USE OF IVALTINOSTAT TO TREAT CANCER

Abstract

Embodiments of the present disclosure relate to the use of ivartinostat in combination with one or more additional anti-cancer agents to treat cancer, particularly in patients with metastatic pancreatic adenocarcinoma.

Description

[Technical field]

[0001] The present invention relates to the use of ivartinostat in combination with one or more additional anti-cancer agents for the treatment of cancer, particularly in patients with metastatic pancreatic adenocarcinoma. [Background technology]

[0002] Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related deaths in the United States and is expected to rise to the second leading cause by 2030 (Siegel RL et al., Cancer statistics, 2021, CA Cancer J Clin 71:7-33). Nearly 90% of patients are diagnosed with inoperable disease (Ryan DP et al., Pancreatic Adenocarcinoma. N Engl J Med 2014;371:1039-1049), and the majority have distant metastases at presentation, which results in a current expected 5-year survival rate of only 3%.

[0003] The mainstay of treatment for metastatic PDAC is cytotoxic chemotherapy. Phase 3 data support FOLFIRINOX and gemcitabine with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as the most effective first-line regimens for patients who can tolerate aggressive treatment (e.g., ECOG performance status 0-1). In the PRODIGE 4 / ACCORD 11 trial (Conroy T et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N Engl J Med 2011;364:1817-1825), FOLFIRINOX produced a median progression-free survival (PFS) of 6.4 months and an overall survival (OS) of 11.1 months. In the MPACT trial (Von Hoff DD, et al., Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, N Engl J Med 2013;369:1691-1703), gemcitabine / nab-paclitaxel produced a median PFS of 5.5 months and a median OS of 8.5 months. In each trial, both regimens statistically significantly improved survival compared with the previous standard of care, gemcitabine monotherapy.

[0004] First-line chemotherapy for metastatic PDAC is generally continued until disease progression or intolerable adverse effects occur, with patients often reaching a plateau of response in 4-6 months. For patients with responsive or stable disease after first-line therapy, appropriate maintenance treatment strategies remain to be defined.

[0005] The POLO trial, the only reported phase 3 study exploring PDAC maintenance therapy, showed that the PARP inhibitor olaparib improved PFS compared with placebo in patients with germline BRCA1 / 2 (gBRCA) mutations ≥16 weeks after platinum-based therapy (median PFS 7.4 vs. 3.8 months; HR 0.53, p=0.004) (Golan T et al., Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, N Engl J Med, 2019;25;381(4):317-327). However, the use of placebo as a control arm does not accurately represent current clinical practice. Furthermore, only 1-2% of individuals with PDAC harbor gBRCA mutations (Shindo K et al., Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma, J Clin Oncol. 2017 Oct 20;35(30):3382-3390), leaving the question of the optimal maintenance approach for biomarker-unselected patients unresolved.

[0006] Maintenance therapy should ideally delay disease progression and preserve disease-related quality of life by minimizing cumulative toxicity and maximizing convenience. In the absence of phase 3 data to guide this decision, efficacy and toxicity are often balanced by reducing the number of first-line chemotherapy agents (Hammel P et al., Maintenance therapies in metastatic pancreatic cancer: present and future with a focus on PARP inhibitors, Ther Adv Med Oncol. 2020;12:1758835920937949; Petrioli R et al., Gemcitabine plus nab-paclitaxel followed by maintenance treatment with gemcitabine alone as first-line treatment for older adults with locally advanced or metastatic pancreatic cancer, J Geriatr Oncol. 2020 May;11(4):647-651; Relias V, Maloney A, Smith MH, et al., Does "OPTINAB" strategy ("stop-and-go") work in treatment of advanced pancreatic cancer (APC) with nab-paclitaxel-gemcitabine? Cancer Chemother Pharmacol. 2017 Aug;80(2):371-375). These current data support maintenance with the FOLFIRI doublet, although further reduction to fluoropyrimidine monotherapy could avoid irinotecan-associated toxicity. Prospective studies are needed to better quantify the efficacy, toxicity, and impact on quality of life of these options.Without conclusive data, current National Comprehensive Cancer Network (NCCN) guidelines list FOLFIRI, FOLFOX (oxaliplatin, leucovorin, and 5-FU) or oral fluoropyrimidine capecitabine as possible post-FOLFIRINOX maintenance therapy (National Comprehensive Cancer Network Guidelines Pancreatic Adenocarcinoma. NCCN.org. Version 2, February 25, 2021).

[0007] Although de-escalation of first-line regimens represents an intuitive approach, the introduction of novel agents with different mechanisms of action could reduce the risk of chemotherapeutic cross-resistance and prolonged disease control.There is a need to develop new therapies for the treatment or maintenance of pancreatic cancer (e.g., pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma), particularly metastatic PDAC. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2018 / 230829 [Patent Document 2] U.S. Patent Application No. 2020 / 0283371 [Non-patent literature]

[0009] [Non-Patent Document 1] Siegel RL et al., Cancer statistics, 2021, CA Cancer J Clin 71:7-33 [Non-Patent Document 2] Ryan DP et al. Pancreatic Adenocarcinoma. N Engl J Med 2014;371:1039-1049 [Non-Patent Document 3] Conroy T et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, N Engl J Med 2011;364:1817 - 1825

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[0010] One aspect of the disclosure relates to a method or use of an effective amount of ivartinostat to treat cancer in a subject in need thereof. In some embodiments, the cancer is pancreatic cancer, the subject is being treated with first-line fluoropyrimidine-based chemotherapy, and ivartinostat is used in combination with one or more additional anti-cancer agents. In further embodiments, the subject's pancreatic cancer is responsive or stable to first-line fluoropyrimidine-based chemotherapy, or the subject's pancreatic cancer has not progressed to first-line fluoropyrimidine-based chemotherapy. In some embodiments, the method or use includes identifying or selecting a subject whose pancreatic cancer is responsive or stable to first-line fluoropyrimidine-based chemotherapy, or a subject whose pancreatic cancer has not progressed to first-line fluoropyrimidine-based chemotherapy.

[0011] In some embodiments, the effective amount of ivartinostat is about 10 mg / m 2 ~about 750mg / m 2 In some embodiments, the effective amount of ivartinostat is about 25 mg / m 2 ~about 500mg / m 2 In a further embodiment, the effective amount of ivartinostat is about 50 mg / m 2 ~about 375mg / m 2 In a further embodiment, the effective amount of ivartinostat is about 60 mg / m 2 , about 125mg / m 2 or about 250 / m 2In some embodiments, ivartinostat is administered by intravenous infusion. In further embodiments, the intravenous infusion spans from about 30 minutes to about 120 minutes. In still further embodiments, the intravenous infusion is from about 50 to 70 minutes, or from about 60 minutes. In some embodiments, ivartinostat is administered on days 1 and 8 of a 21 day cycle. In other embodiments, ivartinostat is administered orally. In some embodiments, ivartinostat is administered orally at about 10 mg to about 1000 mg, about 20 mg to about 500 mg, about 30 mg to about 400 mg, or about 50 mg to about 300 mg. In some further embodiments, oral administration is once, twice, or three times daily. In further embodiments, ivartinostat is orally administered at about 10 mg / day to about 1000 mg / day, about 20 mg / day to about 500 mg / day, about 30 mg / day to about 400 mg / day, or about 50 mg / day to about 300 mg / day. In further embodiments, ivartinostat is orally administered at about 50 mg / day, about 100 mg / day, about 200 mg / day, or about 300 mg / day. In some embodiments, ivartinostat is used in combination with an effective amount of one or more additional anti-cancer agents. In some embodiments, the additional anti-cancer agent is capecitabine. In further embodiments, the effective amount of capecitabine is about 200 mg / m 2 ~about 2000mg / m 2 , about 500mg~about 1500mg / m 2 , or about 750 mg / m 2 ~about 1250mg / m 2 In yet a further embodiment, the effective amount of capecitabine is about 1000 mg / m 2 In some embodiments, capecitabine is administered orally. In further embodiments, capecitabine is administered twice daily, for example for two weeks (e.g., in a 21-day cycle). In other embodiments, the additional anticancer agent is gemcitabine or erlotinib, or a combination thereof. In some such embodiments, the effective amount of gemcitabine is about 500 mg / m 2 ~about 2000mg / m 2 , about 750mg~about 1500mg / m2 , or about 1000 mg / m 2 In further embodiments, gemcitabine is administered by weekly intravenous infusion. In some such embodiments, the effective amount of erlotinib is about 50 mg to about 200 mg, about 75 mg to about 150 mg, or about 100 mg. In further embodiments, erlotinib is administered orally once, twice, three times, or four times daily.

[0012] In some embodiments of the methods or uses described herein, the cancer may include or is pancreatic cancer (e.g., pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma). In further embodiments, the pancreatic cancer is pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma, also referred to as pancreatic ductal adenocarcinoma (PDAC). In further embodiments, the subject is being treated with first-line fluoropyrimidine-based chemotherapy, such as a FOLFIRINOX chemotherapy regimen (an abbreviation for combination chemotherapy used to treat pancreatic cancer that has spread to other parts of the body, which may include, but are not limited to, the drugs leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin). In further embodiments, the subject is being treated with a FOLFIRINOX chemotherapy regimen. In yet further embodiments, the subject has metastatic pancreatic adenocarcinoma, and the subject is responsive or stable to first-line fluoropyrimidine-based chemotherapy. In still a further embodiment, the subject has metastatic pancreatic adenocarcinoma and the disease has not progressed to first-line fluoropyrimidine-based chemotherapy.

[0013] Another aspect of the disclosure relates to a method or use of an effective amount of ivartinostat to treat or ameliorate pancreatic cancer, e.g., pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma, wherein the subject's pancreatic cancer has not progressed to first-line fluoropyrimidine-based chemotherapy, and the effective amount of ivartinostat is used in combination with an effective amount of one or more anti-cancer agents. In some embodiments, the method includes selecting or identifying a subject with metastatic pancreatic adenocarcinoma, the disease has not progressed to first-line fluoropyrimidine-based chemotherapy, and administering to the subject an effective amount of ivartinostat in combination with an effective amount of one or more anti-cancer agents. In some embodiments, the fluoropyrimidine-based chemotherapy can include oxaliplatin, irinotecan, leucovorin, or 5-fluorouracil, or a combination thereof. In some embodiments, the one or more anti-cancer agents can include a fluoropyrimidine-based chemotherapy agent or capecitabine, or a combination thereof. In some embodiments, the effective amount of ivartinostat is about 50 mg / m 2 ~about 375mg / m 2 , about 60mg, about 125mg / m 2 , or about 250 mg / m 2In some embodiments, ivartinostat is administered by intravenous infusion. In further embodiments, the intravenous infusion lasts for about 30 minutes to about 120 minutes, or about 50 to 70 minutes, or about 60 minutes. In some embodiments, ivartinostat is for administration on days 1 and 8 of a 21-day cycle. In other embodiments, ivartinostat is administered orally. In some such embodiments, ivartinostat is administered orally at about 10 mg to about 1000 mg, about 20 mg to about 500 mg, about 30 mg to about 400 mg, or about 50 mg to about 300 mg. In some further embodiments, oral administration is once, twice, or three times daily. In further embodiments, ivartinostat is orally administered at about 10 mg / day to about 1000 mg / day, about 20 mg / day to about 500 mg / day, about 30 mg / day to about 400 mg / day, or about 50 mg / day to about 300 mg / day. In further embodiments, ivartinostat is orally administered at about 50 mg / day, about 100 mg / day, about 200 mg / day, or about 300 mg / day. In some embodiments, the one or more additional anticancer agents can include or is capecitabine. In further embodiments, the effective amount of capecitabine is about 200 mg / m 2 ~about 2000mg / m 2 , about 500mg~about 1500mg / m 2 , or about 750 mg / m 2 ~about 1250mg / m 2 , or about 1000 mg / m 2 In yet a further embodiment, the effective amount of capecitabine is about 1000 mg / m 2 In some embodiments, capecitabine is administered, for example, twice daily or twice daily for two weeks (e.g., in a 21 day cycle).

[0014] Another aspect of the disclosure relates to a method or use of an effective amount of ivartinostat to treat cancer in a subject in need thereof, wherein ivartinostat is not concomitantly administered with one or more drugs that are inhibitors or inducers of CYP3A and / or CYP2D6 enzymes, or one or more drugs that are substrates of CYP2D6 and have a narrow therapeutic index. In some embodiments, the method comprises administering to the subject an effective amount of ivartinostat, and advising the subject not to concomitantly take one or more drugs that are inhibitors or inducers of CYP3A and / or CYP2D6 enzymes, or one or more drugs that are substrates of CYP2D6 and have a narrow therapeutic index.

[0015] In further embodiments, the cancer may include or is pancreatic cancer, pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma. In further embodiments, the cancer may include or is metastatic pancreatic adenocarcinoma or PDAC. In other embodiments, ivartinostat is used as a combination therapy with one or more additional anti-cancer agents. In further embodiments, the one or more additional anti-cancer agents include fluoropyrimidine-based chemotherapeutic agents, oxaliplatin, irinotecan, leucovorin, 5-fluorouracil, capecitabine, gemcitabine, erlotinib, or a combination thereof. In one embodiment, the one or more additional anti-cancer agents include or are capecitabine. In some embodiments, the one or more drugs not administered concomitantly with ivartinostat are alfentanil, cyclosporine, digoxin, dihydroergotamine, ergotamine, fentanyl, mephenytoin, phenytoin, pimozide, quinidine, sirolimus, tacrolimus, tizanidine, theophylline, or warfarin.

[0016] Further embodiments of the present disclosure relate to methods or uses of an effective amount of ivartinostat to treat or ameliorate cancer in a subject in need thereof, wherein ivartinostat is orally administered, and the oral administration provides an ivartinostat plasma Cmax ranging from about 80 μg / L to about 1800 μg / L. In some embodiments, the effective amount of ivartinostat is about 125 mg, and the Cmax of ivartinostat is from about 90 μg / L to about 250 μg / L, or about 150 μg / L. In further such embodiments, the AUC last or AUC inf is about 400 μg.h / L to about 1000 μg.h / L, about 500 μg.h / L to about 850 μg.h / L, or about 650 μg.h / L. In some other embodiments, the effective amount of ivartinostat is about 375 mg and the Cmax of ivartinostat is about 500 μg / L to about 1500 μg / L, about 750 μg / L to about 1250 μg / L, or about 1000 μg / L. In further such embodiments, the AUC last or AUC inf is about 1200 μg.h / L to about 6000 μg.h / L, about 2000 μg.h / L to about 4500 μg.h / L, about 3000 μg.h / L to about 4000 μg.h / L, or about 3700 μg.h / L. In some other embodiments, the effective amount of ivartinostat is about 750 mg and the C is about 750 μg / L to about 1800 μg / L, about 1000 μg / L to about 1500 μg / L, or about 1225 μg / L. In further such embodiments, the AUC of ivartinostat is about 1000 μg / L to about 1500 μg / L. last or AUC inf is about 4000 μg.h / L to about 10000 μg.h / L, about 5000 μg.h / L to about 8500 μg.h / L, about 6000 μg.h / L to about 7500 μg.h / L, or about 7000 μg.h / L. In some embodiments, the mean bioavailability of oral ivartinostat is about 7.5% to about 15%, about 8% to about 12%, or about 10.6%. In further embodiments, ivartinostat is administered in the fasted state.

[0017] In any of the embodiments of the methods or uses of an effective amount of ivartinostat for treating cancer in a subject in need thereof described herein, administration of ivartinostat is discontinued when the subject's absolute neutrophil count (ANC) is less than about 1,000 / μL or platelet count is less than about 100,000 / μL. In some embodiments, if the subject suffers from one or more hematological adverse events associated with ivartinostat administration, the amount of ivartinostat is reduced after the subject has recovered from the one or more hematological adverse events. In some such embodiments, the hematological adverse events can include grade 3 neutropenia or grade 3 thrombocytopenia. In some further embodiments, the amount of ivartinostat is reduced to about 80% when a second episode of grade 3 neutropenia or grade 3 thrombocytopenia occurs. In further embodiments, ivartinostat is discontinued when a third episode of grade 3 neutropenia or grade 3 thrombocytopenia occurs. In another embodiment, the hematological adverse event comprises grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia. In a further embodiment, the amount of ivartinostat is reduced to about 80% if a first episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs. In a further embodiment, the amount of ivartinostat is reduced to about 64% if a second episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs. In yet a further embodiment, ivartinostat is discontinued if a third episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs. In another embodiment, the hematological adverse event comprises grade 4 febrile neutropenia. In a further embodiment, the amount of ivartinostat is reduced by about 80% if a first episode of grade 4 febrile neutropenia occurs. In a further embodiment, ivartinostat is discontinued if a second episode of grade 4 febrile neutropenia occurs.

[0018] In any of the embodiments of the methods or uses described herein, ivartinostat is administered as a combination therapy with one or more additional anti-cancer agents. In further embodiments, ivartinostat combination therapy is used to provide maintenance treatment of pancreatic cancer (e.g., advanced or metastatic pancreatic adenocarcinoma). Ivartinostat may be administered by intravenous infusion (IV) or orally. In some embodiments, ivartinostat is administered orally when the subject is in a fasting state. In other embodiments, ivartinostat is administered orally when the subject is in a fed state.

[0019] Another aspect of the present disclosure relates to a pharmaceutical composition comprising an effective amount of ivartinostat used to treat cancer in a subject in need thereof.Another additional aspect of the present disclosure relates to a pharmaceutical composition comprising an effective amount of ivartinostat used to treat or ameliorate pancreatic adenocarcinoma in a subject in need thereof, wherein the subject's pancreatic adenocarcinoma has not progressed to first-line fluoropyrimidine-based chemotherapy, and wherein the pharmaceutical composition is used in combination with an effective amount of one or more anti-cancer agents.A further aspect of the present disclosure relates to a pharmaceutical composition comprising an effective amount of ivartinostat used to treat cancer in a subject in need thereof, wherein the pharmaceutical composition is not administered concomitantly with one or more drugs that are inhibitors or inducers of CYP3A and / or CYP2D6 enzymes, or one or more drugs that are substrates of CYP2D6 and have a narrow therapeutic index. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 illustrates the Phase 1 clinical study design of single dose ivartinostat as described in Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Ivartinostat, (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)oct-2-enediamide phosphate, is a novel anticancer therapeutic candidate that inhibits the enzymatic activity of histone deacetylase (HDAC).

[0022] [ka]

[0023] Histone acetylation / deacetylation is an essential component of the epigenetic control mechanism in human cells. This process is mediated by balanced enzymes: histone acetyltransferases (HATs), which add acetyl groups to lysine residues present at the N-terminus of histones and other proteins, and histone deacetylases (HDACs), which remove acetyl groups from lysine residues. Acetylation neutralizes the positive charge of histones, uncoupling DNA from nucleosomes and opening chromatin, leading to increased gene transcription. The balance between DHAC and HAT activity can regulate gene expression in response to charges in the molecular environment.

[0024] Essential processes such as cell proliferation, migration, angiogenesis, DNA damage repair and death depend on coordinated HDAC / HAT activity, histone modification, nucleosome remodeling and gene transcription. Aberrant epigenetic regulation due to HDAC overactivity can lead to tumor suppressor gene silencing and neoplastic cell transformation. In fact, HDAC overexpression has been detected in a wide range of cancers.

[0025] The reversible nature of epigenetic modifications creates therapeutic opportunities to restore normal gene expression to malignant cells by inhibiting HDAC activity. In preclinical studies, HDAC inhibition has been shown to limit tumor growth and angiogenesis, control tumor differentiation, and induce DNA damage, cell cycle arrest, apoptosis, and autophagy. HDAC inhibitors (HDACi) can sensitize tumor cells to chemotherapy and radiation and affect antitumor immune responses to overcome immunotherapy resistance.

[0026] HDAC enzymes are overexpressed in PDAC cells and are involved in tumorigenesis as well as tumor progression. In preclinical studies, HDACs have been found to regulate the migration / transmigration of PDAC cells and confer chemotherapy resistance. In humans, HDAC expression in PDAC surgical resection specimens correlates with poor prognosis. Thus, HDAC inhibition represents an attractive therapeutic approach, either as a monotherapy or as an adjunct to established treatments.

[0027] The optimal maintenance treatment for advanced pancreatic adenocarcinoma after first-line fluoropyrimidine-based therapy, most commonly oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil (FOLFIRINOX), remains to be determined. Simplifying multiagent regimens to fluoropyrimidine monotherapy is common practice for maintenance treatment, with the oral fluoropyrimidine capecitabine commonly used to maximize convenience. Capecitabine is administered at 1250 mg / m for the treatment of adjuvant Dukes C colon cancer and metastatic colon cancer. 2 It is presented as monotherapy with the recommended dose of twice daily for 2 weeks followed by 1 week off. This dosing schedule is effective and well tolerated in the first-line setting for patients with pancreatic cancer (Cartwright, J Clin Oncol 2002 Jan 1;20(1):160-1642002).

[0028] Other useful pharmaceutical salts of ivartinostat free base (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)oct-2-enediamide include other acid addition salts, such as the tartaric acid addition salt, which are disclosed in WO 2018 / 230829 and U.S. Patent Application No. 2020 / 0283371, each of which is incorporated by reference in its entirety. In addition to phosphate salts, other pharma- ceutically acceptable salts of ivartinostat free base may also be used in the methods described herein.

[0029] definition The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0030] 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. The use of the term "including" as well as other forms such as "include", "includes" and "included" is not limiting. The use of the term "having" as well as other forms such as "have", "has" and "had" is not limiting. As used herein, whether in transitional clauses or in the body of a claim, the terms "comprise(s)" and "comprising" should be construed as having an open-ended meaning. That is, the above terms should be construed as synonymous with the phrases "having at least" or "including at least". For example, when used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may also include additional steps. When used in the context of a compound, composition, formulation, or device, the term "comprising" means that the compound, composition, formulation, or device includes at least the recited features or ingredients, but may include additional features or ingredients.

[0031] The terms "effective amount" and "therapeutically effective amount" are broad terms and should be given their ordinary and customary meanings to those of skill in the art (and should not be limited to any special or specialized meanings), and refer, without limitation, to an amount of an administered drug or compound sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. This result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in a disease symptom. The appropriate "effective" amount in any individual case can be determined using techniques such as a dose escalation study. If the drug is approved by the U.S. Food and Drug Administration (FDA) or by a corresponding foreign drug agency, the "therapeutically effective amount" optionally refers to the dosage approved by the FDA or by the corresponding foreign drug agency for the treatment of the identified disease or condition.

[0032] "Treat", "treatment" or "treating" as used herein refers to administering a pharmaceutical composition / formulation for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a patient who does not yet suffer from a disease but who is susceptible to or otherwise at risk for a particular disease, thereby reducing the likelihood that the patient will develop the disease. The term "therapeutic treatment" refers to administering a treatment to a patient who already suffers from a disease.

[0033] The term "co-administration" and similar terms, as used herein, are intended to be broad and to be given their ordinary and customary meaning to those of skill in the art (and not to be limited to any special or specialized meaning) and refer, without limitation, to the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0034] The term "pharmaceutical acceptable salt" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art (it should not be limited to any special or specialized meaning), and refers, without limitation, to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids such as hydrohalides (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting the compounds with organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, for example, formic acid, acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting the compound with a base to form a salt, such as an ammonium salt, an alkali metal salt, such as lithium, sodium or potassium salt, an alkaline earth metal salt, such as calcium, magnesium or aluminum salt, an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, (C1-C7 alkyl)amine, cyclohexylamine, dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine salt and an amino acid, such as arginine and lysine salt, or an inorganic base, such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide salt, and the like.

[0035] It is understood that the compounds described herein can be isotopically labeled or labeled by other means, including but not limited to, chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium can provide certain therapeutic benefits, for example resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element depicted in a compound structure may include any isotope of said element. For example, in a compound structure, a hydrogen atom may be expressly disclosed or understood to be present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0036] It is understood that the methods and formulations described herein include the use of pharma- ceutically acceptable salts and / or conformers of the compounds of the preferred embodiments, as well as the metabolites and active metabolites of these compounds that have the same type of activity.Conformers are conformational isomer structures.Conformational isomerization is the phenomenon of molecules (conformers) that have the same structural formula but have different conformations of atoms around a rotating bond.

[0037] Ivartinostat as described in the Examples in connection with various clinical studies refers to a preferred embodiment of a pharmaceutical salt of ivartinostat, namely, its phosphate salt, (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)oct-2-enediamide phosphate. One of skill in the art will appreciate that other pharmaceutical salts of ivartinostat as described herein, including but not limited to the tartaric acid addition salt, may also be used in the cancer treatments described herein.

[0038] Methods of Treating Cancer One aspect of the present disclosure relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of ivartinostat.

[0039] In some embodiments of the methods described herein, the effective amount of ivartinostat is about 10 mg / m 2 ~about 750mg / m 2 , for example, about 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, 200, 205, 210 , 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725 or 750 mg / m 2 or a range defined by any two of the preceding values. In some further embodiments, the effective amount of ivartinostat is about 25 mg / m 2 ~about 500mg / m 2 In a further embodiment, the effective amount of ivartinostat is 50 mg / m 2 ~about 375mg / m 2 In a further embodiment, the effective amount of ivartinostat is about 60 mg / m 2 , about 125mg / m 2 or about 250 / m 2In some other embodiments, the effective amount of ivartinostat is about 10 mg to about 750 mg, for example, about 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, 200 , 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, or 750 mg, or a range defined by any two of the foregoing values. In some further embodiments, the effective amount of ivartinostat is about 25 mg to about 500 mg. In further embodiments, the effective amount of ivartinostat is about 50 mg to about 375 mg. In further embodiments, the effective amount of ivartinostat is about 60 mg, about 125 mg, or about 250 mg. In some embodiments, ivartinostat is administered by intravenous infusion. In further embodiments, the intravenous infusion spans from about 30 minutes to about 120 minutes. In still further embodiments, the intravenous infusion is from about 50 to 70 minutes, or about 60 minutes. In other embodiments, ivartinostat is administered orally. In some embodiments, ivartinostat is administered on days 1 and 8 of a 21-day cycle. In other embodiments, ivartinostat is administered orally once a day, twice a day, or three times a day.In some further embodiments, the effective amount of ivartinostat is from about 10 mg / day to about 1000 mg / day, e.g., about 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, 200, 205, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 750, 760, 770, 780 00, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725 or 750 mg / day, or a range defined by any two of the foregoing values. In some further embodiments, the effective amount of ivartinostat administered orally is about 50 mg / day, about 100 mg / day, about 200 mg / day, or about 300 mg / day.

[0040] In some embodiments of the methods described herein, the methods further comprise administering an effective amount of one or more additional anti-cancer agents. In some embodiments, the additional anti-cancer agent is capecitabine. In further embodiments, the effective amount of capecitabine is about 200 mg / m 2 ~about 2000mg / m 2 , for example, about 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 mg / m 2 or a range defined by any two of the foregoing values. In still further embodiments, the effective amount of capecitabine is about 1000 mg / m 2In some embodiments, capecitabine is administered orally. In further embodiments, capecitabine is administered twice daily, for example for two weeks (e.g., in a 21-day cycle). In other embodiments, the additional anticancer agent is gemcitabine or erlotinib, or a combination thereof. In some such embodiments, the effective amount of gemcitabine is about 500 mg / m 2 ~about 2000mg / m 2 , for example, about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 mg / m 2 or a range defined by any two of the foregoing values. In a further embodiment, the effective amount of gemcitabine is about 750 mg / m 2 ~about 1500mg / m 2 or about 1000 mg / m 2 In further embodiments, gemcitabine is administered by weekly intravenous infusion. In some such embodiments, the effective amount of erlotinib is about 50 mg to about 200 mg, such as about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg, or a range defined by any two of the foregoing values. In further embodiments, the effective amount of erlotinib is about 75 mg to about 150 mg or about 100 mg. In further embodiments, erlotinib is orally administered once, twice, three times, or four times per day. In one example, erlotinib is administered four times per day.

[0041] In some embodiments of the methods described herein, the cancer comprises or is pancreatic cancer (e.g., pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma). In further embodiments, the cancer comprises or is metastatic pancreatic adenocarcinoma, also referred to as pancreatic ductal adenocarcinoma (PDAC). In further embodiments, the subject is being treated with a FOLFIRINOX chemotherapy regimen (an abbreviation for combination chemotherapy used to treat pancreatic cancer that has spread to other parts of the body, which may include, but is not limited to, the drugs leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin). In further embodiments, the method comprises selecting or identifying a subject being treated with a FOLFIRINOX chemotherapy regimen (e.g., oxaliplatin, irinotecan, leucovorin, or 5-fluorouracil, or pharmaceutically acceptable salts and combinations thereof). In yet a further embodiment, the method includes selecting or identifying a subject with metastatic pancreatic adenocarcinoma after the subject has responded or stabilized to a FOLFIRINOX chemotherapy regimen. In yet a further embodiment, the method includes selecting or identifying a subject with metastatic pancreatic adenocarcinoma whose disease has not progressed to first-line fluoropyrimidine-based chemotherapy.

[0042] Selection of patient subpopulations Another aspect of the disclosure relates to a method of treating or ameliorating pancreatic cancer (e.g., pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma) in a subject in need thereof, comprising selecting or identifying a subject with metastatic pancreatic adenocarcinoma whose disease has not progressed to first-line fluoropyrimidine-based chemotherapy, and administering to the subject an effective amount of ivartinostat in combination with an effective amount of one or more anti-cancer agents. In some embodiments, the fluoropyrimidine-based chemotherapy comprises oxaliplatin, irinotecan, leucovorin, or 5-fluorouracil, or a combination thereof. In some embodiments, the one or more anti-cancer agents comprise a fluoropyrimidine-based chemotherapeutic agent or capecitabine, or a combination thereof. In some embodiments, the effective amount of ivartinostat is about 50 mg / m 2 ~about 375mg / m 2 , about 60mg / m 2 , about 125mg / m 2 , or about 250 mg / m 2 In some embodiments, ivartinostat is administered by intravenous infusion. In further embodiments, the intravenous infusion lasts for about 30 minutes to about 120 minutes, or for about 50 to 70 minutes, or for about 60 minutes. In other embodiments, ivartinostat is administered orally. In some embodiments, ivartinostat is administered on days 1 and 8 of a 21 day cycle. In some embodiments, the one or more additional anticancer agents comprises or is capecitabine. In further embodiments, the effective amount of capecitabine is about 200 mg / m 2 ~about 2000mg / m 2 , about 500mg~about 1500mg / m 2 , or about 750 mg / m 2 ~about 1250mg / m 2 , or about 1000 mg / m 2 In yet a further embodiment, the effective amount of capecitabine is about 1000 mg / m 2 In some embodiments, capecitabine is administered orally, for example, twice daily for two weeks (eg, in a 21 day cycle).

[0043] Drug interactions Non-clinical studies demonstrate that ivartinostat is a substrate for CYP3A and CYP2D6. Concomitant use of drugs that are moderate or strong inhibitors or inducers of these CYP enzymes should be avoided. In addition, in vitro studies have shown that ivartinostat inhibits CYP2D6 with an IC50 of 5.5 μM, with IC50 values ​​of >10 μM for CYP 1A2 and 3A4, and >90 μM for CYP 2C9 and 2C19. Concomitant use of drugs that are substrates for CYP2D6 and have narrow therapeutic indices is not recommended.

[0044] Another aspect of the present disclosure relates to a method of providing ivartinostat therapy to a subject in need thereof, comprising administering to the subject an effective amount of ivartinostat and advising the subject not to concomitantly take one or more medications that are inhibitors or inducers of the CYP3A and / or CYP2D6 enzymes.

[0045] A further aspect of the present disclosure relates to a method of providing ivartinostat therapy to a subject in need thereof, comprising administering to the subject an effective amount of ivartinostat and advising the subject not to concomitantly take one or more drugs that are substrates of CYP2D6 and have a narrow therapeutic index.

[0046] In some embodiments of the ivartinostat therapy described herein, the ivartinostat therapy is for treating cancer. In further embodiments, the cancer includes or is pancreatic cancer (e.g., pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma, or metastatic pancreatic adenocarcinoma). In further embodiments, the cancer includes or is metastatic pancreatic adenocarcinoma or PDAC. In further embodiments, the subject is being treated with a FOLFIRINOX chemotherapy regimen (an abbreviation for combination chemotherapy used to treat pancreatic cancer that has spread to other parts of the body, which may include, but is not limited to, the drugs leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin). In further embodiments, the method includes selecting or identifying a subject being treated with a FOLFIRINOX chemotherapy regimen. In yet a further embodiment, the method comprises selecting or identifying a subject with metastatic pancreatic adenocarcinoma after the subject has a response or stable disease to a FOLFIRINOX chemotherapy regimen. In yet a further embodiment, the method comprises selecting or identifying a subject with metastatic pancreatic adenocarcinoma whose disease has not progressed to first-line fluoropyrimidine-based chemotherapy. In some embodiments, the ivartinostat therapy is a monotherapy. In other embodiments, the ivartinostat therapy is a combination therapy with one or more additional anticancer agents. In a further embodiment, the one or more additional anticancer agents include a fluoropyrimidine-based chemotherapy agent, oxaliplatin, irinotecan, leucovorin, 5-fluorouracil, capecitabine, gemcitabine, erlotinib, or a combination thereof. In one embodiment, the one or more additional anticancer agents include or are capecitabine. In some embodiments, the one or more drugs that should not be taken concomitantly with ivartinostat include alfentanil, cyclosporine, digoxin, dihydroergotamine, ergotamine, fentanyl, mephenytoin, phenytoin, pimozide, quinidine, sirolimus, tacrolimus, tizanidine, theophylline, or warfarin.

[0047] Dose adjustment In any embodiment of the methods of treating cancer or providing ivartinostat therapy described herein, the methods can further include measuring the subject's absolute neutrophil count (ANC) and platelet count, and discontinuing administration if the subject's ANC is less than about 1,000 / μL or the platelet count is less than about 100,000 / μL.

[0048] In some embodiments, the method may further include monitoring the subject for one or more hematological adverse events associated with ivartinostat administration and reducing the amount of ivartinostat (e.g., after the subject has recovered from the one or more hematological adverse events). In some such embodiments, the hematological adverse events include grade 3 neutropenia or grade 3 thrombocytopenia. In some further embodiments, the amount of ivartinostat is reduced to about 80% if a second episode of grade 3 neutropenia or grade 3 thrombocytopenia occurs. In further embodiments, ivartinostat is discontinued if a third episode of grade 3 neutropenia or grade 3 thrombocytopenia occurs. In other embodiments, the hematological adverse events include grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia. In a further embodiment, the amount of ivartinostat is reduced to about 80% if a first episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs. In a further embodiment, the amount of ivartinostat is reduced to about 64% if a second episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs. In yet a further embodiment, ivartinostat is discontinued if a third episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs. In other embodiments, the hematological adverse event comprises grade 4 febrile neutropenia. In a further embodiment, the amount of ivartinostat is reduced to about 80% if a first episode of grade 4 febrile neutropenia occurs. In a further embodiment, ivartinostat is discontinued if a second episode of grade 4 febrile neutropenia occurs. A summary of dose modifications of ivartinostat based on one or more adverse events (e.g., hematological adverse events, diarrhea, nausea, vomiting, or those related to liver function tests) can be found below in Tables A, B, C, and E.

[0049] [Table 1]

[0050] [Table 2]

[0051] [Table 3]

[0052] [Table 4]

[0053] [Table 5]

[0054] Pharmacokinetics and pharmacodynamics of oral ivartinostat therapy. Further embodiments of the present disclosure relate to a method of treating or ameliorating cancer in a subject in need thereof, comprising orally administering an effective amount of ivartinostat to the subject, wherein the oral administration provides an ivartinostat plasma Cmax ranging from about 80 μg / L to about 1800 μg / L. In some embodiments, the effective amount of ivartinostat is described herein in the section on methods of treating cancer. Further discussion of the PK / PD of ivartinostat oral therapy is disclosed in detail in Example 3.

[0055] In some embodiments, the effective amount of ivartinostat is about 125 mg, and the Cmax of ivartinostat is about 90 μg / L to about 250 μg / L, e.g., about 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 μg / L, or a range defined by any two of the foregoing values. In further embodiments, the Cmax of ivartinostat is about 150 μg / L. In such embodiments, the AUC last or AUC inf is about 400 μg.h / L to about 1000 μg.h / L, for example, about 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1 In a further embodiment, the AUC of ivartinostat is 10, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990 or 1000 μg.h / L, or a range defined by any two of the foregoing values. last or AUC inf is about 500 μg.h / L to about 850 μg.h / L, about 550 μg.h / L to about 750 μg.h / L, about 640 μg.h / L, or about 650 μg.h / L.

[0056] In some other embodiments, the effective amount of ivartinostat is about 375 mg, and the Cmax of ivartinostat is about 500 μg.h / L to about 1500 μg.h / L, e.g., about 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450 or 1500 μg.h / L, or a range defined by any two of the foregoing values. In further embodiments, the Cmax of ivartinostat is about 750 μg / L to about 1250 μg / L, or about 975 μg / L, or about 1000 μg / L. In further embodiments, the AUC last or AUC inf is about 1200 μg.h / L to about 6000 μg.h / L, for example, about 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600 , 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900 or 6000 μg.h / L, or a range defined by any two of the foregoing values. last or AUC inf is about 2000 μg.h / L to about 4500 μg.h / L, about 3000 μg.h / L to about 4000 μg.h / L, about 3700 μg.h / L, or about 3740 μg.h / L.

[0057] In some other embodiments, the effective amount of ivartinostat is about 750 mg and the Cmax is about 750 μg / L to about 1800 μg / L, e.g., about 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 15 In a further embodiment, the AUC of ivartinostat is about 1000μg / L to about 1500μg / L, about 1100μg / L to about 1400μg / L, or about 1225μg / L. In a further embodiment, the AUC of ivartinostat is about 1000μg / L to about 1500μg / L, about 1100μg / L to about 1400μg / L, or about 1225μg / L. In a further embodiment, the AUC of ivartinostat is about 1000μg / L to about 1500μg / L, about 1100μg / L to about 1400μg / L, or about 1225μg / L. last or AUC inf is about 4000 μg.h / L to about 10000 μg.h / L, for example, about 4000, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 7200 , 7300, 7400, 7500, 7600, 7700, 7800, 7900, 8000, 8100, 8200, 8300, 8400, 8500, 8600, 8700, 8800, 8900, 9000, 9100, 9200, 9300, 9400, 9500, 9600, 9700, 9800, 9900 or 10000 μg.h / L, or a range defined by any two of the foregoing values. last or AUC inf is about 5000 μg.h / L to about 8500 μg.h / L, about 6000 μg.h / L to about 7500 μg.h / L, about 7100 μg.h / L, or about 7060 μg.h / L.

[0058] In some embodiments, the mean bioavailability of oral ivartinostat is about 7.5% to about 15%, e.g., about 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, or a range defined by any two of the foregoing values. In further embodiments, the mean bioavailability of oral ivartinostat is about 7.7% to about 13.4%, about 10.9%, or about 10.6%. In further embodiments, ivartinostat is administered in the fasted state.

[0059] In any of the embodiments of the methods described herein, ivartinostat is administered as a combination therapy with one or more additional anti-cancer agents. In further embodiments, ivartinostat combination therapy is used to provide maintenance treatment of pancreatic cancer (e.g., advanced or metastatic pancreatic adenocarcinoma). Ivartinostat can be administered either by intravenous infusion (IV) or orally. In some embodiments, ivartinostat is administered orally when the subject is in a fasting state. In other embodiments, ivartinostat is administered orally when the subject is in a fed state.

[0060] Pharmaceutical Compositions The ivartinostat described herein may be provided for administration in the form of a pharmaceutical composition comprising an effective amount of ivartinostat or a pharma- ceutically acceptable salt, e.g., a phosphate salt, and at least one pharma- ceutically acceptable excipient or carrier.

[0061] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as one or more excipients. A pharmaceutical composition facilitates administration of a compound to an organism. A pharmaceutical composition is generally adapted for a particular intended route of administration.

[0062] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. Excipients also include ingredients in a pharmaceutical composition that lack appreciable pharmacological activity but may be pharmacologic necessary or desirable, for example, to increase the bulk of potent drugs whose mass is too small to manufacture and / or administer. They may also be liquids for dissolving drugs to be administered by injection, ingestion, or inhalation. For example, buffered aqueous solutions, such as, but not limited to, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0063] The pharmaceutical compositions described herein can be administered to human patients by themselves, or can be administered in pharmaceutical compositions mixed with other active ingredients as a combination therapy, or mixed with excipients, or combinations thereof. The appropriate formulation depends on the route of administration selected. Techniques for the formulation and administration of the compounds described herein are known to those skilled in the art.

[0064] The pharmaceutical compositions disclosed herein can be manufactured by a method known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping or tabletting methods.In addition, the active ingredients (e.g., ivartinostat and one or more additional anticancer agents) are contained in an effective amount to achieve the intended purpose.

[0065] In some embodiments, the pharmaceutical composition also contains at least one pharma- ceutical acceptable inactive ingredient. The pharmaceutical composition may be formulated for intravenous injection, subcutaneous injection, oral administration, buccal administration, inhalation, nasal administration, topical administration, transdermal administration, ocular administration, or aural administration. The pharmaceutical composition may be in the form of a tablet, pill, capsule, liquid, inhalant, nasal spray, suppository, suspension, gel, colloid, dispersion, solution, emulsion, ointment, lotion, eye drop, or ear drop.

[0066] Numerous techniques exist in the art for administering pharmaceutical compositions, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, the pharmaceutical composition of ivartinostat may be administered intravenously. In some other embodiments, the pharmaceutical composition of ivartinostat may be administered orally.

[0067] If desired, the composition may be presented in a pack or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, and sale of pharmaceuticals, which notice reflects the agency's approval of the form of the drug for human or veterinary administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. The pharmaceutical compositions described herein formulated with compatible pharmaceutical excipients may also be prepared, placed in a suitable container, and labeled for the treatment of an indicated condition. In ivartinostat combination therapy, the pharmaceutical composition containing ivartinostat may be in a separate form from the pharmaceutical composition containing one or more additional therapeutic agents (e.g., one or more anticancer agents). For example, a pharmaceutical composition containing ivartinostat is administered IV, while a pharmaceutical composition containing an additional anti-cancer agent is administered by a different route of administration (e.g., orally). In some such embodiments, the pharmaceutical composition of ivartinostat may be packaged separately from the additional therapeutic agent in a kit, or may be marketed as two separate products. In other embodiments, the pharmaceutical composition containing ivartinostat is administered by the same route as the pharmaceutical composition containing the additional anti-cancer agent. Thus, ivartinostat and the additional anti-cancer agent may be in a single unit dosage form, or may be adapted to be administered together. EXAMPLES

[0068] Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0069] Example 1 Phase 1b / 2 Study of Ivartinostat in Combination with Capecitabine or Capecitabine Monotherapy The primary objective of this Phase 1b / 2 study is to determine the efficacy of ivartinostat in combination with capecitabine and capecitabine monotherapy in the maintenance treatment of patients with metastatic pancreatic adenocarcinoma after disease response or stable disease with a FOLFIRINOX chemotherapy regimen, as measured by PFS.

[0070] Phase 1b will study three dose levels of ivartinostat in combination with a fixed dose of capecitabine to determine the recommended phase 2 dose (RP2D) of ivartinostat.

[0071] In Phase 2, patients will be randomized 1:1 to receive ivartinostat plus capecitabine or capecitabine monotherapy. 2 A fixed dose of 100 mg / kg / day will be taken on days 1-14, and the RP2D of ivartinostat will be administered intravenously once a week for 2 weeks, followed by 1 week off. One cycle consists of 21 days. Tumor response during study treatment will be assessed every 6 weeks until cycle 10, then every 9 weeks thereafter using RECIST v1.1 criteria.

[0072] All eligible patients must have a histologically or cytologically confirmed diagnosis of metastatic pancreatic adenocarcinoma, have received a minimum of 16 weeks of FOLFIRINOX treatment, and, in the opinion of the investigator, must have no evidence of progression. Screening will be completed ≥2 to ≤6 weeks after the last dose of first-line therapy. Randomization will occur within 6 weeks of the last dose of first-line therapy. Treatment will begin within 7 days of randomization.

[0073] The study had approximately 70 patients (18 in Phase 1b dose escalation and 52 in Phase 2 randomization). Phase 1b will study three dose levels of ivartinostat in combination with a fixed dose of capecitabine to determine the RP2D. Phase 2 will randomize patients in a 1:1 ratio to the combination of ivartinostat and capecitabine or capecitabine monotherapy, as specified below. Group A Ivartinostat (doses of 60, 125, or 250 mg / m2) administered over 60 minutes (±10 minutes) on days 1 and 8 of a 21-day cycle 2 Intravenous infusion (one of three doses will be selected after reviewing the results of Phase 1b) Capecitabine 1000 mg / m orally twice daily on days 1 through 14 of a 21-day cycle 2 or Group B Capecitabine 1000 mg / m orally twice daily on days 1 through 14 of a 21-day cycle 2

[0074] In Phase 1b, patients will visit for assessments on days 1, 2, 3, 5, 8, and 15 of cycle 1 and will receive treatment on days 1 and 8. After cycle 1, patients will visit on a weekly schedule for treatment (days 1 and 8) and assessments (days 1, 8, and 15) during a 21-day cycle, and will receive study treatment the remainder of the time. In Phase 2, patients will visit on a weekly schedule for treatment (days 1 and 8) and assessments (days 1, 8, and 15) during a 21-day cycle.

[0075] Phase 1b will enroll up to 18 patients (three dose levels of ivartinostat [60, 125 and 250 mg / m 2 ]+1000mg / m 2 Phase 1b will enroll 10 patients (6 patients each in 100 mg / kg and 100 mg / kg BID) to assess the safety and tolerability of the combination of ivartinostat and capecitabine, determine the ivartinostat RP2D, assess the pharmacokinetics (PDy) of ivartinostat, and assess PK parameters of both ivartinostat and capecitabine. Phase 1b data will be used for safety analyses but not efficacy analyses.

[0076] Tumor response during study treatment will be assessed using RECIST v1.1 criteria. Baseline and on-treatment tumor assessments will be performed using CT or MRI scans of the chest, abdomen, and pelvis, as well as other areas clinically indicated for assessment of disease. Baseline assessments should be performed within the 28-day screening period, as close as possible to randomization, prior to initiating study treatment. Follow-up assessments consistent with baseline radiological assessments (i.e., if a CT scan is performed at baseline assessment, a CT scan should be performed for follow-up assessments) should be performed approximately every 6 weeks (± 1 week) until objective disease progression as defined by RECIST v1.1. In addition to the imaging listed above, any other sites with known or suspected new disease should also be imaged as appropriate. Safety assessments will be performed at each protocol-specific study visit.

[0077] Patients will continue to receive study treatment until investigator-assessed RECIST v1.1 objective radiographic disease progression or until unacceptable toxicity occurs.

[0078] If a patient discontinues study treatment, subsequent treatment options will be at the discretion of the treating physician. It is expected (but not required) that patients may be treated again with the first-line regimen. Patients will be visited on an approximately 8-weekly schedule and followed up for survival. Details of any further anti-cancer treatment will be collected until death, loss to follow-up, or withdrawal of consent. In addition to the 8-weekly visits, patients will be visited 7 days after a specified date (data cut-off date) to obtain current survival status for each survival analysis. Any patients who discontinue study treatment for reasons other than objective radiographic progression should continue to receive objective tumor assessments scheduled according to the study plan to be assessed for objective radiographic disease progression.

[0079] [Table 6A]

[0080] [Table 6B]

[0081] Study population Inclusion criteria 1. Provide informed consent prior to any specific procedures of the study. 2.Age: ≥ 18 years old 3. In Phase 1b, histologically or cytologically confirmed pancreatic adenocarcinoma (locally advanced or metastatic) that has had at least one prior treatment in either the advanced or perioperative setting. 4. In Phase 1b, measurable and / or non-measurable disease per RECIST v1.1. 5. In Phase 2, have histologically or cytologically confirmed pancreatic adenocarcinoma with no evidence of disease progression while receiving initial chemotherapy for metastatic disease (e.g., must have had a documented CR, PR or SD after initial chemotherapy). 6. In Phase 2, there is measurable disease and / or non-measurable disease or no evidence of disease as assessed by baseline CT (or MRI if CT is contraindicated). RECIST v1.1 will be used to allow assessment of disease progression due to new lesions in patients with no evidence of disease at baseline. Patients with no evidence of disease after FOLFIRINOX chemotherapy are considered to have radiographic disease progression if new lesions are detected. 7. In Phase 2, there is treatment of metastatic pancreatic adenocarcinoma with FOLFIRINOX at full or modified doses for a minimum of 16 weeks and no evidence of progression based on radiographic imaging. a. Randomization must occur within 6 weeks of the last dose of chemotherapy. b. Patients receiving at least 16 weeks of a FOLFIRINOX combination regimen but who have discontinued non-fluoropyrimidine chemotherapy agents prior to week 16 due to toxicity are eligible if they have no radiographic evidence of disease. 8. In Phase 2, patients who have received prior chemotherapy or prior chemoradiation for a previous cancer or adjuvant / neoadjuvant treatment for pancreatic adenocarcinoma are eligible, provided that at least 12 months have elapsed between the last dose of treatment for metastatic pancreatic adenocarcinoma and the start of FOLFIRINOX chemotherapy. 9. Prior radiation therapy is permitted, provided that radiation is completed >14 days prior to randomization. 10. Normal organ and bone marrow function as defined as follows: Hemoglobin ≥ 9.0 g / dL and no packed red blood cell transfusions within the past 7 days. Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L. C. Platelet count ≥ 100 × 10 9 / L and no platelet transfusion in the past 7 days. d. Total bilirubin is ≤ 1.5x the institutional upper limit of normal (ULN). e. AST(SGOT) / ALT(SGPT) must be ≦2.5× institutional ULN value unless liver metastases are present, in which case they must be ≦5× ULN. f. Creatinine clearance calculated by Cockroft-Gault equation is ≥ 50 mL / min. A 24-hour urine collection can also be used for creatinine clearance. g. Serum albumin is ≥ 2.5 mg / dL. 11. ECOG performance status of 0-1 on the day of signing informed consent. 12. Evidence of postmenopausal or non-pregnant status in women of childbearing potential: negative urine or serum pregnancy test. Postmenopausal is defined as: Amenorrhea ≥ 1 year after cessation of exogenous hormone treatment. b. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the postmenopausal range in women under 50 years of age. c. Radiation-induced oophorectomy ≥ 1 year after last menstrual period. d. Chemotherapy-induced menopause with an interval of ≥ 1 year since the last menstrual period. e. Surgical sterilization (bilateral oophorectomy or hysterectomy). 13. Women of childbearing potential who do not meet the above criteria must not have plans to become pregnant in the next 6 months and must be willing to take effective measures to prevent pregnancy with at least two forms of contraception. Options include: 1) hormonal method of birth control (insertive, injectable, transdermal, or oral combination [estrogen + progestin]) + male condom; 2) intrauterine device + male condom; 3) tubal occlusion + male condom; 4) vasectomy of sexual partner (participant must ensure that partner has received proof of azoospermia after vasectomy) + male condom; and 5) true total abstinence from the first dose of study drug until 90 days after the last dose. 14. Male patients must agree to abstain from sexual intercourse or use double barrier contraception (as above) for the duration of the study treatment period and for at least 90 days after receiving the last dose of study medication. Male patients should also refrain from donating sperm or providing sperm for in vitro fertilization during the above periods. 15. Willing to comply with the protocol for the duration of the study, including undergoing treatment and attending scheduled visits and examinations. Exclusion criteria 1. In phase 2, radiographic progression of tumor according to RECIST 1.1 between the start of first-line FOLFIRINOX chemotherapy for metastatic pancreatic adenocarcinoma and randomization. 2. Cytotoxic chemotherapy or non-hormonally targeted therapy is not permitted within 28 days of Cycle 1, Day 1. Palliative radiation therapy must be completed ≥14 days prior to Cycle 1, Day 1. Patients may receive stable doses of bisphosphonates or RANKL-directed therapy for bone metastases before and during the study as long as they are initiated at least 2 weeks prior to study treatment. 3. In phase 2, patients must not have received FOLFIRINOX as initial therapy for metastatic PDAC. Patients who initially received FOLFIRINOX and had to discontinue irinotecan or oxaliplatin due to toxicity are eligible, but must have received at least 4 weeks (2 cycles) of FOLFIRINOX. 4. In Phase 2, >1 prior first-line therapy for metastatic PDAC. 5. Exposure to investigational drug within 30 days or 5 half-lives (whichever is longer) prior to randomization. 6. Any prior treatment with a histone deacetylase (HDAC) inhibitor, including ivartinostat. 7. Other primary cancer. Exceptions: adequately treated non-melanoma skin cancer, post-resection prostate cancer with undetectable prostate specific antigen (PSA), curatively treated cervical intraepithelial neoplasia, ductal carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial cancer, or other solid tumors, including lymphoma (without bone marrow involvement), curatively treated with no evidence of disease ≥ 2 years prior to study entry. 8. Clinically significant (as judged by the investigator) persistent toxicity (CTCAE v5.0 grade ≥ 2) caused by prior cancer therapy, excluding alopecia and grade 2 neuropathy. 9. Major surgery within 2 weeks of starting treatment. Patients must also have recovered from the effects of any major surgery. 10. Patients with a mean QTc (using Fridericia correction calculation) >470 msec. 11. Known active hepatitis B or C infection (positive HBV expression antigen, positive HCV RNA). Patients with treated hepatitis B or C and no evidence of active viral replication may participate. 12. Known HIV infection. 13. Clinically significant uncontrolled medical conditions are not tolerated (e.g., active infection requiring IV antibiotics), symptomatic congestive heart failure (NYHA class III or IV), unstable angina, recent (3 months) myocardial infarction, extensive bilateral interstitial lung disease, psychiatric illness that limits the ability to comply with study procedures, and any other medical condition that, in the opinion of the investigator, exposes the patient to an unacceptable risk of toxicity. Patients with venous thromboembolism (VTE) (pulmonary embolism [PE] or deep vein thrombosis [DVT]) may participate if they have been on stable anticoagulation for at least 3 months. 14. Refractory ascites (requiring regular paracentesis at <2 week intervals). 15. Gastrointestinal bleeding requiring blood transfusion within 30 days prior to randomization. 16. Known central nervous system (CNS) metastases or leptomeningeal disease. Patients who have had adequately treated CNS metastases and who are no longer receiving steroid or anticonvulsant therapy are eligible. 17. Patients who are unable to swallow orally administered medications and / or have gastrointestinal disorders that may interfere with absorption of the study medication. 18. Pregnant or breastfeeding women. 19. Known hypersensitivity to ivartinostat or capecitabine, or to any of the excipients of these drugs. 20. Have known dihydropyrimidine dehydrogenase (DPD) deficiency. 21. Known pathogenic or likely pathogenic germline variant in the BRCA1 or BRCA2 gene. 22.Patients using strong CYP3A4 and CYP2D6 inhibitors or drugs for which coadministration with capecitabine is not recommended. 23. Patients using cytidine deaminase inhibitors. 24. Patients using full dose Coumadin / warfarin for anticoagulation.

[0082] Study Drug / Treatment Group, Dose and Mode of Administration Ivartinostat is supplied as a 125 mg powder in a glass vial and reconstituted with 0.9% saline. 2 will be infused IV over 60 minutes (± 10 minutes) on days 1 and 8 of a 21-day cycle (Phase 1b and Phase 2 Arm A).

[0083] Capecitabine is commercially available in tablets of 150 and 500 mg. 2 is administered orally twice daily on days 1 through 14 of a 21-day cycle. Capecitabine should be administered within 30 minutes after a meal and within 10 minutes before the start of the ivartinostat IV infusion on ivartinostat infusion days.

[0084] Duration of treatment / study Each patient will continue study treatment until progressive disease (PD), toxicity, death, or discontinuation based on patient or investigator decision.

[0085] The total duration will be up to approximately 34 months, including a 28-day screening period, an approximately 8-month treatment period (approximately 10 cycles of treatment), an approximately 30-day safety follow-up period, followed by post-study long-term survival follow-up for up to approximately 2 years (approximately every 8 weeks after the safety follow-up visit).

[0086] Dose Modification In the event of an AE at least possibly related to either of the study drugs, the dose of ivartinostat and / or capecitabine should be adjusted according to the guidelines provided in the table below. If an AE at least possibly related is not covered in the table, the dose may be reduced or maintained at the investigator's discretion for patient safety. Note that patients who experience a recurrence of a treatment-related AE requiring more than two dose reductions of either / both drugs should be removed from the study.

[0087] Because the two study drugs present potentially overlapping toxicities, if the drug-specific attribution of AEs is unclear and the order of dose reduction rules is not specifically specified, both drugs may be reduced simultaneously at the investigator's discretion, or each drug may be reduced in an alternating manner (i.e., attempt ivartinostat dose reduction first, then capecitabine dose reduction, etc.).

[0088] If one study drug is held or discontinued due to an AE, the other may be continued at the discretion of the investigator after consultation with the study's Medical Monitor. Once a drug dose reduction has been made, it will not be increased again to the starting dose or previous dose level.

[0089] Patients with AEs that can be managed with supportive care may not require dose reduction (e.g., nausea / vomiting can be treated with antiemetics, diarrhea can be treated with loperamide, anemia can be managed with transfusions, and electrolyte abnormalities can be corrected with nutritional supplements rather than dose reduction).

[0090] Dose levels (each drug is considered separately)

[0091] [Table 7]

[0092] Example 2 Phase 1 / 2 Study of Ivartinostat (IV) in Combination with Gemcitabine and Erlotinib In the Phase 1 component of the study, a total of 10 subjects were randomized to receive 187.5 mg / m 2 (n=3), 250 mg / m 2 (n=3) and 312.5 mg / m 2 (n=4) received ivartinostat in combination with gemcitabine (1000 mg / m 2 on days 1, 8, and 15) and in combination with erlotinib (100 mg orally QD). All 10 subjects completed cycle 1 and were eligible for dose-limiting toxicity (DLT) evaluation.

[0093] In the phase 2 component of the study, 24 subjects received 250 mg / m 2 The dose level of ivartinostat was compared with gemcitabine (1000 mg / m 2 Patients received 100 mg PO QD (IV on days 1, 8, and 15) in combination with erlotinib (100 mg PO QD). In Phase 2, the planned treatment duration was up to 6 cycles, but treatment could continue beyond 6 cycles at the discretion of the subject and treating physician in the absence of disease progression. Ten subjects completed the study target of 6 cycles of treatment, and 4 subjects continued treatment beyond 6 cycles.

[0094] In the phase 2 portion of the study, ivartinostat 250 mg / m 2+ Gemcitabine and erlotinib were generally well tolerated, with myelosuppression being the major toxicity. The most common grade ≥3 treatment-related AEs (≥10% frequency) were decreased neutrophil count (grade 3, 13%; grade 4, 17%), decreased platelet count (grade 3, 17%; grade 4, 13%), and anemia (grade 3, 17%; grade 4, 0%). No subjects discontinued study drug due to AEs, and there were no reported deaths associated with SAEs considered to be related to study drug. In 16 subjects who had at least one tumor evaluation, the objective response rate (ORR) was 25.0% and the disease control rate (DCR) was 93.8%, based on partial responses in 4 patients (25%) and stable disease in 11 patients (68.8%).

[0095] Example 3 A randomized phase 1 single-dose study of ivartinostat (IV and oral) The objective of this study was to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of IV (CG-745) and oral (CG-750) formulations of ivartinostat in healthy volunteers.

[0096] research design A randomized, double-blind, placebo-controlled, two-treatment, two-period crossover study was conducted with three cohorts. Subjects were randomized (6:2) to receive either CG-745 (Cohorts 1 and 3: 125 mg; Cohort 2: 250 mg) or placebo followed by a 14-day washout period followed by CG-750 (Cohort 1: 125 mg; Cohort 2: 375 mg; Cohort 3: 750 mg) or placebo. In addition, the effect of food was investigated in Cohort 2 with the same design. Figure 1 illustrates the study design in detail. Subjects were aged 19-50 years and had a body mass index of 18-30 kg / m 2 Healthy male volunteers who met the criteria were eligible for this study.

[0097] Pharmacodynamic Sampling, Assays and Analysis CG-745 (IV): 0 (pre-dose), 0.33 (20 min), 0.67 (40 min), 1, 1.083 (1 hr 5 min), 1.25 (1 hr 15 min), 1.5, 2, 3, 4, 5, 6, 7, 9, 12, 25, 48, and 72 hours after start of IV infusion. CG-750 (PO): 0 (pre-dose), 0.33 (20 min), 0.67 (40 min), 1.5, 2, 3, 4, 5, 6, 7, 9, 12, 25, 48 and 72 hours after oral administration. Urine samples for ivartinostat were collected at time intervals of 0-4, 4-12, 12-24, and 24-48 hours after each dose. Ivartinostat was quantified by a validated liquid chromatography tandem mass spectrometry (LC / MS / MS) method. Maximum plasma concentration (C max ) and the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC last ) was calculated by noncompartmental methods. Bioavailability (F) was calculated as the dose-normalized AUC inf The dose-normalized parameters (C max / dose, AUC last / dose) were analyzed by the Kruskal-Wallis test and dose proportionality was assessed with a power model (Ln(y)=α+β*Ln[dose]).

[0098] Pharmacodynamic Sampling and Analysis Histone H3 acetylation at lysine 9 (K9), lysine 9 / 14 (K9 / K14) and lysine 27 (K27) sites in peripheral blood mononuclear cells (PBMCs) was assessed by Western blot and blood samples were collected for H3 acetylation at 0 (pre-dose), 2, 5, 9, 25, 48 and 72 hours after administration. AUEC, area under the histone acetylation induction %-time curve, was calculated by non-compartmental analysis using Phoenix™ WinNonlin® (Pharsight, CA, USA) software version 8.0. The pharmacodynamic effect of ivartinostat on AUEC was compared between the two formulations (CG-745 vs. CG-750 in the fasting state) within each cohort using the Wilcoxon signed rank test.

[0099] Safety and Tolerability Safety and tolerability were assessed by vital signs, physical examination, clinical laboratory tests, 12-lead electrocardiogram (ECG) and monitoring of adverse events (AEs).

[0100] Research findings A total of 25 subjects were randomized, and 23 completed the study. One patient in cohort 2 did not receive treatment due to withdrawal of consent, and one patient in the placebo group (cohort 2) withdrew consent after periods 1 and 2 of treatment.

[0101] Pharmacokinetic results The mean bioavailability of CG-750 in the fasted state was 7.68%, 13.36%, and 10.86% in cohorts 1, 2, and 3, respectively. The elimination half-life of ivartinostat after a single dose of CG-745 (IV) was consistent between cohorts, ranging from 13.36 to 14.82 hours. After administration of CG-750 (PO), the elimination half-life ranged from 8.77 to 14.41 hours. The C between cohorts max The difference was not significant (p = 0.0516), and the slope (95% CI) of the regression line analyzed by the power model was 1.2199 (0.8477-1.5920). last and AUC inf did not meet the criteria for dose proportionality, but AUClast and AUC inf Both showed dose linearity (p = 0.0691), and the slope of the regression line (95% CI) was AUC last and AUC inf The PK data for each were 1.3692 (1.0486-1.6898) and 1.3643 (1.0457-1.6830), respectively. Detailed PK data are summarized in Table 1 below.

[0102] Pharmacokinetic results Immediately following administration of CG-745 (IV) or CG-750 (PO), a significant induction of histone H3 acetylation was observed in all study cohorts. AUEC (K9, K9 / K14, or K27) ranged from 4,422 to 18,749% h and 321 to 13,714% h after administration of CG-745 (IV) and CG-750 (PO), respectively, in the fasted state. AUC last and AUEC for histone acetylation generally correlated well. The AUEC for total acetylated sites in cohort 3 was similar for CG-745 IV and CG-750 (p=0.3125, 0.8438, 0.3125 for K9, K9 / 14, K27, respectively), with CG-750 showing similar or higher acetylation in all three comparisons, as summarized in Table 2 below.

[0103] [Table 8A]

[0104] [Table 8B]

[0105] [Table 9]

[0106] Safety and Tolerability Results There were no serious AEs reported and no clinically significant findings were observed in vital signs, physical examination, laboratory tests, or ECG. The most common adverse events were leukopenia (23 events in 16 subjects) and neutropenia (23 events in 15 subjects). All AEs were consistent with those expected from the mechanism of study drug and all resolved spontaneously without sequelae.

[0107] conclusion The CG-750 oral formulation and CG-745 IV were generally well tolerated after single oral and IV administration. The mean bioavailability of CG-750 was 10.6%, with dose-dependent PK and PD.

Claims

1. A pharmaceutical composition comprising ivartinostat for use in treating pancreatic cancer in a subject in need thereof, wherein the pharmaceutical composition is used in combination with one or more additional anti-cancer agents, and the subject is being treated with first-line fluoropyrimidine-based chemotherapy.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the subject's pancreatic cancer is responsive or stable to first-line fluoropyrimidine-based chemotherapy, or the subject's pancreatic cancer has not progressed to first-line fluoropyrimidine-based chemotherapy.

3. The ivartinostat is administered at a dose of 10 mg / m 2 ~750mg / m 2 , 25mg / m 2 to 500mg / m 2 , 50mg / m 2 to 375mg / m 2 .

4. The ivartinostat is administered at a dose of 60 mg / m 2 , 125 mg / m 2 , or 250 mg / m 2 4. The pharmaceutical composition for use according to claim 3, wherein the amount of 5. The pharmaceutical composition for use according to claim 1, wherein the ivartinostat is in an amount of 10 mg / day to 1000 mg / day, or 50 mg / day, 100 mg / day, 200 mg / day, or 300 mg / day.

6. A pharmaceutical composition for use according to any one of claims 1 to 5, wherein the composition is administered by intravenous infusion, the intravenous infusion lasting from 30 minutes to 120 minutes, from 50 minutes to 70 minutes, or from 60 minutes.

7. A pharmaceutical composition for use according to any one of claims 1 to 5, wherein the composition is administered orally.

8. The pharmaceutical composition for use according to claim 7, wherein the composition is administered on days 1 and 8 of a 21-day cycle.

9. 6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the one or more additional anti-cancer agents is capecitabine.

10. The capecitabine is 200 mg / m 2 ~2000mg / m 2 , 500mg to 1500mg / m 2 , or 750 mg / m 2 ~1250mg / m 2 or in an amount of 1000 mg / m2.

11. The pharmaceutical composition for use according to claim 9, wherein the capecitabine is administered orally and the capecitabine is administered twice daily.

12. 6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the one or more additional anti-cancer agents are gemcitabine and erlotinib.

13. The gemcitabine is 500 mg / m 2 ~2000mg / m 2 , 750mg to 1500mg / m 2 , or 1000 mg / m 2 13. The pharmaceutical composition for use according to claim 12, wherein the amount of 14. The pharmaceutical composition for use according to claim 13, wherein the gemcitabine is administered by weekly intravenous infusion.

15. The pharmaceutical composition for use according to claim 12, wherein the erlotinib is in an amount of 50 mg to 200 mg, 75 mg to 150 mg, or 100 mg.

16. The pharmaceutical composition for use according to claim 15, wherein the erlotinib is administered orally once, twice, three or four times daily.

17. 6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the pancreatic cancer is pancreatic adenocarcinoma, locally advanced pancreatic adenocarcinoma or metastatic pancreatic adenocarcinoma.

18. 6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the subject is being treated with a FOLFIRINOX chemotherapy regimen.

19. 19. The pharmaceutical composition for use according to claim 18, wherein the subject has metastatic pancreatic adenocarcinoma, the subject has responded to or has stable disease on the first-line fluoropyrimidine-based chemotherapy, and the subject's disease has not progressed on the first-line fluoropyrimidine-based chemotherapy.

20. A pharmaceutical composition for use according to any one of claims 1 to 5, wherein administration of the composition is discontinued if the subject's absolute neutrophil count (ANC) is below 1,000 / μL or the platelet count is below 100,000 / μL.

21. 6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein if the subject suffers from one or more hematological adverse events associated with ivartinostat administration, the amount of ivartinostat is reduced after the subject has recovered from the one or more hematological adverse events.

22. the hematological adverse event comprises grade 3 neutropenia or grade 3 thrombocytopenia; the amount of ivartinostat is reduced by 80% if a second episode of grade 3 neutropenia or grade 3 thrombocytopenia occurs; and / or 22. The pharmaceutical composition for use according to claim 21, wherein administration of the composition is discontinued if a third episode of grade 3 neutropenia or grade 3 thrombocytopenia occurs.

23. the hematological adverse event comprises grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia; the amount of ivartinostat is reduced by 80% if a first episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs; the amount of ivartinostat is reduced by 64% if a second episode of grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 febrile neutropenia occurs; and / or 22. The pharmaceutical composition for use according to claim 21, wherein administration of the composition is discontinued if a third episode of grade 4 neutropenia, grade 4 thrombocytopenia or grade 3 febrile neutropenia occurs.

24. the hematological adverse events include Grade 4 febrile neutropenia; the amount of ivartinostat is reduced by 80% if a first episode of grade 4 febrile neutropenia occurs; and / or 22. The pharmaceutical composition for use according to claim 21, wherein administration of the composition is discontinued if a second episode of grade 4 febrile neutropenia occurs.