WO2024050145A1 - Schémas posologiques de thiostrepton - Google Patents

Schémas posologiques de thiostrepton Download PDF

Info

Publication number
WO2024050145A1
WO2024050145A1 PCT/US2023/031983 US2023031983W WO2024050145A1 WO 2024050145 A1 WO2024050145 A1 WO 2024050145A1 US 2023031983 W US2023031983 W US 2023031983W WO 2024050145 A1 WO2024050145 A1 WO 2024050145A1
Authority
WO
WIPO (PCT)
Prior art keywords
thiostrepton
administration
weeks
dose
single dose
Prior art date
Application number
PCT/US2023/031983
Other languages
English (en)
Inventor
Brian Cunniff
Original Assignee
Rs Oncology, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rs Oncology, Llc filed Critical Rs Oncology, Llc
Publication of WO2024050145A1 publication Critical patent/WO2024050145A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Thiostrepton is a cyclic oligopeptide antibiotic that is also known by other names such as Bryamycin, Thiactin, alaninamide, HR4S203Y18, etc.
  • Thiostrepton has the structure below: or a pharmaceutically acceptable salt thereof. Recent studies have shown that thiostrepton also has promising anticancer activity in addition to its antibiotic properties. There remains a need for safe and effective methods of administering thiostrepton for treating cancer.
  • provided herein are methods of treating cancer, comprising administering to a subject in need thereof thiostrepton in a single dose of about 50 mg to about 500 mg once per week, thereby treating the cancer.
  • pharmaceutical compositions comprising thiostrepton and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises from about 50 mg to about 500 mg of thiostrepton.
  • the disclosure provides for administration of thiostrepton, or any of the pharmaceutical compositions comprising thiostrepton disclosed herein.
  • thiostrepton is administered intraperitoneally, intrapleurally, subcutaneously, or intratum orally.
  • thiostrepton is administered intraperitoneally, for example, using an indwelling intraperitoneal catheter (IPC) or a drainage port catheter.
  • the methods further comprise removing liquid from a body cavity (such as a pleural effusion or asities fluid from the peritoneal cavity), for example, to dryness, before administering thiostrepton.
  • the thiostrepton is administered once per week for at least 3 weeks.
  • a single dose of thiostrepton is administered once per week at about 90 mg to about 450 mg, such as about 90 mg, about 180 mg, about 270 mg, about 360 mg, and about 450 mg.
  • FIG 1A depicts the nucleus and mitochondria of normal mesothelial cells.
  • FIG IB depicts the nucleus and mitochondria of malignant mesothelial cells.
  • FIG 2A depicts the ECso of thiostrepton in normal mesothelial and various mesothelioma cell lines (varying BAP1 expression).
  • FIG 2B depicts PRX3 knock down with siRNA significantly reduces MM (malignant melanoma, HM cell line-pleural biphasic) proliferation (red squares).
  • MM malignant melanoma, HM cell line-pleural biphasic
  • CAT H2O2 scavenger catalase
  • mCAT mitochondrial targeted catalase
  • FIG 2C depicts the weight of residual tumours (grams) resected from mice harboring MM xenografts in the peritoneal cavity following four weeks of treatment with 20 mg/ml of a thiostrepton composition 2x weekly. ** p ⁇ 0.01
  • FIG 3A depicts malignant pleural effusions (MPE) collected from patients with metastatic disease.
  • FIG 3B depicts adherent tumour spheroids grown in MPE supernatant.
  • FIG 3C depicts non-adherent immune cells grown in MPE supernatant.
  • FIG 3D depicts relative PRX3 inactivation by thiostrepton in both tumour (adherent) and immune (non-adherent) cells.
  • FIG 3E indicates MPE derived tumour cells are equally sensitive to thiostrepton compared to established MM cell lines.
  • FIG 4A depicts draining the plural effusion to dryness.
  • FIG 4B depicts administration of thiostrepton using an indwelling intraperitoneal catheter (IPC).
  • IPC intraperitoneal catheter
  • FIG 4C depicts securing the IPC on the patient.
  • FIG 5 depicts a summary of the thiostrepton dose escalation study.
  • FIG 6 depicts an exemplary Phase 1 dose escalation trial for treating cancer with compounds and/or compositions of the disclosure.
  • FIG 7 depicts an exemplary Phase 1 dose expansion trial at RP2D, TS indicating a compound or composition of the disclosure.
  • FIG 8 is a Swimmer’s plot of three exemplary patient outcomes from the Phase 1/2 MITOPE trial. BOR indicates best overall response, PR indicates partial reduction of disease, and SD indicates stable disease.
  • FIG 9 shows a treatment overview for Patient 1.
  • FIG 10 is a chart depicting a decrease in pleural effusion drainage in Patient 1 as a function of time.
  • FIGS 11A-11C show cross-sectional CT scans of the CP node of Patient 1 at pretreatment (A), 6 weeks on treatment (B), and 12 weeks on treatment (C). The scans confirm partial response to treatment.
  • FIGS 12A-12C show cross-sectional CT scans of the right mediastinal pleural nodule of Patient 1 at pre-treatment (A), 6 weeks on treatment (B), and 12 weeks on treatment (C). The scans confirm partial response to treatment.
  • FIG 13 shows a treatment overview for Patient 2.
  • FIGS 14A-14C show cross-sectional CT scans of the right pleural node of Patient 2 at pre-treatment (A), 6 weeks on treatment (B), and 12 weeks on treatment (C). The scans confirm stable disease.
  • FIGS 15A-15C show cross-sectional CT scans of the GB fundus lesion of Patient 2 at pre-treatment (A), 6 weeks on treatment (B), and 12 weeks on treatment (C). The scans confirm stable disease.
  • FIG 16 is a chart depicting a decrease in pleural effusion drainage in Patient 2 as a function of time.
  • FIG 17 shows a treatment overview for Patient 3.
  • FIG 18 is a chart depicting a decrease in pleural effusion drainage in Patient 3 as a function of time.
  • FIGS 19A-19C show cross-sectional CT scans of the tumor of Patient 3 at pretreatment (A), 6 weeks on treatment (B), and 12 weeks on treatment (C). The scans confirm stable disease up to 12 weeks on treatment.
  • FIG 20 shows a cross-sectional CT scan of new liver metastases in Patient 3, which indicates disease progression at the 12 week scan.
  • FIG 21 shows a CT scan of new lytic bone metastases in Patient 3, which indicates disease progression at the 12 week scan.
  • PRX3 is a peroxidase responsible for metabolizing ⁇ 90% of mitochondrial ROS, primarily H2O2.
  • PRX3 transcript levels are upregulated, compared to normal tissues, in approximately 50% of cancers (data from the GEPIA2 database).
  • Genetic knock down of PRX3 in human tumour cells results in sensitization to apoptosis.
  • the mitochondria of malignant mesothelioma (MM) cells are structurally and functionally altered leading to disrupted metabolic function that supports tumour growth and can be therapeutically targeted (see FIG 1 A, IB).
  • Thiostrepton is a covalent inhibitor that inactivates PRX3 peroxidase activity through direct adduction of active site cysteine residues, in turn, inducing oxidative stress to levels incompatible with tumour cell survival.
  • the EC50 of thiostrepton in normal mesothelial and various mesothelioma cell lines with varying BAP1 expression is shown in FIG 2A.
  • PRX3 knock down with siRNA significantly reduces MM (HM cell line-pleural biphasic) proliferation as depicted in FIG 2B.
  • Co-expression of the H2O2 scavenger catalase rescues proliferation in cells lacking PRX3 expression.
  • the weight of the tumor is significantly smaller than that of a control in residual tumours resected from mice harboring MM xenografts in the peritoneal cavity following four weeks of treatment with 20 mg/ml of a thiostrepton composition 2x weekly (FIG 2C), thereby demonstrating the preclinical rationale for thiostrepton’ s biological activity.
  • MPE Malignant pleural effusion
  • MPE Malignant pleural effusion
  • MPE contains tumour and immune cells and allows for evaluation of the efficacy of thiostrepton in this disease, where both cell types are inhibited by thiostrepton.
  • adherent tumour spheroids and non-adherent immune cells can be grown in a medium containing MPE supernatant.
  • PRX3 is inactivated by thiostrepton in both tumour (adherent) and immune (nonadherent) cells (FIG 3D). Moreover, MPE derived tumour cells are equally sensitive to thiostrepton compared to established MM cell lines as shown in FIG 3E.
  • provided herein are methods of treating cancer, comprising administering to a subject in need thereof thiostrepton in a single dose of about 50 mg to about 500 mg once per week, thereby treating the cancer.
  • the single dose is from about 90 mg to about 450 mg. In some such embodiments, the single dose is selected from about 90 mg, about 120 mg, about 180 mg, about 270 mg, about 360 mg, and about 450 mg.
  • the single dose is administered to the subject once per week for at least 3 weeks. In certain embodiments, the single dose in one week is the same amount as the single dose administered in a different week. In various embodiments, first single dose is administered for 3 weeks, followed by administration of a second single dose for the next 3 weeks, wherein the first single dose and the second single dose are different. In certain such embodiments, the second single dose is greater than the first single dose. In other embodiments, the second single dose is less than the first single dose.
  • the thiostrepton is present in a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.
  • the thiostrepton is administered locally. In certain embodiments, the thiostrepton is administered intraperitnoeally, intrapleurally, subcutaneously, or intratum orally. In certain embodiments, the thiostrepton is administered by a catheter, a tube, or a needle. In some embodiments, the thiostrepton is administered by an indwelling intraperitoneal catheter (IPC).
  • IPC intraperitoneal catheter
  • the cancer is selected from lung, breast, prostate, melanoma, esophageal, leukemia, cervical, liver, colon, gastric, colorectal, glioblastoma, head and neck, pancreatic, mesothelioma, and ovarian.
  • the cancer is malignant mesothelioma.
  • the cancer is malignant pleural mesothelioma.
  • the cancer is malignant epitheloid pleural mesothelioma.
  • the cancer is malignant peritoneal mesothelioma.
  • the cancer is lung cancer.
  • the lung cancer is an adenocarcinoma.
  • the cancer is metastatic.
  • the subject experiences stable disease for at least 12 weeks after administration of a first dose of thiostrepton. In some such embodiments, the subject experiences stable disease for at least about 12 weeks to about 52 weeks after administration of a first dose of thiostrepton. In some embodiments, the subject experiences stable disease for at least 18 weeks after administration of a first dose of thiostrepton. In certain such embodiments, the subject experiences stable disease for at least about 18 weeks to about 52 weeks after administration of a first dose of thiostrepton. In certain embodiments, the subject experiences stable disease for at least 24 weeks after administration of a first dose of thiostrepton. In some such embodiments, the subject experiences stable disease for at least about 24 weeks to about 52 weeks after administration of a first dose of thiostrepton.
  • the subject experiences progression free survival for at least 12 weeks after administration of a first dose of thiostrepton. In some such embodiments, the subject experiences progression free survival for at least about 12 weeks to about 52 weeks after administration of a first dose of thiostrepton. In some embodiments, the subject experiences progression free survival for at least 18 weeks after administration of a first dose of thiostrepton. In certain such embodiments, the subject experiences progression free survival for at least about 18 weeks to about 52 weeks after administration of a first dose of thiostrepton. In certain embodiments, the subject experiences progression free survival for at least 24 weeks after administration of a first dose of thiostrepton.
  • the subject experiences progression free survival for at least about 24 weeks to about 52 weeks after administration of a first dose of thiostrepton. In certain embodiments, the subject experiences partial response for at least 12 weeks after administration of a first dose of thiostrepton. In some such embodiments, the subject experiences partial response for at least about 12 weeks to about 52 weeks after administration of a first dose of thiostrepton. In some embodiments, the subject experiences partial response for at least 18 weeks after administration of a first dose of thiostrepton. In certain such embodiments, the subject experiences partial response for at least about 18 weeks to about 52 weeks after administration of a first dose of thiostrepton.
  • the subject experiences partial response for at least 24 weeks after administration of a first dose of thiostrepton. In some such embodiments, the subject experiences partial response for at least about 24 weeks to about 52 weeks after administration of a first dose of thiostrepton.
  • the partial response comprises a reduction in tumor size of at least 10% relative to the tumor size before administration of thiostrepton. In further embodiments, the partial response comprises a reduction in tumor size of at least 30% relative to the tumor size before administration of thiostrepton. In yet further embodiments, the partial response comprises a reduction in tumor size of at least 60% relative to the tumor size before administration of thiostrepton.
  • the subject experiences pleural effusion.
  • the volume of pleural effusion is reduced 10 weeks after administration of a first does of thiostrepton relative to the volume of pleural effusion before administration of thiostrepton.
  • the volume of pleural effusion is reduced 5 weeks after administration of a first does of thiostrepton relative to the volume of pleural effusion before administration of thiostrepton.
  • the volume of pleural effusion is reduced 1 week after administration of a first does of thiostrepton relative to the volume of pleural effusion before administration of thiostrepton.
  • the volume of pleural effusion is about 30% less than the volume of pleural effusion before administration of thiostrepton. In some embodiments, the volume of pleural effusion is about 60% less than the volume of pleural effusion before administration of thiostrepton. In certain embodiments, the volume of pleural effusion is about 90% less than the volume of pleural effusion before administration of thiostrepton.
  • compositions comprising thiostrepton and at least one pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises from about 50 mg to about 500 mg of thiostrepton. In certain embodiments, the composition comprises from about 90 mg to about 450 mg of thiostrepton. In some embodiments, the composition comprises about 90 mg, about 180 mg, about 270 mg, about 360 mg, or about 450 mg of thiostrepton.
  • compositions and methods described herein may be utilized to treat an individual in need thereof.
  • pharmaceutical composition means a composition that comprises thiostrepton and at least one pharmaceutically acceptable carrier.
  • active compound and “active ingredient” refer to thiostrepton.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the subject or the mammal is a human.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, an active compound described herein and a pharmaceutically acceptable carrier.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of an active compound such as an active compound described herein.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound described herein.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, intraperitoneally; intrapleurally; subcutaneously; intratumorally; orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • the pharmaceutical composition is administered locally.
  • the pharmaceutical composition is administered by a catheter, a tube, or a needle.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as thiostrepton, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as thiostrepton
  • the formulations are prepared by uniformly and intimately bringing into association a compound described herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Liquid dosage forms include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example
  • liquid compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intraperitoneal, intrapleural, subcutaneous, intratumoral, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • the pharmaceutical composition is administered intraperitoneally, intrapleurally, subcutaneously, or intratum orally.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug after injection for example, subcutaneous injection.
  • This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility.
  • the rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors that influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound described herein.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable dose of an active compound used in the compositions and methods described herein will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals, optionally, in unit dosage forms.
  • thiostrepton is administered once a week. In certain embodiments, thiostrepton is administered for two, three, four, five or six consecutive weeks. In some embodiments, thiostrepton is administered every other week, once every three weeks, or once every four weeks at a rate of once or twice each week.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds described herein may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • contemplated salts include, but are not limited to, 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxy ethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1- ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)- camphor- 10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-d
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known.
  • a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • a subject may be male or female. In some embodiments, the subject is greater than 18 years old.
  • a subject preferably has an ECOG (Eastern Cooperative Oncology Group) score of 0-1.
  • a patient may have a histological diagnosis of MPE caused by nonmesothelioma solid tumour or mesothelioma.
  • the patient has received at least one prior standard of care treatment regimen, with documented progression and no approved alternative available.
  • the patient has resolution of all acute reversible toxic effects of prior therapy to Grade ⁇ 1.
  • the patient has a paraffin block of his or her most recent biopsy.
  • the patient has adequate organ function as defined by lab values before administration of thiostrepton.
  • the subject is postmenopausal, surgically sterile, or using effective birth control.
  • the patient has not have prior systemic anti-cancer or radiation therapy before administration of thiostrepton. In some embodiments, the patient has not have surgery within 3 weeks or within 5 half-lives before administration of thiostrepton. In some embodiments, the patient has not had treatment with an investigational product/device within 30 days before administration of thiostrepton. In certain embodiments, the patient has not had a previous malignancy other than the cancer to be treated before administration of thiostrepton. In certain embodiments, the patient does not have tumours or loculations that would render intrapleural administration incomplete or ineffective. In certain embodiments, the patient does not have a known hypersensitivity to thiostrepton or a pharmaceutical composition excipient.
  • the patient does not any surgical or medical condition that is likely to interfere with thiostrepton treatment.
  • the patient does not have human immunodeficiency virus (HIV) or active infection with hepatitis B; or hepatitis C in absence of a sustained virologic response.
  • HIV human immunodeficiency virus
  • the patient is not pregnant or breast-feeding.
  • the patient does not have a symptomatic or unstable CNS tumour or metastases or carcinomatous meningitis.
  • the patient has not used systemic corticosteroids within 15 days before administration of thiostrepton or other immunosuppressive drugs within 3 weeks before administration of thiostrepton.
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered intraperitoneally, intrapleurally, subcutaneously, intratumorally, intravenously, arterially, intradermally, intramuscularly, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • administration of thiostrepton or any of the pharmaceutical compositions comprising thiostrepton disclosed herein can be carried out using an indwelling intraperitoneal catheter (IPC).
  • IPC intraperitoneal catheter
  • administration occurs once a week or twice a week, preferably once a week.
  • the methods further comprise removing liquid from a pleural effusion, for example, before administration of thiostrepton (FIG 4A).
  • FIG 4B after administration of thiostrepton
  • the IPC is secured until the next dosing time point (FIG 4C).
  • the single dose amount of thiostrepton ranges from about 50 mg to about 500 mg. In some embodiments, the single dose amount of thiostrepton ranges from about 90 mg to about 450 mg. In preferred embodiments, the single dose is selected from about 90 mg, about 180 mg, about 270 mg, about 360 mg, and about 450 mg. In some embodiments, the single dose is administered to the subject once per week, for example, for at least 3 weeks.
  • the single dose of thiostrepton may be increased every three week period, for example, such that the patient at weeks 1-3 is dosed at 90 mg once each week, then optionally at weeks 4-6 is dosed at 180 mg once each week, then optionally at weeks 7-9 is dosed at 270 mg once each week, then optionally at weeks 10-12 is dosed at 360 mg once each week, and finally optionally at weeks 13-15 is dosed at 450 mg once each week.
  • Each patient may complete any or all of the 3 week sessions (FIG 5).
  • the dosing regimen may be paused, halted, or the patient may move to a lower dose, for example, in the event of toxicity or an adverse event.
  • the methods further comprise obtaining a tumour biopsy from the patient before administering thiostrepton. In some embodiments, the methods further comprise obtaining a tumour biopsy after administration of the third dose of thiostrepton.
  • the pharmaceutical composition comprises from about 5 mg thiostrepton/mL to about 50 mg thiostrepton/mL. In some embodiments, the pharmaceutical composition comprises about 10 mg thiostrepton/mL, about 20 mg thiostrepton/mL, about 30 mg thiostrepton/mL, about 40 mg thiostrepton/mL and about 50 mg thiostrepton/mL. In a preferred embodiment, the pharmaceutical composition comprises 20 mg thiostrepton/mL.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., when at least 5% of drug product is detectable systemically with industry acceptable methodology, or when the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • a first single dose in one week is the same amount as the single dose administered in a different weeks.
  • a first single dose is administered for 3 weeks, followed by administration of a second single dose for the next 3 weeks, wherein the first single dose and the second single dose are different.
  • the second single dose is greater than the first single dose. In other embodiments, the second single dose is less than the first single dose.
  • a “therapeutically effective amount” or a “therapeutically effective dose” of a compound or other agent described herein is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose of such a drug or agent, and may occur only after administration of a series of doses (multiple consecutive doses).
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • modulate includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a cancer e.g., solid tumor or hematological cancer
  • the cancer is selected from lung, breast, prostate, melanoma, esophageal, leukemia, cervical, liver, colon, gastric, colorectal, glioblastoma, head and neck, pancreatic, mesothelioma, and ovarian.
  • the cancer is selected from mesothelioma, lung, ovarian, and breast.
  • the cancer is malignant mesothelioma.
  • a Phase 1/2 Dose-Escalation and Expansion Study was carried out to determine safety, tolerability, and recommended Phase 2 dose of exemplary thiostrepton compositions in patients with malignant pleural effusion due to advanced/metastatic solid tumors including mesothelioma.
  • Preliminary results for three patients are provided herein.
  • Figures 6-20 provide overviews of the trial, treatment details, and exemplary preliminary data for these three patients.
  • Partial Response (“PR”)
  • SD Stable Disease
  • BOR Best Overall Response
  • FIGS. 11 A-l 1C are CT scans of Patient 1 at pre-treatment (11 A), 6 weeks on treatment (1 IB), and 12 weeks on treatment (11C).
  • FIGS 14A-14C and FIGS 15A-15C are CT scans of Patient 2 at pre-treatment (14A, 15 A), 6 weeks on treatment (14B and 15B), and 12 weeks on treatment (14C and 15C).
  • FIGS 19A-19C are CT scans of Patient 3 at pre-treatment (19A), 6 weeks on treatment (19B), and 12 weeks on treatment (19C).
  • FIGS 20 and 21 are CT scans of Patient 3 taken at 12 weeks on treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes d'administration de thiostrepton, ou des compositions pharmaceutiques associées, ainsi que des méthodes de traitement du cancer.
PCT/US2023/031983 2022-09-02 2023-09-05 Schémas posologiques de thiostrepton WO2024050145A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202263403553P 2022-09-02 2022-09-02
US63/403,553 2022-09-02
US202263404728P 2022-09-08 2022-09-08
US63/404,728 2022-09-08

Publications (1)

Publication Number Publication Date
WO2024050145A1 true WO2024050145A1 (fr) 2024-03-07

Family

ID=90098672

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/031983 WO2024050145A1 (fr) 2022-09-02 2023-09-05 Schémas posologiques de thiostrepton

Country Status (1)

Country Link
WO (1) WO2024050145A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190105261A1 (en) * 2017-10-11 2019-04-11 Illustris Pharmaceuticals, Inc. Methods and compositions for topical delivery
US20190321370A1 (en) * 2016-12-05 2019-10-24 G1 Therapeutics, Inc. Preservation of immune response during chemotherapy regimens
US20200030355A1 (en) * 2014-08-13 2020-01-30 Epizyme, Inc. Combination therapy for treating cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200030355A1 (en) * 2014-08-13 2020-01-30 Epizyme, Inc. Combination therapy for treating cancer
US20190321370A1 (en) * 2016-12-05 2019-10-24 G1 Therapeutics, Inc. Preservation of immune response during chemotherapy regimens
US20190105261A1 (en) * 2017-10-11 2019-04-11 Illustris Pharmaceuticals, Inc. Methods and compositions for topical delivery

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG WEIFAN, GONG MENGYUAN, ZHANG WUNAI, MO JIANTAO, ZHANG SIMEI, ZHU ZEEN, WANG XUENI, ZHANG BO, QIAN WEIKUN, WU ZHENG, MA QINGY: "Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling", CELL DEATH & DISEASE, NATURE PUBLISHING GROUP, GB, vol. 13, no. 7, GB , XP093147885, ISSN: 2041-4889, DOI: 10.1038/s41419-022-05082-3 *

Similar Documents

Publication Publication Date Title
CN1315479C (zh) 橄榄苦苷在制备抑制血管生成药物中的用途
US20210267896A1 (en) Formulations for treating bladder cancer
EP1272199B1 (fr) Therapies combinees induisant un effet de deterioration vasculaire
US20190262267A1 (en) Pharmaceutical solution having a toxicity-reducing effect for antitumor drugs, and pharmaceutical composition comprising same
US10828271B2 (en) Method for treating pleuroperitoneal membrane cancers by locally injecting disulfiram preparation
AU2001242581A1 (en) Combination therapies with vascular damaging activity
US20200253917A1 (en) Compositions and methods for modulating hair growth
JP6462147B2 (ja) Ｈｓｐ９０阻害ペプチド結合体及びその腫瘍治療における応用
US20230414723A1 (en) Enhanced hyt-induced protein degradation using lipid nanoparticle delivery
JP2022508807A (ja) 腫瘍内注射製剤
CN100471491C (zh) 含有甲苯磺胺的抗肿瘤成分及其用法
WO2024050145A1 (fr) Schémas posologiques de thiostrepton
JP6591665B2 (ja) Ｔ−ｄｍ１難治性がん患者のｓｙｄ９８５処置
CN111032035A (zh) 用于替司他赛和卡培他滨的给药方案
WO1992011247A1 (fr) Composition anticancereuse et compose
CN105147683A (zh) 用于肾脏细胞癌的治疗的3,3＇,4，4＇-四羟基-2,2＇-联吡啶-n,n＇-二氧化物
TW202023568A (zh) 用於治療癌症之組合療法
US20230040125A1 (en) Targeting the intrinsic apoptotic machinery in glioblastoma
KR20190124951A (ko) Pfi-3를 포함하는 신장암의 예방 또는 치료용 조성물
CN113271935A (zh) 用替司他赛治疗cns肿瘤的方法
WO2023239842A1 (fr) Bêta-carbolines en tant qu'agents anti-inflammatoires topiques pour une application à des membranes muqueuses
WO2023245055A1 (fr) Schémas posologiques faisant appel à des bêta-agonistes thyroïdiens pour le traitement de l'x-ald
EP2056839A1 (fr) Approches combinées pour le traitement du cancer
WO2022197290A1 (fr) Procédés d'administration de tésétaxel avec des inhibiteurs de cyp3a4
WO2022271540A1 (fr) Inhibiteurs de dot1l

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23861386

Country of ref document: EP

Kind code of ref document: A1