WO2025228597A1 - Combination of compound ia and a topoisomerase i inhibitor in the treatment of cancer - Google Patents

Abstract

The present invention relates to therapeutic treatment of cancer, particularly solid and hematological tumors, with combination therapy using Compound IA and a topoisomerase I inhibitor.

Description

TITLE Combination of Compound Ia and a topoisomerase I inhibitor in the treatment of cancer FIELD OF THE INVENTION The present invention relates to therapeutic treatment of cancer, particularly solid and hematological tumors, with combination therapy using Compound IA and a topoisomerase I inhibitor. BACKGROUND TO THE INVENTION Topoisomerase I is an enzyme that plays a role in the normal replication and transcription of DNA. In its physiological state in the chromosome, the DNA helix is supercoiled and tightly packed into chromatin. Replication requires transient relaxation and unwinding of the parent DNA to allow the replication fork to proceed down the DNA strand and serve as a template for synthesis of new strands of DNA. In order to achieve this without creating extreme torsional stress on the parent DNA, transient cleavage of the DNA is required. Topoisomerase I subserves this process through a reversible trans-esterification reaction, which yields a covalent intermediate form with the tyrosine of the enzyme bound to the 3' end of the DNA strand forming a “cleavage complex”. Topoisomerase I inhibitors bind to the topoisomerase I cleavage complex, thereby stabilizing it and preventing the religation of the DNA strands, leading to DNA damage, cell cycle arrest, and apoptosis. Various topoisomerase I inhibitors have been evaluated in solid tumors, and irinotecan and topotecan have been approved for the treatment of epithelial malignancies. Irinotecan (CPT-11 , Campto®, Camptosar®) is a prodrug that converts to a biologically active metabolite SN-38 and inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA, inhibiting DNA replication and triggering apoptotic cell death. Ecteinascidins are exceedingly potent antitumor agents originally isolated from the marine tunicate Ecteinascidia turbinata. WO2018/197663 describes synthetic ecteinascidin compounds including Compound IA which is described as compound 39-S with the following formula: Compound IA demonstrated activity against non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), breast adenocarcinoma, prostate cancer, fibrosarcoma, ovarian carcinoma, gastric carcinoma, melanoma, in xenograft models. Despite the positive results obtained in clinical applications in chemotherapy, there is a need for further effective cancer therapies. SUMMARY OF THE INVENTION The present inventors have surprisingly determined the synergistic effect of the combination of Compound IA and topoisomerase I inhibitor, preferably irinotecan, which is effective in the treatment of cancer, particularly solid and hematological tumors. Accordingly, in an aspect of the present invention, it is provided Compound IA for use in the treatment of cancer, wherein in said treatment Compound IA is administered in combination with topoisomerase I inhibitor to a patient in need thereof. In a further aspect, the present invention provides a method of treatment of cancer, the method comprising administering Compound IA to a patient in need thereof, wherein Compound IA is administered in combination therapy with a topoisomerase I inhibitor, thereby treating the cancer. In a further aspect, the present invention provides the use of Compound IA in the manufacture of a medicament for the treatment of cancer, wherein Compound IA is administered in combination with a topoisomerase I inhibitor. In a further aspect, the present invention provides a pharmaceutical package comprising Compound IA, together with instructions for its use in combination with topoisomerase I inhibitor. In a further aspect, the invention provides a method of prolonging survival of a patient having cancer, the method comprising administering a combination therapy of Compound IA and topoisomerase I inhibitor to a patient in need thereof, thereby prolonging survival of the patient. In a further aspect, the invention provides a method of reducing or delaying growth of cancer, the method comprising administering a combination therapy of Compound IA and topoisomerase I inhibitor to a patient in need thereof, thereby reducing or delaying growth of cancer. In a further aspect, the invention provides a method of delaying disease progression of cancer in a patient, the method comprising administering a combination therapy of Compound IA thereof and topoisomerase I inhibitor to a patient in need thereof, thereby delaying disease progression of cancer. In a further aspect, the invention provides the use of topoisomerase I inhibitor in the treatment of cancer, wherein in said treatment the topoisomerase I inhibitor is administered in combination with Compound IA to a patient in need thereof. In a further aspect, the invention provides the use of Compound IA and topoisomerase I inhibitor in the treatment of cancer, wherein said treatment comprises administering a combination therapy of Compound IA and topoisomerase I inhibitor to a patient in need thereof. In a further aspect, there is provided a combination of Compound IA and a topoisomerase I inhibitor. In a further aspect, there is provided Compound IA and a topoisomerase I inhibitor, for use in a method of inhibiting growth of a cell, said method comprising contacting a cell with the combination of Compound IA and a topoisomerase I inhibitor, either concurrently, sequentially or separately, wherein said cell is a cancer cell. In a further aspect, there is provided Compound IA for use in the treatment of hematological tumors. In a further aspect, the present invention provides a method of treatment of hematological tumors, the method comprising administering Compound IA to a patient in need thereof, thereby treating the hematological tumor. In a further aspect, the present invention provides the use of Compound IA in the manufacture of a medicament for the treatment of hematological tumors. The following embodiments apply to all aspects of the present invention. In an embodiment, the cancer is a solid tumor. In a preferred embodiment, the solid tumor is selected from neuroendocrine tumor, gastrointestinal cancer, lung cancer, non-small cell lung cancer (NSCLC), large cell lung cancer (LCLC), small cell lung cancer (SCLC), sarcoma, Ewing’s sarcoma, fibrosarcoma, gynaecological cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, renal cancer, malignant pleural mesothelioma, extrapulmonary small cell carcinoma, adrenocortical carcinoma, prostate cancer, deleterious germline BRCA1/2 mutation tumors, colorectal cancer, colon cancer, rectal cancer, gastric cancer, melanoma and pancreatic cancer. In a more preferred embodiment, the solid tumor is selected from esophageal carcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, biliary tract carcinoma, hepatocarcinoma and poorly differentiated (grade 3) gastroenteropancreatic neuroendocrine neoplasms, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing’s sarcoma, epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas), endometrial carcinoma, carcinoma of cervix, ductal carcinoma, lobular carcinoma, urothelial bladder carcinoma, clear cell renal carcinoma and prostate adenocarcinoma. In another preferred embodiment, the solid tumor is non-small cell lung cancer. In another preferred embodiment, the solid tumor is gastric cancer. In another preferred embodiment, the solid tumor is cutaneous melanoma. In another embodiment, the cancer is a hematological tumor. In a preferred embodiment, the hematological tumor is selected from leukemia and lymphoma. In a more preferred embodiment, the hematological tumor is selected from acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. In another preferred embodiment, the hematological tumor is selected from acute lymphoblastic leukemia and Burkitt’s lymphoma. In another preferred embodiment, the hematological tumor is Burkitt’s lymphoma. In another embodiment, Compound IA and the topoisomerase I inhibitor are administered concurrently, separately or sequentially. In an embodiment, the molar ratio of the combination of Compound IA : topoisomerase I inhibitor is about 50,000:1, about 40,000:1, about 30,000:1, about 20,000:1, about 19,000:1, about 18,000:1, about 17,000:1, about 16,000:1, about 15,000:1, about 14,000:1, about 13,000:1, about 12,000:1, about 11,000:1, about 10,000:1, about 9,000:1, about 8,000:1, about 7,000:1, about 6,000:1, about 5,000:1, about 4,000:1, about 3,000:1, about 2,000:1, about 1,000:1, about 900:1, about 800:1, about 700:1, about 600:1, about 500:1, about 400:1, about 300:1, about 200:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, or ranges within the aforesaid ratios. In an embodiment, the molar ratio of the combination of topoisomerase I inhibitor : Compound IA is about 50,000:1, about 40,000:1, about 30,000:1, about 20,000:1, about 10,000:1, about 9,000:1, about 8,000:1, about 7,000:1, about 6,000:1, about 5,000:1, about 4,000:1, about 3,000:1, about 2,000:1, about 1,000:1, about 900:1, about 800:1, about 700:1, about 600:1, about 500:1, about 400:1, about 300:1, about 200:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, or ranges within the aforesaid ratios. In an embodiment, the molar ratio of topoisomerase I inhibitor : Compound IA is around 500:1 to around 30,000:1, around 600:1 to around 28,000:1, around 700:1 to around 26,000:1, around 800:1 to around 24,000:1, around 900:1 to around 22,000:1, around 1000:1 to around 20,000:1, around 1000:1 to around 18,000:1, around 1000:1 to around 16,000:1, around 1000:1 to around 14,000:1, around 1000:1 to around 12,000:1, or around 1000:1 to around 10,000:1, or ranges within the aforesaid ratios. In a further embodiment, topoisomerase I inhibitor is selected from topotecan, SN-38, irinotecan, camptothecin, and rubitecan. In a preferred embodiment, the topoisomerase I inhibitor is irinotecan. In embodiments, Compound IA is in the form of a pharmaceutically acceptable salt or ester. BRIEF DESCRIPTION OF THE FIGURES Figure 1A shows tumor growth (median) for mice bearing H460 (NSCLC) xenografted tumors and treated with Compound IA. Figure 1B shows tumor growth (median) for mice bearing H460 (NSCLC) xenografted tumors and treated with irinotecan. Figure 1C shows tumor growth (median) for mice bearing H460 (NSCLC) xenografted tumors and treated with Compound IA - irinotecan combination. Figure 1D shows a combination index plot (CI vs Fa) for mice bearing H460 (NSCLC) xenografted tumors and treated with Compound IA-irinotecan combination. Figure 2A shows tumor growth (median) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with Compound IA. Figure 2B shows tumor growth (median) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with irinotecan. Figure 2C shows tumor growth (median) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with Compound IA-irinotecan combination. Figure 2D shows a combination index plot (CI vs Fa) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with Compound IA-irinotecan combination. Figure 3A shows tumor growth (median) for mice bearing TC71 (sarcoma) xenografted tumors and treated with Compound IA. Figure 3B shows tumor growth (median) for mice bearing TC71 (sarcoma) xenografted tumors and treated with irinotecan. Figure 3C shows tumor growth (median) for mice bearing TC71 (sarcoma) xenografted tumors and treated with Compound IA-irinotecan combination. Figure 3D shows a combination index plot (CI vs Fa) for mice bearing TC71 (sarcoma) xenografted tumors and treated with Compound IA-irinotecan combination. DETAILED DESCRIPTION OF THE INVENTION In the present application, a number of general terms and phrases are used, which should be interpreted as follows. The term “treating”, as used herein, unless otherwise indicated, means reversing, attenuating, alleviating 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 “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above. "Patient" includes 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. Preferably, the subject is a human. Compound IA is a synthetic compound under clinical investigation. Compound IA was first disclosed in WO2018/197663 (as compound 39-S), the contents of which are herein incorporated by reference. Compound IA can be prepared following the synthesis set out in WO2018/197663. The structure for Compound IA is: . In embodiments, Compound IA is in the form of a pharmaceutically acceptable salt or ester. The terms “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. However, it will be appreciated that 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. For instance, pharmaceutically acceptable salts of the compounds provided herein are synthesized from the parent compounds, which contain a basic or acidic moiety, by conventional chemical methods. Generally, 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. Generally, nonaqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred. Examples of the 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. Examples of the 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. In addition, 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. In the present application, by “cancer” it is meant to include tumors, neoplasias and any other malignant disease having as cause malignant tissue or cells. Sarcomas are rare cancers that develop in the muscle, bone, nerves, cartilage, tendons, blood vessels and the fatty and fibrous tissues. They can affect almost any part of the body, on the inside or the outside. Sarcomas commonly affect the arms, legs and trunk. They also appear in the stomach and intestines as well as behind the abdomen (retroperitoneal sarcomas) and the female reproductive system (gynecological sarcomas). Bone sarcomas affect less than 500 people in the UK each year, making it a very rare form of cancer. Not all bone cancers will be sarcomas. “Soft-tissue sarcoma” 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; gynecological 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. Unless detected at an early stage when the tumour can be removed by surgery there is currently no cure for soft tissue sarcoma. Approximately 16% of patients with soft tissue sarcoma have advanced stage (metastatic) disease. For these patients, the relative 5 year survival rate is 16% (American Cancer Society). There are more than 50 different types of soft tissue sarcomas, including: Leiomyosarcoma is a type of cancer that starts in smooth muscle tissue. These tumors often start in the abdomen, but they can also start in other parts of the body, such as the arms or legs, or in the uterus. Liposarcomas are malignant tumors of fat tissue. They can start anywhere in the body, but they most often start in the thigh, behind the knee, and inside the back of the abdomen. Synovial sarcoma is a malignant tumor of the tissue around joints. The most common locations are the hip, knee, ankle, and shoulder. This tumor is more common in children and young adults, but it can occur in older people. The “Ewing family of tumors” is a group of cancers that start in the bones or nearby soft tissues that share some common features. These tumors can develop at any age, but they are most common in the early teen years. The main types of Ewing tumors are: Ewing sarcoma of bone: most Ewing tumors occur in the bones. The most common sites are: the pelvis (hip bones), the chest wall (such as the ribs or shoulder blades), or the legs, mainly in the middle of the long bones. Extraosseous Ewing tumors can occur almost anywhere. Extraosseous Ewing tumor (EOE): Extraosseous Ewing tumors start in soft tissues around bones, but they look and act very much like Ewing sarcomas in bones. They are also known as extraskeletal Ewing sarcomas. Primitive neuroectodermal tumor (PNET): This rare childhood cancer also starts in bone or soft tissue and shares many features with Ewing sarcoma of bone and EOE. PNETs that start in the chest wall are known as Askin tumors. PNETs that start in the bone are known as peripheral neuroectodermal sarcoma of bone. “Chordoma” is a rare tumor that develops from cells of the notochord, a structure that is present in the developing embryo and is important for the development of the spine. Chordomas typically present in adults between the ages of 40 and 70 and can occur anywhere along the spine. About half of all chordomas occur at the bottom of the spine (sacrum); about one third occur at the base of the skull. The remaining cases of chordomas form in the spine at the level of the neck, chest, or other parts of the lower back. Chordomas grow slowly, extending gradually into the surrounding bone and soft tissue. “Chondrosarcoma” is a malignant bone tumor arising from cartilaginous tissue, most frequently occurring at the ends of the femur and tibia, the proximal end of the humerus and the pelvis; and presenting with a palpable mass and progressive pain. “Extraskeletal myxoid chondrosarcoma (ECM)” is distinguished by a biology that is distinct from the genetic heterogeneity observed in other forms of chondrosarcoma (see Kawaguchi S, Wada T, Nagoya S, et al. Extraskeletal myxoid chondrosarcoma: a multi-institutional study of 42 cases in Japan. Cancer. 2003;97:1285-1292). The majority of patients are characterized by translocations that lead to abnormal gene products. “Carcinosarcoma” is a malignant tumor that is a mixture of carcinoma (cancer of epithelial tissue, which is skin and tissue that lines or covers the internal organs) and sarcoma (cancer of connective tissue, such as bone, cartilage, and fat). “Myoepithelial carcinoma” is a rare malignant (cancerous) tumor that usually occurs in the salivary glands in the mouth, but can also occur in skin and soft tissues. Approximately 66% of these tumors occur in a part of the salivary gland, known as the parotid gland. Alveolar soft-part sarcoma is a rare cancer that mostly affects young adults. These tumors most commonly start in legs. Angiosarcoma can start in blood vessels (hemangiosarcomas) or in lymph vessels (lymphangiosarcomas). These tumors sometimes start in a part of the body that has been treated with radiation. Angiosarcomas are sometimes seen in the breast after radiation therapy and in limbs with lymphedema. Clear cell sarcoma is a rare cancer that often starts in tendons of the arms or legs. Under the microscope, it has some features of malignant melanoma, a type of cancer that starts in pigment- producing skin cells. How cancers with these features start in parts of the body other than the skin is not known. Desmoplastic small round cell tumor is a rare sarcoma of teens and young adults. It's found most often in the abdomen. Epithelioid sarcoma most often starts in tissues under the skin of the hands, forearms, feet, or lower legs. Teens and young adults are often affected. Fibromyxoid sarcoma, low-grade is a slow-growing cancer that most often starts as a painless growth in the trunk or arms and legs (particularly the thigh). It is more common in young to middle aged adults. It is sometimes called an Evans’ tumor. Gastrointestinal stromal tumor (GIST) is a type of sarcoma that starts in the digestive tract. Kaposi sarcoma is a type of sarcoma that starts in the cells lining lymph or blood vessels. Malignant mesenchymoma is a rare type of sarcoma that shows features of fibrosarcoma and features of at least 2 other types of sarcoma. Malignant peripheral nerve sheath tumors include neurofibrosarcomas, malignant schwannomas, and neurogenic sarcomas. These are sarcomas that start in the cells that surround a nerve. Myxofibrosarcomas, low-grade are most often found in the arms and legs of elderly patients. They are most common in or just under the skin and there might be more than one tumor. Rhabdomyosarcoma is the most common type of soft tissue sarcoma seen in children. Undifferentiated pleomorphic sarcoma (UPS) was once called malignant fibrous histiocytoma (MFH). It's most often found in the arms or legs. Less often, it can start inside at the back of the abdomen (the retroperitoneum). This sarcoma is most common in older adults. It mostly tends to grow into other tissues around the place it started, but it can spread to distant parts of the body. Intermediate soft tissue tumors may grow and invade nearby tissues and organs, but they tend to not spread to other parts of the body. Dermatofibrosarcoma protuberans is a slow-growing cancer of the fibrous tissue beneath the skin, usually in the trunk or limbs. It grows into nearby tissues but rarely spreads to distant sites. Fibromatosis is the name given to fibrous tissue tumor with features in between fibrosarcoma and benign tumors such as fibromas and superficial fibromatosis. They tend to grow slowly but, often, steadily. They are also called desmoid tumors, musculoaponeurotic fibromatosis or aggressive fibromatosis. They rarely, if ever, spread to distant sites, but they do cause problems by growing into nearby tissues. Hemangioendothelioma is a blood vessel tumor that is considered a low-grade cancer. It does grow into nearby tissues and sometimes can spread to distant parts of the body. It may start in soft tissues or in internal organs, such as the liver or lungs. Infantile fibrosarcoma is the most common soft tissue sarcoma in children under one year of age. It tends to be slow-growing and is less likely to spread to other organs than adult fibrosarcomas. Adult fibrosarcoma usually affects fibrous tissue in the legs, arms, or trunk. Solitary fibrous tumors are most often not cancer (benign) but can be cancer (malignant). Some start in the thigh, underarm, and pelvis. They can also start in the tissue surrounding the lung (called the pleura). Many tumors that were once called hemangiopericytomas are now considered solitary fibrous tumors. “Endometrial carcinoma” is a cancer that forms in the tissue lining the uterus. Most endometrial cancers are adenocarcinomas (cancers that begin in cells that make and release mucus and other fluids). There are various types of endometrial carcinomas including adenocarcinoma (particularly endometrioid cancer), uterine carcinosarcoma, squamous cell carcinoma, small cell carcinoma, transitional carcinoma or serous carcinoma. Clear-cell carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, and serous adenocarcinoma are less common types of endometrial adenocarcinomas. They tend to grow and spread faster than most types of endometrial cancer. Most endometrial cancers are adenocarcinomas, and endometrioid cancer is the most common type of adenocarcinoma. Endometrioid cancers start in gland cells. Some of these cancers have squamous cells (squamous cells are flat, thin cells), as well as glandular cells. There are many sub-types of endometrioid cancers including: adenocarcinoma, (with squamous differentiation), adenoacanthoma, adenosquamous (or mixed cell), secretory carcinoma, ciliated carcinoma, and villoglandular adenocarcinoma. “Ovarian cancer” includes epithelial ovarian carcinoma, primary peritoneal disease, fallopian tube carcinomas, or ovarian germ cell tumors. “Epithelial ovarian tumors” start in the outer surface of the ovaries. These tumors can be benign, borderline, or malignant. Epithelial ovarian tumors that are benign don’t spread and usually don’t lead to serious illness. There are several types of benign epithelial tumors including serous cystadenomas, mucinous cystadenomas, and Brenner tumors. When looked at in the lab, some ovarian epithelial tumors don’t clearly appear to be cancerous and are known as borderline epithelial ovarian cancer. The two most common types are atypical proliferative serous carcinoma and atypical proliferative mucinous carcinoma. Primary peritoneal carcinoma (PPC) is a rare cancer closely related to epithelial ovarian cancer. At surgery, it looks the same as an epithelial ovarian cancer that has spread through the abdomen. Other names for this cancer include extra-ovarian (meaning outside the ovary) primary peritoneal carcinoma (EOPPC) and serous surface papillary carcinoma. PPC appears to start in the cells lining the inside of the fallopian tubes. Fallopian tube cancer is another rare cancer that is similar to epithelial ovarian cancer but begins in the fallopian tube. Like PPC, fallopian tube cancer and ovarian cancer have similar symptoms. Most ovarian germ cell tumors are benign, but <2% of ovarian cancers are germ cell tumors. There are several subtypes of germ cell tumors. The most common germ cell tumors are teratomas, dysgerminomas, endodermal sinus tumors, and choriocarcinomas. Germ cell tumors can also be a mix of more than a single subtype. Teratomas are germ cell tumors which have a benign form called mature teratoma and a cancerous form called immature teratoma. Immature teratomas occur in girls and young women, usually younger than 18. These are rare cancers that contain cells that look like those from embryonic or fetal tissues such as connective tissue, respiratory passages, and brain. Dysgerminoma is rare, but it is the most common ovarian germ cell cancer. It usually affects women in their teens and twenties. Endodermal sinus tumor (yolk sac tumor) and choriocarcinoma are very rare tumors which typically affect girls and young women. They tend to grow and spread rapidly but are usually very sensitive to chemotherapy. The ovarian cancers according to embodiments of the present invention may be selected regardless of platinum sensitivity. “Small cell lung cancer (SCLC)” is a fast growing form of lung cancer. It is sometimes called oat cell cancer. Lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung. The two major types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC comprises only about 13-15% of all lung cancers at diagnosis; however, SCLC is the more aggressive form of lung cancer. With SCLC, the cancer cells tend to grow quickly and travel to other parts of the body, or metastasize, more easily. The median survival of patients with untreated SCLC is two to four months. The most common regimens include cisplatin or carboplatin and etoposide. Unfortunately, despite the 40-90% response rate to first-line chemotherapy, long-term survival is unusual because patients develop resistance to chemotherapy and relapse. The overall expected mean survival after disease relapse without treatment was typically two to four months. “Glioblastoma” is a fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord and has cells that look very different from normal cells. Glioblastoma usually occurs in adults and affects the brain more often than the spinal cord. Also called GBM, glioblastoma multiforme, and grade IV astrocytoma. “Pancreatic adenocarcinoma” is a disease in which malignant (cancer) cells are found in the tissues of the pancreas. Pancreatic cancer can develop from two kinds of cells in the pancreas: exocrine cells and neuroendocrine cells, such as islet cells. The exocrine type is more common and is usually found at an advanced stage. Pancreatic neuroendocrine tumors (islet cell tumors) are less common but have a better prognosis (discussed separately below). The most common type of pancreatic cancer, adenocarcinoma of the pancreas, starts when exocrine cells in the pancreas start to grow out of control. Exocrine cancers are by far the most common type of pancreas cancer. About 95% of cancers of the exocrine pancreas are adenocarcinomas. These cancers usually start in the ducts of the pancreas. Less often, they develop from the cells that make the pancreatic enzymes, in which case they are called acinar cell carcinomas. Other, less common exocrine cancers include adenosquamous carcinomas, squamous cell carcinomas, signet ring cell carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with giant cells. Ampullary cancer (carcinoma of the ampulla of Vater) is a cancer which starts in the ampulla of Vater. Ampullary cancers often block the bile duct while they are still small and have not spread far. This blockage causes bile to build up in the body, which leads to yellowing of the skin and eyes (jaundice). “GEP-NET” is a rare type of tumor that can form in the pancreas or in other parts of the gastrointestinal tract, including the stomach, small intestine, colon, rectum, and appendix. GEP- NETs usually form in cells that secrete hormones. Some of these tumors make extra amounts of hormones and other substances that may cause signs and symptoms of disease, including a condition called carcinoid syndrome. GEP-NETs may be benign or malignant. They are sometimes called carcinoid tumors or islet cell tumors. Also called gastroenteropancreatic neuroendocrine tumor. Pancreatic NETs are classified based on whether they are functioning (making hormones that cause symptoms) or non-functioning (not making hormones). Functioning NETs: About half of pancreatic NETs make hormones that are released into the blood and cause symptoms. These are called functioning NETs. Each one is named for the type of hormone the tumor cells make. 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). Most (up to 70%) functioning NETs are insulinomas. The other types are much less common. Non-functioning NETs: These tumors don’t make enough excess hormones to cause symptoms. Because they don’t make excess hormones that cause symptoms, they can 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: These NETs are much more common in other parts of the digestive system, although rarely they can start in the pancreas. These tumors often make serotonin. “Gastric carcinoma” is a cancer that forms in tissues lining the stomach. Risk factors include smoking, infection with H. pylori bacteria, and certain inherited conditions. “Colorectal carcinoma (CRC)” is a cancer that develops in the colon (the longest part of the large intestine) and/or the rectum (the last several inches of the large intestine before the anus). Colorectal cancer often begins as a growth called a polyp inside the colon or rectum. Most colorectal cancers are adenocarcinomas. These cancers start in cells that make mucus to lubricate the inside of the colon and rectum. Some sub-types of adenocarcinoma, such as signet ring and mucinous, may have a worse prognosis than other subtypes of adenocarcinoma. “Acute lymphoblastic leukemia” (ALL) is an aggressive type of leukemia characterized by the presence of too many lymphoblast or lymphocytes in the bone marrow and peripheral blood. It can spread to the lymph nodes, spleen, liver, central nervous systems (CNS), testicles and other organs. Without treatment, ALL usually progresses quickly. “non-Hodgkin lymphoma” is a disease in which malignant cells form in the lymph system. The lymph system is part of the immune system. It helps protect the body from infection and disease. Non-Hodgkin lymphoma can be indolent or aggressive. “Burkitt’s lymphoma” is a fast-growing type of B-cell non-Hodgkin lymphoma that occurs most often in children and young adults. The disease may affect the jaw, central nervous system, bowel, kidneys, ovaries, or other organs. There are three main types of Burkitt lymphoma: sporadic, endemic and immunodeficiency related. Examples of the administration form include without limitation oral, topical, parenteral, sublingual, rectal, vaginal, ocular and intranasal. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. 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. In a more preferred embodiment, the compound(s) according to the present invention are administered intravenously. Suitable pharmaceutical compositions can be prepared using methodology known in the pharmaceutical art (e.g. “Remington’s Pharmaceutical Sciences” by E. W. Martin). It has found that the combinations of the present invention are particularly effective in the treatment of cancer. Thus, the combinations 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. The present invention is further described in the following non-limiting examples. EXAMPLES Example 1: in vitro antiproliferative activity of Compound IA in combination with irinotecan and determination of the combination index (CI) The objective was to evaluate the antiproliferative activity of Compound IA when combined with irinotecan, with the aim of identifying possible synergistic activities. The combinations were assayed against 13 different human tumor cell lines (Table 1). All the cell lines were obtained from the American Type Culture Collection (ATCC), the European Collection of Authenticated Cell Cultures (ECACC) or the Riken Gene Bank except for IGROV-1 cell line. Under brackets is indicated the culture media used for cell growth, the collection code and the tissue of origin. All the culture media were supplemented with 10% fetal bovine serum, 1% penicillin and streptomycin and 2 mM L-Glutamine: (a) RPMI; (b) DMEM; (c) Waymouth’s medium; (d) IMDM; (e) DMEM-F12. Cells were cultured at 37ºC and 5% CO2 and kept always in a low-passage state. Table 1. Cell lines tested Cell lines Type of cancer VCap (e) (ECACC 06020201) prostate carcinoma 22Rv1 (a) (ATCC CRL-2505) A2780 (a) (ECACC 93112519) ovary adenocarcinoma IGROV-1 (a) A549 (b) (ATCC CCL185) NSCLC NCI-H460 (b) (ATCC HTB-177) LCLC DMS-53 (c) (ATCC CRL-2062) SCLC A-673 (b) (ATCC CRL-1598) Ewing’s sarcoma HeLa (b) (ATCC CRM-CCL-2) cervix adenocarcinoma HGC-27 (d) (Riken Gene Bank, RCB0500) gastric carcinoma HT-29 (b) (ATCC HTB-38) colon adenocarcinoma MDA-MB-231 (b) (ATCC HTB-26) breast adenocarcinoma PSN-1 (a) (ECACC 94060601) pancreatic adenocarcinoma The cytotoxicity effect was determined by the MTT assay. For the test, stock solutions of irinotecan and Compound IA were prepared in 100% DMSO at the appropriate concentration. Subsequent dilutions were prepared in serum-free culture medium at a final 4-fold (4X) concentration. Aliquots of 50 μL of diluted single compounds or in combination were added per well for the assays. 1.1 Growth inhibition assays The values for IC50 (concentration that produces a 50% inhibition of cell growth) and EC50 (half- maximal effective concentration, i.e. a response halfway between the baseline and maximum) were determined for each drug (Table 2 and Table 3). Briefly, cells were harvested and seeded in 96 well microtiter plates at the appropriate cell density (4000-12000 cells) in 150 μL of media and incubated for 24 hours in drug-free medium before treatment with vehicle alone or test compounds for 72 h. For viability quantification, the MTT reduction assay, in which 3-(4,5- Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide, a tetrazole, is reduced to purple formazan in the mitochondria of living cells, was used. MTT solution was added to the wells and incubated for 6-8 hours at 37ºC until formazan crystals are formed. After gently removing the culture medium, DMSO was added to dissolve the insoluble purple formazan product into a colored solution. The absorbance of the wells was quantified by measuring the optical density at 540 nm. Results are expressed as percentage of control cell growth. The IC50 used for the combination studies was calculated using Prism v5.02 software (GraphPad), from 3 or more independent assays. Table 2. IC50 values (molar concentration) for each cell line treated with Compound IA, wherein “n”, indicates the number of experimental replicates. Table 3. IC50 values (molar concentration) for each cell line treated with irinotecan, wherein “n”, indicates number of experimental replicates. 1.2. Combination studies To perform the dose-response experiments with the compounds either alone or in combination, an appropriate dilution factor was selected for each compound to assure enough valid data points for CI determination. For combinations, the following standard potency ratios (%IC50 Compound IA/%IC50 Irinotecan) were used: 50/50 or equipotency ratio, 40/60, 60/40 and 75/25. A summary of the combinations performed, the potency ratios used and their equivalent concentration ratios (fold concentration of the compounds to combine with, respect to Compound IA) and the initial concentration of each compound in the combination assayed are detailed in Table 4. A summary tables show the calculated CI values for each combination ratio in each cell line, for the selected effective concentrations (~ED20, ~ED50 and ~ED70 or~ED75 or ~ED80), and the Dm (median-effect dose signifying the potency) for the dose-effect curves of the drugs alone or in combination (different ratios). A Cl>1 denotes antagonism. A Cl=1 denotes additive. A Cl<1 denotes synergism with the lower the value denoting stronger synergism. ED signifies the effective concentration required to achieve a target %age cell death. ED20 represents the effective dose required to achieve 20% cell death, ED50 represents the effective dose required to achieve 50% cell death, ED70 represents the effective dose required to achieve 70% cell death, ED75 represents the effective dose required to achieve 75% cell death and ED80 represents the effective dose required to achieve 80% cell death. ED75 or ED80 are particularly relevant because they show the effect when a high degree of cells death is achieved which is desirable for an oncology treatment. Table 4. Combinations Compound IA-irinotecan performed in vitro.

The CI method is based on the median-effect principle derived by Chou and Talalay. See: - Chou T. C. (1996) The median-effect principle and the combination index for quantitation of synergism and antagonism, in Synergism and Antagonism in Chemotherapy (Chou, T. C. and Rideout, D. C., eds.), Academic, San Diego, pp.61–102; and - Chou, T.-C. and Talalay, P. (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enyzme Regul.22, 27–55. The CI equation determines the additive effect of drug combinations, such that synergism is defined as a greater-than-the-expected-additive effect, and antagonism is defined as less-than- an-expected-additive effect. Thus, CI = 1 indicates an additive effect, CI < 1 indicates a synergistic effect, and CI > 1 indicates antagonism. Because CI values may change with the fraction affected (Fa) in a non-linear manner, the CI should optimally be presented for each effective dose (ED) with valid results. For the summary table, CI values for ED20, ED50, ED60, ED70 or ED80, representing the compound concentrations that resulted in 20%, 50%, 60%, 70% and 80% cell death, respectively, were calculated. The final CI values presented were calculated applying the Chou and Talalay equations. Within the oncology setting, demonstrating synergy at high effective dose (ED) is advantageous. A successful oncology treatment should achieve high levels of cancer cell death. Demonstrating synergy at these high levels of cell death show synergism present when the combination is most effective. It is therefore desirable to see synergy at the high ED levels. 1.2.1. Combination in 22Rv1 cells Summary table 5 shows CI values at effective doses ED20, ED50 and ED75 and at different ratios (1:3800, 1:2600, 1:1700 and 1:900) in 22Rv1 cells. Synergism is demonstrated at the high ED75. Table 5.

1.2.2. Combination in A2780 cells Summary table 6 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:2250, 1:1500, 1:1000 and 1:500) in A2780 cells. Synergism is demonstrated at the high ED80. Table 6. 1.2.3. Combination in A549 cells Summary table 7 shows CI values at effective doses ED20, ED50 and ED70 and at different ratios (1:17390, 1:11590, 1:7730 and 1:3860) in A549 cells. Synergism is demonstrated at the high ED70. Table 7. 1.2.4. Combination in A-673 cells Summary table 8 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:4590, 1:3060, 1:2040 and 1:1020) in A-673 cells Synergism is demonstrated at the high ED80 for all ratios. Table 8. 1.2.5. Combination in DMS-53 cells Summary table 9 shows CI values at effective doses ED20, ED50 and ED75 and at different ratios (1:14100, 1:9400, 1:6300 and 1:3100) in DMS-53 cells Synergism is demonstrated at the high ED75. Table 9. 1.2.6. Combination in Hela cells Summary table 10 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:13370, 1:8910, 1:5940 and 1:2970) in Hela cells. Synergism is demonstrated at the high ED80. Table 10. 1.2.7. Combination in HGC-27 cells Summary table 11 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:4370, 1:2910, 1:1940 and 1:970) in HGC-27 cells. Synergism is demonstrated at the high ED80. Table 11. 1.2.8. Combination in HT-29 cells Summary table 12 shows CI values at effective doses ED20, ED50 and ED70 and at different ratios (1:5000, 1:3300, 1:2200 and 1:1100) in HT-29 cells. Synergism is demonstrated at the high ED70. Table 12. 1.2.9. Combination in IGROV-1 cells Summary table 13 shows CI values at effective doses ED20, ED50 and ED75 and at different ratios (1:29000, 1:19300, 1:129000 and 1:6400) in IGROV-1 cells. Synergism is demonstrated at the high ED75. Table 13. 1.2.10. Combination in MDA-MB-231 cells Summary table 14 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:8540, 1:5700, 1:2900 and 1:1900) in MDA-MB-231 cells. Synergism is demonstrated at the high ED80. Table 14. 1.2.11. Combination in NCI-H460 cells Summary table 15 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:3770, 1:2510, 1:1670 and 1:840) in NCI-H460 cells. Synergism is demonstrated at the high ED80. Table 15. 1.2.12. Combination in PSN-1 cells Summary table 16 shows CI values at effective doses ED20, ED50 and ED75 and at different ratios (1:2960, 1:1970, 1:1310 and 1:660) in PSN-1 cells. Synergism is demonstrated at the high ED75. Table 16. 1.2.13. Combination in VCap cells Summary table 17 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:54800, 1:36500, 1:24300 and 1:12200) in VCap cells. Synergism is demonstrated at the high ED80. Table 17. 1.2.14 Results The results of the combination of Compound IA with irinotecan in 13 different cell lines demonstrate synergistic activity in all cell lines, namely VCap prostate carcinoma cells, A2780 and IGROV-1 ovary adenocarcinoma cells, A549 NSCLC cells, A-673 Ewing´s sarcoma cells, DMS-53 SCLC cells, HeLa cervix carcinoma cells, HGC-27 gastric adenocarcinoma cells, HT-29 colon adenocarcinoma cells and MDA-MB-231 breast adenocarcinoma cells and PSN-1 pancreatic adenocarcinoma cells, 22Rv1 prostate carcinoma cells and NCI-H460 large cell lung cancer cells. For each of the synergistic combinations, a table that summarizes the values of Dose-Reduction Index is showed (Table 18 to Table 30). The Dose Reduction Index (DRI) determines the magnitude of dose reduction allowed for each drug when given in synergistic combination, as compared with the concentration of a single agent that is needed to achieve the same effect level. This provides a demonstration that it may be possible to administer a reduced dose to achieve the same effect, thereby improving the toxicity profile of the regimen. Table 18. Dose reduction index for the combination of Compound IA with irinotecan in 22Rv1 cells. 22Rv1 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:3800 Ratio 1:2600 Ratio 1:1700 Ratio 1:900 A B A B A B A B A B 0.20 8.41E-10 8.70E-07 5.63 1.53 4.11 1.64 2.58 1.57 1.84 2.12 0.50 1.67E-09 2.51E-06 3.86 1.52 2.93 1.69 2.48 2.19 1.69 2.82 0.75 5.08E-09 7.54E-06 4.55 1.78 3.32 1.89 2.94 2.56 2.62 4.32 Table 19. Dose reduction index for the combination of Compound IA with irinotecan in A2780 cells. A2780 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:2250 Ratio 1:1500 Ratio 1:1000 Ratio 1:500 A B A B A B A B A B 0.20 1.18E-09 8.44E-07 3.32 1.06 2.65 1.27 2.21 1.58 1.76 2.52 0.50 3.06E-09 1.69E-06 4.65 1.14 3.58 1.31 2.69 1.48 2.06 2.27 0.80 7.08E-09 7.18E-06 3.90 1.76 3.51 2.37 2.37 2.40 1.21 2.46 Table 20. Dose reduction index for the combination of Compound IA with irinotecan in A549 cells. A549 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:17390 Ratio 1:11590 Ratio 1:7730 Ratio 1:3860 A B A B A B A B A B 0.20 2.24E-09 1.69E-06 25.13 1.09 11.51 0.75 6.99 0.68 4.61 0.90 0.50 5.84E-09 2.26E-05 8.31 1.85 5.82 1.94 3.62 1.81 2.89 2.89 0.70 1.68E-08 6.16E-05 12.50 2.64 10.38 3.29 6.90 3.27 3.39 3.22 Table 21. Dose reduction index for the combination of Compound IA with irinotecan in A-673 cells. A-673 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:4590 Ratio 1:3060 Ratio 1:2040 Ratio 1:1020 A B A B A B A B A B 0.20 2.23E-09 7.95E-07 15.05 1.17 10.91 1.27 6.67 1.17 4.43 1.55 0.50 3.15E-09 1.28E-06 12.76 1.13 7.51 0.99 6.14 1.22 3.45 1.37 0.80 4.45E-09 2.89E-06 8.53 1.21 6.55 1.39 5.65 1.80 2.88 1.83 Table 22. Dose reduction index for the combination of Compound IA with irinotecan in DMS-53 cells. DMS-53 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:14100 Ratio 1:9400 Ratio 1:6300 Ratio 1:3100 A B A B A B A B A B 0.20 7.10E-10 6.90E-06 1.75 1.20 1.50 1.55 1.25 1.92 1.99 6.22 0.50 3.18E-09 1.73E-05 3.42 1.32 2.64 1.53 2.07 1.78 1.53 2.68 0.75 1.68E-08 1.18E-04 10.75 5.37 7.82 5.85 5.82 6.50 3.40 7.72 Table 23. Dose reduction index for the combination of Compound IA with irinotecan in HeLa cells. HeLa Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:13370 Ratio 1:8910 Ratio 1:5940 Ratio 1:2970 A B A B A B A B A B 0.20 4.47E-09 3.98E-06 26.76 1.78 14.91 1.49 11.24 1.68 5.64 1.69 0.50 1.12E-08 2.11E-05 16.61 2.33 8.25 1.74 6.28 1.99 3.46 2.19 0.80 2.29E-08 1.12E-04 8.09 2.97 5.05 2.79 3.77 3.12 3.71 6.14 Table 24. Dose reduction index for the combination of Compound IA with irinotecan in HGC-27 cells. HGC-27 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:4370 Ratio 1:2910 Ratio 1:1940 Ratio 1:970 A B A B A B A B A B 0.20 7.88E-10 1.99E-06 4.52 2.62 3.53 3.07 2.21 2.88 2.02 5.27 0.50 2.50E-09 3.81E-06 9.09 3.16 4.03 2.11 3.82 3.00 1.19 1.87 0.80 7.11E-09 1.08E-04 2.89 10.06 2.28 11.94 2.16 16.99 2.00 31.32 Table 25. Dose reduction index for the combination of Compound IA with irinotecan in HT-29 cells. HT-29 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:5000 Ratio 1:3300 Ratio 1:2200 Ratio 1:1100 A B A B A B A B A B 0.20 2.14E-09 3.26E-06 5.73 1.75 3.69 1.71 2.95 2.05 3.87 5.37 0.50 4.88E-09 1.99E-05 3.13 2.56 2.58 3.19 2.15 3.99 2.08 7.72 0.70 6.81E-09 3.76E-05 2.47 2.73 2.22 3.71 2.19 5.51 1.59 8.00 Table 26. Dose reduction index for the combination of Compound IA with irinotecan in IGROV-1 cells. IGROV-1 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:29000 Ratio 1:19300 Ratio 1:12900 Ratio 1:6400 A B A B A B A B A B 0.20 1.49E-09 1.56E-06 25.17 0.91 19.26 1.04 14.16 1.15 4.33 0.71 0.50 5.89E-09 9.30E-06 19.64 1.07 15.31 1.25 10.95 1.34 4.31 1.06 0.75 1.19E-08 8.35E-05 7.71 1.87 6.98 2.54 5.62 3.06 3.43 3.77 Table 27. Dose reduction index for the combination of Compound IA with irinotecan in MDA-MB- 231 cells MDA-MB-231 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:8540 Ratio 1:5700 Ratio 1:3800 Ratio 1:1900 A B A B A B A B A B 0.20 9.35E-11 8.06E-07 1.18 1.19 0.74 1.12 0.63 1.43 0.53 2.40 0.50 1.31E-09 2.36E-06 6.99 1.47 4.59 1.45 3.46 1.64 2.14 2.02 0.80 4.94E-09 3.17E-05 4.00 3.00 2.71 3.05 2.57 4.33 1.82 6.16

Table 28. Dose reduction index for the combination of Compound IA with irinotecan in NCI-H460 cells. NCI-H460 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:3770 Ratio 1:2510 Ratio 1:1670 Ratio 1:840 A B A B A B A B A B 0.20 6.14E-10 2.26E-06 1.15 1.12 1.44 2.11 1.49 3.28 1.57 6.85 0.50 1.43E-09 4.53E-06 1.64 1.38 1.90 2.40 2.02 3.83 1.74 6.57 0.80 4.08E-09 9.82E-06 1.82 1.16 2.52 2.41 2.14 3.08 1.97 5.63 Table 29. Dose reduction index for the combination of Compound IA with irinotecan in PSN-1 cells. PSN-1 Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:2960 Ratio 1:1970 Ratio 1:1310 Ratio 1:660 A B A B A B A B A B 0.20 2.13E-09 1.60E-06 5.45 1.38 4.15 1.58 2.63 1.51 1.81 2.06 0.50 5.30E-09 6.28E-06 4.28 1.71 2.68 1.61 1.75 1.58 1.49 2.67 0.75 1.14E-08 3.62E-05 2.70 2.89 3.21 5.18 2.08 5.04 1.97 9.46 Table 30. Dose reduction index for the combination of Compound IA with irinotecan in VCap cells. VCap Fraction Drug alone Drug in Combination (A= Compound IA / B= irinotecan) Affected DRI (Fa) Ratio 1:54800 Ratio 1:36500 Ratio 1:24300 Ratio 1:12200 A B A B A B A B A B 0.20 6.39E-09 2.61E-05 20.55 1.53 12.31 1.38 10.46 1.76 7.08 2.37 0.50 8.82E-09 5.49E-05 11.94 1.36 8.10 1.38 7,27 1.86 4.88 2.49 0.80 1.22E-08 1.44E-04 7.30 1.58 6.29 2.04 5.24 2.55 3.31 3.21 Example 2: antitumor activity of Compound IA in combination with irinotecan in mice The antitumor activity of the combination Compound IA and irinotecan was evaluated in mice implanted with 3 different cell lines tumors: - Xenograft with H460 (NSCLC) tumors - Xenograft with HT-1080 (fibrosarcoma) tumors - Xenograft with TC-71 (sarcoma) tumors Degree of synergism of the combination was calculated by using T/C (%), defined as a percentage of the change in tumor size for each treated (T) and placebo (C) group. 2.1. Combination in xenografts H460 (NSCLC) tumors The antitumor activity of the combination Compound IA and irinotecan was evaluated in mice implanted with H460 (NSCLC) tumors. Four to 6 weeks old athymic nu/nu female mice were subcutaneously implanted into their flank with a suspension of H460 cells. Animals with tumor sizes ca.200 mm³ were randomly allocated (N = 6-8/group) to treatment groups (Table 31). Treatments were intravenously administered once per week for 3 consecutive weeks (days 0 and 7 and 14). MTD for Compound IA (MTD^A) was 1.2mg/kg and for irinotecan (MTD^B) was 50mg/kg. Table 31. Treatment groups in Compound IA-irinotecan combination in mice bearing H460 (NSCLC) tumors. All untreated animals died or were sacrificed due to tumor size (> 1500 mm³) or necrosis from Day 7 to Day 10. In this group, the time to reach a tumor size of 1000 mm³ was 4.7 days and the doubling time was 3.5 days. No mortality was registered. When the combination of Compound IA-irinotecan was administered at their highest dose levels (Compound IA at 3/4MTD+irinotecan at 3/4MTD), the registered reversible body weight decrease was 23.8% on Day 7, with no other clinically relevant signs of systemic toxicity. The rest of the treatments, given as a single agent or in combination, were well tolerated by tumor bearing animals, with moderate decreases in body weights. In this model, Compound IA resulted in no antitumor activity (Figure 1A) unlike irinotecan, which resulted in high antitumor activity (Figure 1B), when administered as single agents and at their highest dose. Compound IA and irinotecan combination (Figure 1C), induced a stronger effect than either Compound IA or irinotecan as single agents. The combination of Compound IA plus irinotecan (at a constant combination ratio) resulted in Combination Index (CI) values of 0.21 (at Fa = 0.97), demonstrating synergism in mice bearing H460 (NSCLC) xenografted tumors (Figure 1D). 2.2. Combination in xenografts HT-1080 (fibrosarcoma) tumors The antitumor activity of the combination of Compound IA and irinotecan was evaluated in mice that were implanted with HT-1080 (fibrosarcoma) tumors. Compound IA or irinotecan treatments were intravenously administered. Compound IA was administered once (on Day 0), and irinotecan was administered twice (on Day 0 and on Day 4) at the doses and schedules presented in Table 32. MTD for Compound IA (MTD^A) was 1.2mg/kg and for irinotecan (MTD^B) was 50mg/kg. Since irinotecan is a very active compound in this sarcoma model, in order to test if the degree of synergy is reached in this combination study, the highest dose of irinotecan administered in this study was reduced to 3/8 MTD. Table 32. Treatment groups in Compound IA-irinotecan combination in mice bearing HT-1080 (sarcoma) tumors. All untreated animals died or were sacrificed due to tumor size (> 2000 mm³) or necrosis from Day 9 to Day 19. In this group, the time to reach a tumor size of 1000 mm³ was 6.0 days and the doubling time was 2.9 days. No mortality was registered. When combining Compound IA-irinotecan treatment and administered at their highest dose levels (Compound IA at 3/4MTD + irinotecan at 3/8MTD), the registered reversible body weight decrease was 22.5% on Day 5. Furthermore, there were body weight loss in the rest of the treatments given, either as a single agent or in combination (ranging from moderate to high). Even the placebo treated group experienced a moderate decrease in body weight due to the model assayed that was known to cause cachexia. Administered as single agents and at their respective highest dose, Compound IA (Figure 2A) or irinotecan (Figure 2B) resulted in a high antitumor activity, in this model. Compound IA and irinotecan combination (Figure 2C) induced stronger effect than either Compound IA or irinotecan as single agents, suggesting strong antitumoral activity. The combination Compound IA plus irinotecan (at a constant combination ratio) resulted in CI values of 0.62 (at Fa = 0.97), demonstrating synergism in mice bearing HT-1080 (fibrosarcoma) xenografted tumors (Figure 2D). 2.3. Combination in xenografts TC-71 (sarcoma) tumors The antitumor activity of the combination Compound IA and irinotecan was evaluated in mice implanted with TC-71 (sarcoma) tumors. Compound IA or irinotecan treatments were intravenously administered once per week for 2 consecutive weeks (Days 0 and 7) at the doses and schedules shown in Table 33. MTD for Compound IA (MTD^A) was 1.2mg/kg and for irinotecan (MTD^B) was 50mg/kg. As irinotecan is a very active compound, in this sarcoma model, in order to test if the degree of synergy is reached in this combination study, the highest dose of irinotecan administered in this study was reduced to 3/8 MTD. Table 33. Treatment groups in Compound IA-irinotecan combination in mice bearing TC-71 (sarcoma) tumors. All untreated animals died or were sacrificed due to tumor size (> 2000 mm³) or necrosis from Day 7 to Day 12. In this group, the time to reach a tumor size of 1000 mm³ was 6.0 days and the doubling time was 2.9 No mortality was registered. When the combination Compound IA-irinotecan (Figure 3C) was administered at their highest dose levels (Compound IA at 3/4MTD + irinotecan at 3/4MTD), the registered reversible body weight decrease was 9.6% on Day 2, with no other clinically relevant signs of systemic toxicity. The rest of the treatments, given as a single agent, were well tolerated by tumor bearing animals, with moderate decreases in body weights. In this model, Compound IA resulted in a moderate antitumor activity (Figure 3A) and irinotecan (Figure 3B) resulted in high antitumor activity, both of them administered as single agents and at their respective highest dose. Compound IA and irinotecan combination induced a stronger effect, suggesting strong antitumoral activity. The combination of Compound IA plus irinotecan (at a constant combination ratio) resulted in Combination Index (CI) values of 0.61 (at Fa = 0.97), demonstrating synergism in mice bearing TC71 (sarcoma) xenografted tumors (Figure 3D). 2.4. Results: The results of the combination of Compound IA with irinotecan in different xenografts demonstrate synergism in NCI-H460 NSCLC cells, HT-1080 fibrosarcoma cells, and TC-71 sarcoma cells. Example 3: In vitro antiproliferative activity of Compound IA in combination with irinotecan and determination of the combination index (CI) The objective was to evaluate the antiproliferative activity of Compound IA when combined with irinotecan, with the aim of identifying possible synergistic activities in hematological malignancies. The combinations were assayed against 2 different tumor cell lines (Table 34). The cell lines were obtained from the American Type Culture Collection (ATCC). Under brackets is indicated the collection code). Cells were maintained in RPMI culture medium supplemented with 10% FBS, 1% penicillin and streptomycin and 2 mM L-Glutamine. Cells were cultivated at 37 ºC and 5% CO2 and kept always in a low-passage state. Table 34. Cell lines tested Cell lines Type of cancer MOLT-4 (ATCC CRL-1582) Acute lymphoblastic leukemia RAMOS (ATCC CRL-1596) Burkitt’s lymphoma The cytotoxicity effect was determined by the MTT assay. For the test, stock solutions of irinotecan and Compound IA were prepared in 100% DMSO at the appropriate concentration. Subsequent dilutions were prepared in serum-free culture medium at a final 4-fold (4X) concentration. Aliquots of 50 μL of diluted single compounds or in combination were added per well for the assays. 3.1 Growth inhibition assays The values for IC50 (concentration that produces a 50% inhibition of cell growth) and EC50 (half- maximal effective concentration, i.e. a response halfway between the baseline and maximum) were determined for each drug (Table 35 and Table 36). Briefly, cells were harvested and seeded in 96 well microtiter plates at the appropriate cell density (4000-12000 cells) in 150 μL of media and incubated for 24 hours in drug-free medium before treatment with vehicle alone or test compounds for 72 h. For viability quantification, the MTT reduction assay, in which 3-(4,5- Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide, a tetrazole, was reduced to purple formazan in the mitochondria of living cells, was used. MTT solution was added to the wells and incubated for 6-8 hours at 37 ºC until formazan crystals are formed. After gently removing the culture medium, DMSO was added to dissolve the insoluble purple formazan product into a colored solution. The absorbance of the wells was quantified by measuring the optical density at 540 nm. Results are expressed as percentage of control cell growth. The IC50 and EC50 values used for the combination studies were calculated using Prism v9.1.0 software (GraphPad), from 3 or more independent assays. Table 35. IC50 values (molar concentration) for each cell line treated with Compound IA, wherein “n” indicates the number of experimental replicates. Cell line n IC50 StdDev MOLT-4 6 1.10E-09 7.19E-10 RAMOS 3 3.60E-09 1.32E-09 Table 36. IC50 values (molar concentration) for each cell line treated with irinotecan, wherein “n” indicates the number of experimental replicates. Cell line n IC50 StdDev MOLT-4 10 8.18E-07 1.53E-07 RAMOS 10 2.89E-06 3.37E-06 3.2 Combination studies To perform the dose-response experiments with the compounds either alone or in combination, an appropriate dilution factor was selected for each compound to assure enough valid data points for CI determination. For combinations, the following standard potency ratios (%IC50 Compound IA / %IC50 Irinotecan) were used: 50/50 or equipotency ratio, 40/60, 60/40 and 75/25. A summary table shows the calculated CI values for each combination ratio in each cell line, for the selected effective concentrations (~ED20, ~ED50 and ~ED80), and the Dm (median-effect dose signifying the potency) for the dose-effect curves of the drugs alone or in combination (different ratios). A Cl>1 denotes antagonism. A Cl=1 denotes additive. A Cl<1 denotes synergism with the lower the value denoting stronger synergism. ED signifies the effective concentration required to achieve a target %age cell death. ED20 represents the effective dose required to achieve 20% cell death, ED50 represents the effective dose required to achieve 50% cell death and ED80 represents the effective dose required to achieve 80% cell death. ED80 is particularly relevant because it shows the effect when a high degree of cells death is achieved which is desirable for an oncology treatment. Table 37. Combinations Compound IA-irinotecan performed in vitro. Potency ratio Concentration Cell line [Compound IA] [Irinotecan] (EC ) ra i i 50 tio 40/60 1:700 1.27E-08 8.91E-06 50/50 1:470 1.27E-08 5.98E-06 MOLT-4 60/40 1:310 1.27E-08 3.94E-06 75/25 1:160 1.27E-08 2.04E-06 40/60 1:7900 1.27E-08 1.01E-04 50/50 1:5300 1.27E-08 6.74E-05 RAMOS 60/40 1:3500 1.27E-08 4.45E-05 75/25 1:1800 1.27E-08 2.29E-05 The CI method is based on the median-effect principle derived by Chou and Talalay. See: - Chou T. C. (1996) The median-effect principle and the combination index for quantitation of synergism and antagonism, in Synergism and Antagonism in Chemotherapy (Chou, T. C. and Rideout, D. C., eds.), Academic, San Diego, pp.61–102; and - Chou, T.-C. and Talalay, P. (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enyzme Regul.22, 27–55. The CI equation determines the additive effect of drug combinations, such that synergism is defined as a greater-than-the-expected-additive effect, and antagonism is defined as less-than- an-expected-additive effect. Thus, CI = 1 indicates an additive effect, CI < 1 indicates a synergistic effect, and CI > 1 indicates antagonism. Because CI values may change with the fraction affected (Fa) in a non-linear manner, the CI should optimally be presented for each effective dose (ED) with valid results. For the summary table, CI values for ED20, ED50 or ED80, representing the compound concentrations that resulted in 20%, 50% and 80% cell death, respectively, were calculated. The final CI values presented were calculated applying the Chou and Talalay equations. Within the oncology setting, demonstrating synergy at high effective dose (ED) is advantageous. A successful oncology treatment should achieve high levels of cancer cell death. Demonstrating synergy at these high levels of cell death show synergism present when the combination is most effective. It is therefore desirable to see synergy at the high ED levels. 3.2.1. Combination in MOLT-4 cells Summary Table 38 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:700, 1:470, 1:310 amd 1:160) in MOLT-4 cells. Moderate synergism is demonstrated at the high ED80. Table 38

3.2.2. Combination in RAMOS cells Summary Table 39 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:7900, 1:5300, 1:3500 and 1:1800) in RAMOS cells. Moderate synergism is demonstrated at the high ED80. Table 39 3.2.3. Results The results of the combination of compound IA with irinotecan in 2 different cell lines demonstrate moderate synergistic activity in both cell lines, namely MOLT-4 lymphoblastic leukemia cells and RAMOS Burkitt’s lymphoma cells. For each of the synergistic combinations, a table that summarizes the values of Dose-Reduction- Index is showed (Tables 40 and 41). The Dose Reduction Index (DRI) determines the magnitude of dose reduction allowed for each drug when given in synergistic combination, as compared with the concentration of a single agent that is needed to achieve the same effect level. This provides a demonstration that it may be possible to administer a reduced dose to achieve the same effect, thereby improving the toxicity profile of the regimen. Table 40. Dose reduction index for the combination of Compound IA with irinotecan in MOLT-4 cells. MOLT-4 Fraction Drug alone Drug in Combination (A= Comp IA / B= irinotecan) Affected DRI by Ratio (Fa) 1:700 1:470 1:310 1:160 A B A B A B A B A B 0.20 1.02E-09 4.47E-07 2.69 1.69 2.74 2.56 2.33 3.30 1.77 4.87 0.50 1.47E-09 8.65E-07 2.68 2.25 2.22 2.78 1.74 3.31 1.38 5.09 0.80 2.32E-09 1.29E-06 2.92 2.31 1.79 2.11 1.61 2.88 1.41 4.87 Table 41. Dose reduction index for the combination of Compound IA with irinotecan in RAMOS cells. RAMOS Fraction Drug alone Drug in Combination (A= Comp IA / B= irinotecan) Affected DRI by Ratio (Fa) 1:7900 1:5300 1:3500 1:1800 A B A B A B A B A B 0.20 1.08E-09 5.23E-07 20.20 1.24 15.35 1.41 8.03 1.11 4.87 1.32 0.50 2.24E-09 1.01E-06 22.34 1.27 13.30 1.13 10.02 1.29 4.74 1.18 0.80 3.79E-09 1.94E-06 13.81 0.90 12.63 1.22 5.99 0.88 3.87 1.10 In summary, the data in the present invention demonstrates the synergistic combination of Compound IA and a topoisomerase I inhibitor. Synergy is demonstrated in vitro across a range of cancer types, demonstrating the broad utility of this combination. The combination is also shown to demonstrate remarkable synergistic activity in vivo across a number of different cancers. The combinations of the present invention are useful in the treatment of cancer.

References -NCT05841563 -M. L. Rothenberg, Topoisomerase I inhibitors: Review and update, Annals of Oncology 8: 837-855, 1997. -P. Schöffski et al., Current Role of Topoisomerase I Inhibitors for the Treatment of Mesenchymal Malignancies and Their Potential Future Use as Payload of Sarcoma- Specific Antibody-Drug Conjugates, Oncol. Res Treat (2024) 47 (1-2): 18–41. -A. Kamal et al., Prospects of Topoisomerase Inhibitors as Promising Anti-Cancer Agents, Pharmaceuticals 2023, 16(10), 1456. -WO2012/062920 -WO2018/197663 -D. Gorgels et al., Ecubectedin and PM54 demonstrate antitumor activity in patient- derived xenograft models of soft tissue sarcoma, AACR 2024, Abstract 1880. -Chou, T. C. (1996) The median-effect principle and the combination index for quantitation of synergism and antagonism, in Synergism and Antagonism in Chemotherapy (Chou, T. C. and Rideout, D. C., eds.), Academic, San Diego, pp.61–102. -Chou, T.-C. and Talalay, P. (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enyzme Regul.22, 27–55. - Gil, A, Phase I/II Clinical and Pharmacokinetic Study of Ecubectedin in Combination with Irinotecan in Patients with Selected Advanced Solid Tumors, ESMO 2024. Abstract 641P.

Claims

CLAIMS 1. Compound IA , for use in the treatment of cancer, wherein in said treatment Compound IA is administered in combination with topoisomerase I inhibitor to a patient in need thereof.

2. Compound IA for use according to claim 1, wherein the cancer is a solid tumor.

3. Compound IA for use according to claim 2, wherein the solid tumor is selected from neuroendocrine tumor, gastrointestinal cancer, lung cancer, non-small cell lung cancer (NSCLC), large cell lung cancer (LCLC), small cell lung cancer (SCLC), sarcoma, Ewing’s sarcoma, fibrosarcoma, gynaecological cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, renal cancer, malignant pleural mesothelioma, extrapulmonary small cell carcinoma, adrenocortical carcinoma, prostate cancer, deleterious germline BRCA1/2 mutation tumors, colorectal cancer, colon cancer, rectal cancer, gastric cancer, melanoma and pancreatic cancer.

4. Compound IA for use according to claim 1, wherein the cancer is a hematological tumor.

5. Compound IA for use according to claim 4, wherein the hematological tumor is selected from acute lymphoblastic leukemia and Burkitt’s lymphoma.

6. Compound IA for use according to any of previous claims, wherein in said treatment Compound IA and the topoisomerase I inhibitor are administered concurrently, separately or sequentially.

7. Compound IA for use according to any previous claims, wherein the topoisomerase I inhibitor is selected from topotecan, SN-38, irinotecan, camptothecin, and rubitecan.

8. Compound IA for use according to claim 6, wherein the topoisomerase I inhibitor is irinotecan.

9. Compound IA for use according to claim 6, wherein the topoisomerase I inhibitor is topotecan.

10. Compound IA for use according to claim 6, wherein the topoisomerase I inhibitor is SN-

11. Compound IA for use according to claim 6, wherein the topoisomerase I inhibitor is camptothecin.

12. Compound IA for use according to claim 6, wherein the topoisomerase I inhibitor is rubitecan.

13. Compound IA, for use in the treatment of hematological tumors.

14. Compound IA for use according to claim 13, wherein the hematological cancer is selected from acute lymphoblastic leukemia and Burkitt’s lymphoma.

15. Compound IA for use according to any one of claims 1 to 14, wherein Compound 1A is in the form of a pharmaceutically acceptable salt or ester.