Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present invention relates to an ecteinascidin compound (PM 14) for use in the treatment of certain cancers.
• the present invention also relates to dosage regimens of PM 14 for use in the treatment of cancer.
• ecteinascidins are exceedingly potent antitumor agents isolated from the marine tunicate Ecteinascidia turbinata.
• WO2018/197663 describes synthetic ecteinascidin compounds including PM 14 which is described as compound 4-S with the following formula:
• PM14 was shown in WO2018/197663 to demonstrate in vitro activity against non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, breast adenocarcinoma, pancreas adenocarcinoma, prostate adenocarcinoma, and prostate carcinoma cell lines and in vivo activity in fibrosarcoma, breast adenocarcinoma, NSCLC, ovarian carcinoma, gastric carcinoma, small cell lung cancer (SCLC), prostatic adenocarcinoma, and prostatic carcinoma xenograph models.
• NSCLC non-small cell lung cancer
• SCLC small cell lung cancer
• prostatic adenocarcinoma prostatic carcinoma xenograph models.
• I or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of cancer wherein the compound is administered to a subject in a three-week cycle at a total dose from about 0.5 mg/m 2 to about 9 mg/m 2 , preferably from about 1.0 mg/m 2 to about 9.0 mg/m 2 , about
• the total dose may be about 3.0 mg/m 2 to about 6.0 mg/m 2 , about 3.0 mg/m 2 to about 5.6 mg/m 2 , about 3.5 mg/m 2 to about 5.6 mg/m 2 , about 4.0 mg/m 2 to about 5.0 mg/m 2 or about 4.5 mg/m 2 .
• the total dose may be about 4.0 mg/m 2 to about 9.0 mg/m 2 , about 4.0 mg/m 2 to about 8.0 mg/m 2 , about 4.5 mg/m 2 to about 7.5 mg/m 2 , about 5.0 mg/m 2 to about 7.0 mg/m 2 , about 5.5 mg/m 2 to about 6.5 mg/m 2 , or about 6.0 mg/m 2 .
• the total dose may be 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 .
• the compound may be administered as a single dose during the three-week cycle.
• the single dose may be about 4.5 mg/m 2 .
• the single dose may be about 5.0 mg/m 2 .
• the compound may be administered at a dose of 4.5 mg/m 2 on day 1 of a three-week cycle.
• the compound may be administered at a dose of 5.0 mg/m 2 on day 1 of a three-week cycle.
• the compound may be administered as a first dose and a second dose during the 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 dose and the second dose may be 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 .
• the total dose for the first dose and the second dose may be about 7.0 mg/m 2 .
• the first dose may be about 3.5 mg/m 2 and the second dose may be about 3.5 mg/m 2 .
• the total dose for the first dose and the second dose may be about 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 .
• the compound may be administered at a dose of 3.0 mg/m 2 on day 1 , day 8 of a three-week cycle.
• the compound may be administered at a dose of 3.5 mg/m 2 on day 1 , day 8 of a three-week cycle.
• the compound may be administered at a dose of 4.0 mg/m 2 on day 1 , day 8 of a three-week cycle.
• the compound may be administered parentally, preferably intravenously.
• 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, pancreas cancer, sarcoma including soft tissue sarcoma and bone sarcoma, ovarian cancer, prostate cancer, gastric cancer, renal cancer, melanoma, neuroendocrine tumor, endometrial cancer, adenoid cystic carcinoma, and adrenocortical carcinoma.
• the renal cancer may be renal carcinoma, kidney clear cell carcinoma or hypernephroma, including poorly differentiated hypernephroma.
• the melanoma may be amelanotic melanoma.
• the soft tissue sarcoma may be selected from fibrosarcoma, leiomyosarcoma and liposarcoma.
• the bone sarcoma may be chondrosarcoma, including myxoid chondrosarcoma.
• a cancer selected from renal cancer, melanoma, neuroendocrine tumor, endometrial cancer, adenoid cystic carcinoma, adrenocortical carcinoma, bone sarcoma and soft tissue sarcoma.
• the present invention has provided for the first time data demonstrating the efficacy of the compound of formula I in the cancers disclosed herein.
• the cancer may be renal cancer and may be selected from renal carcinoma, kidney clear cell carcinoma and hypernephroma, wherein the hypernephroma may be poorly differentiated hypernephroma.
• the cancer may be melanoma and may be amelanotic melanoma.
• the cancer may be soft tissue sarcoma and may be selected from leiomyosarcoma and liposarcoma.
• the cancer may be bone sarcoma and may be chondrosarcoma, including myxoid chondrosarcoma.
• the salt 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-dialkylenethanolamine, triethanolamine and basic amino acids.
• a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, for use as defined herein.
• a dosage form comprising a pharmaceutical composition as defined herein, for use as defined herein.
• a kit comprising a compound, composition or dosage form as defined herein, together with instructions for use as defined herein.
• a compound of formula I or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition as defined herein, or a dosage form as defined herein when used according to a use as defined herein.
• a compound of formula I or a pharmaceutically 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 a cancer, wherein the compound is administered as defined herein.
• a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically 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.
• Figure 3 shows Kaplan-Meier survival curve obtained in mice bearing MRI-H-121 xenografts and treated with Placebo or PM 14 (PM 140014).
• Figure 4A shows efficacy data in human clinical trials at various doses according to Schedule A (D1,D8).
• Figure 4B shows efficacy data in human clinical trials at various doses according to Schedule B (D1).
• Figure 5A shows dose-limiting toxicity data in human clinical trials at various doses according to Schedule A (D1,D8).
• Figure 5B shows dose-limiting toxicity data in human clinical trials at various doses according to Schedule B (D1).
• Figure 6 shows pharmacokinetic data for: (A) PM 14 plasma concentration vs. time; (B) dose adjusted PM 14 vs. time.
• Figure 7 shows simulations of PM 14 pharmacokinetics with different doses and infusion-rates.
• PM14 is a synthetic compound under clinical investigation. PM14 is a specific inhibitor of oncogenic transcription. PM14 has demonstrated encouraging pre-clinical activity in several cancer models. PM14 was first disclosed in WO2018/197663 (as compound 4-S). The structure for PM 14 is:
• PM 14 binds DNA forming adducts that specifically inhibit the active transcription of protein coding genes, by inhibiting mRNA synthesis.
• the mechanism of transcription inhibition involves the irreversible degradation of elongating RNA polymerase II (Pol II) and the subsequent generation of DNA double strand breaks.
• Poly II RNA polymerase II
• PM 14 induces the arrest of the cell cycle on the S-phase and apoptosis of the tumor cell.
• pharmaceutically acceptable salt and “ester” refers to any pharmaceutically acceptable salt or ester which, upon administration to the patient is capable of providing (directly or indirectly) a compound as described herein.
• non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
• the preparation of salts can be carried out by methods known in the art.
• salts of the compounds provided herein are synthesized from the parent compounds, which contain a basic or acidic moiety, by conventional chemical methods.
• such salts are, for example, prepared by reacting the free acid or base of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.
• nonaqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred.
• acid addition salts include mineral 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.
• mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
• organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
• 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-dialkylenethanolamine, triethanolamine and basic amino acids salts.
• the compounds of the invention may be in crystalline or amorphous form either as free compounds or as solvates (e.g. hydrates) and it is intended that all forms are within the scope of the present invention. Methods of solvation are generally known within the art.
• compounds referred to herein may exist in isotopically-labelled forms. All pharmaceutically acceptable salts, esters and isotopically labelled forms of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
• cancer it is meant to include tumors, neoplasias and any other malignant disease having as cause malignant tissue or cells.
• treating means reversing, attenuating, alleviating, delaying or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition.
• the term “subject” refers to a living organism that is treated with a compound of the present invention, including a mammal, such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.
• a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.
• the subject is a human.
• Soft tissue sarcomas can affect any part of the body. They develop in supporting or connective tissue such as the muscle, nerves, fatty tissue, and blood vessels. Soft tissue sarcomas include: GIST which is a common type of sarcoma which develops in the gastrointestinal (Gl) tract; gynaecological sarcomas which occur in the female reproductive system: the uterus (womb), ovaries, vagina, vulva and fallopian tubes; and retroperitoneal sarcomas which occur in the retroperitoneum.
• GIST is a common type of sarcoma which develops in the gastrointestinal (Gl) tract
• gynaecological sarcomas which occur in the female reproductive system: the uterus (womb), ovaries, vagina, vulva and fallopian tubes
• retroperitoneal sarcomas which occur in the retroperitoneum.
• Liposarcoma is a rare cancer of connective tissues that resemble fat cells under a microscope. It accounts for up to 18% of all soft tissue sarcomas. Liposarcoma can occur in almost any part of the body, but more than half of liposarcoma cases involve the thigh, and up to a third involve the abdominal cavity. Liposarcoma tends to affects adults between the ages of 40 and 60. When it does occur in children, it is usually during the teenage years. There are four types of liposarcoma as shown below. The risk of recurrence and metastasis with liposarcoma increases with higher grade.
• Well-differentiated liposarcoma is the most common subtype and usually starts as a low grade tumour.
• Low grade tumour cells look much like normal fat cells under the microscope and tend to grow and change slowly.
• Myxoid liposarcoma is an intermediate to high grade tumour. Its cells look less normal under the microscope and may have a high grade component.
• Dedifferentiated liposarcoma occurs when a low grade tumour changes, and the newer cells in the tumour are high grade.
• LMS Leiomyosarcoma
• the smooth muscles are in the hollow organs of the body, including the intestines, stomach, bladder, and blood vessels. In females, there is also smooth muscle in the uterus. These smooth muscle tissues help move blood, food, and other material through the body and work without you being aware.
• LMS is an aggressive cancer and is found most often in the abdomen or in the uterus.
• LMS is a type of soft tissue sarcoma and makes up between 10% to 20% of soft tissue sarcoma cases. LMS is more common in adults than children. It is estimated that only about 20 to 30 children are diagnosed with LMS in the United States per year.
• LMS of the uterus affects about 6 per 1 million people per year in the United States. Certain genetic conditions are believed to be associated with LMS, including hereditary retinoblastoma, Li-Fraumeni syndrome, neurofibromatosis type 1, tuberous sclerosis, migraine pain syndrome, and Werner syndrome.
• Chondrosarcoma starts in cartilage cells and is the second most common primary bone cancer. It's rare in people younger than 20. After age 20, the risk of getting a chondrosarcoma goes up until about age 75. Women get this cancer as often as men.
• Chondrosarcomas can start anywhere there is cartilage. Most develop in bones like the pelvis, legs, or arms but can also start in the trachea, larynx, chest wall, scapula, ribs, or skull.
• Extraskeletal myxoid chondrosarcoma (EMS) or myxoid chondrosarcoma (and also called EMC) is a rare, slow-growing type of cancer that forms in soft tissues outside the bone, and usually has certain changes in the NR4A3 gene that result in special fusion proteins to be made.
• Extraskeletal myxoid chondrosarcomas usually occur in the thigh, but may also occur in the knee, buttock, or trunk (chest and abdomen). They may grow large and spread to nearby tissue or to other parts of the body, especially the lungs. They may also recur many years after treatment.
• Extraskeletal myxoid chondrosarcomas usually occur in middle-aged or older adults and are rare in children and adolescents.
• Fibrosarcoma develops more often in soft tissues than it does in bones. Fibrosarcoma usually occurs in elderly and middle-aged adults. Bones in the legs, arms, and jaw are most often affected. Melanoma
• Melanoma is a type of skin cancer that develops when melanocytes (the cells that give the skin its tan or brown color) start to grow out of control. Melanoma is much less common than some other types of skin cancers. But melanoma is more dangerous because it’s much more likely to spread to other parts of the body if not caught and treated early. Around 16,200 people are diagnosed with melanoma in the UK each year. The number of people diagnosed with melanoma has increased over the last few decades. Melanoma is the 5th most common cancer in the UK.
• Melanomas can develop anywhere on the skin, but they are more likely to start on the trunk (chest and back) in men and on the legs in women. The neck and face are other common sites.
• Amelanotic melanoma is a form of melanoma in which the malignant cells have little to no pigment.
• the term 'amelanotic' is often used to indicate lesions that are only partially devoid of pigment while truly amelanotic melanoma where lesions lack all pigment is rare.
• Melanomas can also form in other parts of your body, such as the eyes, mouth, genitals, and anal area, but these are much less common than melanoma of the skin.
• Pancreatic neuroendocrine tumors are a type of cancer that starts in the pancreas.
• Pancreatic NETs are a less common type of pancreatic cancer. They make up less than 2% of pancreatic cancers, but tend to have a better prognosis than the more common type.
• Pancreatic neuroendocrine tumors start in neuroendocrine cells. Although neuroendocrine cells (or endocrine cells) are also found in other areas of the body, only cancers that form from neuroendocrine cells in the pancreas are called pancreatic neuroendocrine tumors.
• Neuroendocrine cells in the pancreas are found in small clusters called islets (or islets of Langerhans). These islets make hormones like 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 more like normal cells and are not multiplying quickly.
• Grade 2 also called intermediate-grade or moderately differentiated tumors have features in between those of low- and high-grade tumors.
• Grade 3 also called high-grade or poorly differentiated neuroendocrine tumors have cells that look very abnormal and are multiplying faster. These are also know as neuroendocrine carcinomas (NECs).
• Pancreatic NETs are also named based on whether they are or non-functioning.
• NETs Functioning NETs make hormones that are released into the blood and cause symptoms. Most (up to 70%) functioning NETs are insulinomas. The other types are much less common:
• Insulinomas come from cells that make insulin.
• Glucagonomas come from cells that make glucagon.
• Gastrinomas come from cells that make gastrin.
• Somatostatinomas come from cells that make somatostatin.
• VIPomas come from cells that make vasoactive intestinal peptide (VIP).
• ACTH-secreting tumors come from cells that make adrenocorticotropic hormone (ACTH).
• ACTH adrenocorticotropic hormone
• Non-functioning NETs don’t make enough excess hormones to cause symptoms and can therefore often grow quite large before they're found. Symptoms that may occur when they grow to a large size include abdominal (belly) pain, lack of appetite, and weight loss.
• Carcinoid tumors are much more common in other parts of the digestive system, although rarely they can start in the pancreas. These tumors often make serotonin.
• Endometrial cancer also called endometrial carcinoma
• endometrial carcinoma starts in the cells of the inner lining of the uterus (the endometrium). This is the most common type of cancer in the uterus. Endometrial carcinomas can be divided into different histologic types including:
• Endometrioid cancer most endometrial cancers are adenocarcinomas, and endometrioid cancer is by far the most common type of adenocarcinoma. Endometrioid cancers start in gland cells and look a lot like the normal uterine lining (endometrium). Some of these cancers have squamous cells (squamous cells are flat, thin cells), as well as glandular cells. There are many endometrioid cancer sub-types including:
• CS Uterine carcinosarcoma
• Uterine CS is a type 2 endometrial carcinoma.
• CS tumors are also known as malignant mixed mesodermal tumors or malignant mixed mullerian tumors (MMMTs). They make up about 3% of uterine cancers.
• MMMTs malignant mixed mesodermal tumors
• MMMTs malignant mixed mullerian tumors
• Adenoid cystic carcinoma is a rare form of adenocarcinoma, a type of cancer that begins in glandular tissues. It most commonly arises in the major and minor salivary glands of the head and neck. It can also occur in the breast, uterus, or other locations in the body.
• Adrenal cancer is a rare cancer that begins in one or both of the small, triangular glands (adrenal glands) located on top of the kidneys. Adrenal cancer, also called adrenocortical cancer, can occur at any age. But it's most likely to affect children younger than 5 and adults in their 40s and 50s.
• Renal cancer Renal (or kidney) cancer is a type of cancer that starts in the kidney. There are a number of types of renal cancer.
• Renal cell carcinoma also known as renal cell cancer or renal cell adenocarcinoma
• RCC Renal cell carcinoma
• About 9 out of 10 kidney cancers are renal cell carcinomas.
• RCC usually grows as a single tumor within a kidney, sometimes there are 2 or more tumors in one kidney or even tumors in both kidneys at the same time.
• histologic subtypes of RCC There are several histologic subtypes of RCC:
• Clear cell renal cell carcinoma this is the most common form of renal cell carcinoma. About 7 out of 10 people with RCC have this kind of cancer. The cells that make up clear cell RCC look very pale or clear.
• Non-clear cell renal cell carcinomas o Papillary renal cell carcinoma (also called chromophilic): This is the second most common subtype - about 1 in 10 RCCs are of this type. These cancers form papillae in some, if not most, of the tumor o Chromophobe renal cell carcinoma: This subtype accounts for about 5% (5 cases in 100) of RCCs. The cells of these cancers are also pale, like the clear cells, but are much larger and have certain other features that can be recognized when looked at very closely.
• RCC renal cell carcinoma
• These subtypes are very rare, each making up less than 1% of RCCs: o Collecting duct RCC o Multilocular cystic RCC o Medullary carcinoma o Mucinous tubular and spindle cell carcinoma o Neuroblastoma-associated RCC
• Unclassified renal cell carcinoma Rarely, renal cell cancers are labeled as unclassified because the way they look doesn’t fit into any of the other categories or because there is more than one type of cancer cell present.
• kidney cancers include:
• Transitional cell carcinoma Of every 100 cancers in the kidney, about 5 to 10 are transitional cell carcinomas (TCCs), also known as urothelial carcinomas..
• Wilms tumor (nephroblastoma): Wilms tumors almost always occur in children. This type of cancer is very rare among adults. Renal sarcoma: Renal sarcomas are a rare type of kidney cancer that begin in the blood vessels or connective tissue of the kidney. They make up less than 1 % of all kidney cancers.
• a cancer selected from renal cancer, melanoma, neuroendocrine tumor, endometrial cancer, adenoid cystic carcinoma, adrenocortical carcinoma, bone sarcoma and soft tissue sarcoma.
• the renal cancer is renal carcinoma, kidney clear cell carcinoma or hypernephroma.
• the hypernephroma may be poorly differentiated hypernephroma.
• the melanoma is amelanotic melanoma.
• the soft tissue sarcoma is selected from leiomyosarcoma and liposarcoma. In a preferred embodiment, the soft tissue sarcoma excludes fibrosarcoma.
• the bone sarcoma is chondrosarcoma, including myxoid chondrosarcoma.
• total dose refers to the total amount of compound administered during the three-week cycle.
• the total dose is about 1.0 mg/m 2 to about 9.0 mg/m 2 , about 1.5 mg/m 2 to about 9.0 mg/m 2 , about 2.0 mg/m 2 to about 9.0 mg/m 2 , about 2.5 mg/m 2 to about 8.5 mg/m 2 , about 3.0 mg/m 2 to about 8.0 mg/m 2 , about 3.5 mg/m 2 to about 7.5 mg/m 2 , about 4.0 mg/m 2 to about 7.0 mg/m 2 , about 4.0 mg/m 2 to about 6.5 mg/m 2 , about 4.5 mg/m 2 to about 6.5 mg/m 2 , about 4.5 mg/m 2 to about 6.0 mg/m 2 .
• the total dose is about 3.0 mg/m 2 to about 6.0 mg/m 2 , about 3.0 mg/m 2 to about 5.6 mg/m 2 , about 3.5 mg/m 2 to about 5.6 mg/m 2 , about 4.0 mg/m 2 to about 5.0 mg/m 2 or about 4.5 mg/m 2 .
• the total dose is about 4.0 mg/m 2 to about 9.0 mg/m 2 , about 4.0 mg/m 2 to about 8.0 mg/m 2 , about 4.5 mg/m 2 to about 7.5 mg/m 2 , about 5.0 mg/m 2 to about 7.0 mg/m 2 , about 5.5 mg/m 2 to about 6.5 mg/m 2 , or about 6.0 mg/m 2 .
• the total dose is about 4.5 mg/m 2 to about 8.0 mg/m 2 , about 4.5 mg/m 2 to about 5.0 mg/m 2 , about 7.0 mg/m 2 to about 8.0 mg/m 2 , about 4.5 mg/m 2 , about 5.0 mg/m 2 , about 7.0 mg/m 2 , or about 8.0 mg/m 2 .
• the compound may be administered in one or more doses during the three-week cycle.
• the compound may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times during the three-week cycle.
• the compound may be administered once weekly.
• the compound may be administered once daily.
• the total dose may be split evenly between each individual dose within the three-week cycle. Said another way, the amount of compound administered for each dose may be equal.
• the compound of formula I is administered as a single dose during the three-week cycle.
• the single dose is about 3.0 mg/m 2 to about 6.0 mg/m 2 , more preferably about 3.0 mg/m 2 to about 5.6 mg/m 2 , more preferably about 3.5 mg/m 2 to about 5.6 mg/m 2 , even more preferably about 4.0 mg/m 2 to about 5.0 mg/m 2 . It is particularly preferred that the single dose is about 4.5 mg/m 2 .
• the single dose may be administered on day 1 of the cycle.
• the single dose is about 5.0 mg/m 2 .
• the single dose may be administered on day 1 of the cycle.
• the compound of formula I is administered at a dose of 4.5 mg/m 2 on day 1 of a three-week cycle.
• the compound of formula I is administered at a dose of 5.0 mg/m 2 on day 1 of a three-week cycle.
• the compound of formula I is administered 2, 3, 4, 5, 6, 7, 8, 9 or 10 times during the cycle. In some embodiments the compound is administered 3 times during the cycle. In some embodiments the compound is administered 3 times during the three-week cycle.
• the compound is administered 3 times during the cycle on days 1 , 2 and 3.
• the amount of compound administered for each of the doses may be equal.
• the dose administered on each of these days is the same.
• 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 .
• each individual 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 or 9.0 mg/m 2 .
• the compound of formula I is administered as a first dose and a second dose during the three-week cycle (i.e. 2 times during the three-week schedule).
• the first dose is administered on day 1 of the three-week cycle and the second dose is 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 are equal.
• the total dose for the first dose and the second dose is about 0.5 mg/m 2 to about 9.0 mg/m 2 , more preferably about 1.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 1.5 mg/m 2 to about 9.0 mg/m 2 , more preferably about 2.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 3.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 4.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 5.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 6.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 4.0 mg/m 2 to about 8.0 mg/m 2 , more preferably about 6.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 5.0 mg/m 2 to about 7.0 mg/m 2 , even more preferably about 5.5 mg/m 2 to about 6.5 mg/m 2 . It is particularly
• the first dose and/or the second dose is about 2.25 mg/m 2 to about 3.75 mg/m 2 , more preferably about 2.5 mg/m 2 to about 3.5 mg/m 2 , even more preferably about 2.75 mg/m 2 to about 3.25 mg/m 2 . It is particularly preferred that the first dose and/or the second dose is about 3.0 mg/m 2 .
• the total dose for the first dose and the second dose is about 6.0 mg/m 2 to about 9.0 mg/m 2 , more preferably about 6.5 mg/m 2 to about 8.5 mg/m 2 , more preferably about 7.0 mg/m 2 to about 8.0 mg/m 2 , more preferably 7.0 mg/m 2 or 8.0 mg/m 2 .
• the first dose and/or the second dose is about 3.0 mg/m 2 to about 4.5 mg/m 2 , more preferably about 3.25 mg/m 2 to about 4.25 mg/m 2 , even more preferably about 3.5 mg/m 2 to about 4.0 mg/m 2 . It is particularly preferred that the first dose and/or the second dose is about 3.5 mg/m 2 or about 4.0 mg/m 2 .
• the compound of formula I is administered at a dose of 3.0 mg/m 2 on day 1 and at a dose of 3.0 mg/m 2 on day 8 of a three-week.
• the compound of formula I is administered at a dose of 3.5 mg/m 2 on day 1 and at a dose of 3.5 mg/m 2 on day 8 of a three-week.
• the compound of formula I is administered at a dose of 4.0 mg/m 2 on day 1 and at a dose of 4.0 mg/m 2 on day 8 of a three-week.
• the compound is administered parentally.
• the compound is administered intravenously.
• the dosage regimens as disclosed herein are useful in the treatment of cancer.
• 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, pancreas cancer, sarcoma including soft tissue sarcoma or bone sarcoma, ovarian cancer, prostate cancer, gastric cancer, renal cancer, melanoma, neuroendocrine tumor, endometrial cancer, adenoid cystic carcinoma and adrenocortical carcinoma.
• the lung cancer is non-small cell lung cancer or small cell lung cancer.
• the renal cancer is renal carcinoma, kidney clear cell carcinoma or hypernephroma.
• the hypernephroma may be poorly differentiated hypernephroma.
• the melanoma is amelanotic melanoma.
• the sarcoma is soft tissue sarcoma.
• the soft tissue sarcoma is selected from fibrosarcoma, leiomyosarcoma and liposarcoma.
• the sarcoma is bone sarcoma.
• the bone sarcoma is chondrosarcoma, including myxoid chondrosarcoma.
• a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, for use in the treatment of a cancer as described herein.
• the pharmaceutically acceptable carrier or vehicle can be particulate, so that the compositions are, for example, in tablet or powder form.
• the carrier(s) can be liquid, with the compositions being, for example, an oral syrup or injectable liquid.
• the carrier(s) can be gaseous, or liquid so as to provide an aerosol composition useful in, for example inhalatory administration. Powders may also be used for inhalation dosage forms.
• carrier refers to a diluent, adjuvant or excipient, with which the compound according to the present invention is administered.
• Such pharmaceutical carriers can be liquids, such as water and oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• the carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, disaccharides, and the like.
• auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
• the compounds and compositions according to the present invention, and pharmaceutically 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 employed 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 and the like.
• 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 and the like.
• the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
• compositions are administered parenterally.
• compositions of the invention can be formulated so as to allow a compound according to the present invention to be bioavailable upon administration of the composition to an animal, preferably human.
• Compositions can take the form of one or more dosage units, where for example, a tablet can be a single dosage unit, and a container of a compound according to the present invention may contain the compound in liquid or in aerosol form and may hold a single or a plurality of dosage units.
• composition When intended for oral administration, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
• the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
• a solid composition typically contains one or more inert diluents.
• binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, corn starch and the like; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agent such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
• composition When the composition is in the form of a capsule (e.g. a gelatin capsule), it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrins or a fatty oil.
• a liquid carrier such as polyethylene glycol, cyclodextrins or a fatty oil.
• the composition can be in the form of a liquid, e.g. an elixir, syrup, solution, emulsion or suspension.
• the liquid can be useful for oral administration or for delivery by injection.
• a composition can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
• a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.
• the preferred route of administration is parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal or transdermal.
• the preferred mode of administration is left to the discretion of the practitioner, and will depend in part upon the site of the medical condition (such as the site of cancer).
• the compounds according to the present invention are administered intravenously.
• Infusion times of up to 24 hours are preferred to be used, more preferably 1 to 12 hours, with 1 to 6 hours being most preferred.
• An infusion time may be 24 hours. Further infusion times include 1, 2, 3, 4, 5 or 6 hours.
• An infusion time may be three hours. Short infusion times which allow treatment to be carried out without an overnight stay in a hospital are especially desirable. However, infusion may be 12 to 24 hours or even longer if required. Infusion may be carried out at suitable intervals of, for example, 1 to 4 weeks.
• the liquid compositions of the invention can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological 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 methyl paraben; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• sterile diluents such as water for injection, saline solution, preferably physiological 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 methyl paraben
• agents for the adjustment of tonicity such as sodium chloride or dextrose.
• a parenteral composition can be enclosed in an ampoule,
• the amount is at least about 0.01% of a compound of the present invention, and may comprise at least 80%, by weight of the composition. When intended for oral administration, this amount can be varied to range from about 0.1% to about 80% by weight of the composition.
• Preferred oral compositions can comprise from about 4% to about 50% of the compound of the present invention by weight of the composition.
• compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 10 % by weight of the compound of the present invention. More preferred parenteral dosage unit contains about 0.5 % to about 5 % by weight of the compound of the present invention.
• the compound of the present invention can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings.
• administration can be by direct injection at the site (or former site) of a cancer, tumor or neoplastic or pre-neoplastic tissue.
• Pulmonary administration can also be employed, e.g. by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
• the compound of the present invention can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
• compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
• suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E. W. Martin.
• compositions can be prepared using methodology well known in the pharmaceutical art.
• a composition intended to be administered by injection can be prepared by combining a compound of the present invention with water, or other physiologically suitable diluent, such as phosphate buffered saline, so as to form a solution.
• a surfactant can be added to facilitate the formation of a homogeneous solution or suspension.
• compositions according to the present invention include:
• compositions comprising a compound of the present invention and a disaccharide.
• Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.
• Lyophilised pharmaceutical compositions comprising a compound of the present invention and a disaccharide.
• Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.
• the ratio of the active substance to the disaccharide in embodiments of the present invention is determined according to the solubility of the disaccharide and, when the formulation is freeze dried, also according to the freeze-dryability of the disaccharide. It is envisaged that this active substance:disaccharide ratio (w/w) can be about 1:10 in some embodiments, about 1 :20 in other embodiments, about 1:50 in still other embodiments. It is envisaged that other embodiments have such ratios in the range from about 1 :5 to about 1 :500, and still further embodiments have such ratios in the range from about 1:10 to about 1 :500.
• composition comprising a compound of the present invention may be lyophilized.
• composition comprising a compound of the present invention is usually presented in a vial which contains a specified amount of such compound.
• the compound according to the present invention can be administered to an animal that has also undergone surgery as treatment for the cancer.
• the additional method of treatment is radiation therapy.
• the compound according to the present invention is administered concurrently with radiation therapy.
• the radiation therapy is administered prior or subsequent to administration of the compound of the present invention, preferably at least an hour, three hours, five hours, 12 hours, a day, a week, a month, more preferably several months (e.g. up to three months) prior or subsequent to administration of a compound or composition of the present invention.
• any radiation therapy protocol can be used depending upon the type of cancer to be treated.
• x-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater than 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers.
• Gamma-ray emitting radioisotopes such as radioactive isotopes of radium, cobalt and other elements, can also be administered.
• the compounds and compositions according to the present invention are useful for inhibiting the multiplication, or proliferation, of a tumor cell or cancer cell, or for treating cancer in an animal, preferably a human.
• PM 14 can be obtained following the teaching of WO2018/197663, the contents of which are herein incorporated by reference.
• Example 1 Renal cancer activity in RXF 393 and Caki-1 in vitro assays
• MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
• GI50 compound concentration that produces 50% of cell growth inhibition as compared to control cultures
• TGI compound concentration that causes total cell growth inhibition, i.e. a cytostatic effect, as compared to control cultures
• LC50 compound concentration that produces 50% of net cell killing cytotoxic effect
• Tz is the number of cells at time zero
• C is the number of cells after 72 h in DMSO-treated control wells
• T is the number of cells after 72 h in test wells
• Tz ⁇ T ⁇ C i.e. no effect or growth inhibition
• T ⁇ Tz i.e. net cell killing
• % cell survival 100 GI 50 is finally used as reference value.
• Results presented here correspond to the geometric mean of the GI 50S obtained in at least three independent experiments each of them was performed in triplicate for every compound in every tumour cell line. To define a significant (ca. 70%) confidence interval for the geometric mean, its value must be multiplied and divided by the corresponding geometric standard deviation (GSD) which was also calculated. When the GSD was greater than 4, outliers were identified among the replicates and the mean GI50 was recalculated ignoring those values to prevent from artifactual bias.
• GSD geometric standard deviation
• Example 2 Renal cancer activity in RXF 486L and RXF 1781 L in vitro assays Compound handling: PM14 (Pharma Mar) was supplied as powder, shipped frozen at -80 °C and stored at -20 °C.
• Working stock solution of PM 14 was prepared in DMSO at a concentration of 1.042 mM and small aliquots were stored at -20 °C. On each day of an experiment, a frozen aliquot of the working stock solution was thawed and stored at room temperature prior to and during treatment.
• DMSO stock solutions were first diluted 1:22 (corresponding to 4.5% v/v DMSO). Starting with this solution, serial dilutions in half-log steps with cell culture medium were done using an intermediate dilution plate. Finally, 10 mI taken from the intermediate dilution plate were transferred to 140 mI / 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.
• Non-PDX-derived cell lines were either provided by the NCI (Bethesda, MD), or were purchased from ATCC (Rockville, MD) or DSMZ (Braunschweig, Germany). The following human cancer cell lines have been used in this example:
• Cell lines were routinely passaged once or twice weekly and maintained in culture for up to 20 passages. All cells were grown at 37 °C in a humidified atmosphere with 5% CO2 in RPMI 1640 medium (25 mM HEPES, with L-glutamine, #FG1385, Biochrom, Berlin, Germany) supplemented with 10% (v/v) fetal calf serum (Sigma, Taufkirchen, Germany) and 0.1 mg/ml_ gentamicin (Life Technologies, Düsseldorf, Germany).
• Cell proliferation assay A modified propidium iodide (PI) based monolayer assay was used to assess the anti-cancer activity of the compounds (Dengler WA, Schulte J, Berger DP, Mertelsmann R, Fiebig HH, Anti-Cancer Drugs 1995, 6: 522-532). Briefly, cells were harvested from exponential phase cultures, counted and plated in 96 well flat-bottom microtiter plates at a cell density of 4,000 to 30,000 cells/well dependent on the cell line’s growth rate. After a 24 h recovery period, to allow the cells to resume exponential growth, 10 mI of culture medium (4 control wells/cell line/plate) or of culture medium with test compounds were added.
• PI propidium iodide
• PI propidium iodide
• Triton X-100 0.1%
• IC5 0 and IC7 0 values were calculated by 4 parameter non-linear curve fit using Oncotest Warehouse Software. For calculation of mean IC50 values, the geometric mean was used. Results: The IC5 0 values for RXF 486L and RXF 1781 L are shown below in Table 3, whilst the IC7 0 values for RXF 486L and RXF 1781 L are shown below in Table 4.
• Example 3 Renal cancer activity in MRI-H-121 mouse xenograft studies
• Vials of off-white lyophilized PM 14 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 a 5% glucose solution for injection/USP (Baxter, Inc.). A clear PM 14 solution was obtained.
• 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 a 5% glucose solution for injection/USP (Baxter, Inc.), resulting in a clear solution. Animals: Female athymic nu/nu mice between 4 to 6 weeks of age were purchased from Envigo (Barcelona, Spain).
• mice were housed in individually ventilated cages (Sealsafe® Plus, Techniplast S.P.A.): 10 mice per cage, on a 12-hour light-dark cycle at 21-23 °C and 40-60% humidity. Mice were allowed free access to irradiated standard rodent diet (Tecklad 2914C) and sterilized water. Animals were acclimated for five days prior to being individually tattoo- identified.
• Tumor line is a human renal carcinoma tumor line, originally obtained from the DCT Tumor Bank. Developed by Dr. A. E. Bogden, Mason Research Institute MA and maintained as a serial transplanted tumor line in athymic nude mice. Original tissue came from a patient at U. of Mass. Med. Center.
• mice were subcutaneously implanted into their right flank with a MRI-H-121 tissue from serial transplanted donor mice. Tumors were removed from donor animals and were cut into fragments (3 mm 3 ). Tissue was debrided of membrane, hemorrhagic and necrotic areas, placed in MatrigelTM (Corning Incorporated Life Sciences) and subcutaneously implanted. Recipient mice were anesthetised by inhalation of isoflurane, a small incision into the skin of the back was made and one tumor fragment per mouse was transplanted with tweezers. The mice were monitored daily.
• Tumor measurements were determined using digital calipers (Fowler Sylvac, S235PAT). The formula to calculate volume for a prolate ellipsoid was used to estimate tumor volume (mm 3 ) from 2-dimensional tumor measurements:
• Tumor volume (mm 3 ) (a b 2 )/2.
• a length (longest diameter) and b: width (shortest diameter) in mm of a tumor.
• T umor volume and animal body weights were measured 2-3 times per week starting from the first day of treatment.
• Treatment tolerability was assessed by monitoring body weight evolution, clinical signs of systemic toxicity, as well as evidences of local damage in the injection site.
• Treatments were initiated on Day 0 and were intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14).
• Tumor volume data from groups following the 1st, 2nd, 3rd, 4th and 5th weeks were compared using a two tailed Mann Whitney U test. The data are presented as medians and interquartile range (IQR).
• CR Complete tumor regression
• Treatments were initiated on Day 0 when tumors reached a volume of ca. 190 mm 3 .
• MRI-H-121 tumors had a doubling time of 3.2 days.
• PM14 showed a very strong antitumor activity in MRI-H-121 tumor xenografts.
• the placebo-treated group had a median (IQR) tumor volume of 1147 (956.4 to 1468) and 1727 (1228 to 1955) mm 3 on days 7 and 14, respectively.
• PM14-treated animals had a median (IQR) tumor volume of 401.2 (374.1 to 450.0), 472.7 (412.0 to 597.2), 743.8 (550.1 to 940.6), 1392 (1069 to 2085) and 2015 (1574 to 2161) mm 3 , respectively.
• PM14-treated animals experienced a high, statistically significant tumor reduction from days 7 to 14, that being the last measurement time in the euthanized, placebo-treated group, as shown in Table 5 below.
• the survival time in the PM14-treated group was 32.5 days.
• Table 5 Tumour volume (TV) obtained in mice bearing MRI-H-121 xenografts and treated with Placebo or PM14 administered at 1.25 mg/kg. a Compared to placebo treated group. N.P. No placebo group to compare with.
• Table 6 Survival and statistic results obtained for mice bearing MRI-H-121 xenografts and treated with Placebo or PM 14 administered at 1.25 mg/kg. a Compared to placebo treated group. In conclusion, PM14 displayed a good tolerability profiling in athymic mice bearing MRI- H-121 xenografted tumors.
• Example 4 Melanoma activity in MEXF 276L, MEXL 462NL and MEXL 1341 L in vitro assays
• IC50 values were determined as described in Example 2, but using the following human cancer cell lines:
• Example 5 Melanoma activity in WM-266-4 in vitro assay GI50 values were determined as described in Example 1 , but using the following human cancer cell line:
• Cell line was obtained from the American Type Culture Collection (ATCC). Cells were maintained in MEM mediumCulture medium was supplemented with 10% Fetal Bovine Serum, 1% penicillin and streptomycin and 2 mM L-Glutamine. Cells were cultured at 37°C and 5%
• Table 9 Gko values for WM-266-4
• Example 6 Simulations of PM 14 pharmacokinetics with different doses and infusion-rates
• the D1 simulation (Ihs) simulates 4.5 mg/m 2 with a 24 hour infusion.
• the D1-3 simulation (rhs) simulates x3 1.5 mg/m 2 3 hour infusions.
• the D1-3 schedule simulates a prolonged half-life without exceeding the 100nM concentration.
• Example 7 Phase I, Open-label, Dose-escalating, Clinical and Pharmacokinetic Study of
• DLTs dose limiting toxicities
• RD recommended dose
• PGt pharmacogenetics
• Patients will be included in cohorts of a minimum of three or six patients to receive PM 14 at successively increasing dose levels, starting at 0.25 mg/m2 for the Days 1 and 8 schedule. For the Day 1 schedule, the starting dose will be 4.5 mg/m2.
• Dose escalation will proceed only after all the patients fully evaluable for DLT included at one dose level have completed the first cycle (i.e., three weeks). According to the toxicities observed and pharmacokinetic results, other duration of infusions and/or schedules may be explored if considered appropriate, after agreement between the Sponsor, the Independent Monitoring Committee (IMC) and the Investigators.
• IMC Independent Monitoring Committee
• Radiological tumor assessments will be done every two cycles from treatment start until Cycle 6, and thereafter every three cycles while on treatment. After treatment discontinuation, patients will be followed until resolution or stabilization of all toxicities, if any. Patients discontinuing treatment without progression will be followed every three months until disease progression, start of other antitumor therapy, death or the end-of-study date (clinical cutoff: six months after treatment discontinuation of the last patient [last patient-last visit] or nine months after accrual of the last evaluable patient, whichever occurs first), whichever occurs first. After disease progression or start of a new therapy, patients will be followed up for survival every three months ( ⁇ two weeks) until death or end-of-study date, whichever occurs first (a phone contact will be acceptable).
• Antitumor response will be assessed using the RECIST v.1.1 and/or serum tumor markers as appropriate (see above).
• wash-out periods a) At least three weeks since the last chemotherapy (six weeks if therapy included nitrosoureas or systemic mitomycin C). b) At least four weeks since the last monoclonal antibody (MAb)-containing therapy or curative radiotherapy (RT). c) At least two weeks since the last biological/investigational single-agent therapy (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) analogues in pre-menopausal women or megestrol acetate), all other hormonal therapies must be stopped at least one week before study treatment start. e) Castrate-resistant prostate cancer (CRPC) patients may continue receiving hormone therapy prior to and during study treatment.
• CRPC Castrate-resistant prostate cancer
• ECG abnormalities including any of the following: left bundle branch block, right bundle branch block with left anterior hemiblock, second (Mobitz II) or third degree atrioventricular block.
• Symptomatic arrhythmia excluding anemia-related sinusal tachycardia grade £2) or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade 32; or presence of unstable atrial fibrillation. Patients with stable atrial fibrillation on treatment are allowed provided they do not meet any other cardiac or prohibited drug exclusion criterion.
• WOCBP Women of childbearing potential
• Fertile male patients must agree to refrain from fathering a child or donating sperm and to use an effective contraception method during treatment and for four months after the last infusion.
• WOCBP who are partners of fertile male patients must use an effective contraception method during the patients’ treatment and for four months after the last infusion.
• the number of patients may vary depending both on the tolerability to PM 14 and the number of dose levels required to identify the MTD and the RD. Approximately 50 patients are expected to be recruited during dose escalation at three medical centers.
• the MTD will be the lowest dose level explored during dose escalation in which one third or more of evaluable patients develop a DLT in Cycle 1.
• the CRM could be used to define the RD.
• AEs will be graded according to the NCI-CTCAE v.4. Additionally, treatment-related discontinuations and treatment compliance (dose reduction, skipped doses and/or treatment delays due to AEs), will be described.
• PK analyses will be evaluated in plasma and urine by standard non- compartmental analysis (compartmental modeling may be performed if appropriate). Plasma samples for PM14 PK analysis will be obtained in Cycle 1 from all patients, and also in Cycle 2 from patients treated during Step D of the CRM. In addition, the urine produced during Day 1 of Cycle 1 and Cycle 2 will be collected from patients treated during Step D of the CRM. Pharmacogenetics: the presence or absence of PGt polymorphisms in genes relevant for PM14 disposition (distribution, metabolism and excretion) from a single blood sample collected at any time during the trial (but preferably at the same time as the pre-treatment PK sample on Day 1 of Cycle 1) will be assessed to explain individual variability in main PK parameters.
• Efficacy patients will be evaluable for efficacy if they receive at least one complete infusion of PM14 and have at least one clinical or radiological tumor assessment as per RECIST v.1.1 or serum markers, or if they are considered to have failed treatment. Treatment failure will be defined as clinical deterioration, death due to PD or treatment discontinuation due to any treatment-related toxicity before any appropriate tumor assessments have been performed.
• Antitumor activity will be evaluated according to the RECIST v.1.1 and/or serum markers every two cycles ( ⁇ one week) after treatment start in all patients with evaluable disease until Cycle 6. Those patients continuing treatment after Cycle 6 will thereafter have assessments performed every three cycles ( ⁇ one week) while on treatment, unless otherwise is clinically indicated. Anonymized copies of all images must be submitted to the Sponsor.
• Efficacy endpoints comprise response rates (percentage of patients with PR, with CR, or the sum of both [ORR]), percentage of patients with stable disease (SD) 34 months, percentage of patients with clinical benefit (ORR or SD 34 months), and time-to-event parameters (if appropriate). Efficacy endpoints will be secondary endpoints.
• DLTs are defined as AEs and laboratory abnormalities related to the study drug occurring during the first cycle of treatment and fulfilling at least one of the criteria outlined below: • Grade 4 neutropenia (ANC ⁇ 0.5 x109/L) lasting 33 days.
• Grade 32 ALT or AST increase concomitantly with total bilirubin increase 32.0 x ULN and normal alkaline phosphatase (ALP) (i.e., fulfilling Hy’s Law criteria).
• ALP normal alkaline phosphatase
• Non-clinically relevant biochemical abnormalities e.g., isolated increase in gamma-glutamyltransferase [GGT]). In any case, the clinical relevance should be discussed.
• Dose escalation phase Patients must be replaced if they are not fully evaluable for the assessment of the primary objective (determination of the MTD and RD).
• An evaluable patient for the main objective of the phase must have received at least one complete cycle, except if the discontinuation, missed dose, delay or interruption were due to toxicity, and must have been adequately followed during Cycle 1 (three weeks).
• patients must be replaced if: They are withdrawn from the study before completing a PM 14 cycle (Day 1 and Day 8 infusions for the two infusion schedule plus two resting weeks; or Day 1 for the one infusion schedule; plus three resting weeks) for any reason other than toxicity (excluding hypersensitivity and/or extravasation reactions).
• Patients may be treated with additional cycles of PM 14 as long as no unacceptable toxicity and/or progression of the disease occurred. Criteria for treatment continuation are included in Table 10 and Table 11.
• the administration of a new cycle should be delayed if these criteria are unmet on the corresponding Day 1 of each cycle. Parameters will be re-evaluated after at least 48 hours, or more if appropriate. The new cycle will always start only upon recovery of these parameters. A maximum delay of 14 days will be allowed for recovery from any drug-related AEs. Should recovery not occur after this period, the patient must discontinue treatment except in case of objective patient clinical benefit according to the Investigator’s criteria and request, and upon the Sponsor’s approval.
• AEs adverse events
• ALT alanine aminotransferase
• ANC absolute neutrophil count
• AST aspartate aminotransferase
• GGT gamma-glutamyltransferase
• ULN upper limit of normal.
• AEs adverse events
• ALT alanine aminotransferase
• ANC absolute neutrophil count
• AST aspartate aminotransferase
• GGT gamma-glutamyltransferase
• ULN upper limit of normal.
• Treatment after DLT, a treatment-related infusion delay longer than 14 days, or any treatment- related AE considered as unacceptable by the Investigators may continue only if there is clear evidence of objective patient’s clinical benefit. This will always be discussed with the Sponsor. Under these circumstances, and always following recovery to pre-specified re-treatment criteria, patients will receive a subsequent infusion at the dose level immediately below the one administered during the previous infusion during dose escalation (i.e. , Steps A, B and C).
• Table 12 Summary of patients tested under Schedule A and Schedule B
• the recommended dose (RD) was 3.0 mg/m 2 on D1,D8 (A), and 4.5 mg/m 2 on D1 (B). No DLTs were present at the RDs. Most common toxicities were hematological abnormalities and transaminase increase.
• the efficacy results are shown in Figures 4A and 4B, whilst the safety results are shown in Tables 13 and 14 below and summarised in Figures 5A and 5B.
• the dose escalation study has determined RDs for two PM 14 schedules in patients with advanced solid tumors.
• PM 14 is well tolerated and has a manageable safety profile.
• the most common related adverse events are transient transaminase increase, nausea/vomiting, fatigue and neutropenia.
• Some prolonged tumor stabilizations were observed in patients, including heavily pre-treated patients with soft tissue sarcoma, epithelial ovarian cancer, colorectal cancer and adrenocortical carcinoma.
• PK of PM 14 is linear at the range of doses tested, hepatic extraction ratio is low and distribution into peripheral tissues is moderate, resulting in a half-life of 16 h.
• the study shows stable disease (SD) in respect of various cancers including: SCLC; STS, including leiomyosarcoma and liposarcoma; bone sarcoma including myxoid chondrosarcoma; neuroendocrine tumor; ovarian cancer; breast cancer; endometrial cancer; prostate cancer, pancreatic cancer; adenoid cystic carcinoma; adrenocortical carcinoma; and colorectal cancer.
• SCLC single cell linearcoma
• STS including leiomyosarcoma and liposarcoma
• bone sarcoma including myxoid chondrosarcoma
• neuroendocrine tumor ovarian cancer
• breast cancer endometrial cancer
• prostate cancer pancreatic cancer
• adenoid cystic carcinoma adrenocortical carcinoma
• colorectal cancer colorectal cancer.
• PM 14 can be used in the treatment of various cancers such as SCLC; sarcoma including STS and bone sarcoma; STS including leiomyosarcoma and liposarcoma; bone sarcoma including chondrosarcoma; melanoma including amelanotic melanoma, neuroendocrine tumor; ovarian cancer; breast cancer; endometrial cancer; pancreatic cancer; adenoid cystic carcinoma; adrenocortical carcinoma; renal cancer including renal carcinoma, kidney clear cell carcinoma, hypernephroma or poorly differentiated hypernephroma; and colorectal cancer.
• SCLC various cancers
• sarcoma including STS and bone sarcoma
• STS including leiomyosarcoma and liposarcoma
• bone sarcoma including chondrosarcoma
• melanoma including amelanotic melanoma, neuroendocrine tumor
• ovarian cancer breast cancer
• the present invention has also identified for the first time dosage regimens useful in the treatment of cancer. These dosage 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; pancreas cancer; sarcoma including soft tissue sarcoma and bone sarcoma; soft tissue sarcoma including fibrosarcoma, leiomyosarcoma and liposarcoma; bone sarcoma including chondrosarcoma, or myxoid chondrosarcoma; ovarian cancer; prostate cancer; gastric cancer; renal cancer including renal carcinoma, kidney clear cell carcinoma, hypernephroma and poorly differentiated hypernephroma; melanoma, including amelanotic melanoma; neuroendocrine tumor; endometrial cancer; adenoid cyst
• the present invention provides new effective options for the treatment of cancer.

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