EP4376822A1 - Traitement de cancers avec des associations d'inhibiteur de parp et d'acylfulvènes - Google Patents

Traitement de cancers avec des associations d'inhibiteur de parp et d'acylfulvènes

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Publication number
EP4376822A1
EP4376822A1 EP22850545.9A EP22850545A EP4376822A1 EP 4376822 A1 EP4376822 A1 EP 4376822A1 EP 22850545 A EP22850545 A EP 22850545A EP 4376822 A1 EP4376822 A1 EP 4376822A1
Authority
EP
European Patent Office
Prior art keywords
illudin
cancer
analog
parp inhibitor
treatment
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
EP22850545.9A
Other languages
German (de)
English (en)
Inventor
Aditya Kulkarni
Kishor Bhatia
Jianli ZHOU
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.)
Lantern Pharma Inc
Original Assignee
Lantern Pharma Inc
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 Lantern Pharma Inc filed Critical Lantern Pharma Inc
Publication of EP4376822A1 publication Critical patent/EP4376822A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • This application relates to cancer treatments and more specifically this application relates to cancer treatments using a combination therapy including a PARP inhibitor.
  • Cancer is one of the most common causes of death in people.
  • the development of therapeutic strategies for patients with advanced cancer has markedly improved overall survival.
  • resistance to anticancer reagents is inevitable, and the prognosis of advanced cancer remains poor.
  • cancer drug resistance including alterations to drug transporters, the suppression of apoptosis, mitochondrial alterations, the promotion of DNA damage repair, autophagy, epithelial- mesenchymal transition, and cancer stem cells (CSCs). Appropriate strategies that consider the mechanisms are necessary to cure cancer.
  • Combination-therapy treatments for cancer have become more common, in part due to the perceived advantage of attacking the disease via multiple avenues. Although many effective combination-therapy treatments have been identified over the past few decades; in view of the continuing high number of deaths each year resulting from cancer, a continuing need exists to identify effective therapeutic regimens for use in anticancer treatment.
  • This application discloses the discovery that treatment of a cancer in a subject with a combination of an illudin or illudin analog (e.g., acylfulvene) and a PARP inhibitor has synergistically greater effects (i.e., greater than the effects of each added together) than the effects provided by either acylfulvene or PARP inhibitor treatment, alone.
  • the cytotoxicity delivered from treating a cancer with a combination of illudin or acylfulvene and a PARP inhibitor is unexpectedly greater compared to the cytotoxicity delivered when treating the cancer with illudin or acylfulvene or PARP inhibitor, alone (or greater than the cytotoxicity of both added together).
  • One aspect of this application includes a combination therapy for treating cancers.
  • the therapy includes administering a combination of active agents including an illudin or illudin analog (e.g., acylfulvene), and a PARP inhibitor.
  • active agents including an illudin or illudin analog (e.g., acylfulvene), and a PARP inhibitor.
  • compositions comprising an illudin or illudin analog (e.g., acylfulvene) and a PARP inhibitor or pharmaceutically acceptable salts thereof, mixed with pharmaceutically suitable carriers or excipient(s) at doses to treat or prevent cancer.
  • the pharmaceutical compositions can also be administered in combination with other therapeutic agents or therapeutic modalities simultaneously, sequentially, or in alternation.
  • Another aspect of this application includes therapeutically effective amounts of each illudin or acylfulvene, and a PARP inhibitor used in combination that will be lower when used in combination in comparison to monotherapy with each agent alone. Such lower therapeutically effective amounts could afford for lower toxicity of the therapeutic regimen.
  • Another aspect of this application includes the therapy including an acylfulvene that is (+) - hydroxyureamethyl acylfulvene.
  • Another aspect of this application includes the therapy including an acylfulvene that is Irofulven.
  • Tumors such as, but not limited to, hyperplastic or neoplastic disease, such as a carcinoma, sarcoma, or mixed type cancer, including breast, colon, rectal, endometrial, gastric, prostate or brain, mesothelioma, ovarian, lung or pancreatic cancer can be targeted for therapy.
  • hyperplastic or neoplastic disease such as a carcinoma, sarcoma, or mixed type cancer, including breast, colon, rectal, endometrial, gastric, prostate or brain, mesothelioma, ovarian, lung or pancreatic cancer can be targeted for therapy.
  • FIG. 1 shows the effect of the combination of LP-184 with Olaparib on the survival of cells
  • FIG. 2 shows the effect of the combination of LP-100 with either Olaparib or Rucaparib on shrinking tumors in prostate xenograft mouse models in vivo;
  • FIG. 3A shows IC50 data in which an Olaparib single treatment was 1248. InM;
  • FIG. 3B shows IC50 data in which an Olaparib single treatment was 108.2nM respectively;
  • FIG. 3C shows IC50 data in which Olaparib and LP-184 co-treatment was 278.6nM Olaparib and 13.93nM LP-184;
  • FIG. 3D shows the synergistic effect of LP-184 and Olaparib analyzed through in Isobole plot
  • FIG. 4A shows IC50 data in which a Talazoparib single treatment was 13. InM;
  • FIG. 4B shows IC50 data in which a Talazoparib single treatment was 87.4nM
  • FIG. 4C shows IC50 data in which a Talazoparib and LP-184 co-treatment was 3.6nM Olaparib and 7.2nM LP-184;
  • FIG. 4D shows the synergistic effect of LP-184 and Talazoparib analyzed through an Isobole plot.
  • This application provides a combination therapy for treating solid cancers and blood cancers.
  • the therapy includes administering a combination of active agents including an illudin or an illudin analog (e.g., acylfulvene) and a PARP inhibitor.
  • the therapy includes administering a combination of other therapies.
  • the combination therapy can be used to treat biochemical occurrence or recurrence of solid cancers (e.g., lung cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer, rectum cancer, and bladder cancer), glioblastoma and atypical teratoid rhabdoid, and renal cell carcinoma).
  • the therapy includes the combination therapy that can be used to treat biochemical occurrence and recurrence of blood cancers in which an acylfulvene (e.g., hydroxyureamethyl acylfulvene) or salt thereof and a PARP inhibitor administered in a therapeutically effective amount to the patient.
  • the combination can provide a treatment for lymphoma, such as mantle cell lymphoma (MCL) and double-hit lymphoma (DHL).
  • MCL mantle cell lymphoma
  • DHL double-hit lymphoma
  • MM multiple myeloma
  • the overgrowth of plasma cells in the bone marrow can crowd out normal blood- forming cells.
  • this application includes the use of an illudin or illudin analog (e.g., acylfulvene).
  • Acylfulvene is a class of cytotoxic semi-synthetic derivatives of illudin, a natural product that can be extracted from the jack o'lantem mushroom (Omphalotus olearius).
  • Acylfulvene derived from the sesquiterpene illudin S by treatment with acid (reverse Prins reaction), is far less reactive to thiols than illudin S.
  • the acylfulvene is (-) - hydroxyureamethyl acylfulvene (termed LP- 184 by Lantern Pharma Inc.), which shifts light positively, is shown below:
  • acylfulvene is (+)-hydroxyureamethyl acylfulvene (termed LP-284 by Lantern Pharma Inc.), which shifts light negatively, is shown below:
  • (+) - hydroxyureamethyl acylfulvene and (-) - hydroxyureamethyl acylfulvene are enantiomers and are now known publicly.
  • the acylfulvene is Irofulven.
  • PARP inhibitor are a type of cancer drug.
  • PARP stands for poly adenosine diphosphate-ribose polymerase (poly-ADP ribose polymerase (PARP) inhibitor), a type of enzyme that helps repair DNA damage in cells.
  • PARP inhibitor work by preventing cancer cells from repairing damaged DNA, allowing them to die.
  • PARP enzymes help repair DNA damage. Blocking them can keep cancer cells from repairing, and this allows them to die.
  • compositions that include one or more PARP inhibitor and typically at least one additional substance, such as an excipient, a known therapeutic other than those of the present disclosure, and combinations thereof.
  • a PARP inhibitor can be used in combination with other agents known to have beneficial, additive or synergistic activity with the PARP inhibitor.
  • the PARP inhibitor is a PARP-1 inhibitor.
  • the PARP inhibitor is an inhibitor of any enzyme of the PARP family, e g., PARP1 and/or PARP2.
  • Suitable PARP inhibitors include, but are not limited to, olaparib (AZD-2281, 4-[(3-[(4-cyclopropylcarbonyl)piperazin-4- yl]carbonyl)-4-fluorophenyl]met- hyl(2H)-phthalazin-l-one), veliparib (ABT-888, CAS 912444-00-9, 2-((fi)-2-methylpyrrolidin-2-yl)-lW-benzimidazole-4-carboxamide), CEP- 8983 (ll-methoxy-4,5,6,7-tetrahydro-lH-cyclopenta[a]pyrrolo[3,4-c]car- apelole-l,3(2H)- dione) or a prodrug thereof (e.g.
  • W02006046035 W02006008119, W006008118, W02006042638, US20060229289, US20060229351, W02005023800, W01991007404, W02000042025, W02004096779, U.S. Pat. No. 6,426,415, W02068407, U.S. Pat. No.
  • the PARP inhibitor compound is selected from the group consisting of rucaparib (AG014699, PF-01367338), olaparib (AZD2281), veliparib (ABT888), iniparib (BSI 201), niraparib (MK 4827), talazoparib (BMN673), AZD 2461, CEP 9722, E7016, INO-1001, LT-673, MP-124, NMS-P118, XAV939, analogs, derivatives or a mixture thereof.
  • the PARP inhibitor is selected from the group consisting of rucaparib (AG014699, PF-01367338), olaparib (AZD2281), veliparib (ABT888), iniparib (BSI 201), niraparib (MK 4827), talazoparib (BMN673), AZD 2461, analogs, derivatives or a mixture thereof.
  • acylfulvene or hydroxyureamethyl acylfulvene or its salt may be administered either prior to, concomitantly with, or subsequent to the administration of a PARP inhibitor.
  • One aspect of this application includes a method of treating cancer in a subject in need thereof.
  • the method involves administering to the subject an effective amount of PARP inhibitor and an effective amount of an acylfulvene.
  • PARP inhibitor may be administered prior to or concomitantly with an acylfulvene for optimal synergistic effects.
  • Another embodiment includes a pharmaceutical composition having a therapeutically effective amount of an illudin or an illudin analog thereof, derivative, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a PARP inhibitor or an analog, derivative, or a pharmaceutically acceptable salt thereof.
  • the illudin analog can be HydroxyUreaMethylAcylfulvene.
  • kits for the treatment of cancer in a subject includes a therapeutically effective amount of an illudin or an illudin analog thereof, derivative, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a PARP inhibitor or an analog, derivative, or a pharmaceutically acceptable salt thereof:
  • the second therapeutic is one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab and a Raf kinase inhibitor.
  • camptothecin derivatives selected from camptothecin derivatives, paclitaxel, docetaxel, epothilone B, 5-FU, gemcitabine, oxaliplatin, cisplatinum, carboplatin, melphalam, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab and a Raf kinase
  • the second therapeutic is one or more chemotherapeutic agents selected from paclitaxel or cisplatinum.
  • combination therapy can include or includes the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment).
  • combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • composition or combination therapy herein, or a pharmaceutically acceptable salt or solvate thereof may be administered in combination with radiation therapy.
  • Radiation therapy can also be administered in combination with a composition of the present invention and another chemotherapeutic agent described herein as part of a multiple agent therapy.
  • Combination therapy can be achieved by administering two or more agents, e.g., an acylfulvene, a PARP inhibitor and one or more other therapeutic agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation.
  • agents e.g., an acylfulvene, a PARP inhibitor and one or more other therapeutic agents, each of which is formulated and administered separately, or by administering two or more agents in a single formulation.
  • Other combinations are also encompassed by combination therapy.
  • two agents can be formulated together and administered in conjunction with a separate formulation containing a third agent. While the two or more agents in the combination therapy can be administered simultaneously, they need not be.
  • administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks.
  • the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present within the patient's body at the same time, this need not be so.
  • PARP inhibition indicates a decrease in the baseline activity of a biological activity or process, namely, the activity of PARP.
  • PARP inhibition relies mainly on two different mechanisms: (i) catalytic inhibition that act mainly by inhibiting PARP enzyme activity and (ii) bound inhibition that block PARP enzyme activity and prevent its release from the damage site.
  • “Inhibition of PARP” refers to a decrease in the activity of PARP as a direct or indirect response to the presence of at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein, relative to the activity of PARP in the absence of the at least one compound and/or the at least one pharmaceutically acceptable salt thereof.
  • the decrease in activity can be due to the direct interaction of the at least one compound, stereoisomers thereof, and pharmaceutically acceptable salts thereof disclosed herein with PARP, or due to the interaction of the at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein, with one or more other factors that in turn affect PARP activity.
  • the presence of at least one compound, stereoisomers thereof, and pharmaceutically acceptable salts thereof disclosed herein may decrease PARP activity by directly binding to the PARP, by causing (directly or indirectly) another factor to decrease PARP activity, or by (directly or indirectly) decreasing the amount of PARP present in the cell or organism.
  • the methods of combination therapy may or should result in a synergistic effect, wherein the effect of a combination of compounds or other therapeutic agents is greater than the sum of the effects resulting from administration of any of the compounds or other therapeutic agents as single agents.
  • a synergistic effect may also be an effect that cannot be achieved by administration of any of the compounds or other therapeutic agents as single agents.
  • the synergistic effect may include, but is not limited to, an effect of treating cancer by reducing tumor size, inhibiting tumor growth, or increasing survival of the subject.
  • the synergistic effect may also include reducing cancer cell viability, inducing cancer cell death, and inhibiting or delaying cancer cell growth.
  • Therapeutically effective doses can vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the age and general health condition of the patient, excipient usage, the possibility of co usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for acylfulvene or hydroxyureamethyl acylfulvene or journal discussion the same.
  • the term “effective amount” as used herein refers to the amount of an agent needed to alleviate at least one or more symptoms of the disease or disorder, and relates to a sufficient amount of pharmacological composition to provide the desired effect.
  • the term “therapeutically effective amount” therefore refers to an amount of the agent that is sufficient to provide a particular effect when administered to atypical subject.
  • An effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of PARP.
  • efficacy in vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life.
  • Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and co-usage with other agents.
  • An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact “effective amount”. However, for any given case, an appropriate “effective amount” can be determined by one of ordinary skill in the art using only routine experimentation.
  • the dosage ranges for the administration of an agent according to the methods described herein depend upon, for example, the form of the agent, its potency, and the extent to which symptoms, markers, or indicators of a condition described herein are desired to be reduced, for example, the percentage reduction desired for tumor growth.
  • the dosage should not be so large as to cause adverse side effects.
  • the dosage will vary with the age, condition, and sex of the patient and can be determined by one of skill in the art.
  • the dosage can also be adjusted by the individual physician in the event of any complication.
  • the term “therapeutically effective amount”, as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the disease or condition to be treated is cancer.
  • the disease or condition to be treated is a cell proliferative disorder.
  • an agent described herein in, e.g., the treatment of a condition described herein, or to induce a response as described herein can be determined by the skilled clinician.
  • a treatment is considered “effective treatment,” as the term is used herein, if one or more of the signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically accepted symptoms are improved, or even ameliorated, or a desired response is induced e.g., by at least 10% following treatment according to the methods described herein.
  • Efficacy can be assessed, for example, by measuring a marker, indicator, symptom, and/or the incidence of a condition treated according to the methods described herein or any other measurable parameter appropriate, e.g. tumor size and/or growth rate. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization, or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or are described herein.
  • Treatment includes any treatment of a disease in an individual or an animal (some non-limiting examples include a human or an animal) and includes: (1) inhibiting the disease, e.g., preventing a worsening of symptoms (e.g., pain or inflammation); or (2) relieving the severity of the disease, e.g., causing regression of symptoms.
  • An effective amount for the treatment of a disease means that amount which, when administered to a subject in need thereof, is sufficient to result in effective treatment as that term is defined herein, for that disease.
  • Efficacy of an agent can be determined by assessing physical indicators of a condition or desired response. It is well within the ability of one skilled in the art to monitor efficacy of administration and/or treatment by measuring any one of such parameters, or any combination of parameters.
  • Efficacy can be assessed in animal models of a condition described herein, for example, treatment of blood cancers in a mouse model.
  • efficacy of treatment is evidenced when a statistically significant change in a marker is observed, e.g. tumor size and/or growth rate.
  • the therapeutically effective amount of hydroxyureamethyl-acylfulvene, acylfulvene, Irofulven or a pharmaceutically acceptable salt thereof is selected from the group consisting of 0.5 mg/day, 1 mg/day, 2.5 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 30 mg/day, 60 mg/day, 90 mg/day, 120 mg/day, 150 mg/day, 180 mg/day, 210 mg/day, 240 mg/day, 270 mg/day, 300 mg/day, 360 mg/day, 400 mg/day, 440 mg/day, 480 mg/day, 520 mg/day 580 mg/day, 600 mg/day, 620 mg/day, 640 mg/day, 680 mg/day, and 720 mg/day.
  • the administered dosage of the PARP inhibitor is 1-120 mg (in terms of the parent compound), preferably, 1-80 mg (in terms of the parent compound), and the administration frequency is twice a day (BID);
  • the administered dosage of the PARP inhibitor is 1-120-240 mg (in terms of the parent compound), preferably, 60-120 mg (in terms of the parent compound), and the administration frequency is once a day (QD).
  • QD once a day
  • treat is used and includes both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • a disease e.g., a disease or disorder delineated herein
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • composition of the present invention is capable of further forming salts.
  • the composition of the present invention can form more than one salt per molecule, e.g., mono- , di-, tri-. All of these forms are also contemplated within the scope of the claimed invention.
  • pharmaceutically acceptable salts refer to derivatives of the compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • compositions include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l- carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present invention also encompasses salts formed when an acidic proton in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the term “selectively” means tending to occur at a higher frequency in one population than in another population.
  • the compared populations can be cell populations.
  • an event occurs selectively in population A relative to population B if it occurs greater than two times more frequently in population A as compared to population B.
  • An event occurs selectively if it occurs greater than five times more frequently in population A.
  • An event occurs selectively if it occurs greater than ten times more frequently in population A; more preferably, greater than fifty times; even more preferably, greater than 100 times; and most preferably, greater than 1000 times more frequently in population A as compared to population B.
  • cell death would be said to occur selectively in cancer cells if it occurred greater than twice as frequently in cancer cells as compared to normal cells.
  • compositions, or pharmaceutically acceptable salts or solvates thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compound is administered orally.
  • One skilled in the art will recognize the advantages of certain routes of administration.
  • the dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • a “subject in need thereof’ is a subject having a precancerous condition.
  • a subject in need thereof has cancer.
  • a “subject” includes a mammal.
  • the mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the mammal is a human.
  • the subject of the present invention includes any human subject who has been diagnosed with, has symptoms of, or is at risk of developing a cancer or a precancerous condition.
  • a subject in need thereof may have refractory or resistant cancer.
  • “Refractory or resistant cancer” means cancer that does not respond to treatment. The cancer may be resistant at the beginning of treatment or it may become resistant during treatment.
  • the subject in need thereof has cancer recurrence following remission on most recent therapy.
  • the subject in need thereof received and failed all known effective therapies for cancer treatment.
  • the subject in need thereof received at least one prior therapy. In certain embodiments the prior therapy is monotherapy. In certain embodiments the prior therapy is combination therapy.
  • a subject in need thereof may have a secondary cancer as a result of a previous therapy.
  • Secondary cancer means cancer that arises due to or as a result from previous carcinogenic therapies, such as chemotherapy.
  • Cancer is a group of diseases that may cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, the size of the cancer, and how much it affects the nearby organs or structures. If a cancer spreads (metastasizes), then symptoms may appear in different parts of the body.
  • Treating cancer can result in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be referred to as “tumor regression”.
  • tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer results in a decrease in number and size of tumors.
  • tumor number or size is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number or size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • Treating cancer can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • the number of metastatic lesions may be measured by any reproducible means of measurement.
  • the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 5 Ox.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease- related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.
  • Treating cancer can result in a decrease in tumor growth rate.
  • tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate can be measured according to a change in tumor diameter per unit time.
  • Treating cancer can result in a decrease in tumor regrowth.
  • tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • Treating or preventing a cell proliferative disorder can result in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • Treating or preventing a cell proliferative disorder can result in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells can be equivalent to the mitotic index.
  • Treating or preventing a cell proliferative disorder can result in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • the size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • Treating or preventing a cell proliferative disorder can result in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
  • the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement.
  • An abnormal cellular morphology can be measured by microscopy, e.g., using an inverted tissue culture microscope.
  • An abnormal cellular morphology can take the form of nuclear pleiomorphism.
  • Administering a composition of the present invention to a cell or a subject in need thereof can result in modulation (i.e., stimulation or inhibition) of an activity of a protein methyltransferase of interest.
  • Treating cancer or a cell proliferative disorder can result in cell death, and preferably, cell death results in a decrease of at least 10% in number of cells in a population. More preferably, cell death means a decrease of at least 20%; more preferably, a decrease of at least 30%; more preferably, a decrease of at least 40%; more preferably, a decrease of at least 50%; most preferably, a decrease of at least 75%.
  • Number of cells in a population may be measured by any reproducible means. A number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy and light microscopy. Methods of measuring cell death are as shown in Li et al., Proc. Natl. Acad. Sci. USA. 100(5): 2674-8, 2003. In an aspect, cell death occurs by apoptosis.
  • an effective amount of a composition of the present invention, or a pharmaceutically acceptable salt or solvate thereof is not significantly cytotoxic to normal cells.
  • a therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells.
  • a therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells. In an aspect, cell death occurs by apoptosis.
  • Contacting a cell with a composition of the present invention, or a pharmaceutically acceptable salt or solvate thereof can induce, or activate cell death selectively in cancer cells.
  • Administering to a subject in need thereof a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof can induce or activate cell death selectively in cancer cells.
  • Contacting a cell with a composition of the present invention, or a pharmaceutically acceptable salt or solvate thereof can induce cell death selectively in one or more cells affected by a cell proliferative disorder.
  • administering to a subject in need thereof a composition of the present invention, or a pharmaceutically acceptable salt or solvate thereof induces cell death selectively in one or more cells affected by a cell proliferative disorder.
  • the present invention relates to a method of treating or preventing cancer by administering a composition of the present invention, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, where administration of the composition of the present invention, or a pharmaceutically acceptable salt or solvate thereof, results in one or more of the following: prevention of cancer cell proliferation by accumulation of cells in one or more phases of the cell cycle (e.g. Gl, Gl/S, G2/M), or induction of cell senescence, or promotion of tumor cell differentiation; promotion of cell death in cancer cells via cytotoxicity, necrosis or apoptosis, without a significant amount of cell death in normal cells, antitumor activity in animals with a therapeutic index of at least 2.
  • therapeutic index is the maximum tolerated dose divided by the efficacious dose.
  • kit means a combination partners as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e. simultaneously or at different time points.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the ratio of the total amounts of the combination partners to be administered in the combined preparation can be varied.
  • the combination partners can be administered by the same route or by different routes.
  • LP-100 (Irofulven) and LP-184 ((-) - hydroxyureamethyl acylfulvene) belong to the acylfulvene compound family known to induce DNA lesions repaired by the Transcription- Coupled Nucleotide Excision Repair (TC-NER) pathway. If the TC-NER pathway is impaired, DNA damage can no longer be repaired, and cell death will occur.
  • TC-NER Transcription- Coupled Nucleotide Excision Repair
  • PARP inhibitor selectively induces cell death and inhibits the growth of cancer cells. In combination with an acylfulvene, the cells or tumors were killed or reduced.
  • FIGs. 3 A, 3B, 3C, and 3D show that LP-184 and Olaparib have a synergistic effect on the BRCA2 mutant ovarian tumor cell line PEOl.
  • Cell sensitivity analysis was performed to evaluate the synergistic effect of LP- 184 and Olaparib on PEOl cell line, which is an established BRCA2 mutant ovarian tumor cell line.
  • Cells were seeded onto 96- well plate and were continuously exposed to drug treatment for 8.5 days.
  • IC50 data were obtained from Olaparib, LP-184 single treatment and combination treatment.
  • IC50 data for Olaparib and LP184 alone was 1248. InM and 108.2nM respectively (FIGs. 3A and 3B).
  • IC50 data of Olaparib and LP-184 single treatment was 1248. InM (FIG. 3A) and 108.2nM (FIG.3B) respectively.
  • IC50 data of Olaparib and LP-184 co-treatment was 278.6nM Olaparib and 13.93nM LP-184 (FIG. 3C).
  • the synergistic effect of LP-184 and Olaparib was analyzed through an Isobole plot (FIG. 3Dt). The interaction index was 0.352.
  • FIGs 4A-4D shows LP-184 and Talazoparib have synergistic effect on BRCA2 mutant ovarian cancer cell line PEOL IC50 data of Talazoparib and LP-184 single treatment was 13. InM (FIG. 4A) and 87.4nM (FIG. 4B) respectively. IC50 of Talazoparib and LP-184 co-treatment was 3.6nM Olaparib and 7.2nM LP-184 (FIG. 4C). Synergistic effect of LP-184 and Talazoparib was analyzed through an Isobole plot (FIG. 4D). The interaction index was 0.357.
  • MacSynergy II software was used to score the combination of LP-184/LP-100 and PARP inhibitor. This program allows the three-dimensional examination of drug interactions of all data points generated from the checkerboard combination of two inhibitors with Bliss-Independence model (not shown). Confidence bounds are determined from replicate data. If the 95% confidence limits (CL) do not overlap the theoretic additive surface, then the interaction between the two drugs differs significantly from additive.
  • the volumes of synergy or antagonism can be determined and graphically depicted in three dimensions and represent the relative quantity of synergism or antagonism per change in the two drug concentrations.
  • Synergy and antagonism volumes are based on the Bliss independence model, which assumes that both compounds act independently on different targets.
  • a bliss synergy score >10 indicates synergy between the two testing compounds.
  • Table 1 shows the bliss synergistic score of LP-100 and Olaparib, Rucaparib, and Niraparib.

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Abstract

La présente invention concerne une méthode de traitement du cancer qui comprend une association d'une quantité thérapeutiquement efficace d'une illudine ou d'un analogue de l'illudine associé, d'un dérivé ou d'un sel pharmaceutiquement acceptable associé; et une quantité thérapeutiquement efficace d'un inhibiteur de PARP ou d'un analogue, d'un dérivé ou d'un sel pharmaceutiquement acceptable associé. L'invention englobe également des compositions et des kits associés.
EP22850545.9A 2021-07-29 2022-07-29 Traitement de cancers avec des associations d'inhibiteur de parp et d'acylfulvènes Pending EP4376822A1 (fr)

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