HK1250475B - Methods for the treatment of leptomeningeal carcinomatosis - Google Patents

Description

Methods for treating leptomeningeal carcinomatosis

Background Art

Leptomeningeal carcinomatosis (LC) is a rare complication of cancer in which the disease spreads to the membranes surrounding the brain and spinal cord (meninges). LC occurs in approximately 5% of people with cancer and is usually advanced. Without treatment, median survival is 4-6 weeks; with treatment, median survival is 2-3 months. LC can occur at any stage of cancer, as a presenting sign or as a late complication, although it is often associated with a recurrence of cancer elsewhere in the body.

LC is generally considered incurable and difficult to treat. Treatment goals generally include improvement or stabilization of the patient's neurological status, prolonged survival, and remission. Therefore, there is a need for treatments and therapeutic options that can treat LC.

Summary of the Invention

The present invention is based on the discovery that ANG1005, a conjugate of angiopep-2 and three molecules of paclitaxel, successfully treats patients with leptomeningeal carcinomatosis (LC). This conjugate is capable of treating patients with LC even when they do not respond to standard chemotherapeutics. Because cancer cells in LC are located in the CSF and/or in the meninges, to treat LC, compounds may need to be transported across the blood-CSF barrier, which, unlike the blood-brain barrier, which is primarily composed of epithelial cells with tight junctions, is composed primarily of endothelial cells. It has recently been shown that cells of the blood-CSF barrier express LRP receptors (see Fujiyoshi et al. Journal of Neurochemistry, 2011, 118:407-415). Because Angiopep-2 is known to interact with LRP receptors, it is likely that it can cross the blood-CSF barrier through LRP-mediated transcytosis, thereby transporting paclitaxel to cancer cells in the CSF and/or meninges.

Thus, the invention features a method for treating leptomeningeal carcinomatosis comprising administering to a subject in need thereof (e.g., a subject determined to have leptomeningeal carcinomatosis or suspected of having leptomeningeal carcinomatosis based on radiological, neurological, and/or cytological assessment, for example), an effective amount of a compound or a pharmaceutically acceptable salt thereof comprising: (a) a polypeptide comprising the sequence: Angiopeptide-1 (TFFYGGCRGKRNNFKTEEY, SEQ ID NO: 1), Angiopeptide-2 (TFFYGGSRGKRNNFKTEEY SEQ ID NO: 2), or Angiopeptide-2-4D (TFFYGGS(D-R)G(D-K)(D-R)NNF(D-K)TEEY, SEQ ID NO: 3, wherein D-R refers to D-arginine and D-K refers to D-lysine); and (b) an anticancer agent (e.g., paclitaxel), wherein the anticancer agent is conjugated to the polypeptide. In some embodiments, the compound comprises a polypeptide having the sequence of Angiopeptide-2. In some embodiments, the anticancer agent is a taxane such as paclitaxel or docetaxel, vinblastine, vincristine, etoposide, doxorubicin, cyclophosphamide, melphalan, or chlorambucil. In some embodiments, the anticancer agent is conjugated to the polypeptide via a linker. In some embodiments, the linker has the structure: In some embodiments, the anticancer agent is conjugated to the polypeptide via a primary amine at the N-terminus, a lysine at position 10, and/or a primary amine at a lysine at position 15. In some embodiments, the compound has the following structure:

In some embodiments, the compound has the structure:

In some embodiments, the compound has the structure:

In some embodiments, the primary origin of the leptomeningeal carcinoma is a solid tumor (e.g., a brain tumor such as a glioblastoma or medulloblastoma, a breast tumor (e.g., a breast tumor determined to be a HER2-positive tumor, a breast tumor determined to be a HER2-negative tumor, a breast tumor determined to be ER-positive, a breast tumor determined to be ER-negative, a breast tumor determined to be PR-positive, a breast tumor determined to be PR-negative, or a breast tumor determined to be a triple-negative breast tumor), a lung tumor such as a non-small cell lung tumor or a small cell lung tumor, a gastrointestinal tumor In some embodiments, the primary origin of the leptomeningeal carcinomatosis is a breast tumor, e.g., a breast tumor determined to be a HER2 positive tumor, a breast tumor determined to be a HER2 negative tumor, a breast tumor determined to be ER positive, a breast tumor determined to be ER negative, a breast tumor determined to be PR positive, a breast tumor determined to be PR negative, a breast tumor determined to be HER2 positive, ER positive, and PR positive. In some embodiments, the primary origin of the leptomeningeal carcinomatosis is a breast tumor, e.g., a breast tumor determined to be HER2-positive, ER-positive, and PR-negative, a breast tumor determined to be HER2-positive, ER-negative, and PR-positive, a breast tumor determined to be HER2-positive, ER-negative, and PR-negative, a breast tumor determined to be ER-positive, HER2-negative, and PR-negative, a breast tumor determined to be ER-positive, HER2-negative, and PR-positive, a breast tumor determined to be PR-positive, HER2-negative, and ER-negative, or a breast tumor determined to be a triple-negative breast tumor. In some embodiments, the primary origin of the leptomeningeal carcinomatosis is a breast tumor, e.g., a breast tumor determined to be a HER2-positive tumor, a breast tumor determined to be a HER2-negative tumor, or a breast tumor determined to be a triple-negative breast tumor.

In some embodiments, the primary cancer has also metastasized to the liver, lung, brain, bone, the lining of the abdomen or pelvis (peritoneum), an organ in the abdomen (such as the intestine, bladder, or uterus). In some embodiments, the primary cancer is in the lymphatic system. In some embodiments, the subject has at least one metastasis outside of the brain, lung, liver, kidney, or eye.

In some embodiments, the subject has previously received another anti-cancer therapy (e.g., an anti-cancer therapy comprising a chemotherapeutic agent such as a taxane, a platinum-based agent, an anthracycline, an anthraquinone, an alkylating agent, a HER2-targeted therapy (e.g., a HER2 antibody), vinorelbine, a nucleoside analog, ixabepilone, eribulin, cytarabine, hormone therapy, methotrexate, capecitabine, lapatinib, 5-FU, vincristine, etoposide, or any combination thereof). In some embodiments, the primary cancer and/or LC has failed to respond to the previously received anti-cancer therapy and/or has recurred after the previously received anti-cancer therapy. In some embodiments, the primary cancer and/or LC has failed to respond to the previously received anti-cancer therapy and/or has recurred after treatment with a taxane, such as paclitaxel or docetaxel. In some embodiments, the primary cancer and/or LC has failed to respond to the previously received anti-cancer therapy and/or has recurred after treatment with methotrexate. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with a HER2-targeted therapy. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with a platinum-based agent. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with an anthracycline. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with an anthraquinone. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with an alkylating agent. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with vinorelbine. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with a nucleoside analog. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with ixabepilone. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with eribulin. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with cytarabine. In some embodiments, the primary cancer and/or LC has failed to respond to a previously received anticancer therapy and/or has recurred after treatment with hormone therapy.

In some embodiments, the primary cancer and/or LC can be drug-resistant (e.g., the cancer includes cells that do not respond to treatment with one or more anticancer agents) or include drug-resistant cells (e.g., cells that express MDR1). The primary cancer and/or LC can be or include cells that are resistant to any chemotherapeutic agent, including paclitaxel, carboplatin, cisplatin, doxorubicin, topotecan, gemcitabine, docetaxel, taxane derivatives, or any agent described herein. In some embodiments, the primary cancer and/or LC is resistant to previously received anticancer therapy.

In some embodiments, the above method further includes the step of administering another anticancer therapy (for example, including radiotherapy such as whole brain radiotherapy or stereotactic radiosurgery and/or chemotherapeutic agents such as taxanes, platinum-based agents, anthracyclines, anthraquinones, alkylating agents, HER2 targeted therapy, vinorelbine, nucleoside analogs, ixabepilone, eribulin, cytarabine, hormone therapy, bisphosphonates, methotrexate, capecitabine, lapatinib, 5-FU, vincristine, or anticancer therapy of etoposide). In some embodiments, the above method further includes administering methotrexate, alkylating agents, cytarabine, or HER2 antibodies. In some embodiments, the above method further includes administering radiotherapy. In some embodiments, another anticancer therapy is administered before the compound of the present invention. In some embodiments, another anticancer therapy is administered after the compound of the present invention. In some embodiments, another anticancer therapy is administered simultaneously with the compound of the present invention. In some embodiments, the above methods further comprise the step of administering palliative therapy such as analgesics, anticonvulsants, antidepressants, anxiolytics, psychostimulants, modafinil, palliative radiation therapy, corticosteroids, H1 antagonists, hematopoietic growth factors, and/or blood transfusions.

In some embodiments, the above methods comprise administering a compound of the invention in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises: (a) a compound of the invention (e.g., ANG1005); (b) an optional tonicity agent; (c) a buffer (e.g., a buffer that maintains a pH of 4.5-6); (d) a filler; (e) a solubilizer (e.g., a solubilizer that is not ethoxylated castor oil); and (f) 0.2 to 10% DMSO. In some embodiments, the tonicity agent is sodium chloride. In some embodiments, the buffer is glycine, citric acid, or lactic acid. In some embodiments, the filler is mannitol or sorbitol. In some embodiments, the solubilizer is a polyoxyethylene ester of a fatty acid (e.g., 12-hydroxystearic acid-polyethylene glycol copolymer). In some embodiments, the composition is substantially free of or free of ethoxylated castor oil. In some embodiments, the composition is dissolved in water. In some embodiments, the composition comprises:

Compound Percentage (by non-water weight) ANG1005 1.8-2.3% Tonicity agents 9-11% Buffering agents (e.g., lactic acid or citric acid) 4.5-6% Bulking agents (eg, mannitol) 8-10% 12-Hydroxystearic acid-polyethylene glycol copolymer 69-75% DMSO 0.2-2%

In some embodiments, the composition comprises:

Compound Percentage (by non-water weight) ANG1005 About 2% Tonicity agents About 10% Buffering agents (e.g., lactic acid or citric acid) About 5% Bulking agents (eg, mannitol) About 9% 12-Hydroxystearic acid-polyethylene glycol copolymer About 72% DMSO About 1%

The compounds or compositions of the present invention can be administered at a dosage of about 1, 10, 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1200 ^, 1400, 1600, 1800, 2000, 2500, or 3000 mg/m ² or any range therebetween. In some embodiments, the dosage is 100 mg/m ² to 2000 mg/m ² or 300 mg/m 2 to 1000 mg/ ^m 2. In some embodiments, the dosage is 300 to 650 mg/m ² (e.g., 550-625 mg/m ² ). In some embodiments, the dosage is 400 to 650 mg/m ² . In further embodiments, the dosage is 400 to 600 mg/m ² (e.g., 400, 470, 550, or 600 mg/m ² ). The compounds of the present invention may be administered to a patient by any means known in the art, for example, intravenously, orally, intraarterially, intranasally, intraperitoneally, intramuscularly, subcutaneously, transdermally, or orally. In some embodiments, the compound is administered intravenously. In some embodiments, the compound is not administered intrathecally. In some embodiments, the compounds of the present invention are administered weekly (i.e., approximately every seven days). In some embodiments, the compounds of the present invention are administered for two weeks (i.e., approximately every fourteen days). In some embodiments, the compounds of the present invention are administered for three weeks (i.e., approximately every 21 days). In some embodiments, the compounds of the present invention are administered at intervals greater than twenty-one days.

In some embodiments, after the administration of the compound of the present invention, at least one neurological symptom of the subject (e.g., headache, gait difficulty, memory loss, incontinence, sensory disturbance or any neurological symptom described herein) is partially or completely alleviated, improved, alleviated, suppressed, delayed, or severity is reduced. In some embodiments, after the administration of the compound of the present invention, the size of at least one lesion or leptomeningeal metastasis in the subject is reduced. In some embodiments, after the administration of the compound of the present invention, the amount of cancer cells in CSF is reduced in the subject. In some embodiments, after the administration of the compound of the present invention, the flow of CSF is increased in the subject.

definition

As used herein, the term "administer" refers to administering a composition (e.g., a compound, a conjugate, or a formulation comprising a compound or a conjugate as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any appropriate route. For example, in some embodiments, administration can be intrabronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreous.

As used herein, a cancer "determined to be resistant" refers to a cancer that is resistant based on non-responsiveness or decreased responsiveness to a chemotherapeutic agent, or that is predicted to be resistant based on a prognostic assay (eg, a gene expression assay).

A "resistant" cancer is one that does not respond, shows a reduced response, or is predicted to be resistant based on a prognostic assay (eg, a gene expression assay) to one or more chemotherapeutic agents (eg, any of the agents described herein).

The term "effective amount" refers to an amount that, when administered according to a therapeutic dosage regimen to a population suffering from or susceptible to a disease, disorder, and/or condition, is sufficient to treat the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and/or severity of the disease, disorder, and/or condition, and/or delays the onset of one or more symptoms of the disease, disorder, and/or condition. One of ordinary skill in the art will recognize that the term "effective amount" does not, in fact, require that successful treatment be achieved in a particular individual. Rather, an effective amount can be an amount that, when administered to a patient in need of such treatment, provides a particularly desired pharmacological response in a substantial number of subjects. It is specifically understood that a particular subject may, in fact, be "refractory" to an "effective amount." As just one example, a refractory subject may have low bioavailability such that clinical efficacy cannot be achieved. In some embodiments, reference to an effective amount can be a reference to an amount as measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). One of ordinary skill in the art will recognize that in some embodiments, an effective amount can be formulated and/or administered in a single dose. In some embodiments, an effective amount can be formulated and/or administered in multiple doses, for example, as part of a dosing regimen.

As used herein, an "ER-positive tumor" refers to a tumor, such as a breast tumor, that has ER receptors on the surface of cancer cells in the tumor and/or a tumor that expresses a gene for ER. As used herein, an "ER-negative tumor" refers to a tumor, such as a breast tumor, that does not have ER receptors on the surface of cancer cells in the tumor, a tumor that has a number of ER receptors below a predetermined level, or a tumor that does not express a gene for ER. The ER status of a tumor can be determined using methods known in the art, for example, tests performed on biopsy samples such as immunohistochemistry or fluorescence in situ hybridization or by measurement of serum ER by ELISA.

As used herein, the term "failure to respond to previous therapy" or "refractory to previous therapy" means that the cancer or LC progresses despite treatment with therapy.

As used in this article, " HER2 positive tumor " refers to the tumor of the breast tumor of the HER2 receptor on the surface of the cancerous cell in the tumor and/or the tumor expressing the gene of HER2. As used in this article, " HER2 negative tumor " refers to the tumor of the breast tumor of the HER2 receptor on the surface of the cancerous cell in the tumor, the tumor with the HER2 receptor number lower than a predetermined level or the tumor not expressing the gene of HER2. Methods as known in the art can be utilized to determine the HER2 state of a tumor, for example, the test carried out by biopsy specimens such as immunohistochemistry or fluorescence in situ hybridization or by means of the measurement of the serum HER2 of ELISA.

As used herein, "palliative therapy" refers to therapy administered to a subject for the purpose of improving quality of life, for example, by alleviating one or more symptoms or side effects associated with a disease.

As used herein, the term "pharmaceutical composition" refers to an active compound formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active compound is present in a unit dosage suitable for administration in a therapeutic regimen that, when administered to a relevant population, shows a statistically significant probability of achieving a predetermined therapeutic effect. In some embodiments, the pharmaceutical compositions can be specially formulated for administration in solid or liquid form, including those suitable for the following: oral administration, e.g., drench doses (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes suitable for use on the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, as, e.g., sterile solutions or suspensions, or sustained-release formulations; topical application, e.g., as a cream, ointment, or controlled-release patch or spray (to the skin, lungs, or mouth); intravaginal or intrarectal, e.g., as a vaginal suppository, cream, or foam; sublingual; ophthalmic; transdermal; or nasal, lung, and to other mucosal surfaces.

As used herein, a "pharmaceutically acceptable excipient" refers to any inactive ingredient (e.g., a carrier capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in a subject. Typical excipients include, for example, anti-adhesives, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), demulcents, emulsifiers, fillers (diluents), film formers or coatings, flavorings, flavoring agents, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with the various agents and materials that can be used as excipients.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts of the compounds described herein that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or the like, within the scope of sound medical judgment, and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (P. H. Stahl and C. G. Wermuth, eds.), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base groups with a suitable organic acid.

The compounds of the present invention may have ionizable groups to enable preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids, or salts, in the case of acidic forms of the compounds of the present invention, may be prepared from inorganic or organic bases. Typically, the compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc. for forming basic salts. Methods for preparing appropriate salts are well established in the art.

Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

As used herein, "PR-positive tumor" refers to a tumor of a breast tumor, for example, having PR receptors on the surface of cancer cells in the tumor and/or a tumor that expresses a gene for PR. As used herein, "PR-negative tumor" refers to a tumor of a breast tumor, for example, that does not have PR receptors on the surface of cancer cells in the tumor, a tumor with a PR receptor number below a predetermined level, or a tumor that does not express a gene for PR. The PR status of a tumor can be determined using methods known in the art, for example, tests performed on a biopsy sample, such as immunohistochemistry or fluorescence in situ hybridization or by measuring serum PR by means of ELISA.

As used herein, the term "primary origin" refers to the organ in the subject's body where the cancer begins (e.g., breast, lung, skin, gastrointestinal tract). The primary origin of a cancer can be determined using methods known in the art, for example, medical imaging, examination of a biopsy sample by immunohistochemistry, and/or gene expression analysis.

As used herein, the term "subject" refers to a human or a non-human animal (eg, a mammal such as a non-human primate, horse, cow, or dog).

The term "substantially" refers to the qualitative condition of exhibiting a characteristic or property of interest to a total or nearly total degree. One of ordinary skill in the biological field will appreciate that biological and chemical phenomena are rarely, if ever, completed and/or carried out to perfection or to achieve or avoid an absolute result. Therefore, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

A "therapeutic regimen" refers to a dosing regimen, the administration of which across a relevant population is associated with desired or beneficial therapeutic outcomes.

The term "treatment" (also referred to as "treating" or "treating") in its broadest sense refers to any administration of a substance (e.g., a provided composition) that partially or completely alleviates, ameliorates, alleviates, inhibits, delays the onset of, reduces the severity of, and/or reduces the incidence of one or more symptoms, characteristics, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment can be administered to a subject who does not exhibit signs of the relevant disease, disorder, and/or condition and/or a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, in some embodiments, treatment can be administered to a subject who exhibits one or more established signs of the relevant disease, disorder, and/or condition. In some embodiments, treatment can be for a subject who has been diagnosed with the relevant disease, disorder, and/or condition. In some embodiments, treatment can be for a subject who is known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, and/or condition.

As used herein, "triple-negative tumor" refers to a tumor, e.g., a breast tumor, that does not have estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 and/or does not substantially express the genes for estrogen receptor, progesterone receptor, or HER2 on the surface of cancer cells in the tumor. The ER, PR, and HER2 status of a tumor can be determined using methods known in the art, e.g., tests performed on a biopsy sample such as immunohistochemistry or fluorescence in situ hybridization or by measurement of serum ER, PR, and/or HER2 by ELISA.

Other features and advantages of the present invention will be apparent from the following detailed description, the accompanying drawings, and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is an image showing the accumulation of angiopeptide-Cy5.5 conjugate in the meninges and parenchyma of living mouse brain 24 hours after intravenous administration.

FIG2 is an image of a CT scan of a patient's brain before ( FIG2A ) and after ( FIG2B ) treatment with ANG1005.

FIG3 is a waterfall plot of intracranial responses to ANG1005 in patients with leptomeningeal carcinomatosis.

FIG4 is a graph of Kaplan-Meier estimates of survival of patients with leptomeningeal carcinomatosis treated with ANG1005.

DETAILED DESCRIPTION

The present inventors have discovered that administration of a peptide-drug conjugate (eg, ANG1005) can treat leptomeningeal carcinomatosis (LC) in a subject. Because LC is generally considered incurable, there is a need for treatments and therapeutic regimens that can treat LC.

Leptomeningeal carcinomatosis

The methods of the present invention include treating a subject with leptomeningeal metastasis (LC). LC (also known as leptomeningeal metastases or leptomeningeal disease) is a rare complication of cancer in which the disease spreads to the membranes surrounding the brain and spinal cord (meninges). LC occurs in approximately 5% of people with cancer and is usually advanced. Without treatment, the median survival is 4-6 weeks; with treatment, the median survival is 2-3 months. LC can occur at any stage of cancer, either as a presenting sign or as a late complication, although it is often associated with recurrence of cancer elsewhere in the body.

LC develops with invasion into the subarachnoid space and subsequent proliferation of neoplastic cells in the subarachnoid space. Malignancies of various origins may spread into this subarachnoid space through pial attachment. Spread of leukemias into this subarachnoid space and direct CSF seeding of intraparenchymal intraaxial CNS tumors are also recognized.

The pia mater is composed of the arachnoid and pia mater membranes; the space between them contains the CSF. When tumor cells enter the CSF (either by direct extension, as in primary brain tumors, or by hematogenous spread, as in leukemia), they are transported throughout the nervous system by the flow of the CSF, causing multifocal or diffuse infiltration of the pia mater in a patchy manner along the surface of the brain and spinal cord. This multifocal infiltration of the pia mater by malignant cells is leukemia. Leukemia is often referred to as lymphomatous meningitis or leukemic meningitis (if the primary tumor is not a solid tumor).

In some patients, meningeal symptoms are the first manifestation and include headache (often associated with nausea, vomiting, and dizziness), gait difficulties from weakness or ataxia, memory loss, incontinence, and sensory disturbances. Pain and seizures are the most common presenting complaints. The CNS symptoms of LC are generally divided into three anatomic groups: (1) brain involvement, including headache, lethargy, papilledema, behavioral changes, and gait unsteadiness; (2) cranial nerve involvement, including impaired vision, diplopia, hearing loss, and sensory deficits, including vertigo; and cranial nerve palsies; and (3) spinal root involvement, including neck stiffness and neck and back pain, or invasion of the spinal roots.

The prognosis for patients with LC is generally poor because LC often indicates the presence of metastatic disease elsewhere, and the course of systemic cancer is the major determinant of patient survival. The exception is leukemic or lymphomatous meningitis, which tends to be sensitive to methotrexate and cytarabine and can often be completely eradicated from the CNS. Among patients with LC arising from solid tumors, the best response to chemotherapy and radiation occurs in those with LC arising from breast cancer, with 60% improving or stabilizing and a median survival of 7 months; 15% survive at one year, and survival rates are rare in patients with LC arising from primary tumors other than breast tumors. Only 40% of LC arising from small cell lung cancer improves or stabilizes, and patients with this disease have a median survival of only 4 months. Melanoma-derived LC has the worst prognosis: with a median survival of 3.6 months, only 20% of these patients stabilize or improve with treatment. Non-responders to chemotherapy rarely survive beyond one month. Despite increases in incidence and diagnosis, the prognosis for LC has not improved significantly over the past 20 years.

Standard therapy for LC

Leptomeningeal carcinomatosis is generally considered to be incurable and difficult to treat. Treatment goals generally include improvement or stabilization of the patient's neurological status, extension of survival and relief. Most patients require a combination of surgery, radiotherapy and chemotherapy. Standard therapy includes radiotherapy to symptomatic sites and regions, where imaging has shown bulk disease and intrathecal chemotherapy (e.g., methotrexate, cytarabine, thiotepa). Radiation alleviates local symptoms, relieves CSF flow obstruction, and treats areas such as nerve root sleeves, Wei-Luo gaps, and the inside of bulky lesions that chemotherapy does not reach. Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, thereby preventing further inoculation. Supportive care for patients includes analgesia with the aid of opioids, anticonvulsants for epileptic seizures, antidepressants, and anxiolytics. Attention problems and drowsiness from whole-brain radiation can be treated with psychostimulants or modafinil.

Treatment of drug-resistant or refractory cancers

Patients treated using the methods of the invention may have drug-resistant or refractory cancers and/or LC. Because the conjugates of the invention are active even in cancers that have demonstrated resistance to standard chemotherapeutic agents, the methods of the invention are particularly useful for treating such drug-resistant cancers and/or LC.

Drug resistance often develops after treatment with specific chemotherapeutic agents. Multidrug resistance (MDR) can develop when cells overproduce the p-glycoprotein (P-gp) efflux transporter. Because many chemotherapy drugs can be P-gp substrates, including vinblastine, doxorubicin, etoposide, colchicine, and paclitaxel, overexpression of P-gp in cancer cells can lead to broad-spectrum resistance to chemotherapeutic agents.

The present inventors have previously shown that paclitaxel conjugated to Angiopeptide-1 or Angiopeptide-2 is not a P-gp substrate and thus should not be sensitive to P-gp overexpression in tumor cells; see, e.g., International Application Publication No. WO 2007/009229, pages 46-47 and Figure 9A. Thus, the drug conjugates described herein may be used to treat patients with cancer and/or LC that is resistant to standard chemotherapy drugs.

Enhanced uptake into LRP-expressing cells

The methods of the present invention are particularly useful for treating cancers in cells that express low-density lipoprotein-related protein (LRP) receptors. LRP receptors are expressed on the surface of cells and are capable of binding to various substrates, including aprotinin. The polypeptides described herein were designed based on consensus Kunitz domain sequences that act as LRP receptor ligands (see, for example, PCT Publication No. WO 2004/060403). LRP ligands inhibit the uptake of conjugates comprising AngioPeptide-1 or AngioPeptide-2, thereby indicating that LRP is involved in this process. Specifically, the LRP ligands RAP (200 nM) and aprotinin (10 μM) were able to reduce brain uptake of AngioPeptide conjugates. AngioPeptide-2 (10 or 100 μM) similarly reduced conjugate uptake into cells.

The blood-CSF barrier has been shown to express LRP (see Fujiyoshi et al. Journal of Neurochemistry, 2011, 118:407-415). Therefore, LC is well suited for treatment using therapies targeting LRP-expressing cells. As shown in Figure 1, the Angiopeptide-2 conjugate was able to accumulate in the meninges of living mouse brains.

Combination therapy

The methods of the present invention may include administering a second therapeutic agent or treatment with a second therapy (e.g., a therapeutic agent or therapy that is standard in the art). Exemplary therapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, amifostine, anakinra, anastrozole, arsenic trioxide, asparaginase, azacitidine, live BCG (BCG Live), bevacizumab, bexarotene, bleomycin, bleomycin, bortezomib, bortezomib, busulfan, busulfan, carboplatin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cisplatin, cladribine, cloralbine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, actinomycin D, dalteparin (e.g., sodium), darbepoetin alfa, dasatinib, daunorubicin, daunorubicin, decitabine, denileukin, denileukin-toxin conjugate, dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, epirubicin (e.g., HCl), epoetin alfa, erlotinib, estramustine, etoposide (e.g., phosphate), exemestane, fentanyl (e.g., citrate), filgrastim, floxuridine, fludarabine, fluorouracil, 5-FU, fulvestrant, gefitinib, gemcitabine (e.g., HCl), gemtuzumab, ozogamicin, goserelin (e.g., acetate), histrelin (e.g., acetate), hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib (e.g., mesylate), interferon alfa-2b, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, folinic acid, leuprorelin lin (e.g., acetate), levamisole, lomustine, CCNU, mechlorethamine (nitrogen mustard), megestrol acetate, melphalan (L-PAM), mercaptopurine (6-MP), mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, novoflutamab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, panitumumab, pegaspargase, pegfilgrastim, peginterferon alfa-2b, pemetrexed (e.g., disodium), pentostatin, pipobroman, plicamycin (mithramycin), porfimer (e.g., [00135] In some embodiments, the present invention relates to paclitaxel derivatives, such as paclitaxel, nab-1-4, nab-1-6, nab-1-7, nab-2-9, nab-3-10, nab-4-11, nab-5-12, nab-6-13, nab-7-14, nab-8-16, nab-9-17, nab-1-9, nab-1-18, nab-1-19, nab-20, nab-21, nab-22, nab-23, nab-24, nab-25, nab-26, nab-27, nab-28, nab-29, nab-30, nab-31, nab-32, nab-33, nab-34, nab-35, nab-36, nab-37, nab-38, nab-39, nab-40, nab-41, nab-42, nab-43, nab-44, nab-45, nab-46, nab-47, nab-48, nab-49, nab-51, nab-52, nab-53, nab-54, nab-55, nab-56, nab-57, nab-58, nab-59, nab-60, nab-61, nab-62, nab-63, nab-64, nab-65, nab-66, nab-67, nab-68, nab-69, nab-71, nab-72

Other agents that may be used include antiestrogens such as tamoxifen (eg, citrate), raloxifene, toremifene, and SCH 57068.

Peptide conjugates

The methods of the present invention include administering peptide-anticancer agent conjugates, such as those described in U.S. Patent Application Publication Nos. 2006/0182684 and 2006/0189515, and U.S. Provisional Application No. 61/008,880 (filed December 20, 2007). Such conjugates can include any of the polypeptides described herein, an agent capable of treating LC, such as paclitaxel or a paclitaxel analog (e.g., those described herein), and a linker (e.g., those described herein). The paclitaxel conjugate is exemplified by ANG1005, which includes the AngioPeptide-2 peptide (SEQ ID NO: 97) conjugated to three paclitaxel molecules via an ester bond at the N-terminus and via lysines at positions 10 and 15.

In some embodiments, the conjugate can pass through the blood-brain barrier (BBB), blood-CSF barrier, or can preferentially target certain cell types, such as mammary gland, ovary, liver, lung, kidney, muscle cells, or can target tumor cells (any cell type described herein). The medicament combined with these peptides can show the uptake of the increase of entering the target cell (for example, by receptor-mediated endocytosis (for example, by LRP receptor)) through the BBB mainly formed by endothelial cells with tight junctions and the blood-CSF barrier mainly formed by epithelial cells in contrast to the BBB. The combined medicament can alternatively or additionally show the stability of improvement or the discharge (for example, due to the outflow mediated by P glycoprotein) from the reduction of the cell. The conjugate can further have activity in cancer cells resistant to standard chemotherapy.

Conjugate

Polypeptides described herein or their derivatives are combined with anticancer agents (e.g., any anticancer agent known in the art). Each polypeptide can be bound to at least 1, 2, 3, 4, 5, 6, or 7 agents. In other embodiments, each agent has at least 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, or more polypeptides connected thereto. The conjugates of the present invention can be able to promote the accumulation of agents in specific cell types or tissues (e.g., due to increased uptake or reduced removal), such as experimenter's ovary, liver, lung, kidney, spleen, or muscle.

After being transported to a specific cell type or crossing the BBB, the agent can be released from the carrier. The agent can be released, for example, by enzymatic cleavage or other cleavage of a chemical bond between the carrier and the agent. The released agent can then exert its intended ability without the carrier.

In certain embodiments, the agent is paclitaxel or a paclitaxel analog (e.g., those described herein). Other anticancer agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, amifostine, anakinra, anastrozole, arsenic trioxide, asparaginase, azacitidine, live BCG, bevacizumab, bexarotene, bleomycin, bleomycin, bortezomib, bortezomib, busulfan, busulfan, carotesterone, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cisplatin, cladribine, cloralbine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, actinomycin D, dalteparin (e.g., sodium), darbepoetin alfa, dasatinib, daunorubicin, daunorubicin, decitabine, Denileukin, denileukin-toxin conjugate, dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, epirubicin (e.g., HCl), epoetin alfa, erlotinib, estramustine, etoposide (e.g., phosphate), exemestane, fentanyl (e.g., citrate), filgrastim, floxuridine, fludarabine, fluorouracil, 5-FU, fulvestrant, gefitinib, gemcitabine (e.g., HCl), gemtuzumab, ozogamicin, goserelin (e.g., acetate), histrelin (e.g., acetate), hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib (e.g., mesylate), interferon alfa 2b, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, folinic acid, leuprorelin (e.g., acetate), levamisole, lomustine, CCNU, mechlorethamine (nitrogen mustard), megestrol acetate, melphalan (L-PAM), mercaptopurine (6-MP), mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, novoflunomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, panitumumab, pegaspargase, pegfilgrastim, peginterferon alfa-2b, pemetrexed (e.g., disodium), pentostatin, pipobroman, p-termitinib, pemetrexed ... Carbamycin (mithramycin), porfimer (e.g., sodium), procarbazine, quinacrine, rasburicase, rituximab, sarmustine, sorafenib, streptozotocin, sunitinib (e.g., maleate), talc, tamoxifen, temozolomide, teniposide (VM-26), testolactone, thalidomide, thioguanine (6-TG), thiotepa, thiotepa, thiotepa, topotecan (e.g., hcl), toremifene, tositumomab/I-131 (tositumomab), trastuzumab, trastuzumab, tretinoin (ATRA), uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, zoledronic acid, and zoledronic acid.

Other anticancer agents include antibodies. Any method known in the art (e.g., utilizing the binding strategies described herein) can be used to complete the combination of such antibodies. Any diagnostic or therapeutic antibody can be combined with one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) carriers of the present invention. In addition, antibody fragments (e.g., capable of binding to antigens) can also be incorporated into carriers of the present invention. Antibody fragments include Fab and Fc regions, heavy chains, and light chains of antibodies (e.g., any antibodies described herein). Exemplary antibodies for diagnosis and treatment of cancer include ABX-EGF (panitumumab), OvaRex (ogivomab), Theragyn (pemtumomabytrrium-90), Therex, bivacumab, MAb 17-1A (edrecolomab), ReoPro (abciximab), Bexxar (tositumomab), MAb, idiotype 105AD7, anti-EpCAM (catumaxomab), MAb lung cancer (from Cytoclonal), Herceptin (trastuzumab), Rituxan (rituximab), Avastin (bevacizumab), AMD Fab (ranibizumab), E-26 (second-generation IgE) (omalizumab), Zevalin (rituximab + yttrium-90) (ibritumomab tiuxetan), cetuximab, BEC2 (mitumomab), IMC-1C11, nuC242-DM1, LymphoCide (epratuzumab), LymphoCide Y-90, CEA-Cide (labetuzumab), CEA-Cide Y-90, CEA-Scan (Tc-99m-labeled acitumomab), LeukoScan (Tc-99m-labeled thiosomab), LymphoScan (Tc-99m-labeled betumomab), AFP-Scan (Tc-99m-labeled), HumaRAD-HN (+yttrium-90), HumaSPECT (futumomab), MDX-101 (CTLA-4), MDX-210 (her-2 overexpression), MDX-210/MAK, Vitaxin, MAb 425, IS-IL-2, Campas (alemtuzumab), CD20 streptavidin, Avidicin, (albumin+NRLU13), Oncolym (+iodine-131), Cotara (+iodine-131), C215 (+staphylococcal enterotoxin, MAb lung cancer/kidney cancer (from Pharmacia Corp.), tadalafil (C242 Staphylococcal enterotoxin), Nuvion (Visilizumab), SMARTM195, SMART 1D10, CEAVac, TriGem, TriAb, NovoMAb-G2 radiolabeled, Monopharm C, GlioMAb-H (+ gelonin toxin), Rituxan (rituximab), and ING-1. Additional therapeutic antibodies include 5G1.1 (eculizumab), 5G1.1-SC (pexilizumab), ABX-CBL (golimumab), ABX-IL8, Antegren (natalizumab), anti-CD11a (efalizumab), anti-CD18 (from Genetech), anti-LFA1, Antova, BTI-322, CDP571, CDP850, Corsevin M, D2E7 (adalimumab), Humira (adalimumab), Hu23F2G (rovizumab), IC14, IDEC-114, IDEC-131, IDEC-151, IDEC-152, infliximab (Infliximab), LDP-01, LDP-02, MAK-195F (Afelimumab), MDX-33, MDX-CD4, MEDI-507 (Siplizumab), OKT4A, OKT3 (Muromonab-CD3), and ReoPro (Abciximab).

Joint

The conjugates used in the present invention can include the use of any cross-linking (binding) reagents or protocols known in the art, many of which are commercially available. Such protocols and reagents include cross-linking agents that react with amino, carboxyl, sulfhydryl, carbonyl, carbohydrate and/or phenol groups. The amount, time, and conditions of such protocols can be varied to optimize the combination. The cross-linking agent contains at least two reactive groups and is generally divided into homofunctional cross-linking agents (containing the same reactive groups) and heterofunctional cross-linking agents (containing different reactive groups). The cross-linking agent of the present invention can be homobifunctional and/or heterobifunctional. In addition, the cross-linking agent can incorporate a 'spacer' between the reactive moieties, or can directly connect the two reactive moieties in the cross-linking agent. The bond can include an ester bond.

Exemplary linkers include BS ³ [bis(sulfosuccinimidyl) suberate], NHS/EDC (N-hydroxysuccinimide and N-ethyl-(dimethylaminopropyl)carbodiimide), sulfo-EMCS ([N-maleimidocaproic acid] hydrazide), SATA (N-succinimidyl-S-acetylthioacetate), and hydrazide. BS ³ is a homobifunctional N-hydroxysuccinimide ester that targets accessible primary amines. NHS/EDC allows the conjugation of primary amine groups to carboxyl groups. Sulfo-EMCS is a heterobifunctional reactive group (maleimide and NHS ester) that reacts with sulfhydryls and amino groups. Amine coupling activated by sulfo-NHS/EDC can be used to crosslink therapeutic antibodies to polypeptides. The resulting conjugate can be stable and retain the biological activity of the antibody. In addition, it has high binding capacity and low nonspecific interactions that can be reliably controlled during the coupling process. SATA is reactive toward amines and adds protected sulfhydryls. NHS esters react with primary amines to form stable amide bonds. Hydroxylamine can be used to deprotect sulfhydryl groups. Hydrazides can be used to link carboxyl groups to primary amines and can therefore be used to link glycoproteins.

Small molecules such as therapeutic agents can be bound to polypeptides (e.g., those described herein). The exemplary small molecule paclitaxel has two important positions (positions C2' and C7) that can be used for binding. The combination of the carrier of the present invention and paclitaxel can be carried out as follows. Briefly, at room temperature, paclitaxel reacts with anhydride succinate pyridine for three hours to connect the succinyl group at position 2'. 2'-succinylpaclitaxel has a cleavable ester bond at position 2' that can simply release succinic acid. If desired, this cleavable ester bond can be further used for various modifications (utilizing a linker). Then in DMSO, at room temperature, the resulting 2'-O-succinyl-paclitaxel reacts with EDC/NHS for 9 hours, then, at room temperature, the carrier is added to Ringer's/DMSO for another 4 hours of reaction time. Each intermediate, such as paclitaxel, 2'-O-succinyl-paclitaxel, and 2'-O-NHS-succinyl-paclitaxel, was purified and confirmed using various methods, such as HPLC, thin-film liquid chromatography, NMR ( ¹³ C or ¹ H exchange), melting point, and mass spectrometry. The final conjugates were analyzed by mass spectrometry and SDS-polyacrylamide gel electrophoresis. This allowed the determination of the number of paclitaxel molecules bound to each support.

dose

The dosage of any conjugate or composition described herein depends on several factors, including: the method of administration, the severity of the disease, cancer being treated or prevented, and the age, weight, and health of the subject being treated.

With respect to the therapeutic methods of the present invention, it is not intended that the administration of a vector, conjugate, or composition to a subject be limited to a particular mode of administration, dosage, or frequency of administration; all modes of administration are contemplated by the present invention. The conjugate or composition can be administered to a subject in a single dose or in multiple doses. For example, the compounds described herein or identified using the screening methods of the present invention can be conjugates that are administered, for example, once every 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more weeks. It will be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition. For example, if a lower dose does not provide sufficient activity in the treatment of a disease or condition described herein (e.g., cancer and/or LC), the dose of the composition can be increased. Conversely, if the disease (e.g., cancer and/or LC) is reduced or eliminated, the dose of the composition can be reduced.

Although the attending physician will ultimately determine the appropriate amount and dosage regimen, the therapeutically effective amount of a carrier, conjugate, or composition described herein can be, for example, in the range of 0.0035 μg to 20 μg/kg body weight/day or 0.010 μg to 140 μg/kg body weight/week. Desirably, a therapeutically effective amount is in the range of 0.025 μg to 10 μg/kg, for example, at least 0.025, 0.035, 0.05, 0.075, 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, or 9.0 μg/kg body weight administered every day, every other day, or twice a week. In addition, a therapeutically effective amount can be in the range of 0.05 μg to 20 μg/kg, for example, at least 0.05, 0.7, 0.15, 0.2, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 14.0, 16.0, or 18.0 μg/kg body weight, administered weekly, every other week, every three weeks, or monthly. In addition, a therapeutically effective amount of a compound can be in the range of 0.1 mg/m ² to 2,000 mg/m ² , administered, for example, every other day, weekly, every other week, or every three weeks. For example, ANG1005 can be administered at 50, 100, 200, 300, 400, 420, 500, 600, 650, 700, 800, or 1,000 mg/m ² every week, every two weeks, every three weeks, every four weeks, every month, or every other month. In a specific embodiment, ANG1005 is administered at 300 mg/m ² to 650 mg/m ² every three weeks. In another embodiment, the therapeutically effective amount is in the range of 1000 μg/m ² to 20,000 μg/m ² , for example, at least 1000, 1500, 4000, or 14,000 μg/m ² of the compound administered daily, every other day, twice a week, weekly, or every other week.

Dosage form of the pharmaceutical composition

Administration of the conjugates or compositions containing the conjugates described herein can be by any suitable means that results in a concentration of the compound that is effective for treating LC. The conjugate can be in any suitable amount of any suitable carrier material and is generally present in an amount of 1-95% by weight of the total weight of the composition. The compositions can be provided in dosage forms suitable for oral, parenteral (e.g., intravenous or intramuscular), rectal, dermal, nasal, vaginal, inhalation, dermal (patch), topical, ophthalmic, or intracranial administration. Thus, the compositions can have the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drench remedies, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, or aerosols. Pharmaceutical compositions can be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, edited by A. R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

Pharmaceutical compositions can be formulated to release the conjugate immediately after administration or at any predetermined time or time period after administration. The latter type of composition is generally referred to as a controlled-release formulation, which includes (i) dosage forms that produce a substantially constant concentration of the conjugate in vivo over a long period of time; (ii) dosage forms that produce a substantially constant concentration of the conjugate in vivo over a long period of time after a predetermined lag time; (iii) dosage forms that maintain the effect of the conjugate over a predetermined period of time by maintaining a relatively stable, effective level of the conjugate in the body while minimizing the adverse side effects associated with fluctuations in the plasma level of the conjugate (sawtooth kinetics); (iv) dosage forms that localize the effect of the conjugate, for example, spatial placement of the controlled-release composition adjacent to or in a diseased tissue or organ; (v) dosage forms that achieve convenient dosing, for example, administration of the composition once a week or once every two weeks; and (vi) dosage forms that localize the effect of the conjugate to deliver the compound to a specific target cell type by using a carrier or chemical derivative. For conjugates that have a narrow absorption window or a relatively short biological half-life in the gastrointestinal tract, administration of the conjugate in a controlled release formulation is particularly preferred.

Any number of strategies can be pursued to obtain controlled release, wherein the rate of release exceeds the metabolic rate of the conjugate under consideration. In one embodiment, controlled release is obtained by various dosage form parameters and ingredients, including, for example, the appropriate selection of various types of controlled release compositions and coatings. Thus, the conjugate is formulated into a pharmaceutical composition with a suitable excipient that, after administration, releases the conjugate in a controlled manner. Examples include single or multiple unit tablets or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, molecular complexes, microspheres, nanoparticles, patches, and liposomes.

Example

Example 1. Treatment of LC in breast cancer subjects

Methods: 28 subjects diagnosed with LC were given ANG1005 at 600 mg/m ² intravenously on a three-week schedule. Subjects received between one and nine cycles of ANG1005. The receptor status of the subjects is shown in the table below.

Table 1. Receptor status of subjects

markers Positive patients/negative patients HER2+17/28 17/28 HER/-11/28 11/28 ER+16/28 16/28 ER-12/28 12/28 PgR+13/28 13/28 PgR-15/28 15/28

Results: The treatment outcomes of the subjects based on brain parenchymal tumor responses according to CNS Response Evaluation Criteria in Solid Tumors (RECIST) are shown in Table 2.

Table 2. Subject results

As shown in Table 2, the patient benefit response rate, which includes subjects who showed partial response or stable disease, was 74%. For subjects with HER2-positive breast cancer, the patient benefit response rate was 80%. Example 2. Treatment of Subject 2

Subject 2 was a 59-year-old woman diagnosed with HER2+/ER-/PgR+ invasive ductal carcinoma in October 2012. In January 2014, Subject 2 was diagnosed with brain metastases, and the brain metastases recurred with soft tissue carcinoma in October 2014. Subject 2 had previously received several courses of therapy, including cyclophosphamide, taxotere, and Herceptin from November 2012 to March 2013, Herceptin from March 2013 to October 2013, a right mastectomy in May 2013, a craniotomy and SRS in February 2014, a craniotomy in July 2014, and nevatinib and capecitabine in August 2014.

While receiving ANG1005, subject 2 demonstrated active tumor extension from the deep portion of the surgical cavity to the right tentorial surface and along the lateral right temporo-occipital dural surface. Subject 2 began treatment with ANG1005 in October 2014 and received seven cycles (once every three weeks). Treatment was discontinued due to clinical disease progression.

Subject 2's leptomeningeal carcinomatosis responded to ANG1005, as indicated by the lesion on the lateral right middle fossa dural surface being no longer evident after treatment, and a reduction in the size of a small nodule of leptomeningeal metastasis on the inferior surface of the right hippocampus superior only to the right tentorial lobule.

Example 3. Treatment of Subject 3

Subject 3 was a 44-year-old woman diagnosed with HER2+/ER-/PgR- invasive ductal carcinoma in May 2009. In March 2012, Subject 3 was diagnosed with brain metastases and suffered a recurrence of brain metastases in September 2014. Subject 3 had previously received several courses of therapy, including nab-paclitaxel (abraxane) and lapatinib from May to August 2009, vinblastine and trastuzumab from August 2012 to April 2013, WRBT in September 2012, TDM1 from April to July 2013, capecitabine and lapatinib from April to July 2014, and capecitabine and TDM1 in September 2014.

While on ANG1005 treatment, Subject 3 presented with numerous (>10) brain metastases that had increased in size despite prior treatment. There was also extensive, scattered bone metastases in the head/neck. Subject 3 was also found to have leptomeningeal disease after presenting with jaw numbness (left trigeminal nerve defect). Subject 3 began treatment with ANG1005 in September 2014 and received five cycles (once every three weeks). Treatment was discontinued due to an adverse event (pneumonitis).

Radiographically and clinically, Subject 3's leptomeningeal carcinomatosis improved. After the first two cycles, Subject 3 was able to ambulate better and had no cranial nerve or bowel/bladder symptoms. As shown in Figures 2A and B, both brain metastases and LC in Subject 3 responded to treatment with ANG1005.

Example 4. Treatment of Subject 4

Subject 4 was a 58-year-old woman diagnosed with HER2+/ER-/PgR- ductal carcinoma in situ in October 2011. In November 2012, Subject 4 was diagnosed with brain metastases, which recurred with leptomeningeal carcinomatosis in March 2015. Subject 4 had previously received several courses of therapy, including carboplatin from October to November 2011, denosumab from November 2011 to November 2012, paclitaxel from December 2011 to March 2012, WBRT and trastuzumab from May 2012 to November 2012, and Kadcyla from April 2013 to December 2014.

While on ANG1005 treatment, subject 4 presented with parenchymal metastases in the cerebellum and extensive LC in the cerebellum and cerebral hemispheres. Furthermore, subject 4 presented with mild ventricular enlargement with compression of the fourth ventricle and outflow tract. Subject 4 began treatment with ANG1005 in March 2015 and received eight cycles (once every three weeks). Due to a low performance score, the subject was withdrawn from treatment.

Subject 4's leptomeningeal carcinomatosis responded to ANG1005, as indicated by a decrease in the size and extent of nodular leptomeningeal enhancement associated with the cerebellum and disappearance of the fourth ventricle. In addition, Subject 4 showed a symptomatic decrease in the volume of leptomeningeal tumor burden following treatment.

Example 5. Treatment of Subject 8

Subject 8 was a 42-year-old woman diagnosed with HER2+/ER+/PgR- invasive ductal carcinoma in April 2014. In December 2014, Subject 8 was diagnosed with brain metastases, which recurred with leptomeningeal carcinomatosis in March 2015. Subject 8 had previously received several courses of therapy, including docetaxel from May to October 2014, trastuzumab and pertuzumab from May to December 2014, and capecitabine and lapatinib from January to April 2015.

While on ANG1005 treatment, Subject 8 presented with numerous enhancing lesions throughout the supratentorial and infratentorial brain, the presence of supratentorial white matter lesions suggestive of an unexplained demyelinating disease, negative CSF for malignant cells, and multiple stable metastases in the liver. Subject 8 began treatment with ANG1005 in April 2015 and received two cycles (once every three weeks). In July 2015, Subject 8 discontinued treatment due to clinical progression.

Subject 8's leptomeningeal carcinomatosis responded to ANG1005, as indicated by improvement of extensive LC in the cerebellum.

Example 6. Kaplan-Meier Estimates of Survival of Subjects with LC

The Kaplan-Meier method was used to estimate overall survival for LC subjects treated with ANG 1005. As shown in Figure 4, treatment with ANG 1005 was estimated to increase median overall survival after active treatment compared to the historical median overall survival of 3-6 months.

Example 7. Treatment Protocol

All patients will receive ANG1005 by intravenous (IV) infusion starting at a dose of 600 mg/m ² every 3 weeks (1 cycle). Dose reductions or delays will be permitted in any dosing cycle if toxicity is observed. Patients will be monitored during the infusion and for at least 1 hour after completion of each infusion.

Intracranial and extracranial tumor assessments will be performed by MRI/CT at baseline and after every 2 cycles (i.e., every 6 ± 2 weeks). If a partial or complete response is seen, a subsequent MRI should be performed at ≥4 weeks and ≤6 weeks to confirm the response. Patients who develop extracranial disease progression in the absence of intracranial disease progression should be removed from the study unless the following conditions are met: (1) there is evidence of clinical benefit attributable to ANG1005 therapy, such as: (a) improvement in clinical symptoms from brain metastases, (b) radiographic improvement of brain metastases, and (2) systemic progression is asymptomatic. However, if the investigator decides to initiate non-protocol systemic anti-tumor therapy (as needed), ANG1005 will be discontinued. Patients who discontinue study treatment before the 1-year maximum treatment period and whose disease has not progressed will continue to be followed for disease progression. Disease assessments, including radiographic assessments, will be performed at approximately 8-week intervals or according to institutional standard practice: starting from the date of the last dose of study treatment until intracranial and extracranial disease progression is documented. Survival follow-up will be performed at approximately 8-week intervals from the date of the last dose. Under this protocol, patients will continue study treatment for a maximum of one year unless they develop disease progression or unacceptable toxicity. Further treatment beyond the maximum period of one year will be considered on a case-by-case basis.

Other Implementations

Although the invention has been described with reference to particular embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention which, in general, follow from the principles of the invention and include such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains and which may be applied to the basic features herein above described.

Claims (8)

1. Use in an effective amount of a compound having the following structure in the preparation of a medicament for treating leptomeningeal carcinoma, said treatment comprising administering said compound to a subject in need: 2. The use according to claim 1, wherein the primary origin of the leptomeningeal carcinoma is a solid tumor. 3. The use according to claim 2, wherein the solid tumor is a breast tumor, lung tumor, gastrointestinal tumor, or malignant melanoma. 4. The use according to claim 3, wherein the solid tumor is a breast tumor. 5. The use according to claim 3 or 4, wherein the breast tumor is identified as a HER2-positive tumor. 6. The use according to claim 3 or 4, wherein the breast tumor is identified as a triple-negative tumor. 7. The use according to any one of claims 2 to 4, wherein the tumor comprises cells expressing MDR1. 8. The use according to claim 1, wherein the compound is administered intravenously.