WO2025228596A1 - Combinaison de pm14 et d'un inhibiteur de topoisomérase i dans le traitement du cancer - Google Patents

Combinaison de pm14 et d'un inhibiteur de topoisomérase i dans le traitement du cancer

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Publication number
WO2025228596A1
WO2025228596A1 PCT/EP2025/058536 EP2025058536W WO2025228596A1 WO 2025228596 A1 WO2025228596 A1 WO 2025228596A1 EP 2025058536 W EP2025058536 W EP 2025058536W WO 2025228596 A1 WO2025228596 A1 WO 2025228596A1
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Prior art keywords
irinotecan
administered
cancer
dose
combination
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English (en)
Inventor
Gema Santamaría Núñez
Marta MARTÍNEZ DÍEZ
María José GUILLÉN NAVARRO
Pablo Manuel AVILÉS MARÍN
Cristian FERNÁNDEZ
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Pharmamar SA
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Pharmamar SA
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Publication of WO2025228596A1 publication Critical patent/WO2025228596A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • 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.
  • 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®
  • 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.
  • SCLC small cell lung cancer
  • ecubectedin 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.
  • 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.
  • 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.
  • the present invention provides a pharmaceutical package comprising PM14 together with instructions for its use in combination with topoisomerase I inhibitor.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PM14 for use in the treatment of hematological tumors.
  • 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.
  • the present invention provides the use of PM14 in the manufacture of a medicament for the treatment of hematological tumors.
  • the cancer is a solid tumor.
  • 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.
  • 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.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • liposarcoma leiomyosarcoma
  • 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.
  • 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 ratio
  • 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.
  • 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.
  • PM14 and the topoisomerase I inhibitor are administered concurrently, separately or sequentially.
  • the topoisomerase I inhibitor is administered initially, followed by PM14.
  • the administration cycle in combination with topoisomerase I inhibitor is once every three to four weeks, preferably once every 21 days.
  • PM14 is administered in combination with topoisomerase I inhibitor on day 1 of a cycle.
  • PM14 is administered at least 2 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes.
  • PM14 is administered as 3 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes.
  • PM14 is administered over 3 hours intravenous infusion during each administration cycle allowing -15 minutes to +30 minutes.
  • 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.
  • 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.
  • 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.
  • 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.
  • the administration of the prophylactic compound is followed by administration of a dopamine antagonist compound.
  • the treatment further comprises administration of granulocyte-colony stimulating factor (G-CSF).
  • G-CSF granulocyte-colony stimulating factor
  • topoisomerase I inhibitor is selected from topotecan, SN-38, irinotecan, camptothecin, and rubitecan.
  • the topoisomerase I inhibitor is irinotecan.
  • PM14 is administered at a dose from 3 to 5 mg/m 2 and irinotecan is administered at a dose from 30 to 50 mg/m 2 .
  • PM14 is administered at a dose from 4.5 to 5 mg/m 2 and irinotecan is administered at a dose from 40 to 50 mg/m 2 .
  • PM14 is administered at a dose of 3 mg/m 2 and irinotecan is administered at a dose of 40 mg/m 2 .
  • PM14 is administered at a dose of 3 mg/m 2 and irinotecan is administered at a dose of 50 mg/m 2 .
  • PM14 is administered at a dose of 4.5 mg/m 2 and irinotecan is administered at a dose of 50 mg/m 2 .
  • PM14 is administered at a dose of 4.5 mg/m 2 and irinotecan is administered at a dose of 40 mg/m 2 .
  • 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/m 2 as 90 minutes intravenous infusion followed by PM14 which is administered at a dose of 4.5 mg/m 2 as 3 hours intravenous infusion with an interval between both administrations of 10 minutes on Day 1 during the cycle 1 and a primary profile.
  • PM14 is in the form of a pharmaceutically acceptable salt or ester.
  • 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 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.
  • 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.
  • 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: .
  • PM14 is in the form of a pharmaceutically acceptable salt or ester.
  • pharmaceutically acceptable salt and “ester” refers to any pharmaceutically acceptable salt or ester which, upon administration to the patient is capable of providing (directly or indirectly) a compound as described herein.
  • non- pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts can be carried out by methods known in the art. 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.
  • such salts are, for example, prepared by reacting the free acid or base of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.
  • nonaqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.
  • alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine and basic amino acids salts.
  • the compounds of the invention may be in crystalline or amorphous form either as free compounds or as solvates (e.g. hydrates) and it is intended that all forms are within the scope of the present invention. Methods of solvation are generally known within the art.
  • compounds referred to herein may exist in isotopically-labelled forms.
  • 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.
  • 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).
  • 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.
  • 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.
  • PNET Primitive neuroectodermal tumor
  • Basitive neuroectodermal tumor PNET
  • 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.
  • chordomas 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.
  • ECM Extraskeletal myxoid chondrosarcoma
  • 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).
  • carcinoma cancer of epithelial tissue, which is skin and tissue that lines or covers the internal organs
  • 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 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.
  • endometrial cancers are adenocarcinomas (cancers that begin in cells that make and release mucus and other fluids).
  • 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.
  • 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.
  • squamous cells are flat, thin cells
  • 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.
  • PPC Primary peritoneal carcinoma
  • EOPPC extra-ovarian primary peritoneal carcinoma
  • SPC serous surface papillary carcinoma
  • 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.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • 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.
  • pancreatic neuroendocrine tumors is less common but have a better prognosis (discussed separately below).
  • 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.
  • 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 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.
  • 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.
  • 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.
  • extended oral corticosteroids for example dexamethasone not exceeding 20 mg/days
  • 5-HT3 receptor antagonists for example oral (or i.v.) ondansetron 4-8 mg (or equivalent)
  • the patient may also be administered granulocyte-colony stimulating factor G-CSF.
  • G-CSF granulocyte-colony stimulating factor
  • 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).
  • 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.
  • infusion 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.
  • 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).
  • cells were harvested and seeded in 96 well microtiter plates at the appropriate cell density (4000-12000 cells) in 150 ⁇ L of media and incubated for 24 hours in drug-free medium before treatment with vehicle alone or test compounds for 72 h.
  • 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.
  • %IC50 PM14 / %IC50 Irinotecan 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 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
  • ED70 represents the effective dose required to achieve 70% cell death
  • 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.
  • 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.
  • CI 1 indicates an additive effect
  • CI ⁇ 1 indicates a synergistic effect
  • CI > 1 indicates antagonism.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • Dose Reduction Index 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.
  • H460 (NSCLC) tumors The antitumor activity of the combination PM14 and irinotecan was evaluated in mice implanted with H460 (NSCLC) tumors.
  • N H460
  • 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).
  • MTD for PM14 is 1.2mg/kg and for irinotecan is 50 mg/kg, Animals were euthanized when their tumors reached ca.2000 mm 3 and/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 3 ⁇ 4 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.
  • 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.
  • 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).
  • Table 35 shows ⁇ H2AX, (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.
  • 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).
  • 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 mm 3 and/or severe necrosis was seen.
  • 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).
  • 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 mm 3 and/or severe necrosis was seen.
  • Example 3 Clinical trial Prospective, open-label, uncontrolled phase I/II study with PM14 in combination with irinotecan in patients with selected solid tumors.
  • 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.
  • PGt pharmacogenetics
  • ⁇ 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.
  • 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.
  • 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.
  • neutropenia i.e., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis
  • 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.
  • FFPE formalin-fixed paraffin-embedded
  • 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%).
  • Lung non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
  • Sarcoma liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing’s sarcoma.
  • Gynecological epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas), endometrial carcinoma and carcinoma of cervix.
  • Breast ductal or lobular carcinoma.
  • Genitourinary tract tumors urothelial bladder carcinoma, clear cell renal carcinoma and prostate adenocarcinoma.
  • Other malignant pleural mesothelioma, extrapulmonary small cell carcinoma, and adrenocortical carcinoma.
  • 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).
  • Adequate bone marrow, renal, hepatic, and metabolic function (assessed ⁇ 7 days before registration): a) Platelet count ⁇ 100 x 10 9 /L, hemoglobin ⁇ 9.0 g/dL and absolute neutrophil count (ANC) ⁇ 2.0 x 10 9 /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).
  • 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.
  • HIV human immunodeficiency virus
  • HCV hepatitis C virus
  • hepatitis B this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR).
  • hepatitis C this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR.
  • HBsAg Hepatitis B surface antigen
  • PCR quantitative Hepatitis B polymerase chain reaction
  • hepatitis C this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR.
  • h Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days.
  • 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.
  • CT contrast enhanced- computed tomography
  • MRI magnetic resonance imaging
  • 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.
  • ⁇ 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).
  • irinotecan will be administered by i.v.
  • Dose level Irinotecan dose (Day1) mg/m 2 PM14 dose (Day 1, after irinotecan) mg/m 2 DL –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 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.
  • 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.
  • neutropenia i.e., febrile neutropenia, grade 4 neutropenia lasting > 3 days or neutropenic sepsis
  • 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.
  • 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.
  • 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.
  • Ki values were 0.58 and 2.21 ⁇ M for CYP3A4-mediated midazolam 1’-hydroxylation (CYP3A4m) and testosterone 6 ⁇ -hydroxylation reactions (CYP3A4t), respectively.
  • 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 ⁇ M, 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 ⁇ g/L and 156.5 ⁇ g/L, respectively (ca.0.16 ⁇ M and 0.21 ⁇ M, or ca.0.0096 ⁇ M and 0.012 ⁇ M when expressed as unbound concentration, assuming a fu of 0.06).
  • 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.
  • 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.
  • 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 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.
  • 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.
  • irinotecan could even be permanently discontinued and treatment may continue with PM14 alone at its single- agent RD of 4.5 mg/m 2 q3wk (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/m 2 and then to 3.0 mg/m 2 ). On the contrary, patients cannot discontinue PM14 alone and continue treatment with single-agent irinotecan as part of this trial. 12.
  • 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.
  • 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.
  • NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • 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.
  • 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.
  • ⁇ 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).
  • 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.
  • 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).
  • time-to-event parameters i.e., DoR, PFS, and overall survival [OS]
  • Tumor types represented in both the dose escalation stage and in tumor-specific expansion cohort(s) (expansion stage) will be grouped if appropriate.
  • PK parameters will be tabulated and selected parameters will be graphically displayed per dose level/escalation group.
  • Cmax maximum plasma concentration
  • AUC area under the curve
  • PK parameters 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.
  • 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.
  • categorical clinical outcomes e.g., objective response rate according to RECIST v.1.1
  • 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).
  • Treatment 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.
  • EOT End of treatment
  • 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.
  • 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/m 2 + Irinotecan 40 mg/m 2 D1 + 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.
  • 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).
  • ATCC American Type Culture Collection
  • 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.
  • 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.
  • 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.
  • 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 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
  • ED80 represents the effective dose required to achieve 80% cell death.
  • 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.
  • CI 1 indicates an additive effect
  • CI ⁇ 1 indicates a synergistic effect
  • CI > 1 indicates antagonism.
  • 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.
  • CI values for ED20, ED50 or ED80 representing the compound concentrations that resulted in 20%, 50% and 80% cell death, respectively, were calculated.
  • the Dose Reduction Index 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.
  • 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.
  • PM14 for use according to clause 1, wherein the cancer is a solid tumor.
  • 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.
  • NSCLC non-small cell lung cancer
  • LCLC large cell lung cancer
  • SCLC small cell lung cancer
  • Ewing’s sarcoma fibrosarcoma
  • gynaecological cancer cervical cancer
  • ovarian cancer breast cancer
  • breast cancer bladder cancer
  • renal cancer malignant pleural mesothelioma
  • 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).
  • G-CSF granulocyte-colony stimulating factor
  • the topoisomerase I inhibitor is selected from topotecan, SN-38, irinotecan, camptothecin, and rubitecan.
  • 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 any previous clauses wherein PM14 is administered at a dose from 3 to 5 mg/m 2 . 28. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose from 4.5 to 5 mg/m 2 . 29. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 3 mg/m 2 . 30. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 3.5 mg/m 2 . 31. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 4 mg/m 2 . 32. PM14 for use according to any previous clauses, wherein PM14 is administered at a dose of 4.5 mg/m 2 .
  • PM14 for use according to any previous clauses wherein PM14 is administered at a dose of 5 mg/m 2 . 34.
  • irinotecan is administered at a dose of 30 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 3.5 mg/m 2 and wherein irinotecan is administered at a dose of 35 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 3.5 mg/m 2 and wherein irinotecan is administered at a dose of 40 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 3.5 mg/m 2 and wherein irinotecan is administered at a dose of 45 mg/m 2 . 45.
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 3.5 mg/m 2 and wherein irinotecan is administered at a dose of 50 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4 mg/m 2 and irinotecan is administered at a dose of 30 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4 mg/m 2 and wherein irinotecan is administered at a dose of 35 mg/m 2 . 48.
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4 mg/m 2 and wherein irinotecan is administered at a dose of 40 mg/m 2 . 49. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4 mg/m 2 and wherein irinotecan is administered at a dose of 45 mg/m 2 . 50. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4 mg/m 2 and wherein irinotecan is administered at a dose of 50 mg/m 2 . 51.
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4.5 mg/m 2 and irinotecan is administered at a dose of 30 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4.5 mg/m 2 and wherein irinotecan is administered at a dose of 35 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4.5 mg/m 2 and wherein irinotecan is administered at a dose of 40 mg/m 2 . 54.
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 4.5 mg/m 2 and wherein irinotecan is administered at a dose of 45 mg/m 2 . 55. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 4.5 mg/m 2 and wherein irinotecan is administered at a dose of 50 mg/m 2 . 56. PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 5 mg/m 2 and irinotecan is administered at a dose of 30 mg/m 2 . 57.
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 5 mg/m 2 and wherein irinotecan is administered at a dose of 35 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 5 mg/m 2 and wherein irinotecan is administered at a dose of 40 mg/m 2 .
  • PM14 for use according to previous clauses 24 to 33 wherein PM14 is administered at a dose of 5 mg/m 2 and wherein irinotecan is administered at a dose of 45 mg/m 2 . 60.
  • PM14 for use according to previous clauses 24 to 33, wherein PM14 is administered at a dose of 5 mg/m 2 and wherein irinotecan is administered at a dose of 50 mg/m 2 . 61.
  • 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/m 2 and irinotecan is administered at a dose from 40 to 50 mg/m 2 .
  • 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/m 2 and irinotecan is administered at a dose of 40 mg/m 2 . 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/m 2 and irinotecan is administered at a dose of 40 mg/m 2 . 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/m 2 and irinotecan is administered at a dose of 50 mg/m 2 . 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/m 2 and irinotecan is administered at a dose of 50 mg/m 2 . 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/m 2 as 90 minutes intravenous infusion followed by PM14 which is administered at a dose of 4.5 mg/m 2 as 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.
  • 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 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.

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Abstract

La présente invention concerne le traitement thérapeutique du cancer, en particulier des tumeurs solides et hématologiques, avec une polythérapie utilisant le PM14 et un inhibiteur de la topoisomérase I.
PCT/EP2025/058536 2024-04-30 2025-03-27 Combinaison de pm14 et d'un inhibiteur de topoisomérase i dans le traitement du cancer Pending WO2025228596A1 (fr)

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Citations (4)

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