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WO2025188680A1 - Utilisation d'un inhibiteur de plk1 en combinaison de gemcitabine ou de carboplatine dans le traitement du carcinome ovarien - Google Patents

Utilisation d'un inhibiteur de plk1 en combinaison de gemcitabine ou de carboplatine dans le traitement du carcinome ovarien

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Publication number
WO2025188680A1
WO2025188680A1 PCT/US2025/018236 US2025018236W WO2025188680A1 WO 2025188680 A1 WO2025188680 A1 WO 2025188680A1 US 2025018236 W US2025018236 W US 2025018236W WO 2025188680 A1 WO2025188680 A1 WO 2025188680A1
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WO
WIPO (PCT)
Prior art keywords
dna
days
subject
damaging agent
treatment
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Pending
Application number
PCT/US2025/018236
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English (en)
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WO2025188680A8 (fr
Inventor
Maya RIDINGER
Tod Smeal
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Cardiff Oncology Inc
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Cardiff Oncology Inc
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Publication of WO2025188680A1 publication Critical patent/WO2025188680A1/fr
Publication of WO2025188680A8 publication Critical patent/WO2025188680A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Definitions

  • the present disclosure relates generally to the field of treating cancer, more specifically, treatment of ovarian cancer.
  • HGOC high grade ovarian carcinoma
  • the method can comprise: administering a PLK1 inhibitor and a DNA-damaging agent to a subject with the ovarian cancer, thereby inhibiting or reducing progression of the ovarian cancer in the subject.
  • the ovarian cancer can be, e.g., high-grade serous ovarian carcinoma (HGSOC), endometrioid carcinoma, low-grade serous ovarian carcinoma (LGSOC), mucinous carcinoma, ovarian clear cell carcinoma (OCCC), or primary squamous cell carcinoma (SCC) of the ovary.
  • the DNA-damaging agent is an alkylating agent, an antimetabolite, a topoisomerase inhibitor, or an antitumor antibiotic. In some embodiments, the DNA-damaging agent is a platinum-based DNA-damaging agent.
  • the DNA-damaging agent is altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechlorethamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5- fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin, pralatrexate, thioguanine, trifluridine/tipiracil combination, etoposide, irinotecan,
  • the DNA-damaging agent is gemcitabine or carboplatin.
  • the method can comprise administering the PLK1 inhibitor, gemcitabine and carboplatin to the subject.
  • the PLK1 inhibitor is onvansertib.
  • the subject with the ovarian cancer is resistant to or does not respond effectively to a platinum-based chemotherapeutic agent.
  • the DNA-damaging agent is a platinum-based DNA-damaging agent.
  • the platinum-based DNA-damaging agent and the platinum-based chemotherapeutic agent are the same or different.
  • the subject with the ovarian cancer developed stable disease or progressive disease when treated with the platinum-based chemotherapeutic agent, or developed resistance to the platinum-based chemotherapeutic agent.
  • the subject with the ovarian cancer is resistant to at least one platinum-based chemotherapeutic agent.
  • the at least one platinum-based chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • the resistance is acquired resistance or intrinsic resistance.
  • the subject with the ovarian cancer has received a prior PLK1 inhibitor treatment or a prior DNA-damaging agent treatment. In some embodiments, the subject with the ovarian cancer did not respond to the treatment with the prior PLK1 inhibitor or the prior DNA-damaging agent. In some embodiments, the subject with the ovarian cancer has stable or progressive disease following the treatment with the prior PLK1 inhibitor or the prior DNA-damaging agent. In some embodiments, the subject with the ovarian cancer is known to be resistant to the PLK1 inhibitor or the DNA-damaging agent alone.
  • the PLK1 inhibitor and the DNA-damaging agent are co-administered simultaneously.
  • the PLK1 inhibitor and the DNA- damaging agent are administered sequentially.
  • the PLK1 inhibitor, the DNA-damaging agent, or both are administered to the subject in a cycle of 7 days, 14 days, 28 days, 35 days, 42 days, or 49 days.
  • the DNA-damaging agent is administered to the subject about once a week and the PLK1 inhibitor is administered to the subject about 5 days a week.
  • each cycle of treatment is at least about 14 days. In some embodiments, each cycle of treatment is from about 14 days to about 28 days.
  • the PLK1 inhibitor is administered on at least five days, at least ten days, or at least fifteen days in a cycle. In some embodiments, the PLK1 inhibitor is not administered on at least one day, at least three days, or at least seven days in a cycle. In some embodiments, the PLK1 inhibitor is administered daily. In some embodiments, the DNA-damaging agent is administered once or twice weekly. In some embodiments, the DNA-damaging agent is administered once weekly for two, three, four, five, six or seven consecutive weeks in a cycle. In some embodiments, the DNA-damaging agent is administered once every two, three, or four weeks in a cycle. In some embodiments, the subject undergoes at least two cycles of the administration of the PLK1 inhibitor and the DNA-damaging agent.
  • the PLK1 inhibitor is onvansertib (NMS-P937), BI2536, volasertib (BI 6727), GSK461364, adavosertib (AZD1775), CYC140, HMN-176, HMN- 214, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960, GTPL10072, Ro3280; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; or any combination thereof.
  • the PLK1 inhibitor is onvansertib.
  • the subject has received at least one prior cancer treatment.
  • the at least one prior cancer treatment does not comprise the use of a DNA-damaging agent, a PLK1 inhibitor, or both.
  • the PLK1 inhibitor is onvansertib.
  • the subject was in remission for cancer.
  • the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
  • the method can comprise determining cancer status of the subject.
  • the method can comprise determining responsiveness of the subject to the treatment with the PLK1 inhibitor and/or the DNA-damaging agent.
  • the method can comprise administering one or more additional cancer therapeutics or therapies for the cancer.
  • the subject is a human.
  • the subject achieves a complete response.
  • body weight of the subject decreases by no more than 20%, following at least one cycle of treatment.
  • weight of one or more tumors of the subject decreases by at least 25%, following at least one cycle of treatment.
  • volume of one or more tumors of the subject decreases by at least 25%, following at least one cycle of treatment.
  • caspase levels are increased in a plurality of cancer cells of the subject, following at least one cycle of treatment.
  • kits can comprise: a PLK1 inhibitor; a DNA- damaging agent; and a manual providing instructions for co-administering the PLK1 inhibitor and the DNA-damaging agent to a subject in need thereof for treating ovarian cancer.
  • the ovarian cancer is high-grade serous ovarian carcinoma (HGSOC), endometrioid carcinoma, low-grade serous ovarian carcinoma (LGSOC), mucinous carcinoma, ovarian clear cell carcinoma (OCCC), or primary squamous cell carcinoma (SCC) of the ovary.
  • HGSOC high-grade serous ovarian carcinoma
  • LGSOC low-grade serous ovarian carcinoma
  • OCCC ovarian clear cell carcinoma
  • SCC primary squamous cell carcinoma
  • the DNA-damaging agent is an alkylating agent, an antimetabolite, a topoisomerase inhibitor, or an antitumor antibiotic.
  • the DNA-damaging agent is altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechlorethamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5- fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexe
  • the PLK1 inhibitor can be, e.g., onvansertib (NMS-P937), BI2536, volasertib (BI 6727), GSK461364, adavosertib (AZDI 775), CYC 140, HMN-176, HMN-214, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960, GTPL10072, Ro3280; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; or any combination thereof.
  • the DNA-damaging agent is gemcitabine or carboplatin and/or the PLK1 inhibitor is onvansertib.
  • the instructions comprise instructions for coadministrating the PLK1 inhibitor and the DNA-damaging agent simultaneously. In some embodiments, the instructions comprise instructions for administrating the PLK1 inhibitor and the DNA-damaging agent sequentially. In some embodiments, the instructions comprise instructions for administering to a subject that did not respond to treatment with the PLK1 inhibitor or the DNA-damaging agent alone.
  • the instructions comprise instructions for administering to a subject resistant to at least one platinum-based chemotherapeutic agent.
  • the at least one platinum-based chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • the DNA-damaging agent is a platinum-based DNA-damaging agent.
  • the platinum-based DNA-damaging agent and the platinum-based chemotherapeutic agent are the same or different.
  • FIG. 1A-FIG. IB display non-limiting exemplary data related to the in vitro combination of onvansertib and carboplatin and combination of onvansertib and gemcitabine in Ovcar 8 cells.
  • FIG. 1A depicts cellular viability of carboplatin and onvansertib at different concentrations (upper panel) and synergy between onvansertib and carboplatin (lower panel).
  • FIG. IB depicts cellular viability of gemcitabine and onvansertib at different concentrations (upper panel) and synergy between onvansertib and gemcitabine (lower panel).
  • FIG. 2A-FIG. 2D display non-limiting exemplary data of antitumor activity of single agents and combinations in #266R and #315 HGSOC PDXs.
  • FIG. 2A depicts mice body weight (upper panel) and Kaplan Meier survival curves (lower panel) of MNHOC#226R-bearing mice treated with onvansertib, carboplatin and their combination. Log-rank Mantel-Cox test was used for statistics.
  • FIG. 2B depicts mice body weight (upper panel) and Kaplan Meier survival curves (lower panel) of MNHOC#226R-bearing mice treated with onvansertib, gemcitabine and their combination.
  • FIG. 1A depicts mice body weight (upper panel) and Kaplan Meier survival curves (lower panel) of MNHOC#226R-bearing mice treated with onvansertib, gemcitabine and their combination.
  • FIG. 2C depicts tumor growth curves (upper panel) and tumor volumes at the end of the treatment (lower panel) in MNHOC#315-bearing mice treated with onvansertib, carboplatin and their combination.
  • FIG. 2D depicts tumor growth curves (upper panel) and tumor volumes at the end of the treatment (lower panel) in MNHOC#315 -bearing mice treated with onvansertib, gemcitabine and their combination. Data are shown as the mean ⁇ SD of the tumor volumes and each group consisted of 8-10 animals.
  • FIG. 3A-FIG. 3D display exemplary results of in vivo pharmacodynamic assessment of mitotic block, DNA damage and apoptosis in PDXs treated with vehicle, single agents or combinations.
  • FIG. 3 A-FIG. 3B depict caspase-3 activity in tumor protein extracts from #266R xenografts treated with onvansertib/carboplatin combination (FIG. 3A upper panel) or onvansertib/gemcitabine combination (FIG. 3 A lower panel) and #315 xenografts treated with onvansertib/carboplatin combination (FIG. 3B upper panel) or onvansertib/gemcitabine combination (FIG.
  • FIG. 3C-FIG. 3D depict Western blot analysis showing pSerlO H3 (pH3) and pSerl39 H2AX (yH2AX) protein levels in tumor protein extracts from #266R xenografts treated with onvansertib/gemcitabine combination (FIG. 3C upper panel) or onvansertib/carboplatin combination (FIG. 3C lower panel) and #315 xenograftstreated with onvansertib/gemcitabine combination (FIG. 3D upper panel) or onvansertib/carboplatin combination (FIG. 3 D lower panel).
  • FIG. 4A-FIG. 4B depict body weights from #315 tumor-bearing mice.
  • FIG. 4A depicts body weights of mice transplanted with #315 xenografts and treated with vehicle (CTR), onvansertib 40 mg/kg (ONV), carboplatin 50 mg/kg (CARBO), onvansertib+carboplatin (COMBO ).
  • FIG. 4B depicts body weights of mice transplanted with #315 xenografts and treated with vehicle (CTR), onvansertib 40 mg/kg (ONV), gemcitabine 60 mg/kg (GEM) or onvansertib+gemcitabine (COMBO). Mice body weights were recorded every three days.
  • FIG. 5A-FIG. 5B depict exemplary results of densitometric analyses.
  • FIG. 5A depicts quantification of pSerl39 H2AX (yH2AX) protein levels by densitometric analyses in #266R tumors treated with onvansertib/gemcitabine combination (FIG. 5A upper panel) or onvansertib/carboplatin combination (FIG. 5 A lower panel) and pSerlO H3 (pH3) protein levels in #266R xenografts treated with onvansertib/gemcitabine combination (FIG.
  • FIG. 5A depicts quantification of pSerl39 H2AX (yH2AX) protein levels by densitometric analyses in #315 tumors treated with onvansertib/gemcitabine combination (FIG. 5B upper panel) or onvansertib/carboplatin combination (FIG. 5B lower panel) and pSerlO H3 (pH3) protein levels in #315 xenografts treated with onvansertib/gemcitabine combination (FIG. 5B (continued) upper panel) or onvansertib/carboplatin combination (FIG. 5B (continued) lower panel).
  • pSerl39 H2AX yH2AX
  • Disclosed herein include methods of treating cancer.
  • Disclosed herein include methods of treating ovarian cancer.
  • the method comprises: administering a PLK1 inhibitor and a DNA-damaging agent to a subject with the ovarian cancer, thereby inhibiting or reducing progression of the ovarian cancer in the subject.
  • kits can comprise, e.g., a PLK1 inhibitor; a DNA-damaging agent; and a manual providing instructions for co-administering the PLK1 inhibitor and the DNA-damaging agent to a subject in need thereof for treating ovarian cancer.
  • a “subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animals include cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • a “patient” refers to a subject that is being treated by a medical professional, such as a Medical Doctor (z.e., oncologist) or a Doctor of Veterinary Medicine, to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
  • a medical professional such as a Medical Doctor (z.e., oncologist) or a Doctor of Veterinary Medicine
  • the patient is a human or an animal.
  • the patient is a mammal.
  • administering refers to a method of giving a dosage of a pharmaceutically active ingredient to a vertebrate.
  • a “dosage” refers to the combined amount of the active ingredients (e.g., gemcitabine and onvansertib).
  • a “unit dosage” refers to an amount of therapeutic agent administered to a patient in a single dose.
  • the term “daily dose” or “daily dosage” refers to a total amount of a pharmaceutical composition or a therapeutic agent that is to be taken within 24 hours.
  • the term “delivery” refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical composition or a therapeutic agent into the body of a patient as needed to safely achieve its desired therapeutic effect.
  • an effective amount of the composition or agent is formulated for delivery into the blood stream of a patient.
  • formulated refers to the process in which different chemical substances, including one or more pharmaceutically active ingredients, are combined to produce a dosage form.
  • two or more pharmaceutically active ingredients can be co-formulated into a single dosage form or combined dosage unit, or formulated separately and subsequently combined into a combined dosage unit.
  • a sustained release formulation is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time
  • an immediate release formulation is a formulation which is designed to quickly release a therapeutic agent in the body over a shortened period of time.
  • the term “pharmaceutically acceptable” indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile.
  • the term “pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any supplement or composition, or component thereof, from one organ, or portion of the body, to another organ, or portion of the body, or to deliver an agent to a diseased tissue or a tissue adjacent to the diseased tissue.
  • Carriers or excipients can be used to produce compositions. The carriers or excipients can be chosen to facilitate administration of a drug or pro-drug.
  • Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents.
  • physiologically compatible solvents include sterile solutions of water for injection (WFI), saline solution, and dextrose.
  • the term “pharmaceutically acceptable salt” refers to any acid or base addition salt whose counter-ions are non-toxic to the patient in pharmaceutical doses of the salts.
  • a host of pharmaceutically acceptable salts are well known in the pharmaceutical field. If pharmaceutically acceptable salts of the compounds of this disclosure are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases.
  • acid salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate,
  • Pharmaceutically acceptable base addition salts include, without limitation, those derived from alkali or alkaline earth metal bases or conventional organic bases, such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • alkali or alkaline earth metal bases or conventional organic bases such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D
  • hydrate refers to a complex formed by combination of water molecules with molecules or ions of the solute.
  • solvate refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrate, hemi-hydrate, channel hydrate and the likes.
  • solvents include, but are not limited to, methanol, /f,/f-di methyl form am ide, tetrahydrofuran, dimethylsulfoxide, and water.
  • therapeutically effective amount refers to an amount of therapeutic agent, which has a therapeutic effect.
  • dosages of a pharmaceutically active ingredient which are useful in treatment when administered alone or in combination with one or more additional therapeutic agents are therapeutically effective amounts.
  • a therapeutically effective amount refers to an amount of therapeutic agent which produces the desired therapeutic effect as judged by clinical trial results and/or model animal studies. The therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
  • the term “treat,” “treatment,” or “treating,” refers to administering a therapeutic agent or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes.
  • the term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition.
  • therapeutic treatment refers to administering treatment to a subject already suffering from a disease or condition.
  • a “therapeutic effect” relieves, to some extent, one or more of the symptoms of a disease or disorder. For example, a therapeutic effect may be observed by a reduction of the subjective discomfort that is communicated by a subject (e.g., reduced discomfort noted in self-administered patient questionnaire).
  • the term “prophylaxis,” “prevent,” “preventing,” “prevention,” and grammatical variations thereof as used herein refers the preventive treatment of a subclinical disease-state in a subject, e.g., a mammal (including a human), for reducing the probability of the occurrence of a clinical disease-state.
  • the method can partially or completely delay or preclude the onset or recurrence of a disorder or condition and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject’s risk of acquiring or requiring a disorder or condition or one or more of its attendant symptoms.
  • the subject is selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.
  • “Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention.
  • Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
  • each of the terms “partial response,” “partial remission” and “PR” refers to the amelioration of a cancerous state, as measured by, for example, tumor size and/or cancer marker levels, in response to a treatment.
  • a “partial response” means that a tumor or tumor-indicating blood marker has decreased in size or level by about 50% in response to a treatment.
  • the treatment can be any treatment directed against cancer, including but not limited to, chemotherapy, radiation therapy, hormone therapy, surgery, cell or bone marrow transplantation, and immunotherapy.
  • the size of a tumor can be detected by clinical or by radiological means.
  • Tumor-indicating markers can be detected by means well known to those of skill, e.g., ELISA or other antibody-based tests.
  • a partial response of the target lesion can refer to at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • each of the terms “complete response” or “complete remission” or “CR” means that a cancerous state, as measured by, for example, tumor size and/or cancer marker levels, has disappeared following a treatment, including but are not limited to, chemotherapy, radiation therapy, hormone therapy, surgery, cell or bone marrow transplantation, and immunotherapy.
  • the presence of a tumor can be detected by clinical or by radiological means.
  • Tumor-indicating markers can be detected by means well known to those of skill, e.g., ELISA or other antibody-based tests.
  • a “complete response” does not necessarily indicate that the cancer has been cured, however, a complete response may be followed by a relapse.
  • a complete response of a target lesion includes disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) having reduction in short axis to ⁇ 10 mm.
  • a complete response of a non-target lesion includes disappearance of all non-target lesions and normalization of tumor marker level (all lymph nodes must be non-pathological in size ( ⁇ 10 mm short axis)). If tumor markers are initially above the upper normal limit, they need to normalize for a patient to be considered in complete clinical response of a non-target lesion.
  • the duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation.
  • stable disease or “SD” means neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Duration of stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
  • the term “progressive disease” or “PD” when refers to a target lesion means at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
  • progressive disease or PD refers to a non-target lesion, it means the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
  • the term “best overall response” means the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment depends on the achievement of both measurement and confirmation criteria. The duration of an overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).
  • DLT rate means dose-limiting toxicity rate
  • ICso means inhibitory drug concentration that produces 50% of the maximal effect.
  • AUC(x-y) means area under the curve, wherein “x” is the starting time in hours and “y” is the ending time in hours.
  • Cavg means average concentration.
  • Cmax means maximum concentration.
  • ANC absolute neutrophil count
  • CT computed tomography
  • ctDNA means circulating tumor DNA.
  • MRI magnetic resonance imaging
  • PK pharmacokinetic
  • PBMC peripheral blood mononuclear cells
  • the term “tolerable” means a dose level where ⁇ 1/6 participants have experienced a DLT, or the dose level that is declared the RP2D.
  • AE reverse event
  • An AE means an untoward medical occurrence in a subject administered a medicinal product that does not necessarily have a causal relationship with this treatment.
  • An AE can be an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational product, whether or not related to the investigational medicinal product.
  • An adverse events may include worsening or exacerbation of the disease under study; worsening or exacerbation of pre-existing conditions or events; intercurrent illnesses; or drug interactions. Anticipated fluctuations of pre-existing conditions that do not represent a clinically significant exacerbation or worsening are not considered AEs.
  • Surgical procedures are not adverse events; they are therapeutic measures for conditions that require surgery.
  • Disease progression is an efficacy endpoint and is not an AE.
  • a clinical event in the setting of disease progression would be considered an AE if it could not be unequivocally attributed to or consistent with expected disease progression.
  • expected adverse event means an adverse event that are listed or characterized in the current adverse event list, the Package Insert (P.I ), the Investigator Brochure (LB.) or is included in the informed consent document as a potential risk.
  • the term “unexpected adverse event” means an adverse event that is not listed in the P.I. or current I.B. or not identified. This includes adverse events for which the specificity or severity is not consistent with the description in the P.I. or I.B. For example, under this definition, hepatic necrosis would be unexpected.
  • the term “severe adverse event” or “SAE” means an AE that (1) results in death (z.e., the AE actually causes or leads to death); (2) is life threatening (z.e., the AE, in the view of the investigator, places the subject at immediate risk of death, but does not include an AE that, had it occurred in a more severe form, might have caused death.); (3) requires or prolongs inpatient hospitalization; (4) results in persistent or significant disability/incapacity (z.e., the AE results in substantial disruption of the subject’s ability to conduct normal life functions); or (5) results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the IMP.
  • the term “definite AE” means the AE is clearly related to the study treatment.
  • the term “probable AE” means the AE is likely related to the study treatment.
  • the term “possible AE” means the AE may be related to the study treatment.
  • unrelated AE means the AE is clearly not related to the study treatment.
  • expected disease progression means an event that is unequivocally related to disease progression, and that the clinical course is consistent with what would be expected for the patient’s disease.
  • measurable lesion means a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm by chest x-ray or >10 mm with CT scan, MRI, or calipers by clinical exam. Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. Cystic lesion thought to represent cystic metastases are measurable lesions if they meet the definition of measurability described above. However, they are target lesions if non-cystic lesions are also present in the same participant. Clinical lesions are measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and >10 mm in diameter as assessed using calipers (e.g., skin nodules).
  • malignant lymph node means a pathologically enlarged and measurable lymph node with >15 mm in short axis when assessed by CT scan.
  • non-measurable disease means a small lesion (or a site of disease) where the longest diameter ⁇ 10 mm or pathological lymph nodes with >10 to ⁇ 15 mm short axis.
  • Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are examples of non-measurable disease. Cystic lesions that meet the criteria for radiographically defined simple cysts are not malignant lesions (neither measurable nor non-measurable) and are simple cysts.
  • target lesion means all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, that is representative of all involved organs. Target lesions are selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. When the largest lesion does not lend itself to reproducible measurement, the next largest lesion that can be measured reproducibly is the target lesion.
  • non-target lesions means all lesions (or sites of disease) that are not target lesions. Non-target lesions include any measurable lesions over and above the 5 target lesions.
  • all survival means the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
  • progression-free survival means the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.
  • time to progression means the time from randomization (or registration) to progression, or censored at date of last disease evaluation for those without progression reported.
  • cancer refers to a process in which cancer cells travel from one organ or tissue to another non-adjacent organ or tissue. Cancer cells in the ovaries can spread to other tissues and organs of a subject, and conversely, cancer cells from other organs or tissue can invade or metastasize to the ovaries. Cancerous cells from the ovaries may invade or metastasize to any other organ or tissue of the body. Ovarian cancer cells often invade lymph node cells and/or metastasize to the liver, brain and/or bone and spread cancer in these tissues and organs.
  • the term “invasion,” in some embodiments, refers to the spread of cancerous cells to adjacent surrounding tissues.
  • Disclosed herein include methods of treating ovarian cancer.
  • the method can comprise: administering a PLK1 inhibitor and a DNA-damaging agent to a subject with the ovarian cancer, thereby inhibiting or reducing progression of the ovarian cancer in the subject.
  • PLK1 is a master regulator of mitosis and plays a role in several DNA repair mechanisms.
  • OCV onvansertib
  • CARBO carboplatin
  • GEM gemcitabine
  • the ovaries are mainly comprised of three kinds of cells which can develop into a different type of tumor.
  • Epithelial tumors start from the epithelial cells that cover the outer surface of the ovary. Most ovarian tumors are epithelial cell tumors.
  • Germ cell tumors start from germline cells (ova).
  • Stromal tumors start from the structural tissue cells (stromal cells) of the ovary together and produce the female hormones estrogen and progesterone.
  • Epithelial ovarian cancer is the most common type of ovarian cancer. This cancer develops in the epithelial tissue. Cancer may also form in the lining of a fallopian tube or it can begin in the peritoneum. In some embodiments, fallopian tube cancers and primary peritoneal cancers can be epithelial ovarian cancers. The diseases share many similarities, including treatments.
  • Ovarian cancer is the second most common cancer that affects the female reproductive system (gynecological cancer).
  • Uterine (endometrial) cancer is the most common.
  • a female has a 1 in 78 lifetime risk of getting ovarian cancer.
  • Epithelial ovarian cancer accounts for more than 9 in 10 of ovarian cancer. More than half of epithelial ovarian cancer cases affect people over 65.
  • About 3 out of 4 epithelial ovarian cancers are high-grade serous ovarian carcinomas (HGSOC). Cancer cells that are high-grade grow and spread faster than those that are low-grade. The cancer often affects the peritoneum and metastasizes outside of the ovaries. Nearly 70% of HGSOCs are stage 3 or 4 at the time of diagnosis. This means the cancer has spread outside of the original tumor and is now metastatic cancer.
  • LGSOC Low-grade serous ovarian carcinoma
  • OCCC ovarian clear cell carcinoma
  • SCC Primary squamous cell carcinoma
  • Endometrioid carcinoma more common in people who have endometriosis. It affects the endometrium (the inner lining of the uterus).
  • Low-grade serous ovarian carcinoma (LGSOC) is a slow-growing cancer that can affect people at a younger age (between 45 and 57). It accounts for about 10% of epithelial ovarian cancers. The disease is often advanced at the time of diagnosis and doesn’t respond well to chemotherapy.
  • SCC Primary squamous cell carcinoma
  • a standard treatment for ovarian cancer is to perform surgery in combination with a platinum-based therapy. Surgeons will, in some embodiments, perform debulking surgery, which removes as much of the tumor as possible, followed by chemotherapy. Most patients are initially cured, but the majority will get it again later (e.g., relapse).
  • the surgery may include removal of only the diseased ovary and fallopian tube cases of early-stage disease. In more advanced stages, one or both fallopian tubes, one or both ovaries or both the fallopian tubes and both the ovaries (bilateral salpingo-oophorectomy) can be removed.
  • the Uterus hysterectomy
  • fatty tissue covering the abdomen osteoectomy
  • nearby lymph nodes e.g., small intestine, large intestine or spleen.
  • Plantinum-based treatments include platinum compounds (e.g., carboplatin) and paclitaxel (Taxol®) or docetaxel (Taxotere®).
  • platinum compounds e.g., carboplatin
  • paclitaxel Texol®
  • docetaxel Texotere®
  • intraperitoneal chemotherapy to treat stage 3 ovarian cancer is performed by injecting cisplatin and paclitaxel directly into the abdominal cavity through a surgically placed catheter.
  • Targeted therapies and radiation therapy may also be used.
  • High-grade serous ovarian carcinoma is the most common and lethal gynaecologic malignancy, of which standard treatment includes cytoreductive surgery followed by platinum-based chemotherapy. Most patients respond to first-line chemotherapy. However, 75% of women will relapse with a much less platinum-sensitive tumor.
  • anti- angiogenic drugs and poly-ADP-ribose polymerase inhibitors PARPis
  • PARPis poly-ADP-ribose polymerase inhibitors
  • resistance to platinum-based therapy or platinum resistance
  • Intrinsic resistance accounts for 20% of cases.
  • PFI platinum-free interval
  • Approved agents for relapse include gemcitabine, liposomal doxorubicin, and taxane.
  • PLD platinum-sensitive doxorubicin
  • PLD and trabectedin might also be an option in patients hypersensitive to platinum.
  • monotherapies paclitaxel, gemcitabine, PLD, or topotecan are the best therapeutic options, although the overall response rates to these agents are low (8 to 20%).
  • combination therapies that can be used to treat, e.g., platinum-based chemotherapeutic resistant ovarian cancer.
  • Polo-like kinases are a family of five highly conserved serine/threonine protein kinases.
  • PLK1 is a master regulator of mitosis and is involved in several steps of the cell cycle, including mitosis entry, centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. It is also critical for the entry and progression through mitosis, regulates progression of cells through the G2 phase of the cell cycle by phosphorylating forkhead box protein Ml (F0XM1), which then regulates the expression of cyclins and other genes necessary for cells to progress through the cell cycle. PLK1 has been shown to be overexpressed in solid tumors and hematologic malignancies.
  • PLK1 inhibition induces G2-M-phase arrest with subsequent apoptosis in cancer cells, and has emerged as a promising targeted therapy.
  • PLK inhibitors have been studied in clinical trials. In the early pre-clinical development of PLK1 targeted drugs, cancer cells with TP53 mutation (mutp53) were more responsive and had lower IC50 than cell lines with wild type (wtp53), which are consistent with the lack of checkpoint control and genomic instability associated with mutp53 and increases the importance of PLK1 function for progression through G2 and M phases of the cell cycle.
  • Pyruvate dehydrogenases kinase 1 (PDK1), PLK1, and MYC have also been suggested to be important in driving the expression of a set of genes associated with cancer stem cell self-renewal.
  • PLK1 has been identified as a therapeutic target for TNBC through siRNA-mediated screen and inhibition of PLK1 by siRNA-mediated knockdown or a chemical inhibitor promoted cell cycle arrest and apoptosis in multiple TNBC lines.
  • the lack of a druggable target is the problem for poor prognosis of TNBC, and the effectiveness and unique action profile of PLK1 inhibition, in addition to relatively specific expression to TNBC tissue, suggest that PLK1 is a promising molecular target for TNBC.
  • pan-PLK inhibitor volasertib (BI6727)
  • LDAC pan-PLK inhibitor
  • a subsequent randomized phase III study identified no benefit of the combination and described an increased risk of severe infections.
  • PLK1 facilitates HR during Double Strand DNA Break (DSB) Repair.
  • DSB Double Strand DNA Break
  • PLK1 phosphorylates Rad51 and BRCA1, facilitating their recruitment to DSB sites and thereby HR-mediated DNA repair.
  • Onvansertib (also known as PCM-075, NMS-1286937, NMS-937, “compound of formula (I)” in U.S. Patent No. 8,927,530; IUPAC name l-(2-hydroxyethyl)-8- ⁇ [5-(4- methylpiperazin-l-yl)-2-(trifluorom ethoxy) phenyl] amino ⁇ -4,5-dihydro-lH-pyrazolo[4,3-h] quinazoline-3-carboxamide), or a pharmaceutically acceptable salt, is a selective ATP- competitive PLK1 inhibitor.
  • Onvansertib can be formulated, for example, with an additive such as free base, lactose monohydrate, pregelatinized starch and glyceryl beneate.
  • the onvansertib is formulated for oral administration, such as in a hard gelatin capsule
  • Biochemical assays demonstrated high specificity of onvansertib for PLK1 among a panel of 296 kinases, including other PLK members.
  • Onvansertib has potent in vitro and in vivo antitumor activity in models of both solid and hematologic malignancies.
  • Onvansertib is the first PLK1 specific ATP competitive inhibitor administered by oral route to enter clinical trials with proven antitumor activity in different preclinical models.
  • Onvansertib has shown a promising safety profile in a phase 1 clinical trial as single agent.
  • onvansertib in combination with abiraterone and prednisone in adult patients with metastatic castration-resistant prostate cancer, onvansertib in combination with FOLFIRI and bevacizumab in adult patients with KRAS-mutated metastatic colorectal cancer, and onvansertib in combination with nanoliposomal irinotecan and 5-FU in patients with metastatic pancreatic cancer.
  • Onvansertib also inhibited cell proliferation at nanomolar concentrations in AML cell lines and tumor growth in xenograft models of AML. In addition, onvansertib significantly increased cytarabine antitumor activity in disseminated models of AML.
  • Onvansertib shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid as well as hematologic tumors.
  • ICso > 500 nM
  • PLK2 and PLK3 ICso > 10 pM
  • Onvansertib potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with a clear PLKl-related mechanism of action at well tolerated doses in mice after oral administration.
  • onvansertib shows activity in combination therapy with approved cytotoxic drugs, such as irinotecan, in which there is enhanced tumor regression in HT29 human colon adenocarcinoma xenografts compared to each agent alone, and shows prolonged survival of animals in a disseminated model of AML in combination therapy with cytarabine.
  • Onvansertib has favorable pharmacologic parameters and good oral bioavailability in rodent and nonrodent species, as well as proven antitumor activity in different nonclinical models using a variety of dosing regimens, which may potentially provide a high degree of flexibility in dosing schedules, warranting investigation in clinical settings.
  • Onvansertib has several advantages over volasertib (BI6727, another PLK1 inhibitor), including a higher degree of potency and specificity for the PLK1 isozyme, and oral bioavailability.
  • onvansertib has proven antitumor activity in different nonclinical models using a variety of dosing regimens, which can provide flexibility in dosing schedules, and therefore, warrants investigation in clinical settings.
  • a phase I, first-in-human, dose-escalation study of onvansertib in patients with advanced/metastatic solid tumors identified neutropenia and thrombocytopenia as the primary dose-limiting toxicities. These hematologic toxicities were anticipated on the basis of the mechanism of action of the drug and were reversible, with recovery occurring within 3 weeks.
  • the half-life of onvansertib was established between 20 and 30 hours. The oral bioavailability of onvansertib plus its short half-life provide the opportunity for convenient, controlled, and flexible dosing schedules with the potential to minimize toxicities and improve the therapeutic window.
  • onvansertib towards the major human cytochrome P450 (CYP) isoforms that are responsible for hepatic drug metabolism in human (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was investigated using human liver microsomes.
  • Onvansertib was able to inhibit the metabolic activities of CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 isoforms to different extents, with 50% inhibitory concentration (ICso) values ranging from 20 pM to 66 pM.
  • ICso inhibitory concentration
  • DNA-damaging agents treat cancer by inducing the DNA-damage response in proliferating cancer cells, thereby inducing, e.g., apoptosis.
  • the DNA-damaging agent can be an alkylating agent.
  • Alkylating agents damage cell DNA through addition of an alkyl group.
  • Nitrosoureas are a particular type of alkylating agent. Unlike other alkylating agents, nitrosoureas can travel into the brain and kill cancer cells there. Nitrosoureas are used to treat some brain tumors.
  • alkylating agents include: Altretamine, Bendamustine, Busulfan, Carboplatin, Chlorambucil, Cisplatin, Cyclophosphamide, dacarbazine, Ifosfamide, Mechlorethamine, Melphalan, Oxaliplatin, Procarbazine, Temozolomide, Thiotepa, and Trabectedin.
  • exemplary nitrosoureas include: Carmustine, Lomustine, and Streptozocin.
  • the DNA-damaging agent can be an antimetabolite.
  • Antimetabolites prevent cancer cells from replicating DNA, often DNA is also damaged.
  • Exemplary antimetabolites include: 5-fluorouracil, 6-mercaptopurine, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Decitabine, Floxuridine, Fludarabine, Gemcitabine, Hydroxyurea, Methotrexate, Nelarabine, Pemetrexed, Pentostatin, Pralatrexate, Thioguanine, and Trifluridine/tipiracil combination.
  • the DNA-damaging agent can be a topoisomerase inhibitor.
  • Topoisomerase inhibitors inhibit DNA replication. Inhibiting this enzyme prevents cancer cells from multiplying and can also damage the cell DNA.
  • Exemplary topoisomerase inhibitors include: Etoposide, Irinotecan, Irinotecan liposomal, Mitoxantrone (also classified as an antitumor antibiotic, see below), Teniposide, and Topotecan.
  • the DNA-damaging agent can be an antitumor antibiotic (including anthracyclines).
  • Antitumor antibiotics prevent the cancer-cell DNA from replication and can induce DNA damage.
  • Anthracyclines are a specific type of antitumor antibiotic.
  • Exemplary anthracyclines include: Daunorubicin, Doxorubicin, Doxorubicin liposomal, Epirubicin, Idarubicin, Mitoxantrone, and Valrubicin.
  • Other antitumor antibiotics include: Bleomycin, Dactinomycin, and Mitomycin-C.
  • the DNA-damaging agent is Gemcitabine.
  • This antimetabolite drug has been used to treat multiple cancer types including non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell cancer, germ cell tumors, lymphomas (cutaneous T-cell and Hodgkins' disease), mesothelioma, and tumors of the bladder, breast, ovary, cervix, pancreas, and biliary tract, as well as some hematologic malignancies.
  • the compound was first reported by Lilly Research Laboratories, Eli Lilly and Co.; Indianapolis, Ind. Hertel etal., Cancer Res. 50, 4417-4422 (1990); U.S. Pat. Nos. 4,808,614 and 5,464,826) and sold by Lilly under the trade name, Gemzar®.
  • Gemcitabine is a deoxycytidine analog with structural similarities to cytarabine (Ara-C®).
  • the cytotoxic effect of gemcitabine is generally attributed to the actions of diphosphate and the triphosphate nucleotides, which lead to inhibition of DNA synthesis.
  • Gemcitabine diphosphate (dFdCDP) inhibits ribonucleotide reductase (RNR), which is essential for DNA synthesis and is responsible for catalyzing the reactions that generate the deoxynucleotide triphosphates for DNA synthesis.
  • RNR ribonucleotide reductase
  • Inhibition of RNR by the diphosphate nucleotide causes a reduction in the concentration of the deoxynucleotides, including deoxy cytidine triphosphate (dCTP).
  • gemcitabine triphosphate (dFdCTP) competes with dCTP for incorporation into DNA.
  • gemcitabine is a potent radiosensitizer.
  • Gemcitabine has been investigated as a radiosensitizer for rodent and human tumor cells, including those found in pancreatic, non-small cell lung, head and neck, colorectal, breast, and cervical cancer. Pauwels etal., Oncologist 10(1), 34-51 (2005).
  • the DNA-damaging agent is carboplatin.
  • Carboplatin is a derivative of (and can be synthesized from) the platinum-based chemotherapeutic agent cisplatin. These two drugs operate by the same mechanism.
  • the labile ligands of the coordination complexes, chloride for cisplatin and 1,1 -cyclobutanedicarboxylate (CBDCA) for carboplatin are displaced by water or other biological nucleophiles, and the reactive cis-diammineplatinum(II) moiety binds to nuclear DNA, thus damaging the DNA.
  • the resulting platinum-DNA adducts ultimately lead to cell death through transcription inhibition and the ensuing downstream effects.
  • cisplatin and carboplatin bear the same NH3 non-leaving group ligands, the nature of the resulting DNA adducts are the same, and therefore the drugs exhibit a similar spectrum of activity.
  • Carboplatin is significantly less toxic than cisplatin.
  • the typical patient dose for carboplatin is approximately ten times greater than that of cisplatin (400 mg/m 2 versus 40 mg/m 2 ), and the dose-limiting toxic side effect of carboplatin is myelosuppression in contrast to nephrotoxicity, which is dose-limiting for cisplatin treatment.
  • the DNA-damaging agent can induce an increase in the levels of markers of DNA damage (e.g., double strand break (DSB)) or cell division.
  • the marker can be phosphorylation of histone H2AX on serine 139 (yH2AX). Phosphorylation of histone H2AX on serine 139 (yH2AX) is an early step in cellular response to DNA damage, when the damage results in formation of a double-strand break (DSB).
  • Another exemplary marker can be phosphorylation of histone H3. Phosphorylation of histone H3 at SerlO is crucial for chromosome condensation and traditionally regarded as a marker of mitosis.
  • the method comprises: administering a PLK1 inhibitor and a DNA-damaging agent to a subject with the ovarian cancer, thereby inhibiting or reducing progression of the ovarian cancer in the subject.
  • the ovarian cancer can be high-grade serous ovarian carcinoma (HGSOC), endometrioid carcinoma, low-grade serous ovarian carcinoma (LGSOC), mucinous carcinoma, ovarian clear cell carcinoma (OCCC), or primary squamous cell carcinoma (SCC) of the ovary.
  • HGSOC high-grade serous ovarian carcinoma
  • LGSOC low-grade serous ovarian carcinoma
  • OCCC mucinous carcinoma
  • SCC primary squamous cell carcinoma
  • the DNA-damaging agent can be an alkylating agent, an antimetabolite, a topoisomerase inhibitor, or an antitumor antibiotic.
  • the DNA-damaging agent can be a platinumbased DNA-damaging agent.
  • the DNA-damaging agent can be altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechlorethamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5-fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate,
  • the subject with the ovarian cancer is resistant to or does not respond effectively to a platinum-based chemotherapeutic agent.
  • the DNA-damaging agent can be a platinum-based DNA-damaging agent.
  • the platinum-based DNA-damaging agent and the platinum-based chemotherapeutic agent can be the same or different.
  • the subject with the ovarian cancer developed stable disease or progressive disease when treated with the platinum-based chemotherapeutic agent, or developed resistance to the platinum-based chemotherapeutic agent.
  • the subject with the ovarian cancer can be resistant to at least one platinum-based chemotherapeutic agent.
  • the at least one platinum-based chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • the resistance can be acquired resistance or intrinsic resistance.
  • the subject with the ovarian cancer has received a prior PLK1 inhibitor treatment or a prior DNA-damaging agent treatment. In some embodiments, the subject with the ovarian cancer did not respond to the treatment with the prior PLK1 inhibitor or the prior DNA-damaging agent. In some embodiments, the subject with the ovarian cancer has stable or progressive disease following the treatment with the prior PLK1 inhibitor or the prior DNA-damaging agent. In some embodiments, the subject with the ovarian cancer is known to be resistant to the PLK1 inhibitor or the DNA-damaging agent alone.
  • the PLK1 inhibitor can be onvansertib (NMS-P937), BI2536, volasertib (BI 6727), GSK461364, adavosertib (AZDI 775), CYC 140, HMN-176, HMN-214, rigosertib (ON- 01910), MLN0905, TKM-080301, TAK-960, GTPL10072, Ro3280; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; or any combination thereof.
  • the PLK1 inhibitor can be onvansertib.
  • the PLK1 inhibitor and the DNA-damaging agent can be administered to the subject with the ovarian cancer in a manner sufficient to inhibit or reduce progression of the cancer.
  • the PLK1 inhibitor and the DNA-damaging agent can be administrated to a subject with cancer simultaneously, separately, or sequentially.
  • the PLK1 inhibitor and the DNA- damaging agent can be administered in any suitable order.
  • the DNA-damaging agent can be administered followed by the PLK1 inhibitor.
  • the PLK1 inhibitor can be administered followed by the DNA-damaging agent. It is expected that the combination treatment using the PLK1 inhibitor and the DNA-damaging agent can result in significantly enhanced efficacy against ovarian cancer, causing tumor regression and cancer survival.
  • the resulting tumor regression and cancer survival rate/duration by the combination can be surprisingly synergistic (i.e., more than additive, superior to the cumulated anti-tumor efficacy caused by PLK1 inhibitor and the DNA-damaging agent separately).
  • onvansertib in combination with carboplatin or gemcitabine showed synergy in ovarian cancer models that are resistant to treatment with, e.g., platinum-based chemotherapeutic agents, relative to a PLK1 inhibitor or a DNA-damaging agent alone.
  • a PLK1 inhibitor can increase the responsiveness of the cancer cells that may have escaped from platinum-based chemotherapeutic agent.
  • the inhibition or reduction of cancer progression is not merely additive, but is enhanced or synergistic (that is, the inhibition is greater than the combined inhibition of progression caused by PLK1 inhibitor and the DNA-damaging agent alone).
  • the enhanced or synergistic efficacy or inhibition of any combination of the PLK1 inhibitor and the DNA-damaging agent of the present disclosure can be different in different embodiments.
  • the enhanced or synergistic efficacy or inhibition of any combination of a PLK1 inhibitor and a DNA-damaging agent of the present disclosure is, is about, is at least, is at least about, is at most, or is at most about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, or a number or a range between any two of these values, higher than the combined inhibition of progression caused by PLK1 inhibitor and the DNA-damaging agent alone.
  • the molar ratio of the PLK1 inhibitor (e.g., onvansertib) to the DNA-damaging agent (e.g., carboplatin or gemcitabine) can be, for example, about 1 :200, 1 : 100, 1 :90, 1 :80, 1 :70, 1 :60, 1 :50, 1 :40, 1 :30, 1 :20, 1 : 10, 1 : 1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 100: 1, 1000: 1, or 2000: 1, or a number or a range between any two of these values.
  • the enhanced or synergistic efficacy or inhibition of cancer progression caused by a combination of thePLKl inhibitor and the DNA-damaging agent is, is about, is at least, is at least about, is at most, or is at most about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, or a number or a range between any two of these values, higher than the combined inhibition of progression caused by the DNA-damaging agent (e.g., carboplatin) alone plus the PLK1 inhibitor (e.g., onvansertib) alone.
  • the DNA-damaging agent e.g., carboplatin
  • PLK1 inhibitor e.g., onvansertib
  • a combination of the PLK1 inhibitor and the DNA-damaging agent can cause a 50%, 60%, 70%, 80%, 90%, or more, inhibition of cancer progression (cancer cell viability of 50%, 40%, 30%, 20%, 10%, or less), whereas under the same conditions the combined inhibition of PLK1 inhibitor and the DNA-damaging agent alone can be 10%, 20%, 25%, 30%, or less) inhibition of cancer progression (cancer cell viability of 90%, 80%, 75%, 70%, or more).
  • the enhanced or synergistic efficacy or inhibition of cancer progression caused by the combination of PLK1 inhibitor and the DNA-damaging agent is, for example, 50%, 60%, 70%, 80%, 90%, 100%, or more higher than the combined inhibition of progression caused by the PLK1 inhibitor alone plus the DNA-damaging agent alone.
  • the PLK1 inhibitor is onvansertib and the DNA-damaging agent is carboplatin or gemcitabine.
  • the patient can achieve complete response or partial response after treatment with the PLK1 inhibitor and the DNA-damaging agent. In some embodiments, the patient achieves a complete response. In some embodiments, the patient achieves a partial response. In some embodiments, the patient did not respond to or developed stable or progressive disease following treatment with the DNA-damaging agent alone (without the PLK1 inhibitor).
  • the PLK1 inhibitor and the DNA-damaging agent can be administered to the patient in any manner deemed effective to treat the cancer.
  • the PLK1 inhibitor can be administered together with, or separately from, the DNA-damaging agent.
  • the PLK1 inhibitor can be administered before or after the DNA-damaging agent, or in different administration cycles.
  • the PLK1 inhibitor and the DNA-damaging agent can be coadministered simultaneously.
  • the PLK1 inhibitor and the DNA-damaging agent can be administered sequentially.
  • the PLK1 inhibitor and the DNA-damaging agent can each be administered in any schedule, e.g., once or multiple times per day or week; once, twice, three times, four times, five times, six times or seven times (daily) per week; for one or multiple weeks; monthly etc.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is, or is only, administered to a patient daily for 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 consecutive days during a cycle, for example, on the first 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 consecutive days of the cycle; and the DNA-damaging agent is, or is only, administered to the patient once in each of the weeks that onvansertib is administered.
  • the cycle can be, for example, 21-28 days in length.
  • the PLK1 inhibitor is administered to a patient daily for the first 21 consecutive days during a 28-day cycle, and the patient is administered with the DNA-damaging agent once a week for the first two, three, or four weeks in the 28-day cycle. In some embodiments, the PLK1 inhibitor is administered to a patient daily for the first 21 consecutive days during a 28-day cycle, and the patient is administered with the DNA-damaging agent once (e.g., on Day 1) in the 28-day cycle. In some embodiments, the PLK1 inhibitor is administered to a patient 5 days a week during a 28-day cycle, and the patient is administered the DNA-damaging agent once a week for the first two, three, or four weeks or once in the 28-day cycle.
  • no PLK1 inhibitor nor DNA-damaging agent is administered to the patient in the last 7 days of the 28-day cycle.
  • the patient can undergo one or more cycles of treatment/administration, for example at least two cycles of treatment/administration.
  • the administration schedule of the PLK1 inhibitor and the DNA-damaging agent can be the same or different in each of the cycles of treatment/administration.
  • the PLK1 inhibitor and/or the DNA-damaging agent is administered in a cycle of 14-28 days of administration. In some embodiments, the PLK1 inhibitor and/or the DNA-damaging agent is administered in a cycle of 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, or 50 days. In some embodiments, the PLK1 inhibitor and/or the DNA-damaging agent is administered on 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,
  • the PLK1 inhibitor and/or the DNA-damaging agent is administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, day 28, day 29, day 30, day 31, day 32, day 33, day 34, day 35, day 36, day 37, day 38, day 39, day 40, day 41, day 42, day 43, day 44, day 45, day 46, day 47, day 48, day 49, and/or day 50.
  • the PLK1 inhibitor and/or the DNA-damaging agent is not administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day
  • day 30 29, day 30, day 31, day 32, day 33, day 34, day 35, day 36, day 37, day 38, day 39, day 40, day
  • onvansertib and/or gemcitabine can be administered in a cycle of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 days.
  • the DNA-damaging agent can be administrated to the patient once weekly or twice weekly.
  • the DNA-damaging agent can be administrated to the patient once every 2, 3, or 4 weeks.
  • the DNA-damaging agent is administrated weekly on each week or on selected weeks of the administration cycle.
  • the DNA-damaging agent is administered in a cycle of 28 days with a weekly administration for three weeks (e.g., on Day 1, 8 and 15) and no administration for the remaining days of the cycle, including Days 16-28.
  • the DNA-damaging agent is administered in a cycle of 18 days with a weekly administration for three weeks (e.g., on Day 1, 8 and 15) and no administration for the remaining days of the cycle.
  • the DNA-damaging agent is administered in a cycle of 32 days with a weekly administration for five weeks (e.g., on Day 1, 8, 15, 22, and 29) and no administration for the remaining days of the cycle. In some embodiments, the DNA-damaging agent is administered in a cycle of 39 days with a weekly administration for six weeks (e.g., on Day 1, 8, 15, 22, 29, and 36) and no administration for the remaining days of the cycle. In some embodiments, there is no administration of the DNA-damaging agent in one or more weeks of a cycle.
  • the DNA-damaging agent is gemcitabine and is administered to the subject once weekly, for two weeks of a 21 -day or 28-day cycle. In some embodiments, the gemcitabine is administered on Day 1 and 8 of a 21 -day or 28-day cycle. In some embodiments, the DNA-damaging agent is carboplatin and is administered to the subject once in a 21 -day or 28-day cycle. In some embodiments, the carboplatin is administered on Day 1 of a 21 -day or 28-day cycle.
  • the DNA-damaging agent can be administered to the patient at any appropriate dosage in different embodiments.
  • the DNA-damaging agent can be administered to the patient at a dosage of about, at least or at most 50 mg/m 2 , 55 mg/m 2 , 60 mg/m 2 , 65 mg/m 2 , 70 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 85 mg/m 2 , 90 mg/m 2 , 95 mg/m 2 , 100 mg/m 2 , 105 mg/m 2 , 110 mg/m 2 , 115 mg/m 2 , 120 mg/m 2 , 125 mg/m 2 , 130 mg/m 2 , 135 mg/m 2 , 140 mg/m 2 , 145 mg/m 2 , 150 mg/m 2 , 155 mg/m 2 , 160 mg/m 2 , 165 mg/m 2 , 170 mg/m 2 , 175 mg/m 2 , 180 mg/m 2 , 185 mg
  • the dosage unit based on the body surface area can be converted to the dosage unit based on body weight (mg/kg) using a conversion chart such as the body surface area (BSA) conversion chart as will be understood by a person of skill in the art.
  • the DNA-damaging agent is carboplatin.
  • Carboplatin can be administered at a dosage of about, at least or at most 200 mg/m 2 , 205 mg/m 2 , 210 mg/m 2 , 215 mg/m 2 , 220 mg/m 2 , 225 mg/m 2 , 230 mg/m 2 , 240 mg/m 2 , 245 mg/m 2 , 250 mg/m 2 , 255 mg/m 2 , 260 mg/m 2 , 265 mg/m 2 , 270 mg/m 2 , 275 mg/m 2 , 280 mg/m 2 , 285 mg/m 2 , 290 mg/m 2 , 295 mg/m 2 , 300 mg/m 2 , 305 mg/m 2 , 310 mg/m 2 , 315 mg/m 2 , 320 mg/m 2 , 325 mg/m 2 , 330 mg/m 2 , 335 mg/m 2 , 340 mg/m 2 , 345 mg/m 2 , 350 mg/m 2
  • the DNA-damaging agent is gemcitabine.
  • Gemcitabine can be administered at a dosage of about, at least or at most 500 mg/m 2 , 510 mg/m 2 , 520 mg/m 2 , 530 mg/m 2 , 540 mg/m 2 , 550 mg/m 2 , 560 mg/m 2 , 570 mg/m 2 , 580 mg/m 2 , 590 mg/m 2 , 600 mg/m 2 ,
  • the DNA-damaging agent is administered at a dosage of about, at least or at most 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 100 mg/kg or a number between any two of these values.
  • the PLK1 inhibitor can be administered to the patient at any appropriate dosage in different embodiments.
  • the PLK1 inhibitor can be administered to the patient at a dosage of about, at least or at most 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 105 mg/kg, 110 mg/kg, 115 mg/kg, 125 mg/kg, 130 mg/kg, 135 mg/kg, 140 mg/kg, 145 mg/kg, 150 mg/kg, 155 mg/kg, 160 mg/kg, 165 mg/kg, 170 mg/kg, 175 mg/kg, 180 mg/kg, 185 mg/kg, 190 mg/kg, 195 mg/kg,
  • the PLK1 inhibitor is onvansertib.
  • the onvansertib can be administered to the patient at any appropriate dosage, e.g., a dosage of less than 12 mg/m 2 , less than or equal to 24 mg/m 2 , or greater than 24 mg/m 2 .
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is be administered at a dosage from about 10 mg/kg of body weight to about 80 mg/kg of body weight, optionally at a dose from about 20 mg/kg of body weight to about 60 mg/kg of body weight, optionally at a dose from about 30 mg/kg of body weight to about 50 mg/kg of body weight.
  • onvansertib is administered to the patient daily. In some embodiments, onvansertib is administered in a cycle of 5-14 days of daily onvansertib administration with 2-16 days with no onvansertib administration. For example, in some embodiments, onvansertib is administered daily for 21 consecutive days followed by no onvansertib administration for 7 days in a cycle. In some embodiments, onvansertib is administered for 5 consecutive days a week followed by no onvansertib administration for 2 days each week or on selected weeks of an administration cycle.
  • the combination treatment with the PLK1 inhibitor and the DNA-damaging agent can be administered at the same dose as single treatment with the PLK1 inhibitor and the DNA-damaging agent.
  • the amount of co-administration of the PLK1 inhibitor and the DNA-damaging agent, and the timing of co-administration can depend on the type (species, gender, age, weight, etc.) and condition of the subject being treated and the severity of the disease or condition being treated.
  • the PLK1 inhibitor and the DNA- damaging agent can formulated into a single pharmaceutical composition, or two separate pharmaceutical compositions.
  • the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interracial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • the PLK1 inhibitor and the DNA-damaging agent can be administered by any suitable routes, including but not limited to oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration.
  • Parenteral administration e.g., injection
  • the DNA-damaging agent can be, for example, administered by intravenous infusion (e.g., over about 30 minutes to about 3 hours) and the PLK1 inhibitor (e.g., onvansertib) can be, for example, administered orally.
  • the PLK1 inhibitor e.g., onvansertib
  • the subject can be a subject receiving a cancer treatment, a subject at cancer remission, a subject who has received one or more cancer treatments, or a subject suspected of having cancer.
  • the subject can have a stage I cancer, a stage II cancer, a stage III cancer, and/or a stage IV cancer.
  • the methods can further comprise administering an additional therapeutic intervention to the subject.
  • the additional therapeutic intervention can comprise a different therapeutic intervention than administering the PLK1 inhibitor and the DNA-damaging agent, such as an antibody, an adoptive T cell therapy, a chimeric antigen receptor (CAR) T cell therapy, an antibody-drug conjugate, a cytokine therapy, a cancer vaccine, a checkpoint inhibitor, a radiation therapy, surgery, a chemotherapeutic agent, or any combination thereof.
  • the therapeutic intervention can be administered at any time of the treatment, for example at a time when the subject has an early-stage cancer, and wherein the therapeutic intervention is more effective that if the therapeutic intervention were to be administered to the subject at a later time.
  • the ovarian cancer can be high-grade serous ovarian carcinoma (HGSOC), endometrioid carcinoma, low-grade serous ovarian carcinoma (LGSOC), mucinous carcinoma, ovarian clear cell carcinoma (OCCC), or primary squamous cell carcinoma (SCC) of the ovary.
  • HGSOC high-grade serous ovarian carcinoma
  • LGSOC low-grade serous ovarian carcinoma
  • OCCC mucinous carcinoma
  • OCCC ovarian clear cell carcinoma
  • SCC primary squamous cell carcinoma
  • the subject with the ovarian cancer develops stable disease or progressive disease when treated with the platinum-based chemotherapeutic agent, or develops resistance to the platinum-based chemotherapeutic agent.
  • platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. These drugs can induce DNA-damage through cross-linking, ultimately resulting in apoptosis in rapidly proliferating tumor cells.
  • the subject with the ovarian cancer can be resistant to cisplatin. The resistance can be acquired resistance or intrinsic resistance.
  • the subject has received at least one prior cancer treatment.
  • the at least one prior cancer treatment does not comprise the use of a DNA-damaging agent, a PLK1 inhibitor, or both.
  • the PLK1 inhibitor can be onvansertib.
  • the subject was in remission for cancer.
  • the subject in remission for cancer was in complete remission (CR) or in partial remission (PR).
  • the method can comprise determining cancer status of the subject.
  • the method can comprise determining responsiveness of the subject to the treatment with the PLK1 inhibitor and/or the DNA-damaging agent.
  • the method can comprise administering one or more additional cancer therapeutics or therapies for the cancer.
  • the subj ect can be a human. In some embodiments, the subject achieves a complete response.
  • the combination treatment does not cause, e.g., weight loss or other side effect in the subject.
  • body weight of the subject decreases by no more than 20% (e.g., by 0.000000001%, 0.00000001%, 0.0000001%, 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a number or a range between any two of these values) following at least one cycle of treatment.
  • weight of one or more tumors of the subject decreases by at least 25% (e.g., by at least 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, or a number or
  • the combination treatment of the disclosure can result in induction of apoptosis in a plurality of cancer cells in the subject, thereby, killing the cancer cells and treating the cancer.
  • Caspase levels (a marker of apoptosis) can be increased in a plurality of cancer cells of the subject, following at least one cycle of treatment.
  • caspase levels can be increased in a plurality of cancer cells of the subject by at about or at least about 2-fold (e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or a number or a range between any of these values), following at least one cycle of treatment.
  • 2-fold e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or a number or a range between any of these values
  • the treatment described herein can comprise administration of the PLK1 inhibitor and the DNA-damaging agent for a desired duration in one or more cycles of treatment.
  • Administration of a DNA-damaging agent can be at, or be about, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or a number or a range between any two of these values.
  • the dose of the DNA-damaging agent can be adjusted (e.g., increased or decreased with the range) during the treatment of the subject.
  • the administration of the DNA-damaging agent can be at different amounts on different days or during different weeks or different cycles.
  • the treatment can comprise weekly or monthly administration of the DNA-damaging agent at 1 g during week 1, 450 mg during week 2, 200 mg during week 3, 150 mg during week 4, and 50 mg during week 5 and beyond.
  • the DNA-damaging agent is carboplatin or gemcitabine and is administered at a daily or weekly dose of about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1 g, or a number or a range between any two of these values.
  • Administration of a DNA-damaging agent can be at, or be about, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.45 mg/kg, 0.5 mg/kg, 0.55 mg/kg, 0.6 mg/kg, 0.65 mg/kg, 0.7 mg/kg, 0.75 mg/kg, 0.8 mg/kg, 0.85 mg/kg, 0.9 mg/kg, 0.95 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, 1000 mg/kg, 1100 mg/kg, 1200 mg/kg, or a number or a range between any two of these values
  • the dose of the DNA-damaging agent can be adjusted (e.g., increased or decreased with the range) during the treatment of the subject.
  • the administration of the DNA-damaging agent can be at different amounts on different days or during different weeks or different cycles.
  • the treatment can comprise weekly or monthly administration of the DNA-damaging agent at 1 g/kg during week 1, 450 mg/kg during week 2, 200 mg/kg during week 3, 150 mg/kg during week 4, and 50 mg/kg during week 5 and beyond.
  • the DNA-damaging agent is carboplatin or gemcitabine and is administered at a daily or weekly dose of about 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, 1 g/kg, or a number or a range between any two of these values.
  • the DNA-damaging agent can be administered at a drug/body surface area unit dose of about 10 mg/m 2 to about 2000 mg/m 2 .
  • the DNA-damaging agent can be administered at, or at about 10 mg/m 2 , 11 mg/m 2 , 12 mg/m 2 , 13 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , 17 mg/m 2 , 18 mg/m 2 , 19 mg/m 2 , 20 mg/m 2 , 21 mg/m 2 , 22 mg/m 2 , 23 mg/m 2 , 24 mg/m 2 , 25 mg/m 2 , 26 mg/m 2 , 27 mg/m 2 , 28 mg/m 2 , 29 mg/m 2 , 30 mg/m 2 , 31 mg/m 2 , 32 mg/m 2 , 33 mg/m 2 , 34 mg/m 2 , 35 mg/m 2 , 36 mg/m 2 , 37 mg/
  • the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 100 mg/m 2 - 2000 mg/m 2 drug/body surface area, for example, as a monthly or semi-weekly dose.
  • the PLK1 inhibitor e.g., onvansertib
  • the DNA-damaging agent is carboplatin or gemcitabine and can be administered at, or at about 100 mg/m 2 , 110 mg/m 2 , 120 mg/m 2 , 130 mg/m 2 , 140 mg/m 2 , 150 mg/m 2 , 160 mg/m 2 , 170 mg/m 2 , 180 mg/m 2 , 190 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 230 mg/m 2 , 240 mg/m 2 , 250 mg/m 2 , 260 mg/m 2 , 270 mg/m 2 , 280 mg/m 2 , 290 mg/m 2 , 300 mg/m 2 , 310 mg/m 2 , 320 mg/m 2 , 330 mg/m 2 , 340 mg/m 2 , 360 mg/m 2 , 370 mg/m 2 , 380 mg/m 2 , 390 mg/m 2 , 400 mg/
  • Each cycle of treatment/administration can have various lengths, for example, at least 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more.
  • the DNA-damaging agent is administered daily, semi-weekly, or weekly, for three weeks in a 28 day cycle.
  • the DNA-damaging agent is administered once in a 28 day cycle.
  • the DNA-damaging agent is administered for 1 to 10 cycles, for example, 1 to 9 cycles, 1 to 8 cycles, 1 to 7 cycles, 1 to 6 cycles, 1 to 5 cycles, 1 to 4 cycles, 1 to 3 cycles, 1 to 2 cycles, or 1 cycle.
  • the administration of the DNA-damaging agent can be daily weekly or monthly, and/or with break(s) between the administrations.
  • the break can be, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or more. In some embodiments, the break can be 6 days and/or 13 days.
  • the daily, weekly, or monthly dose of the DNA-damaging agent can be adjusted (e.g., increased or decreased with the range) during the treatment of the subject.
  • Each of the daily, weekly, or monthly administration of the DNA-damaging agent can be at different amounts.
  • the treatment can comprise weekly administration of the DNA-damaging agent at 360 mg/m 2 on day 1, 300 mg/m 2 on day 8, and 150 mg/m 2 on day 15.
  • the daily, weekly or monthly dose of the DNA-damaging agent can be, or be about, 10 mg/m 2 , 50 mg/m 2 , 100 mg/m 2 , 150 mg/m 2 , 200 mg/m 2 , 250 mg/m 2 , 300 mg/m 2 , 350 mg/m 2 , 400 mg/m 2 , 450 mg/m 2 , 500 mg/m 2 , 550 mg/m 2 , 600 mg/m 2 , 650 mg/m 2 , 700 mg/m 2 , 750 mg/m 2 , 800 mg/m 2 , 850 mg/m 2 , 900 mg/m 2 , 950 mg/m 2 , 1000 mg/m 2 , 1500 mg/m 2 , 2000 mg/m 2 , or a number or a range between any two of these values.
  • a patient is administered an effective dose of a corticosteroid (e.g., dexamethasone), a diphenhydramine, and/or H2 antagonists (e.g., cimetidine or famotidine) prior to administering the DNA-damaging agent.
  • a corticosteroid e.g., dexamethasone
  • a diphenhydramine e.g., a diphenhydramine
  • H2 antagonists e.g., cimetidine or famotidine
  • the DNA-damaging agent is carboplatin or gemcitabine.
  • a maximum concentration (C max ) of the DNA-damaging agent in a blood of the subject (during the treatment or after the treatment) when the DNA-damaging agent is administered alone or in combination with the PLK1 inhibitor can be from about 1 pg/mL to about 40 mg/mL.
  • the Cmax of the DNA-damaging agent in a blood of the subject when administered alone or in combination with the PLK1 inhibitor can be, or be about, 1 pg/mL, 1.1 pg/mL, 1.2 pg/mL, 1.3 pg/mL, 1.4 pg/mL, 1.5 pg/mL, 1.6 pg/mL, 1.7 pg/mL, 1.8 pg/mL, 1.9 pg/mL, 2 pg/mL, 2.1 pg/mL, 2.2 pg/mL, 2.3 pg/mL, 2.4 pg/mL, 2.5 pg/mL, 2.6 pg/mL, 2.7 pg/mL, 2.8 pg/mL, 2.9 pg/mL, 3 pg/mL, 3.1 pg/mL, 3.2 pg/mL, 3.3 pg/mL, 3.4 pg/m
  • the treatment of the present disclosure can comprise administration of the PLK1 inhibitor (e.g., onvansertib) for a desired duration in one or more cycles.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered for 1 to 10 cycles, for example, 1 to 9 cycles, 1 to 8 cycles, 1 to 7 cycles, 1 to 6 cycles, 1 to 5 cycles, 1 to 4 cycles, 1 to 3 cycles, 1 to 2 cycles, or 1 cycle.
  • Each cycle of treatment can have various lengths, for example, at least 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more.
  • the administration of the PLK1 inhibitor can be daily or with break(s) between days of administrations.
  • the break can be, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or more.
  • the administration can be once, twice, three times, four times, or more on a day when the PLK1 inhibitor is administered to the patient.
  • the administration can be, for example, once every two days, every three days, every four days, every five days, every six days, or every seven days.
  • the length of the desired duration can vary, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or more days.
  • Each cycle of treatment can have various lengths, for example, at least 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more.
  • a single cycle of the treatment can comprise administration of the PLK1 inhibitor for four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, fourteen days, fifteen days, sixteen days, seventeen days, eighteen days, nineteen days, twenty days, twenty-one days, twenty-two days, twenty-three days, twenty-four days, twenty -five days, twenty-six days, twenty-seven days, twenty-eight days, or more in a cycle (e.g., in a cycle of at least 21 days (e.g., 21 to 28 days)).
  • the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) for, or for at least, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, fourteen days, fifteen days, sixteen days, seventeen days, eighteen days, nineteen days, twenty days, or a range between any two of these values, in a cycle (e.g., a cycle of at least 21 days (e.g., 21 to 28 days)).
  • the administration of the PLK1 inhibitor in a single cycle of the treatment can be continuous or with one or more intervals (e.g., one day or two days of break).
  • the treatment comprises administration of the PLK1 inhibitor (e.g., onvansertib) for five days in a cycle of 14 to 28 days.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered daily for about 14 days, followed by a 7-day break.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered orally.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor (e.g., onvansertib) can be administered to the subject in need thereof on twenty days (e.g., Days 1-10 and 15-24) during a 28-day cycle.
  • the twenty days can be, for example, a continuous daily administration for ten days (e.g., Days 1-10) and another continuous daily administration (e.g., Days 15-24) for ten days, or a continuous daily administration for four sets of five days (e.g., Days 1-5, 8-12, 15-19, and 22-26).
  • the PLK1 inhibitor (e.g., onvansertib) is administered to the subject in need thereof on twenty-one days (e.g., Days 1-21) during a 28-day cycle.
  • the PLK1 inhibitor is administered to the subject in need thereof on ten days (e.g., Days 1-5 and 15- 19) during a 28-day cycle.
  • the ten days can be, for example, a continuous daily administration for ten days (e.g., Days 1-10) or two continuous daily admiration for five days each (e.g., Days 1-5 and Days 15-19).
  • the PLK1 inhibitor e.g., onvansertib
  • the subject can receive one, two, three, four, five, six, or more cycles of treatment.
  • the administration cycles, dosing schedules, and/or dosage amounts of the PLK1 inhibitor and the DNA-damaging agent can be the same or different.
  • the administration cycle, dosing schedule, and/or dosage amount of the DNA-damaging agent can be adjusted according to the administration cycle, dosing schedule, and/or dosage amount of the PLK1 inhibitor.
  • the DNA-damaging agent can be administered three times in a 28- day cycles (e.g., daily dose on Days 1, 8 and 15), which corresponds to a 28-day cycle for administration of the PLK1 inhibitor (e.g., onvansertib).
  • a 28-day cycle for administration of the PLK1 inhibitor (e.g., onvansertib).
  • the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 6 mg/m 2 - 90 mg/m 2 drug/body surface area, for example, as a daily dose.
  • the treatment can comprise daily administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 6 mg/m 2 , 8 mg/m 2 , 10 mg/m 2 , 12 mg/m 2 , 14 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , 20 mg/m 2 , 23 mg/m 2 , 27 mg/m 2 , 30 mg/m 2 , 35 mg/m 2 , 40 mg/m 2 , 45 mg/m 2 , 50 mg/m 2 , 55 mg/m 2 , 60 mg/m 2 , 65 mg/m 2 , 70 mg/m 2 , 80 mg/m 2 , 85 mg/m 2 , 90 mg/m 2 , a number or
  • the daily dose of the PLK1 inhibitor can be adjusted (e.g., increased or decreased with the range) during the treatment, or during a single cycle (e.g., the first cycle, the second cycle, the third cycle, and a subsequent cycle) of the treatment, for the subject.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered at 12 mg/m 2 on twenty days (e.g., Days 1-10 and 15-24) during a 28-day cycle.
  • the PLK1 inhibitor (e.g., onvansertib) is administered at 15 mg/m 2 on ten days (e.g., Days 1-5 and 15-19) during a 28-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 8 mg/m 2 or 10 mg/m 2 everyday (e.g., Days 11-28) during a 28-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg/m 2 5 days a week during an 18-day cycle.
  • the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg/m 2 5 days a week during a 32-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg/m 2 5 days a week during a 39-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg/m 2 5 days a week during a 45-day cycle.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered at 45 mg/m 2 5 days a week during a cycle (e.g., 30-day, 31-day, 32-day, 33-day, 34- day, 35-day, 36-day, 37-day, 38-day, 39-day or 40-day cycle) with no administration of the PLK1 inhibitor (e.g., onvansertib) for one week.
  • the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 5 mg - 200 mg, for example, as a daily dose.
  • the treatment can comprise daily administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 5 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 23 mg, 27 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, a number or a range between any two of these values, or any value between 5 mg - 200 mg.
  • the daily dose of the PLK1 inhibitor can be adjusted (e.g., increased or decreased with the range) during the treatment, or during a single cycle (e.g., the first cycle, the second cycle, the third cycle, and a subsequent cycle) of the treatment, for the subject.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered at 12 mg on twenty days (e.g., Days 1-10 and 15-24) during a 28-day cycle.
  • the PLK1 inhibitor (e.g., onvansertib) is administered at 15 mg on ten days (e.g., Days 1-5 and 15-19) during a 28- day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 8 mg or 10 mg everyday (e.g., Days 11-28) during a 28-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg 5 days a week during a 18-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg 5 days a week during a 32-day cycle.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered at 45 mg 5 days a week during a 39-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg 5 days a week during a 45-day cycle.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered at 45 mg 5 days a week during a cycle (e.g., 30-day, 31-day, 32-day, 33-day, 34-day, 35-day, 36-day, 37-day, 38-day, 39- day or 40-day cycle) with no administration of the PLK1 inhibitor (e.g., onvansertib) for one week.
  • a cycle e.g., 30-day, 31-day, 32-day, 33-day, 34-day, 35-day, 36-day, 37-day, 38-day, 39- day or 40-day cycle
  • other dosing unit mg/kg
  • the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 5 mg/kg - 200 mg/kg, for example, as a daily dose.
  • the treatment can comprise daily administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 5 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, 14 mg/kg, 16 mg/kg, 18 mg/kg, 20 mg/kg, 23 mg/kg, 27 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 100 mg/kg, 110 mg/kg, 120 mg/kg, 130 mg/kg, 140 mg/kg, 150 mg/kg, 160 mg/kg, 170 mg/kg, 180 mg/kg, 190 mg/kg, 200 mg
  • the treatment can comprise administration of the PLK1 inhibitor (e.g., onvansertib) at, or at about, 0.05 mg/kg - 50 mg/kg, for example, as a daily dose.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered at 45 mg/kg 5 days a week during a 18-day cycle.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor is administered at 45 mg/kg 5 days a week during a 32-day cycle.
  • the PLK1 inhibitor e.g., onvansertib
  • the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg/kg 5 days a week during a 45-day cycle. In some embodiments, the PLK1 inhibitor (e.g., onvansertib) is administered at 45 mg/kg 5 days a week during a cycle (e.g., 30- day, 31-day, 32-day, 33-day, 34-day, 35-day, 36-day, 37-day, 38-day, 39-day or 40-day cycle) with no administration of the PLK1 inhibitor (e.g., onvansertib) for one week.
  • a cycle e.g., 30- day, 31-day, 32-day, 33-day, 34-day, 35-day, 36-day, 37-day, 38-day, 39-day or 40-day cycle
  • the daily dose of the PLK1 inhibitor can be adjusted (e.g., increased or decreased with the range) during the treatment, or during a single cycle (e.g., the first cycle, the second cycle, the third cycle, and a subsequent cycle) of the treatment, for the subject.
  • a maximum concentration (Cmax) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject (during the treatment or after the treatment) when the PLK1 inhibitor is administered alone or in combination with DNA-damaging agent can be from about 100 nmol/L to about 1500 nmol/L.
  • the Cmax of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the DNA- damaging agent can be, or be about, 100 nmol/L, 200 nmol/L, 300 nmol/L, 400 nmol/L, 500 nmol/L, 600 nmol/L, 700 nmol/L, 800 nmol/L, 900 nmol/L, 1000 nmol/L, 1100 nmol/L, 1200 nmol/L, 1300 nmol/L, 1400 nmol/L, 1500 nmol/L, a range between any two of these values, or any value between 200 nmol/L to 1500 nmol/L.
  • the PLK1 inhibitor e.g., onvansertib
  • An area under curve (AUC) of a plot of a concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject over time (e.g., AUC0-24 for the first 24 hours after administration) when the PLK1 inhibitor is administered alone or in combination with the DNA- damaging agent can be from about 1000 nmol/L. hour to about 400000 nmol/L. hour.
  • the AUC of a plot of a concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject over time (e.g., AUC0-24 for the first 24 hours after administration) when the PLK1 inhibitor is administered alone or in combination with the DNA-damaging agent can be, or be about, 1000 nmol/L. hour, 5000 nmol/L. hour, 10000 nmol/L. hour, 15000 nmol/L. hour, 20000 nmol/L. hour, 25000 nmol/L. hour, 30000 nmol/L. hour, 35000 nmol/L. hour, 40000 nmol/L. hour, a range between any two of these values, or any value between 1000 nmol/L. hour and 400000 nmol/L. hour.
  • the PLK1 inhibitor e.g., onvansertib
  • a time (T max ) to reach a maximum concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the DNA-damaging agent can be from about 1 hour to about 5 hours.
  • the time (Tmax) to reach a maximum concentration of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the DNA-damaging agent can be, or be about, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, a range between any two of these values, or any value between 1 hour and 5 hours.
  • An elimination half-life (T1/2) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the DNA-damaging agent can be from about 10 hours to about 60 hours.
  • the elimination half-life (T1/2) of the PLK1 inhibitor (e.g., onvansertib) in a blood of the subject when the PLK1 inhibitor is administered alone or in combination with the DNA-damaging agent can be, or be about, 10 hours, 15 hours, 20 hours, 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 50 hours, 55 hours, 60 hours, a range between any two of these values, or any value between 10 hours and 60 hours.
  • Patients administered one or more dose cycles of the PLK1 inhibitor in combination with one or more dose cycles of the DNA-damaging agent can exhibit very tolerable AE, including in some cases undetectable definite AE or definite SAE.
  • a remarkable, but unlikely result is the finding that the patient has no probable or even possible AE or SAE.
  • treated with the combined therapy of the PLK1 inhibitor and the DNA-damaging agent can lead to remarkable therapeutic effect.
  • a therapeutic effect greater than the therapeutic effect predicted from in vitro or in silico is indicative of a surprising result.
  • a therapeutic dose lower than the therapeutic dose predicted from in vitro or in silico is indicative of a surprising result. It is expected that the combination treatment can mitigate disease progression in patients.
  • a highly positive result is the finding that the combination therapy can lead to stable disease.
  • a remarkable, but unlikely result is the finding of a complete response or complete remission of the cancer, a progression-free survival, an overall survival rate exceeding values predicted from in vitro or in silico analysis, is free of any measurable lesion, free of any target lesion, or free of any malignant lymph nodes.
  • a method for treating cancer comprises administrating a PLK1 inhibitor and a DNA-damaging agent to a subject (e.g., a patient) in need thereof.
  • the method can comprise administering a therapeutically effective amount of the PLK1 inhibitor and a therapeutically effective amount of the DNA-damaging agent.
  • the treatment can comprise administration of at least one additional cancer therapeutics or cancer therapy.
  • the treatment can comprise administration of a therapeutically effective amount of at least one additional cancer therapeutics or cancer therapy.
  • the PLK1 inhibitor and the cancer therapeutics or cancer therapy can, for example, be co-administered simultaneously or sequentially.
  • the DNA-damaging agent and the cancer therapeutics or cancer therapy can, for example, be co-administered simultaneously or sequentially.
  • Additional cancer therapeutics or therapies in treating cancer are identifiable to a skilled artisan.
  • the at least one additional cancer therapeutics or cancer therapy is not administered to the subject (e.g., PLK1 inhibitor and the DNA-damaging agent only are administered to the subject).
  • Exemplary additional cancer therapeutics or therapies in treating cancer include, but are not limited to, surgery, chemotherapy, targeted therapy, immunotherapy, radiation therapy, hormone therapy, and neoadjuvant systemic therapy.
  • Also disclosed herein include methods, compositions, kits, and systems for predicting/determining clinical outcome for a combination treatment of cancer of the present disclosure, monitoring of the combination treatment, predicting/determining responsiveness of a subject to the combination treatment, determining the status of the cancer in a subject, and improving combination treatment outcome.
  • the methods, compositions, kits and systems can be used to guide the combination treatment, provide combination treatment recommendations, and/or reduce or avoid unnecessary ineffective combination treatment for patients.
  • ctDNA can be analyzed to predict/determine clinical outcome for cancer treatment using a combination of the PLK1 inhibitor and the DNA-damaging agent of the present disclosure, monitor the combination treatment, predict/determine responsiveness of a subject to the combination treatment, determine cancer status in a subject, improve combination treatment outcome, guide combination treatment, provide combination treatment recommendations, and/or to reduce or avoid ineffective combination treatment.
  • ctDNA can be analyzed to predict/determine clinical outcome for cancer treatment, monitor cancer treatment, predict/determine responsiveness of a subject to a cancer treatment, determine cancer status in a subject, improve cancer treatment outcome, guide cancer treatment, provide treatment recommendations, and/or to reduce or avoid ineffective cancer treatment.
  • Such analysis of ctDNA has been described in PCT Application No. PCT/US2021/013287, the content of which is incorporated herein by reference in its entirety.
  • a method of determining responsiveness of a subject to a combination treatment comprising the PLK1 inhibitor and the DNA-damaging agent of the disclosure can comprise, for example, analyzing circulating tumor DNA (ctDNA) of a subject with cancer, the subject is undergoing a treatment and/or has received the combination treatment, thereby determining the responsiveness of the subj ect to the combination treatment.
  • determining the responsiveness of the subject comprises determining if the subject is a responder of the treatment, if the subject is or is going to be in CR, or if the subject is or is going to be in partial remission (PR).
  • analyzing ctDNA can comprise detecting variant allele frequency in the ctDNA in a first sample obtained from the subject at a first time point, detecting variant allele frequency in the ctDNA obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, a decrease in the variant allele frequency in at least one of the additional samples relative to the first sample indicates the subject as responsive to the cancer treatment.
  • the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
  • the method comprises continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment.
  • the method comprises discontinuing the combination treatment to the subject and/or starting a different combination treatment to the subject if the subject is not indicated as responsive to the combination treatment.
  • Disclosed herein include methods of determining cancer status of a subject, comprising analyzing circulating tumor DNA (ctDNA) of a subject, thereby determining cancer status of the subject.
  • the subject can be a subject undergoing a current combination treatment comprising the PLK1 inhibitor and the DNA-damaging agent of the present disclosure, a subject that has received a prior combination treatment of the present disclosure, and/or a subject that is in remission for the cancer.
  • the subject in remission for cancer can be in complete remission (CR), or in partial remission (PR).
  • analyzing the ctDNA comprises detecting variant allele frequency in the ctDNA. In some embodiments, analyzing the ctDNA comprises detecting variant allele frequency in the ctDNA obtained from the subject at a first time point in a first sample, detecting variant allele frequency in the ctDNA obtained from the subject at one or more additional time points in one or more additional samples, and determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, an increase in the variant allele frequency at the additional sample(s) relative to the first sample indicates that the subject is at risk of cancer relapse or is in cancer relapse.
  • the first time point is prior or immediately prior to the combination treatment, and the one or more additional time points are at the end of or after at least a cycle of the combination treatment, optionally the cycle of the combination treatment is the first cycle of the combination treatment.
  • the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment, optionally the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
  • the method comprises starting an additional treatment of the subject if the subject is indicated as in cancer relapse.
  • the additional treatment can be the same or different from the current or prior combination treatment.
  • the variant allele frequency in ctDNA can be determined, for example, by total mutation count in the ctDNA in each of the first sample and one or more additional samples, or by the mean variant allele frequency in each of the first sample and one or more additional samples.
  • the variant allele frequency is mutant allelic frequency (MAF) for a driver mutation of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, or a combination thereof).
  • the variant allele frequency is MAF for one or more driver mutations of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, or a combination thereof).
  • Log2(Ci/Co) ⁇ a MAF threshold indicates a decrease in ctDNA MAF Co is ctDNA MAF in the first sample and Ci is ctDNA MAF in one of the additional samples.
  • the MAF threshold is, or is about, 0.01 to -0.10. In some embodiments, the MAF threshold is, or is about, 0.06. In some embodiments, the MAF threshold is, or is about, 0.05.
  • the first sample comprises ctDNA from the subject before treatment
  • the one of additional samples comprises ctDNA from the subject after treatment.
  • the driver mutation is a mutation in one of the below 75 genes: ABL1, ANKRD26, ASXL1, ATRX, BCOR, BCORL1, BRAF, BTK, CALR, CBL, CBLB, CBLC, CCND2, CDC25C, CDKN2A, CEBPA, CSF3R, CUX1, CXCR4, DCK, DDX41, DHX15, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, LUC7L2, MAP2K1, MPL, MYC, MYD88, NF1, NOTCH1, NPM1, NRAS,
  • the driver mutation or at least one of the one or more driver mutations can be in a gene selected from the group consisting of TP53, ASXL1, DNMT3A, NRAS, SRSF2, TET2, SF3B1, FLT3, FLT3 ITD, IDH2, NPM1, RUNX1, CDKN2A, KRAS, STAG2, CALR, CBL, CSF3R, DDX41, GATA2, JAK2, PHF6, and SETBP1.
  • the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of DNMT3A, TET2, NPM1, SRSF2, NRAS, CDKN2A, SF3B1, FLT3, ASXL1, SRSF2, IDH2, NRAS, and SF3B1.
  • the method further comprises determining variant allele frequency in one or more of the ctDNA, PBMCs and BMMCs of the subject.
  • the ctDNA can be analyzed using, for example, polymerase chain reaction (PCR), next generation sequencing (NGS), and/or droplet digital PCR (ddPCR).
  • PCR polymerase chain reaction
  • NGS next generation sequencing
  • ddPCR droplet digital PCR
  • the sample disclosed herein can be derived from, for example, whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
  • the ctDNA is from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
  • the method comprises analyzing ctDNA of the subject before the treatment.
  • the treatment comprises one or more cycles, and the ctDNA is analyzed before, during and after each cycle of the treatment.
  • Each cycle of treatment can be at least 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, the subject is human.
  • the method can comprise: detecting variant allele frequency in circulating tumor DNA (ctDNA) obtained from a subject at a first time point in a first sample before the subject undergoes a combination treatment comprising the PLK1 inhibitor and the DNA-damaging agent of the present disclosure; detecting variant allele frequency in ctDNA obtained from the subject at one or more additional time points in one or more additional samples after the subject undergoes the combination treatment; determining the difference of the variant allele frequency in ctDNA between the first and at least one of the one or more additional samples, a decrease in the variant allele frequency in at least one of the additional samples relative to the first sample indicates the subject as responsive to the combination treatment; and continuing the combination treatment to the subject if the subject is indicated as responsive to the combination treatment, or discontinuing the combination treatment to the subject and/or starting a different cancer treatment to the subject if the subject is not indicated as responsive to the combination treatment.
  • ctDNA circulating tumor DNA
  • Also disclosed herein include methods of treating cancer (e.g., ovarian cancer).
  • the method can comprise: administering a combination treatment comprising the PLK1 inhibitor and the DNA-damaging agent of the present disclosure to a subject in need thereof; determining a decrease, relative to a variant allele frequency in a first sample of the subject obtained at a first time point before the subject receives the combination treatment, in a variant allele frequency in a second sample of the subject obtained at a second time point after the subject receives the combination treatment; and continuing with the combination treatment.
  • the subject is a subject newly diagnosed with cancer, for example a subject that has not received any prior cancer treatment before the combination treatment.
  • the subject has received prior cancer treatment and was in remission for the cancer, for example a subject in complete remission (CR), or in partial remission (PR) after receiving the prior combination treatment.
  • the first time point can be, for example, prior or immediately prior to the combination treatment.
  • the at least one of the one or more additional time points can be, for example, at the end of or after at least a cycle of the combination treatment.
  • the cycle of the combination treatment is the first cycle of the combination treatment.
  • the first time point is prior or immediately prior to a first cycle of the combination treatment, and the one or more additional time points are at the end of or after a second cycle of the combination treatment.
  • the first cycle of the combination treatment is immediately prior to the second cycle of the combination treatment.
  • the variant allele frequency in ctDNA can be determined, for example, by total mutation count in the ctDNA in each of the first sample and one or more additional samples, and/or by the mean variant allele frequency in each of the first sample and one or more additional samples.
  • the variant allele frequency is mutant allelic frequency (MAF) for a driver mutation of the cancer (e.g., ovarian cancer, breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, or a combination thereof).
  • the variant allele frequency is mutant allelic frequency (MAF) for one or more driver mutations of the cancer (e.g., ovarian cancer).
  • Log2(Ci/Co) ⁇ a MAF threshold indicates a decrease in ctDNA MAF Co is ctDNA MAF in the first sample and Ci is ctDNA MAF in one of the additional samples.
  • the MAF threshold is -0.05.
  • the driver mutation can be, for example, a mutation in one of the following 75 genes: ABL1, ANKRD26, ASXL1, ATRX, BCOR, BCORL1, BRAF, BTK, CALR, CBL, CBLB, CBLC, CCND2, CDC25C, CDKN2A, CEBPA, CSF3R, CUX1, CXCR4, DCK, DDX41, DHX15, DNMT3A, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, LUC7L2, MAP2K1, MPL, MYC, MYD88, NF1, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PPM1D, PTEN, PTPN11, RAD21, RBBP6, RPS14, RUNX1,
  • the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of TP53, ASXL1, DNMT3A, NRAS, SRSF2, TET2, SF3B1, FLT3, FLT3 ITD, IDH2, NPM1, RUNX1, CDKN2A, KRAS, STAG2, CALR, CBL, CSF3R, DDX41, GATA2, JAK2, PHF6, and SETBP 1.
  • the driver mutation or at least one of the one or more driver mutations is in a gene selected from the group consisting of DNMT3A, TET2, NPM1, SRSF2, NRAS, CDKN2A, SF3B1, FLT3, ASXL1, SRSF2, IDH2, NRAS, and SF3B1.
  • the method further comprises determining variant allele frequency in one or more of the ctDNA, PBMCs and BMMCs of the subject.
  • the variant allele frequency in ctDNA can be detected, for example, using polymerase chain reaction (PCR) or next generation sequencing (NGS).
  • PCR polymerase chain reaction
  • NGS next generation sequencing
  • the variant allele frequency in ctDNA is detected using droplet digital PCR (ddPCR).
  • At least one of the first sample, the one or more additional samples, and the second sample can be derived from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
  • the ctDNA is from whole blood of the subject, plasma of the subject, serum of the subject, or a combination thereof.
  • the subject whose ctDNA is analyzed is undergoing or will be undergoing treatment for the cancer.
  • the method can comprise analyzing ctDNA of the subject before the treatment.
  • the treatment can comprise one or more cycles, and the ctDNA is analyzed before, during and after one or more cycles of the treatment.
  • the ctDNA can be analyzed before, during and after two or more cycle of the treatment, three or more cycle of the treatment, or each cycle of the treatment.
  • Each cycle of treatment can be at least 21 days, for example, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or more, or a range between any two of these values.
  • each cycle of treatment is from about 21 days to about 28 days.
  • each cycle of treatment is from 21 days to 28 days.
  • the subject is human.
  • one or more markers of DNA-damage and/or apoptosis are elevated in the subject (e.g., the cancer cells), following treatment.
  • Caspase levels can be increased in a plurality of cancer cells of the subject, following at least one cycle of treatment.
  • administration of the PLK1 inhibitor and the DNA-damaging agent results in an increase in apoptosis and/or induction of mitotic arrest of cancer cells in the subject, relative to the cancer cells prior to the administration.
  • administration of the PLK1 inhibitor and the DNA-damaging agent results in at least a 0.5-fold decrease in phosphorylated translationally-controlled tumor protein (p-TCTP) levels, relative to the cancer cells prior to the administration.
  • p-TCTP phosphorylated translationally-controlled tumor protein
  • administration of the PLK1 inhibitor and the DNA- damaging agent results in at least a 0.5-fold increase in cleaved caspase-3 (cl-casp3) levels, relative to the cancer cells prior to the administration.
  • administration of the PLK1 inhibitor and the DNA-damaging agent results in at least a 0.5-fold increase in cleaved Poly (ADP -ribose) polymerase (cl-PARP) levels, relative to the cancer cells prior to the administration.
  • administration of the PLK1 inhibitor and the DNA-damaging agent results in at least a 0.5-fold decrease in c-Myc protein levels, relative to the cancer cells prior to the administration.
  • administration of the PLK1 inhibitor and the DNA- damaging agent results in at least a 0.5-fold increase in phosphorylated histone H3 (p-HH3) relative to the cancer cells prior to the administration.
  • the phosphorylation of histone H3 is on serine 10.
  • administration of the PLK1 inhibitor and the DNA-damaging agent results in at least a 0.5-fold increase in phosphorylated histone H2AX to the cancer cells prior to the administration.
  • the phosphorylation of histone H2AX is on serine 139.
  • administration of the PLK1 inhibitor and the DNA- damaging agent results in at least a 0.5-fold decrease in phosphorylated translationally-controlled tumor protein (pTCTP) levels, relative to administration of PLK1 inhibitor alone and/or the DNA- damaging agent alone.
  • administration of the PLK1 inhibitor and the DNA- damaging agent results in at least a 0.5-fold increase in cleaved caspase-3 (cl-casp3) levels, relative to administration of the PLK1 inhibitor alone and/or the DNA-damaging agent alone.
  • administration of the PLK1 inhibitor and the DNA-damaging agent results in at least a 0.5-fold increase in cleaved Poly (ADP-ribose) polymerase (cl -P ARP) levels, relative to administration of the PLK1 inhibitor alone and/or the DNA-damaging agent alone. In some embodiments, administration of the PLK1 inhibitor and the DNA-damaging agent results in at least a 0.5-fold decrease in c-Myc protein levels, relative to administration of the PLK1 inhibitor alone and/or the DNA-damaging agent alone.
  • cl -P ARP cleaved Poly (ADP-ribose) polymerase
  • administration of the PLK1 inhibitor and the DNA-damaging agent results in at least a 0.5-fold increase in phosphorylated histone H3 (p-HH3), relative to administration of the PLK1 inhibitor alone and/or the DNA- damaging agent alone. In some embodiments, administration of the PLK1 inhibitor and the DNA- damaging agent results in at least a 0.5-fold increase in phosphorylated histone H2AX, relative to administration of the PLK1 inhibitor alone and/or the DNA-damaging agent alone.
  • body weight of the subject decreases by no more than 20% (e.g., by 0.000000001%, 0.00000001%, 0.0000001%, 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a number or a range between any two of these values) following at least one cycle of treatment.
  • weight of one or more tumors of the subject decreases by at least 25% (e.g., by at least 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, or a number or
  • kits comprising: a PLK1 inhibitor; a DNA-damaging agent; and a manual providing instructions for co-administering the PLK1 inhibitor and the DNA-damaging agent to a subject in need thereof for treating ovarian cancer.
  • the ovarian cancer can be high-grade serous ovarian carcinoma (HGSOC), endometrioid carcinoma, low-grade serous ovarian carcinoma (LGSOC), mucinous carcinoma, ovarian clear cell carcinoma (OCCC), or primary squamous cell carcinoma (SCC) of the ovary.
  • HGSOC high-grade serous ovarian carcinoma
  • LGSOC low-grade serous ovarian carcinoma
  • OCCC mucinous carcinoma
  • OCCC ovarian clear cell carcinoma
  • SCC primary squamous cell carcinoma
  • the DNA-damaging agent can be an alkylating agent, an antimetabolite, a topoisomerase inhibitor, or an antitumor antibiotic.
  • the DNA-damaging agent can be altretamine, bendamustine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechlorethamine, melphalan, oxaliplatin, procarbazine, temozolomide, thiotepa, trabectedin, carmustine, lomustine, streptozocin, 5 -fluorouracil, 6-mercaptopurine, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, nelarabine, pemetrexed, pentostatin
  • the PLK1 inhibitor can be onvansertib (NMS-P937), BI2536, volasertib (BI 6727), GSK461364, adavosertib (AZD1775), CYC140, HMN-176, HMN-214, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960, GTPL10072, Ro3280; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; or any combination thereof.
  • the DNA-damaging agent can be gemcitabine or carboplatin and/or the PLK1 inhibitor can be onvansertib.
  • the instructions can comprise instructions for co-administrating the PLK1 inhibitor and the DNA-damaging agent simultaneously.
  • the instructions can comprise instructions for administrating the PLK1 inhibitor and the DNA-damaging agent sequentially.
  • the instructions can comprise instructions for administering to a subject that did not respond to treatment with the PLK1 inhibitor or the DNA-damaging agent alone.
  • the instructions can comprise instructions for administering to a subject resistant to at least one platinum-based chemotherapeutic agent.
  • the at least one platinum-based chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • the DNA-damaging agent can be a platinum based DNA-damaging agent.
  • the platinum-based DNA-damaging agent and the platinum-based chemotherapeutic agent can be the same or different.
  • the instructions comprise instructions for administering the PLK1 inhibitor and/or the DNA-damaging agent orally.
  • the instructions comprise instructions for administering the PLK1 inhibitor and/or the DNA-damaging agent intravenously. In some embodiments, the instructions comprise instructions for administering the PLK1 inhibitor (e.g., onvansertib) orally and the DNA-damaging agent (e.g., gemcitabine and/or carboplatin) intravenously.
  • the PLK1 inhibitor e.g., onvansertib
  • the DNA-damaging agent e.g., gemcitabine and/or carboplatin
  • the instructions can comprise instructions the subject has received at least one prior treatment for the cancer.
  • the prior treatment does not comprise the use of a PLK1 inhibitor, a DNA-damaging agent, or both.
  • the instructions comprise instructions the subject was in remission for the cancer.
  • the subject in remission for cancer was in complete remission (CR), or in partial remission (PR).
  • the instructions can comprise instructions for administering each of the PLK1 inhibitor and the DNA-damaging agent to the subject in a cycle of at least once or twice within a week. In some embodiments, the instructions comprise instructions for administering each of the PLK1 inhibitor and the DNA-damaging agent to the subject in a cycle of at least five times within a week. In some embodiments, the instructions comprise instructions for administering the PLK1 inhibitor, the DNA-damaging agent, or both are in a cycle of at least 7 days. In some embodiments, each cycle of treatment is at least about 14 days to about 21 days. In some embodiments, each cycle of treatment is from about 21 days to about 28 days. In some embodiments, each cycle of treatment is from about 28 days to about 35 days.
  • each cycle of treatment is from about 35 days to about 42 days. In some embodiments, each cycle of treatment is from about 42 days to about 49 days.
  • the instructions comprise instructions for administering the PLK1 inhibitor on at least four days in the cycle. In some embodiments, the instructions comprise instructions for not administering the PLK1 inhibitor on at least one day in the cycle. In some embodiments, the instructions comprise instructions for administrating PLK1 inhibitor daily. In some embodiments, the instructions comprise instructions for administrating the DNA-damaging agent once or twice a week. In some embodiments, the instructions comprise instructions for administrating the DNA-damaging agent once or twice a month (e.g., in a 28-day cycle). In some embodiments, the instructions comprise instructions for administrating the DNA- damaging agent and the PLK1 inhibitor for at least two cycles (e.g., 2, 3, 4, 5, 6, or more cycles).
  • the instructions comprise dosing guidelines for administering the PLK1 inhibitor and the DNA-damaging agent. In some embodiments, the instructions comprise instructions for administering the PLK1 inhibitor at 8 mg/m 2 - 90 mg/m 2 . In some embodiments, the instructions comprise instructions for administering the PLK1 inhibitor (e.g., onvansertib) at a dose from about 10 mg/kg of body weight to about 80 mg/kg of body weight, optionally at a dose from about 20 mg/kg of body weight to about 60 mg/kg of body weight, optionally at a dose from about 30 mg/kg of body weight to about 50 mg/kg of body weight.
  • the PLK1 inhibitor e.g., onvansertib
  • the instructions comprise instructions for administering the DNA- damaging agent at a dose from about 100 mg/m 2 -2000 mg/m 2 . In some embodiments, the instructions comprise instructions for administering the DNA-damaging agent at a dose from about 200 mg/m 2 -360 mg/m 2 . In some embodiments, the instructions comprise instructions for administering the DNA-damaging agent at a dose from about 500 mg/m 2 -1250 mg/m 2 .
  • Example 1 Onvansertib-based second line therapies in combination with gemcitabine and carboplatin in patient derived-platinum resistant ovarian carcinomas
  • onvansertib ONV
  • CARBO carboplatin
  • GEM gemcitabine
  • PLK1 has been identified as a new potential therapeutic target in cancer and onvansertib is an oral, third-generation PLK1 inhibitor in clinical development in both haematological and solid tumors. Recently, the manageable safety profile and promising antitumor activity of the combination of onvansertib/FOLIFRI/bevacizumab in second-line treatment of patients with AVMS'-mutant metastatic colorectal cancer was reported. A Phase lb study with a small number of patients reported overall response rate (ORR) was remarkable (43.7%) and higher than the historical response rate to FOLFIRI/bevacizumab.
  • ORR overall response rate
  • Ovcar 8 cells were seeded and after 48 hrs were treated with different concentrations of onvansertib and carboplatin or gemcitabine After 5 days, cellular viability was evaluated by MTS assay. Data were analyzed using Combenefit software.
  • PDXs patient-derived xenografts
  • PDXs patient-derived xenografts
  • MNHOC266R derived from a cisplatin (DDP)-sensitive PDX was made resistant through multiple in vivo DDP treatment cycles.
  • NCr-nu/nu mice Five-week-old female NCr-nu/nu mice were obtained from Envigo Laboratories (Italy) and maintained under specific pathogen-free conditions. Procedures involving animals were conducted in conformity with the following laws, regulations, and policies governing the care and use of laboratory animals: Italian Governing Law (D. 1g 26/2014; authorization no,19/2008-A issued 6 March 2008 by the Ministry of Health); Mario Negri Institutional Regulations and Policies (Quality Management System Certificate: UNI EN ISO 9001 :2015, reg. no. 6121), and the NIH Guide for the Care and Use of Laboratory Animals (2011 edition); and EU directive and guidelines (EEC Council Directive 2010/63/UE).
  • Italian Governing Law D. 1g 26/2014; authorization no,19/2008-A issued 6 March 2008 by the Ministry of Health
  • Mario Negri Institutional Regulations and Policies Quantality Management System Certificate: UNI EN ISO 9001 :2015, reg. no. 6121), and the NIH Guide for the Care and Use
  • Tumor growth was measured twice weekly with a Vernier caliper, and tumor volume (mm 3 ) were calculated as follows: (length (mm) x width 2 (mm 2 ))/2, where width ⁇ length).
  • mice were weighted three times a week.
  • the selected PDXs were intraperitoneally (i.p.) or subcutaneously (s.c.) transplanted in NCr-nu/nu mice and randomized into the following groups: 1) Control/ vehicle- treated group; 2) Onvansertib (40 mg/kg, oral, 5 days/week for 4 weeks, p.o.); 3) Carboplatin (50 mg/kg, i.v. q7x4, once a week for 4 weeks); 4) Gemcitabine (60 mg/kg, i.p. q7x4, once a week for 4 weeks); 5) Combination of onvansertib and carboplatin; and 6) Combination of onvansertib and gemcitabine.
  • Onvansertib 40 mg/kg, oral, 5 days/week for 4 weeks, p.o.
  • Carboplatin 50 mg/kg, i.v. q7x4, once a week for 4 weeks
  • Gemcitabine 60 mg/kg, i.p
  • MNHOC315 and MNHOC266R bearing mice were treated with the doses previously reported for four consecutive days at the same dose and frequency as for the efficacy studies, and then euthanized at 4 hrs and 24 hrs after the last treatment.
  • Tumor samples were both formalin-fixed paraffin-embedded (FFPE) and snap frozen for apoptosis induction measured by the Caspase-Glo3/7® kit (Promega).
  • the proteins were transferred to nitrocellulose membranes (PROTRAN, Schleicher and Shull) and immunoblotting carried out with the following antibodies and visualized using Odyssey FC Imaging System (Li-COR): anti-Pactin (C-l l) (sc-47778, Santa Cruz Biotechnology); anti-phospho-Histone H3 (SerlO) (6G3) (#9706, Cell Signaling Technology); anti- phospho-H2AX (pSerl39) (#9718, Cell Signaling); and anti-goat (sc-2354 Santa Cruz Biotechnology), anti-rabbit and anti-mouse (#1706515, #1706516, Bio-Rad Laboratories S.r.l.) secondary antibodies conjugated with horseradish peroxidase (HRP).
  • HRP horseradish peroxidase
  • Caspase-3 activity was measured by an enzymatic assay using the Caspase- Glo®3/7 kit (Promega Corporation) following manufacturer instructions. Tumor protein extracts were dispensed in a white 96-well plate and incubated at room temperature for 45 min. Then, luminescence was read by using a plate reader (GloMax Discover, Promega Corporation). Caspase activity was expressed as mean relative light units (RLU) normalized to the protein concentration.
  • RLU relative light units
  • Onvansertib was synergistic in combination with carboplatin or gemcitabine in the human ovarian cancer cell line OVCAR8 (FIG. 1A-FIG. IB). Both combinations were well tolerated in vivo. Even if a decrease in body weight was observed, it never exceeded 20% and reverted upon drugs withdrawal (FIG. 2A-FIG. 2B).
  • Two PDX models were selected from a xenobank: one with acquired resistance to DDP (#266R) obtained after multiple in vivo drug treatments and the other (#315) with intrinsic DDP resistance to test the antitumor activity of onvansertib, gemcitabine, carboplatin and their combinations. After randomization, mice were treated with vehicle, single agents or the combinations; Onvansertib/gemcitabine and onvansertib/carboplatin combinations were well tolerated, as body weight loss never exceeded 8% and was reversible in all cases after drug withdrawal (FIG. 2A-FIG. 2B and FIG. 4A-FIG. 4B).

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Abstract

L'invention propose des procédés, des compositions et des kits pour le traitement du cancer de l'ovaire (par exemple, le cancer de l'ovaire résistant au platine) chez un sujet. Le procédé peut consister à administrer une combinaison d'un inhibiteur de PLK1 et d'un agent endommageant l'ADN (par exemple, le carboplatine ou la gemcitabine) au sujet d'une manière suffisante pour inhiber la progression du cancer.
PCT/US2025/018236 2024-03-04 2025-03-03 Utilisation d'un inhibiteur de plk1 en combinaison de gemcitabine ou de carboplatine dans le traitement du carcinome ovarien Pending WO2025188680A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210222228A1 (en) * 2018-08-26 2021-07-22 Cardiff Oncology, Inc. Plk1 target phosphorylation status and treatment of cancer with plk1 inhibitors
WO2022217060A1 (fr) * 2021-04-09 2022-10-13 Cardiff Oncology, Inc. Cancérothérapie à l'aide d'inhibiteurs de parp et d'inhibiteurs de plk1
WO2022213204A1 (fr) * 2021-04-07 2022-10-13 Repare Therapeutics Inc. Polythérapies comprenant des inhibiteurs de mytl
WO2023167549A1 (fr) * 2022-03-04 2023-09-07 Sillajen, Inc. Combinaisons pharmaceutiques destinées à être utilisées dans le traitement du maladies néoplasiques
WO2023235716A2 (fr) * 2022-05-31 2023-12-07 Cardiff Oncology, Inc. Traitement du cancer à l'aide d'inhibiteurs de topoisomérase i et d'inhibiteurs de plk1

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210222228A1 (en) * 2018-08-26 2021-07-22 Cardiff Oncology, Inc. Plk1 target phosphorylation status and treatment of cancer with plk1 inhibitors
WO2022213204A1 (fr) * 2021-04-07 2022-10-13 Repare Therapeutics Inc. Polythérapies comprenant des inhibiteurs de mytl
WO2022217060A1 (fr) * 2021-04-09 2022-10-13 Cardiff Oncology, Inc. Cancérothérapie à l'aide d'inhibiteurs de parp et d'inhibiteurs de plk1
WO2023167549A1 (fr) * 2022-03-04 2023-09-07 Sillajen, Inc. Combinaisons pharmaceutiques destinées à être utilisées dans le traitement du maladies néoplasiques
WO2023235716A2 (fr) * 2022-05-31 2023-12-07 Cardiff Oncology, Inc. Traitement du cancer à l'aide d'inhibiteurs de topoisomérase i et d'inhibiteurs de plk1

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