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WO2025202900A1 - Inhibiteurs de cdk4 destinés à être utilisés dans le traitement d'un lymphome à cellules du manteau - Google Patents

Inhibiteurs de cdk4 destinés à être utilisés dans le traitement d'un lymphome à cellules du manteau

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Publication number
WO2025202900A1
WO2025202900A1 PCT/IB2025/053148 IB2025053148W WO2025202900A1 WO 2025202900 A1 WO2025202900 A1 WO 2025202900A1 IB 2025053148 W IB2025053148 W IB 2025053148W WO 2025202900 A1 WO2025202900 A1 WO 2025202900A1
Authority
WO
WIPO (PCT)
Prior art keywords
subject
cancer
cdk4
bid
inhibitor
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
PCT/IB2025/053148
Other languages
English (en)
Inventor
Lars ANDERS
Danan Li
Chonghua ZHANG
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.)
Pfizer Corp Belgium
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Corp SRL
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 Pfizer Corp Belgium, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Publication of WO2025202900A1 publication Critical patent/WO2025202900A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to therapies useful for treating mantle cell lymphoma in a subject.
  • the invention relates to therapies comprising a cyclin dependent kinase 4 inhibitor.
  • the invention also relates to associated methods of treatment, pharmaceutical compositions, and pharmaceutical uses.
  • CDK4 is a cyclin-dependent kinase that plays a crucial role in regulating the cell cycle. It works in conjunction with cyclin D1 (CCND1) to initiate the transition from the G1 to the S phase of the cell cycle. CDK4 inhibitors work by specifically inhibiting the CDK4/cyclin D complex, blocking the transition from the G1 to the S phase of the cell cycle and potentially inhibiting the growth of cancer cells.
  • Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin lymphomas (NHLs) characterized by a translocation resulting in overexpression of CCND1 , with an annual incidence of one case per 200,000 people. Nat Lib Med, Jul 2023, https://www.ncbi.nlm.nih.gov/books/NBK536985/.
  • MCL patients dysregulated CDK4 signalling has been frequently reported due to elevated expression of CCND1 , results in rapid disease progression.
  • the compounds, compositions and methods of the present invention are believed to have one or more advantages, such as greater efficacy; potential to reduce side effects; potential to reduce drug-drug interactions; potential to enable an improved dosing schedule; or potential to overcome resistance mechanisms, and the like.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject comprises a therapeutically effective amount of a cyclin-dependent kinase 4 (CDK4) inhibitor, wherein the cancer is mantle cell lymphoma.
  • CDK4 cyclin-dependent kinase 4
  • FIG. 1 shows average tumor growth inhibition by PF-07220060 (5, 15, and 30 mg/kg twice per day BID) as single agent compared to palbociclib (10 mg/kg BID) in the Jeko-1-Luc disseminated MCL model.
  • E1 A method of treating mantle cell lymphoma in a subject in need thereof, as defined above.
  • CDK4 selective inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is H, F or Cl
  • R 2 is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 5 ;
  • R 3 is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R 6 ;
  • R 4 is H or F; and each R 5 and R 6 is independently OH, F or C1-C2 alkoxy.
  • E4 The method of any of embodiments 1 to 3, wherein the daily dose is about from 100 mg BID to about 400 mg BID.
  • E6 The method of any of embodiments 1 to 5, wherein the daily dose is 300 mg BID.
  • E10 A pharmaceutical composition comprising a CDK4 inhibitor and a pharmaceutically acceptable carrier.
  • a dose of about 5mg/kg should be understood to mean that the dose may vary between 4.5mg/kg and 5.5mg/kg.
  • CDK inhibitors include Pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target specific CDK(s).
  • cyclin/CDK heterodynes include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan DO, Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).
  • CDK inhibitors have been demonstrated to be useful in treating cancer. Increased activity or temporally abnormal activation of cyclin-dependent kinases has been shown to result in the development of human tumors, and human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (Cordon-Cardo C. Mutations of cell cycle regulators: biological and clinical implications for human neoplasia. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat. Med. (1995) 1 :309-320; Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. (1996) 68:67-108).
  • CDK4 selective inhibitors include, but are not limited to, PF-07220060 (Pfizer), BGB- 43395 (BeiGene), HRS-6209 (Jiangsu HengRui) and AU2-94 (Aucentra Therapeutics).
  • CDK4 selective inhibitors of the present invention include “PF- 07220060” which refers to 1 ,5-anhydro-3-( ⁇ 5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1- (propan-2-yl)-1 /7-benzimidazol-6-yl]pyrimidin-2-yl ⁇ amino)-2,3-dideoxy-D-f/7/'eo-pentitol, which has the following chemical structure, including hydrates, salts and polymorphs thereof:
  • PF-07220060 is disclosed in International Publication No. WO 2019/207463, U.S. Patent Nos. 10,766,884 and 1 1 ,220,494, and US Patent Publication US 2022/0089580; and International Publication No. WO 2022/058871 , the contents of which are incorporated herein by reference in their entirety. Unless indicated otherwise, all references herein to PF-07220060 include references to salts, solvates, hydrates, and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.
  • the CDK4 selective inhibitor having a structure of Formula (I) or a pharmaceucially acceptable salt thereof.
  • compositions described herein include the acid addition and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts.
  • suitable acid addition salts i.e., salts containing pharmacologically acceptable anions, include, but are not limited to, the acetate, acid citrate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methane
  • Suitable base addition salts are formed from bases which form non-toxic salts.
  • suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • the compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds described herein are those that form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfon
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds described herein that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N- methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • Treating or “treating” a cancer and/or a cancer-associated disease means to administer a monotherapy or combination therapy according to the present invention to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment or “therapy,” as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer.
  • Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1 S-10S (2009)).
  • the terms, “subject”, “participant” and “patient,” are used interchangeably, to refer to any animal, including mammals.
  • Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero.
  • humans are suitable subjects. Human subjects may be of any gender and at any stage of development.
  • An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured).
  • Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects I symptoms, consequences or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome.
  • a therapeutically effective amount also means an amount of an agent, alone, or in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer.
  • Therapeutic or pharmacological effectiveness of the doses and administration regimens may also be characterized as the ability to induce, enhance, maintain or prolong disease control and/or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.
  • ameliorate refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular disease.
  • Symptom refers to any subjective evidence of disease or of a subject's condition.
  • Administration of the compounds of the present invention may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. Each compound may be administered according to the same or different route of administration.
  • the daily dose of a CDK4 inhibitor or a pharmaceutically acceptable salt thereof is administered orally.
  • a CDK4 inhibitor, or a pharmaceutically acceptable salt may be present in a pharmaceutical composition which includes a pharmaceutically acceptable excipient.
  • “Pharmaceutically acceptable excipient” refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the amount of a CDK4 inhibitor, or a pharmaceutically acceptable salt, in the pharmaceutical compositions may be any amounts disclosed herein.
  • the compounds of the method, use or combination of the present invention may be formulated prior to administration.
  • the formulation will preferably be adapted to the particular mode of administration.
  • These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art.
  • Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses.
  • the dosage of a compound or pharmaceutical composition described herein may vary within the range depending upon the dosage form employed and the route of administration utilized.
  • an amount of a compound or pharmaceutical composition described herein administered to a subject may be dependent upon factors known to a skilled artisan, including bioactivity and bioavailability of the compound (e.g., half-life and stability of the compound in the body), chemical properties of the compound (e.g., molecular weight, hydrophobility and solubility), route and frequency of administration, and the like.
  • bioactivity and bioavailability of the compound e.g., half-life and stability of the compound in the body
  • chemical properties of the compound e.g., molecular weight, hydrophobility and solubility
  • route and frequency of administration e.g., route and frequency of administration, and the like.
  • the specific dose of a pharmaceutical composition comprising a compound as disclosed herein may depend on a variety of factors including physical condition of the subject (e.g., age, gender, weight), and medical history of the subject (e.g., medications being taken, health condition other diseases or disorders).
  • the CDK4 inhibitor is administered to a subject at a dosage of from about 25 mg to about 300 mg per day. In some embodiments the CDK4 inhibitor is administered to a subject at dosages of about: 1 , 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 1 15,
  • the CDK4 inhibitor is administered to a subject at dosages of about 50 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 75 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 100 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 200 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 300 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 400 mg QD. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 500 mg QD.
  • the CDK4 inhibitor is administered to a subject at dosages of about 50 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 75 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 100 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 200 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 300 mg BID. In one embodiment, the CDK4 inhibitor is administered to a subject at dosages of about 400 mg BID.
  • a “continuous dosing schedule”, as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule.
  • the compounds of the combination of the present invention may be administered in a continuous dosing schedule. In an embodiment, the compounds of the combination of the present invention may be administered concurrently in a continuous dosing schedule.
  • the disclosure provides a method of treating a cancer in a subject in need thereof, which includes administering to the subject an amount of a cyclin-dependent kinase 4 (CDK4) inhibitor as described herein.
  • CDK4 cyclin-dependent kinase 4
  • Treating or “treating” a cancer and/or a cancer-associated disease means to administer a monotherapy or combination therapy according to the present invention to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment or “therapy,” as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer.
  • Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1 S-10S (2009)).
  • the terms, “subject”, “participant” and “patient,” are used interchangeably, to refer to any animal, including mammals.
  • Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero.
  • humans are suitable subjects. Human subjects may be of any gender and at any stage of development.
  • An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured).
  • Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects I symptoms, consequences or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome.
  • a therapeutically effective amount also means an amount of an agent, alone, or in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor.
  • a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer.
  • Therapeutic or pharmacological effectiveness of the doses and administration regimens may also be characterized as the ability to induce, enhance, maintain or prolong disease control and/or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.
  • ameliorate refers to any reduction in the extent, severity, frequency, and/or likelihood of a symptom or clinical sign characteristic of a particular disease.
  • Symptom refers to any subjective evidence of disease or of a subject's condition.
  • Administration of the compounds of the present invention may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration. Each compound may be administered according to the same or different route of administration.
  • an “effective dosage”, “effective amount” or “therapeutically effective amount” of a compound or pharmaceutical composition is the amount that, when used as indicated (which may be alone if used as a single agent or together with other agents if used in combination) is sufficient to affect one or more beneficial or desired outcomes, including preventing, ameliorating or treating the biochemical, histological or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired outcomes may include: eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease.
  • beneficial or desired outcomes may include: reducing the incidence or ameliorating one or more symptoms of the disease, reducing the dose of another medication used to treat the disease, enhancing the efficacy or safety of another medication used to treat the disease, or delaying the time to disease progression.
  • beneficial or desired outcomes provided by the invention may include: (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) reducing the incidence or ameliorating (that is, reducing to some extent, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dosage of another medication required to treat the cancer, (6) enhancing the efficacy or safety of another medication used to treat the cancer, and/or (7) delaying the time to progression of the cancer.
  • the patient or subject may be a human or non-human mammal in need of treatment. In one embodiment, the patient is human.
  • Example 1 The antitumor efficacy of PF-07220060 in the Jeko-1-Luc mantle cell lymphoma (MCL) disseminated model (in vivo efficacy studies)
  • Jeko-1 Luc disseminated model was established by IV implanting 1 x 106 cells into the tail vein of female NSG mice. Leukemic disease progression was monitored longitudinally on an IVIS200 system. Treatment was initiated when the mean value of bioluminescence intensity (BLI) in each group reached approximately 1 .2 x 106 photons/sec. Mice were subsequently treated with 1) vehicle (10% ETOH Z45% Tween 80/35% PEG300 /10% Capmul MCM) BID, PO; 2) palbociclib at 10 mg/kg BID, PO; 3-5) PF-07220060 at 5, 15 and 60mg/kg BID, PO respectively. All mice were treated continuously for a total of 8 weeks, with follow up observation of disease progression.
  • BID bioluminescence intensity
  • mice were subsequently treated with 1) vehicle (10% ETOH /45% Tween 80/35% PEG300 Z10% Capmul MCM); 2) palbociclib at 10 mg/kg; 3-5) PF-07220060 at 5, 15 and 60 mg/kg respectively. All mice received treatment continuously for total of 8 weeks with follow up observation of the disease progression. All groups treated with either palbociclib or PF07220060 demonstrated significant (p ⁇ 0.05) antitumor activity. On day 24, the TGI% values are 60% (palbo 10 mg/kg), 67% (PF0060, 5 mg/kg), 89% (PF0060, 15 mg/kg), and 98% (PF0060, 60 mg/kg).
  • PF07220060 at 15mg/kg and 60mg/kg exhibited significantly (p ⁇ 0.05) improved antitumor efficacy compared to palbociclib treatment.
  • the Jeko-1 -Luc disease mice were euthanized once developing signs of hind-leg paralysis or lethargy.
  • Kaplan Meier analysis was performed by tracking the survival readout. The median survival in vehicle-treated mice was 32 days, palbociclib (10 mg/kg) and PF07220060 (60 mg/kg) prolonged survival of mice with median survival time as 45 and 73 days, respectively.
  • PF07220060 significantly improved survival (p ⁇ 0.05) compared to palbociclib. No toxicity or any adverse effect was observed throughout the treatment period.

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Abstract

La présente invention concerne des thérapies pour le traitement d'un lymphome à cellules du manteau comprenant un inhibiteur de kinase 4 dépendante de la cycline (CDK4) ou un sel pharmaceutiquement acceptable de celui-ci, et des méthodes de traitement, des compositions pharmaceutiques et des utilisations associées.
PCT/IB2025/053148 2024-03-27 2025-03-25 Inhibiteurs de cdk4 destinés à être utilisés dans le traitement d'un lymphome à cellules du manteau Pending WO2025202900A1 (fr)

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