Treatment of cancer with acyl fulvene in combination with ibrutinib or bortezomib

Abstract

A method of treating cancer comprises a combination of: a therapeutically effective amount of pachymutilin or a pachymutilin analogue, a derivative, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of bortezomib, ibrutinib, or an analog, derivative, or pharmaceutically acceptable salt thereof. Compositions and kits including such combinations are provided herein. The cancer may be refractory to bortezomib and / or ibrutinib.

Description

Technical Field

[0001] The present application relates to cancer treatment, and more specifically, the present application relates to cancer treatment using a combination therapy comprising ibrutinib and / or bortezomib or a derivative thereof. More specifically, the combination therapy can be used to treat cancer in a refractory or relapsed subject previously treated with ibrutinib and / or bortezomib. Background Art

[0002] Cancer is one of the most common causes of death in humans. The development of therapeutic strategies for patients with advanced cancer has significantly improved overall survival. However, resistance to anticancer agents is inevitable, and the prognosis of advanced cancer remains poor. There are several potential sources of cancer resistance, including changes in drug transporters, inhibition of apoptosis, mitochondrial changes, promotion of DNA damage repair, autophagy, epithelial-mesenchymal transition, and cancer stem cells (CSC). Appropriate strategies that take these mechanisms into account are necessary for curing cancer.

[0003] Combination therapies for cancer have become more prevalent, in part due to the perceived advantages of attacking the disease through multiple pathways. Although many effective combination therapies have been identified over the past several decades; given the continued large number of deaths caused by cancer each year, there is a continuing need to identify effective therapeutic regimens for anticancer treatment.

[0004] Therefore, there is a constant need for improved methods to treat cancer. Summary of the invention

[0005] The present application discloses the discovery that treating a subject's cancer with a combination of illudin or an illudin analog (e.g., acylfulvene) and ibrutinib and / or bortezomib (or derivatives thereof) has a greater effect than that provided by treatment with acylfulvene or ibrutinib and / or bortezomib alone.

[0006] One aspect of the present application includes a combination therapy for treating cancer. In an embodiment, the therapy includes administering a combination of active agents, the combination of which includes illudin or illudin analogs (e.g., acylfulvene) and ibrutinib and / or bortezomib. The method includes administering a combination of active agents to a subject in need of treatment, the combination of which has a therapeutically effective amount of illudin or its illudin analog, its derivative or a pharmaceutically acceptable salt; and a therapeutically effective amount of ibrutinib and / or bortezomib or its analog, derivative or pharmaceutically acceptable salt. The subject may have recurrent cancer and / or refractory cancer. The subject may have previously been treated with ibrutinib and / or bortezomib. After the cancer is refractory and resistant to ibrutinib and / or bortezomib, the subject may be treated with the combination.

[0007] One aspect includes a method wherein the subject subsequently relapses more than about 1 month, 2 months, 3 months, 4 months, or more after discontinuation of treatment with ibrutinib and / or bortezomib.

[0008] Another aspect includes a method wherein the illudin analog is an acylfulvene.

[0009] Another aspect includes a method wherein the illudin analog is hydroxyureamethylylfulvene.

[0010] Another aspect includes a method wherein the illudin analog has the structure:

[0011]

[0012] Another aspect includes a method wherein the illudin analog has the structure:

[0013]

[0014] Another aspect includes a method wherein the illudin analog is iloforfen.

[0015] Another aspect of the present application provides a pharmaceutical composition comprising an illudin or illudin analog (e.g., acylfulvene) and ibrutinib and / or bortezomib or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically suitable carrier or excipient at a dosage for treating or preventing cancer (primarily those cancers that have been previously treated with ibrutinib and / or bortezomib). The pharmaceutical composition can also be administered in combination with other therapeutic agents or treatment modalities simultaneously, sequentially or alternately.

[0016] Another aspect of the present application includes a therapy comprising an acylfulvene which is a (+)-hydroxycarbamidomethylacylfulvene.

[0017] Another aspect of the present application includes treating cancer, which may include solid tumors and hematological malignancies. Tumors such as, but not limited to, proliferative or neoplastic diseases, such as carcinomas, sarcomas, or mixed cancers, including breast cancer, colon cancer, rectal cancer, endometrial cancer, gastric cancer, prostate cancer, or brain cancer, mesothelioma, ovarian cancer, lung cancer, or pancreatic cancer can be used as targets for treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It was shown that after a few days of treatment with ibrutinib and / or bortezomib, cancer cells became refractory and relapsed;

[0019] Figure 2A It was shown that the tumor volume decreased rapidly in the LP-284 group;

[0020] Figure 2Bshows representative photographs showing large tumors in mice after switching to vehicle / control treatment (upper panel) and near complete tumor regression in mice after switching to LP-284 treatment (lower panel); and

[0021] Figure 2C Kaplan-Meier survival curves are shown, demonstrating prolonged survival of the LP-284 rescue group. DETAILED DESCRIPTION

[0022] The application provides a combination therapy for treating solid cancer and blood cancer. In embodiments, the therapy includes mainly, for example, to those suffering from recurrent or refractory cancer and treated with ibrutinib and / or bortezomib, administering a combination including illudin or illudin analogs (e.g., acylfulvene) and ibrutinib and / or bortezomib. In other embodiments, the therapy includes administering a combination of other therapies. In other embodiments, the combination therapy can be used to treat biochemical occurrence or recurrence of solid cancer (e.g., lung cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer, rectal cancer and bladder cancer), glioblastoma and atypical teratoid rhabdoid tumor and renal cell carcinoma). In other embodiments, the therapy includes a combination therapy that can be used to treat biochemical occurrence and recurrence of blood cancer, wherein a therapeutically effective amount of acylfulvene (e.g., hydroxyurea methyl acylfulvene) or its salt and ibrutinib and / or bortezomib are administered to the patient. In certain embodiments, the combination may provide treatment for lymphomas, such as mantle cell lymphoma (MCL) and double-hit lymphoma (DHL).In multiple myeloma (MM), an overgrowth of plasma cells in the bone marrow crowds out normal hematopoietic cells.

[0023] Illin or acylfulvene

[0024] In one embodiment, the present application includes the use of illudin or illudin analogs (e.g., acylfulvenes). Acylfulvenes are a class of cytotoxic semisynthetic derivatives of illudin, which are natural products that can be extracted from jack o'lantern mushrooms (Omphalotus olearius). Acylfulvenes derived from the sesquiterpene illudin S by treatment with acid (reverse Prins reaction) are much less reactive than illudin S.

[0025] In one example, the acylfulvene is (-)-hydroxycarbamidomethylacylfulvene (designated LP-184 by Lantern Pharma Inc), which shifts light negatively as shown below:

[0026]

[0027] In another example, the acylfulvene is (+)-hydroxycarbamidomethylacylfulvene (designated LP-284 by Lantern Pharma Inc.), which shifts light in the positive direction as shown below:

[0028]

[0029] (+)-Hydroxycarbamidoylfulvene and (-)-hydroxycarbamidoylfulvene are enantiomers and are now well known.

[0030] In another example, the acylfulvene is ilofurofen.

[0031] Bortezomib

[0032] Bortezomib is a class of drugs called antineoplastic agents. They work by killing cancer cells. Bortezomib, sold under the brand name Velcade and others, is an anticancer drug used to treat multiple myeloma and mantle cell lymphoma.

[0033] Bortezomib ([(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propionyl}amino)butyl]boronic acid) is a proteasome inhibitor having the structure shown below. Bortezomib can be obtained from Janssen. The term "bortezomib" includes pharmaceutically acceptable salts, solvates and hydrates thereof.

[0034]

[0035] Stable liquid pharmaceutical compositions of bortezomib are described in WO2016 / 166653, and any such compositions may be used in the methods, compositions and uses of the present invention.

[0036] In some embodiments, the composition comprising bortezomib is a "ready-to-use" formulation, which contains bortezomib in dissolved or solubilized form and is intended for use as is or after further dilution in an intravenous diluent. In a preferred embodiment, the pharmaceutical composition comprising bortezomib is formulated for parenteral administration, such as injection or infusion.

[0037] Bortezomib may be administered in any suitable pharmaceutical form. For example, bortezomib may be provided as a pharmaceutical composition comprising bortezomib or a salt, solvate or hydrate thereof together with a pharmacologically (or pharmaceutically) acceptable excipient.

[0038] Suitable solvents can be selected from aqueous and non-aqueous solvents, such as but not limited to glycerol, ethanol, n-propanol, n-butanol, isopropanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, cyclohexane, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMT), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), propylene carbonate (PC), dimethyl isosorbide, water and mixtures thereof. Preferred solvents are ethanol, glycerol and water.

[0039] The bortezomib formulation used in the present invention may contain stabilizers such as sugars and amino acids. Suitable stabilizers include glucose, trehalose, sucrose, mannitol, sorbitol, arginine, glycine, proline, methionine, lysine, and the like.

[0040] The bortezomib formulation used in the present invention may contain a chelating agent. Suitable chelating agents include DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTA (ethylenediaminetetraacetic acid), ODDA (1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7), TTT A (1,7,13-triaza-4,10,16-trioxacyclooctadecane-N,N′,N″-triacetic acid), DOTRP (tetraethylene glycol-1,5,9-triazacyclododecane-N,N′,N″-tri(methylenephosphonic acid), EGTA (ethylene glycol-bis(p-aminoethyl ether)-tetraacetic acid), and the like.

[0041] The bortezomib preparations used in the present invention may also contain one or more antioxidants. Suitable antioxidants include, but are not limited to, monothioglycerol, ascorbic acid, sodium bisulfite, sodium pyrosulfite, L-cysteine, thioglycolic acid, citric acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid, etc. The most preferred antioxidant is monothioglycerol.

[0042] The most preferred aspect of administering a combination of bortezomib and an additional drug for treating cancer is subcutaneous or intravenous form of bortezomib.

[0043] The bortezomib injection to be used according to the present invention is preferably in the form of a water-soluble boric acid ester; the most preferred ester is mannitol borate.

[0044] The borate ester preparation, preferably mannitol ester, is usually in the form of a sterile dry powder preparation. The powder is usually a freeze-dried powder. The powder is dissolved in sterile water, usually a sterile isotonic sodium chloride aqueous solution, before administration.

[0045] The bortezomib formulations used in the present invention may optionally contain other pharmaceutically acceptable adjuvants, such as buffers, pH adjusters, preservatives, tonicity adjusters, etc. Unless otherwise indicated, the above-listed list of solvents, stabilizers, chelators and antioxidants may also be used in pharmaceutical compositions containing other cytotoxic agents described herein.

[0046] The above-mentioned bortezomib-based formulations may preferably contain mannitol, and may be provided in injection vials or in pre-filled syringes under a nitrogen atmosphere.

[0047] Bruton's tyrosine kinase (BTK) compounds including ibrutinib and pharmaceutically acceptable salts thereof

[0048] In some embodiments, the Btk inhibitor compounds described herein are selective for Btk and kinases having a cysteine ​​residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine ​​481 in Btk. The Btk inhibitor compound can form a covalent bond with Cys 481 of Btk (e.g., via a Michael reaction).

[0049] In some embodiments, the Btk inhibitor is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (ie, PCI-32765 / ibrutinib)

[0050] Another embodiment includes a pharmaceutical composition having a therapeutically effective amount of illudin or an illudin analog, derivative or pharmaceutically acceptable salt thereof; and a therapeutically effective amount of ibrutinib and / or bortezomib or an analog, derivative or pharmaceutically acceptable salt thereof. The illudin analog may be hydroxyureamethylacylfulvene.

[0051] In another embodiment, a kit for treating cancer in a subject comprises a therapeutically effective amount of illudin or an illudin analog, derivative or pharmaceutically acceptable salt thereof; and a therapeutically effective amount of ibrutinib and / or bortezomib or an analog, derivative or pharmaceutically acceptable salt thereof:

[0052] In another embodiment, the second therapeutic agent 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 Raf kinase inhibitors.

[0053] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from paclitaxel or cisplatin.

[0054] The term "combination therapy" may include or include the further combined administration of the above therapeutic agents with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy). When the combination therapy further includes non-drug therapy, the non-drug therapy may be performed at any appropriate time, as long as the beneficial effects from the combined action of the therapeutic agent and the non-drug therapy are achieved. For example, in appropriate cases, when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, it may be for days or even weeks or months, and still achieve a beneficial effect.

[0055] In another aspect, the compositions or combination therapies herein, or pharmaceutically acceptable salts or solvates thereof, can be administered in combination with radiation therapy.Radiation therapy can also be administered in combination with a composition of the invention and another chemotherapeutic agent described herein as part of a multi-agent therapy.

[0056] Combination therapy can be achieved by administering two or more agents, for example, acylfulvene, ibrutinib and / or bortezomib 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. Combination therapy also encompasses other combinations. For example, two agents can be formulated together and administered in combination with a separate formulation containing a third agent. Although two or more agents in combination therapy can be administered simultaneously, they are not necessary. For example, the administration of the first agent (or combination of agents) can be minutes, hours, days, or weeks before the administration of the second agent (or combination of agents). Therefore, two or more medicaments can be used within a few minutes or within 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours or 24 hours or within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, 14 days or within 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks or 10 weeks. In some cases, even longer intervals are also possible. Although it is desired that the two or more medicaments used in the combination therapy are present in the patient's body simultaneously in many cases, this is not necessary.

[0057] The method of combination therapy can or should produce a synergistic effect, wherein the effect of the combination of compounds or other therapeutic agents is greater than the sum of the effects produced by the administration of any compound or other therapeutic agent as a single agent. A synergistic effect can also be an effect that cannot be achieved by administering any compound or other therapeutic agent as a single agent. A synergistic effect can include, but is not limited to, the effect of treating cancer by reducing tumor size, inhibiting tumor growth, or increasing subject survival. A synergistic effect can also include reducing cancer cell viability, inducing cancer cell death, and inhibiting or delaying cancer cell growth.

[0058] As will be appreciated by those skilled in the art, therapeutically effective doses may vary, depending on the disease being treated, the severity of the disease, the route of administration, the age and general health of the patient, the use of excipients, the possibility of co-use with other therapeutic treatments (such as the use of other agents), and the judgment of the treating physician. For example, guidance for selecting an effective dose may be determined by reference to the prescribing information or journal discussion of acylfulvene or hydroxycarbamidemethylacylfulvene.

[0059] The term "effective amount" as used herein refers to the amount of the agent required to alleviate at least one or more symptoms of a disease or disorder, and relates to the amount of the pharmaceutical composition sufficient to provide the desired effect. Therefore, the term "therapeutically effective amount" refers to the amount of the agent sufficient to provide a specific effect when administered to a typical subject. The effective amount can be an amount sufficient to reduce the symptoms of a disease that responds to ibrutinib and / or bortezomib. For cancer therapy, in vivo efficacy can be measured, for example, by assessing survival duration, disease progression time (TTP), response rate (RR), response duration, and / or quality of life. As recognized by those skilled in the art, the effective amount can vary depending on the route of administration, the use of excipients, and the use of other agents. In various cases, the effective amount used herein will also include an amount sufficient to delay the development of disease symptoms, change the course of disease symptoms (for example, but not limited to, slowing the progression of disease symptoms) or reverse disease symptoms. Therefore, it is usually not feasible to specify an exact "effective amount". However, for any given situation, a person of ordinary skill in the art can determine the appropriate "effective amount" using only routine experiments.

[0060] The dosage range for administering the agent according to the methods described herein depends on, for example, the form of the agent, its efficacy, and the degree to which the symptoms, markers or indicators of the conditions described herein need to be reduced, such as the percentage reduction required for tumor growth. The dosage should not be too large to avoid causing adverse side effects. Generally, the dosage will vary with the age, condition and gender of the patient and can be determined by those skilled in the art. In the event of any complications, the dosage can also be adjusted by the individual physician.

[0061] The term "therapeutically effective amount" as used herein refers to an amount of an agent that treats, ameliorates or prevents an identified disease or condition, or exhibits 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 on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder.

[0062] A skilled clinician can determine the efficacy of an agent described herein in the treatment of, for example, a condition described herein, or in inducing a response as described herein (e.g., a solid tumor or a blood cancer). However, a treatment is considered to be "effective treatment," as the term is used herein, if one or more signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically acceptable symptoms are improved, or even alleviated, or a desired response is induced, for example, by at least 10%, following treatment according to the methods described herein. For example, efficacy can be assessed by measuring markers, indicators, symptoms, and / or incidence of a condition treated according to the methods described herein, or any other suitable measurable parameter, such as tumor size and / or growth rate. Efficacy can also be measured by assessing the failure of an individual to deteriorate by hospitalization or the need for pharmacological intervention (i.e., cessation of progression of the disease). Methods for measuring these indicators are known to those skilled in the art and / or are described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include humans or animals), and includes: (1) inhibiting the disease, such as preventing worsening of symptoms (e.g., pain or inflammation); or (2) reducing the severity of the disease, such as causing amelioration of symptoms. The effective amount for treating a disease refers to an amount sufficient to cause effective treatment of the disease when administered to a subject in need, as the term is defined herein. The efficacy of a medicament can be determined by assessing physical indicators of a condition or desired response. Those skilled in the art are fully capable of monitoring the efficacy of administration and / or treatment by measuring any one or any combination of such parameters. Efficacy can be assessed in animal models of the conditions described herein, such as treating blood cancer in a mouse model. When an experimental animal model is used, the efficacy of treatment is demonstrated when statistically significant changes in markers (e.g., tumor size and / or growth rate) are observed. In some embodiments, the therapeutically effective amount of hydroxyureamethyl-acylfulvene, acylfulvene, ilofofene, 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.

[0063] The dosage should be adjusted according to the needs of individuals in need. For example, the dosage of ibrutinib and / or bortezomib is 1 mg to 120 mg (based on the parent compound), preferably 1 mg to 80 mg (based on the parent compound), and the frequency of administration is twice a day (BID); the dosage of ibrutinib and / or bortezomib is 1 mg to 120 mg to 240 mg (based on the parent compound), preferably 60 mg to 120 mg (based on the parent compound), and the frequency of administration is once a day (QD). In some cases, it is more appropriate to apply the lower limit of the above dosage range, while in other cases, higher doses can be used without causing harmful side effects.

[0064] The typical dose of ibrutinib depends on the medical condition being treated. In most cases, the starting dose for adult patients is 420 mg once daily, while for pediatric patients, the starting dose can range from 160 mg to 440 mg, depending on their height and weight. However, the dose can be adjusted based on the response and tolerability of the individual patient.

[0065] The term "treat" is used and includes therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean reducing, inhibiting, attenuating, reducing, preventing or stabilizing the development or progression of a disease (e.g., a disease or condition described herein), lessening the severity of the disease, or ameliorating symptoms associated with the disease.

[0066] The typical dose of bortezomib depends on the medical condition being treated and the patient's weight. For multiple myeloma and mantle cell lymphoma, the recommended dose is 1.3 mg / m2 twice a week for two weeks, followed by a 10-day rest period. This 21-day cycle is repeated for up to eight cycles. However, the dose can be adjusted based on the individual's response and tolerability to treatment.

[0067] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0068] The composition of the present invention can further form salts. The composition of the present invention can form more than one salt per molecule, such as a monosalt, a disalt, a trisalt. All these forms are also encompassed within the scope of the claimed invention.

[0069] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the invention in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines), alkali metal or organic salts of acidic residues (such as carboxylic acids), and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylparaaminophenylarsonic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, Hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0070] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic 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-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present invention also encompasses salts formed when an acidic proton in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or coordinated with an organic base (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.).

[0071] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) of the same salts.

[0072] As used herein, the term "selectively" means a tendency to occur at a higher frequency in one population than in another population. The populations compared may be cell populations. Preferably, if an event occurs more than twice as frequently in population A as in population B, the event occurs selectively in population A relative to population B. If an event occurs more than five times as frequently in population A, the event occurs selectively. If an event occurs more than ten times as frequently in population A as in population B; more preferably, more than fifty times; even more preferably, more than 100 times; and most preferably, more than 1000 times, the event occurs selectively. For example, if cell death occurs more than twice as frequently in cancer cells as in normal cells, cell death is considered to occur selectively in cancer cells.

[0073] The composition or its pharmaceutically acceptable salt or solvate is administered orally, nasally, transdermally, pulmonary, by inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectal, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0074] The dosage regimen for using the compound is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and liver function; and the specific compound or salt thereof employed. An ordinary 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.

[0075] The disclosed formulation and administration techniques of the compounds of the present invention can be found in Remington: the Science and Practice of Pharmacy, 19th Supplement, Mack Publishing Co., Easton, Pa. (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. These compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0076] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of the present invention are apparent from different examples. The provided embodiments illustrate different components and methods that can be used to implement the present invention. These examples do not limit the claimed invention. Based on the disclosure of the present invention, those skilled in the art can identify and use other components and methods that can be used to implement the present invention.

[0077] As used herein, a "subject in need" is a subject having a precancerous condition. Preferably, the subject in need has cancer. "Subject" includes mammals. The mammal can be, for example, any mammal, such as a human, a primate, a bird, a mouse, a rat, a dog, a cat, a cow, a horse, a goat, a camel, a sheep, or a pig. Preferably, the mammal is a human. Subjects of the present invention include any human subject who has been diagnosed with cancer or a precancerous condition, has symptoms of cancer or a precancerous condition, or is at risk of developing cancer or a precancerous condition.

[0078] A subject in need thereof may have a refractory or resistant cancer. "Refractory or resistant cancer" refers to a cancer that does not respond to treatment. The cancer may be resistant at the beginning of treatment, or it may become resistant during treatment. In some embodiments, the subject in need thereof has had a recurrence of cancer after remission from a most recent therapy. In some embodiments, the subject in need thereof has received and failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof has received at least one prior therapy. In certain embodiments, the prior therapy is a monotherapy. In certain embodiments, the prior therapy is a combination therapy.

[0079] "Recurrent cancer" is a cancer that has been previously treated, and as a result of that treatment, the subject fully or partially recovered (i.e., the subject is said to be in remission), but after treatment was discontinued, the cancer recurred or worsened. In other words, a recurrent cancer is a cancer that has become resistant to treatment after a period of time when treatment was effective and the subject fully or partially recovered. Typically, in patients with multiple myeloma, the development of resistance and refractory disease occurs after multiple rounds of treatment. In addition, ibrutinib may become refractory, leading to treatment resistance, when cancer cells mutate or alter signaling pathways that bypass the drug's mechanism of action. This may occur at different stages of treatment and may vary depending on the type of cancer being treated and the patient's individual response to the drug.

[0080] In some embodiments, the subject in need thereof may have a secondary cancer as a result of a previous therapy."Secondary cancer" refers to a cancer that developed as a result of a previous carcinogenic therapy, such as chemotherapy.

[0081] Cancer is a group of diseases that can cause almost any sign or symptom. Signs and symptoms will depend on where the cancer is, how big it is, and how much it has affected nearby organs or structures. If the cancer has spread (metastasized), symptoms may appear in different parts of the body.

[0082] Treatment of cancer can result in a decrease in tumor size. A decrease in tumor size can also be referred to as "tumor regression." Preferably, after treatment, the tumor size decreases by 5% or more relative to its size before treatment; more preferably, the tumor size decreases by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by greater than 75% or more. Tumor size can be measured by any reproducible means of measurement. Tumor size can be measured as the diameter of the tumor.

[0083] Treating cancer results in a reduction in the number and size of tumors. Preferably, after treatment, the number or size of tumors is reduced by 5% or more relative to the number before treatment; more preferably, the number or size of tumors is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by greater than 75%. The number of tumors can be measured by any reproducible means of measurement. The number of tumors can be measured by counting tumors visible to the naked eye or visible at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.

[0084] Treating cancer can reduce the number of metastatic lesions in other tissues or organs away from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more relative to the number before treatment; more preferably, the number of metastatic lesions is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measurement means. The number of metastatic lesions can be measured by counting tumors visible to the naked eye or visible at a specified magnification. Preferably, the specified magnification is 2×, 3×, 4×, 5×, 10× or 50×.

[0085] Treating cancer can increase the average survival time of a population of treated subjects compared to a population that receives only the vehicle. Preferably, the average survival time is increased by more than 30 days; more preferably, more than 60 days; more preferably, more than 90 days; and most preferably, more than 120 days. The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can be measured, for example, by calculating the average survival time of a population after starting treatment with an active compound. The increase in the average survival time of a population can also be measured, for example, by calculating the average survival time of a population after completing a first round of treatment with an active compound.

[0086] Treating cancer can increase the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, more than 60 days; more preferably, more than 90 days; and most preferably, more than 120 days. The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can be measured, for example, by calculating the average survival time of a population after starting treatment with an active compound. The increase in the average survival time of a population can also be measured, for example, by calculating the average survival time of a population after completing a first round of treatment with an active compound.

[0087] Treating cancer can increase the average survival time of a population of treated subjects compared to a population receiving a monotherapy with a drug that is not a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof. Preferably, the average survival time is increased by more than 30 days; more preferably, more than 60 days; more preferably, more than 90 days; and most preferably, more than 120 days. The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can be measured, for example, by calculating the average survival time of a population after starting treatment with an active compound. The increase in the average survival time of a population can also be measured, for example, by calculating the average survival time of a population after completing a first round of treatment with an active compound.

[0088] Treating cancer can reduce the mortality rate of the treated subject population compared to the population receiving only the carrier. Treating cancer can reduce the mortality rate of the treated subject population compared to the untreated population. Treating cancer can reduce the mortality rate of the treated subject population compared to the population receiving monotherapy with a drug that is not a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof. Preferably, the mortality rate is reduced by more than 2%; more preferably, more than 5%; more preferably, more than 10%; and most preferably, more than 25%. The reduction in the mortality rate of the treated subject population can be measured by any reproducible means. The reduction in the mortality rate of the population can be measured, for example, by calculating the average number of disease-related deaths per unit time in the population after the start of treatment with the active compound. The reduction in the mortality rate of the population can also be measured, for example, by calculating the average number of disease-related deaths per unit time in the population after the first round of treatment with the active compound.

[0089] Treatment of cancer can result in a decrease in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% relative to the amount before treatment; more preferably, the tumor growth rate is reduced 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%. Tumor growth rate can be measured by any reproducible means of measurement. Tumor growth rate can be measured based on the change in tumor diameter per unit time.

[0090] Treatment of cancer can result in reduced tumor regrowth. Preferably, after treatment, 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 can be measured by any reproducible measurement means. Tumor regrowth is measured, for example, by measuring an increase in tumor diameter after a previous tumor reduction after treatment. The absence of a tumor recurring after treatment has stopped indicates a reduction in tumor regrowth.

[0091] Treatment or prevention of a cell proliferative disorder may result in a decrease in the rate of cell proliferation. Preferably, after treatment, the rate of cell proliferation is decreased by at least 5%; more preferably, at least 10%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40%; more preferably, at least 50%; even more preferably, at least 50%; and most preferably, at least 75%. The rate of cell proliferation may be measured by any reproducible means of measurement. The rate of cell proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0092] Treatment or prevention of a cell proliferative disorder may result in a decrease in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least 5%; more preferably, at least 10%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40%; more preferably, at least 50%; even more preferably, at least 50%, and most preferably, at least 75%. The proportion of proliferating cells may be measured by any reproducible means of measurement. Preferably, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample. The proportion of proliferating cells may be equal to the mitotic index.

[0093] Treatment or prevention of a cell proliferative disorder may result in a decrease in the size of an area or zone of cell proliferation. Preferably, after treatment, the size of an area or zone of cell proliferation is reduced by at least 5% relative to its size prior to treatment; 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 size of an area or zone of cell proliferation may be measured by any reproducible means of measurement. The size of an area or zone of cell proliferation may be measured as the diameter or width of the area or zone of cell proliferation.

[0094] Treatment or prevention of a cell proliferative disorder may result in a decrease in the number or proportion of cells having an abnormal appearance or morphology. Preferably, after treatment, the number of cells having an abnormal morphology is reduced by at least 5% relative to their size prior to treatment; 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%. Abnormal cell appearance or morphology may be measured by any reproducible means of measurement. Abnormal cell morphology may be measured microscopically, for example, using an inverted tissue culture microscope. Abnormal cell morphology may take the form of nuclear polymorphism.

[0095] Administration of the compositions of the invention to a cell or subject in need thereof can result in modulation (ie, stimulation or inhibition) of the activity of a protein methyltransferase of interest.

[0096] Treatment of cancer or a cell proliferative disorder may result in cell death, and preferably, cell death results in a decrease in the number of cells in a population by at least 10%. 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%; more preferably, a decrease of at least 75%. The number of cells in a population may be measured by any reproducible means. The number of cells in a population may be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy, and light microscopy. Methods for measuring cell death are as shown in Li et al., Proc. Natl. Acad. Sci. USA. 100(5): 2674-8, 2003. In one aspect, cell death occurs by apoptosis.

[0097] Preferably, an effective amount of the composition of the invention or a pharmaceutically acceptable salt or solvate thereof is not significantly cytotoxic to normal cells. If the compound is administered in a therapeutically effective amount, it does not induce cell death in more than 10% of normal cells, then the therapeutically effective amount of the compound is not significantly cytotoxic to normal cells. If the compound is administered in a therapeutically effective amount, it does not induce cell death in more than 10% of normal cells, then the therapeutically effective amount of the compound does not significantly affect the viability of normal cells. In one aspect, cell death occurs by apoptosis.

[0098] Contacting cells with a composition of the invention, or a pharmaceutically acceptable salt or solvate thereof, can selectively induce or activate cell death in cancer cells. Administering a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof can selectively induce or activate cell death in cancer cells. Contacting cells with a composition of the invention, or a pharmaceutically acceptable salt or solvate thereof, can selectively induce cell death in one or more cells affected by a cell proliferative disorder. Preferably, administering a composition of the invention, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof selectively induces cell death in one or more cells affected by a cell proliferative disorder.

[0099] The present invention relates to a method for 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, wherein administration of the composition of the present invention or a pharmaceutically acceptable salt or solvate thereof results in one or more of the following: preventing cancer cell proliferation by accumulating cells in one or more phases of the cell cycle (e.g., G1, G1 / S, G2 / M) or inducing cell senescence or promoting tumor cell differentiation; promoting cell death in cancer cells by cytotoxicity, necrosis or apoptosis without a significant amount of cell death in normal cells, and having an anti-tumor activity in animals with a therapeutic index of at least 2. As used herein, "therapeutic index" is the maximum tolerated dose divided by the effective dose.

[0100] The term "kit of parts" means that the combination partners as defined above can be administered independently or by using different fixed combinations with different amounts of the combination partners, i.e. simultaneously or at different time points. The parts of the kit of parts can then be administered, for example, simultaneously or chronologically staggered, i.e. 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 may vary. The combination partners can be administered by the same route or by different routes.

[0101] Those skilled in the art can refer to general reference texts to describe in detail the known technologies or equivalent technologies discussed herein. Of course, these texts can also be referred to when making or using one aspect of the present invention.

[0102] Example

[0103] In order to more effectively understand the disclosure disclosed herein, examples are provided below. It should be understood that these examples are only for illustrative purposes and should not be construed as limiting the present disclosure in any way.

[0104] Example 1

[0105] The effects of LP-284 and ibrutinib and / or bortezomib on the growth of MCL xenograft tumors are shown in Figure 1 and Figure 2A In. On the days indicated by the arrows in the figure, JeKo-1MCL cell line-derived xenograft mice (n=8 / group) were treated with vehicle, LP-284 (2 mg / kg or 4 mg / kg, iv), bortezomib (1 mg / kg, ip) or ibrutinib (50 mg / kg, po). Tumor volume was measured every 2 to 4 days after the start of treatment. Figure 1 It was shown that after a few days of treatment, the cancer cells became refractory and relapsed. Low-dose LP-284, ibrutinib, and / or bortezomib treatment each resulted in refractory cancer after initially controlling cell growth in the tumor.

[0106] As in the same study Figure 2A and Figure 2C As shown, LP-284 was able to almost completely eliminate lymphomas as large as 2000 mm3 that were refractory to bortezomib or ibrutinib ( Figure 2A ). There are many resistance mechanisms to these two drugs, such as mutations and dysregulation of proteasome subunits, BTK mutations, NF-KB upregulation, and cell survival pathways. These results suggest that LP-284 treatment rescues treatment plans for patients who are refractory to bortezomib or ibrutinib.

[0107] Example 2

[0108] Figure 2A , Figure 2B and Figure 2C LP-284 was shown to reduce bortezomib-refractory and ibrutinib-refractory MCL xenograft tumors with either bortezomib or ibrutinib. Figure 2AJeKo-1MCL xenograft tumors were refractory to bortezomib and ibrutinib at the dose regimen shown, resulting in a tumor volume of approximately 2000 mm3 on day 17. Both drugs were replaced with one cycle of 4 mg / kg LP-284 or vehicle (saline). Bortezomib and ibrutinib refractory mice were divided into two groups of four mice based on mouse tumor size and then treated with LP-284 or vehicle. Although vehicle-treated tumors continued to expand until all mice died or were sacrificed due to excessive tumor size, one cycle of 4 mg / kg LP-284 resulted in almost complete tumor regression ( Figure 2A and Figure 2B ). Furthermore, in these refractory xenograft mice pretreated with bortezomib or ibrutinib, LP-284 resulted in approximately two-fold longer survival than vehicle (p<0.001)( Figure 2C At the end of treatment (EOT), no significant weight loss was observed in any treatment group (one-tailed T-test, p>0.05).

[0109] LP-284 rescues bortezomib and ibrutinib-refractory MCL xenograft mice. JeKo-1MCL cell line-derived xenograft mice were treated with bortezomib (1 mg / kg, ip) or ibrutinib (50 mg / kg, po) until the tumor size reached approximately 2000 mm3 on day 16. Each treatment group was then further separated into two subgroups (n=4 / subgroup), one of which was treated with vehicle and the other with 4 mg / kg LP-284 (iv), as indicated by the arrows in the figure. Figure 2A It was shown that the tumor volume decreased rapidly in the LP-284 group. Figure 2B Representative photographs showing large tumors in mice after switching to vehicle treatment (upper panel) and near complete tumor regression in mice after switching to LP-284 treatment (lower panel) are shown. Figure 2C Kaplan-Meier survival curves are shown, indicating prolonged survival of the LP-284 rescue group.

[0110] Methodology

[0111] In vivo animal studies

[0112] Five-week-old NOD.Scid mice were obtained by Envigo (Item 17003F). Mice were fed a Teklad irradiated (sterilized) mouse diet and immobilized with Teklad irradiated (sterilized) corncob litter from Envigo (Indianapolis, IN). Mice were housed in an Optimice carousel sterile field with a filtered air supply in disposable cages from Animal Care Systems, Inc. (Centennial, CO). A total of 1x10 7 JeKo-1 cells were injected subcutaneously into the right hind flank of each animal. Vehicle (saline), 4 mg / kg or 2 mg / kg LP-284 were administered intravenously on days 1, 3, 5, 7, 9, 17, 19, 21, 23, and 25. 50 mg / kg of ibrutinib was administered orally daily from day 1 to day 16. 1 mg / kg of bortezomib was administered intraperitoneally on days 1, 4, 7, and 10. Ibrutinib and bortezomib groups were further treated intravenously with vehicle or 4 mg / kg LP-284 on days 17, 19, 21, 23, and 25. Tumors were measured in two dimensions using calipers and the volume was calculated using the following formula:

[0113] Tumor volume (mm 3 )=w2×l / 2

[0114] Where w = width of the tumor and l = length of the tumor in mm. For this study, the caliper was aligned to the edge of the tumor (the caliper did not compress the tumor).

[0115] Although a number of exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. Therefore, the following appended claims and claims thereafter are intended to be interpreted as including all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.

Claims

1. A method of treating cancer, the method comprising administering to a subject in need of treatment a combination comprising: a. a therapeutically effective amount of illudin or an illudin analog, derivative or pharmaceutically acceptable salt thereof; and b. a therapeutically effective amount of bortezomib or an analog, derivative or pharmaceutically acceptable salt thereof, wherein the subject has relapsed cancer and / or refractory cancer; and the subject has been previously treated with bortezomib; and the subject is treated with the combination after the cancer is refractory and resistant to bortezomib.

2. The method of claim 1, wherein the subject subsequently relapses more than about 1 month after discontinuation of treatment with bortezomib.

3. The method of claim 1, wherein the illudin analog is an acylfulvene.

4. The method of claim 1, wherein the illudin analog is hydroxyureamethylacylfulvene.

5. The method of claim 1, wherein the illudin analog has the following structure:

6. The method of claim 1, wherein the illudin analog has the following structure:

7. The method of claim 1, wherein the illudin analog is iloforfen.

8. The method of claim 1, wherein the bortezomib is administered after at least two cycles of bortezomib treatment.

9. The method of claim 1, wherein the bortezomib or a pharmaceutically acceptable salt, solvate or hydrate thereof and the illudin or illudin analog are for separate, simultaneous or sequential use or administration.

10. The method of claim 1, wherein the bortezomib is administered at a dose of 160 mg to 440 mg per day.

11. The method of claim 1, wherein the active agent is administered alone.

12. The method of claim 1, wherein the active agent is administered daily.

13. The method of claim 1, wherein the active agents are administered sequentially.

14. The method of claim 1, wherein the active agent is administered as a co-formulation.

15. The method of claim 1, wherein the illudin or analog thereof is administered before, during, or after administration of bortezomib.

16. The method of claim 1, further comprising administering radiation therapy, chemotherapy, or performing surgery on the subject before, during, or after administering the illudin and / or the bortezomib.

17. The method of claim 1, wherein the cancer is MCL.

18. The method of claim 1, wherein the subject is an animal.

19. The method of claim 1, wherein the subject or mammal is a human.

20. The method of claim 2 or 3, further comprising subjecting the subject to radiation therapy before, after, or during treatment with hydroxycarbamidomethylfulvene.

21. The method of claim 1, further comprising administering an additional therapeutic agent selected from the group consisting of cisplatin, paclitaxel, and other available therapies.

22. The method of claim 1, wherein the cancer comprises a solid tumor.

23. The method of claim 1, wherein the cancer is lymphoma, leukemia, or melanoma.

24. A pharmaceutical composition comprising a therapeutically effective amount of illudin or an illudin analog, derivative or pharmaceutically acceptable salt thereof; and a therapeutically effective amount of ibrutinib or an analog, derivative or pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition of claim 24, wherein the illudin analog is hydroxyureamethylacylfulvene.

26. The pharmaceutical composition of claim 24, wherein the illudin analog has the following structure:

27. The pharmaceutical composition of claim 24, wherein the illudin analog has the following structure:

28. The pharmaceutical composition of claim 24, wherein the illudin analog is iloforfen.

29. A kit for treating cancer in a subject, the kit comprising a therapeutically effective amount of illudin or an illudin analog, derivative or pharmaceutically acceptable salt thereof; and a therapeutically effective amount of ibrutinib or an analog, derivative, or pharmaceutically acceptable salt thereof, wherein the subject has relapsed cancer and / or refractory cancer; and the subject has previously been treated with the ibrutinib; and after the cancer is refractory and resistant to ibrutinib, the subject is treated with the combination.

30. The pharmaceutical composition of claim 29, wherein the illudin analog is hydroxyureamethylacylfulvene.

31. The pharmaceutical composition of claim 29, wherein the illudin analog has the following structure:

32. The pharmaceutical composition of claim 30, wherein the illudin analog is iloforfen.

33. The pharmaceutical composition of claim 30, wherein the illudin analog has the following structure:

34. A method of treating cancer, the method comprising administering to a subject in need of treatment a combination of active agents comprising: A therapeutically effective amount of illudin or an illudin analog, derivative or pharmaceutically acceptable salt thereof; and A therapeutically effective amount of ibrutinib or an analog, derivative, or pharmaceutically acceptable salt thereof, wherein the subject has relapsed cancer and / or refractory cancer; and the subject has previously been treated with ibrutinib; and after the cancer is refractory and resistant to ibrutinib, the subject is treated with the combination.

35. The pharmaceutical composition of claim 30, wherein the illudin analog is hydroxyureamethylacylfulvene.

36. The pharmaceutical composition of claim 30, wherein the illudin analog has the following structure:

37. The pharmaceutical composition of claim 30, wherein the illudin analog is iloforfen.

38. The pharmaceutical composition of claim 30, wherein the illudin analog has the following structure:

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