Dosing regimen for ecubectedin

Abstract

The present invention relates to a compound of formula (I), or a pharma- ceutically acceptable salt or ester thereof, for use in the treatment of cancer.The present invention also relates to a compound of formula I, or a pharma- ceutically acceptable salt or ester thereof, for use in the treatment of cancer in certain dosing regimens. JPEG2024521122000026.jpg40170

Description

[Technical field]

[0001] The present invention relates to an ecteinascidin compound (PM14) for use in the treatment of certain cancers. The present invention also relates to dosing regimens of PM14 for use in the treatment of cancer. [Background technology]

[0002] Ecteinascidin is a highly potent antitumor agent isolated from the marine tunicate Ecteinascidia turbinata. WO2018 / 197663 describes a compound of the formula: [ka] The present invention describes synthetic ecteinascidin compounds, including PM14, described as compound 4-S having the formula:

[0003] PM14 was shown in WO2018 / 197663 to demonstrate in vitro activity against non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, breast adenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, and prostate cancer cell lines, and in vivo activity in fibrosarcoma, breast adenocarcinoma, NSCLC, ovarian cancer, gastric cancer, small cell lung cancer (SCLC), prostate adenocarcinoma, and prostate cancer xenograft models.

[0004] There remains a need to develop new and / or improved treatments for cancer(s). The present invention addresses this need. Summary of the Invention

[0005] According to an aspect of the invention, there is provided a compound of formula I for use in the treatment of cancer [ka] or a pharma- ceutically acceptable salt or ester thereof, wherein the compound is administered at a concentration of about 0.5 mg / m 2 ~about 9mg / m 2 , preferably about 1.0 mg / m 2~about 9.0mg / m 2 , about 1.5mg / m 2 ~about 9.0mg / m 2 , about 2.0mg / m 2 ~about 9.0mg / m 2 , about 2.5mg / m 2 ~about 8.5mg / m 2 , about 3.0mg / m 2 ~about 8.0mg / m 2 , about 3.5mg / m 2 ~about 7.5mg / m 2 , about 4.0mg / m 2 ~about 7.0mg / m 2 , about 4.0mg / m 2 ~about 6.5mg / m 2 , about 4.5mg / m 2 ~about 6.5mg / m 2 , about 4.5mg / m 2 ~about 6.0mg / m 2 will be administered to subjects in 3-week cycles at a total dose of

[0006] For the first time, a clinical dosing regimen has been identified that is well tolerated and has a manageable safety profile, and in addition, efficacy in humans has been demonstrated in association with the dosing regimen.

[0007] The total dose is approximately 3.0 mg / m 2 ~about 6.0mg / m 2 , about 3.0mg / m 2 ~about 5.6mg / m 2 , about 3.5mg / m 2 ~about 5.6mg / m 2 , about 4.0mg / m 2 ~about 5.0mg / m 2 or about 4.5 mg / m 2 may be also possible.

[0008] The total dose is approximately 4.0 mg / m 2 ~about 9.0mg / m 2 , about 4.0mg / m 2 ~about 8.0mg / m 2 , about 4.5mg / m 2 ~about 7.5mg / m 2 , about 5.0mg / m2 ~about 7.0mg / m 2 , about 5.5mg / m 2 ~about 6.5mg / m 2 , or about 6.0 mg / m 2 may be also possible.

[0009] The total dose was 4.5 mg / m 2 The total dose may be 5.0 mg / m 2 The total dose may be 7.0 mg / m 2 The total dose may be 8.0 mg / m 2 may be also possible.

[0010] The compound may be administered as a single dose in a three week cycle. A single dose is about 4.5 mg / m 2 A single dose may be about 5.0 mg / m 2 may be also possible.

[0011] The compound was administered at 4.5 mg / m on day 1 of a 3-week cycle. 2 may be administered at a dose of

[0012] The compound was administered at 5.0 mg / m on day 1 of a 3-week cycle. 2 may be administered at a dose of

[0013] The compound may be administered as a first dose and a second dose during a three-week cycle. The first dose may be administered on day 1 of the three-week cycle, and the second dose may be administered on day 8 of the three-week cycle. The amount of compound administered for the first dose and the amount of compound administered for the second dose may be equal. The total dose for the first and second doses is about 6.0 mg / m 2 The first dose may be about 3.0 mg / m 2 and the second dose may be about 3.0 mg / m 2 may be also possible.

[0014] The total dose for the first and second doses is approximately 7.0 mg / m 2The first dose may be about 3.5 mg / m 2 and the second dose may be about 3.5 mg / m 2 may be also possible.

[0015] The total dose for the first and second doses is approximately 8.0 mg / m 2 The first dose may be about 4.0 mg / m 2 and the second dose may be about 4.0 mg / m 2 may be also possible.

[0016] The compound was administered at 3.0 mg / m on days 1 and 8 of a 3-week cycle. 2 may be administered at a dose of

[0017] The compound was administered at 3.5 mg / m on days 1 and 8 of a 3-week cycle. 2 may be administered at a dose of

[0018] The compound was administered at 4.0 mg / m on days 1 and 8 of a 3-week cycle. 2 may be administered at a dose of

[0019] The compounds may be administered parenterally, preferably intravenously.

[0020] The cancer may be selected from lung cancer, including non-small cell lung cancer and small cell lung cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, pancreatic cancer, sarcoma, including soft tissue sarcoma and osteosarcoma, ovarian cancer, prostate cancer, gastric cancer, renal cancer, melanoma, neuroendocrine tumors, endometrial cancer, adenoid cystic carcinoma, and adrenocortical carcinoma. The renal cancer may be renal carcinoma, renal clear cell carcinoma, or adrenal tumor, including poorly differentiated adrenal tumor. The melanoma may be amelanotic melanoma. The soft tissue sarcoma may be selected from fibrosarcoma, leiomyosarcoma, and liposarcoma. The osteosarcoma may be chondrosarcoma, including myxoid chondrosarcoma.

[0021] According to an aspect of the invention, there is provided a compound of formula I for use in the treatment of cancer [ka] or a pharma- ceutically acceptable salt or ester thereof, wherein the cancer is selected from renal carcinoma, melanoma, neuroendocrine tumors, endometrial carcinoma, adenoid cystic carcinoma, adrenocortical carcinoma, osteosarcoma, and soft tissue sarcoma.

[0022] The present invention provides, for the first time, data demonstrating the efficacy of compounds of formula I in cancer as disclosed herein.

[0023] The cancer may be renal cancer and may be selected from renal carcinoma, renal clear cell carcinoma, and adrenal gland tumor, where the adrenal gland tumor may be a poorly differentiated adrenal gland tumor.

[0024] The cancer may be melanoma or amelanotic melanoma.

[0025] The cancer may be a soft tissue sarcoma, and may be selected from leiomyosarcoma and liposarcoma.

[0026] The cancer may be osteosarcoma or chondrosarcoma, including myxoid chondrosarcoma.

[0027] The salts may be selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, sodium, potassium, calcium, ammonium, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, and basic amino acids.

[0028] In a further aspect, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt or ester thereof, for use as defined herein, and a pharma- ceutically acceptable carrier.

[0029] In a further aspect, there is provided a dosage form comprising a pharmaceutical composition as defined herein, for a use as defined herein.

[0030] In a further aspect, there is provided a kit comprising a compound, composition or dosage form as defined herein together with instructions for use as defined herein.

[0031] In a further aspect, there is provided a compound of formula I, or a pharma- ceutically acceptable salt or ester thereof, or a pharmaceutical composition as defined herein, or a dosage form as defined herein, when used in accordance with the uses defined herein.

[0032] In a further aspect, there is provided the use of a compound of formula I, or a pharma- ceutically acceptable salt or ester thereof, or a pharmaceutical composition as defined herein, or a dosage form as defined herein, in the manufacture of a medicament for the treatment of cancer, wherein the compound is administered as defined herein.

[0033] In a further aspect, there is provided a method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt or ester thereof, or a pharmaceutical composition as defined herein, or a dosage form as defined herein, wherein the compound is administered as defined herein.

[0034] The invention is further illustrated by the following non-limiting examples. [Brief description of the drawings]

[0035] [Figure 1] MRI - Tumor growth (mean) and body weight (inset) curves of mice bearing H-121 xenografts and treated with placebo or PM14 (PM140014) (N=10 / group). [Diagram 2] MRI - Median tumor growth curves for mice bearing H-121 xenografts and treated with placebo or PM14 (PM140014) (N=10 / group). [Diagram 3] MRI-Kaplan-Meier survival curves obtained in mice bearing H-121 xenografts and treated with placebo or PM14 (PM140014) are shown. [Figure 4A] FIG. 1 shows efficacy data from human clinical trials at various doses according to Schedule A (D1, D8). [Figure 4B] 1 shows efficacy data from human clinical trials at various doses according to Schedule B (D1). [Figure 5A] FIG. 1 shows dose-limiting toxicity data from human clinical trials at various doses according to Schedule A (D1, D8). [Figure 5B] 1 shows dose-limiting toxicity data from human clinical trials at various doses according to Schedule B (D1). [Figure 6] The following pharmacokinetic data are shown: (A) PM14 plasma concentration versus time, (B) dose-adjusted PM14 versus time. [Figure 7] 1 shows a simulation of the pharmacokinetics of PM14 at different doses and infusion rates. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The following applies to all aspects of the invention.

[0037] PM14 is a synthetic compound in clinical trials. PM14 is a specific inhibitor of oncogenic transcription. PM14 has shown encouraging preclinical activity in several cancer models. PM14 was first disclosed in WO2018 / 197663 (as compound 4-S). The structure of PM14 is: [ka] .

[0038] PM14 binds to DNA forming adducts that specifically inhibit active transcription of protein-coding genes by inhibiting mRNA synthesis. The mechanism of transcription inhibition involves irreversible degradation of elongating RNA polymerase II (PolII) and subsequent generation of DNA double-strand breaks. As a net effect, PM14 induces cell cycle arrest to S phase and apoptosis of tumor cells.

[0039] The terms "pharmaceutically acceptable salt" and "ester" refer to any pharmaceutically acceptable salt or ester that is capable of providing (directly or indirectly) a compound described herein upon administration to a patient. However, it will be understood that non-pharmaceutically acceptable salts are also within the scope of the invention, since they may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts can be carried out by methods known in the art.

[0040] For example, pharma- ceutically acceptable salts of the compounds provided herein can be synthesized from parent compounds that contain a basic or acidic moiety by conventional chemical methods. In general, such salts are prepared, for example, by reacting the free acid or base of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of both. In general, non-aqueous media such as ether, ethyl acetate, ethanol, 2-propanol, or acetonitrile are preferred. Examples of acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine and basic amino acid salts.

[0041] The compounds of the present invention may be in crystalline or amorphous form, either as free compounds or as solvates (e.g., hydrates), and all forms are intended to be within the scope of the present invention. Methods of solvation are generally known in the art.

[0042] In addition, the compounds referred to herein may exist in isotopically labeled form. All pharma- ceutically acceptable salts, esters, and isotopically labeled forms of the compounds referred to herein, and mixtures thereof, are considered to be within the scope of the present invention.

[0043] In order to provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". Regardless of whether the term "about" is explicitly used, it is understood that all amounts given herein refer to actual given values, and also refer to approximations to such given values ​​that are reasonably estimated based on the person skilled in the art, including equivalent values ​​and close values ​​resulting from experimental and / or measurement conditions for such given values.

[0044] In this application, "cancer" is meant to include tumors, neoplasms, and any other malignant disease caused by malignant tissues or cells.

[0045] As used herein, unless otherwise indicated, the term "treat" means to reverse, attenuate, alleviate, slow, or inhibit the progression of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0046] As used herein, the term "subject" refers to a living organism to be treated with a compound of the invention, including mammals such as humans, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats. Preferably, the subject is a human.

[0047] Soft tissue sarcomas Soft tissue sarcomas can affect any part of the body. They develop in supporting or connective tissues such as muscles, nerves, fat tissue, and blood vessels. Soft tissue sarcomas include GIST, a common type of sarcoma that occurs in the gastrointestinal (GI) tract, gynecological sarcomas that occur in the female reproductive system: uterus (uterus), ovaries, vagina, vulva, and fallopian tubes, and retroperitoneal sarcomas that occur in the retroperitoneum.

[0048] There is currently no cure for soft tissue sarcoma unless it is detected at an early stage when the tumor can be removed by surgery. Approximately 16% of patients with soft tissue sarcoma have advanced stage (metastatic) disease. For these patients, the 5-year relative survival rate is 16% (American Cancer Society).

[0049] Liposarcoma One particular soft tissue sarcoma is liposarcoma. Liposarcoma is a rare cancer of connective tissue that resembles fat cells under a microscope. It accounts for up to 18% of all soft tissue sarcomas. Although liposarcoma can occur in almost any part of the body, more than half of liposarcoma cases involve the thigh, and up to one-third involve the abdominal cavity. Liposarcoma tends to affect adults between the ages of 40 and 60. When it occurs in children, it usually occurs during the teenage years. There are four types of liposarcoma, as shown below. The risk of recurrence and metastasis from liposarcoma increases with the higher the grade.

[0050] Well-differentiated liposarcoma is the most common subtype and usually begins as a low-grade tumor whose cells look similar to normal fat cells under a microscope and tend to grow and change slowly.

[0051] Myxoid liposarcoma is a medium to high grade tumor whose cells are not normal under a microscope and may have high-grade components.

[0052] Dedifferentiated liposarcoma occurs when a low-grade tumor changes and the new cells within the tumor are high-grade.

[0053] Leiomyosarcoma Leiomyosarcoma, or LMS, is a rare type of cancer that grows in smooth muscle. Smooth muscles are found in hollow organs of the body, including the intestines, stomach, bladder, and blood vessels. In women, there are also smooth muscles in the uterus. These smooth muscle tissues help move blood, food, and other substances through the body and work without you even noticing. LMS is an invasive cancer and is most often found in the abdomen or uterus. LMS is a type of soft tissue sarcoma and accounts for 10% to 20% of soft tissue sarcoma cases. LMS is more common in adults than in children. It is estimated that only about 20 to 30 children are diagnosed with LMS in the United States annually. Uterine LMS affects about 6 per million people annually in the United States. Certain genetic conditions are thought to be associated with LMS, including hereditary retinoblastoma, Li-Fraumeni syndrome, neurofibromatosis type 1, tuberous sclerosis, nevoid basal cell carcinoma syndrome, Gardner syndrome, and Werner syndrome.

[0054] Osteosarcoma There are a variety of primary bone cancers, named for the part of the bone or nearby tissue that is affected and the type of cell that forms the tumour.

[0055] Chondrosarcoma Chondrosarcoma begins in cartilage cells and is the second most common primary bone cancer. It is rare in people under the age of 20. After age 20, the risk of developing chondrosarcoma increases until about age 75. Women are affected by this cancer as often as men.

[0056] Chondrosarcoma can start anywhere there is cartilage. Most often it occurs in bones such as the pelvis, legs, or arms, but it can also start in the trachea, larynx, chest wall, shoulder blades, ribs, or skull.

[0057] Extraskeletal myxoid chondrosarcoma Extraskeletal myxoid chondrosarcoma (EMS) or myxoid chondrosarcoma (also called EMC) is a rare, slow-growing type of cancer that forms in soft tissue outside of bone, usually with a specific change in the NR4A3 gene that causes a special fusion protein to be made. Extraskeletal myxoid chondrosarcomas usually occur in the thigh, but may also occur in the knee, hip, or trunk (chest and abdomen). They can grow large and spread to nearby tissues or other parts of the body, especially the lungs. They may recur many years after treatment. Extraskeletal myxoid chondrosarcoma usually occurs in middle-aged or elderly people and is rare in children and adolescents.

[0058] Fibrosarcoma Fibrosarcoma develops more frequently in soft tissue than in bone. It usually occurs in older and middle-aged adults. The bones of the legs, arms, and jaw are most frequently affected.

[0059] melanoma Melanoma is a type of skin cancer that develops when melanocytes (the cells that give skin its tan or brown color) begin to grow out of control. Melanoma is much less common than other types of skin cancer. However, melanoma is more dangerous because it is much more likely to spread to other parts of the body if not detected and treated early. Around 16,200 people are diagnosed with melanoma each year in the UK. The number of people diagnosed with melanoma has been increasing over the past few decades. Melanoma is the fifth most common cancer in the UK.

[0060] Melanoma can start anywhere on the skin, but it is more likely to start on the trunk (chest and back) in men and the legs in women. The neck and face are other common sites.

[0061] Amelanotic melanoma is a form of melanoma in which the malignant cells have little or no pigment. Although the term "amelanotic" is often used to describe lesions that are only partially devoid of pigment, true amelanotic melanoma, in which the lesions lack all pigment, is rare.

[0062] Anyone can get melanoma in the palms of the hands, soles of the feet, or under the fingernails, although having darker skin reduces the risk of melanoma in these more common sites. Melanomas in these areas account for a much higher proportion of melanomas in African Americans than in whites.

[0063] Melanomas can also form in other parts of the body, such as the eyes, mouth, genitals, and anal areas, but these are much less common than melanoma of the skin.

[0064] Neuroendocrine tumors Pancreatic neuroendocrine tumors (NETs), or pancreatic islet cell tumors, are a type of cancer that begins in the pancreas. Pancreatic NETs are a less common type of pancreatic cancer. They account for less than 2% of pancreatic cancers, but tend to have a better prognosis than the more common types. Pancreatic neuroendocrine tumors begin in neuroendocrine cells. Although neuroendocrine cells (or endocrine cells) are found in other areas of the body, only cancers that form from neuroendocrine cells in the pancreas are called pancreatic neuroendocrine tumors.

[0065] Neuroendocrine cells in the pancreas are found in small clusters called islets (or islets of Langerhans). These islets make hormones such as insulin and glucagon and release them directly into the blood. -Grade 1 (also called low grade or well-differentiated) neuroendocrine tumors have cells that look like normal cells and are not rapidly proliferating. - Grade 2 (also called intermediate grade or moderately differentiated) tumors have characteristics between low-grade and high-grade tumors. -Grade 3 (also called high-grade or poorly differentiated) neuroendocrine tumors have very abnormal looking cells and grow more quickly. These are also known as neuroendocrine carcinomas (NECs).

[0066] Pancreatic NETs are named based on whether they are functioning or nonfunctioning.

[0067] Functioning NETs make hormones that are released into the bloodstream and cause symptoms. Most functioning NETs (up to 70%) are insulinomas. Other types are less common. -Insulinomas arise from cells that make insulin. -Glucagonomas arise from cells that make glucagon. -Gastrinomas arise from cells that make gastrin. -Somatostatinomas arise from cells that make somatostatin. -VIPomas arise from cells that make vasoactive intestinal peptide (VIP). -ACTH-secreting tumors arise from cells that make adrenocorticotropic hormone (ACTH).

[0068] Non-functioning NETs can often become quite large before they are discovered because they do not produce enough excess hormones to cause symptoms. Symptoms that can occur when they grow to a large size include abdominal pain, loss of appetite, and weight loss.

[0069] Carcinoid tumors are much more common in other parts of the digestive system, but rarely begin in the pancreas. These tumors often make serotonin.

[0070] Endometrial cancer Endometrial cancer (also called endometrial carcinoma) begins in the cells of the lining of the uterus (endometrium). It is the most common type of cancer in the uterus. Endometrial cancer can be classified into different histological types, including: -Adenocarcinoma -Uterine carcinosarcoma or CS -Squamous cell carcinoma -Small cell carcinoma -Transitional cancer - Serous carcinoma

[0071] Clear cell carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, and serous adenocarcinoma are less common types of endometrial adenocarcinoma. They tend to grow and spread faster than most types of endometrial cancer. They often have spread outside the uterus by the time they are diagnosed.

[0072] Endometrioid cancer - Most endometrial cancers are adenocarcinomas, and endometrioid cancer is by far the most common type of adenocarcinoma. Endometrioid cancers begin in glandular cells and look a lot like the normal endometrium. Some of these cancers have squamous cells (squamous cells are flat, thin cells) as well as glandular cells. There are many subtypes of endometrioid cancer, including: - Adenocarcinoma, (with squamous differentiation) -Adenoacanthocytoma - Adenosquamous (or mixed cell) -Secretory carcinoma -Ciliary carcinoma -Villous adenocarcinoma

[0073] Uterine carcinosarcoma (CS) originates in the endometrium and has features of both endometrial carcinoma and sarcoma. Previously, CS was considered a distinct type of uterine cancer called uterine sarcoma, but it is not considered to be a poorly differentiated endometrial cancer.

[0074] Uterine CS is a type 2 endometrial cancer. CS tumors are also known as malignant mixed mesodermal tumors or malignant mixed Müllerian tumors (MMMTs). They account for approximately 3% of uterine cancers.

[0075] Adenoid cystic carcinoma Adenoid cystic carcinoma (ACC) is a rare form of adenocarcinoma, a type of cancer that begins in glandular tissue. It most commonly occurs in the major and minor salivary glands of the head and neck. It can also start in the breasts, uterus, or other places in the body.

[0076] Adrenal cortical carcinoma Adrenal cancer is a rare cancer that begins in one or both of the small triangular glands above the kidneys (the adrenal glands). Also called adrenal cortical carcinoma, adrenal cancer can occur at any age. However, it is most likely to affect children under the age of 5 and adults in their 40s and 50s.

[0077] Kidney cancer Renal (or kidney) cancer is a type of cancer that begins in the kidney. There are many types of kidney cancer.

[0078] Renal cell carcinoma (RCC), also known as renal cell carcinoma or renal cell adenocarcinoma, is the most common type of kidney cancer. Approximately 9 out of 10 cases of kidney cancer are renal cell carcinoma. RCC usually grows as a single tumor in the kidney, but there can be two or more tumors in one kidney or tumors in both kidneys at the same time. There are several histologic subtypes of RCC: -Clear cell renal cell carcinoma: This is the most common form of renal cell cancer. About 7 in 10 people with RCC have this type of cancer. The cells that make up clear cell RCC appear very pale or clear. -Non-clear cell renal cell carcinoma: Papillary renal cell carcinoma (also called chromophilic): This is the second most common subtype, accounting for approximately 1 in 10 cases of RCC. These cancers form papillae in some, if not most, of the tumor. Chromophobe renal cell carcinoma: This subtype accounts for about 5% of RCCs (5 in 100 cases). The cells of these cancers are also pale like clear cell cancers, but they are much larger and have certain other characteristics that make them recognizable when viewed up close. -Rare types of renal cell cancer: These subtypes are very rare, each accounting for less than 1% of RCC. ○Collecting pipe RCC Multilocular cystic RCC Medullary cancer Mucinous tubular spindle cell carcinoma Neuroblastoma-related RCC -Unclassified renal cell cancer: Renal cell cancers are rarely labeled as unclassified because their appearance doesn't fit into any of the other categories or because there is more than one type of cancer cell.

[0079] Other types of kidney cancer include: -Transitional cell carcinoma: Approximately 5-10 out of 100 cases of cancer in the kidney are transitional cell carcinoma (TCC), also known as urothelial carcinoma. -Wilms tumor (nephroblastoma): Wilms tumor occurs most often in children. This type of cancer is very rare in adults. - Renal sarcoma: Renal sarcomas are rare types of kidney cancer that begin in the blood vessels or connective tissue of the kidney. They account for less than 1% of all kidney cancers.

[0080] According to an embodiment of the present invention, there is provided a compound of formula I: [ka] or a pharma- ceutically acceptable salt or ester thereof, wherein the cancer is selected from renal carcinoma, melanoma, neuroendocrine tumors, endometrial carcinoma, adenoid cystic carcinoma, adrenocortical carcinoma, osteosarcoma, and soft tissue sarcoma.

[0081] In a preferred embodiment, the renal cancer is renal carcinoma, renal clear cell carcinoma or adrenal tumor. The adrenal tumor may be a poorly differentiated adrenal tumor.

[0082] In a preferred embodiment, the melanoma is amelanotic melanoma.

[0083] In a preferred embodiment, the soft tissue sarcoma is selected from leiomyosarcoma and liposarcoma. In a preferred embodiment, the soft tissue sarcoma excludes fibrosarcoma.

[0084] In a preferred embodiment, the osteosarcoma is a chondrosarcoma, including myxoid chondrosarcoma.

[0085] According to an embodiment of the present invention, there is provided a compound of formula I for use in the treatment of cancer: [ka] or a pharma- ceutically acceptable salt or ester thereof, wherein the compound is administered at a concentration of about 0.5 mg / m 2 ~about 9mg / m 2 will be administered to subjects in 3-week cycles at a total dose of

[0086] As used herein, the term "total dose" refers to the total amount of compound administered during a three-week cycle.

[0087] In a preferred embodiment, the total dose is about 1.0 mg / m 2 ~about 9.0mg / m 2 , about 1.5mg / m 2 ~about 9.0mg / m 2 , about 2.0mg / m 2 ~about 9.0mg / m 2 , about 2.5mg / m 2 ~about 8.5mg / m 2 , about 3.0mg / m 2 ~about 8.0mg / m 2 , about 3.5mg / m 2 ~about 7.5mg / m 2 , about 4.0mg / m 2 ~about 7.0mg / m 2 , about 4.0mg / m 2 ~about 6.5mg / m 2 , about 4.5mg / m 2 ~about 6.5mg / m 2 , about 4.5mg / m 2 ~about 6.0mg / m 2 It is.

[0088] In a preferred embodiment, the total dose is about 3.0 mg / m 2 ~about 6.0mg / m 2 , about 3.0mg / m 2 ~about 5.6mg / m 2 , about 3.5mg / m 2 ~about 5.6mg / m 2 , about 4.0mg / m 2~about 5.0mg / m 2 or about 4.5 mg / m 2 It is.

[0089] In a preferred embodiment, the total dose is about 4.0 mg / m 2 ~about 9.0mg / m 2 , about 4.0mg / m 2 ~about 8.0mg / m 2 , about 4.5mg / m 2 ~about 7.5mg / m 2 , about 5.0mg / m 2 ~about 7.0mg / m 2 , about 5.5mg / m 2 ~about 6.5mg / m 2 , or about 6.0 mg / m 2 It is.

[0090] In a preferred embodiment, the total dose is about 4.5 mg / m 2 ~about 8.0mg / m 2 , about 4.5mg / m 2 ~about 5.0mg / m 2 , about 7.0mg / m 2 ~about 8.0mg / m 2 , about 4.5mg / m 2 ~about 5.0mg / m 2 , about 7.0mg / m 2 , or about 8.0 mg / m 2 It is.

[0091] The compound may be administered in one or more doses during a three week cycle. For example, the compound may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during a three week cycle. In some embodiments, the compound may be administered once a week. In other embodiments, the compound may be administered once a day.

[0092] The total dose may be divided equally between each individual dose within the three-week cycle, or, stated another way, the amount of compound administered for each dose may be equal.

[0093] In some embodiments, the compound of formula I is administered as a single dose during a three week cycle.

[0094] Preferably, the single dose is about 3.0 mg / m 2 ~about 6.0mg / m 2 , more preferably about 3.0 mg / m 2 ~about 5.6mg / m 2 , more preferably about 3.5 mg / m 2 ~about 5.6mg / m 2 , and even more preferably about 4.0 mg / m 2 ~about 5.0mg / m 2 The single dose is approximately 4.5 mg / m 2 It is particularly preferred that the single dose is administered on day 1 of the cycle.

[0095] The single dose is approximately 5.0 mg / m 2 It is even more particularly preferred that the single dose is administered on day 1 of the cycle.

[0096] In a particularly preferred embodiment, the compound of formula I is administered at 4.5 mg / m on day 1 of a 3-week cycle. 2 is administered at a dose of

[0097] In a more particularly preferred embodiment, the compound is administered at 5.0 mg / m on day 1 of a 3 week cycle. 2 is administered at a dose of

[0098] In some embodiments, the compound of formula I is administered 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during a cycle. In some embodiments, the compound is administered 3 times during a cycle. In some embodiments, the compound is administered 3 times during a 3 week cycle.

[0099] In some embodiments, the compound is administered three times during a cycle, on days 1, 2 and 3.

[0100] Preferably, the amount of compound administered for each dose may be equal, for example, if the drug is administered three times on days 1, 2 and 3 of a three week cycle, the dose administered on each of these days is the same.

[0101] Preferably, the total dose is about 0.5 mg / m 2 , 1.0 mg / m 2 , 1.5 mg / m 2 , 2.0 mg / m 2 , 2.5 mg / m 2 , 3.0 mg / m 2 , 3.5 mg / m 2 , 4.0 mg / m 2 , 4.5 mg / m 2 , 5.0 mg / m 2 , 5.5 mg / m 2 , 6.0 mg / m 2 , 6.5 mg / m 2 , 7.0 mg / m 2 , 7.5 mg / m 2 , 8.0 mg / m 2 , 8.5 mg / m 2 , 9.0 mg / m 2 , 9.5 mg / m 2 , 10.0 mg / m 2 , 10.5 mg / m 2 , or 11.0 mg / m 2 It is.

[0102] Preferably, each individual dose (i.e., daily) is about 0.5 mg / m 2 , 1.0 mg / m 2 , 1.5 mg / m 2 , 2.0 mg / m 2 , 2.5 mg / m 2 , 3.0 mg / m 2 , 3.5 mg / m 2 , 4.0 mg / m 2 , 4.5 mg / m 2 , 5.0 mg / m 2 , 5.5 mg / m 2 , 6.0 mg / m 2 , 6.5 mg / m 2 , 7.0 mg / m 2 , 7.5 mg / m 2 , 8.0 mg / m 2 , 8.5 mg / m 2 , or 9.0 mg / m 2 It is.

[0103] In some embodiments, the compound of formula I is administered as a first dose and a second dose during a three week cycle (ie, twice during a three week schedule).

[0104] The first dose is administered on day 1 of a 3-week cycle and the second dose is administered on day 8 of a 3-week cycle.

[0105] Preferably, the amount of compound administered for the first dose and the amount of compound administered for the second dose are equal.

[0106] Preferably, the total dose for the first and second doses is about 0.5 mg / m 2 ~about 9.0mg / m 2 , more preferably about 1.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 1.5 mg / m 2 ~about 9.0mg / m 2 , more preferably about 2.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 3.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 4.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 5.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 6.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 4.0 mg / m 2 ~about 8.0mg / m 2 , more preferably about 6.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 5.0 mg / m 2 ~about 7.0mg / m 2 , and even more preferably about 5.5 mg / m 2 ~about 6.5mg / m 2 The total dose for the first and second doses is approximately 6.0 mg / m 2 It is particularly preferred that:

[0107] Preferably, the first and second doses are about 2.25 mg / m 2 ~about 3.75mg / m 2 , more preferably about 2.5 mg / m 2 ~about 3.5mg / m 2 , and even more preferably about 2.75 mg / m 2 ~about 3.25mg / m 2 The first and second doses are approximately 3.0 mg / m 2 It is particularly preferred that:

[0108] In a particularly preferred embodiment, the total dose for the first and second doses is about 6.0 mg / m 2 ~about 9.0mg / m 2 , more preferably about 6.5 mg / m 2 ~about 8.5mg / m 2 , more preferably about 7.0 mg / m 2 ~about 8.0mg / m 2 , more preferably about 7.0 mg / m 2 or about 8.0 mg / m 2 It is.

[0109] Preferably, the first dose and / or the second dose is about 3.0 mg / m 2 ~about 4.5mg / m 2 , more preferably about 3.25 mg / m 2 ~about 4.25mg / m 2 , and even more preferably about 3.5 mg / m 2 ~about 4.0mg / m 2 The first and / or second dose is about 3.5 mg / m 2 , or about 4.0 mg / m 2 It is particularly preferred that:

[0110] In a particularly preferred embodiment, the compound of formula I is administered at 3.0 mg / m on day 1 of 3 weeks. 2 and 3.0 mg / m on day 8. 2 is administered at a dose of

[0111] In a further particularly preferred embodiment, the compound of formula I is administered at 3.5 mg / m on day 1 of 3 weeks. 2 and 3.5 mg / m on day 8. 2 is administered at a dose of

[0112] In a further particularly preferred embodiment, the compound of formula I is administered at 4.0 mg / m on day 1 of 3 weeks. 2 and 4.0 mg / m on day 8. 2 is administered at a dose of

[0113] In some embodiments, the compound is administered parenterally. Preferably, the compound is administered intravenously.

[0114] The dosing regimens disclosed herein are useful for the treatment of cancer. In preferred embodiments, the cancer is selected from lung cancer, including non-small cell lung cancer and small cell lung cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, pancreatic cancer, sarcoma, including soft tissue sarcoma or osteosarcoma, ovarian cancer, prostate cancer, gastric cancer, renal cancer, melanoma, neuroendocrine tumors, endometrial cancer, adenoid cystic carcinoma, and adrenal cortical carcinoma.

[0115] In a preferred embodiment, the lung cancer is non-small cell lung cancer or small cell lung cancer.

[0116] In a preferred embodiment, the renal cancer is renal carcinoma, renal clear cell carcinoma or adrenal tumor. The adrenal tumor can be a poorly differentiated adrenal tumor.

[0117] In a preferred embodiment, the melanoma is amelanotic melanoma.

[0118] In a preferred embodiment, the sarcoma is a soft tissue sarcoma.

[0119] In preferred embodiments, the soft tissue sarcoma is selected from fibrosarcoma, leiomyosarcoma, and liposarcoma.

[0120] In a preferred embodiment, the sarcoma is osteosarcoma.

[0121] In a preferred embodiment, the osteosarcoma is a chondrosarcoma, including myxoid chondrosarcoma.

[0122] In a further embodiment of the invention, there is provided a pharmaceutical composition comprising a compound of formula I or a pharma- ceutically acceptable salt or ester thereof and a pharma- ceutically acceptable carrier for use in the treatment of cancer as described herein.

[0123] The pharma- ceutically acceptable carrier or vehicle may be particulate, so that the composition is, for example, in tablet or powder form. The carrier(s) may be liquid, so that the composition is, for example, an oral syrup or injectable liquid. In addition, the carrier(s) may be gaseous or liquid, so as to provide an aerosol composition, for example, useful for inhalation administration. Powders may also be used for inhalation dosage forms. The term "carrier" refers to a diluent, adjuvant or excipient with which the compound according to the invention is administered. Such pharmaceutical carriers may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Carriers may be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, disaccharides, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used. In one embodiment, when administered to animals, the compounds and compositions according to the present invention and pharma- ceutically acceptable carriers are sterile. Water is a preferred carrier when the compounds according to the present invention are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. If desired, the composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0124] Examples of modes of administration include, but are not limited to, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Preferably, the composition is administered parenterally.

[0125] The pharmaceutical composition of the present invention can be formulated to allow the compound according to the present invention to be bioavailable upon administration of the composition to an animal, preferably a human.The composition can be in the form of one or more dosage units, for example, a tablet can be a single dosage unit, and a container of the compound according to the present invention can contain the compound in liquid or aerosol form and can hold single or multiple dosage units.

[0126] When intended for oral administration, the compositions are preferably in solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms being included within the forms considered herein as either solid or liquid.

[0127] As a solid composition for oral administration, the composition may be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers, etc. Such solid compositions typically contain one or more inert diluents. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose, or dextrin; disintegrating agents such as alginic acid, sodium alginate, corn starch, etc.; lubricants such as magnesium stearate, lubricants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, flavoring agents such as peppermint, methyl salicylate, or orange flavor, and coloring agents.

[0128] When the composition is in the form of a capsule (eg, a gelatin capsule), it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or fatty oils.

[0129] The composition may be in the form of liquid, for example, elixir, syrup, solution, emulsion or suspension. This liquid may be useful for oral administration or delivery by injection. When intended for oral administration, the composition may contain one or more of sweeteners, preservatives, dyes / colorants, and flavor enhancers. In the composition for administration by injection, one or more of surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers, and isotonic agents may also be included.

[0130] A preferred route of administration is parenteral, including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal, or transdermal. The preferred method of administration is at the discretion of the practitioner and depends, in part, on the site of the pathology (such as the site of cancer). In a more preferred embodiment, the compounds according to the invention are administered intravenously. Infusion times of up to 24 hours are preferably used, more preferably 1 to 12 hours, and most preferably 1 to 6 hours. The infusion time may be 24 hours. Further infusion times include 1, 2, 3, 4, 5, or 6 hours. The infusion time may be 3 hours. Short infusion times that allow treatment to be performed without an overnight stay in a hospital are particularly desirable. However, the infusion may be for 12 to 24 hours, or even longer if necessary. Infusions may be given at suitable intervals, for example, 1 to 4 weeks.

[0131] Whether in solution, suspension, or other similar form, the liquid composition of the present invention can also contain one or more of the following: a sterile diluent such as water for injection, a saline solution, preferably saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono- or diglycerides, polyethylene glycols, glycerin, or other solvents, antibacterial agents such as benzyl alcohol or methylparabens, and agents for adjusting isotonicity such as sodium chloride or dextrose. Parenteral compositions can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other materials. Saline is a preferred adjuvant.

[0132] Typically, this amount is at least about 0.01% of the compound of the present invention and may comprise at least 80% by weight of the composition. When intended for oral administration, this amount may vary from about 0.1% to about 80% by weight of the composition. A preferred oral composition may contain about 4% to about 50% of the compound of the present invention by weight of the composition.

[0133] Preferred compositions of the invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 10% by weight of a compound of the invention, and more preferred parenteral dosage units contain from about 0.5% to about 5% by weight of a compound of the invention.

[0134] The compounds of the invention may be administered by any convenient route, for example by infusion or bolus injection, via absorption through epithelial or mucocutaneous linings.

[0135] In certain embodiments, it may be desirable to administer one or more compounds or compositions of the invention locally to the area in need of treatment, hi one embodiment, administration may be by direct injection at the site (or former site) of a cancer, tumor, or neoplastic or pre-neoplastic tissue.

[0136] Pulmonary administration can also be employed, for example, by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the compounds of the invention can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0137] The composition can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing liquid, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, or any other form suitable for use. Other examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.

[0138] Pharmaceutical compositions can be prepared using methodology well known in the pharmaceutical field.For example, the composition intended to be administered by injection can be prepared by combining the compound of the present invention with water or other physiologically suitable diluents such as phosphate buffered saline to form a solution.A surfactant can be added to facilitate the formation of a homogeneous solution or suspension.

[0139] Preferred compositions according to the present invention include: - A pharmaceutical composition comprising a compound of the invention and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof. - A lyophilized pharmaceutical composition comprising a compound of the invention and a disaccharide. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.

[0140] The ratio of active agent to disaccharide in the embodiments of the present invention is determined according to the solubility of the disaccharide and, when the formulation is lyophilized, also according to the lyophilizability of the disaccharide. It is contemplated that the active agent:disaccharide ratio (w / w) may be about 1:10 in some embodiments, about 1:20 in other embodiments, and about 1:50 in still other embodiments. It is contemplated that other embodiments have such ratios ranging from about 1:5 to about 1:500, and yet further embodiments have such ratios ranging from about 1:10 to about 1:500.

[0141] Compositions containing the compounds of the invention may be lyophilized. Compositions containing the compounds of the invention are usually presented in vials containing a particular amount of such compound.

[0142] The compound according to the present invention can be administered to animals undergoing surgery as a treatment for cancer. In one embodiment of the present invention, the additional therapy is radiation therapy. In a specific embodiment of the present invention, the compound according to the present invention is administered simultaneously with radiation therapy. In another specific embodiment, radiation therapy is administered before or after the administration of the compound of the present invention, preferably before or after the administration of the compound or composition of the present invention, at least 1 hour, 3 hours, 5 hours, 12 hours, 1 day, 1 week, 1 month, more preferably several months (e.g., up to 3 months).

[0143] Any radiotherapy protocol can be used depending on the type of cancer to be treated. For example, but not limited to, X-ray radiation can be administered, particularly high energy megavoltage (radiation with energy above 1 MeV) can be used for deep tumors, and electron beam and orthogonal voltage X-ray radiation can be used for skin cancer. Gamma-ray emitting radioisotopes, such as radioisotopes of radium, cobalt, and other elements, can also be administered.

[0144] The compounds of the present invention and compositions of the present invention have been found to be particularly effective in the treatment of certain types of cancer.

[0145] Thus, the compounds and compositions according to the present invention are useful for inhibiting the doubling or proliferation of tumor or cancer cells or for treating cancer in animals, preferably humans.

[0146] The invention is further illustrated by the following non-limiting examples. EXAMPLES

[0147] PM14 can be obtained according to the teachings of WO2018 / 197663, the contents of which are incorporated herein by reference.

[0148] Example 1: Renal cancer activity in RXF 393 and Caki-1 in vitro assays Cell lines and cell culture: In this example, the following human cancer cell lines are used (collection codes and tissue of origin are indicated in brackets): -RXF 393 (NCI) (renal cancer) -Caki-1 (ATCC HTB-46) (renal clear cell carcinoma)

[0149] Cell lines were obtained from the American Type Culture Collection (ATCC) or the National Cancer Institute (NCI). Cells were cultured in appropriate culture media, i.e. -RPMI for RXF 393 -Caki-1 were maintained in McCoy's 5A.

[0150] All media were supplemented with 10% FBS, 2 mM L-glutamine, and 100 units / mL penicillin-streptomycin.

[0151] Cell viability assay: To evaluate the antiproliferative activity of compounds, a colorimetric assay based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction was used. MTT is a tetrazolium salt that is reduced to purple formazan by functional mitochondria, so the intensity of the purple color is proportional to the amount of viable cells. To reach a final cell density in the assay ranging from 5,000 to 15,000 cells per well depending on the cell line, an appropriate number of cells were seeded in 96-well plates and left undisturbed in culture medium for 24 h at 37 °C with 5% CO2 and 98% humidity. Compounds or DMSO in culture medium were then added to reach a final volume of 200 μL and the intended compound concentration in a range covering ten serial 2 / 5 dilutions starting from 0.1 μg / mL (10 μg / mL for doxorubicin) in 1% (v / v) DMSO. At this point, a set of "time zero control plates" treated with 1% (v / v) DMSO were treated with MTT as described below. The remaining plates were incubated for 72 h under the aforementioned environmental conditions. Afterwards, 50 μL of a 1 mg / mL MTT solution in culture medium was added to the wells and incubated at 37 °C for 6–8 h to generate formazan crystals. The culture medium was then removed and 100 μL of pure DMSO was added to each well to dissolve the formazan product into a colored solution, whose absorbance at 540 nm was finally measured with a PolarStar Omega microplate multilabel reader (BMG Labtech, Ortenberg, Germany).

[0152] All evaluations were performed in triplicate and the data obtained were fitted by nonlinear regression to a four-parameter logistic curve using Prism v5.0 software (GraphPad Software, La Jolla, CA, USA) according to the algorithm developed by the National Cancer Institute (Boyd MR and Paull KD (1995) Drug Dev. Res. 34:91-104). Such an algorithm involves the fitting of three parameters that define compound effect: GI 50(Compound concentration that produces 50% cell growth inhibition compared to the control culture), TGI (total cell growth inhibition compared to the control culture, i.e., the compound concentration that causes a cell growth inhibitory effect), and LC 50 enable the calculation of LC (compound concentration that produces 50% net cell killing cytotoxic effect). Briefly, if "Tz" is the cell count at time zero, "C" is the cell count after 72 hours in the DMSO-treated control well, and "T" is the cell count after 72 hours in the test well, two different scenarios can be considered:

Equation

Equation

[0153] GI 50 is ultimately used as a reference value. The results presented here correspond to the geometric mean of the GIs 50 obtained in at least three independent experiments, each of which was performed three times for all compounds in all tumor cell lines. To define the significant (approx. 70%) confidence interval of the geometric mean, it is necessary to multiply and divide that value by the corresponding geometric standard deviation (GSD), which was also calculated. When the GSD exceeded 4, outliers were identified between replicates and the mean GI50 was recalculated ignoring those values to prevent artificial bias.

[0154] Results: The GI 50 values for RXF 393 and Caki-1 are shown in Table 1 below, while the GSD values are shown in Table 2 below.

Table 1

Table 2

[0155] Example 2: RXF 486L and RXF 1781L Renal Cancer Activity in In Vitro Assays Compound Handling: PM14 (Pharma Mar) was supplied as a powder, shipped frozen at -80°C, and stored at -20°C.

[0156] A working stock solution of PM14 was prepared in DMSO at a concentration of 1.042 mM and small aliquots were stored at −20° C. On each day of the experiment, frozen aliquots of the working stock solution were thawed and stored at room temperature before and during treatment.

[0157] Subsequent dilutions were performed with complete RPMI1640 cell culture medium. The DMSO stock solution was first diluted 1:22 (corresponding to 4.5% (v / v) DMSO). From this solution, serial dilutions in half-log steps with cell culture medium were performed using the intermediate dilution plate. Finally, 10 μl taken from the intermediate dilution plate was transferred to 140 μl / well of the cell culture plate. Thus, at the highest test concentration, the DMSO stock was diluted 1:330, corresponding to a maximum DMSO concentration of 0.3% (v / v) in the assay.

[0158] Cell lines and cell culture: Non-PDX derived cell lines were either provided by NCI (Bethesda, MD) or purchased from ATCC (Rockville, MD) or DSMZ (Braunschweig, Germany). In this example, the following human cancer cell lines are used: -RXF 486L (adrenal tumor, poorly differentiated type) -RXF 1781L (adrenal tumor, poorly differentiated type)

[0159] Cell lines were routinely passaged once or twice a week and maintained in culture for up to 20 passages. All cells were grown in RPMI 1640 medium (25 mM HEPES with L-glutamine, #FG1385, Biochrom, Berlin, Germany) supplemented with 10% (v / v) fetal bovine serum (Sigma, Taufkirchen, Germany) and 0.1 mg / mL gentamicin (Life Technologies, Karlsruhe, Germany) at 37°C in a humidified atmosphere of 5% CO2.

[0160] Cell proliferation assay: A modified propidium iodide (PI)-based monolayer assay was used to evaluate the anticancer activity of compounds (Dengler WA, Schulte J, Berger DP, Mertelsmann R, Fiebig HH, Anti-Cancer Drugs 1995, 6:522-532). Briefly, cells were harvested from exponentially growing cultures, counted and seeded into 96-well flat-bottom microtiter plates at a cell density of 4,000-30,000 cells / well depending on the growth rate of the cell line. After a 24-h recovery period, 10 μl of culture medium (4 control wells / cell line / plate) or culture medium containing test compound was added to allow cells to resume exponential growth. PM14 was applied in duplicate at 10 concentrations in half-log increments up to 3.16 μM and treatments were continued for 4 days. After 4 days of treatment, cells were then washed with 200 μl of PBS to remove dead cells and debris, followed by the addition of 200 μl of a solution containing 7 μg / ml propidium iodide (PI) and 0.1% (v / v) Triton X-100. After a 1-2 hour incubation period at room temperature, fluorescence (FU) was measured using an Enspire multimode plate reader (excitation λ=530 nm, emission λ=620 nm) to quantitate the amount of attached viable cells.

[0161] I C 50 and IC 70Values ​​were calculated by four-parameter non-linear curve fitting using the Oncotest Warehouse Software. The geometric mean was used to calculate the mean IC50 value.

[0162] Results: RXF 486L and RXF 1781L ICs 50 The values ​​are shown in Table 3 below, while the ICs of RXF 486L and RXF 1781L 70 The values ​​are shown below in Table 4. [Table 3] [Table 4]

[0163] Example 3: MRI-H-121 renal cell carcinoma activity in mouse xenograft studies Compound: Vials of off-white lyophilized PM14 cake were stored at -20°C. The cake was reconstituted with 2 ml of water for injection (Sigma-Aldrich, Co) to a concentration of 0.5 mg / ml. Further dilutions were made with 5% Glucose Solution for Injection / USP (Baxter, Inc.). A clear PM14 solution was obtained.

[0164] Placebo: Vials of white to off-white lyophilized placebo cake (composition: sucrose 200 mg, lactic acid 5.52 mg, sodium hydroxide 1.28 mg) were stored at 5° C. The cake was reconstituted with 1.5 ml of water for injection (Sigma-Aldrich, Co). Further dilutions were made with 5% Glucose Solution for Injection / USP (Baxter, Inc.) to obtain a clear solution.

[0165] Animals: Female athymic nu / nu mice aged 4-6 weeks were purchased from Envigo (Barcelona, ​​Spain).

[0166] Animals were housed in individually ventilated cages (Sealsafe® Plus, Techniplast SPA): 10 mice per cage, at 21-23°C and 40-60% humidity with a 12-h light / dark cycle.

[0167] Mice were allowed free access to irradiated standard rodent chow (Tecklad 2914C) and sterile water. Animals were allowed to acclimate for 5 days before individual tattoos were identified.

[0168] Animal protocols were reviewed and approved in accordance with local Institutional Animal Care and Use Committees.

[0169] Tumor line: MRI-H-121 is a human renal carcinoma tumor line originally obtained from the DCT tumor bank. It was developed by Dr. AEBogden, Mason Research Institute MA, and maintained as a serially transplanted tumor line in athymic nude mice. The original tissue was derived from a patient at the University of Massachusetts Medical Center.

[0170] Test Groups: Briefly, 4-6 week old female athymic nu / nu mice were subcutaneously implanted with MRI-H-121 tissue from serially transplanted donor mice. Tumors were removed from donor animals and cut into fragments (3 mm 3 The tissue was excised from membranes, hemorrhagic and necrotic areas, placed in Matrigel™ (Corning Incorporated Life Sciences) and implanted subcutaneously. Recipient mice were anesthetized by inhalation of isoflurane, a small incision was made in the skin on the back and one tumor fragment was implanted per mouse with forceps. Mice were monitored daily.

[0171] Tumor-bearing animals were randomly assigned to two groups (N=10 / group): PM14 administered at 1.25 mg / kg and placebo. All treatments were administered intravenously once a week for three consecutive weeks (days 0, 7, and 14).

[0172] Tumor measurements were determined using digital calipers (Fowler Sylvac, S235PAT). Tumor volume (mm) was calculated from bidimensional tumor measurements using the formula for calculating the volume of a prolate ellipsoid. 3 ) was estimated. Tumor volume (mm 3 )=(a b 2 ) / 2.

[0173] where a: length (longest diameter) and b: width (shortest diameter) of the tumor in mm.

[0174] Tumor volumes and animal body weights were measured 2-3 times a week starting from the first day of treatment.

[0175] Treatment tolerability was assessed by monitoring the evolution of body weight, clinical signs of systemic toxicity, and evidence of local damage at the injection site.

[0176] Treatments resulting in greater than 20% mortality and / or 20% net body weight loss were considered toxic. Animals were cultured until their tumors reached approximately 2,000 mm 3 Mice were euthanized when they reached 0.05 mg / kg and / or when severe necrosis was observed.

[0177] The tumor is approximately 190 mm 3 Once tumor-bearing animals reached maturity, they were randomly assigned to the following experimental groups (N=10 / group): 1. Placebo 2. PM14 (1.25mg / kg)

[0178] Treatment began on day 0 and was administered intravenously once weekly for three consecutive weeks (days 0, 7, and 14).

[0179] Tumor volume data from groups after weeks 1, 2, 3, 4, and 5 were compared using a two-tailed Mann-Whitney U test. Data are presented as median and interquartile range (IQR).

[0180] Complete tumor regression (CR) was defined as a tumor volume of 63 mm on 2 or more consecutive measurements.3 Statistical differences in survival between groups were evaluated by Kaplan-Meier curves applying the log-rank test.

[0181] Statistical analyses and graphs were performed using GraphPad Prism, version 5.02 (GraphPad Software Inc., San Diego, USA) and NewLab Oncology Software (version 2.25.06.00).

[0182] Results: No mortality was recorded. PM14 was well tolerated by MRI-H-121 tumor-bearing animals, although it was important to note that a reversible mean weight loss (approximately -15.0%) was recorded on day 16 (Figure 1). No other clinical signs of systemic toxicity were seen.

[0183] The tumor is approximately 190 mm 3 Treatment was initiated on day 0 when the tumor volume reached 100 μg / ml.

[0184] Animals in the placebo group were randomly assigned to receive 100 mg / kg of placebo at 100 mg / kg for 1 week after tumor volume (>2,000 mm 3 ) and / or were euthanized due to tumor necrosis between days 9 and 30. In this experiment, MRI-H-121 tumors had a doubling time of 3.2 days.

[0185] Tumor growth curves are shown in Figures 1 and 2. PM14 demonstrated very strong antitumor activity in MRI-H-121 tumor xenografts. The placebo-treated group had tumor growth rates of 1147 (956.4-1468) and 1727 (1228-1955) mm on days 7 and 14, respectively. 3 On days 7, 14, 21, 28, and 35, PM14-treated animals had median (IQR) tumor volumes of 401.2 (374.1–450.0), 472.7 (412.0–597.2), 743.8 (550.1–940.6), 1392 (1069–2085), and 2015 (1574–2161) mm, respectively. 3Compared to placebo, PM14-treated animals experienced high and statistically significant tumor reduction from day 7 to day 14, the last measurement time in the placebo-treated group, which was euthanized, as shown in Table 5 below.

[0186] The survival time in the PM14 treatment group was 32.5 days. As shown in Table 6 below and in Figure 3, PM14 treatment statistically significantly increased survival time compared to placebo (median survival time 13 days; p=0.0001). [Table 5] [Table 6]

[0187] In conclusion, PM14 showed a well-tolerated profile in athymic mice bearing MRI-H-121 xenograft tumors.

[0188] Compared to placebo, PM14 treatment of mice bearing MRI-H-121 xenografts resulted in a highly statistically significant reduction in tumor volume (p<0.0007) as well as a highly statistically significant increase in survival time of PM14-treated animals (p=0.0001).

[0189] Example 4: Melanoma activity in in vitro assays of MEXF 276L, MEXL 462NL, and MEXL 1341L I C 50 Values ​​were determined as described in Example 2, but using the following human cancer cell lines: -MEXF 276L (melanoma) -MEXF 462NL (melanoma) -MEXF 1341L (melanoma)

[0190] Results: IC for MEXF 276L, MEXL 462NL, and MEXL 1341L 50The values ​​are shown in Table 7 below, while the IC values ​​for MEXF 276L, MEXL 462NL, and MEXL 1341L are 70 The values ​​are shown in Table 8 below. [Table 7] [Table 8]

[0191] Example 5: Melanoma Activity in In Vitro Assays of WM-266-4 G.I. 50 Values ​​were determined as described in Example 1, but using the following human cancer cell lines: -WM-266-4 (ATCC® CRL-1676) (melanoma)

[0192] Cell lines were obtained from the American Type Culture Collection (ATCC). Cells were maintained in MEM medium supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin, and 2 mM L-glutamine. Cells were cultured at 37°C and 5% CO2 and were always maintained in low passage conditions.

[0193] Results: GI of WM-266-4 50 The values ​​are shown below in Table 9. [Table 9]

[0194] Example 6: Simulation of the pharmacokinetics of PM14 at different doses and infusion rates Simulations of the pharmacokinetics of PM14 at different doses and infusion rates are shown in Figure 7. D1 simulation (lhs) shows a 24-hour infusion of 4.5 mg / m 2 D1-3 simulation (rhs) is 3 hours of infusion × 3 1.5 mg / m 2The D1-3 schedule simulates an extended half-life without exceeding a concentration of 100 nM.

[0195] Example 7: A Phase I, open-label, dose-escalation, clinical and pharmacokinetic study of PM14 administered intravenously to patients with advanced solid tumors. Primary Study Objective -Dose Escalation Phase: Identify dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) and recommended dose (RD) of PM14 administered intravenously (iv) over 3 hours on 2 days (days 1 and 8) or only on day 1, both every 3 weeks (q3wk) in patients with advanced solid tumors.

[0196] Secondary study objectives -To evaluate the safety and tolerability of PM14 administered iv on days 1 and 8 or on day 1 (both q3wk over 3 hours) in patients with advanced solid tumors. -To determine the pharmacokinetics (PK) of PM14. -To evaluate the pharmacogenomics (PGt) in germline DNA by the presence or absence of PGt polymorphisms in genes related to the disposition (distribution, metabolism and excretion) of PM14 that may explain the individual variability in key PK parameters. -To conduct exploratory pharmacogenomic (PGx) analyses in tumor tissue samples and circulating tumor DNA (ctDNA) from patients treated with PM14. -Dose escalation phase: To obtain information on the antitumor activity of PM14.

[0197] Study design A first-in-human, open-label, dose-finding Phase I study using a classical 3+3 design followed by continuous reassessment methodology (CRM) (see dose escalation schedule below).

[0198] Patients are included in cohorts of at least 3 or 6 patients and receive PM14 at successively increasing dose levels starting at 0.25 mg / m2 on a day 1 and day 8 schedule. On the day 1 schedule, the starting dose is 4.5 mg / m2.

[0199] Dose escalation will proceed only after all patients fully evaluable for DLT included at one dose level have completed the first cycle (ie, 3 weeks).

[0200] Depending on the toxicity and pharmacokinetic results observed, other infusion durations and / or schedules may be considered if deemed appropriate after agreement between the Sponsor, the Independent Monitoring Committee (IMC), and the Investigator.

[0201] Patients will receive PM14 until progression, unacceptable toxicity, withdrawal of consent, or as long as it is deemed to be in the patient's best interest. Radiological tumor assessments (and serum tumor markers, if necessary) will be performed every 2 cycles from treatment initiation until cycle 6, and then every 3 cycles during treatment. After treatment discontinuation, patients will be followed until resolution or stabilization of all toxicity, if observed. Patients who discontinue treatment without progression will be followed every 3 months until disease progression, initiation of other antitumor therapy, death, or study end date (clinical cutoff: 6 months after discontinuation of treatment of the last patient [last patient-last visit], or 9 months after accrual of the last evaluable patient, whichever occurs first). After disease progression or initiation of new therapy, patients will be followed for survival every 3 months (± 2 weeks) until death or study end date, whichever occurs first (telephone contact is permitted).

[0202] Anti-tumor responses are assessed using RECIST v.1.1 and / or serum tumor markers, as appropriate (see above).

[0203] Inclusion Criteria: 1. Have willingly signed and dated written informed consent (IC) obtained prior to any specific study procedures. 2. Be 18 years of age or older. 3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≦1. 4. For the dose escalation phase: Patients have a pathologically confirmed diagnosis of advanced solid tumors for which no curative standard therapy exists. 5. Life expectancy ≥ 3 months. 6. Patients with measurable or non-measurable disease per RECIST v.1.1 are eligible during the dose escalation phase. 7. Recovery from drug-related adverse events (AEs) from prior treatment to Grade ≤1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v.4), excluding alopecia and Grade 1 / 2 asthenia or fatigue. 8. Laboratory values ​​within 7 days prior to the first injection: a) Absolute neutrophil count (ANC) ≥ 1.5 x 109 / L, platelet count ≥ 100 x 109 / L, and hemoglobin ≥ 9 g / dL (patients may be transfused for anemia prior to study entry as clinically indicated). b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN). c) Total bilirubin ≤ ULN (up to 1.5 times ULN for patients with Gilbert's syndrome). d) Creatinine clearance of 30 mL / min or greater (calculated using the Cockcroft-Gault formula). e) Serum albumin ≥ 3g / dL. 9. Washout Period: a) At least 3 weeks have elapsed since the last chemotherapy treatment (6 weeks if the treatment included nitrosoureas or systemic mitomycin C). b) At least 4 weeks have elapsed since the last monoclonal antibody (MAb)-containing therapy or definitive radiation therapy (RT). c) At least 2 weeks have elapsed since the last biologic / investigational monotherapy (excluding MAbs) and / or palliative RT (≤10 fractions or ≤30 Gy total dose). d) In patients with hormone-sensitive breast cancer progressing while on hormone therapy (except for luteinizing hormone-releasing hormone (LHRH) analogs or megestrol acetate in premenopausal women), all other hormone therapy must be stopped at least 1 week before initiating study treatment. e) Patients with castration-resistant prostate cancer (CRPC) may continue hormonal therapy prior to and during study treatment.

[0204] Exclusion criteria: 1. Concomitant diseases / conditions: a) Increased cardiac risk: • Uncontrolled arterial hypertension (≥160 / 100mmHg) despite optimal management. • Presence of clinically relevant valvular disease. • History of long QT syndrome. - Corrected QT interval (QTcF, Fridericia correction method) ≥ 450 milliseconds at screening with electrocardiogram (ECG). • History of ischemic heart disease within 6 months prior to study entry, including myocardial infarction, angina pectoris, coronary angiography or cardiac stress test with findings consistent with coronary artery occlusion or infarction. • History of heart failure or left ventricular dysfunction (left ventricular ejection fraction [LVEF] below normal) by multi-gated acquisition scan (MUGA) or echocardiography (ECHO). • Any of the following: ECG abnormalities including left bundle branch block, right bundle branch block with left anterior half block, second (Mobitz II) or third degree atrioventricular block. Presence of symptomatic arrhythmias (excluding anemia-associated sinus tachycardia grade ≤2) or arrhythmias requiring ongoing treatment, and / or prolonged QT-QTc grade ≥2, or unstable atrial fibrillation. Patients with stable atrial fibrillation on treatment will be allowed if they do not meet other cardiac or prohibited drug exclusion criteria. • Clinically significant bradycardia at rest (<50 beats / min). Concomitant medications with a risk of inducing torsades de pointes that cannot be discontinued or substituted before initiating PM14 treatment. ●Use of a cardiac pacemaker. b) Active infection requiring systemic treatment. c) Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B. d) Any other major illness that, in the Investigator's judgment, substantially increases the risks associated with the patient's participation in the study (e.g., COVID-19). 2. Symptomatic, high-dose steroid-requiring, and progressive central nervous system (CNS) disease. Exclusions will be made for (i) patients who have completed radiation therapy at least 4 weeks prior to inclusion (asymptomatic, non-progressing patients already on steroids in the process of being tapered within 2 weeks of inclusion) and (ii) patients with asymptomatic brain metastases not requiring radiation therapy or steroids. 3. Patients with carcinomatous meningitis, regardless of clinical stability. 4. Previous bone marrow or stem cell transplant, or radiation therapy to more than 35% of the bone marrow. 5. Prior treatment with trabectedin or lurbinectedin (PM01183) within 6 months prior to starting study treatment. 6. Known hypersensitivity to any of the ingredients of the medicine. 7. Limitation of the patient's ability to comply with treatment or follow protocol procedures. 8. Pregnant or breastfeeding women. Women of childbearing potential (WOCBP) must agree to use effective contraception to avoid pregnancy during study treatment and for at least 6 months after the last infusion. Male patients of reproductive potential must agree to refrain from fathering a child or donating sperm and to use effective contraception during treatment and for 4 months after the last infusion. WOCBP who are partners of male patients of reproductive potential must use effective contraception during the patient's treatment and for 4 months after the last infusion.

[0205] Expected number of patients The number of patients may vary depending on both the tolerability to PM14 and the number of dose levels required to identify the MTD and RD. Approximately 50 patients are expected to be recruited during the dose escalation phase at the three medical centers.

[0206] method An open-label, dose-escalation phase I study of PM14 administered as a 3-h infusion every 3 weeks (q3wk) in human patients (pts) with advanced solid tumors, adequate organ function, and an ECOG PS score of 0 to 1. Two schedules were investigated: Schedule A (day 1 [D1], day 8 [D8]) and Schedule B (D1).

[0207] Evaluation criteria Primary Endpoint: Dose escalation phase: Determination of MTD and RD: The MTD will be the lowest dose level explored during dose escalation at which ≥1 / 3 of evaluable patients develop DLT in cycle 1. The CRM can be used to define the RD.

[0208] This protocol follows European terminology, therefore RD and MTD are not equivalent.

[0209] Secondary Endpoints: - Safety: Patients can be assessed for safety if they have received at least one partial infusion of PM14. AEs will be graded according to NCI-CTCAE v.4. In addition, treatment-related discontinuations and treatment compliance (dose reductions, skipped doses and / or treatment delays due to AEs) will be documented. - Pharmacokinetics: PK analysis will be assessed in plasma and urine by standard noncompartmental analysis (compartmental modeling may be performed if appropriate). Plasma samples for PK analysis of PM14 will be obtained from all patients in Cycle 1, and also in Cycle 2 from patients treated during Step D of CRM. In addition, urine produced on Day 1 of Cycle 1 and Cycle 2 will be collected from patients treated during Step D of CRM. -Pharmacogenetics: Evaluate the presence or absence of PGt polymorphisms in genes related to the disposition (distribution, metabolism and excretion) of PM14 from a single blood sample collected at any time during the study (preferably at the same time as the pre-treatment PK sample on Day 1 of Cycle 1) to account for individual variability in key PK parameters. -Pharmacogenomics: This exploratory analysis will be performed in patients who have signed the Informed Consent Form (ICF) for the PGx study. The mRNA or protein expression levels of factors involved in DNA repair mechanisms or related to the mechanism of action of PM14 will be evaluated from available tumor tissue samples and cell-free ctDNA obtained at diagnosis or recurrence. If necessary, their mutational status may also be analyzed. Correlation with clinical response and outcome after treatment will be evaluated. - Efficacy: Patients are evaluable for efficacy if they have received at least one complete infusion of PM14 and have had at least one clinical or radiological tumor assessment according to RECIST v.1.1 or serum markers, or if treatment is considered unsuccessful. Treatment failure is defined as clinical deterioration, death due to PD, or treatment discontinuation due to any treatment-related toxicity before any appropriate tumor assessment is performed.

[0210] Antitumor activity will be assessed according to RECIST v.1.1 and / or serum markers every 2 cycles (± 1 week) after initiation of treatment in all patients with evaluable disease through cycle 6. Patients continuing treatment after cycle 6 will undergo evaluations every 3 cycles (± 1 week) during treatment unless otherwise clinically indicated. Anonymized copies of all images must be provided to the sponsor.

[0211] Patients who discontinue treatment without progression will be followed every 3 months until disease progression, initiation of other anti-tumor therapy, death, or end of study date (clinical cut-off), whichever occurs first. After disease progression or initiation of new therapy, patients will be followed for survival every 3 months (± 2 weeks) until death or end of study date, whichever occurs first (telephone contact is permitted).

[0212] Efficacy endpoints include response rate (percentage of patients with PR, patients with CR, or both combined [ORR]), percentage of patients with stable disease (SD) for ≥4 months, percentage of patients with clinical benefit (ORR or SD >4 months), and time-to-event parameters (where appropriate). Efficacy endpoints will be secondary endpoints.

[0213] Definition of dose-limiting toxicity DLTs are defined as study drug-related AEs and laboratory abnormalities occurring during the first cycle of treatment and meeting at least one of the criteria outlined below: Grade 4 neutropenia (ANC<0.5×109 / L) lasting for 3 days or more. Febrile neutropenia or neutropenic sepsis of any duration. Grade 4 thrombocytopenia (platelet count <25 x 109 / L) or grade 3 thrombocytopenia with bleeding requiring platelet transfusion. ● Grade 4 increase in ALT or AST or Grade 3 increase lasting for 7 days or more. • Grade ≥ 2 increase in ALT or AST is accompanied by an increase in total bilirubin ≥ 2.0 x ULN and normal alkaline phosphatase (ALP) (i.e., meeting criteria for Hy's law). Other grade 3 / 4 non-hematologic AEs related to the study drug, except: 1) Nausea / vomiting (unless receiving standard antiemetic therapy). 2) Grade 3 diarrhea lasting less than 2 days (unless receiving standard treatment). 3) Grade 3 asthenia lasting less than 1 week. 4) Hypersensitivity reactions. 5) Extravasation. 6) Non-clinically relevant biochemical abnormalities (e.g., sporadic increases in gamma-glutamyltransferase [GGT]). In any case, the clinical relevance should be discussed. ●Failure to administer day 8 infusion (treatment period + 72 hours) for days 1 and 8 schedule only due to AE(s) related to the study drug in cycle 1. • Administration of the second cycle of PM14 delayed by more than 14 days due to AE(s) related to the investigational drug. The next situation needs to be discussed and the final consensus documented. - Delayed onset (i.e., after completion of cycle 1) DLT. Non-compliance with the intended dose intensity or frequent dose delays or omissions due to AE(s) related to the investigational drug.

[0214] Patient replacement Dose Escalation Phase: If a patient is not fully evaluable for the primary objective evaluation (determination of MTD and RD), the patient must be replaced.

[0215] Unless discontinuation, dose insufficiency, delay or interruption is due to toxicity, evaluable patients for the primary objective of the phase must have received at least one complete cycle and been adequately followed during Cycle 1 (3 weeks).

[0216] Specifically, patients should be rotated if: - Withdrawal from the study prior to completing 14 PM cycles (infusions on days 1 and 8 for a two infusion schedule with two weeks rest, or day 1 of a single infusion schedule with three weeks rest) for reasons other than toxicity (excluding hypersensitivity and / or extravasation reactions). - If they receive a prohibited concomitant medication or have another therapeutic procedure (i.e., major surgery) within 3 weeks after the first dose, unless they have previously had a DLT. - If there is a protocol deviation during Cycle 1 that prevents a safety conclusion from being drawn.

[0217] Criteria for continuing treatment Patients may be treated with additional cycles of PM14 unless unacceptable toxicity and / or disease progression occurs. Criteria for continuing treatment are included in Tables 10 and 11.

[0218] If these criteria are not met on the corresponding day 1 of each cycle, administration of the new cycle should be delayed. Parameters are reevaluated after at least 48 hours, or longer if necessary. A new cycle is always started only upon recovery of these parameters. A delay of up to 14 days is permitted for recovery from drug-related AEs. If recovery does not occur after this period, the patient must discontinue treatment, except according to the investigator's criteria and requirements and with the sponsor's approval.

[0219] For days 1 and 8 schedules only, if treatment continuation criteria are not met on day 8 of any cycle, the scheduled day 8 infusion will be held for up to 72 hours, and if the criteria are not met after this period, the scheduled day 8 infusion will be skipped. Only the infusion scheduled for day 1 may be delayed. [Table 10]

[0220] The decision to continue treatment for a patient who has missed a dose will be evaluated on a case-by-case approach and after agreement between the investigator and the sponsor. [Table 11]

[0221] Weight loss Treatment after DLT, treatment-related infusion delays of more than 14 days, or treatment-related AEs that the investigator deems unacceptable may only be continued if there is clear evidence of objective patient clinical benefit; this will always be discussed with the sponsor. Under these circumstances, and always following recovery to pre-specified retreatment criteria, patients will receive a subsequent infusion at the dose level immediately below the dose level administered during the previous infusion during dose escalation (i.e., steps A, B, and C).

[0222] If a dose reduction is required at the starting dose or at dose level 2, the decision regarding study continuation and the subsequent dose to be administered to the affected patient will be discussed between the sponsor and the investigator. Patients who require a dose reduction during Step D due to the aforementioned circumstances will receive the subsequent infusion at a dose level 20% lower than the dose level administered during the previous infusion.

[0223] A maximum of two individual dose reductions will be permitted per patient, and patients requiring more than two dose reductions will discontinue treatment. Once an individual patient's dose has been reduced, it will not be re-escalated.

[0224] result The results of the dose escalation study are as follows:

[0225] Patient background Patient demographics are summarized in Table 12 below. [Table 12]

[0226] Results: 37 patients were treated (schedule A / B: 28 / 9 patients). Patient baseline characteristics (A / B): median age 56 / 47 years, male 57% / 56%, ECOG PS 0: 57% / 56%, median (range) prior lines of therapy: 3 (1-8) / 4 (1-10). Most common tumor types (A+B): STS (n=7 patients), ovarian (n=6), pancreatic (n=4), prostate cancer (n=3). Maximum tolerated dose was 4.5 mg / m for A. 2 (dose-limiting toxicity [DLT]: D8 omitted due to lack of recovery of laboratory parameters for retreatment [n = 2 patients]) and B at 5.6 mg / m 2 (DLT: G4 febrile neutropenia [n=1], increased G4 transaminase [n=1]).

[0227] The recommended dose (RD) is 3.0 mg / m on D1 and D8. 2 (A) and 4.5 mg / m 2 (B). There were no DLTs in the RD. The most common toxicities were hematological abnormalities and increased transaminases. Efficacy results are shown in Figures 4A and 4B, while safety results are shown in Tables 13 and 14 below and summarized in Figures 5A and 5B. [Table 13] [Table 14]

[0228] Pharmacokinetics The doses tested (0.25–5.6 mg / m 2 Linear pharmacokinetics were observed for PM14 at 100 mg / mL with a geometric mean (CV%) total plasma clearance of 5.9 L / h (88%), a volume of distribution of 128 L (81%), and a median (range) terminal half-life of 15.9 h (7.5-34.3 h). Less than 1.6% of the administered dose was recovered in the urine. Pharmacokinetic data are shown in Figure 6A and Figure 6B.

[0229] A dose escalation study determined the RD of two PM14 schedules in patients with advanced solid tumors. In the RD, PM14 was well tolerated with a manageable safety profile. The most common associated adverse events were transient transaminase increases, nausea / vomiting, fatigue and neutropenia. Some long-term tumor stabilization was observed in patients, including many pretreated patients with soft tissue sarcoma, epithelial ovarian cancer, colorectal cancer and adrenocortical cancer. The PK of PM14 was linear over the dose range tested, with low hepatic clearance and moderate distribution to peripheral tissues, resulting in a half-life of 16 hours.

[0230] This study has shown stable disease (SD) in a variety of cancers, including: SCLC; STS, including leiomyosarcoma and liposarcoma; osteosarcoma, including myxoid chondrosarcoma; neuroendocrine tumors; ovarian cancer; breast cancer; endometrial cancer; prostate cancer, pancreatic cancer; adenoid cystic carcinoma; adrenal cortical carcinoma; and colorectal cancer.

[0231] Overall, the data of the present invention demonstrate that PM14 may be used to treat a variety of cancers, such as SCLC; sarcomas, including STS and osteosarcoma; STS, including leiomyosarcoma and liposarcoma; osteosarcomas, including chondrosarcoma; melanoma, including amelanotic melanoma; neuroendocrine tumors; ovarian cancer; breast cancer; endometrial cancer; pancreatic cancer; adenoid cystic carcinoma; adrenocortical carcinoma; renal carcinoma, including renal carcinoma, renal clear cell carcinoma, adrenal tumor, or poorly differentiated adrenal tumor; and colorectal cancer.

[0232] Separately, the present invention also identifies for the first time dosing regimens useful in the treatment of cancer. These dosing regimens have been determined to be well tolerated with a manageable safety profile. Evidence of efficacy in humans has also been demonstrated. The cancer may be selected from lung cancer, including non-small cell lung cancer and small cell lung cancer; colon cancer; rectal cancer; colorectal cancer; breast cancer; pancreatic cancer; sarcoma, including soft tissue sarcoma and osteosarcoma; soft tissue sarcoma, including fibrosarcoma, leiomyosarcoma, and liposarcoma; osteosarcoma, including chondrosarcoma or myxoid chondrosarcoma; ovarian cancer; prostate cancer; gastric cancer; renal cancer, including renal carcinoma, renal clear cell carcinoma, adrenal tumor, and poorly differentiated adrenal tumor; melanoma, including amelanotic melanoma; neuroendocrine tumors; endometrial cancer; adenoid cystic carcinoma, and adrenal cortical carcinoma.

[0233] Thus, the present invention provides a new and effective option for treating cancer.

Claims

1. A compound of formula I: 【Chemical 1】 A pharmaceutical composition for use in the treatment of cancer, comprising, wherein the treatment comprises administering the compound of formula I intravenously on day 1, once every 3 weeks, at a dose of 4.5 mg / m ２ with an infusion time of 3 hours.

2. The pharmaceutical composition according to claim 1, wherein the cancer is lung cancer including non-small cell lung cancer and small cell lung cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, pancreatic cancer, sarcoma including soft tissue sarcoma or osteosarcoma, ovarian cancer, prostate cancer, gastric cancer, renal cancer, melanoma, neuroendocrine tumor, endometrial cancer, adenoid cystic cancer, and adrenocortical cancer.

3. The pharmaceutical composition according to claim 2, wherein the cancer is prostate cancer.

4. The pharmaceutical composition according to claim 2, wherein the cancer is a neuroendocrine tumor.

5. The pharmaceutical composition according to claim 2, wherein the cancer is a pancreatic neuroendocrine tumor.

6. The pharmaceutical composition according to claim 2, wherein the cancer is renal cancer, and the renal cancer is renal carcinoma, clear cell renal carcinoma, or adrenal tumor including poorly differentiated adrenal tumor.

7. The pharmaceutical composition according to claim 2, wherein the cancer is melanoma.

8. The pharmaceutical composition according to claim 7, wherein the melanoma is amelanotic melanoma.

9. The pharmaceutical composition according to claim 2, wherein the cancer is soft tissue sarcoma, and the soft tissue sarcoma is selected from fibrosarcoma, leiomyosarcoma, and liposarcoma.

10. The pharmaceutical composition according to claim 2, wherein the cancer is osteosarcoma, and the osteosarcoma is chondrosarcoma or myxoid chondrosarcoma.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the compound is in the form of its pharmaceutically acceptable salt or ester.

12. The pharmaceutical composition according to claim 11, wherein the compound is in the form of a pharmaceutically acceptable salt, and the salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, sodium, potassium, calcium, ammonium, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, and basic amino acids.

13. A compound of formula I: 【Chemical 2】 A pharmaceutical composition for use in the treatment of cancer selected from renal cancer, melanoma, pancreatic neuroendocrine tumor, endometrial cancer, adenoid cystic cancer, adrenocortical cancer, osteosarcoma, and soft tissue sarcoma, excluding fibrosarcoma.

14. The pharmaceutical composition according to claim 13, wherein the cancer is a pancreatic neuroendocrine tumor.

15. The pharmaceutical composition according to claim 13, wherein the cancer is selected from renal cancer, and the renal cancer is selected from renal carcinoma, renal clear cell carcinoma, and adrenal tumor, and the adrenal tumor can be a poorly differentiated adrenal tumor.

16. The pharmaceutical composition according to claim 13, wherein the cancer is melanoma.

17. The pharmaceutical composition according to claim 13, wherein the melanoma is amelanotic melanoma.

18. The pharmaceutical composition according to claim 13, wherein the cancer is a soft tissue sarcoma, and the soft tissue sarcoma is selected from leiomyosarcoma and liposarcoma.

19. The pharmaceutical composition according to claim 13, wherein the cancer is osteosarcoma, and the osteosarcoma is chondrosarcoma or myxoid chondrosarcoma.

20. The pharmaceutical composition according to any one of claims 13 to 19, wherein the compound is in the form of a pharmaceutically acceptable salt or ester.

21. The pharmaceutical composition according to claim 20, wherein the compound is in the form of a pharmaceutically acceptable salt, and the salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, sodium, potassium, calcium, ammonium, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, and basic amino acids.

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