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EP4580650A1 - Schémas posologiques de thiostrepton - Google Patents

Schémas posologiques de thiostrepton

Info

Publication number
EP4580650A1
EP4580650A1 EP23861386.3A EP23861386A EP4580650A1 EP 4580650 A1 EP4580650 A1 EP 4580650A1 EP 23861386 A EP23861386 A EP 23861386A EP 4580650 A1 EP4580650 A1 EP 4580650A1
Authority
EP
European Patent Office
Prior art keywords
thiostrepton
administration
weeks
dose
single dose
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP23861386.3A
Other languages
German (de)
English (en)
Inventor
Brian Cunniff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rs Oncology LLC
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 EP4580650A1 publication Critical patent/EP4580650A1/fr
Pending legal-status Critical Current

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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 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.

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  • 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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des méthodes d'administration de thiostrepton, ou des compositions pharmaceutiques associées, ainsi que des méthodes de traitement du cancer.
EP23861386.3A 2022-09-02 2023-09-05 Schémas posologiques de thiostrepton Pending EP4580650A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US202263403553P 2022-09-02 2022-09-02
US202263404728P 2022-09-08 2022-09-08
PCT/US2023/031983 WO2024050145A1 (fr) 2022-09-02 2023-09-05 Schémas posologiques de thiostrepton

Publications (1)

Publication Number Publication Date
EP4580650A1 true EP4580650A1 (fr) 2025-07-09

Family

ID=90098672

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23861386.3A Pending EP4580650A1 (fr) 2022-09-02 2023-09-05 Schémas posologiques de thiostrepton

Country Status (6)

Country Link
EP (1) EP4580650A1 (fr)
JP (1) JP2025527861A (fr)
CN (1) CN119816315A (fr)
AU (1) AU2023333543A1 (fr)
CA (1) CA3265388A1 (fr)
WO (1) WO2024050145A1 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170232030A1 (en) * 2014-08-13 2017-08-17 Epizyme, Inc. Combination therapy for treating cancer
CN117530948A (zh) * 2016-12-05 2024-02-09 G1治疗公司 化疗方案期间免疫反应的保持
EP3694489A4 (fr) * 2017-10-11 2021-06-30 Illustris Pharmaceuticals, Inc. Procédés et compositions à administration topique

Also Published As

Publication number Publication date
WO2024050145A1 (fr) 2024-03-07
JP2025527861A (ja) 2025-08-22
CN119816315A (zh) 2025-04-11
AU2023333543A1 (en) 2025-03-13
CA3265388A1 (fr) 2024-03-07

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