Combination of pm14 and a topoisomerase i inhibitor in the treatment of cancer

Abstract

The present invention relates to therapeutic treatment of cancer, particularly solid and hematological tumors, with combination therapy using PM14 and a topoisomerase I inhibitor.

Description

[0001] TITLE Combination of PM14 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 PM14 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 PM14 which is described as compound 4-S with the following formula: PM14, also named PM140014, was shown in WO2018 / 197663 and WO2022 / 2434482 to demonstrate in vitro activity against lung cancer, colorectal adenocarcinoma, gastric cancer, breast adenocarcinoma, pancreas adenocarcinoma, prostate adenocarcinoma, prostate carcinoma cell lines, melanoma, renal cancer and in vivo activity in fibrosarcoma, breast adenocarcinoma, NSCLC, ovarian carcinoma, gastric carcinoma, small cell lung cancer (SCLC), prostatic adenocarcinoma, and prostatic carcinoma 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 PM14 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 ecubectedin (PM14) for use in the treatment of cancer, wherein in said treatment PM14 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 PM14 wherein PM14 is administered in combination therapy with a topoisomerase I inhibitor, thereby treating the cancer. In a further aspect, there is provided the use of PM14 in the manufacture of a medicament for the treatment of cancer, wherein PM14 is administered in combination with a topoisomerase I inhibitor. In a further aspect, the present invention provides a pharmaceutical package comprising PM14 together with instructions for its use in combination with topoisomerase I inhibitor. In a further aspect, the present invention provides a method of prolonging survival of a patient having cancer, the method comprising administering a combination therapy of PM14 and topoisomerase I inhibitor to a patient in need thereof, thereby prolonging survival of the patient. In a further aspect, the present invention provides a method of reducing or delaying growth of cancer, the method comprising administering a combination therapy of PM14 and topoisomerase I inhibitor to a patient in need thereof, thereby reducing or delaying growth of cancer. In a further aspect, the present invention provides a method of delaying disease progression of cancer in a patient, the method comprising administering a combination therapy of PM14 and topoisomerase I inhibitor to a patient in need thereof, thereby delaying disease progression of cancer. In a further aspect, the invention provides use of topoisomerase I inhibitor in the treatment of cancer, wherein in said treatment the topoisomerase I inhibitor is administered in combination with PM14 to a patient in need thereof. In a further aspect, the invention provides use of PM14 and topoisomerase I inhibitor in the treatment of cancer, wherein said treatment comprises administering a combination therapy of PM14 and topoisomerase I inhibitor to a patient in need thereof. In a further aspect, there is provided a combination of PM14 and a topoisomerase I inhibitor. In a further aspect, there is provided PM14 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 PM14 and a topoisomerase I inhibitor, either concurrently, sequentially or separately, wherein said cell is a cancer cell. In a further aspect, there is provided PM14 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 PM14 to a patient in need thereof, thereby treating the hematological tumor. In a further aspect, the present invention provides the use of PM14 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, colorectal cancer, colon cancer, rectal cancer, gastric cancer, melanoma, biliary cancer 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 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 an embodiment, the molar ratio of the combination of PM14 : 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 : PM14 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 : PM14 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 another embodiment, PM14 and the topoisomerase I inhibitor are administered concurrently, separately or sequentially. In another embodiment, the topoisomerase I inhibitor is administered initially, followed by PM14. In another embodiment, the administration cycle in combination with topoisomerase I inhibitor is once every three to four weeks, preferably once every 21 days. In a further embodiment, PM14 is administered in combination with topoisomerase I inhibitor on day 1 of a cycle. In another embodiment, PM14 is administered at least 2 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes. In another embodiment, PM14 is administered as 3 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes. In a preferred embodiment, PM14 is administered over 3 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes. In another embodiment, the topoisomerase I inhibitor is administered at least 1 hour intravenous infusion during each administration cycle allowing -5 minutes to +30 minutes. In a preferred embodiment, the topoisomerase I inhibitor is administered as 90 minutes intravenous infusion during each administration cycle allowing -5 minutes to +30 minutes. In a further embodiment, the topoisomerase I inhibitor is administered as at least 1 hour intravenous infusion followed by PM14 which is administered as at least 2 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1. In another embodiment, the topoisomerase I inhibitor is administered as 90 minutes intravenous infusion followed by PM14 which is administered as 3 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1. In another embodiment, the topoisomerase I inhibitor is administered as at least 1 hour intravenous infusion followed by PM14 which is administered as at least 2 hours intravenous infusion with an interval between both administrations of a maximum of 20 minutes on Day 1 from cycle 2 onwards. In another embodiment, irinotecan is administered as at least 1 hour intravenous infusion followed by PM14 which is administered as at least 2 hours intravenous infusion with an interval between both administrations of a maximum of 20 minutes on Day 1 from cycle 2 onwards. In a further embodiment, the treatment further comprises administration of a prophylactic compound before the administration of PM14 in combination with topoisomerase I inhibitor, wherein the prophylactic compound is selected from corticosteroid and 5-HT3 receptor antagonist. In another embodiment, the administration of the prophylactic compound is followed by administration of a dopamine antagonist compound. In a preferred embodiment, the treatment further comprises administration of granulocyte-colony stimulating factor (G-CSF). 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 another embodiment, PM14 is administered at a dose from 3 to 5 mg / m2and irinotecan is administered at a dose from 30 to 50 mg / m2. In another embodiment, PM14 is administered at a dose from 4.5 to 5 mg / m2and irinotecan is administered at a dose from 40 to 50 mg / m2. In a further embodiment, PM14 is administered at a dose of 3 mg / m2and irinotecan is administered at a dose of 40 mg / m2. In an embodiment, PM14 is administered at a dose of 3 mg / m2and irinotecan is administered at a dose of 50 mg / m2. In a preferred embodiment, PM14 is administered at a dose of 4.5 mg / m2and irinotecan is administered at a dose of 50 mg / m2. In another preferred embodiment, PM14 is administered at a dose of 4.5 mg / m2and irinotecan is administered at a dose of 40 mg / m2. In a more preferred embodiment, the cancer is non-small cell lung cancer and wherein in said treatment a prophylactic compound is administered before the administration of the combination of PM14 and irinotecan, and wherein irinotecan is administered at a dose of 40 mg / m2as 90 minutes intravenous infusion followed by PM14 which is administered at a dose of 4.5 mg / m2as 3 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1 and a primary profile. In embodiments, PM14 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 PM14. 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 PM14- irinotecan combination. Figure 1D shows a combination index plot (CI vs Fa) for mice bearing H460 (NSCLC) xenografted tumors and treated with PM14-irinotecan combination. Figure 2A shows tumor growth (median) for mice bearing Calu-6 (NSCLC) xenografted tumors and treated with PM14. Figure 2B shows tumor growth (median) for mice bearing Calu-6 (NSCLC) xenografted tumors and treated with irinotecan. Figure 2C shows tumor growth (median) for mice bearing Calu-6 (NSCLC) xenografted tumors and treated with PM14-irinotecan combination. Figure 2D shows a combination index plot (CI vs Fa) for mice bearing Calu-6 (NSCLC) xenografted tumors and treated with PM14-irinotecan combination. Figure 2E shows tumor growth (median) for mice bearing Calu-6 (NSCLC) xenografted tumors and treated with PM14, irinotecan or with PM14-irinotecan combination, at their highest doses. Figure 3A shows tumor growth (median) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with PM14. Figure 3B shows tumor growth (median) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with irinotecan. Figure 3C shows tumor growth (median) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with PM14-irinotecan combination. Figure 3D shows a combination index plot (CI vs Fa) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with PM14-irinotecan combination. Figure 3E shows tumor growth (median)) for mice bearing HT1080 (fibrosarcoma) xenografted tumors and treated with PM14, irinotecan or with PM14-irinotecan combination, at their medium doses. Figure 4A shows tumor growth (median) for mice bearing TC71 (sarcoma) xenografted tumors and treated with PM14. Figure 4B shows tumor growth (median) for mice bearing TC71 (sarcoma) xenografted tumors and treated with irinotecan. Figure 4C shows tumor growth (median) for mice bearing TC71 (sarcoma) xenografted tumors and treated with PM14-irinotecan combination. Figure 4D shows a combination index plot (CI vs Fa) for mice bearing TC71 (sarcoma) xenografted tumors and treated with PM14-irinotecan combination. Figure 4E shows tumor growth (median) for mice bearing TC71 (sarcoma) xenografted tumors and treated with PM14, irinotecan or with PM14-irinotecan combination at their highest doses. Figure 5A shows tumor growth (median) for mice bearing HT- 29 (colon) xenografted tumors and treated with PM14. Figure 5B shows tumor growth (median) for mice bearing HT-29 (colon) xenografted tumors and treated with irinotecan. Figure 5C shows tumor growth (median) for mice bearing HT- 29 (colon) xenografted tumors and treated with PM14-irinotecan combination. Figure 5D shows a combination index plot (CI vs Fa) for mice bearing HT- 29 (colon) xenografted tumors and treated with PM14-irinotecan combination. Figure 5E shows tumor growth (median) for mice bearing HT-29 (colon) xenografted tumors and treated with PM14, irinotecan or with PM14-irinotecan combination, at their highest doses. Figure 6A shows tumor growth (median) for mice bearing HCT116 (colon) xenografted tumors and treated with PM14. Figure 6B shows tumor growth (median) for mice bearing HCT116 (colon) xenografted tumors and treated with irinotecan. Figure 6C shows tumor growth (median) for mice bearing HCT116 (colon) xenografted tumors and treated with PM14-irinotecan combination. Figure 6D shows a combination index plot (CI vs Fa) for mice bearing HCT116 (colon) xenografted tumors and treated with PM14-irinotecan combination. Figure 6E shows tumor growth (median) for mice bearing HCT116 (colon) xenografted tumors and treated with PM14, irinotecan or with PM14-irinotecan combination, at their highest doses. Figure 7A shows tumor growth (median) for mice bearing H23 (NSCLC) xenografted tumors and treated with PM14. Figure 7B shows tumor growth (median) for mice bearing H23 (NSCLC) xenografted tumors and treated with irinotecan. Figure 7C shows tumor growth (median) for mice bearing H23 (NSCLC) xenografted tumors and treated with PM14-irinotecan combination. Figure 7D shows a combination index plot (CI vs Fa) for mice bearing H23 (NSCLC) xenografted tumors and treated with PM14-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. “G-CSF” or granulocyte-colony stimulating factor is a growth factor which encourages production of neutrophils. Ecubectedin, which is also known as PM14 is a synthetic compound under clinical investigation. PM14 was first disclosed in WO2018 / 197663 (as compound 4-S), the contents of which are herein incorporated by reference. PM14 can be prepared following the synthesis set out in WO2018 / 197663. The structure for PM14 is: . In embodiments, PM14 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 tumor 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 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. In embodiments, the present invention provides dosing schedules to treat the cancer defined herein. The patient may also receive prophylactic medication whilst getting treatment as described in the present invention. Prophylactic medication includes corticosteroids and 5-HT3 receptor antagonists. Particular corticosteroids include dexamethasone. Particular 5-HT3 receptor antagonists include ondansetron. Particular dosages include dexamethasone 8 mg i.v. (or an equivalent dose of another i.v. corticosteroid) and ondansetron 8 mg i.v. (or an equivalent dose of another i.v.5-HT3 receptor antagonist). Another particular dosage includes dexamethasone 20 mg i.v. (or an equivalent dose of another i.v. corticosteroid). Prophylactic medication may be administered on Day 1 and Day 8 of each cycle. In addition, further prophylactic medication may be administered as needed. An example includes metoclopramide or equivalent, which in embodiments may be administered every eight hours. After Day 1 of each cycle extended oral corticosteroids (for example dexamethasone not exceeding 20 mg / days) and / or 5-HT3 receptor antagonists (for example oral (or i.v.) ondansetron 4-8 mg (or equivalent)) may be administered. The patient may also be administered granulocyte-colony stimulating factor G-CSF. In embodiments, In Cycle 1, patients may receive primary prophylaxis with G-CSF starting 24-72 hours after Day 1 of Cycle 1, and during five days. Primary G-CSF prophylaxis for further cycles may be administered at the same regimen, but could also be administered according to physician discretion. 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. Suitable pharmaceutical compositions can be prepared using methodology known in the pharmaceutical art (e.g. “Remington’s Pharmaceutical Sciences” by E. W. Martin). In a more preferred embodiment, the compound(s) 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. 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, and preferably once every three weeks. In a further embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles are administered, and preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 administration cycles are administered. In a preferred embodiment, 10, 11, 12, 13, 14, 15, 16, administration cycles are administered. The invention will now be described further with reference to the following examples. 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 PM14 in combination with irinotecan and determination of the combination index (CI) The objective was to evaluate the antiproliferative activity of PM14 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 PM14 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 PM14, 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 PM14 / %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 PM14) 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, ~ED60 or ~ED70 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, ED60 represents the effective dose required to achieve 60% cell death and ED70 represents the effective dose required to achieve 70% cell death and ED80 represents the effective dose required to achieve 80% cell death. ED70 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 PM14-irinotecan performed in vitro.

[0002] 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 ED70 and at different ratios (1:3420, 1:2280, 1:1520 and 1:760) in 22Rv1 cells. Synergism is demonstrated at the high ED70. Table 5. 1.2.2. Combination in A2780 cells Summary Table 6 shows CI values at effective doses ED20, ED50 and ED70 and at different ratios (1:3380, 1:2250, 1:1500 and 1:750) in A2780 cells. Synergism is demonstrated at the high ED70. Table 6. 1.2.3. Combination in A549 cells Summary Table 7 shows CI values at effective doses ED20, ED50 and ED60 and at different ratios (1:12520, 1:8340, 1:5560 and 1:2780) in A549 cells. Synergism is demonstrated at the high ED60. 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 (1:3000, 1:2000, 1:1330 and 1:670) in A-673 cells. Synergism is demonstrated at the high ED80. Table 8. 1.2.5. Combination in DMS-53 cells Summary Table 9 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:48270, 1:32180, 1:21450 and 1:10730) in DMS-53 cells. Synergism is demonstrated at the high ED80. 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 (1:1720, 1:1150, 1:770 and 1:380) 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 ED70 and at different ratios (1:6610, 1:4410, 1:2940 and 1:1470) in HGC-27 cells. Synergism is demonstrated at the high ED70. Table 11. 1.2.8. Combination in HT-29 cells Summary Table 12 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:19090, 1:12730, 1:8480 and 1:4240) in HT-29 cells. Synergism is demonstrated at the high ED80. Table 12. 1.2.9. Combination in IGROV-1 cells Summary Table 13 shows CI values at effective doses ED20, ED50 and ED60 and at different ratios (1:15600, 1:10400, 1:6930 and 1:3470) in IGROV-1 cells. Synergism is demonstrated at the high ED60. 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 (1:6480, 1:4320, 1:2880 and 1:1440) 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 (1:1360, 1:900, 1:600 and 1:300) 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 ED80 and at different ratios (1:4610, 1:3080, 1:2050 and 1:1030) in PSN-1 cells. Synergism is demonstrated at the high ED80. 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 (1:6710, 1:4470, 1:2980 and 1:1490) in VCap cells. Synergism is demonstrated at the high ED80. Table 17. 1.2.14 Results The results of the combination of PM14 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 PM14 with irinotecan in 22Rv1 cells. 22Rv1 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:3420 Ratio 1:2280 Ratio 1:1520 Ratio 1:760 A B A B A B A B A B 0.20 1.13E-09 8.00E-07 6.65 1.38 3.95 1.23 3.46 1.61 2.70 2.51 0.50 1.92E-09 1.49E-06 6.25 1.42 3.43 1.17 3.23 1.65 2.29 2.34 0.70 4.75E-09 3.63E-06 7.51 1.68 4.50 1.51 3.68 1.84 2.56 2.57 Table 19. Dose reduction index for the combination of PM14 with irinotecan in A2780 cells. A2780 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:3380 Ratio 1:2250 Ratio 1:1500 Ratio 1:750 A B A B A B A B A B 0.20 3.95E-09 3.32E-06 3.98 0.99 3.20 1.20 3.26 1.83 2.44 2.74 0.50 6.78E-09 9.46E-06 3.24 1.34 2.72 1.69 2.76 2.57 1.84 3.42 0.70 8.76E-09 1.22E-04 2.78 11.42 2.36 14.57 2.12 19.68 1.30 24.13 Table 20. Dose reduction index for the combination of PM14 with irinotecan in A549 cells. A549 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:12520 Ratio 1:8340 Ratio 1:5560 Ratio 1:2780 A B A B A B A B A B 0.20 7.37E-10 3.40E-06 3.10 1.14 2.46 1.36 2.02 1.68 1.80 3.00 0.50 2.04E-09 4.42E-05 2.16 3.73 1.92 4.99 1.74 6.75 1.54 11.98 0.60 2.61E-09 7.79E-05 2.20 5.25 1.60 5.71 1.71 9.16 1.31 14.08 Table 21. Dose reduction index for the combination of PM14 with irinotecan in A-673 cells. A-673 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:3000 Ratio 1:2000 Ratio 1:1330 Ratio 1:670 A B A B A B A B A B 0.20 2.29E-09 9.42E-07 12.19 1.67 6.36 1.31 5.48 1.70 3.34 2.06 0.50 3.18E-09 1.99E-06 6.45 1.34 4.64 1.45 3.22 1.51 2.37 2.21 0.80 4.42E-09 1.13E-05 3.54 3.01 3.04 3.87 2.25 4.32 1.71 6.49 Table 22. Dose reduction index for the combination of PM14 with irinotecan in DMS-53 cells. DMS-53 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:48270 Ratio 1:32180 Ratio 1:21450 Ratio 1:10730 A B A B A B A B A B 0.20 3.83E-10 3.04E-06 7.55 1.24 5.36 1.32 4.15 1.54 2.84 2.10 0.50 7.66E-10 7.99E-06 6.25 1.35 4.98 1.61 4.07 1.98 2.55 2.48 0.80 1.57E-09 8.13E-05 4.10 4.39 3.06 4.92 2.72 6.55 1.96 9.47 Table 23. Dose reduction index for the combination of PM14 with irinotecan in HeLa cells. Hela Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:1720 Ratio 1:1150 Ratio 1:770 Ratio 1:380 A B A B A B A B A B 0.20 9.59E-10 2.55E-06 1.67 2.58 1.45 3.35 1.74 5.99 1.52 10.63 0.50 2.66E-09 1.99E-05 2.00 8.71 1.68 10.93 1.75 16.96 1.25 24.63 0.80 5.52E-09 1.08E-04 1.80 20.44 2.14 36.36 2.15 54.53 1.03 52.71 Table 24. Dose reduction index for the combination of PM14 with irinotecan in HGC-27 cells. HGC-27 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:6610 Ratio 1:4410 Ratio 1:2940 Ratio 1:1470 A B A B A B A B A B 0.20 4.88E-10 1.45E-06 4.22 1.90 2.94 1.98 2.11 2.14 2.47 4.99 0.50 2.49E-09 1.85E-05 2.97 3.35 2.85 4.82 2.34 5.93 2.10 10.62 0.70 3.32E-09 1.06E-04 2.68 12.91 2.55 18.38 1.87 20.21 1.44 31.18 Table 25. Dose reduction index for the combination of PM14 with irinotecan in HT-29 cells. HT-29 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:19090 Ratio 1:12730 Ratio 1:8480 Ratio 1:4240 A B A B A B A B A B 0.20 1.10E-09 3.66E-06 7.54 1.32 5.18 1.36 3.47 1.36 2.76 2.17 0.50 3.13E-09 1.58E-05 7.60 2.01 6.08 2.41 3.98 2.37 2.88 3.43 0.80 5.88E-09 4.49E-05 5.40 2.16 4.67 2.80 3.02 2.72 2.89 5.22 Table 26. Dose reduction index for the combination of PM14 with irinotecan in IGROV-1 cells. IGROV-1 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:15600 Ratio 1:10400 Ratio 1:6930 Ratio 1:3470 A B A B A B A B A B 0.20 2.97E-09 6.96E-06 6.29 0.95 5.45 1.23 5.09 1.72 3.00 2.03 0.50 5.18E-09 8.62E-05 2.73 2.91 1.56 2.49 2.15 5.16 1.84 8.84 0.60 6.11E-09 1.27E-04 2.26 3.01 1.78 5.33 Table 27. Dose reduction index for the combination of PM14 with irinotecan in MDA-MB-231 cells MDA-MB-231 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:6480 Ratio 1:4320 Ratio 1:2880 Ratio 1:1440 A B A B A B A B A B 0.20 9.88E-10 1.06E-06 11.93 1.98 5.81 1.45 4.82 1.80 3.04 2.27 0.50 2.36E-09 3.49E-06 8.04 1.84 4.41 1.51 3.60 1.85 3.12 3.20 0.80 7.40E-09 8.87E-05 5.10 9.44 3.35 9.29 2.85 11.88 3.06 25.50 Table 28. Dose reduction index for the combination of PM14 with irinotecan in NCI-H460 cells. NCI-H460 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:1360 Ratio 1:900 Ratio 1:600 Ratio 1:300 A B A B A B A B A B 0.20 1.06E-09 1.79E-06 2.76 3.44 2.11 3.96 1.49 4.20 1.26 7.10 0.50 1.62E-09 3.48E-06 1.99 3.14 1.53 3.66 1.31 4.69 1.19 8.55 0.80 3.19E-09 7.98E-06 1.85 3.39 1.70 4.73 1.61 6.71 1.28 10.66 Table 29. Dose reduction index for the combination of PM14 with irinotecan in PSN-1 cells. PSN-1 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:4610 Ratio 1:3080 Ratio 1:2050 Ratio 1:1030 A B A B A B A B A B 0.20 1.49E-09 1.17E-06 7.06 1.20 5.65 1.44 3.60 1.38 2.29 1.74 0.50 4.29E-09 3.76E-06 6.58 1.25 4.88 1.39 3.38 1.44 2.68 2.28 0.80 8.03E-09 3.63E-05 3.89 3.81 3.22 4.73 2.00 4.40 2.55 11.18 Table 30. Dose reduction index for the combination of PM14 with irinotecan in VCap cells. VCap Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI (Fa) Ratio 1:6710 Ratio 1:4470 Ratio 1:2980 Ratio 1:1490 A B A B A B A B A B 0.20 1.52E-09 7.90E-06 2.24 1.73 1.71 1.99 1.60 2.79 1.18 4.11 0.50 6.67E-09 4.45E-05 4.19 4.17 3.83 5.72 3.34 7.49 2.65 11.89 0.80 5.73E-08 1.47E-04 19.21 7.35 14.82 8.51 15.31 13.19 10.15 17.49 Example 2: antitumor activity of PM14 in combination with irinotecan in mice The antitumor activity of the combination PM14 and irinotecan was evaluated in mice implanted with 8 different cell lines tumors: - Xenograft with H460 (NSCLC) tumors - Xenograft with Calu-6 (NSCLC) tumors - Xenograft with H23 (NSCLC) tumors - Xenograft with HT-1080 (fibrosarcoma) tumors - Xenograft with TC-71 (sarcoma) tumors - Xenograft with HT-29 (colon) tumors - Xenograft with HCT-116 (colon) 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 PM14 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 mm3were randomly allocated (N = 6-8 / group) to treatment groups (Table 31). Treatments were intravenously administered once per week for 2 consecutive weeks (days 0 and 7). Tumor dimensions and body weights were recorded 3 times per week starting from the first day of treatment (Day 0). Animals were euthanized when their tumors reached ca.2000 mm3and / or severe necrosis was seen. MTD for PM14 (MTDA) was 1.2mg / kg and for irinotecan (MTDB) was 50 mg / kg, Table 31. Treatment groups in PM14-irinotecan combination in mice bearing H460 (NSCLC) tumors. All untreated animals died or were sacrificed due to tumor size (> 2000 mm3) or necrosis by Day 11. In this group, the time to reach a tumor size of 1000 mm3was 7.8 days. At their respective highest doses, PM14 and irinotecan administered as single agents resulted in a moderate antitumor activity in this model. Mortality was registered among the animals treated with the combination PM14-irinotecan at their MTD´s. PM14 and irinotecan combination induced stronger effect than either PM14 (Figure 1A) or irinotecan (Figure 1B) as single agents, suggesting strong antitumoral activity (Figure 1C). The combination PM14 plus irinotecan (at a constant combination ratio) resulted in CI values of 0.43 (at Fa = 0.97), demonstrating synergism in mice bearing H460 (NSCLC) xenografted tumors (Figure 1D). 2.2. Combination in xenografts Calu-6 (NSCLC) tumors The antitumor activity of the combination PM14 and irinotecan was evaluated in mice implanted with Calu-6 (NSCLC) tumors. Four to 6 weeks old athymic nu / nu female mice were subcutaneously implanted into their flank with a suspension of Calu-6 cells. Animals with tumor sizes ca.170 mm3were randomly allocated (N = 6-8 / group) to treatment groups (Table 32). PM14 treatment was intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and irinotecan treatment was intravenously administered every 4 days (days 0, 4, 8, 12 and 16). Tumor dimensions and body weights were recorded 3 times per week starting from the first day of treatment (Day 0). MTD for PM14 is 1.2mg / kg and for irinotecan is 50 mg / kg, Animals were euthanized when their tumors reached ca.2000 mm3and / or severe necrosis was seen. 24h post-treatment, one placebo, one PM14-treated tumor, one irinotecan-treated tumor and one PM14+irinotecan-treated tumor, all of them treated at ¾ of their MTD´s, were dissected free, formalin-fixed, paraffin embedded for Hoescht 33258 staining, looking for apoptosis by a blinded, independent pathologist. Table 32. Treatment groups in PM14-irinotecan combination in mice bearing Calu-6 (NSCLC) tumors. All placebo-treated control animals died or were sacrificed due to tumor size (> 2000 mm3) or necrosis from day 14 to day 21. In this group, the time to reach a tumor size of 1000 mm3was 9.1 days and the doubling time was 3.8. At their respective highest doses, PM14 and irinotecan, administered as single agents, resulted, in this model, in a moderate antitumor activity for PM14 treatment (Figure 2A) and a great antitumor activity for irinotecan treatment (Figure 2B). When the combination PM14-irinotecan was administered at their 3 / 4MTD´s (Figure 2E) the registered reversible body weight decrease was 19.1% on day 4. PM14 and irinotecan combination induced stronger effect than either PM14 or irinotecan as single agents, suggesting strong antitumoral activity. The combination (Figure 2C) of PM14 + irinotecan (at a constant combination ratio) resulted in CI values of 0.59 (at Fa = 0.97), demonstrating synergism in mice bearing Calu-6 (NSCLC) xenografted tumors (Figure 2D). Moreover, Table 33 shows the results of apoptosis determination by Hoescht 33258 staining and that at 24-h post-dosing, PM14+irinotecan treatment induced an increase in apoptosis levels, resulting in a synergistic effect in the antitumor activity. Table 33. Control PM14 (3 / 4MTD) Irinotecan (3 / 4MTD) PM14+irinotecan (3 / 4MTD+3 / 4MTD) 10.3 ± 3.5 3.6 ± 0.4 3.6 ± 0.9 48.0 ± 9.9 2.3. Combination in xenografts HT-1080 (fibrosarcoma) tumors The antitumor activity of the combination PM14 and irinotecan was evaluated, in mice implanted with HT1080 (fibrosarcoma) tumors. Four to 6 weeks old athymic nu / nu female mice were orthotopically implanted, into gastrocnemius muscle with a HT-1080 cell suspension. Animals with tumor sizes ca.390 mm3were randomly allocated (N = 6-8 / group) to treatment groups (Table 34). PM14 treatment was intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and irinotecan treatment was intravenously administered every 4 days (days 0, 4, 8, 12 and 16). MTD for PM14 was 1.2mg / kg and for irinotecan was 50 mg / kg, The tumor volume was measured 3 times per week and determined using the equation (D×d2) / 6 × 3.12 (where D is the maximum diameter and d is the minimum diameter). Body weights were recorded 3 times per week starting from the first day of treatment (Day 0). Animals were euthanized when their tumors diameter reached ca.1.8 cm in any direction.24h post-treatment, one placebo, one PM14-treated tumor, one irinotecan-treated tumor and one PM14+irinotecan- treated tumor, all of them treated at the highest doses, were dissected free, formalin-fixed, paraffin embedded for immunohistochemistry (IHC) determination of γH2AX by a blinded, independent pathologist. Table 34. Treatment groups in PM14-irinotecan combination in mice bearing HT-1080 (fibrosarcoma) tumors. All placebo-treated control animals died or were sacrificed due to tumor size (> 1.8 cm) from day 12 to day 16. In this group, the time to reach a tumor size of 1000 mm3was 4.0 days and the doubling time was 4.4. At their respective highest doses, PM14 administered as a single agent (Figure 3A) resulted in an antitumor activity and irinotecan, administered as single agent (Figure 3B), in this model, resulted in a high antitumor activity. The administration of PM14-irinotecan as a combination (Figure 3C), resulted in strong antitumor activity in this model. When PM14-irinotecan was administered at a combination at the highest doses, the registered reversible body weight decrease was 17.9% on day 9. PM14 and irinotecan combination induced stronger effect than either PM14 or irinotecan as single agents, suggesting a synergistic antitumor effect. The combination PM14 + irinotecan (at a constant combination ratio) resulted in CI values of 0.55 (at Fa = 0.97), demonstrating synergism in mice bearing HT1080 (fibrosarcoma) xenografted tumors, Figure 3D. On Day 26 onwards an art factual low median was recorded, due to mortality of animals bearing largest tumors (group treated with irinotecan ¼ MTD) was recorded (Figure 3E). Moreover, Table 35 shows γH2AX, (marker for DNA damage) immunohistochemistry analysis and that at 24-h post-dosing, PM14+irinotecan treatment induced DNA damage, resulting in a synergistic effect in the antitumor activity. Table 35. Control PM14 (3 / 4MTD) Irinotecan (3 / 4MTD) PM14+irinotecan (3 / 4MTD+3 / 4MTD) 10% 60% 85% 90% 2.4. Combination in xenografts TC-71 (sarcoma) tumors The antitumor activity of the combination PM14 and irinotecan was re-evaluated, dropping the irinotecan dose, in mice implanted with TC-71 (sarcoma) tumors. Four to 6 weeks old athymic nu / nu female mice were orthotopically implanted, into gastrocnemius muscle with a TC-71 cell suspension. Animals with tumor sizes ca. 135mm3were randomly allocated (N = 6-8 / group) to treatment groups (Table 36). PM14 treatment was intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and irinotecan treatment was intravenously administered every 4 days (days 0, 4, 8, 12 and 16). MTD for PM14 was 1.2mg / kg and for irinotecan was 50 mg / kg, The tumor volume was measured 3 times per week and determined using the equation (D×d2) / 6 × 3.12 (where D is the maximum diameter and d is the minimum diameter). Body weights were recorded 3 times per week starting from the first day of treatment (Day 0). Animals were euthanized when their tumors diameter reached ca.1.8 cm in any direction (volume approx.3,000 mm3).24h post-treatment, one placebo, one PM14-treated tumor, one irinotecan- treated tumor and one PM14+irinotecan-treated tumor, all of them treated at the highest doses, were dissected free, formalin-fixed, paraffin embedded for Hoescht 33258 staining, looking for apoptosis determination by a blinded, independent pathologist. Table 36. Treatment groups in PM14-irinotecan combination in mice bearing TC-71 (sarcoma) tumors. All placebo-treated control animals died or were sacrificed due to tumor size (> 1.8 cm) on day 12. In this group, the time to reach a tumor size of 1000 mm3was 7.0 days and the doubling time was 2.5. At their respective highest doses, PM14 administered as a single agent (Figure 4A), resulted in antitumor activity and irinotecan, administered as single agent (Figure 4B), in this model, resulted in a strong antitumor activity. The administration of PM14-irinotecan as a combination (Figure 4C), resulted in very strong antitumor activity in this model. When PM14-irinotecan was administered at a combination at the highest doses (Figure 4E), the registered reversible body weight decrease was 6.1% on day 2. PM14 and irinotecan combination induced stronger long lasting effect than either PM14 or irinotecan as single agents, suggesting a synergistic antitumor effect. The combination PM14 + irinotecan (at a constant combination ratio) resulted in CI values of 0.81 (at Fa = 0.97), demonstrating synergism in mice bearing TC71 (sarcoma) xenografted tumors (Figure 4D). Moreover, Table 37 shows apoptosis determination by Hoescht 33258 staining and that at 24-h post-dosing, PM14+irinotecan treatment induced an increase in apoptosis levels, resulting in a synergistic effect in the antitumor activity. Table 37. Control PM14 (3 / 4MTD) Irinotecan (3 / 4MTD) PM14+irinotecan (3 / 4MTD+3 / 4MTD) 0.4 ± 0.2 28.0 ± 3.3 62.4 ± 11.9 >150 2.5. Combination in xenografts HT-29 (colon) tumors The antitumor activity of the combination PM14 and irinotecan was evaluated in mice implanted with HT-29 (colon) tumors. Four to 6 weeks old athymic nu / nu female mice were subcutaneously implanted into their flank with a suspension of HT-29 cells. Animals with tumor sizes ca.140 mm3were randomly allocated (N = 6-8 / group) to treatment groups (Table 38). PM14 treatment was intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and irinotecan treatment was intravenously administered every 4 days (days 0, 4, 8, 12 and 16). MTD for PM14 is 1.2mg / kg and for irinotecan is 50 mg / kg, Tumor dimensions and body weights were recorded 3 times per week starting from the first day of treatment (Day 0). Animals were euthanized when their tumors reached ca.2000 mm3and / or severe necrosis was seen. Table 38. Treatment groups in PM14-irinotecan combination in mice bearing HT-29 (colon) tumors. All placebo-treated control animals died or were sacrificed due to tumor size (> 2000 mm3) or necrosis from day 17 to day 26. In this group, the time to reach a tumor size of 1000 mm3 was 18.2 days and the doubling time was 5.9. When PM14 was administered, as a single agent (Figure 5A), at ¾ MTD, resulted in no antitumor activity in this model. The administration of irinotecan, as a single agent (Figure 5B), at ¾ MTD, or PM14-irinotecan as a combination (Figure 5C), resulted in strong antitumor activity in this model. When PM14-irinotecan was administered at a combination at 3 / 4 MTD´s, 2 out 6 animals experienced complete tumor remissions that lasted 13 days, the registered reversible body weight decrease was 17.5% on day 3. PM14 and irinotecan combination induced stronger effect than either PM14 or irinotecan as single agents, suggesting very strong antitumoral activity (Figure 5E). The combination PM14 + irinotecan (at a constant combination ratio) resulted in CI values of 0.0015 (at Fa = 0.97), demonstrating synergism in mice bearing HT-29 (colon) xenografted tumors (Figure 5D). 2.6. Combination in xenografts HCT116 (colon) tumors The antitumor activity of the combination PM14 and irinotecan was evaluated in mice implanted with HCT116 (colon) tumors. Four to 6 weeks old athymic nu / nu female mice were subcutaneously implanted into their flank with a suspension of HCT116 cells. Animals with tumor sizes ca.153 mm3were randomly allocated (N = 6-8 / group) to treatment groups (Table 39). PM14 treatment was intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and irinotecan treatment was intravenously administered every 4 days (days 0, 4, 8, 12 and 16). MTD for PM14 is 1.2mg / kg and for irinotecan is 50 mg / kg, Tumor dimensions and body weights were recorded 3 times per week starting from the first day of treatment (Day 0). Animals were euthanized when their tumors reached ca.2000 mm3and / or severe necrosis was seen. Table 39. Treatment groups in PM14-irinotecan combination in mice bearing HCT116 (colon) tumors. All placebo-treated control animals died or were sacrificed due to tumor size (> 2000 mm3) or necrosis from day 12 to day 14. In this group, the time to reach a tumor size of 1000 mm3was 5.1 days and the doubling time was 3.6. At their respective highest doses, PM14 and irinotecan, administered as single agents (Figures 6A and 6B respectively), resulted in antitumor activity in this model. The administration of PM14-irinotecan as a combination resulted in strong antitumor activity in this model, 2 out of 6 animals experienced tumor remissions that lasted a mean of 6.5 days. When PM14-irinotecan was administered at a combination at 3 / 4 MTD´s the registered reversible body weight decrease was 23.5% on day 13. PM14 and irinotecan combination induced stronger effect than either PM14 or irinotecan as single agents, suggesting a strong antitumoral activity, especially reflected in the anti-ulcerative tumor effect of the combination compared to the administration of irinotecan as a single agent (Figures 6C and 6E). The combination PM14 + irinotecan (at a constant combination ratio) resulted in CI values of 0.81 (at Fa = 0.97), demonstrating synergism in mice bearing HCT116 (colon) xenografted tumors (Figure 6D). 2.7. Combination in xenografts H23 (NSCLC) tumors The antitumor activity of the combination PM14 and irinotecan was evaluated in mice implanted with H23 (NSCLC) tumors. Four to 6 weeks old athymic nu / nu female mice were subcutaneously implanted into their flank with a suspension of H23 cells. Animals with tumor sizes ca.128 mm3were randomly allocated (N = 6-8 / group) to treatment groups Table 40. PM14 treatment was intravenously administered once per week for 3 consecutive weeks (days 0, 7 and 14) and irinotecan treatment was intravenously administered every 4 days (days 0, 4, 8, 12 and 16). MTD for PM14 is 1.2mg / kg and for irinotecan is 50 mg / kg, Tumor dimensions and body weights were recorded 3 times per week starting from the first day of treatment (Day 0). Animals were euthanized when their tumors reached ca.2000 mm3and / or severe necrosis was seen. 24h post-treatment, one placebo, one PM14-treated tumor, one irinotecan-treated tumor and one PM14+irinotecan-treated tumor, all of them treated at ¾ of their MTD´s, were dissected free, formalin-fixed, paraffin embedded for Hoescht 33258 staining, looking for apoptosis by a blinded, independent pathologist. Table 40. Treatment groups in PM14-irinotecan combination in mice bearing H23 (NSCLC) tumors. All placebo-treated animals died or were sacrificed due to tumor size (> 2000 mm3) or necrosis from day 30 to day 38. In this group, the time to reach a tumor size of 1000 mm3was 37 days and the doubling time was 5.1. At their respective highest doses, PM14 and irinotecan, administered as single agents (Figure 7A and 7B respectively), resulted in antitumor activity in this model, 1 out of 6 animals treated with irinotecan at ¾ MTD experienced tumor regression that one week. The administration of PM14- irinotecan as a combination (Figure 7C) resulted in strong antitumor activity in this model. Six out of 6 animals treated with the combination experienced complete tumor remissions, starting from the first week of treatment until the last measurement day (D42). When PM14-irinotecan was administered as a combination at their highest doses, the registered reversible body weight decrease was 13.2% on day 4, one animal was found dead on D16 and other animal was sacrificed on D32 due to tumor ulceration and cachexia. PM14 and irinotecan combination induced stronger effect than either PM14 or irinotecan as single agents, suggesting a strong antitumoral activity. The combination PM14 + irinotecan (at a constant combination ratio) resulted in CI values of 0.23 (at Fa = 0.97), demonstrating synergism in mice bearing H23 (NSCLC) xenografted tumors. (Figure 7D). Moreover, Table 41 shows γH2AX, (marker for DNA damage) immunohistochemistry analysis and that 24-h post-dosing, PM14+irinotecan treatment induced DNA damage, resulting in a synergistic effect in the antitumor activity. Table 42 shows apoptosis determination by Hoescht 33258 staining and that at 24-h post-dosing, PM14+irinotecan treatment induced an increase in apoptosis levels, resulting in a synergistic effect in the antitumor activity. Table 41. Control PM14 (3 / 4MTD) Irinotecan (3 / 4MTD) PM14+irinotecan (3 / 4MTD+3 / 4MTD) 30% 75% 30% 90% Table 42. Control PM14 (3 / 4MTD) Irinotecan (3 / 4MTD) PM14+irinotecan (3 / 4MTD+3 / 4MTD) 3.8 ± 0.6 4.0 68.2 ± 11.2 >200 2.8. Results: The results of the combination of PM14 with irinotecan in different xenografts demonstrate synergistic activity in HT-29 colon adenocarcinoma cells, H-23 NSCLC cells, CI-H460 NSCLC cells, Calu-6 NSCLC cells and HT-1080 fibrosarcoma cells, and HCT-116 colon cancer cells and TC-71 sarcoma cells. Example 3: Clinical trial Prospective, open-label, uncontrolled phase I / II study with PM14 in combination with irinotecan in patients with selected solid tumors. 3.1. Study objectives Primary: ^ Phase I escalation stage: To determine the MTD and the RD of PM14 in combination with irinotecan in patients with selected advanced solid tumors (Note: dose escalation with primary G-CSF prophylaxis may be implemented to determine the RD, in the event of DLTs of the combination being exclusively related to neutropenia). ^ Phase II expansion stage: To confirm the RD determined during the dose escalation stage, and to evaluate the antitumor activity of PM14 and irinotecan in terms of ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 in patients with selected advanced solid tumors. Secondary: ^ To evaluate the safety and tolerability of this combination in patients with selected advanced solid tumors. ^ To characterize the PK of this combination and to detect potential major drug-drug PK interactions. ^ To evaluate pharmacogenetics (PGt) in germline DNA by the presence or absence of PGt polymorphisms in genes relevant for PM14 disposition (distribution, metabolism and excretion) that may explain individual variability in main PM14 PK parameters. ^ To conduct an exploratory PGx analysis substudy in tumor and blood samples from patients consenting to the substudy and exposed to PM14 and irinotecan, to identify potential biomarkers of response and / or resistance to the combination of PM14 and irinotecan. ^ Dose escalation stage: To obtain information on the antitumor activity of PM14 in combination with irinotecan. ^ Expansion stage: To evaluate clinical benefit (ORR or SD lasting over four months [SD ≥4 months]) and time-to-event endpoints in terms of progression-free survival (PFS) and duration of response (DoR), if appropriate. 3.2. Study design Prospective, open-label, uncontrolled phase I / II study with PM14 in combination with irinotecan in patients with selected solid tumors. Both drugs will be administered intravenously (i.v.) on Day 1 every 3 weeks (q3wk) (3 weeks = 1 cycle). The study will be divided into two stages: a phase I dose escalation stage and a phase II expansion stage. Dose escalation stage: Three to six patients will be included at each dose level. If DLTs occur in less than one third of evaluable patients in each cohort, escalation can proceed to the next dose level. The MTD will be the lowest dose level explored during dose escalation at which one third or more of evaluable patients develop a DLT in Cycle 1. At any dose level, if one of the first three evaluable patients has a DLT, the dose level should be expanded to six patients. Dose escalation will be terminated once the MTD or the last dose level is reached, whichever occurs first, except if DLTs occurring at a given dose level are related to neutropenia (i.e., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis), in which case dose escalation may be resumed, starting at the same dose level and following the same original schedule but with mandatory primary G-CSF prophylaxis. Once the MTD is reached, a minimum of nine additional evaluable patients will be recruited at the immediately lower dose level (or at the last dose level, if the MTD is not defined yet): this level will be confirmed as the RD if less than one third of the first nine evaluable patients develop DLT during Cycle 1. Other dose levels and schedules of both drugs may be tested on agreement between the Investigator and the Sponsors, if deemed appropriate. Expansion stage: If antitumor activity is observed in any tumor type during the dose escalation stage, a phase II expansion stage will be implemented once the RD has been defined. At least 15 patients per tumor type will be enrolled in this expansion stage. The tumor types chosen to be explored will be agreed between the Investigators and the Sponsors. 3.2.1 Pharmacogenomic / Pharmacogenetic substudy The aim of the PGx analysis is to identify and validate putative molecular biomarkers associated with the clinical outcome of patients treated with PM14 combined with irinotecan. These molecular biomarkers would help to select future patients who might preferentially benefit from the PM14 and irinotecan combination, thus contributing to a more individualized medicine. Available formalin-fixed paraffin-embedded (FFPE) tumor tissue sections and / or blood samples obtained at diagnosis and / or during treatment (at response and / or relapse) from patients consenting to the PGx substudy will be analyzed for molecular biomarkers of response and / or resistance to treatment. These studies will be carried out by high throughput molecular screening techniques (e.g., Next Generation Sequencing [NGS] and immunohistochemistry [IHC]). Blood samples will be additionally used for germline comparison analyses, when available. The aim of the PGt component of this study is to explore genetic factors that may help explain individual variability in main PM14 PK parameters. 3.3. Study population Inclusion criteria 1) Voluntarily signed and dated written informed consent prior to any specific study procedure. 2) Age ≥ 18 years. 3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1. 4) Histologically or cytologically-confirmed selected advanced solid tumors (see below) for which the standard of care therapies have failed, or are intolerant to standard of care therapies that are known to provide clinical benefit. a) Gastrointestinal: esophageal carcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, biliary tract carcinoma, hepatocarcinoma and poorly differentiated (grade 3) gastroenteropancreatic neuroendocrine neoplasms (Ki 67 index >20%; mitotic count >20%). b) Lung: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). c) Sarcoma: liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing’s sarcoma. d) Gynecological: epithelial ovarian carcinoma (including primary peritoneal disease and / or fallopian tube carcinomas and / or endometrial adenocarcinomas), endometrial carcinoma and carcinoma of cervix. e) Breast: ductal or lobular carcinoma. f) Genitourinary tract tumors: urothelial bladder carcinoma, clear cell renal carcinoma and prostate adenocarcinoma. g) Other: malignant pleural mesothelioma, extrapulmonary small cell carcinoma, and adrenocortical carcinoma. In the Expansion stage only (tumor-specific cohort[s] at the RD): h) Measurable disease according to RECIST v.1.1. i) Documented disease progression per RECIST v.1.1 during or immediately after last therapy according to any of the aforementioned criteria. 5) Washout periods: a) At least three weeks since the last chemotherapy, radiotherapy (RT) >30 Gy, or monoclonal antibody (MAb)-containing therapy. b) 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). c) 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. d) Castrate-resistant prostate cancer (CRPC) patients may continue receiving hormone therapy prior to and during study treatment. Washout periods are referred to the day of first cycle administration (Day 1), not to the day of registration. 6) Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days before registration): a) Platelet count ≥ 100 x 109 / L, hemoglobin ≥ 9.0 g / dL and absolute neutrophil count (ANC) ≥ 2.0 x 109 / L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x the upper limit of normal (ULN), even in the presence of liver metastases. c) Alkaline phosphatase (AP) ≤ 2.5 x ULN (≤ 5 x ULN if disease-related / in the case of liver metastases). d) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN. e) Calculated creatinine clearance (CrCL) ≥ 30 mL / minute (using Cockcroft-Gault formula). f) Creatine phosphokinase (CPK) ≤ 2.5 x ULN. g) Serum albumin ≥ 3.0 g / dL.* 7) Recovery to grade ≤ 1 or to baseline from any adverse event (AE) derived from previous treatment (excluding alopecia and / or cutaneous toxicity and / or peripheral neuropathy and / or fatigue grade ≤ 2). * Albumin transfusion to increase the blood level in order to fulfill the inclusion criterion is strictly forbidden. Exclusion criteria 1) Concomitant diseases / conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 x ULN in two different determinations performed one week apart). d) Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. Known Gilbert disease. e) Active uncontrolled infection. f) Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B. For hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. g) Any past or present chronic inflammatory colon and / or liver disease, past intestinal obstruction, pseudo or sub-occlusion or paralysis. h) Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and / or necessitating prompt local treatment within seven days. i) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study (e.g., COVID-19). 2) Prior treatment with lurbinectedin (Zepzelca®), trabectedin (Yondelis®) or topoisomerase I inhibitors is excluded, if the last dose was administered within six months prior to the first infusion of PM14 and irinotecan. 3) Use of (strong or moderate) inhibitors or strong inducers of CYP3A4 activity within two weeks prior to the first infusion of PM14 and irinotecan. 4) Active or untreated central nervous system (CNS) involvement. Exception: patients with previously treated CNS metastases are eligible provided they have to show radiographic stability (defined as no CNS progression for at least four weeks from post-radiotherapy brain scan to brain scan performed during study screening), and patients should not have neurologic sign / symptoms secondary to the brain metastases or RT. Any steroid treatment must be completed ≥14 days before the first dose of study treatment. Note: for all SCLC patients regardless of prior history of brain metastases or patients with other solid tumors and previously treated CNS metastases, adequate CNS imaging (contrast enhanced- computed tomography [CT] or magnetic resonance imaging [MRI], if applicable) will be performed at baseline to document any disease involvement. 5) Limitation of the patient’s ability to comply with the treatment or follow-up protocol. 6) Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception. Women of childbearing potential (WOCBP) must agree to use an effective contraception method to avoid pregnancy during the course of the trial (and for at least six months after the last infusion). Fertile male patients must agree to refrain from fathering a child or donating sperm during the trial and for four months after the last infusion. 3.3.1. Pharmacogenomic / Pharmacogenetic substudy eligibility criteria Patients who are eligible for the trial will also be eligible for the PGx / PGt substudy with a separate, voluntarily signed and dated informed consent form. Refusal to participate in the PGx / PGt components will not affect patient participation in the clinical trial PM1183-A-014-15. 3.3.2. Expected number of patients The number of patients will vary depending on tolerability of the PM14 / irinotecan combination and on the number of dose levels required to identify the MTD. It may also vary according to the number of tumor-specific cohorts in the expansion stage. Approximately 80-100 evaluable patients are expected to be enrolled in the study: 20-25 evaluable patients in the dose escalation stage, and 60-75 evaluable patients in the expansion stage. 4. Study drug Formulation PM14: ^ Pharmaceutical form: PM14 drug product (DP) is provided as a sterile lyophilized powder for concentrate for solution for infusion. ^ Route of administration: PM14 DP was developed for administration by the i.v. route. Before use, the vials are reconstituted with sodium chloride 9 mg / mL (0.9%) solution for infusion to give a solution containing 0.5 mg / mL of PM14. Prior to administration, the reconstituted DP solution should be further diluted with sodium chloride 9 mg / mL (0.9%) solution for infusion. ^ Vial composition: The composition of the PM14 vial is PM14, sucrose, potassium dihydrogen phosphate, phosphoric acid, potassium hydroxide, sodium chloride for the reconstitution and water for injection. Irinotecan: Commercially-available irinotecan (injection) will be provided. Patients will consecutively receive the following on Day 1 q3wk (every three weeks = one treatment cycle): ^ Irinotecan: a total volume of 250 mL to 500 mL dilution on 0.9% sodium chloride or 5% glucose by i.v. infusion lasting 90 minutes (-5-min / +30-min) via a central or peripheral venous catheter (after appropriate visual confirmation of effective venous blood return through the line), followed by: ^ PM14: as an i.v. infusion (central or peripheral line) in a total volume of 250 mL of 0.9% sodium chloride. The infusion will be administered over three hours (-15-min / +30-min). During Cycle 1, irinotecan will be administered by i.v. infusion lasting 90 minutes followed by that of PM14 lasting three hours within a permitted window of 10 minutes between both treatments. (From Cycle 2 onwards, the time between the end of infusion of irinotecan and the start of infusion of PM14 should not exceed 20 minutes). Whenever possible, central venous access is preferred over peripheral line infusion to ensure optimal tolerance. During the dose escalation stage, body surface area (BSA) will be calculated every cycle according to the DuBois formula. PM14 and irinotecan doses will be recalculated before a new cycle is started. During the expansion stage, the DuBois formula is recommended and PM14 and irinotecan doses will have to be recalculated for patients showing a ≥ 10% variation in total body weight from baseline or from last dose adjustment, before treatment administration. Doses of both PM14 and irinotecan will be rounded to the tenth of one milligram. From Cycle 2, a window of - / + 2 days is allowed for administration of the combination of PM14 and irinotecan in a cycle. 5. Dose escalation schedule Dose escalation will be conducted in accordance with the following guidelines: Table 43. Dose escalation schedule. No. of patients evaluable* No. of patients with DLT in Action for DLT Cycle 1 3 0 Escalate DL until the last dose level is reached 1 Add 3 patients >1 MTD 6 1 Escalate DL until the last dose level is reached >1 MTD * Patients not evaluable for DLT during dose escalation must be replaced. DL, dose level; DLT, dose-limiting toxicity; MTD, maximum tolerated dose. Pre-defined dose levels, starting at DL1 and including a minimum of three evaluable patients per dose level, are summarized below: Table 44. Dose escalation levels. Dose level Irinotecan dose (Day1) mg / m2PM14 dose (Day 1, after irinotecan) mg / m2DL –1 30 3.0 DL1 (starting dose) 40 3.0 DL2 40 4.5 DL3 50 4.5 DLX Further dose levels, or intermediate dose levels (in case of PM14- and / or irinotecan-related AEs), may be evaluated after discussion between the Investigator, the Sponsors, and the IMC AE, adverse event; D. day; DL, dose level; IMC, Independent Monitoring Committee. Once the first patient has been included and treated at the first dose level (DL1), the second and third patients at DL1 will be included three weeks later. Otherwise (at subsequent dose levels), all patients within a dose level may be treated simultaneously. All evaluable patients within a dose level will be followed for at least one cycle (i.e., three weeks) before dose escalation may proceed. If DLT occurs in at least two of the first three evaluable patients at DL1, DL1 will be closed and accrual into DL–1 will be started. Dose escalation will be terminated once the MTD or the last dose level is reached, whichever occurs first, except if DLTs occurring at a given dose level are related to neutropenia (i.e., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis), in which case dose escalation may be resumed, starting at the same dose level and following the same original schedule but with mandatory primary G-CSF prophylaxis. Once the MTD is reached, a minimum of nine additional evaluable patients will be recruited at the immediately lower dose level (or at the last dose level, if the MTD is not defined yet): this level will be confirmed as the RD if less than one third of the first nine evaluable patients develop DLT during Cycle 1. According to the toxicity observed, intermediate dose levels may be explored if considered appropriate, after discussion between the Investigator and the Sponsors, and in agreement with the Independent Monitoring Committee (IMC). In the event of antitumor activity being observed in any tumor type during the dose escalation stage, tumor-specific expansion cohort(s) treated at the RD will include at least 15 evaluable patients per tumor type. Intrapatient dose escalation will not be allowed. 6. Prophylactic medication All patients must receive the following prophylactic medication before infusion of study treatment: ^ Dexamethasone 8 mg i.v. (or an equivalent dose of another i.v. corticosteroid). ^ Ondansetron 8 mg i.v. (or an equivalent dose of another i.v.5-HT3 receptor antagonist). ^ If necessary and in addition to the above, 10 mg of oral or i.v. metoclopramide or equivalent can be administered every eight hours (according to tolerance and Investigator criteria). After Day 1 of each cycle, extended oral dexamethasone not exceeding 20 mg / day and / or oral (or i.v.) ondansetron 4–8 mg (or equivalent) will be optional and according to Investigator criteria. For the purpose of safety evaluations, an optimal antiemetic prophylaxis is defined as all the medications at their respectively maximum dose of either option described above. Additional antiemetics might be used, if needed. Use of moderate inhibitors of CYP3A4 based on aprepitant or any other NK-1 antagonist or related Substance P-antagonists (except for rolapitant) is forbidden. An acceptable alternative is the use of rolapitant. Antidiarrheal prophylaxis with 0.25-1 mg of i.v. or subcutaneous atropine (unless clinically contraindicated) should be considered in patients experiencing cholinergic syndrome. 7. Allowed medications / therapies ^ Therapies for preexisting and treatment-emergent medical conditions, including pain management. ^ Blood products and transfusions, as clinically indicated. ^ Bisphosphonates. ^ In case of nausea or vomiting, secondary prophylaxis and / or symptomatic treatment for nausea and / or emesis according to American Society of Clinical Oncology (ASCO) guidelines. ^ Erythropoietin use according to ASCO guidelines. ^ Palliative local radiation may be applied, if needed, after the first cycle of study treatment is completed. Any lesion within the irradiated area will then not be considered an area of measurable / evaluable disease. ^ Megestrol acetate for appetite stimulation. ^ Secondary G-CSF prophylaxis after Cycle 1. Inactivated vaccines (e.g., COVID-19). 8. Prohibited medications / therapies ^ Concomitant administration of any other antineoplastic therapy. ^ Medroxyprogesterone (if given for the treatment of endometrial cancer). ^ Other investigational agents. ^ Immunosuppressive therapies other than corticosteroids given as antiemetic prophylaxis or pain control, or low-dose cortisol replacement. ^ Primary G-CSF prophylaxis (unless dose escalation with primary G-CSF is implemented during the trial) Note: a patient who develops severe non-febrile neutropenia during Cycle 1 of the dose escalation stage should not receive therapeutic G-CSF unless the DLT criterion for neutropenia is met or it is clinically indicated. ^ Strong and moderate CYP3A4 inhibitors and strong CYP3A4 inducers. This includes aprepitant or any other NK-1 antagonist or related Substance P-antagonists (except for rolapitant), as they are moderate inhibitors of CYP3A4. Substrates of CYP3A4, OATP1B1 and OATP1B3 should be avoided. A washout period of at least two weeks prior to the first infusion of PM14 and irinotecan is recommended. If this is not possible, patients receiving these co-medications should be carefully monitored. 9. Drug-drug interactions In vitro studies using human liver microsomes have shown that PM14 has the potential to inhibit cytochrome CYP3A4. The calculated Ki values were 0.58 and 2.21 µM for CYP3A4-mediated midazolam 1’-hydroxylation (CYP3A4m) and testosterone 6β-hydroxylation reactions (CYP3A4t), respectively. Moreover, PM14 showed mechanism-based inhibition effect on CYP3A4 with kinact values of 0.03 and 0.02 min-1, and KI values of 6.05 and 4.45 μM, for CYP3A4m and CYP3A4t, respectively. The total mean maximum plasma concentration (or [I]) at the RD of 3.0 mg / m² with the Day 1 and 8 q3wk schedule, and of 4.5 mg / m² with the Day 1 q3wk schedule, in study PM14-A-001- 17 were 121.3 µg / L and 156.5 µg / L, respectively (ca.0.16 μM and 0.21 μM, or ca.0.0096 μM and 0.012 μM when expressed as unbound concentration, assuming a fu of 0.06). The basic models for CYP3A4m and CYP3A4t reversible inhibition (R1) and time-dependent inhibition (R2), proposed at the Food and Drug Administration (FDA) Guidance for in vitro Drug Interaction Studies (January 2020), showed potential reversible inhibition of CYP3A4-mediated midazolam 1’-hydroxylation in vivo (R1,CYP3A4m ≥ 1.02) for average exposure at the RD of 4.5 mg / m² on Day 1 q3wk. However, when applying the mechanistic static model proposed at the aforementioned FDA Guidance, the area under the curve ratio (AUCR) accounting for reversible and time-dependent inhibition potential at the RD of 4.5 mg / m² on Day 1 q3wk was below the cutoff limit of 1.25. Therefore, owing to the discrepancy observed between the results of the applied models, the potential inhibition of CYP3A4 by PM14 in vivo cannot be completely ruled out. Furthermore, in vitro experiments showed PM14 inhibits both OATP1B1 and OATP1B3 (uptake) transporters, with calculated half-maximal inhibitory concentration (IC50) values of 7.9 μM and 1.4 μM, respectively. The basic model (R) proposed at the FDA Guidance for in vitro Drug Interaction Studies (January 2020) to estimate the potential inhibition of OATP1B1 and OATP1B3 transporters by PM14 in vivo showed R values below the threshold of 1.1 for average exposure at the two RDs determined in the PM14-A-001-17 study. Hence, the inhibitory potential of PM14 in vivo is unlikely. In summary, PM14 inhibits CYP3A4, OATP1B1 and OATP1B3 in vitro. Consequently, concomitant drugs that are substrates of CYP3A4, OATP1B1 and OATP1B3 should be carefully monitored or avoided, whenever possible. 10. Criteria for treatment continuation Patients will be treated with additional cycles of PM14 combined with irinotecan as long as no unacceptable toxicity and / or progression of the disease and / or withdrawal of consent occurs. Administration should be delayed if the criteria in the table below are not met on Day 1 of any cycle after Cycle 1. If a patient does not meet the requirements for treatment continuation, re- assessments should be performed at least every 48-72 hours (dose escalation stage) or at least every 7 days (expansion stage) until recovery. Treatment will be withheld, until appropriate recovery, for a maximum of 15 days after the treatment due date. If there is no recovery after 15 days of treatment delay, treatment must be discontinued, except if objective clinical benefit is adequately documented by the Investigator, and upon agreement with the Sponsors. Then, treatment may continue after appropriate dose reduction, appropriate secondary prophylaxis with G-CSF (when due to neutropenia exclusively), or irinotecan discontinuation, but only with the Sponsors’ approval. Table 45. Criteria for treatment continuation. Criteria for Treatment Continuation Day 1 ANC^ 1.5 x 109 / L Platelets ^ 100 x 109 / L Hemoglobin ^ 9 g / dL Total bilirubin ^ 1.5 x ULN (or direct bilirubin) (^ ULN) AST / ALT ^ 3.0 x ULN Albumin ≥ 3.0 g / dL * ECOG PS 0–2 Calculated CrCL ≥ 30 mL / min (Cockcroft-Gault formula) Muscular toxicity Grade ≤ 1 (myalgia, muscular weakness, CPK increase) Criteria for Treatment Continuation Day 1 Non-hematological drug-related AEs except increased GGT, grade 2 AP increase, alopecia, Grade ≤ 1 constipation, peripheral neuropathy, nausea, fatigue, and isolated laboratory abnormalities. ** Mucositis Grade ≤ 1 These criteria do not apply to Day 1 of Cycle 1. If a patient does not meet the requirements for treatment continuation on Day 1 of further cycles, both drug infusions (PM14 and irinotecan) will be withheld until recovery for a maximum of 15 days after the theoretical treatment date. If recovery has not occurred after a delay of > 15 days, discontinue treatment except if objective clinical benefit is adequately documented by the Investigator, and upon agreement with the Sponsors. * Albumin transfusion for meeting the re-treatment criterion is forbidden. ** Non-symptomatic metabolic abnormalities (e.g., increase / decrease of sodium, potassium, calcium). AEs, adverse event(s); ALT, alanine aminotransferase; ANC, absolute neutrophil count; AP, alkaline phosphatase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; CrCL, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; GGT, gamma- glutamyltransferase; PS, performance status; ULN, upper limit of normal. 11. Dose reduction Dose reduction should be implemented when any of the following occurs: ^ An event fulfilling the criteria for defining a DLT (regardless of cycle number and stage of the trial). ^ Any other toxicity that is considered unacceptable by the Investigator. Under these circumstances, and following recovery to pre-specified re-treatment criteria, the patient will be re-treated at the immediately lower dose level within the dose escalation scheme (except if, according to the seriousness of the event, a different dose reduction scheme is required for a specific patient; this will be agreed between the Investigator and the Sponsors). Up to two dose reductions will be allowed per patient; any patients requiring more than two dose reductions will be withdrawn from the study (unless clinical benefit is observed, in which case the patient could continue treatment after an agreement between the Investigator and the Sponsors). Once the dose has been reduced for an individual patient, it will not be re-escalated again under any circumstances. Patients requiring dose reduction exclusively due to grade 4 neutropenia or any grade febrile neutropenia that occurred during the preceding cycle will be allowed to receive secondary prophylaxis with G-CSF instead of undergoing a dose reduction per Investigator decision. If toxicity re-occurs despite G-CSF use, dose reduction should then be implemented. In case of severe toxicity considered by the investigator to be specifically or mainly related to irinotecan (e.g., diarrhea, cholinergic syndrome, etc.), only this drug may be reduced by 10 mg / m2for the next cycle (i.e., a 20-25% irinotecan dose reduction). In the worst cases, irinotecan could even be permanently discontinued and treatment may continue with PM14 alone at its single- agent RD of 4.5 mg / m2q3wk (if clinically appropriate, and with the Sponsors’ approval). Patients treated with single-agent PM14 can have two additional dose reductions (i.e., first to 3.6 mg / m2and then to 3.0 mg / m2). On the contrary, patients cannot discontinue PM14 alone and continue treatment with single-agent irinotecan as part of this trial. 12. Evaluability of patients Dose escalation stage: An evaluable patient for the primary objective of this phase I dose escalation stage (i.e., determination of the MTD and RD) should have received at least one complete infusion of both PM14 and irinotecan and be followed for at least one complete cycle (i.e., three weeks = 21 days). Patients who discontinue treatment before completing Cycle 1 will be evaluable for the primary endpoint if the reason for the treatment discontinuation is a treatment-related AE (excluding hypersensitivity reactions and / or extravasations). Expansion stage: A patient evaluable for efficacy should have received at least one complete dose of PM14 and irinotecan and have had one disease evaluation per RECIST v.1.1. If treatment discontinuation occurs before any disease evaluation per RECIST v.1.1 could be performed, the patient will be considered evaluable for efficacy if the reason for treatment discontinuation was related to treatment-related AE, disease-related symptomatic / clinical deterioration or clinical progression, or death due to malignant disease. 13. Evaluation criteria Primary endpoint Phase I escalation stage: Determination of MTD and RD: the MTD will be the lowest dose level explored during dose escalation at which one third or more of evaluable patients develop a DLT in Cycle 1. This protocol follows European terminology; thus, the RD and the MTD are not equivalent. Expansion cohorts will be performed starting at this resultant RD, not at the MTD. Expansion stage: Overall response rate, defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR), from the start of treatment to the date of progression or the start of a subsequent therapy or end of patient’s follow-up, according to the RECIST v.1.1, as appropriate. Secondary endpoint Both stages: ^ Safety: patients will be evaluable for safety if they have received at least one partial infusion of irinotecan and / or PM14. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. Additionally, treatment-related discontinuations and treatment compliance (dose reduction, skipped doses and / or treatment delays due to AEs), will be described. ^ Pharmacokinetics: PK analyses will be evaluated in plasma by standard non- compartmental analysis (population pharmacokinetic modeling may be performed if appropriate). Plasma samples for PK analysis will be obtained in Cycle 1 from all patients. ^ 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 PM14 PK parameters. ^ Pharmacogenomics: the mutational status and the expression levels of potential predictive factors of response and / or resistance to PM14 and irinotecan treatment will be analyzed from available tumor and / or blood samples obtained at diagnosis and / or during treatment (at response and / or relapse). Their correlation with the clinical response and outcome after treatment will be assessed. Efficacy: patients will be evaluable for efficacy if they receive at least one complete infusion of both PM14 and irinotecan and have at least one clinical or radiological tumor assessment as per RECIST v.1.1, or if they are considered to have failed treatment. Treatment failure will be defined as symptomatic / clinical deterioration (disease related) or clinical progression, death due to malignant disease or treatment discontinuation due to any treatment-related AE before any appropriate tumor assessments have been performed. Antitumor activity will be evaluated according to the RECIST v.1.1 every six weeks (± two weeks). All images should be available; if requested by the Sponsors, anonymized copies should be provided. Patients discontinuing treatment without progression will be followed every eight weeks (± two weeks) until disease progression, start of other antitumor therapy, death or the end-of-study date (clinical cutoff), whichever occurs first. After disease progression or start of new therapy, patients will be followed up for survival at least every four months (± two weeks) until death or until the end-of-study date, whichever occurs first (a phone contact will be acceptable). Efficacy endpoints comprise response rates (percentage of patients with PR, with CR, or the sum of both [ORR]), percentage of patients with SD ≥ 4 months, percentage of patients with clinical benefit (ORR or SD ≥ 4 months), and time-to-event parameters (if appropriate). ORR will be a primary endpoint in the expansion stage and a secondary endpoint in the dose escalation stage. All other efficacy endpoints will be secondary endpoints in both stages. 14. Determination of MTD and RD Dose-limiting toxicities DLTs are defined as any AE or laboratory abnormalities related to the study treatment in an evaluable patient during the first cycle of treatment and fulfilling at least one of the criteria outlined below: ^ Grade 4 neutropenia (ANC < 0.5 x 109 / L) lasting > 3 days. ^ Febrile neutropenia of any duration or neutropenic sepsis. ^ Grade 4 thrombocytopenia (platelet count < 25 x 109 / L) or grade 3 thrombocytopenia with clinically significant bleeding requiring a platelet transfusion. ^ Grade 4 ALT and / or AST increase (or grade 3 lasting > 7 days or cause treatment delay of next infusion). ^ Treatment-related grade ≥ 2 ALT or AST increase concomitantly with total bilirubin increase ≥ 2.0 x ULN and normal AP (i.e. fulfilling Hy’s law criteria). ^ Grade 3 diarrhea lasting ≥ 4 days and despite adequate corrective treatment (loperamide, hydration, atropine or as determined by Investigator). ^ Any other grade ≥ 3 non-hematological, treatment-related AE, excluding nausea / vomiting (unless the patient is receiving an optimal antiemetic regimen), hypersensitivity reactions, extravasations, grade 3 fatigue lasting ≤ 3 days, and non-clinically relevant, isolated biochemical abnormalities (e.g., isolated increased gamma-glutamyltransferase [GGT]). In any case, the clinical relevance should be discussed between the Investigators and the Sponsors. ^ Delay in the administration of Cycle 2 of the combination exceeding 7 days from the theoretical date (Day 22) due to any AEs related to the study drug(s). DLTs with delayed onset (i.e., those occurring after Cycle 1) will be discussed between the Investigator and the Sponsors, and the final consensus will be documented. 15. Pharmaco-kinetics All patients included in the study will be sampled for PK analysis. The plasma PK of irinotecan (and its metabolite SN-38) and PM14 will be evaluated during Cycle 1 with a schedule of 10 samples. The sampling schedule will be as follows: Table 46. Sampling schedule for pharmacokinetic samples. Sample Reference Irinotecan Sampling Day PM14 No. sampling / infusion times and SN-38 window -15 to -1 min #1a,b1 Preinfusion^ ^before irinotecan SOI #2 1 45 min after irinotecan SOI ^ - ± 5 min #3 1 5 min before irinotecan EOI ^ - ± 2 min #4 1 30 min after PM14 SOI ^ ^ ± 5 min #5 1 5 min before PM14 EOI ^ ^ ± 2 min #6 1 1 h after PM14 EOI ^ ^ ± 10 min #7 1 3 h after PM14 EOI ^ ^ ± 15 min #8 1 5 h after PM14 EOI ^ ^ ± 30 min #9 2 24 h (one day) after PM14 EOI ^ ^ ± 4 h #10 4 72 h (three days) after PM14 EOI ^ ^ ± 24 h At each time-point except for time-points #2 and #3, draw one 9-mL blood sample and after centrifuging separate the plasma in three aliquots: two for PM14 analysis and one for irinotecan and metabolite SN-38 analysis. At time-points #2 and #3, draw one 6-mL blood sample and after centrifuging transfer the plasma to a single tube for irinotecan and metabolite SN-38 analysis. a Draw one additional sample for AAG analysis. b If written IC has been given, draw one additional sample for PGt analysis (see below). AAG, alpha-1 acid glycoprotein; EOI, end of infusion; IC, informed consent; min, minutes; h, hours; PGt, pharmacogenetics; SOI, start of infusion. PK parameters will be calculated using non-compartmental analysis and population methods if appropriate, after pooling data with other studies to check any PK interaction. 16. Replacement of patients Dose escalation stage: Patients must be replaced if they are not fully evaluable for the assessment of the primary objective, i.e. if: ^ They are withdrawn from the study before completing a PM14 and irinotecan cycle (Day 1 infusion plus three resting weeks) for any reason other than toxicity (excluding hypersensitivity and / or extravasation reactions). ^ They receive any forbidden concomitant medication or have other therapeutic procedure (i.e., major surgery) within three weeks after the first dose, unless they previously had a DLT. ^ There is a protocol deviation resulting in the impossibility to obtain any conclusion regarding safety during Cycle 1. All replaced patients will be included in the general safety analysis and in the efficacy analysis (if appropriate). Expansion stage: Patients enrolled in the tumor-specific expansion cohort(s) at the RD must be replaced if they are not evaluable for efficacy as per RECIST v.1.1 for reasons other than radiological disease progression or treatment failure (drug-related AE, disease related- symptomatic / clinical deterioration or clinical progression, or death due to malignant disease, before the first radiological assessment planned as per protocol). All replaced patients will be included in the general safety analysis. 17. Statistical methods Sample size: Approximately 80-100 evaluable patients are expected to participate in this trial (dose escalation stage: 20-25 patients; expansion stage: 60-75 patients). In the tumor-specific expansion cohort(s) (i.e., the expansion stage) at least 15 patients will be enrolled per tumor type. Demographics: Descriptive statistics (mean, median, standard deviation and 95% confidence interval, range of value, frequencies and percentages) will be used. Tables will be displayed by dose level / escalation group (and by tumor type if appropriate). Safety: Descriptive statistics will be used to characterize DLTs, the profiles of AEs regardless of relationship, drug-related AEs, drug-related deaths, serious adverse events (SAEs), drug- related delays, dose reductions, and / or treatment discontinuations. All AEs will be graded according to the current version of the NCI-CTCAE v.5. Tables will be displayed by dose level / escalation group. Efficacy: Response rates (percentage of patients with any response [PR or CR: overall response rate], percentages for PR and CR separately, as well as percentage of patients with SD ≥ 4 months) will be characterized using descriptive statistics (95% exact binomial confidence interval). In specific tumor types in the expansion cohort at the RD (and if any type is adequately represented in the escalation phase), time-to-event parameters (i.e., DoR, PFS, and overall survival [OS]) will be analyzed according to the Kaplan-Meier method as appropriate. Tumor types represented in both the dose escalation stage and in tumor-specific expansion cohort(s) (expansion stage) will be grouped if appropriate. The characteristics of the patients achieving an objective response or SD ≥ 4 months by RECIST v.1.1 will be described. All patients will be followed for up to 12 months after the inclusion of the last evaluable patient. Pharmacokinetics: The PK parameters will be tabulated and selected parameters will be graphically displayed per dose level / escalation group. The dose-exposure relationships for maximum plasma concentration (Cmax) and area under the curve (AUC) will be evaluated. Any potential PK interaction between PM14, irinotecan and SN-38 will be also explored. The potential influence on selected PK parameters of selected demographic and clinical dichotomous variables (gender, laboratory test results above / below selected cutoff values, etc.) will be evaluated by Student’s t test or Mann-Whitney’s U test as appropriate. For multinomial variables, analysis of variance will be used. For selected continuous demographic and clinical variables, relationship with selected PK parameters will be graphically explored and assessed using correlation and regression methods. Pharmacogenetics: The influence of genetic polymorphisms on main PM14 PK parameters will not be assessed or reported for individual clinical trials. PGt analysis will instead be performed using data aggregated from across the PM14 clinical development program and presented in a separate report. Pharmacogenomics: Analysis of DNA biomarkers, RNA / protein expression and IHC scoring will be performed blind, and clinical data compiled only after all analyses are completed. Germline and somatic genetic variants and transcript levels will be evaluated in FFPE and blood samples when available, in order to compare the biomarkers before and after treatment. Fisher’s exact test will be used to test whether a specific biomarker is associated with the categorical clinical outcomes (e.g., objective response rate according to RECIST v.1.1) after treatment with PM14 and irinotecan. The prognosis value of biomarkers will be explored for objective clinical response, PFS and OS. In each case, if applicable, a multivariate model will be developed by backwards elimination, starting with all markers with a p-value lower than 0.10 in the univariate analysis. If applicable, odds ratios and hazard ratios will be calculated with the univariate Logistic Regression and Cox models. Comparison between Kaplan-Meier survival (whenever available) and PFS curves will be performed with the log-rank test. All tests of statistical significance will be two-sided, and significance will be set at 0.05. 18. Duration of study period (per patient) Patients will be evaluated at scheduled visits in three study periods: ^ Pre-treatment: from signature of informed consent to first infusion of study treatment. ^ Treatment: from the first infusion of a study drug to the last study treatment administration plus 30 days (end of treatment). Follow-up: after treatment discontinuation, patients with treatment-related grade > 2 AEs will be followed until resolution or stabilization at a level acceptable to the Investigator and the Sponsors or until the start of new therapy. Patients who finish treatment without disease progression will be followed every eight weeks (± two weeks) until disease progression, other antitumor therapy, death or the end of study, whichever occurs first. After disease progression or a new antitumor therapy is started, patients will be followed up at least every four months (± two weeks) until death or the end of study, whichever occurs first ^ Patients will be considered to be on-study from the signature of the informed consent to the end of the follow-up period (or screening failure, if applicable). Patients will be considered to be on-treatment for the duration of their treatment and until the day of end of treatment. Investigators can appraise potential study candidates in a pre-screening period but only perform study-specific screening assessments after the patient formally consents. End of treatment (EOT) is defined as 30 days after treatment discontinuation, unless the patient starts a new antitumor therapy or dies (whichever occurs first). An EOT visit will be performed at 30 days (± 7 days) after administration of the last dose of study treatment unless the patient dies or starts any new antitumor therapy outside this clinical study, in which case the EOT visit should be performed immediately before the start of the new therapy (ideally the day before or the same day). Patients will receive the study medications for as long as it is considered to be in their best interest. Specifically, treatment will continue until: ^ Disease progression. * ^ Unacceptable toxicity. ^ Intercurrent illness of sufficient magnitude to preclude fulfillment of appropriate retreatment criteria and / or safety continuation of the study. ^ Non-compliance with study requirements. * ^ Cycle delay > 15 days due to toxicity. * ^ Requirement of > 2 dose reductions. * ^ Patient refusal. Patients discontinuing irinotecan only, at any time after Cycle 1, can continue receiving PM14 at its single-agent RD (4.5 mg / m2) if appropriate. If PM14 treatment needs to be discontinued, the patient will proceed to EOT. *except if objective clinical benefit is adequately documented by the Investigator, and upon agreement with the Sponsors. In these cases, treatment may continue. An early off study can be determined for safety reasons, or a Sponsor decision. Patients who are under study treatment at the time of study termination may continue treatment under compassionate use. 19. Results The combination of PM14 and irinotecan has been tested in with solid tumors (ovarian, NSCLC, sarcoma (including leiomyosarcoma and liposarcoma), gastric, breast, pancreas, urothelial, bladder, cervix, neuroendocrine and biliary). Phase I During the dose escalation (Phase I), 30 patients have been treated. The patients had the following characteristics (Table 47): Table 47. Characteristics of patients. TOTAL (N: 30 pts) Gender Female 21 (70%) Age Median (range ) 60.5 (20-78) Tumor type Ovarian 7 (23.3%) NSCLC 5 (16.6%) Sarcoma 4 (13.3%) Gastric 2 (6.7%) Breast 2 (6.7%) Pancreas 2 (6.7%) Urothelial 2 (6.7%) Other* 6 (19.8%) BSA Median ( range ) 1.7 (1.4-2.3) ECOG –median (range) 0 13 (43.3%) 1 17 (56.6%) Sites of disease involvement Median ( range ) 3 (1-7) Lymph node 21 (70.0%) Lung 20 (66.7%) Pleura 10 (33.3%) Liver 8 (26.7%) Peritoneum 7 (23.3%) Bone 6 (20.0%) Adrenal 5 (16.7%) Prior lines Median ( range ) 4 (1-8) Prior QT Lines Median ( range ) 4 (0-7) Time from metastatic diagnosis Median ( range ) 2.97 (0.08-7.65) to study entry (years) Target lesion (mm) Median ( range ) 107.5 (10-264) TOTAL (N: 30 pts) Best response to last line of PR 3 (10%) therapy SD 3 (10%) PD 13 (43.3%) NE / NA / UNK 11 (36.6%) CRP Abnormal 24 (80%) LDH Abnormal 16 (53.3%) Albumin gdL Median ( range ) 4.2 (3-4.7) Efficacy Patients have been treated at 3 different dose levels: a) DL1: PM143 mg / m2+ irinotecan 40 mg / m2D1 b) DL2: PM144.5 mg / m2+ irinotecan 40 mg / m2D1+ (with and without) GCSF c) DL3: PM144.5 mg / m2+ irinotecan 50 mg / m2D1+ (with and without) GCSF Responses are summarized in Table 48. Table 48. Best response Phase I Response N % SD16 53.3PD10 33.3PR. .NE4 13.3SD = Stable Disease PD = Disease Progression PR = Partial Response NE = Non Evaluable Mean (CV%) plasma clearance of PM14 was 4.9 L / h (56%), thus similar to that from the first-in- human study (6.6 L / h). Mean CL and median HL of IRI were 24.8 L / h and 7.4 h, so similar to the reported values in the IRI label (25 L / h and 11.7 h); and median HL of SN-38 was 17.6 h, also similar to the reported 21 h. Safety The main treatment related adverse events and lab anormalities regardless relationship per patient during the dose escalation Phase I were the following (Table 49): Table 49. Main treatment related adverse events and lab abnormalities regardless relationship per patient (worst grade per patient) DL1 DL3 DL2 PM14 3 / Irino 40 PM14 4.5 / Irino 50 PM14 4.5 / Ir2mg / m2ino 40 mg / m mg / m2N=(15) N=(6) N=(9) n (%) n (%) n (%) Gr 3 Gr4 All Gr 3 Gr 4 All Gr 3 Gr 4 All Anemia . . 5 (83.3) 4 (26.7) . 14 (93.3) 1 (11.1) . 8 (88.9) Neutropenia . 1 (16.7) 2 (33.3) 3 (20.3) 2 (13.3) 7 (46.7) 1 (11.1) 3 (33.3) 5 (55.6) Febrile neutropenia . . . 1 (6.7) . . . Thrombocytopenia . . 2 (33.3) 2 (13.3) . 6 (40.0) 1 (11.1) 1 (11.1) 4 (44.4) ALT increased . . 5 (83.3) 6 (40.0) - 12 (80) 1 (11.1) . 8 (88.9) AST increased . . - - . 9 (60.0) 1 (11.1) . 5 (55.6) Bilirubin increased . . 1 (16.7) . . 1 (6.7) 1 (11.1) . 4 (44.4) Creatinine increased . . . . 3 (20.0) . . 3 (33.3) Constipation . . 1 (16.7) . . 1 (6.7) . . 2 (22.2) Diarrhoea . . 1 (16.7) 1 (6.7) . 4 (26.7) . . 2 (22.2) Nausea . . 5 (83.3) 2 (13.3) . 9 (60.0) .1 (11.1) . 5 (55.6) Vomiting . . 1 (16.7) 2 (13.3) . 4 (26.7) . . 4 (44.4) Abdominal pain . 2 (13.3) Asthenia / Fatigue . . 5 (83.3) 2 (13.3) . 13 (80.0) 1 (11.1) - 8 (88.9) Decreased appetite . . 1 (16.7) . . 5 (33.3) . . 2 (22.2) Alopecia . . . . 1 (6.7) . . 1 (11.1) Finally, the recommended Dose (RD) chosen has been DL2, at PM144.5 mg / m2+ Irinotecan 40 mg / m2D1+ GCSF. The main treatment related adverse events and lab abnormalities regardless relationship per patient with DL2 with or without the administration of G-CSF were the following (Table 50): Table 50. Main treatment related adverse events and lab abnormalities regardless relationship per patient at the RD (worst grade per patient) DL2 w / o GCSF (N= 6) DL 2 + GCSF (N= 9) (RD) n (%) n (%) Gr3 Gr4 All Gr 3 Gr 4 All Anemia - - 5 (83.3) 4 (44.4) . 9 (100) DL2 w / o GCSF (N= 6) DL 2 + GCSF (N= 9) (RD) n (%) n (%) Gr3 Gr4 All Gr 3 Gr 4 All Neutropenia 1 (16,7) 1 (16.7) 3 (50.0) 2(22.2) 1 (11.1) 4 (44.4) Febrile neutropenia 1 (16.7) - 1 (16.7) . . . Thrombocytopenia 1 (16.7) - 1 (16.7) 1 (11.1) . 5 (55.6) ALT increased 1 (16.7) 4 (66.7) 5 (55.6) 8 (88.9) AST increased 3 (50.0) . 6 (66.7) Bilirubin increased . . 1 (11.1) Creatinine increased . - 3 (33.3) Constipation . . 1 (11.1) Diarrhoea 1 (16.7) 2 (33.3) . . 2 (22.2) Nausea 1 (16.7) 5 (83.3) 1 (11.1) . 4 (44.4) Vomiting 1 (16.7) 1 (16.7) 111.1) . 3 (33.3) Abdominal pain 1 (16.7) 1 (11.1) Asthenia / Fatigue 1 (16.7) 6 (100) 1 (11.1) . 6 (66.7) Decreased appetite 4 (66.7) . . 1 (11.1) Alopecia . . 1 (11.1) Phase II According to the protocol, if it is demonstrated an antitumor activity in any type of tumor during the escalation phase, cohorts of at least 15 patients will be opened in the expansion phase. Phase II has been started and included a cohort of NSCLC patients. In total 20 NSCLC patients were treated at the RD ( PM144.5 mg / m2+ Irinotecan 40 mg / m2D1 + prophylactic GCSF) in the expansion phase. The recruitment for the phase II is currently closed. Table 51: Patient Characteristics TOTAL (N: 20 pts) Gender Male 12 (60%) Age Median (range ) 60.5 (20-78) Tumor type NSCLC 20 (100%) BSA Median ( range ) 1.85 (1.43-2.14) ECOG –median (range) 0 5 (25%) 1 15 (75%) Sites of disease involvement Median ( range ) 2.5 (1-7) TOTAL (N: 20 pts) (most common) Lung 20 (100%) Lymph Node 14 (70) Pleura 9 (45) Adrenal 5 (25) Bone 4 (20) Liver 3 (15) Prior lines Median ( range ) 2.5 (1-6) Prior QT Lines Median ( range ) 2 (1-5) Time from metastatic diagnosis Median ( range ) 1.52 (0.58-13.81) to study entry (years) Target lesion (mm) Median ( range ) 74.5 (32-205) Best response to last line of PR 9 (45%) therapy SD 5 (25%) PD 2 (10%) NE / NA / UNK 4 (20.0%) CRP Abnormal 16 (80%) LDH Abnormal 8 (40%) Albumin g / dL Median ( range ) 4.1 (3.5-4.9) Efficacy Table 52: Best response all NSCLC patients and according to the histologic subtype All NCSLC NSCLC NSCLC patients Adenocarcinoma Squamous cell Best Response (n: 20) (n: 14) (n: 6) N % N (%) N (%) PR 1 5.0 1 (7.1) - SD 17 85.0 11 (78.6) 6 (100.0) PD 2 10.0 2 (14.3) - Safety The main treatment related adverse events and lab abnormalities regardless relationship per patient during the expansion Phase II are the following (Table 53): Table 53. Main treatment related adverse events and lab abnormalities regardless relationship (worst grade per patient). Expansion phase (N= 20) n (%) Gr 3 Gr 4 All Anemia 2 (10) . 18 (90) Neutropenia 3 (15) 6 (30) 10 (50) Febrile neutropenia 1 (5) . 1 (5) Thrombocytopenia 3 (15) . 11 (55) ALT increased 7 (35) 1 (5) 17 (85) AST increased 2 (10) . 12 (60) Bilirubin increased . . 6 (30) Creatinine increased 1 (5) . 5 (25) Constipation . . 2 (10) Diarrhoea 1 (5) . 15 (75) Nausea . . 11(55) Vomiting . . 3 (15) Abdominal pain 4 (20) Dyspepsia 3 (15) Dysgeusia 2 (10) Mucosal inflammation 2 (10) Asthenia / Fatigue 10 (50) . 19 (95) Decreased appetite 1 (5) . 10 (50) Arthralgia . . 2 (10) Musculoeskeletal pain . . 2 (10) Oedema . . 3 (15) Alopecia . . 1 (5) At the RD, PM14 and irinotecan + primary GCSF prophylaxis has a manageable safety profile. Hematological abnormalities, fatigue, transaminase increase and nausea were the main toxicities. This increase of the hepatic enzymes / bilirubin could be controlled by the further administration of steroids in combination with the RD. Major PK drug-drug interactions between PM14 and IRI did not become apparent. Example 4: In vitro antiproliferative activity of PM14 in combination with irinotecan and determination of the combination index (CI) The objective was to evaluate the antiproliferative activity of PM14 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 54). 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 54. 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 PM14 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. 4.1 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 55 and Table 56). 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 55. IC50 values (molar concentration) for each cell line treated with PM14, wherein “n” indicates the number of experimental replicates. Cell line n IC50 StdDev MOLT-4 7 4.90E-10 3.48E-10 RAMOS 3 2.56E-09 7.61E-10 Table 56. 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 4.2 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 PM14 / %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 57. Combinations PM14-irinotecan performed in vitro. Cell line Potency ratio (EC50) Concentration ratio [PM14]i [Irinotecan]i 40 / 60 1:3830 1.27E-08 4.88E-05 50 / 50 1:2550 1.27E-08 3.25E-05 MOLT-4 60 / 40 1:1700 1.27E-08 2.17E-05 75 / 25 1:850 1.27E-08 1-08E-05 40 / 60 1:3830 1.27E-08 4.88E-05 50 / 50 1:2550 1.27E-08 3.25E-05 RAMOS 60 / 40 1:1700 1.27E-08 2.17E-05 75 / 25 1:850 1.27E-08 1-08E-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. 4.2.1 Combination in MOLT-4 cells Summary Table 58 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:3830, 1:2550, 1:1700 and 1:850) in MOLT-4 cells. Moderate synergism is demonstrated at the high ED80. Table 58 4.2.2. Combination in RAMOS cells Summary Table 59 shows CI values at effective doses ED20, ED50 and ED80 and at different ratios (1:3830, 1:2550, 1:1700 and 1:850) in RAMOS cells. Synergism is demonstrated at the high ED80. Table 59 4.2.3. Results The results of the combination of PM14 with irinotecan in 2 different cell lines demonstrate 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 in showed (Tables 60 and 61). 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 60. Dose reduction index for the combination of PM14 with irinotecan in MOLT-4 cells. MOLT-4 Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI by Ratio (Fa) 1:3830 1:2550 1:1700 1:850 A B A B A B A B A B 0.20 2.81E-10 2.83E-07 4.43 1.16 3.96 1.56 3.41 2.02 2.05 2.43 0.50 5.33E-10 8.29E-07 3.45 1.40 3.03 1.85 2.43 2.23 1.36 2.49 0.80 9.98E-10 1.28E-06 4.02 1.34 3.68 1.85 2.14 1.61 1.61 2.43 Table 61. Dose reduction index for the combination of PM14 with irinotecan in RAMOS cells. RAMOS Fraction Drug alone Drug in Combination (A= PM14 / B= irinotecan) Affected DRI by Ratio (Fa) 1:3830 1:2550 1:1700 1:850 A B A B A B A B A B 0.20 2.12E-09 7.66E-07 13.63 1.28 9.08 1.29 8.22 1.74 2.81 1.20 0.50 2.95E-09 5.25E-06 3.15 1.46 3.07 2.14 2.96 3.10 2.40 5.02 0.80 4.10E-09 1.47E-05 2.74 2.57 2.67 3.77 2.59 5.49 2.12 8.97 In summary, the data in the present invention demonstrates the synergistic combination of PM14 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. Finally, the combination has shown clinical efficacy. The combinations of the present invention are useful in the treatment of cancer.

[0003] References - 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 -WO2022 / 243482 -NCT05076396 -C. Cuevas et al., Ecubectedin is a novel transcriptional inhibitor that displays potent antitumor effects in vitro and in vivo, Cancer Res (2023) 83 (7, Supplement): 1622. -E. Garralda et al., First-in-human study of PM14 in patients with advanced solid tumors, J. Clin. Onc., Vol.39, Numb.15, suppl. -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. -EudraCt number 2021-000415-23. - 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

[0004] CLAUSES 1. PM14, which is a compound of formula I: I, for use in the treatment of cancer, wherein in said treatment PM14 is administered in combination with topoisomerase I inhibitor to a patient in need thereof. 2. PM14 for use according to clause 1, wherein the cancer is a solid tumor. 3. PM14 for use according to clause 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, colorectal cancer, colon cancer, rectal cancer, gastric cancer, melanoma, biliary cancer, and pancreatic cancer. 4. PM14 for use according to clause 3, wherein the solid tumor is non-small cell lung cancer. 5. PM14 for use according to clause 3, wherein the solid tumor is gastric cancer. 6. PM14 for use according to clause 1, wherein the cancer is a hematological tumor. 7. PM14 for use according to clause 6, wherein the hematological tumor is selected from acute lymphoblastic leukemia and Burkitt’s lymphoma. 8. PM14 for use according to clause 7, wherein the hematological tumor is Burkitt’s lymphoma. 9. PM14 for use according to any of previous clauses, wherein in said treatment PM14 and the topoisomerase I inhibitor are administered concurrently, separately or sequentially. 10. PM14 for use according to clause 9, wherein the topoisomerase I inhibitor is administered initially, followed by PM14. 11. PM14 for use according to any previous clauses, wherein the administration cycle in combination with the topoisomerase I inhibitor is once every three to four weeks, preferably once every 21 days. 12. PM14 for use according to any of any previous clauses, wherein in said treatment PM14 is administered in combination with the topoisomerase I inhibitor on day 1 of a cycle. 13. PM14 for use according to any of clauses 1 to 11, wherein in said treatment PM14 is administered in combination with the topoisomerase I inhibitor on day 1 and day 8 of a cycle. 14. PM14 for use according to any of previous clauses, wherein PM14 is administered at least 2 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes. 15. PM14 for use according to clause 1 to 14, wherein PM14 is administered as 3 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes. 16. PM14 for use according to clauses 1 to 14, wherein PM14 is administered over 3 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes. 17. PM14 for use according to any clause of previous clauses, wherein the topoisomerase I inhibitor is administered at least 1 hour intravenous infusion during each administration cycle allowing -5 minutes to +30 minutes. 18. PM14 for use according to clauses 1 to 16, wherein topoisomerase I inhibitor is administered as 90 minutes intravenous infusion during each administration cycle allowing -5 minutes to +30 minutes. 19. PM14 for use according to any of previous clauses, wherein said treatment further comprises administration of a prophylactic compound before the administration of PM14 in combination with topoisomerase I inhibitor. 20. PM14 for use according to clause 19, wherein said prophylactic compound is selected from corticosteroid and 5-HT3 receptor antagonist. 21. PM14 for use according to any of previous clauses, wherein the administration of the prophylactic compound is followed by administration of a dopamine antagonist compound. 22. PM14 for use according to any previous clauses, wherein said treatment further comprises administration of granulocyte-colony stimulating factor (G-CSF). 23. PM14 for use according to any previous clauses, wherein the topoisomerase I inhibitor is selected from topotecan, SN-38, irinotecan, camptothecin, and rubitecan. 24. PM14 for use according to clause 23, wherein the topoisomerase I inhibitor is irinotecan, 25. PM14 for use in according to clause 24, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein irinotecan is administered as at least 1 hour intravenous infusion followed by PM14 which is administered as at least 2 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1. 26. PM14 for use according to clause 24, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein irinotecan is administered as 90 minutes intravenous infusion followed by PM14 which is administered as 3 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1. 27. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose from 3 to 5 mg / m2. 28. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose from 4.5 to 5 mg / m2. 29. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 3 mg / m2. 30. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 3.5 mg / m2. 31. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 4 mg / m2. 32. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 4.5 mg / m2. 33. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 5 mg / m2. 34. PM14 for use according to previous clauses 24 to 33, wherein irinotecan is administered at a dose of 30 to 50 mg / m2. 35. PM14 for use according to previous clauses 24 to 33, wherein irinotecan is administered at a dose of 40 to 50 mg / m2. 36. PM14 for use according to previous clauses 24 to 33, wherein irinotecan is administered at a dose of 30 mg / m2. 37. PM14 for use according to previous clauses 24 to 33, wherein irinotecan is administered at a dose of 35 mg / m2. 38. PM14 for use according to previous clauses 24 to 33, wherein irinotecan is administered at a dose of 40 mg / m2. 39. PM14 for use according to previous clauses 24 to 33, wherein irinotecan is administered at a dose of 45 mg / m2. 40. PM14 for use according to previous clauses 24 to 33, wherein irinotecan is administered at a dose of 50 mg / m2. 41. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 3.5 mg / m2and irinotecan is administered at a dose of 30 mg / m2. 42. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 3.5 mg / m2and wherein irinotecan is administered at a dose of 35 mg / m2. 43. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 3.5 mg / m2and wherein irinotecan is administered at a dose of 40 mg / m2. 44. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 3.5 mg / m2and wherein irinotecan is administered at a dose of 45 mg / m2. 45. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 3.5 mg / m2and wherein irinotecan is administered at a dose of 50 mg / m2. 46. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4 mg / m2and irinotecan is administered at a dose of 30 mg / m2. 47. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4 mg / m2and wherein irinotecan is administered at a dose of 35 mg / m2. 48. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4 mg / m2and wherein irinotecan is administered at a dose of 40 mg / m2. 49. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4 mg / m2and wherein irinotecan is administered at a dose of 45 mg / m2. 50. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4 mg / m2and wherein irinotecan is administered at a dose of 50 mg / m2. 51. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4.5 mg / m2and irinotecan is administered at a dose of 30 mg / m2. 52. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4.5 mg / m2and wherein irinotecan is administered at a dose of 35 mg / m2. 53. PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4.5 mg / m2and wherein irinotecan is administered at a dose of 40 mg / m2. 54. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4.5 mg / m2and wherein irinotecan is administered at a dose of 45 mg / m2. 55. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4.5 mg / m2and wherein irinotecan is administered at a dose of 50 mg / m2. 56. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 5 mg / m2and irinotecan is administered at a dose of 30 mg / m2. 57. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 5 mg / m2and wherein irinotecan is administered at a dose of 35 mg / m2. 58. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 5 mg / m2and wherein irinotecan is administered at a dose of 40 mg / m2. 59. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 5 mg / m2and wherein irinotecan is administered at a dose of 45 mg / m2. 60. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 5 mg / m2and wherein irinotecan is administered at a dose of 50 mg / m2. 61. PM14 for use according to clauses 24 to 33, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein PM14 is administered at a dose from 3 to 5 mg / m2and irinotecan is administered at a dose from 30 to 50 mg / m2. 62. PM14 for use according to clause 61, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein PM14 is administered at a dose from 4.5 to 5 mg / m2and irinotecan is administered at a dose from 40 to 50 mg / m2. 63. PM14 for use according to clause 61, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein PM14 is administered at a dose of 3 mg / m2and irinotecan is administered at a dose of 40 mg / m2. 64. PM14 for use according to clause 61, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein PM14 is administered at a dose of 4.5 mg / m2and irinotecan is administered at a dose of 40 mg / m2. 65. PM14 for use according to clause 61, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein PM14 is administered at a dose of 3 mg / m2and irinotecan is administered at a dose of 50 mg / m2. 66. PM14 for use according to clause 61, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein PM14 is administered at a dose of 4.5 mg / m2and irinotecan is administered at a dose of 50 mg / m2. 67. PM14 for use according to clause 64, wherein the cancer is non-small cell lung cancer and wherein in said treatment a prophylactic compound is administered before the administration of the combination of PM14 and irinotecan, and wherein irinotecan is administered at a dose of 40 mg / m2as 90 minutes intravenous infusion followed by PM14 which is administered at a dose of 4.5 mg / m2as 3 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1 and a primary prophylaxis with G-CSF is administered starting 24 to 72 hours after the Day 1 of cycle 1. 68 A pharmaceutical package comprising PM14 together with instructions for its use in combination with topoisomerase I inhibitor according to any one of clauses 1 to 67. 69. A method of prolonging survival of a patient having cancer, the method comprising administering a combination therapy of PM14 and topoisomerase I inhibitor to a patient in need thereof, thereby delaying disease progression of cancer. 70. A method of reducing or delaying growth of cancer, the method comprising administering a combination therapy of PM14 and topoisomerase I inhibitor to a patient in need thereof, thereby reducing or delaying growth of cancer. 71. A method of delaying disease progression of a cancer in a patient, the method comprising administering a combination therapy of PM14 and topoisomerase I inhibitor to a patient in need thereof, thereby delaying disease progression of cancer. 72. PM14 for use in the treatment of hematological tumors. 73. PM14 for use in the treatment of acute lymphoblastic leukemia. 74. PM14 for use in the treatment of Burkitt’s lymphoma. 75. PM14 for use according to any one of clauses 1 to 67 and 72 to 74 wherein PM14 is in the form of a pharmaceutically acceptable salt or ester. 76. The pharmaceutical package according to clause 68, wherein PM14 is in the form of a pharmaceutically acceptable salt or ester. 77. The method according to any one of clauses 69 to 71, wherein PM14 is in the form of a pharmaceutically acceptable salt or ester.

Claims

CLAIMS 1. PM14, which is a compound of formula I:I for use in the treatment of cancer, wherein in said treatment PM14 is administered in combination with topoisomerase I inhibitor to a patient in need thereof.

2. PM14 for use according to claim 1, wherein the cancer is a solid tumor.

3. PM14 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, gastric cancer, colorectal cancer, colon cancer, rectal cancer, melanoma, biliary cancer, and pancreatic cancer.

4. PM14 for use according to claim 3, wherein the solid tumor is non-small cell lung cancer.

5. PM14 for use according to claim 3, wherein the solid tumor is gastric cancer.

6. PM14 for use according to claim 1, wherein the cancer is a hematological tumor.

7. PM14 for use according to claim 6, wherein the hematological tumor is selected from acute lymphoblastic leukemia and Burkitt’s lymphoma.

8. PM14 for use according to any of previous claims, wherein in said treatment PM14 and the topoisomerase I inhibitor are administered concurrently, separately or sequentially.

9. PM14 for use according to claim 8, wherein the topoisomerase I inhibitor is administered initially, followed by PM14.

10. PM14 for use according to any previous claims, wherein the administration cycle in combination with the topoisomerase I inhibitor is once every three to four weeks, preferably once every 21 days.

11. PM14 for use according to any of any previous claims, wherein in said treatment PM14 is administered in combination with the topoisomerase I inhibitor on day 1 of a cycle.

12. PM14 for use according to any of claims 1 to 10, wherein in said treatment PM14 is administered in combination with the topoisomerase I inhibitor on day 1 and day 8 of a cycle.

13. PM14 for use according to any of any previous claims, wherein the topoisomerase I inhibitor is selected from topotecan, SN-38, irinotecan, camptothecin, and rubitecan, preferably irinotecan.

14. PM14 for use according to any previous claims, wherein PM14 is administered at a dose from 3 to 5 mg / m2.

15. PM14 for use according to any previous claims, wherein the topoisomerase I inhibitor is irinotecan and wherein irinotecan is administered at a dose of 30 to 50 mg / m2.

16. PM14 for use according to claim 15, wherein in said treatment PM14 is administered in combination with irinotecan to a patient in need thereof, wherein PM14 is administered at a dose of 3 mg / m2and irinotecan is administered at a dose of 40 mg / m2, or wherein PM14 is administered at a dose of 4.5 mg / m2and irinotecan is administered at a dose of 40 mg / m2, or wherein PM14 is administered at a dose of 3 mg / m2and irinotecan is administered at a dose of 50 mg / m2, or wherein PM14 is administered at a dose of 4.5 mg / m2and irinotecan is administered at a dose of 50 mg / m2.

17. PM14 for use according to claim 14, wherein the cancer is non-small cell lung cancer and wherein in said treatment a prophylactic compound is administered before the administration of the combination of PM14 and irinotecan, and wherein irinotecan is administered at a dose of 40 mg / m2as 90 minutes intravenous infusion followed by PM14 which is administered at a dose of 4.5 mg / m2as 3 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1 and a primary prophylaxis with G-CSF is administered starting 24 to 72 hours after the Day 1 of cycle 1.

18. PM14 for use according to any one of claims 1 to 17, wherein PM14 is in the form of a pharmaceutically acceptable salt or ester.

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