WO2024098032A1 - Utilisation de dianhydrogalactitol dans le traitement d'épendymomes - Google Patents

Utilisation de dianhydrogalactitol dans le traitement d'épendymomes Download PDF

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WO2024098032A1
WO2024098032A1 PCT/US2023/078737 US2023078737W WO2024098032A1 WO 2024098032 A1 WO2024098032 A1 WO 2024098032A1 US 2023078737 W US2023078737 W US 2023078737W WO 2024098032 A1 WO2024098032 A1 WO 2024098032A1
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ependymoma
dianhydrogalactitol
patient
treatment
alkylating hexitol
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PCT/US2023/078737
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English (en)
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Dennis M. Brown
John Michael LANGLANDS
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Del Mar Pharmaceuticals (Bc) Ltd.
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Publication of WO2024098032A1 publication Critical patent/WO2024098032A1/fr

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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin

Definitions

  • Neuroepithelial tumors originate from neuroepithelial cells (NE cells), which are stem cells that can produce all neurons and macroglial cells of the central nervous system.
  • Ependymal cells are ciliated-epithelial glial cells that develop from radial glia along the surface of the ventricles of the brain and the spinal canal. Ependymal cells play a critical role in cerebrospinal fluid (CSF) homeostasis, brain metabolism, and clearance of waste from the brain (MacDonald A. et al., Front. Cell. Neurosci., 15:703951, 2021.).
  • Ependymoma is a relatively rare CNS tumor that accounts for 2-9% of all neuroepithelial tumors.
  • ependymoma can be malignant
  • a myxopapillary ependymoma is a benign tumor that can occur in the spine.
  • Ependymoma arises from the ependymal cells lining the cerebrospinal fluid sacs (ventricles) of the brain, and commonly affects children, but can occur at any age.
  • a low-grade malignancy ependymoma can be treated by surgically removing as much of the tumor as is possible and safe.
  • Ependymoma tumor cells can spread through the spinal fluid, and while radiation therapy can be used, it has not yet been determined whether chemotherapy is useful in these tumors.
  • RELA RELA proto-oncogene, NF-KB subunit
  • RELA that can complex with NFKB1 to form a commonly occurring complexed form of NF-KB.
  • RELA fusion-positive ependymoma is a subgroup of ependymoma that is associated with supratentorial location, higher WHO grade, and worse prognosis.
  • GBM primary central nervous system
  • CNS central nervous system
  • GBM also referred to as a grade IV astrocytoma
  • astrocytes which are star-shaped glial cells in the brain and spinal cord.
  • GBM is a rapidly growing, destructive tumor that can lead to death of the patient within months.
  • Microscopic imaging shows that GBM tumors have features of an anaplastic astrocytoma with the addition of areas of dead tissue as necrosis, which occurs because the tumor cells grow faster than new blood vessels can be produced to nourish the tumor cells.
  • Surgery, radiation, and chemotherapy are first line treatments that may prolong life to about a year, and not all patients are candidates for surgical removal of the tumor; for example, if the tumor has spread into vital structures or to both sides of the brain (e.g., "‘butterfly glioma") at the time of diagnosis, treatment options may be limited. As a result, it is extremely rare for a GBM tumor to be completely removed by surgery' and removing the part of the tumor that is detected with the MRI or CT scan does not necessarily mean that all malignant cells have been removed. While radiation therapy helps most patients live somewhat longer, chemotherapy only benefits about a quarter of patients. Another treatment that has been approved by the U.S.
  • FDA Food and Drug Administration
  • Such a method should involve delivery' of the active agent or agents to the affected regions of the brain and central nervous system and should be compatible with other treatment modalities, especially surgery, chemotherapy, radiation therapy, and chemoradiation therapy.
  • therapeutic modalities that can cross the blood-brain barrier (BBB), that can suppress the grow th and division of cancer stem cells (CSC), and that can overcome resistance-mechanisms related to O 6 -methylguanine-DNA methyltransferase (MGMT).
  • a method for treating ependymoma comprising the step of administering a therapeutically effective quantity' of an alkylating hexitol to a patient with ependymoma to treat the ependymoma.
  • the alky lating hexitol is selected from dianhydrogalactitol (referred to herein as DAG or VAL-083), a derivative or analog of dianhydrogalactitol, diacetyldianhydrogalactitol (DADAG), a derivative or analog of diacetyldianhydrogalactitoL dibromodulcitol, and a denvative or analog of dibromodulcitol.
  • the alkylating hexitol is dianhydrogalactitol.
  • the method further comprises administering an agent for treatment of an adverse event associated with a treatment of the ependymoma.
  • the method further comprises administering an additional anti-cancer treatment to the patient.
  • the additional anti-cancer treatment can be radiation, chemotherapy, chemoradiation therapy, temozolomide, antibody therapy, bevacizumab, l-[2-chloroethyl]-3-cyclohexyl-l-nitroso-urea (CCNU; Lomustine), and the like.
  • the alkylating hexitol and the additional anti-cancer treatment are administered in any sequential order, for example, on different days or on the same day.
  • the alky lating hexitol and the additional anti-cancer treatment can be administered in any order or simultaneously.
  • the ependymoma is a RELA fusion-positive ependymoma refractory to a temozolomide (TMZ)-based treatment regimen.
  • the patient can have an unmethylated MGMT promoter, a wild-type IDH (IDH-WT), a TERT promoter mutation, a PTEN mutation, an EGFR mutation, and/or one or more other mutations.
  • a method of suppressing proliferation of an ependymoma cell comprising delivering or administering to the cell an alkylating hexitol, for example, dianhydrogalactitol, diacety ldianhydrogalactitoL and/or dibromodulcitol.
  • the alkylating hexitol is dianhydrogalactitol.
  • the cell is in vivo, for example, in a human subject.
  • the administering can be done in vivo, for example, in a human subject with ependymoma by administering a therapeutically effective quantity' of an alky lating hexitol to the human subject.
  • the methods disclosed herein are particularly used for treatment of patients with ependymoma.
  • the ependymoma is a RELA fusion-positive ependymoma refractory to a temozolomide-based treatment regimen.
  • the ependymoma patient can have an unmethy lated MGMT promoter, a wild-ty pe IDH (IDH-WT), a TERT promoter mutation, a PTEN mutation, an EGFR mutation, and/or one or more other mutations.
  • IDH-WT wild-ty pe IDH
  • TERT promoter mutation a wild-ty pe IDH
  • PTEN mutation a PTEN mutation
  • an EGFR mutation and/or one or more other mutations.
  • FIGURE 1A is an MRI of a patient’s brain showing progressive nodular enhancement in the right occipital lobe after treatment with temozolomide.
  • FIGURE IB is an MRI of the patient’s brain after the patient underwent a right occipital craniotomy with gross total resection of the tumor.
  • FIGURE 1C is an MRI of the patient's brain wherein 8 weeks after a second resection. Nodular enhancement was noticed in the operative site suggesting tumor progression.
  • FIGURE ID is an MRI of the patient’s brain at 18 months after completion of treatment with VAL-083.
  • Figure 2A is an MRI of the patient’s brain at day 1 of the first cycle of VAL-083 administration.
  • Figure 2B is an MRI of the patient’s brain at day 1 of cycle 6 of VAL-083 administration.
  • Figure 3A is an MRI of the patient’s brain at day 1 of the first cycle of VAL-083 administration.
  • Figure 3B is an MRI of the patient’s brain at day 1 of cycle 5 of VAL-083 administration prior to radiation therapy.
  • Figure 3C is an MRI of the patient’s brain at day 1 of cycle 6 of VAL-083 administration.
  • the alkylating hexitol is selected from dianhydrogalactitol (DAG), derivatives of DAG, diacetyldianhydrogalactitol (DADAG), derivatives of DADAG, dibromodulcitol (DBD), and derivatives of DBD, unless otherwise specified.
  • DAG diacetyldianhydrogalactitol
  • DADAG diacetyldianhydrogalactitol
  • DBD dibromodulcitol
  • the alkylating hexitol is DAG, unless otherwise specified.
  • derivatives of DAG such as a compound analog or a prodrug are preferred, as stated below.
  • Alkylating hexitols and derivatives that can be used in compositions and methods according to the present invention include galactitols, substituted galactitols, dulcitols, and substituted dulcitols.
  • the alkylating hexitol or derivative is selected from DAG, derivatives of DAG, analogs of DAG, DADAG, derivatives of DAD AG, analogs of DADAG, DBD, derivatives of DBD, and analogs of DBD. More typically, the alkydating hexitol or derivative is selected from DAG, derivatives of DAG, DADAG, derivatives of DADAG, DBD, and derivatives of DBD. In certain embodiments, the alkylating hexitol or derivative is DAG.
  • substituted hexitol derivative As used herein, the terms “substituted hexitol derivative,” “alkylating hexitol derivative,” and “alkylating hexitol” are used interchangeably and encompass these alternatives unless specifically limited to a compound, a compound with defined substituents, or a class of compounds within the broad definitions provided above.
  • the alkylating hexitol is DAG, including its stereoisomers.
  • the terms “dianhydrogalactitol,” “DAG,” and “VAL-083” are used herein interchangeably.
  • the structure of dianhydrogalactitol (DAG or VAL-083) is shown in Formula (I), below .
  • galactitols, substituted galactitols, dulcitols, and substituted dulcitols included in the methods and combinations disclosed herein are either alkylating agents or prodrugs of alky lating agents, as discussed further below .
  • derivatives of DAG that, for example, have one or both hydrogens of the two hydroxyl groups of DAG replaced with lower alkyl, have one or more of the hydrogens attached to the two epoxide rings replaced with a lower alkyl, or have the methyl groups present in DAG and that are attached to the same carbons that bear the hydroxyl groups replaced with C2-C6 lower alkyl or substituted with, for example, halo groups by replacing a hydrogen of the methyl group with, for example, a halo group.
  • halo group refers to fluoro, chloro, bromo, or iodo.
  • lower alkyl refers to C1-C6 groups and includes methyl.
  • the term “‘lower alkyl” can be further limited, such as “C2-C6 lower alkyl,” which excludes methyl.
  • lower alkyl unless further limited, refers to both straight-chain and branched alkyl groups. These groups can, optionally, be further substituted, for example, with halo groups.
  • the alkylating hexitol or derivative is DADAG.
  • DADAG The structure of DADAG is shown in Formula (II). below.
  • derivatives of DAD AG that, for example, have one or both of the methyl groups that are part of the acetyl moieties replaced with C2-C6 lower alkyl, have one or both of the hydrogens attached to the epoxide ring replaced with lower alkyl, or have the methyl groups attached to the same carbons that bear the acetyl groups replaced with lower alkyl or substituted with, for example, halo groups by replacing a hydrogen with, for example, a halo group.
  • the alkylating hexitol derivative is DBD of Formula (III):
  • Dibromodulcitol can be produced by the reaction of dulcitol with hydrobromic acid at elevated temperatures, followed by crystallization of the DBD.
  • DBD Dibromodulcitol
  • Some of the properties of DBD are described in N. E. Mischler el al. , “Dibromoduci tol,” Cancer Treat. Rev. 6: 191-204 (1979).
  • dibromodulcitol as an a, co-dibrominated hexitol, dibromodulcitol shares many of the biochemical and biological properties of similar drugs such as dibromomannitol and mannitol myleran.
  • dibromodulcitol Activation of dibromodulcitol to the di epoxide dianhydrogalactitol occurs in vivo, and dianhydrogalactitol can represent a major active form of the drug; this means that dibromogalactitol has many of the properties of a prodrug. Absorption of dibromodulcitol by the oral route is rapid and fairly complete.
  • dibromodulcitol that, for example, have one or more hydrogens of the hydroxyl groups replaced with a lower alkyl, or have one or both of the bromo groups replaced with another halo group such as chloro, fluoro, or iodo.
  • the compounds described herein can contain one or more chiral centers and therefore, can exist as stereoisomers, such as enantiomers or diastereomers.
  • the disclosure herein includes each of the isolated stereoisomeric forms (such as the enantiomerically pure isomers and other alternatives for stereoisomers) as well as mixtures of stereoisomers in varying degrees of chiral purity or percentage, including racemic mixtures and mixtures of diastereomers, unless a specific stereoisomer is specified.
  • the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • the stereoisomerically pure form e.g., geometrically pure, enantiomerically pure, or diastereomerically pure
  • enantiomeric and stereoisomeric mixtures e.g., geometrically pure, enantiomerically pure, or diastereomerically pure
  • the chemical name does not specify the isomeric form of the compound, it denotes any one of the possible isomeric forms or mixtures of those isomeric forms of the compound.
  • the compounds can also exist in several tautomeric forms, and the depiction herein of one tautomer is for convenience only and is also understood to encompass other tautomers of the form shown. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • solvate means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that includes a solute ion or molecule, i.e., a compound of the invention, with one or more solvent molecules.
  • solvate When water is the solvent, the corresponding solvate is “hydrate.” Examples of hydrate include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other water-containing species. It should be understood by one of ordinary skill in the art that the pharmaceutically acceptable salt, and/or prodrug of the present compound can also exist in a solvate form.
  • the solvate is typically formed via hydration which is either part of the preparation of the present compound or through natural absorption of moisture by the anhydrous compound of the present invention.
  • dianhydrogalactitol Additional derivatives of dianhydrogalactitol are known in the art. These derivatives include dimethyldianhydrogal actitol and disuccinyldianhydrogalactitol and are disclosed in Y. Zhou et al. , “Research Progress in New Anti-Cancer Drugs with Hexitols,” Chin. J. Cancer 12:257-260 (1993).
  • the derivative or analog of dianhydrogalactitol can be a prodrug.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug is a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound as described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug can be inactive when administered to a subject, but is then converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood or a tissue).
  • a prodrug has improved physical and/or delivery properties over a parent compound from which the prodrug has been derived.
  • the term “prodrug” is also meant to include any covalently bonded carriers which release the active compound in vivo when the prodrug is administered to a subject.
  • Prodrugs of a therapeutically active compound, as described herein, can be prepared by modifying one or more functional groups present in the therapeutically active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent therapeutically active compound.
  • compositions and methods for treatment of ependymoma disclosed herein include a combination of an alkylating hexitol or derivative and an additional agent.
  • the additional agent is an agent for treatment of an adverse event associated with a treatment of the ependymoma.
  • An example adverse event can include thrombocytopenia, anemia, neutropenia, or lymphopenia.
  • Agents useful for inclusion in the compositions and methods disclosed herein for treatment of thrombocytopenia can include steroids (e.g., prednisone and/or dexamethasone), immunoglobulin agents, and other medications that reduce platelet destruction and stimulate platelet production.
  • the additional agent is an additional anti-cancer agent, such as a chemotherapy agent, such as temozolomide (TMZ), an antibody therapy, such as bevacizumab (BEV), and/or CCNU. and the like.
  • a chemotherapy agent such as temozolomide (TMZ)
  • an antibody therapy such as bevacizumab (BEV)
  • CCNU bevacizumab
  • an additional anti -cancer treatment that includes radiation therapy is utilized.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e.. not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the results of treatment can be determined by methods known in the art, such as determination of reduction of pain as measured by reduction of requirement for administration of opiates or other pain medication, determination of reduction of tumor burden, determination of restoration of funchon as determined by an improvement in the Kamofsky Performance Score, or other methods known in the art.
  • the use of terms such as “treat” or “treatment” is not to be understood as implying a cure for any disease or condition.
  • the term “synergistic,” refers to a therapeutic combination which is more effective than the additive effects of the two or more single agents.
  • a determination of a synergistic interaction between: (i) dianhydrogalactitol, diacetyldianhydrogalactitol, or a derivative or analog thereof; and (ii) one or more additional agents or chemotherapeutic agents can be assessed using assays as known in the art and, for example, can be analyzed using the Chou and Talalay combination method and Dose-Effect Analysis with CalcuSyn software in order to obtain a Combination Index (Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984)).
  • Combination Index values less than 0.8 indicate synergy
  • values greater than 1.2 indicate antagonism
  • values between 0.8 and 1.2 indicate additive effects.
  • the combination therapy can provide “synergy” and prove “synergistic,” i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect can be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect can be attained when the compounds are administered or delivered at the same time or sequentially, e.g, by different injections in separate syringes or using other routes of administration.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • effective dosages of two or more active ingredients are administered together.
  • Combination effects can also be evaluated using both the BLISS independence model and the highest single agent (HSA) model (Lehar et al., Mol. Systems Biol. 3:80 (2007)).
  • HSA highest single agent
  • combination effects can be evaluated using both the BLISS independence model and the highest single agent (HSA) model (Lehar et al.. Mol. Systems Biol. 3:80 (2007)).
  • BLISS scores quantify degree of potentiation from single agents and a BLISS score > 0 suggests greater than simple additivity.
  • An HSA score > 0 suggests a combination effect greater than the maximum of the single agent responses at corresponding concentrations.
  • An HSA score > 0 suggests a combination effect greater than the maximum of the single agent responses at corresponding concentrations.
  • a method for treating an ependymoma malignancy comprising the step of administering a therapeutically effective quantity of an alkylating hexitol to a patient with ependymoma to treat the ependymoma.
  • the alkylating hexitol is dianhydrogalactitol.
  • the method further comprises administering a therapeutically effective quantify of an additional agent, such as an anti-cancer agent.
  • a therapeutically effective dose is a dose that is sufficient to achieve the intended purpose.
  • the therapeutically effective dose of an agent administered in a combination with another agent or in combination with another method of treatment, e.g, surgery can be lower than the dose of the agent administered alone.
  • the methods and compositions disclosed herein can be particularly useful for treatment of patients with ependymoma.
  • the ependymoma is a RELA fusion-positive ependymoma refractory to a temozolomide-based treatment regimen
  • the patient has an unmethylated MGMT promoter
  • the patient has a wild-type IDH (IDH-WT).
  • the patient has a TERT promoter mutation
  • the patient has a PTEN mutation
  • the patient has an EGFR mutation
  • the patient has one or more other mutations.
  • compositions disclosed herein can be employed as either first-line or second-line therapy or can be used as adjunct therapy or in combination with another method of ependymoma treatment.
  • a given pharmacologically active agent such as an alkylating hexitol or derivative such as dianhydrogalactitol or an analog or derivative of dianhydrogalactitol as described above, or an additional agent that is included in a unit dose of a pharmaceutical composition according to the present invention will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g. , weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • a '“composition” can comprise one or more agents, such as DAG and an additional agent.
  • the composition can comprise each of the agents combined in a single container with a pharmaceutically acceptable carrier, or the composition can comprise each of the active agents in a separate container with a pharmaceutically acceptable carrier, which can be either the same or different, wherein the composition comprises a treatment regimen.
  • the therapeutically effective quantities are the quantities of the alkylating hexitol or derivative and the additional agent, that produces synergism between the activities of the alkylating hexitol or derivative and the additional agent.
  • the alkydating hexitol derivative is dianhydrogalactitol (DAG or VAL-083).
  • a method of suppressing proliferation of an ependymoma cell comprising administering to the cell an alkylating hexitol, for example, dianhydrogalactitol, diacetyldianhydrogalactitol, or dibromodulcitol.
  • the alkylating hexitol is dianhydrogalactitol.
  • the administering or contacting can be done in vivo, for example, in a human subject by administering a therapeutically effective quantity of an alkylating hexitol to the human subject in need thereof.
  • each therapeutic agent can be administered separately, or two or more therapeutic agents can be administered in a single pharmaceutical composition.
  • the amount of a given pharmacologically active agent such as an alkylating hexitol or derivative such as dianhydrogalactitol or an analog or derivative of dianhydrogalactitol as described above, that is included in a unit dose will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • such pharmaceutical compositions include a therapeutically effective quantity of the pharmacologically active agent and an inert pharmaceutically acceptable carrier or diluent.
  • these compositions are prepared in unit dosage form appropriate for the chosen route of administration, such as oral administration or parenteral administration.
  • a pharmacologically active agent as described above can be administered in conventional dosage form prepared by combining a therapeutically effective amount of such a pharmacologically active agent as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures can involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed can be either a solid or liquid.
  • Example solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like.
  • Example liquid carriers are syrup, peanut oil, olive oil, water, and the like.
  • the carrier or diluent can include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate, and the like.
  • a variety of pharmaceutical forms can be employed.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
  • a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
  • the agent can be dissolved in a suitable cosolvent or combinations of cosolvents.
  • suitable co solvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.
  • the agent is in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • the alkylating hexitol is administered to a subject in need thereof in a pharmaceutical formulation comprising one or more excipients.
  • a pharmaceutical formulation comprising one or more excipients.
  • Any suitable formulation can be used.
  • the alkylating hexitol is in lyophilized form. Lyophilized dosage fills are well known in the art.
  • preparation of lyophilized dosage forms of dianhydrogalactitol, dibromodulcitol, diacetyldianhydrogalactitol, and derivatives thereof comprises the following steps:
  • Secondary drying is started after the condenser (set at - 60° C) and vacuum are turned on.
  • the shelf temperature is controlled at + 5° C for 1 to 3 hours, typically 1.5 hours, then at 25° C for 1 to 3 hours, typically 1.5 hours, and finally at 35 to 40° C for at least 5 hours, typically for 9 hours, or until the product is completely dried.
  • Vials are removed from the lyophilizer chamber and sealed with aluminum flip-off seals. All vials are visually inspected and labeled with approved labels.
  • the lyophilized alkylating hexitol is reconstituted in sterile saline for injection.
  • the required dose then can be diluted further into a pre-determined volume of sterile saline, e.g., 500 mL of saline, and infused intravenously over a specified period, for example, over 120 minutes, 60 minutes, or 30 minutes.
  • the other agents can be administered at the same time or close together in time as an alkylating hexitol or derivative.
  • the dosages of dianhydrogalactitol and the other agent can be selected to provide a synergistic or super additive effect.
  • the dose can be further optimized as disclosed above.
  • compositions of the disclosure can be manufactured using techniques generally known for preparing pharmaceutical compositions, e.g, by conventional techniques such as mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping, or lyophilizing.
  • Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, which can be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations, which can be used pharmaceutically.
  • the compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit-dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions according to the present disclosure are usually administered to the subjects on multiple occasions. Intervals between single dosages can be weekly, monthly, or y early. Intervals can also be irregular as indicated by therapeutic response or other parameters well known in the art.
  • the pharmaceutical composition can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life in the subject of the pharmacologically active agent included in a pharmaceutical composition. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some subjects can continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the subject shows partial or complete amelioration of symptoms of disease. Thereafter, the subject can be administered a prophylactic regime.
  • treatment can be monitored by observing one or more of the improving symptoms associated with the disease, disorder, or condition being treated, or by observing one or more of the improving clinical parameters associated with the disease, disorder, or condition being treated.
  • treatment can be monitored by observing one or more of the improving symptoms associated with the disease, disorder, or condition being treated, or by observing one or more of the improving clinical parameters associated with the disease, disorder, or condition being treated.
  • treatment can be monitored by observing one or more of the improving symptoms associated with the disease, disorder, or condition being treated, or by observing one or more of the improving clinical parameters associated with the disease, disorder, or condition being treated.
  • Example 1 Recurrent RELA Fusion-Positive Ependymoma Treated with VAL-083 under Expanded Access: A Case Report
  • Ependymoma is a relatively rare central nervous system tumor accounting for 2 to 9 % of all neuroepithelial tumors.
  • RELA fusion-positive ependymoma is a subgroup associated with supratentorial location, higher WHO grade and worse prognosis.
  • VAL-083 offers a suitable treatment alternative.
  • VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N 7 -guanine, leading to DNA double-strand breaks (DSBs) and ultimately cell death.
  • DSBs DNA double-strand breaks
  • VAL-083 ’s unique cytotoxic mechanism circumvents MGMT-mediated chemoresistance, acts independent of MGMT DNA-repair in high-grade gliomas, and maintains cytotoxic activity 7 in cancer cells deficient in DNA mismatch repair (MMR).
  • MMR DNA mismatch repair
  • the N 7 -targeting mechanism differs from temozolomide (TMZ) and nitrosoureas, enabling VAL-083 to overcome MGMT-mediated chemoresistance. It is suggested herein that this distinct mechanism of action of VAL-083 suggests that VAL-083 offers a treatment alternative against tumors with MMR-, or MGMT-mediated resistance to chemotherapeutic agents, including temozolomide and nitrosoureas. VAL-083 has been studied in phase II clinical studies of MGMT-unmethylated recurrent GBM, recurrent setting, as an adjuvant therapy in newly diagnosed MGMT-unmethylated GBM, and in combination with radiation therapy in newly diagnosed MGMT-unmethylated GBM patients.
  • a 40-year-old male was initially diagnosed with a right parieto-occipital high-grade glioma, with no somatic mutations including IDHl '2 genes, and with an unmethylated MGMT promoter status.
  • the patient initially underwent gross total resection, followed by chemoradiation with concurrent and adjuvant temozolomide for 12 cycles.
  • Inter- and intra-genic fusion analysis of tumor tissue revealed a Cl lorf95-RELA fusion and the diagnosis of RELA fusion-positive ependymoma was established.
  • VAL-083 The patient was not eligible to participate in any clinical trial and received VAL-083 under an expanded access program. He was then treated with VAL-083 (30 mg/m 2 for 3 consecutive days every 21 days) and completed 12 cycles during a period of 9 months. No grade 3/4 adverse events such as thrombocytopenia, anemia, neutropenia, or lymphopenia were observed. His liver and renal functions were normal. No dose reduction was required during the course of treatment w ith VAL-083. The patient also received levetiracetam, alprazolam, and prochlorperazine, with no drug interactions. Steroids were not required.
  • VAL-083 can be a treatment option for recunent RELA fusion-positive ependymoma refractory to temozolomide-based regimens.
  • an MRI of the patient’s brain showed progressive nodular enhancement in the right occipital lobe after treatment with temozolomide (see enlarged inset at lower right of figure sheet).
  • the patient developed left visual field deficit.
  • VAL-083 w as well tolerated with no significant adverse events and no dose reductions required. The patient has continued to remain stable with no evidence of disease 18 months after completion of 9 cycles of VAL-083. This case highlights that VAL-83 is a treatment option for recurrent RELA fusion-positive ependymoma refractory to temozolomide-based regimens.
  • VAL-083 administration at 30 mg/m 2 on days 1, 2 and 3 of a 21-day cycle was carried out. Six cycles have been completed, and treatment was continuing (data cut-off w as 31 March 2023).
  • VAL-083 can be a treatment option for recurrent RELA fusion-positive ependymoma refractory to temozolomide-based regimens.
  • Diffuse Midline Glioma is a relatively rare CNS tumor, originating in the midline locations of the brain (including thalamus, pons and spinal cord), accounting for 10 % of all childhood and less than 4 % of adult central nervous system (CNS) tumors.
  • CNS central nervous system
  • VAL-083 30 mg/m 2 on days 1, 2 and 3 of a 21-day cycle. 5 cycles of treatment were completed without dose reduction. The patient underwent radiation therapy (24 Gy over 12 fractions). VAL-083 was resumed after radiation therapy and the patient completed 1 additional cycle. [0118] Safety-
  • VAL-083 can also be a treatment option for recurrent diffuse midline glioma.

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Abstract

L'invention concerne des compositions et des méthodes de traitement d'épendymomes, y compris d'épendymomes positifs à la fusion RELA réfractaires à des régimes à base de témozolomide. Les procédés comprennent l'administration d'une quantité thérapeutiquement efficace d'un hexitol alkylant ou d'un dérivé (tel que le dianhydrogalacitol, le diacétyldianhydrogalactitol et le dibromodulcitol). Les procédés peuvent en outre comprendre l'administration d'autres agents ou traitements tels que des agents ou des traitements anticancéreux.
PCT/US2023/078737 2022-11-04 2023-11-03 Utilisation de dianhydrogalactitol dans le traitement d'épendymomes WO2024098032A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220142941A1 (en) * 2019-04-24 2022-05-12 Eleison Pharmaceuticals LLC Combination therapeutic regimens with 1,6-dibromo-1,6-dideoxy-dulcitol
US11446274B2 (en) * 2015-10-28 2022-09-20 Del Mar Pharmaceuticals (Bc) Ltd. Use of dianhydrogalactitol or derivatives or analogs thereof for treatment of pediatric central nervous system malignancies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11446274B2 (en) * 2015-10-28 2022-09-20 Del Mar Pharmaceuticals (Bc) Ltd. Use of dianhydrogalactitol or derivatives or analogs thereof for treatment of pediatric central nervous system malignancies
US20220142941A1 (en) * 2019-04-24 2022-05-12 Eleison Pharmaceuticals LLC Combination therapeutic regimens with 1,6-dibromo-1,6-dideoxy-dulcitol

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LEVIN VA ET AL.: "Phase II Evaluation of Dibromodulcitol in the Treatment of Recurrent Medulloblastoma, Ependymoma, and Malignant Astrocytoma", J NEUROSURG, vol. 61, no. 6, December 1984 (1984-12-01), pages 1063 - 1068, XP009188303, DOI: 10.3171/jns.1984.61.6.1063 *
RUDA R ET AL.: "Ependymoma: Evaluation and Management Updates", CURRENT ONCOLOGY REPORTS, vol. 22, 2022, pages 985 - 993, XP037888082, DOI: 10.1007/s11912-022-01260-w *

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