Novel drug combination regimen for treating chemotherapy-refractory cancers

Abstract

A novel combination regimen for the treatment of cancer refractory to chemotherapy, pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), a therapeutically effective amount of paclitaxel and a low dose of gemcitabine and their use in the treatment of cancer in a subject, as well as kits comprising the above combinations.

Description

[0001] This application is a divisional application of the invention patent with the application number "201980066957.7" and the invention name "New combination drug therapy for chemotherapy-refractory cancers". This application claims the priority of Chinese Patent Application No. 201811195239.3 with the filing date of October 12, 2018. The entire content of this application is incorporated herein by reference. Technical Field

[0002] The present invention relates to a pharmaceutical composition for the treatment of chemotherapy-refractory cancers. Background Art

[0003] Currently, cancer remains a major cause of death worldwide. Despite progress in treating certain types of cancer through surgery, radiotherapy, and chemotherapy, cancer remains incurable. Even when effective treatments are available for a particular cancer, the side effects of such treatments can be severe, leading to a reduced quality of life for the patient, and the cancer always progresses to become chemotherapy-refractory.

[0004] Most conventional chemotherapy drugs have significant toxicity and limited efficacy, especially for patients with advanced solid tumors. While conventional chemotherapy drugs kill cancer cells, they also damage normal human cells. This chemotherapy index (i.e., a measure of the ability to distinguish between cancer cells and normal cells) can be very low. Typically, the dose of a chemotherapy drug that effectively kills cancer cells will also kill normal cells, especially those normal cells that undergo frequent cell division (such as epithelial cells and bone marrow cells). When normal cells are affected by such treatment, side effects typically include hair loss, hematopoietic suppression, and nausea. Depending on the overall health of the patient, these adverse events may prevent further administration of chemotherapy, or at least subject cancer patients to extremely unpleasant side effects. Even in cancer patients who respond with tumor regression to chemotherapy, the cancer often recurs soon after the initial response to chemotherapy. This recurrent cancer is typically highly resistant or refractory to chemotherapy.

[0005] Cancer stem cells (CSCs, also referred to as, for example, tumor-initiating cells, cancer stem-like cells, stem-like cancer cells, highly tumorigenic cells, or super malignant cells) or cancer cells with high stemness (cancer cells with high stemness) cause rapid tumor recurrence and resistance to further conventional chemotherapy. Increasing evidence indicates that CSCs exist as a distinct population in almost all tumor types, and they give rise to most of the differentiated cells that form the tumor mass and the differentiated cells that phenotypically characterize the disease. It has been demonstrated that CSCs are fundamentally associated with cancer initiation, cancer metastasis, cancer recurrence, and cancer relapse (as Figure 1)。CSCs are inherently resistant to conventional chemotherapy, meaning that they are left behind by conventional treatments that kill most ordinary tumor cells (such as Figure 2 )。Therefore, the existence of CSCs has multiple implications for cancer and its treatment. This includes, for example, disease identification, drug target selection, prevention of cancer metastasis and recurrence, treatment of cancers refractory to chemotherapy and / or radiotherapy, treatment of cancers inherently resistant to chemotherapy or radiotherapy, and development of new anti-cancer strategies.

[0006] STAT3 is a potent transcriptional regulator that targets a large number of genes involved in cell cycle, cell survival, tumorigenesis, tumor invasion, and metastasis, including but not limited to Bcl-xl, c-Myc, cyclin D1, IDO1, PDL1, VEGF, MMP-2, and survivin (such as Figure 3 )。The collective expression of these STAT3-responsive genes maintains the stemness of cancer stem cells (CSCs) required for the survival and propagation of cancer stem cells. Therefore, STAT3 has emerged as a promising target for inhibiting the survival of cancer stem cells and controlling metastasis. Anti-STAT3 agents with anti-CSCs activity hold great promise for cancer patients (Boman, B.M., et al. J. Clin. Oncol. 2008. 26(17): p. 2795-99).

[0007] According to PCT patent WO2009 / 036059, the compound of formula (I) is an inhibitor of CSCs growth and survival. The compound of formula (I) inhibits Stat3 pathway activity with a cellular IC of ~0.25 μM. 50 The compound of formula (I) can be synthesized according to PCT patent WO2009 / 036059, for example, Example 13. In some embodiments, the compound of formula (I) is used in a method of treating cancer. According to PCT patent WO2014 / 169078, Example 6, the compound of formula (I) was selected for clinical trials for the treatment of advanced cancer patients. According to PCT patent WO2009 / 036101, the two-drug combination regimen of the compound of formula (I) with another second anti-cancer agent has potential synergistic anti-cancer effects. Based on the potential of inhibiting the CSCs pathway in the development of new anti-cancer strategies for preventing cancer metastasis and recurrence, treating cancers refractory to chemotherapy and / or radiotherapy, and treating cancers inherently resistant to chemotherapy or radiotherapy, there is an urgent need to further develop new, alternative, and more effective new combination drug treatment regimens based on the compound of formula (I) for specific cancer patients.

[0008] Pancreatic cancer is a common type of cancer, characterized by rapid disease progression, poor prognosis of patients, occult early disease, low surgical resection rate, easy recurrence after surgery, and low chemotherapy efficiency. Currently, surgery is the only possible cure method. However, more than 80% of patients with metastatic pancreatic cancer have developed local advanced stage or metastases at the time of diagnosis. For the few patients who can undergo surgical treatment, most will eventually develop advanced pancreatic cancer, and the 5-year survival rate is less than 5% (Hidalgo, 2010). Currently, the first-line standardized chemotherapy regimens for this unresectable metastatic pancreatic cancer mainly include: FOLFIRINOX (5-fluorouracil (5-FU), leucovorin / LV, irinotecan, and oxaliplatin) combination chemotherapy. For untreated patients, the median overall survival (mOS) is 11.1 months (Conroy, 2011); and the combination chemotherapy regimen of gemcitabine and albumin-bound paclitaxel. In a recently completed phase II / III trial MPACT (Von Hoff, 2013), the mOS of this combination treatment group is 8.7 months, and the 3-year survival rate of the combination treatment group reaches an unprecedented 4% (Goldstein, 2014). For patients who still have disease progression after first-line treatment, the currently available treatments are very limited. For example, for patients who have not used gemcitabine in the first line, standard-dose gemcitabine can be used for treatment in the second line; for patients who have used gemcitabine in the first line, 5-FU / LV is usually selected for second-line treatment. The mOS of pancreatic cancer patients after first-line treatment failure is about 4 - 5 months. Recently, a study on the Onivyde combined with 5-FU / LV treatment regimen showed that for metastatic pancreatic cancer patients who progressed after first-line gemcitabine-based treatment, the mOS of this combined treatment regimen was increased to 6.1 months (Chen, 2015). Currently, researchers are still constantly working hard and there is an urgent need to develop new treatment regimens to improve the survival status of metastatic pancreatic cancer patients, especially those who have failed first-line treatment. Summary of the Invention

[0009] The present disclosure relates to the use of a novel pharmaceutical composition in the treatment of chemotherapy-refractory cancers, said composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a low dose of gemcitabine or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of paclitaxel or a pharmaceutically acceptable salt or solvate thereof.

[0010] The present invention unexpectedly discovers that a treatment regimen of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in combination with a low dose of gemcitabine or a pharmaceutically acceptable salt or solvate thereof, and paclitaxel or a pharmaceutically acceptable salt or solvate thereof, produces anti-tumor activity and a durable response in patients with metastatic pancreatic cancer who have failed prior treatment.

[0011] In some embodiments, the present disclosure provides methods of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a low dose of gemcitabine or a pharmaceutically acceptable salt or solvate thereof, and a therapeutically effective amount of paclitaxel or a pharmaceutically acceptable salt or solvate thereof.

[0012] The compound of formula (I), the low dose of gemcitabine, and paclitaxel can be administered to the patient simultaneously, concurrently, separately, and / or sequentially. Thus, in certain embodiments, the compound of formula (I) and the low dose of gemcitabine are administered to the patient simultaneously, concurrently, separately, and / or sequentially. In certain embodiments, the compound of formula (I) and paclitaxel are administered to the patient simultaneously, concurrently, separately, and / or sequentially.

[0013] The compound of formula (I) can be administered daily in a single or divided dose. Wherein the therapeutically effective amount of the compound of formula (I) is administered daily at a dose of about 80 - 960 mg, about 80 - 480 mg. Wherein the compound of formula (I) is administered twice daily at a dose of about 80 mg, about 160 mg, or about 240 mg. The paclitaxel can be administered weekly. Wherein paclitaxel can be administered at 10 - 100 mg / m 2 weekly. Wherein the therapeutically effective amount of paclitaxel is administered at about 80 mg / m 2 , about 60 mg / m 2 , about 40 mg / m 2 by weekly infusion. The low dose of gemcitabine can be administered weekly. Wherein the low dose of gemcitabine can be administered at 100 - 800 mg / m 2 weekly, wherein the low dose of gemcitabine is less than 50% of the recommended effective dose. Wherein the low dose of gemcitabine is at about 600 mg / m 2 , about 550 mg / m 2 , about 500 mg / m 2 , about 450 mg / m 2 , about 400 mg / m 2 , about 300 mg / m 2 , about 200 mg / m 2 or about 100 mg / m 2Administered by weekly infusion.

[0014] In some embodiments, the cancer is advanced, metastatic, unresectable, refractory, or recurrent pancreatic cancer. In some embodiments, the cancer is chemotherapy-refractory pancreatic cancer. In some embodiments, the cancer is pancreatic cancer that has progressed after at least one prior treatment. In some embodiments, the cancer is pancreatic cancer that has progressed after at least one prior chemotherapy. In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma. In some embodiments, the pancreatic cancer is metastatic pancreatic cancer that has progressed after at least one prior treatment.

[0015] In some embodiments, the present disclosure provides the use of a pharmaceutical composition in a method of resensitizing a subject to at least one treatment regimen, comprising administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I): or a pharmaceutically acceptable salt and solvate thereof.

[0016] In some embodiments, the present disclosure provides a method of resensitizing a subject to at least one treatment regimen, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0017] In some embodiments, the present disclosure provides a method of resensitizing a subject to at least one prior treatment regimen, comprising administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I): or a pharmaceutically acceptable salt and solvate thereof.

[0018] In some embodiments, the present disclosure provides the use of a pharmaceutical composition in a method of resensitizing a subject to at least one prior treatment regimen, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0019] In some embodiments, the present disclosure provides the use of a pharmaceutical composition in a method of resensitizing a subject to at least one prior treatment regimen, comprising administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I): or a pharmaceutically acceptable salt and solvate thereof.

[0020] In some embodiments, the at least one prior treatment regimen is selected from chemotherapy regimens. In some embodiments, the at least one prior treatment regimen is selected from gemcitabine regimens. In some embodiments, the at least one prior treatment regimen is selected from gemcitabine-based monotherapy or combination chemotherapy regimens. In some embodiments, the at least one prior treatment regimen is selected from paclitaxel chemotherapy regimens. In some embodiments, the at least one prior treatment regimen is selected from FOLFIRINOX, mFOLFIRINOX or Gem-Abraxane (gemcitabine-albumin-bound paclitaxel) regimens. In some embodiments, the at least one prior treatment regimen is selected from common cancer treatment regimens such as surgery, radiotherapy, targeted therapy, immunotherapy, etc.

[0021] In some embodiments, methods are disclosed herein for resensitizing a subject to a chemotherapy regimen, which comprise administering to a subject in need thereof: a therapeutically effective amount of a compound of formula (I), selected from compounds having formula (I): or a pharmaceutically acceptable salt and solvate thereof, a low dose of gemcitabine, and a therapeutically effective amount of paclitaxel. In some embodiments, the subject is a pancreatic cancer patient who has failed prior treatment. In some embodiments, the subject is a metastatic pancreatic cancer patient who has failed prior treatment.

[0022] In some embodiments, methods are disclosed herein for resensitizing a subject to a chemotherapy regimen, which comprise administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0023] In some embodiments, the use of a pharmaceutical composition in a method for simultaneously inhibiting, reducing, and / or attenuating the survival and / or proliferation of cancer stem cells and heterogeneous cancer cells selected from subjects with pancreatic cancer is disclosed, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a low dose of gemcitabine, and a therapeutically effective amount of paclitaxel.

[0024] In some embodiments, kits are disclosed that comprise at least one compound selected from compounds of formula (I), prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing. In some embodiments, kits are disclosed that comprise at least one gemcitabine selected from gemcitabine, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing. In some embodiments, kits are disclosed that comprise at least one paclitaxel selected from paclitaxel, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing. In some embodiments, kits are disclosed that comprise at least one compound selected from compounds of formula (I), prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing, at least one gemcitabine selected from gemcitabine, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing, and at least one paclitaxel selected from paclitaxel, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing.

[0025] Aspects and embodiments disclosed herein are set forth in the following detailed description of the invention or will become apparent therefrom. It should be understood that the foregoing summary and the following detailed description are merely exemplary and explanatory and are not intended to limit the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Shows the formation of heterogeneous cancer cells from cancer stem cells.

[0027] Figure 2 Shows cancer stem cell-specific therapies and conventional cancer therapies.

[0028] Figure 3 Shows the STAT3 pathway in cancer.

[0029] Figure 4 According to certain embodiments disclosed herein, shows exemplary effects on tumor volume of 2-acetylnaphtho[2,3-b]furan-4,9-dione, gemcitabine (Gemzer), and combination therapy of 2-acetylnaphtho[2,3-b]furan-4,9-dione and gemcitabine in a xenograft tumor mouse model.

[0030] Figure 5 Shows the therapeutic effects on the protein levels of cancer stemness markers p-Stat3 and β-catenin in vitro of 2-acetylnaphtho[2,3-b]furan-4,9-dione, paclitaxel, and combination of 2-acetylnaphtho[2,3-b]furan-4,9-dione and paclitaxel in pancreatic cancer stem cells (Panc-1). DETAILED DESCRIPTION

[0031] The following are definitions of terms used in this specification. The initial definitions provided for a group or term herein apply to that group or term throughout this specification, alone or as part of other groups, unless otherwise indicated.

[0032] When the term "about" is used in connection with a numerical range, it modifies that range by extending the upper and lower boundaries of those numerical values. In general, the term "about" is used herein to modify a numerical value by a variance of 20%, 10%, 5%, or 1% above and below the set value. In some embodiments, the term "about" is used to modify a numerical value by a variance of 10% above and below the set value. In some embodiments, the term "about" is used to modify a numerical value by a variance of 5% above and below the set value. In some embodiments, the term "about" is used to modify a numerical value by a variance of 1% above and below the set value. When the term "less than" is used in connection with a numerical range, it is intended to encompass every alternative numerical value and subrange less than the range, including the range itself. For example, "less than 5 mg" is intended to include 1 mg, 2 mg, 3 mg, 4 mg. In some embodiments, such as less than 600 mg / m 2 Administration includes at 599 mg / m 2 Administration, 598 mg / m 2 Administration, and so on.

[0033] The phrase "and / or" as used in this disclosure and the claims should be understood to mean "one or both" of the connected elements, i.e., in some instances they are present in combination and in some other instances they are present separately. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can, in one embodiment, refer only to A (optionally including other elements besides B); in another embodiment, only to B (optionally including other elements besides A); in yet another embodiment, to both A and B (optionally including other elements); and so on. When a series of numerical values is listed herein, it is intended to encompass every numerical value and subrange within that range. For example, "1 - 5 mg" is intended to include 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 1 - 2 mg, 1 - 3 mg, 1 - 4 mg, 1 - 5 mg, 2 - 3 mg, 2 - 4 mg, 2 - 5 mg, 3 - 4 mg, 3 - 5 mg, and 4 - 5 mg.

[0034] The terms "administer", "administering", "administration" are used herein in their broadest sense. These terms refer to any method of intervening to administer to a subject a compound or pharmaceutical composition described herein, and can include, for example, systemically, locally or in situ administering the compound to the subject. Thus, the compounds disclosed herein that result from a composition (whether or not it includes the present compound) in the body of a subject are included within these terms. When these terms are used in conjunction with "systemic" or "systemically", they generally refer to the systemic absorption or accumulation in the blood of a compound or composition in the body, followed by distribution throughout the body.

[0035] The term "subject" generally refers to an organism to which a compound or pharmaceutical composition described herein can be administered. A subject can be a mammal or mammalian cell, including a human or human cell. The term also refers to an organism that includes a cell or a donor or recipient of the cell. In various embodiments, the term "subject" refers to any animal (e.g., a mammal), including but not limited to a human, a mammal and a non-mammal, such as a non-human primate, a mouse, a rabbit, a sheep, a dog, a cat, a horse, a cow, a chicken, an amphibian, a reptile, a fish, a nematode and an insect, which will be a recipient of a compound or pharmaceutical composition described herein. In certain cases, the terms "subject" and "patient" are used interchangeably herein with respect to a human subject.

[0036] As used herein, the term "therapeutically effective amount" has its meaning as commonly accepted in the art. The term generally refers to the amount of a compound or composition that will elicit the desired biological or medical response in a cell, tissue, system, animal or human body. For example, if a given clinical treatment is considered effective when there is at least about a 25% reduction in a measurable parameter associated with a disease or disorder, then the therapeutically effective amount of a drug for treating that disease or disorder is the amount necessary to reduce that parameter by at least about 25%.

[0037] For treating cancer, a "therapeutically effective amount" means an amount capable of producing one or more of the following effects: (1) inhibiting cancer or tumor growth to some extent, including slowing growth or completely arresting growth; (2) reducing the number of cancer or tumor cells; (3) decreasing the size of the tumor; (4) inhibiting (i.e., reducing, slowing or completely stopping) infiltration of cancer or tumor cells into peripheral organs; (5) inhibiting (i.e., reducing, slowing or completely stopping) metastasis; (6) enhancing the anti-tumor immune response, which may but need not result in regression or rejection of the tumor; or (7) alleviating one or more measurable symptoms associated with the cancer or tumor to some extent. In some embodiments, a "therapeutically effective amount" means an amount administered systemically, locally or in situ (e.g., the amount of a compound produced in situ in a subject). A therapeutically effective amount can vary depending on factors such as the individual's disease state, age, sex and weight, as well as the ability of one or more anti-cancer agents to produce a desired response in the individual. A "therapeutically effective amount" is also an amount in which any toxic or adverse effects are outweighed by the therapeutic beneficial effects.

[0038] As used herein, the terms such as "treating", "treatment", "to treat", "alleviating" or "to alleviate" mean (1) curing, slowing, alleviating symptoms and / or arresting the progression of a diagnosed pathological condition or disorder, and (2) prophylactic or preventative measures to prevent or slow the progression of a target pathological condition or disorder ("preventing" or "to prevent"). Thus those in need of treatment include those who already have the disorder; those who are predisposed to the disorder; and those who need to prevent the disorder.

[0039] The term "treating cancer", "treatment of cancer" or synonyms thereof means reducing, decreasing, or inhibiting the replication of cancer cells; reducing, decreasing, or inhibiting the spread of cancer (formation of metastases); decreasing the size of the tumor; reducing the number of tumors (i.e., reducing the tumor burden); decreasing or reducing the number of cancer cells in the body; preventing recurrence of cancer after surgical removal or other anti-cancer therapies; and / or improving a measurable treatment endpoint (i.e., outcome).

[0040] As used herein, the term "standard of care" is a term recognized in the art and is understood to refer to cancer treatment methods widely used in the clinic, typically referring to chemotherapy for treating cancer, which can be combined with surgery and / or radiotherapy. Specific protocols can be found on websites such as those maintained by the National Cancer Institute (www.cancer.gov), the American Society for Clinical Oncology (www.asco.org), and the National Comprehensive Cancer Network (www.nccn.org). In some embodiments, the term "first-line treatment" or "first-line therapy" is a term recognized in the art and is understood to refer to the first treatment of a disease, which is typically part of the standard treatment protocol, such as surgical treatment followed by chemotherapy and radiotherapy, used as the best treatment, also known as primary treatment or primary therapy. In some embodiments, the term "second-line treatment" or "second-line therapy" is a term recognized in the art and is understood to refer to chemotherapy treatment given when the initial or primary treatment (first-line or primary therapy) fails or ceases to be effective, which can also be combined with surgery, radiotherapy, and / or immunotherapy. As used herein, the term "prior treatment" can include all treatments for the disease that a patient has received prior to receiving the treatment regimen of the present invention, including but not limited to first-line treatment, second-line treatment, third-line treatment, etc.

[0041] As used herein, the terms "synergistic", "synergy", "synergistically", or "enhanced" refer to two or more components interacting or combining to produce an effect greater than the sum of their individual effects (or "additive effect").

[0042] The term "cancer" refers to cells that exhibit typical cancer cell characteristics, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth rate, and rapid proliferation rate, and specific morphological characteristics. Typically, cancer cells will be in the form of a tumor or mass, but such cells can exist alone within a subject or can circulate in the blood as independent cells, such as leukemia or lymphoma cells.

[0043] The term "cancer" encompasses, for example, AIDS-related cancers, breast cancer, digestive / gastrointestinal cancers, endocrine and neuroendocrine cancers, eye cancer, genitourinary cancers, germ cell cancers, gynecological cancers, head and neck cancers, hematological cancers, musculoskeletal cancers, nervous system cancers, respiratory / chest cancers, skin cancer, childhood cancers, and cancers of unknown primary site.

[0044] Exemplary AIDS-related cancers include, but are not limited to, AIDS-related lymphoma, primary central nervous system lymphoma, and Kaposi's sarcoma.

[0045] Exemplary cancers of the digestive tract / gastrointestinal tract include, but are not limited to, anal cancer, anal area cancer, appendiceal cancer, gastrointestinal benign neoplasms, cholangiocarcinoma, carcinoid tumors, gastrointestinal cancer, colon cancer, esophageal cancer, gallbladder cancer, gastrointestinal stromal tumors (GISTs), islet cell tumors, pancreatic neuroendocrine tumors, liver cancer, pancreatic cancer, rectal cancer, colorectal adenocarcinoma, small intestine cancer, gastroesophageal junction (GEJ) cancer, gastric adenocarcinoma, and gastric cancer.

[0046] Exemplary endocrine and neuroendocrine cancers include, but are not limited to, adrenocortical carcinoma, gastrointestinal carcinoid tumors, islet cell tumors, pancreatic neuroendocrine tumors, adrenocortical carcinoma, Merkel cell carcinoma, non-small cell lung neuroendocrine tumors, small cell lung neuroendocrine tumors, parathyroid carcinoma, pheochromocytoma, pituitary tumors, and thyroid cancer.

[0047] Exemplary urogenital system cancers include, but are not limited to, bladder cancer, renal (renal cell) cancer, penile cancer, prostate cancer, renal pelvis and ureteral cancer, transitional cell carcinoma, testicular cancer, urethral cancer, Wilms' tumor, and other childhood renal tumors.

[0048] Exemplary gynecological cancers include, but are not limited to, cervical cancer, endometrial cancer, uterine cancer, fallopian tube cancer, gestational trophoblastic neoplasia, ovarian epithelial cancer, ovarian germ cell tumors, ovarian low malignant potential tumors, primary peritoneal cancer, uterine sarcoma, vaginal cancer, and vulvar cancer.

[0049] Exemplary head and neck cancers include, but are not limited to, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, squamous neck cancer of unknown primary with metastasis, oral cancer, nasopharyngeal cancer, oral cavity cancer, lip and oropharyngeal cancer, sinus and nasal cavity cancer, parathyroid carcinoma, pharyngeal cancer, salivary gland cancer, laryngeal cancer, and thyroid cancer.

[0050] Exemplary hematological cancers include, but are not limited to, leukemia, acute lymphoblastic leukemia, adult, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, mycosis fungoides, childhood non-Hodgkin lymphoma, adult non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy, primary central nervous system lymphoma, Sezary syndrome, cutaneous T-cell lymphoma, Waldenstrom macroglobulinemia, chronic myeloproliferative neoplasms, Langerhans cell histiocytosis, multiple myeloma / plasmacytoma, myelodysplastic syndromes, and myelodysplastic / myeloproliferative neoplasms.

[0051] Exemplary musculoskeletal cancers include, but are not limited to, bone cancer, Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma of bone, rhabdomyosarcoma in children, chondrosarcoma, and soft tissue sarcoma.

[0052] Exemplary neurological cancers include, but are not limited to, adult brain tumors, pediatric brain tumors, astrocytoma, brain and spinal cord tumors, brainstem glioma, glioblastoma multiforme, atypical teratoid / rhabdoid central nervous system tumors, embryonal central nervous system tumors, germ cell central nervous system tumors, astrocytoma, ependymoma, schwannoma, medulloblastoma, meningioma craniopharyngioma, neuroblastoma, pituitary tumor, pituitary adenoma, and primary central nervous system (CNS) lymphoma.

[0053] Exemplary respiratory / chest cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, thymoma, and thymic carcinoma.

[0054] Exemplary skin cancers include, but are not limited to, cutaneous T-cell lymphoma, Kaposi's sarcoma, melanoma, Merkel cell carcinoma, skin cancer, cutaneous T-cell lymphoma, mycosis fungoides, uveal melanoma, and Sézary syndrome.

[0055] Cancer includes refractory types of any of the above, or combinations of one or more of the above cancers. Some exemplary cancers are included in both the general terms and in this term. For example, genitourinary cancers, a general term, include bladder cancer, prostate cancer, kidney cancer, testicular cancer, etc.; and hepatobiliary cancers, another general term, include liver cancer (itself a general term that includes hepatocellular carcinoma or cholangiocarcinoma), gallbladder cancer, biliary tract cancer, or pancreatic cancer. Both genitourinary cancers and hepatobiliary cancers are covered by the present invention and included in the term "cancer".

[0056] "Solid tumors" are also included in the term "cancer" of the present invention. As used herein, "solid tumors" refers to those conditions that form abnormal tumor masses (such as sarcomas, carcinomas, and lymphomas), such as cancers. Examples of solid tumors include, but are not limited to, non-small cell lung cancer (NSCLC), neuroendocrine tumors, thyroid tumors, fibrous tumors, metastatic colorectal cancer (mCRC), etc. In some embodiments, the solid tumor disease is adenocarcinoma, squamous cell carcinoma, large cell carcinoma, etc.

[0057] In some embodiments, the cancer is selected from pancreatic cancer, gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, gastroesophageal adenocarcinoma, non-small cell lung cancer (NSCLC), breast cancer, triple-negative breast cancer (TNBC; i.e., breast cancer that is negative for the following tests: estrogen receptor (ER-), progesterone receptor (PR-), and HER2 (receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, ERBB2 (human); HER2-), ovarian cancer, platinum-resistant ovarian cancer (PROC), melanoma, small cell lung cancer, and cholangiocarcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma.

[0058] Exemplary pancreatic neuroendocrine tumors (pNETs or PNETs) include, but are not limited to, gastrinoma (Zollinger-Ellison syndrome), glucagonoma, insulinoma, somatostatinoma, VIPomas (Verner-Morrison syndrome), watery diarrhea and hypokalemia with achlorhydria (WDHA), non-functional islet cell tumors, and multiple endocrine neoplasia type 1 (MEN1; also known as Werner syndrome).

[0059] Exemplary pancreatic exocrine tumors include, but are not limited to, adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), acinar cell carcinoma, intraductal papillary mucinous neoplasm (IPMN), mucinous cystadenocarcinoma, solid pseudopapillary tumor, and pancreatoblastoma.

[0060] In some embodiments, the cancer is unresectable, advanced, refractory, recurrent, or metastatic.

[0061] As used herein, the terms “progress,” “progressed,” and “progression” refer to at least one of the following: (1) a response indicative of disease progression (PD) to a previous treatment (such as chemotherapy); (2) the appearance of one or more new lesions following a previous treatment (such as chemotherapy); (3) an increase in the sum total diameter of target lesions of at least 5% (such as 10%, 20%), using the smallest sum total in the study as the reference (which includes the baseline sum total if it is the smallest sum total in the study); and (4) unequivocal progression of non-target lesions.

[0062] As used herein, the term "sensitizing" or its synonyms (e.g., "sensitize" or "sensitization") means making a subject who is tolerant, unresponsive, or slightly responsive to a previous treatment regimen (e.g., conventional chemotherapy, targeted therapy, or immunotherapy) sensitive, responsive, or more responsive to the previous treatment regimen. In certain embodiments, the term "sensitize" or its synonyms includes "resensitize" or its synonyms, and means making a subject who is tolerant, unresponsive, or slightly responsive to a treatment regimen (e.g., conventional chemotherapy, targeted therapy, or immunotherapy) due to previous exposure to the treatment regimen sensitive, responsive, or more responsive to the treatment regimen.

[0063] As used herein, the term "at least one compound of formula (I)" means a compound selected from the compounds having formula (I) prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing. The term "compound of formula (I)" means a compound selected from the compounds having formula (I) or its pharmaceutically acceptable salts and solvates.

[0064] In some embodiments, prodrugs and derivatives of the compounds of formula (I) are Stat3 inhibitors. Non-limiting examples of prodrugs of the compounds of formula (I) are the phosphates and phosphodiesters of compound numbers 4011 and 4012 described in PCT patent WO2009 / 036099, and are also suitable compounds described in U.S. Patent No. 9,150,530. Non-limiting examples of derivatives of the compounds of formula (I) include the derivatives disclosed in PCT patent WO2009 / 036059. PCT patents WO2009 / 036099, WO2009 / 036059 and U.S. Patent No. 9,150,530 are hereby incorporated by reference in their entirety for any purpose.

[0065] As shown below, the compound having formula (I), is also known as 2-acetylnaphtho[2,3-b]furan-4,9-dione, napabucasin and includes its tautomers.

[0066] Suitable methods for preparing 2-acetylnaphtho[2,3-b]furan-4,9-dione (including its crystalline forms and additional cancer stem cell inhibitors) have been described in PCT applications WO2009 / 036099, WO2009 / 036101, WO2011 / 116398, WO2011 / 116399, and WO2014 / 169078, the entire contents of each of which are incorporated herein by reference for any purpose.

[0067] As used herein, the term "at least one gemcitabine" means a compound selected from gemcitabine, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing. In some embodiments, the "gemcitabine" means a compound selected from gemcitabine, or a pharmaceutically acceptable salt and solvate thereof.

[0068] As used herein, the term "at least one paclitaxel" means a compound selected from paclitaxel, prodrugs, derivatives, any pharmaceutically acceptable salts of the foregoing, and any solvates of the foregoing. The term "paclitaxel" means a compound selected from paclitaxel, or a pharmaceutically acceptable salt and solvate thereof. In some embodiments, the "paclitaxel" means a paclitaxel injection approved for production by the National Medical Products Administration.

[0069] As used herein, the "compound of formula (I)", "paclitaxel", and "gemcitabine" contained in the "pharmaceutical composition" can either be mixed together to form a single dosage unit or can be separate and independent dosage units, and these active ingredients can be used together, simultaneously, successively, continuously, or separately.

[0070] The term "salt" as used herein includes acidic salts and / or basic salts formed with inorganic and / or organic acids and bases. The term "pharmaceutically acceptable salt" as used herein means those salts that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of a subject and that do not have undue toxicity, irritation, allergic response, and / or the like, and that have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al in J. Pharmaceutical Sciences, 66:1-19 (1977).

[0071] Pharmaceutically acceptable salts can be prepared from inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Non-limiting examples of suitable organic acids include acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. Other non-limiting examples of suitable pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, besylates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylates, undecanoates, and valerates. In some embodiments, the organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0072] Salts can be prepared in situ during the isolation and purification of the compounds disclosed herein, or separately, for example, by reacting the compounds with a suitable base or acid. Non-limiting examples of base-derived pharmaceutically acceptable salts include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 alkyl)4 salts. Non-limiting examples of suitable alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Further non-limiting examples of suitable pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Non-limiting examples of suitable organic bases from which salts can be derived include primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine). In some embodiments, the pharmaceutically acceptable base addition salts can be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0073] The term "solvate" refers to a composition comprising one or more molecules of a compound disclosed herein and one or more solvent molecules or aggregates of solvents. Solvates of the compounds disclosed herein include, for example, hydrates.

[0074] As used herein, the term "low dose" refers to a therapeutically effective amount that is lower than the standard therapeutic dose. For example, the recommended standard dose of gemcitabine is 1000 - 1200 mg / m 2 . In some embodiments, the low dose of gemcitabine is less than about 800 mg / m 2 , about 600 mg / m 2 , about 550 mg / m 2 , about 500 mg / m 2 , about 450 mg / m 2 , about 400 mg / m 2 , about 350 mg / m 2 , about 300 mg / m 2 , about 250 mg / m 2 , about 200 mg / m 2 , about 150 mg / m 2 or about 100 mg / m 2 administered weekly. In some embodiments, the low dose of gemcitabine is less than 50% or lower of the recommended effective dose.

[0075] In some embodiments, gemcitabine and paclitaxel are administered on days 1, 8, and 15 of each 28-day cycle according to a regimen. In some embodiments, a low dose of gemcitabine (e.g., about 600 mg / m 2 , about 550 mg / m 2 , about 500 mg / m 2 , about 450 mg / m 2 , about 400 mg / m 2 , about 350 mg / m 2 , about 300 mg / m 2 , about 250 mg / m 2 , about 200 mg / m 2 , about 150 mg / m 2 or about 100 mg / m 2 ) is administered weekly. In some embodiments, a low dose of gemcitabine (e.g., about 600 mg / m 2 , about 550 mg / m 2 , about 500 mg / m 2 , about 450 mg / m 2 , about 400 mg / m 2 , about 350 mg / m 2 , about 300 mg / m 2, about 250 mg / m 2 , about 200 mg / m 2 , about 150 mg / m 2 or about 100 mg / m 2 ) until 7 weeks. In some embodiments, for 3 weeks out of every 4 weeks, gemcitabine is administered weekly at a low dose (e.g., about 600 mg / m 2 , about 550 mg / m 2 , about 500 mg / m 2 , about 450 mg / m 2 , about 400 mg / m 2 , about 350 mg / m 2 , about 300 mg / m 2 , about 250 mg / m 2 , about 200 mg / m 2 , about 150 mg / m 2 or about 100 mg / m 2 ). In some embodiments, gemcitabine is administered weekly at a low dose of 100 - 800 mg / m 2 , preferably 100 - 600 mg / m 2 . In some embodiments, gemcitabine is administered weekly at a low dose of about 800 mg / m 2 , about 600 mg / m 2 , about 300 mg / m 2 , or about 100 mg / m 2 . In some embodiments, gemcitabine is administered weekly at a low dose of less than 600 mg / m 2 . In some embodiments, paclitaxel is administered weekly at about 100 mg / m 2 , about 80 mg / m 2 , about 70 mg / m 2 , about 60 mg / m 2 , about 50 mg / m 2 , about 40 mg / m 2 , about 30 mg / m 2 , about 20 mg / m 2 , or about 10 mg / m 2 . In some embodiments, paclitaxel is administered weekly at about 100 mg / m 2 , about 80 mg / m 2 , about 70 mg / m 2 , about 60 mg / m 2 , about 50 mg / m 2 , about 40 mg / m 2 , about 30 mg / m 2 , about 20 mg / m 2 , or about 10 mg / m2 Up to 7 weeks. In some embodiments, for 3 weeks out of every 4 weeks, paclitaxel is administered weekly at about 100 mg / m 2 , about 80 mg / m 2 , about 70 mg / m 2 , about 60 mg / m 2 , about 50 mg / m 2 , about 40 mg / m 2 , about 30 mg / m 2 , about 20 mg / m 2 , or about 10 mg / m 2 . In some embodiments, for 3 weeks out of every 4 weeks, paclitaxel is administered weekly at about 100 mg / m 2 , about 80 mg / m 2 , about 70 mg / m 2 , about 60 mg / m 2 , about 50 mg / m 2 , about 40 mg / m 2 , about 30 mg / m 2 , about 20 mg / m 2 , or about 10 mg / m 2 . In some embodiments, paclitaxel is administered weekly at 10 - 100 mg / m 2 , preferably 40 - 80 mg / m 2 . In some embodiments, paclitaxel is administered weekly at about 80 mg / m 2 , about 60 mg / m 2 , or about 40 mg / m 2 . In some embodiments, paclitaxel is administered weekly at less than 80 mg / m 2 . In some embodiments, paclitaxel is administered intravenously at 80 mg / m 2 according to the protocol, starting at least 2 hours after taking the compound of formula (I) on the same day, and the infusion duration is about 60 minutes. In some embodiments, gemcitabine is administered intravenously at 600 mg / m 2 immediately after the paclitaxel infusion according to the protocol, and the duration is about 30 - 60 minutes.

[0076] In some embodiments, the compound of formula (I) is administered at a total daily dose in the range of about 80 mg to about 960 mg. In some embodiments, the compound of formula (I) is administered at a total daily dose in the range of about 80 mg to about 480 mg. In some embodiments, the compound of formula (I) is administered at a total daily dose in the range of about 160 mg to about 480 mg. In some embodiments, the total daily dose of the compound of formula (I) is administered once daily. In some embodiments, the compound of formula (I) is administered at a dose of about 480 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 400 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 320 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 240 mg per day. In some embodiments, the compound of formula (I) is administered at a dose of about 160 mg per day. In some embodiments, the total amount of the compound of formula (I) is administered in divided doses more than once a day, such as twice a day (BID) or more frequently. In some embodiments, the compound of formula (I) is administered twice a day at a total daily dose in the range of about 80 mg to 480 mg. In some embodiments, the compound of formula (I) is administered twice a day at a total daily dose in the range of about 80 mg to 240 mg. In some embodiments, the compound of formula (I) is administered twice a day at a total daily dose of about 240 mg. In some embodiments, the compound of formula (I) is administered twice a day at a total daily dose of about 480 mg. In some embodiments, the compound of formula (I) is administered twice a day at a total daily dose of about 160 mg. In some embodiments, the compound of formula (I) is administered twice a day at a total daily dose of about 80 mg. In some embodiments, the compound of formula (I) is administered at about 240 mg, twice daily, at an interval of 8 - 12 hours. In some embodiments, the compound of formula (I) is administered at about 80 mg, twice daily, at an interval of 8 - 12 hours.

[0077] The compounds disclosed herein may be in the form of a pharmaceutical composition (drug formulation). In some embodiments, the pharmaceutical composition (drug formulation) may comprise a compound of formula (I) and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition (drug formulation) may comprise a compound of formula (I), paclitaxel, and low-dose gemcitabine. In some embodiments, the pharmaceutical composition (drug formulation) may comprise a compound of formula (I) and paclitaxel. In some embodiments, the pharmaceutical composition (drug formulation) may comprise a compound of formula (I) and low-dose gemcitabine.

[0078] As used herein, the term "carrier" refers to a pharmaceutically acceptable material, composition or vehicle, e.g., a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in or capable of carrying or transporting a subject pharmaceutical compound from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifying agents and lubricants (such as sodium lauryl sulfate, magnesium stearate and polyoxyethylene-polyoxypropylene copolymers), as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and perfuming agents, preservatives and antioxidants may also be present in the compositions.

[0079] The pharmaceutical compositions (pharmaceutical formulations) disclosed herein are suitable for oral administration and may be in the form of capsules, cachets, pills, tablets, lozenges (using flavoring agents, usually sucrose and acacia or tragacanth), powders, granules, solutions in aqueous or non-aqueous liquids, suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, water-in-oil emulsions, elixirs, syrups, troches (using inert bases such as gelatin, glycerin, sucrose and / or acacia) and / or mouthwashes, each form containing a predetermined amount of at least one compound of formula (I).

[0080] The pharmaceutical compositions (pharmaceutical formulations) disclosed herein may be administered in the form of pellets, boluses, or pastes.

[0081] Solid dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) for oral administration can be mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dibasic calcium phosphate, and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants such as glycerin; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarders such as paraffin; absorption promoters such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol monostearate, and polyoxyethylene-polyoxypropylene copolymers; absorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may be employed as fillers in soft and hard gelatin capsules using excipients such as lactose (lactose) or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0082] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins (e.g., hydroxypropyl - β - cyclodextrin) may be used to solubilize the compounds.

[0083] The pharmaceutical compositions (pharmaceutical formulations) may also include adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives. In addition to the compounds of the present invention, the suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0084] The pharmaceutical compositions (drug formulations) disclosed herein can be administered rectally or vaginally in the form of suppositories, which can be prepared by mixing one or more of the compounds disclosed herein with one or more suitable non-irritating excipients or carriers, said excipients or carriers including, such as cocoa butter, polyethylene glycol, suppository wax or salicylate esters, which are solids at room temperature and liquids at body temperature, and thus, they will melt in the rectal or vaginal cavity and release the active pharmaceutical agents disclosed herein. Pharmaceutical compositions suitable for vaginal administration may also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations containing suitable carriers known in the art.

[0085] The dosage forms of the pharmaceutical compositions (drug formulations) or drug tablets disclosed herein for topical or transdermal administration may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The pharmaceutical compositions or drug tablets can be mixed with pharmaceutically acceptable carriers, and any preservatives, buffers, or propellants that may be required, under sterile conditions.

[0086] In addition to the pharmaceutical compositions (drug formulations) or drug tablets disclosed herein, ointments, pastes, creams and gels can contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycol, polysiloxanes, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0087] In addition to the pharmaceutical compositions (drug formulations) or drug tablets disclosed herein, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Additionally, sprays can contain conventional propellants (such as chlorofluorocarbons) and volatile unsubstituted hydrocarbons (such as butane and propane).

[0088] Ophthalmic preparations, eye ointments, powders, solutions, etc. are also included within the scope disclosed herein.

[0089] Compositions (drug formulations) suitable for parenteral administration may include at least one pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersant, suspension or emulsion or sterile powder (which can be reconstituted into a sterile injectable solution or dispersion immediately before use), which can contain antioxidants, buffers, bacteriostatic agents, solutes that render the preparation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0090] In various embodiments, the compounds of formula (I) described herein are included in pharmaceutical compositions. The pharmaceutical compositions (pharmaceutical formulations) include compounds selected from the compounds of formula (I) and their pharmaceutically acceptable salts and solvates, and one or more surfactants. In some embodiments, the surfactant is sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS), or one or more polyoxyglycerol acyl esters. For example, the polyoxyglycerol acyl ester can be lauroyl polyoxyglycerol ester (sometimes referred to as Gelucire TM ) or linoleoyl polyoxyglycerol ester (sometimes referred to as Labrafil TM ). Examples of these compositions are shown in PCT patent WO2014 / 169078, the entire content of which is incorporated herein by reference.

[0091] At least four properties of CSCs are thought to contribute to malignancy: self-renewal, dysregulation of the self-renewal signaling pathway, resistance to conventional cancer therapies, and a propensity to metastasize. As used herein, "self-renewal" generally refers to the ability of a stem cell population to renew itself and give rise to cancer stem cells (Gupta PB et al., Nat. Med. 2009; 15(9):1010-1012). Although CSCs represent only a small percentage of the cancer cell population in a tumor (Clarke MF, Biol. Blood Marrow Transplant. 2009; 11(2suppl 2):14-16), they can give rise to a heterogeneous spectrum of differentiated cancer cells that make up the majority of the tumor (Gupta et al. 2009). In addition, CSCs have the ability to migrate to different parts of the body and thereby regenerate tumors at these sites (Jordan CT et al. N. Engl. J. Med. 2006; 355(12):1253-1261).

[0092] The induction and maintenance of the stem cell properties of CSCs are caused by progressive dysregulation of the self-renewal signaling pathway, which includes but is not limited to those signaling pathways associated with Janus kinase / signal transducer and activator of transcription (JAK / STAT), Hedgehog (Desert (DHH), Indian (IHH), and Sonic (SHH)) / PATCHED / (PTCH1) / SMOOTHENED (SMO), NOTCH / DELTA-LIKE (DLL1, DLL3, DLL4) / JAGGED (JAG1, JAG2) / CSL (CBF1 / Su(H) / Lag-1), WNT / APC / GSK3 / β-CATENIN / TCF4, and NANOG (Boman BM et al., J. Clin. Oncol. 2008; 26(17):2828-2838).

[0093] It is speculated that the abnormal regulation of the stemness signaling pathway in these CSCs (Boman et al. 2008) leads to the resistance of CSCs to chemotherapy and radiotherapy, ultimately resulting in the recurrence and spread of cancer. Thus, although chemotherapy and radiotherapy can kill most of the rapidly dividing cancer cells in the tumor, the abnormal regulation of the stemness signaling pathway in CSCs can enable CSCs to avoid chemotherapy- and radiotherapy-induced cell death and explain how the surviving CSCs acquire the ability to metastasize to sites in the body distant from the primary tumor site.

[0094] Signal transducer and activator of transcription 3 (also known as acute-phase response factor, APRF, DNA-binding protein APRF, ADMI03, HIES; referred to herein as STAT3) acts at the junction of the signal transduction pathways of multiple cytokines. For example, Figure 3 . (Catlett-Falcone, R., et al. Immunity, 1999. 10(1): p. 105-15; Bromberg, J. F., et al. Cell, 1999. 98(3): p. 295-303; Kanda, N., et al. Oncogene, 2004. 23(28): p. 4921-29; Schlette, E. J., et al. J Clin Oncol, 2004. 22(9): p. 1682-88; Niu, G., et al. Oncogene, 2002. 21(13): p. 2000-08; Xie, T. X., et al. Oncogene, 2004. 23(20): p. 3550-60) STAT3 not only regulates the gene expression of cell cycle control (CYCLIN D1, D2, and c-MYC), cell survival (BCL-XL, BCL-2, MCL-1), and angiogenesis (HIF1a, VEGF) (Furqan et al. Journal of Hematology & Oncology (2013) 6:90), but is also a key negative regulator of tumor immune surveillance and immune cell recruitment. (Kortylewski, M., et al. Nat. Med., 2005. 11(12): p. 1314-21; Burdelya, L., et al. J. Immunol., 2005. 174(7): p. 3925-31; and Wang, T., et al. Nat. Med., 2004. 10(1): p. 48-54)

[0095] In normal cells, STAT3 activation is transient and tightly regulated, for example, lasting approximately 30 minutes to several hours. However, in a variety of human tumors, including all major cancers and some hematological malignancies, STAT3 has been found to be abnormally active (Lin et al., Oncogene (2000) 19, 2496 - 2504; Bromberg J. Clin. Invest. (2002) 109:1139 - 1142; Buettner et al., Clinical Cancer Research (2002) 8, 945 - 954; Frank Cancer Letters 251 (2007) 199 - 210; Yu et al. Nature Reviews Cancer (2004) 4, 97 - 105). Constitutive activation of STAT3 occurs in more than half of breast cancers, lung cancers, colorectal cancers (CRC), ovarian cancers, hepatocellular carcinomas, multiple myelomas, and pancreatic cancers, etc., as well as in more than 95% of head and neck cancers.

[0096] Blocking STAT3 signaling through antisense oligonucleotides, siRNA, dominant-negative forms of STAT3, and / or targeting the inhibition of STAT3-dependent tyrosine kinase activity results in cancer cell growth arrest, apoptosis, and reduced frequency of metastasis in vitro and / or in vivo, suggesting that the stemness of CSCs depends on the constitutive activation of the STAT3 transcription factor. Pedranzini, L., et al. J Clin. Invest., 2004. 114(5): p. 619 - 22; Bromberg, J. F., et al. Cell, 1999. 98(3): p. 295 - 303; Darnell, J. E. Nat. Med., 2005. 11(6): p. 595 - 96; and Zhang, L., et al. Cancer Res, 2007. 67(12): p. 5859 - 64. Thus, STAT3 may play a key role in the survival and self-renewal ability of CSCs in a broad spectrum of cancers.

[0097] As described above, the present disclosure provides methods for treating at least one disease associated with abnormal STAT3 pathway activity in a subject. Abnormal STAT3 pathway activity can be identified by phosphorylation of STAT3 ("pSTAT3") or the expression of regulators upstream or downstream of its surrogate.

[0098] The STAT3 pathway can be activated in response to cytokines, such as IL-6, or by one or more tyrosine kinases, such as EGFR, JAKs, ABL, KDR, c-MET, SRC, and HER2, see, for example, Figure 3Downstream effectors of STAT3 include, but are not limited to, BCL-XL, c-MYC, cyclin D1, VEGF, MMP-2, and survivin. Ibid. The STAT3 pathway has been found to be aberrantly activated in many types of cancers. Persistently activated STAT3 pathway can occur in more than half of breast cancers, lung cancers, hepatocellular carcinomas, multiple myelomas, and more than 95% of head and neck cancers. Blocking the STAT3 pathway in vitro and / or in vivo causes cancer cell growth arrest, apoptosis, and reduced frequency of metastasis. Activation of STAT3 has also been demonstrated in many autoimmune and inflammatory diseases. In addition, since it has been disclosed that interleukin-6 (IL-6)-mediated inflammation is a common pathogenic source of atherosclerosis, peripheral vascular disease, coronary artery disease, hypertension, osteoporosis, type 2 diabetes, and dementia, and gp130-JAKS-STATs has been disclosed as the main pathway for IL-6 activation, inhibiting the STAT3 pathway may also treat or prevent these diseases. (Libby, P., et al. Circulation, 2002. 105(9): p. 1135-43; Stephens, J.W., et al. Mol. Genet. Metab., 2004. 82(2): p. 180-86; Cesari, M., et al. Circulation, 2003. 108(19): p. 2317-22; Orshal, J.M. and R.A. Khalil. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2004. 286(6): p. R1013-23; Manolagas, S.C. Bone, 1995. 17(2 Suppl): p. 63S-67S; and Yaffe, K., et al. Neurology, 2003. 61(1): p. 76-80)

[0099] In some embodiments, the at least one disorder is selected from cancers associated with aberrant STAT3 pathway activity, such as activated pSTAT3 detected in pancreatic cancer cells (Wei et al. Oncogene (2003) 22(3): 319-329; Scholz et al. Gastroenterology (2003) 125: 891-905; Toyonaga et al. Cancer Lett. (2003) 10; 201(1): 107-16; Qiu et al. Cancer Sci. (2007) 98(7): 1099-106).

[0100] In some embodiments, the at least one disorder can be selected from autoimmune diseases associated with abnormal STAT3 pathway activity and inflammatory diseases associated with abnormal STAT3 pathway activity. In some embodiments, diseases associated with abnormal STAT3 pathway activity can be selected from inflammatory bowel disease, arthritis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, asthma, allergy, and systemic lupus erythematosus.

[0101] In some embodiments, the at least one disorder can be selected from CNS diseases associated with abnormal STAT3 pathway activity. In some embodiments, CNS diseases can be selected from autoimmune demyelinating disorders, Alzheimer's disease, stroke, ischemia-reperfusion injury, and multiple sclerosis. In some embodiments, the at least one disorder is selected from diseases caused by inflammation and associated with abnormal STAT3 pathway activity. In some embodiments, diseases caused by inflammation and associated abnormal STAT3 pathway activity can be selected from peripheral vascular disease, coronary artery disease, hypertension, osteoporosis, type 2 diabetes, and dementia.

[0102] As discussed above, CSCs are a subset of cancer cells (found in solid tumors or blood cancers) that possess characteristics normally associated with stem cells. These cells grow faster after chemotherapy reduces non-stem common cancer cells, which may be the mechanism leading to frequent cancer recurrence after chemotherapy. In contrast to the majority of non-tumorigenic cancer cells, CSCs are tumorigenic (tumor-forming). In human acute myeloid leukemia, the proportion of these cells is less than one in ten thousand. Bonnet, D. and J. E. Dick. Nat. Med., 1997. 3(7): p. 730-37.

[0103] In the early stages of testing, the efficacy of cancer treatments is typically measured by the number and size of the tumor masses they eliminate. Since CSCs form a very small proportion of the tumor cell population and have significantly different biological characteristics compared to their differentiated progeny, measurement of tumor masses may not be useful for the selection of drugs that specifically act on CSCs. In fact, CSCs are resistant to radiation and refractory to chemotherapeutic drugs and targeted drugs. Normal human stem cells are naturally resistant to chemotherapeutic drugs - they have multiple pumps that efflux drugs (e.g., multidrug resistance protein pumps), higher DNA repair capacity, and have a slow cell renewal rate (chemotherapeutic drugs naturally target rapidly replicating cells). CSCs are mutant copies of normal stem cells and they can also have similar functions that allow them to survive treatment. In other words, conventional chemotherapy kills differentiated (or differentiating) cells that form the bulk of the tumor but cannot give rise to new tumor cells. For example, Figure 2。The CSCs population that generates new tumor cells can remain unchanged, thus causing disease recurrence. Moreover, after treatment with chemotherapeutic drugs, only CSCs resistant to chemotherapy may remain, increasing the likelihood of subsequent tumor resistance to chemotherapy. In addition, cancer stem cells have also been shown to be resistant to radiotherapy (XRT). Hambardzumyan, et al. Cancer Cell, 2006. 10(6): p. 454-56; and Baumann, M., et al. Nat. Rev. Cancer, 2008. 8(7): p. 545-54.

[0104] Because the surviving CSCs can regenerate tumors and cause recurrence, anti-cancer therapies targeting CSCs hold great promise for treating malignant tumors. Jones RJ et al., J Natl Cancer Inst. 2004; 96(8): 583-585. Treatment of patients with aggressive, non-resectable tumors and refractory or recurrent tumors, as well as prevention of tumor metastasis and recurrence, can be achieved through CSCs-targeted treatment approaches. Therefore, the development of specific therapies targeting the CSCs pathway is expected to extend the survival of cancer patients and improve the quality of life of cancer patients, especially for those with cancer metastasis.

[0105] Recent studies have revealed that cancer stem cells (CSCs) can regenerate tumors (such as Figure 1 ). It has been revealed that these cancer stem cells are functionally related to the continued malignant growth, metastasis, recurrence, and drug resistance of tumors. Cancer stem cells and their differentiated progeny show significantly different biological characteristics. They persist as a unique but rare population in tumors. Conventional cancer drug screening relies on measuring the amount of tumor mass, so it is impossible to identify drugs that specifically act on stem cells. In fact, cancer stem cells have been shown to be resistant to standard chemotherapy and enriched after standard chemotherapy treatment. See, for example, Figure 2This leads to refractory cancers and cancer recurrence. CSCs have also been shown to be resistant to radiotherapy. Baumann, M., et al. Nat. Rev. Cancer, 2008. 8(7): p. 545-54. Cancer types from which cancer stem cells have been reported to be isolated include pancreatic cancer, breast cancer, head and neck cancer, lung cancer, ovarian cancer, colorectal cancer, prostate cancer, melanoma, multiple myeloma, Kaposi's sarcoma, Ewing's sarcoma, liver cancer, medulloblastoma, brain tumors, and leukemia. STAT3 has been identified as a factor for cancer stem cell survival and self-renewal. Thus, STAT3 inhibitors are capable of killing cancer stem cells and / or inhibiting the self-renewal of cancer stem cells. According to some embodiments, cancer stem cells refer to a micro-population of cancer stem cells having the ability of self-renewal and tumorigenicity. In previous studies, it has been shown that the compound of formula (I) can effectively inhibit the STAT3 pathway, thereby inhibiting the growth and survival of CSCs. In clinical trials, the compound of formula (I) can be used to treat advanced cancer patients. Based on previous trials, the present invention unexpectedly discovers for the first time that a novel drug combination of the compound of formula (I), low-dose gemcitabine, and paclitaxel can also effectively treat advanced cancer patients, especially metastatic pancreatic cancer patients after previous treatment failure. And prior to this, it has never been reported that a combination chemotherapy regimen containing low-dose gemcitabine and paclitaxel can be effectively used for the treatment of advanced pancreatic cancer patients. Therefore, the present invention provides a new option for improving the survival of advanced, especially metastatic pancreatic cancer patients after failure of first-line treatment.

[0106] Disclosed herein are methods of inhibiting, reducing, and / or attenuating cancer stem cell survival and / or self-renewal, which comprise administering a therapeutically effective amount of a compound of formula (I) in combination with low-dose gemcitabine. Also disclosed herein are methods of inhibiting, reducing, and / or attenuating cancer stem cell survival and / or self-renewal, which comprise administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective amount of paclitaxel. Also disclosed herein are methods of inhibiting, reducing, and / or attenuating cancer stem cell survival and / or self-renewal, which comprise administering a therapeutically effective amount of a compound of formula (I) in combination with low-dose gemcitabine and a therapeutically effective amount of paclitaxel. In some embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0107] The present disclosure provides methods for treating cancer in a subject who is refractory to conventional chemotherapy and / or targeted therapy, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. The present disclosure provides methods for treating cancer in a subject who is refractory to conventional chemotherapy and / or targeted therapy, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective or low dose of paclitaxel administered weekly. The present disclosure provides methods for treating cancer in a subject who is refractory to conventional chemotherapy and / or targeted therapy, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine and a therapeutically effective or low dose of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0108] The present disclosure provides methods for treating or preventing cancer recurrence or metastasis in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. The present disclosure also provides methods for treating or preventing cancer recurrence or metastasis in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective or low dose of paclitaxel administered weekly. The present disclosure also provides methods for treating or preventing cancer recurrence or metastasis in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine and a therapeutically effective or low dose of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition. In various embodiments, the subject is a patient with pancreatic cancer after prior treatment failure. In various embodiments, the subject is a patient with metastatic pancreatic cancer after prior treatment failure.

[0109] The present disclosure provides methods for treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine. The present disclosure provides methods for treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective or low dose of paclitaxel administered weekly. The present disclosure provides methods for treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a low dose of gemcitabine and a therapeutically effective or low dose of paclitaxel administered weekly. In various embodiments, the compound of formula (I) is included in a pharmaceutical composition.

[0110] The present disclosure provides the use of a pharmaceutical composition in a method for treating cancer in a subject, the composition comprising a therapeutically effective amount of a compound of formula (I), a low dose of gemcitabine, and a therapeutically effective or low dose of paclitaxel administered weekly. The compound of formula (I) is administered daily at a dose of 80 - 960 mg. The paclitaxel can be administered at 10 - 100 mg / m 2 weekly. The gemcitabine can be administered at 100 - 800 mg / m 2Administered weekly. In some preferred embodiments, the compound of formula (I) is administered at a total daily dose in the range of about 80 mg to about 480 mg. In some preferred embodiments, the paclitaxel is administered at 40 - 80 mg / m 2 Administered weekly. In some preferred embodiments, the gemcitabine is administered at 100 - 600 mg / m 2 Administered weekly. In some embodiments, the subject is a patient with pancreatic cancer after prior treatment failure. In various embodiments, the subject is a patient with metastatic pancreatic cancer after prior treatment failure.

[0111] In some embodiments, the cancer can be advanced, metastatic, unresectable, refractory, or recurrent. In some embodiments, the cancer can be pancreatic cancer. In some embodiments, the cancer can be pancreatic cancer that has progressed after prior treatment. In some embodiments, the pancreatic cancer can be pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer can be pancreatic ductal adenocarcinoma. In some embodiments, the cancer can be metastatic pancreatic cancer. In some embodiments, the cancer is metastatic pancreatic cancer that has progressed after prior treatment. In some embodiments, the cancer can be associated with overexpression of activated pSTAT3. In some embodiments, the cancer can be associated with nuclear β-catenin localization. Examples

[0112] Examples are provided below to further illustrate the different features of the present invention. These examples also illustrate useful methods of practicing the present invention. These examples do not limit the claimed invention.

[0113] Disclosed herein is a method of administering a low dose of gemcitabine, paclitaxel administered weekly, and a compound of formula (I) to a subject in need thereof. Example 1

[0114] The compound of formula (I) 2-acetylnaphtho[2,3-b]furan-4,9-dione, gemcitabine, and the combination of 2-acetylnaphtho[2,3-b]furan-4,9-dione and gemcitabine were studied. Specifically, vehicle control, 2-acetylnaphtho[2,3-b]furan-4,9-dione (100 mg / kg, PO, bid), gemcitabine (Gemzar, 80 mg / kg, IV, q3d), or the combination of 2-acetylnaphtho[2,3-b]furan-4,9-dione and gemcitabine was administered to immunosuppressed mice bearing human pancreatic cancer (Panc-1). Tumor size was evaluated regularly during the treatment period. Each point represents the mean ± SEM of five tumors. As Figure 4 shown, while 2-acetylnaphtho[2,3-b]furan-4,9-dione or gemcitabine showed some effect in inhibiting tumor growth, the combination significantly reduced tumor growth in the mouse model. Example 2

[0115] The effect of the compound of formula (I), 2-acetylnaphtho[2,3-b]furan-4,9-dione, on cancer stem cell markers was detected in a cancer xenograft model with and without paclitaxel.

[0116] Human cancer cells were subcutaneously implanted into the right flank of 5- to 7-week-old athymic nude mice. When the tumor size reached 200 mm 3 , the animals were treated with 2-acetylnaphtho[2,3-b]furan-4,9-dione (e.g., at 50 mg / kg (BID) by oral gavage (n = 3 / group)), paclitaxel, or 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with paclitaxel. Tumors were harvested 24 hours after the first dose.

[0117] The harvested tissues were fixed overnight at 4 °C in 3.7% neutral buffered formaldehyde. Paraffin embedding was performed. Sections were cut at approximately 5 μm and mounted onto positively charged slides. After baking and deparaffinization, the slides with tumor or control tissues were incubated in 10 mM sodium citrate (pH 6.0) for 10 minutes. After antigen retrieval, the slides were incubated overnight at 4 °C with primary antibodies P-STAT3 (rabbit, Cell Signaling, 1:100), β-catenin (mouse, Santa Cruz, 1:400), and then with secondary antibodies conjugated with Alexa Fluor fluorescent dyes (1:500, Invitrogen). After mounting, the slides containing DAPI (Invitrogen) with Prolong mounting medium were examined under a Zeiss fluorescence microscope with a 20x objective lens and analyzed using Zen software.

[0118] As Figure 5 shown, single-agent paclitaxel led to enhanced staining of stem cell markers, single-agent 2-acetylnaphtho[2,3-b]furan-4,9-dione significantly reduced the expression of both stem cell markers p-STAT3 and β-catenin, and when 2-acetylnaphtho[2,3-b]furan-4,9-dione was combined with paclitaxel, the expression of stem cell markers was reduced even further. Example 3

[0119] In an open-label international multicenter phase II / III extension trial, the effect of the compound of formula (I), 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with paclitaxel and low-dose gemcitabine, on patients with advanced pancreatic cancer who had failed prior treatment was investigated.

[0120] In this clinical study, the anti-tumor activity and safety of 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with weekly paclitaxel and low-dose gemcitabine were observed in patients with advanced pancreatic cancer who had failed previous treatments. The patients had previously received at least one line of systemic treatment and had failed, showing radiological disease progression. Previous treatments included gemcitabine-based monotherapy or combination chemotherapy, and / or FOLFIRINOX / mFOLFIRINOX chemotherapy.

[0121] The enrolled patients received 2-acetylnaphtho[2,3-b]furan-4,9-dione orally at a dose of 240 mg twice a day (total daily dose of 480 mg) daily for each 4-week (28-day) treatment cycle, in combination with paclitaxel and low-dose gemcitabine. Paclitaxel 80 mg / m 2 IV was administered on the first day of the first treatment cycle, followed by gemcitabine 600 mg / m 2 IV, administered on days 1, 8, and 15 of each 28-day treatment cycle. Dose adjustment (reduction or discontinuation) could be made in case of drug toxicity reactions.

[0122] Tumor remission and progression were evaluated according to the RECIST 1.1 criteria. The anti-tumor activity of 2-acetylnaphtho[2,3-b]furan-4,9-dione combined with paclitaxel and low-dose gemcitabine was evaluated.

[0123] Among the enrolled patients with advanced pancreatic cancer, 1 patient had received three lines of chemotherapy before enrollment (first line: gemcitabine + tegafur; second line: gemcitabine; third line: avelumab) and had disease progression. After enrollment and treatment, at the first evaluation (8 weeks after randomization into the trial), the target lesions shrank by 9.1%, and the tumor evaluation was SD (stable disease). At the second evaluation (20 weeks after randomization into the trial), the target lesions shrank by 41%, and the tumor evaluation reached PR (partial response), with significant shrinkage of non-target lesions; 1 patient had received one line of chemotherapy (capecitabine + tegafur) before enrollment and had disease progression. After enrollment and treatment, at the first evaluation (8 weeks after randomization into the trial), the target lesions shrank by 25.6%, and the tumor evaluation was SD, with significant shrinkage of non-target lesions. Both patients are currently still receiving the protocol treatment.

[0124] The adverse events related to 2-acetylnaphtho[2,3-b]furan-4,9-dione observed in all treated patients were mainly gastrointestinal adverse events (such as diarrhea, constipation, nausea, vomiting, etc.). This combined treatment regimen did not increase the toxic side effects of patients and had good safety.

[0125] This trial showed that 2-acetylnaphtho[2,3-b]furan-4,9-dione in combination with paclitaxel and low-dose gemcitabine had good synergistic effects. In patients with metastatic pancreatic cancer who had failed previous treatments, 2-acetylnaphtho[2,3-b]furan-4,9-dione (240 mg BID) in combination with 80 mg / m 2 IV paclitaxel and 600 mg / m 2 IV gemcitabine was safe, tolerable, and had good anti-tumor activity.

[0126] Many of the features and advantages disclosed herein will be apparent from the detailed description. Accordingly, the appended claims are intended to cover all such features and advantages that fall within the true spirit and scope of the disclosure herein. In addition, since many modifications and variations will be readily apparent to those skilled in the art, it is not desired to limit the disclosure to the exact constructions and operations shown and described. All suitable modifications and equivalents may be resorted to as falling within the scope of the invention.

[0127] Unless defined otherwise herein, 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 invention belongs. The methods recited herein may be performed in any logically possible order other than the particular order disclosed. Incorporated by reference

[0128] This disclosure makes reference to and incorporates by reference other documents such as patents, patent applications, patent publications, journals, books, papers, website content. All such documents are hereby incorporated by reference in their entirety for all purposes. Any material or a portion thereof incorporated by reference herein that conflicts with the definitions, statements, or other disclosed material set forth expressly herein is incorporated only to the extent that there is no conflict between the incorporated material and the present disclosure. In the event of a conflict, the conflict shall be resolved in favor of the present disclosure as the preferred disclosure.

Claims

1. Use of a pharmaceutical composition in the preparation of a medicament for treating a patient with pancreatic cancer, said composition comprising a compound of formula (I): or a pharmaceutically acceptable salt thereof, gemcitabine or a pharmaceutically acceptable salt thereof, and paclitaxel or a pharmaceutically acceptable salt thereof.

2. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient with pancreatic cancer, said compound of formula (I) being used in combination with gemcitabine or a pharmaceutically acceptable salt thereof, and paclitaxel or a pharmaceutically acceptable salt thereof.

3. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for rendering a patient with pancreatic cancer who has failed at least one previous treatment responsive to a chemotherapy regimen, said compound of formula (I) being used in combination with gemcitabine or a pharmaceutically acceptable salt thereof, and paclitaxel or a pharmaceutically acceptable salt thereof.

4. Use according to any one of claims 1 - 3, wherein the pancreatic cancer is advanced, metastatic, unresectable, refractory, or recurrent chemoresistant cancer.

5. Use according to any one of claims 1 - 3, wherein the pancreatic cancer is a pancreatic cancer refractory to conventional chemotherapy and / or targeted therapy.

6. Use according to any one of claims 1 - 3, wherein the patient is a patient with pancreatic cancer who has failed at least one previous treatment or a patient with metastatic pancreatic cancer who has progressed after at least one previous treatment.

7. Use according to claim 6, wherein the at least one previous treatment includes first-line treatment, second-line treatment, or third-line treatment.

8. Use according to claim 6, wherein the at least one previous treatment is selected from gemcitabine-based monotherapy or combination chemotherapy, or a combination chemotherapy regimen comprising 5-fluorouracil (5-FU), leucovorin / LV, irinotecan, and / or oxaliplatin as active ingredients.

9. Use according to claim 8, wherein the gemcitabine-based combination chemotherapy includes the Gem-Abraxane chemotherapy regimen.

10. Use according to claim 6, wherein the at least one previous treatment includes the FOLFIRINOX or mFOLFIRINOX chemotherapy regimen.

11. Use according to any one of claims 1-3, 7-10, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, administered orally daily at a dose of about 80-960 mg; the gemcitabine or a pharmaceutically acceptable salt thereof is a low dose of gemcitabine or a pharmaceutically acceptable salt thereof, administered by infusion weekly at a dose of about 100-800 mg / m 2 ; the paclitaxel or a pharmaceutically acceptable salt thereof is a low dose of paclitaxel or a pharmaceutically acceptable salt thereof, administered by infusion weekly at a dose of about 10-100 mg / m 2 .

12. Use according to any one of claims 1-3, 7-10, wherein the compound of formula (I), gemcitabine, and paclitaxel can be administered to a patient simultaneously, separately, and / or sequentially.

13. Use according to claim 11, wherein the compound of formula (I) is administered in divided doses.

14. Use according to claim 11, wherein the compound of formula (I) is administered twice daily at a dose of about 80 mg, about 160 mg, about 240 mg, about 320 mg, about 400 mg, or about 480 mg.

15. Use according to claim 11, wherein gemcitabine is administered by infusion weekly at a dose of about 800 mg / m 2 , about 700 mg / m 2 , about 600 mg / m 2 , about 550 mg / m 2 , about 500 mg / m 2 , about 450 mg / m 2 , about 400 mg / m 2 , about 300 mg / m 2 , about 200 mg / m 2 , or about 100 mg / m 2 for 3 weeks out of every 4 weeks.

16. Use according to claim 11, wherein paclitaxel is administered by infusion weekly at a dose of about 80 mg / m 2 , about 70 mg / m 2 , about 60 mg / m 2 , about 50 mg / m 2 , about 40 mg / m 2 , about 30 mg / m 2 , about 20 mg / m 2 , or about 10 mg / m 2 .

17. Use according to claim 11, wherein the gemcitabine is administered weekly for 3 weeks out of every 4 weeks or gemcitabine is administered on days 1, 8, and 15 of each 28-day cycle.

18. The use according to claim 11, wherein the paclitaxel is administered by weekly infusion for 3 weeks out of every 4 weeks or paclitaxel is administered on days 1, 8, and 15 of each 28-day cycle.

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