficial or desired results, including, but not limited to, therapeutic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient, even though the patient may still be afflicted by the underlying disorder.

[0029] As used herein, a "subject" or "patient" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age) or other primates.

[0030] The term "including or including" means "including, but not limited to."

[0031] The present disclosure provides a method for treating cancer in a patient in need of such treatment. The method comprises administering to the patient in need thereof a therapeutically effective amount of (i) Compound 1

[0032] [ka]

[0033] and / or a tautomer thereof, or a pharma- ceutically acceptable salt or hydrate thereof, and (ii) one or more poly(ADP-ribose) polymerase (PARP) inhibitors.

[0034] The present disclosure further provides a pharmaceutical composition comprising Compound 1 and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof and a PARP inhibitor.

[0035] The disclosure further provides a pharmaceutical combination comprising a composition comprising Compound 1 and / or a tautomer thereof, or a pharma- ceutically acceptable salt or hydrate thereof, and a composition comprising a PARP inhibitor.

[0036] The disclosure further provides a kit that includes an article for sale containing a combination comprising Compound 1 and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof and a PARP inhibitor, each packaged separately with instructions for use to treat cancer.

[0037] The combination therapy of the present disclosure includes Compound 1 and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof. Compound 1 has the following structure:

[0038] [ka]

[0039] The chemical name of compound 1 is 2-[(2S)-1-azabicyclo[2.2.2]oct-2-yl]-6-(3-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one. Compound 1 is a Cdc7 kinase inhibitor.

[0040] CDC7 inhibitors other than Compound 1 are also expected to show good antitumor effects in combination with PARP inhibitors. Thus, in another embodiment, the present disclosure further provides a combination therapy comprising (i) a CDC7 kinase inhibitor other than Compound 1 and (ii) a PARP inhibitor. In some embodiments, the CDC7 kinase inhibitor may be selected from LY3143921, KC-459, MSK-777 or RXDX-103. Thus, the present disclosure also provides a method for treating cancer in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a CDC7 kinase inhibitor and one or more PARP inhibitors.

[0041] Also encompassed in the present disclosure are tautomers of Compound 1 or pharma- ceutically acceptable salts or hydrates of Compound 1. When Compound 1 has tautomers, each isomer is also encompassed in the present disclosure.

[0042] As used herein, all phrases such as "Compound 1 and / or its tautomers" are understood to mean Compound 1 and all its tautomeric forms. As a non-limiting example, tautomerization may occur at the pyrazole and pyrimidine groups of Compound 1. Specific examples of tautomerization that may occur in Compound 1 include the following:

[0043] [ka]

[0044] Compound 1 and / or its tautomer may be used in the form of a pharma- ceutically acceptable salt. Examples of the pharma-ceutically acceptable salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

[0045] Compound 1 and / or its tautomers may be hydrated (e.g., hemihydrate), non-hydrated, solvated or non-solvated, all of which are encompassed by the present disclosure. In some embodiments, Compound 1 and / or its tautomers are hemihydrates.

[0046] Compound 1 and / or its tautomers or its pharma- ceutically acceptable salts or its hydrates or its crystalline forms can be obtained according to the preparation methods described in PCT Publication No. WO2011 / 102399, U.S. Patent No. 8,722,660, U.S. Patent No. 8,921,354, U.S. Patent No. 8,933,069, and U.S. Patent Publication No. US2015 / 158882, which are incorporated herein by reference in their entirety and for all purposes, or methods analogous thereto.

[0047] Compound 1 and / or its tautomers or pharma- ceutically acceptable salts or hydrates thereof may be in the form of a crystal (e.g., crystalline Form A, crystalline Form I, etc.), and the crystal may be in a single or multiple crystalline forms, both of which are included in Compound 1. The crystal may be in the form or produced by the methods described in PCT Publication No. WO2017 / 172565, published October 5, 2017, which is incorporated by reference in its entirety for all purposes. In some embodiments, Compound 1 and / or its tautomers or pharma- ceutically acceptable salts or hydrates thereof may be in the form of crystalline Form I, as described in WO 2017 / 172565. In some embodiments, Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate is a crystalline form of Compound 1 hemihydrate (i.e., 2-[(2S)-l-azabicyclo[2.2.2]oct-2-yl]-6-(3-methyl-lH-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one hemihydrate). For example, Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate can be the crystalline form I of Compound 1 hemihydrate.

[0048] In some embodiments, the combination therapy comprises a PARP inhibitor.

[0049] In some embodiments, the PARP inhibitor is selected from the group consisting of niraparib, olaparib, veliparib, rucaparib, pamiparib, iniparib, and terazoparib.

[0050] In some embodiments, the PARP inhibitor is niraparib.

[0051] In some embodiments, the PARP inhibitor is olaparib.

[0052] In the following example section, the in vivo test of combination therapy using PARP inhibitor is described.Multiple PARP inhibitors were tested in cancer cell lines.The results show the effectiveness of the combination therapy of the present disclosure.

[0053] In some embodiments, compound 1 and / or its tautomer or a pharma- ceutically acceptable salt or hydrate thereof and the PARP inhibitor may be formulated as a pharmaceutical composition together with a pharma- ceutically acceptable carrier or diluent and any other known adjuvants and excipients according to conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

[0054] Pharmaceutical compositions used in embodiments of the present disclosure may also include diluents, bulking agents, salts, buffers, surfactants (e.g., non-ionic surfactants such as Tween-80), stabilizers (e.g., sugars or non-protein amino acids), preservatives, tissue fixatives, solubilizing agents, and / or other materials suitable for inclusion in a pharmaceutical composition.

[0055] The compounds used in the embodiments of the present disclosure may be administered via any suitable route, such as oral, nasal, inhalation, topical (including buccal, transdermal, and sublingual), rectal, vaginal, and / or parenteral routes.

[0056] In certain embodiments, one or more compounds used in the present disclosure are orally administered, for example, with inert diluents or assimilable edible carriers.Active ingredient can be encapsulated in hard or soft shell gelatin capsules or compressed into tablets.The pharmaceutical composition suitable for oral administration includes digestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, oblates, etc., which contain carriers as known to be suitable in the art.

[0057] In certain embodiments, one or more compounds used in the present disclosure are administered parenterally. As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion.

[0058] The disclosed methods provide effective treatment for patients with cancer. In some embodiments, the cancer treated with the disclosed combination therapy is a Cdc7-related cancer (e.g., colorectal cancer (e.g., metastatic colorectal cancer), lung cancer (e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer, such as locally advanced squamous non-small cell lung cancer and metastatic squamous non-small cell lung cancer)), mesothelioma, pancreatic cancer (e.g., metastatic pancreatic cancer), pharyngeal cancer, laryngeal cancer, esophageal cancer (e.g., squamous esophageal cancer), gastric cancer, duodenal cancer, small intestine cancer, breast cancer, ovarian cancer, testicular tumor, prostate cancer, liver cancer, thyroid cancer, kidney cancer, uterine cancer, brain tumor, retinoblastoma, skin cancer, bone tumor, bladder cancer, blood cancer (e.g., multiple myeloma, leukemia, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disorder).

[0059] In some embodiments, the cancer treated with the combination therapy of the present disclosure is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer, including locally advanced squamous non-small cell lung cancer and metastatic squamous non-small cell lung cancer)), colorectal cancer (e.g., metastatic colorectal cancer), ovarian cancer, breast cancer, and pancreatic cancer (e.g., metastatic pancreatic cancer).

[0060] In some embodiments, the cancer treated with the combination therapy of the present disclosure is ovarian cancer. In some embodiments, the cancer treated with the combination therapy of the present disclosure is breast cancer.

[0061] In some embodiments, the dosage strength of Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate ranges from 5 to 200 mg. For example, in some embodiments, the medicament comprises a dosage strength of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate. In some embodiments, the daily dose of Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate administered to an adult (body weight about 60 kg) ranges from 10 to 200 mg. In other embodiments, the daily dose of Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate for an adult is about 1 to 1000 mg, about 3 to 300 mg, or about 10 to 200 mg, given in a single dose or administered in divided doses two or three times daily. In some embodiments, Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate is administered orally.

[0062] In some embodiments, the combination therapy includes niraparib, and niraparib is administered at a dose of about 100 mg / day to about 300 mg / day. In some embodiments, niraparib is administered orally. In some embodiments, niraparib is administered daily.

[0063] In some embodiments, the combination therapy includes olaparib, and olaparib is administered at a dose of about 400 mg / day to about 600 mg / day. In some embodiments, olaparib is administered orally. In some embodiments, olaparib is administered daily.

[0064] In certain embodiments, Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate is administered orally. In some embodiments, Compound 1 and / or its tautomer or its pharma- ceutically acceptable salt or hydrate is administered daily, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, or once every 4 weeks.

[0065] In certain embodiments, Compound 1 and / or its tautomer or a pharma- ceutically acceptable salt or hydrate and the PARP inhibitor may be administered simultaneously or sequentially in any order, in certain embodiments, they may be administered separately or together in one or more pharmaceutical compositions.

[0066] In some embodiments, Compound 1 and / or a tautomer thereof, or a pharma- ceutically acceptable salt or hydrate thereof may be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a PARP inhibitor to a patient with cancer.

[0067] In some embodiments, the combination therapy comprises a 28 day cycle, where compound 1 and / or its tautomer, or a pharma- ceutically acceptable salt or hydrate thereof, is administered once daily on days 1-28, and niraparib is administered once daily on days 1-28.

[0068] In some embodiments, the combination therapy comprises a 28 day cycle, where compound 1 and / or its tautomer, or a pharma- ceutically acceptable salt or hydrate thereof, is administered once daily on days 1-28, and olaparib is administered twice daily on days 1-28. EXAMPLES

[0069] Example 1 In vivo antitumor activity of Compound 1 in combination with PARP inhibitors in patient-derived xenograft (PDX) models To investigate the in vivo antitumor activity of Compound 1 in combination with a PARP inhibitor, studies were conducted using patient-derived xenograft (PDX) models. Patient-derived tumors were inoculated by the following method. Methods: Patient-derived tumors were maintained in nude mice by subcutaneous inoculation of tumor pieces (approximately 2 × 2 × 2 mm) into the nude mice. For xenograft studies, tumors were grown to approximately 130 mm. 3 (For example, 125~130mm 3 ) mice were randomly assigned to each dose group on the day before the start of dosing (day 0). Compound 1 (crystalline form I) was suspended in a solution containing 0.5 w / v% methylcellulose and orally administered to the mice. Concomitant drugs were administered as shown in Table 2. Tumor size was measured by calipers and tumor volume was calculated according to the equation V = (LW 2 ) / 2, where L and W are the length and width of the tumor, respectively, reported in cubic millimeters. The results of this study are shown in Table 2. Statistical analysis of the combination effect on tumor growth was performed as follows. All tumor values ​​(tumor volume or photon flux) were calculated using the log 10 A value of 1 is added to them before transformation. These values ​​were compared across treatment groups to assess whether differences in trends over time were statistically significant. To compare pairs of treatment groups, the following mixed-effects linear regression model was fitted to the data using maximum likelihood:

[0070]

number

[0071] where Yijk is the log 10 is the tumor value, and Y i0k is the logarithm of day 0 (baseline) of the kth animal in the ith treatment 10Tumor value, day j is the median value at the central time point, (day 2 j (along with e ijk is the residual error. A spatial power law covariance matrix was used to account for repeated measurements over time on the same animal. Interaction terms as well as day 2 j Terms were removed if they were not statistically significant. A likelihood ratio test was used to assess whether a given set of treatment groups showed a statistically significant difference. The -2 log likelihood of the full model was compared to that without any treat terms (constrained model) and the difference in values ​​was tested using a chi-square test. The degrees of freedom for the test were calculated as the difference between the degrees of freedom of the full model and the restricted model. The expected difference in log tumor values ​​(Y ijk -Y i0k , log 10 (which can be interpreted as fold change from day 0) was obtained from the above model to calculate the mean AUC value for each treatment group. dAUC values ​​were then calculated as follows:

[0072]

number

[0073] This assumed AUC ctl was positive. AUC ctl If was negative, the above formula was multiplied by -1. In synergy analysis, the difference in logarithmic tumor values ​​observed was used to calculate the AUC value for each animal. When an animal in a treatment group was removed from the study, the last observed tumor value was carried forward to all subsequent time points. The AUC of the control or vehicle group was calculated using the predicted value from the pairwise model above. We defined the measure of synergy as follows:

[0074]

number

[0075] In the formula, A k and B.k is the kth animal in each treatment group, and AB k is the kth animal in the combination treatment group. AUC ctl is the AUC of the control group predicted by the model and was treated as a constant with no variation. The standard error of the synergy score was calculated as the square root of the sum of the squares of the standard errors of groups A, B, and AB. The degrees of freedom were estimated using the Welch-Satterthwaite formula. A hypothesis test was performed to determine whether the synergy score was different from 0. P values ​​were calculated by dividing the synergy score by the standard error and tested with the degrees of freedom calculated above for a t-distribution (two-tailed). The effect was classified into four different categories. A synergy score less than 0 was considered synergistic, and a synergy score not statistically different from 0 was considered additive. A combination was less than additive if the synergy score was greater than 0 but the mean AUC of the combination was lower than the lowest mean AUC between the two monotherapies. A combination was antagonistic if the synergy score was greater than 0 and the mean AUC of the combination was higher than the mean AUC of at least one monotherapies. Interval analyses involved a specified treatment group and time interval being compared to another treatment group and time interval, where appropriate. For a given group, time interval, and animal, daily tumor growth rate was estimated by:

[0076]

number

[0077] where ΔY is the log 10 where is the difference in tumor volume and Δt is the length of the time interval. If one or both of these time points are missing, the animal was ignored. The mean rates across animals were then compared using a two-tailed unpaired t-test with unequal variances. Due to the exploratory nature of this study, there were no prespecified adjustments for the multiple comparisons and endpoints investigated. In this analysis, all P values ​​less than 0.05 were considered statistically significant.

[0078] [Table 1]

[0079] The changes in the mean tumor volume after the start of administration are shown in Figures 1 and 2. Compound 1 in combination with niraparib or olaparib showed good antitumor effects.

[0080] [Table 2]

[0081] Figure 3 shows another combination antitumor activity of Compound 1 and the PARP inhibitor, Niraparib, in BALB / c nude mice bearing PHTXS-13O human primary ovarian cancer xenografts. Xenografted mice were administered Compound 1 at 60 mg / kg and Niraparib at 50 mg / kg once daily (qd) for 21 days. Efficacy data are plotted as the mean tumor volume (n=8) in vehicle controls. After the end of drug treatment, tumor size was continuously measured for the indicated time periods.

Claims

1. A composition for treating cancer in a patient in need thereof, the composition comprising a therapeutically effective amount of Compound 1. 【Chemistry 1】 and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof; and one or more PARP inhibitors.

2. The composition of claim 1 , wherein the PARP inhibitor is niraparib.

3. 2. The composition of claim 1, wherein the PARP inhibitor is olaparib.

4. The composition of claim 1 , wherein the cancer is ovarian cancer.

5. The composition of claim 1 , wherein the cancer is breast cancer.

6. Compound 1 【Chemistry 2】 and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof; and one or more PARP inhibitors.

7. 7. The pharmaceutical composition of claim 6, further comprising a pharma- ceutically acceptable excipient.

8. 1. A composition for use in combination with one or more PARP inhibitors for the treatment of cancer, said composition comprising: Compound 1 【Chemistry 3】 and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof.

9. 2. The method of claim 1, wherein the compound is a medicament for use in combination with one or more PARP inhibitors for the treatment of cancer. 【Chemistry 4】 and / or a tautomer thereof or a pharma- ceutically acceptable salt or hydrate thereof.

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