Uses and Methods for Recurrent Primary CNS Tumors

Abstract

The present disclosure relates, at least in part, to a method of treatment, hi one embodiment, the method of treatment comprises administering to a subject in need of such treatment at least a first therapeutic agent comprising ONC-206, 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, for the treatment of one or more CNS tumors.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a PCT international application claiming priority to U.S. Provisional Application No. 63 / 188,133, filed May 13, 2021, which is incorporated by reference in its entirety herein. [Background technology]

[0002] The majority of recurrent tumor types, such as CNS neuroendocrine tumors and endometrial tumors, lack effective systemic therapeutic options following surgical resection and adjuvant radiation therapy.ONC201, which may be referred to herein as Compound 1 or NSC350625, is a founding member of the small molecule imipridone class and induced durable tumor regression in patients with diffuse midline glioma H3 K27M mutant (DMG H3K27M).

[0003] ONC206, which may be referred to herein as Compound 2, is the second imipridone to enter clinical development, and is a DRD2 antagonist and ClpP agonist that displays distinct receptor pharmacology and gene expression profiles in tumors compared to ONC201.

[0004] The structure of each of the compounds is as follows: [ka]

[0005] ONC-201 may also be referred to as 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, and in one embodiment is provided as the dihydrochloride salt.

[0006] ONC-206 may also be referred to as 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, and in one embodiment is provided as the dihydrochloride salt. Summary of the Invention

[0007] One embodiment of the present disclosure includes a method of treating one or more cancers, including one or more CNS tumors, the method comprising administering ONC-206, 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, or a salt thereof.

[0008] In one embodiment, the CNS tumor is one or more tumors represented in the 2021 WHO Classification of Tumors of the Central Nervous System, Neuro-Oncology, Volume 23, Issue 8, August 2021, pages 1231-1251, https: / / doi.org / 10.1093 / neuonc / noab106 (published June 29, 2021) (with respect to such classification, the present specification is incorporated by reference).

[0009] In one embodiment, the CNS tumor is selected from the group consisting of glioma, glioneuronal tumor, and neuronal tumor, adult diffuse glioma, astrocytoma IDH mutant, oligodendroglioma IDH mutant, and 1p / 19q codeletion, glioblastoma, IDH wild type, pediatric diffuse low grade glioma, diffuse astrocytoma, MYB or MYBL1 mutant, angiocentric glioma, polymorphic low grade neuroepithelial tumor of the juvenile, diffuse low grade glioma, MAPK pathway mutant, pediatric diffuse high grade glioma, diffuse midline glioma, H3 K27 mutant, diffuse hemispheric glioma, H3 G34 mutant, diffuse juvenile high-grade glioma, H3 wild type and IDH wild type, infantile hemispheric glioma, focal astrocytoma, pilocytic astrocytoma, high-grade astrocytoma with pilocytic features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoma-like glioma, astroblastoma, MN1 alteration, glioneuronal and neuronal tumors, ganglioglioma, desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma, dysembryoplastic neuroblastoma Epithelial tumors, diffuse glioneuronal tumors with oligodendroglioma-like features and nuclear clusters, papillary glioneuronal tumors, rosette-forming glioneuronal tumors, myxoid glioneuronal tumors, diffuse leptomeningeal glioneuronal tumors, ganglioneuromas, multinodular and vacuolar neuromas, dysplastic cerebellar ganglioneuromas (Lhermitte-Duclos disease), central neurocytoma, extraventricular neurocytoma, cerebellar liponeurocytoma, ependymal tumors, supratentorial ependymoma, supratentorial Ependymoma ZFTA fusion positive, supratentorial ependymoma YAP1 fusion positive, posterior fossa ependymoma, posterior fossa ependymoma PFA group, posterior fossa ependymoma PFB group, spinal cord ependymoma, spinal cord ependymoma MYCN amplified, myxopapillary ependymoma, subependymoma, choroid plexus tumor, choroid plexus papilloma, atypical choroid plexus papilloma, choroid plexus carcinoma, embryonal tumor, medulloblastoma, medulloblastoma (molecular definition), medulloblastoma WNT activated, medulloblastoma SHH activated and TP53 wild type, medulloblastoma SHH activated and TP53 mutant, Medulloblastoma non-WNT / non-SHH, Medulloblastoma (histological definition), Other CNS embryonal tumors, Atypical terato / rhabdoid tumor, Cribriform neuroepithelial tumor, Embryonal tumor with multilayered rosettes, CNS neuroblastoma FOXR2 active, CNS tumor with BCOR internal tandem duplication, CNS embryonal tumor, Pineal tumor, Pineocytoma, Moderately differentiated pineal parenchymal tumor, Pineoblastoma, Papillary tumor of the pineal region, Desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant,Cranial nerve tumors and paraspinal nerve tumors, schwannoma, neurofibroma, perineurioma, hybrid nerve sheath tumor, malignant melanotic nerve sheath tumor, malignant peripheral nerve sheath tumor, paraganglioma, meningioma, mesenchymal meningioma, non-meningothelial tumor, soft tissue tumor, fibroblastic tumor and myofibroblastic tumor, solitary fibrous tumor, vascular tumor, hemangioma and vascular malformation, hemangioblastoma, skeletal muscle tumor, rhabdomyosarcoma (unspecified), intracranial mesenchymal tumor FET-CREB fusion positive, CIC-rearranged sarcoma , primary intracranial sarcoma DICER1 mutant, Ewing's sarcoma, cartilage and bone forming tumors, chondrogenic tumors, mesenchymal chondrosarcoma, chondrosarcoma, notochord tumor, chordoma (including poorly differentiated chordoma), melanocytic tumor, diffuse meningeal melanocytic tumor, meningeal melanocytosis and meningeal melanoma, localized meningeal melanocytoma, meningeal melanocytoma and meningeal melanoma, hematolymphoid tumors, lymphoma, CNS lymphoma, primary CNS diffuse large cell type B-cell lymphoma, Immunodeficiency-associated CNS lymphoma, Lymphomatoid granulomatosis, Intravascular large B-cell lymphoma, Other rare lymphomas of the CNS, Dural MALT lymphoma, Other low-grade B-cell lymphomas of the CNS, Anaplastic large cell lymphoma (ALK+ / ALK-), T-cell and NK / T-cell lymphomas, Histiocytic neoplasms, Erdheim-Chester disease, Rosai-Dorfman disease, Juvenile xanthogranuloma, Langerhans cell histiocytosis, Histiocytic sarcoidosis and one or more of the following: pericytoma, germ cell tumor, mature teratoma, immature teratoma, teratoma with somatic malignancy, germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, mixed germ cell tumor, sellar tumor, ameloblastoma craniopharyngioma, papillary craniopharyngioma, pituitary cell tumor, sellar granular cell tumor, and spindle cell oncocytoma, pituitary adenoma / PitNET, pituitary blastoma, metastasis to CNS, metastasis to brain and spinal cord parenchyma, and metastasis to meninges.

[0010] In one embodiment, the CNS tumor is one or more of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglial tumor, ependymal tumor, medulloblastoma, pineal tumor, meningeal tumor, and germ cell tumor. In one embodiment, administration reduces one or more symptoms of the CNS tumor. In one embodiment, administration reduces tumor growth. In one embodiment, administration provides one or more of: (i) reduction in tumor size, (ii) progression-free survival, (iii) overall survival, (iv) patient-reported outcomes, (v) disease-free survival, (vi) objective response, (vii) complete response, (viii) increased time to progression, (ix) reduction in corticosteroid use, (x) reduction in supportive medication, (xi) reduction in incidence of seizures, (xii) reduction in use of anti-seizure medications, (xiii) improved quality of life, (xiv) reduction in neuropathy, and (xv) other objective response. In one embodiment, administration is in combination with one or more additional therapies or therapeutic agents. In one embodiment, the dose of ONC-206 or a salt thereof is about 25 mg to about 75 mg based on the free base form. In one embodiment, the upper dose can be about 2 to 3 grams. In one embodiment, the dose is about 50 mg. In one embodiment, the dose of ONC-206 or a salt thereof is about 5 mg / kg to about 100 mg / kg. In one embodiment, the dose is about 50 mg / kg. In one embodiment, the dose of ONC-206 or a salt thereof in a volume of 10 ml / kg is about 0.6 mg / l to about 10 mg / ml. In one embodiment, the dose is about 5 mg / ml. In one embodiment, the dose of ONC-206 or a salt thereof is about 12.5 mg / kg / day to about 25 mg / kg / day. In one embodiment, the dose is about 12.5 mg / kg / day. In one embodiment, the dose of ONC-206 or a salt thereof is about 8 mg / kg / day to about 20 mg / kg / day. In one embodiment, the dose of ONC-206 or a salt thereof is about 5 mg / kg / day to about 50 mg / kg / day. In one embodiment, the dose is less than about 50 mg / kg / day. In one embodiment, the dose of ONC-206 or a salt thereof is about 1.7 mg / kg / day to about 16.7 mg / kg / day. In one embodiment, the dose is more than about 16.7 mg / kg / day.In one embodiment, the dose provided is once a day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, or once a month. In one embodiment, the dose is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In one embodiment, the Cmax is about 4 μM to about 20 μM. In one embodiment, the terminal half-life is about 6 hours. In one embodiment, the target tissue distribution relative to the plasma ONC-206 concentration is at least one of 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher. In one embodiment, the ONC-206 is a dihydrochloride salt. In one embodiment, the treatment is for recurrent tumors. In one embodiment, the treatment is other than a first line treatment. In one embodiment, the treatment is for an advanced cancer. In one embodiment, the treatment is administered at least 30 days after radiation. In one embodiment, the treatment is administered at least 60 days after radiation. In one embodiment, the treatment is administered at least 90 days after radiation. In one embodiment, the treatment is administered after surgical resection. In one embodiment, the CNS tumor is one or more of recurrent glioblastoma, WHO grade 2 and 3 infiltrating glial tumors, DMG H3K27M, DMG H3 K27 mutation, DMG H3 K27me deletion (H3K27me3), ependymoma, medulloblastoma, malignant meningioma, and other rare primary CNS tumors. In one embodiment, the administration is monitored with one or more of DRD2, DRD2 dimer, ClpP, ClpP substrates (e.g., SDHA, SDHB), and markers of oxidative phosphorylation (DRD5, c-myc, and n-myc expression). In one embodiment, the objective response rate is measured by one or more of RANO criteria, RECIST criteria overall survival, progression free survival, and disease control rate.

[0011] One embodiment of the present disclosure includes the use of ONC-206, 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, or a salt thereof, in the preparation of a medicament for treating one or more CNS tumors.

[0012] In one embodiment, the CNS tumor is one or more of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglial tumor, ependymal tumor, medulloblastoma, pineal tumor, meningeal tumor, and germ cell tumor. In one embodiment, the administration reduces one or more symptoms of the CNS tumor. In one embodiment, the administration reduces tumor growth. In one embodiment, the administration provides one or more of: (i) a reduction in tumor size, (ii) progression-free survival, (iii) overall survival, (iv) patient-reported outcomes, (v) disease-free survival, (vi) objective response, (vii) complete response, and (viii) increased time to progression. In one embodiment, the administration is in combination with one or more additional therapies or therapeutic agents. In one embodiment, the dose of ONC-206 or a salt thereof is about 25 mg to about 75 mg based on the free base form. In one embodiment, the dose is about 50 mg. In one embodiment, the dose of ONC-206 or a salt thereof is about 5 mg / kg to about 100 mg / kg. In one embodiment, the dose is about 50 mg / kg. In one embodiment, the dose of ONC-206 or a salt thereof in a volume of 10 ml / kg is about 0.6 mg / l to about 10 mg / ml. In one embodiment, the dose is about 5 mg / ml. In one embodiment, the dose of ONC-206 or a salt thereof is about 12.5 mg / kg / day to about 25 mg / kg / day. In one embodiment, the dose is about 12.5 mg / kg / day. In one embodiment, the dose of ONC-206 or a salt thereof is about 8 mg / kg to about 20 mg / kg. In one embodiment, the dose of ONC-206 or a salt thereof is about 5 mg / kg / day to about 50 mg / kg / day. In one embodiment, the dose is less than about 50 mg / kg / day. In one embodiment, the dose of ONC-206 or a salt thereof is about 1.7 mg / kg / day to about 16.7 mg / kg / day. In one embodiment, the dose is greater than about 16.7 mg / kg / day. In one embodiment, the dose provided is once a day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, or once a month. In one embodiment, the dose is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In one embodiment, Cmax is about 4 μM to about 20 μM.In one embodiment, the terminal half-life is about 6 hours. In one embodiment, the target tissue distribution relative to the plasma ONC-206 concentration is at least one of 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher. In one embodiment, the ONC-206 is a dihydrochloride salt. In one embodiment, the treatment is for a recurrent tumor. In one embodiment, the treatment is other than a first line treatment. In one embodiment, the treatment is for an advanced cancer. In one embodiment, the treatment is administered at least 30 days after radiation. In one embodiment, the treatment is administered at least 60 days after radiation. In one embodiment, the treatment is administered at least 90 days after radiation. In one embodiment, the treatment is administered after surgical resection. In one embodiment, the CNS tumor is one or more of recurrent glioblastoma, WHO grade 2 and 3 infiltrating glial tumor, DMG H3K27M, ependymoma, medulloblastoma, malignant meningioma, and other rare primary CNS tumors. In one embodiment, administration is monitored by one or more of DRD2, DRD2 dimer, ClpP, DRD5, c-myc, and n-myc expression. In one embodiment, the objective response rate is measured by one or more of RANO criteria, overall survival, progression-free survival, and disease control rate.

[0013] One embodiment of the present disclosure includes the compound ONC-206, 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, or a salt thereof, for use in the preparation of a medicament for treating one or more CNS tumors.

[0014] In one embodiment, the CNS tumor is one or more of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglial tumor, ependymal tumor, medulloblastoma, pineal tumor, meningeal tumor, and germ cell tumor. In one embodiment, the administration reduces one or more symptoms of the CNS tumor. In one embodiment, the administration reduces tumor growth. In one embodiment, the administration provides one or more of: (i) a reduction in tumor size, (ii) progression-free survival, (iii) overall survival, (iv) patient-reported outcomes, (v) disease-free survival, (vi) objective response, (vii) complete response, and (viii) increased time to progression. In one embodiment, the administration is in combination with one or more additional therapies or therapeutic agents. In one embodiment, the dose of ONC-206 or a salt thereof is about 25 mg to about 75 mg based on the free base form. In one embodiment, the dose is about 50 mg. In one embodiment, the dose of ONC-206 or a salt thereof is about 5 mg / kg to about 100 mg / kg. In one embodiment, the dose is about 50 mg / kg. In one embodiment, the dose of ONC-206 or a salt thereof in a volume of 10 ml / kg is about 0.6 mg / l to about 10 mg / ml. In one embodiment, the dose is about 5 mg / ml. In one embodiment, the dose of ONC-206 or a salt thereof is about 12.5 mg / kg / day to about 25 mg / kg / day. In one embodiment, the dose is about 12.5 mg / kg / day. In one embodiment, the dose of ONC-206 or a salt thereof is about 8 mg / kg to about 20 mg / kg. In one embodiment, the dose of ONC-206 or a salt thereof is about 5 mg / kg / day to about 50 mg / kg / day. In one embodiment, the dose is less than about 50 mg / kg / day. In one embodiment, the dose of ONC-206 or a salt thereof is about 1.7 mg / kg / day to about 16.7 mg / kg / day. In one embodiment, the dose is greater than about 16.7 mg / kg / day. In one embodiment, the dose provided is once a day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, or once a month. In one embodiment, the dose is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week. In one embodiment, Cmax is about 4 μM to about 20 μM.In one embodiment, the terminal half-life is about 6 hours. In one embodiment, the target tissue distribution relative to the plasma ONC-206 concentration is at least one of 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher. In one embodiment, the ONC-206 is a dihydrochloride salt. In one embodiment, the treatment is for a recurrent tumor. In one embodiment, the treatment is other than a first line treatment. In one embodiment, the treatment is for an advanced cancer. In one embodiment, the treatment is administered at least 30 days after radiation. In one embodiment, the treatment is administered at least 60 days after radiation. In one embodiment, the treatment is administered at least 90 days after radiation. In one embodiment, the treatment is administered after surgical resection. In one embodiment, the CNS tumor is one or more of recurrent glioblastoma, WHO grade 2 and 3 infiltrating glial tumor, DMG H3K27M, ependymoma, medulloblastoma, malignant meningioma, and other rare primary CNS tumors. In one embodiment, administration is monitored by one or more of DRD2, DRD2 dimer, ClpP, DRD5, c-myc, and n-myc expression. In one embodiment, the objective response rate is measured by one or more of RANO criteria, overall survival, progression-free survival, and disease control rate.

[0015] One embodiment of the disclosure includes treating one or more cancers in a subject in need thereof by administering ONC-206:7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one or a salt thereof at a dose of about 50 mg twice daily for three consecutive days.

[0016] In one embodiment, three consecutive days of administration are followed by four days without dosing with ONC-206 (which may be referred to as drug holidays). In one embodiment, the cancer is a CNS tumor selected from the group consisting of one or more of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglial tumor, epithelial tumor, medulloblastoma, pineal tumor, meningeal tumor, and germ cell tumor. In one embodiment, administration relieves one or more symptoms of the cancer. In one embodiment, administration reduces tumor growth. In one embodiment, administration provides one or more of: (i) a reduction in tumor size, (ii) progression-free survival, (iii) overall survival, (iv) patient-reported outcomes, (v) disease-free survival, (vi) objective response, (vii) complete response, and (viii) increased time to progression. In one embodiment, the total weekly dose of ONC-206 is about 300 mg. In one embodiment, the total weekly AUClast is less than about 5270 h*ng / mL.

[0017] One embodiment of the present disclosure includes a dose of ONC-206:7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, or a salt thereof, administered twice daily for at least one day, followed by at least one drug-free day.

[0018] In one embodiment, ONC-206 is administered twice a day for two or more consecutive days, followed by at least one drug holiday. In one embodiment, ONC-206 is administered twice a day for two or more consecutive days, followed by at least two consecutive drug holidays. In one embodiment, ONC-206 is administered twice a day for three or more consecutive days, followed by at least two consecutive drug holidays. In one embodiment, ONC-206 is administered twice a day for three or more consecutive days, followed by at least three consecutive drug holidays. In one embodiment, ONC-206 is administered twice a day for three or more consecutive days, followed by at least four consecutive drug holidays. In one embodiment, the dose of ONC-206 is about 5 mg to about 150 mg. In one embodiment, the dose of ONC-206 is about 25 mg to about 100 mg. In one embodiment, the dose of ONC-206 is one of 25 mg, 50 mg, 75 mg, or 100 mg. In one embodiment, the dose of ONC-206 is 50 mg.

[0019] The above is a summary to provide an introduction and understanding of some embodiments of the present disclosure. This summary is not intended to be an extensive or exhaustive presentation of the present disclosure and its various embodiments. As will be understood, other embodiments of the present disclosure can utilize, alone or in combination, one or more of the features, embodiments, and aspects shown above or described in detail below. Each of these combinations of features, embodiments, and aspects should be considered a disclosed embodiment itself.

[0020] This brief description, as well as the following detailed description of the embodiments of the present disclosure, will be better understood when read in conjunction with the accompanying drawings of example embodiments, it being understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown. [Brief description of the drawings]

[0021] [Figure 1]FIG. 1 shows an exemplary pharmacokinetic profile of ONC206 in Sprague-Dawley rats following a single oral gavage dose (PO) of 50 and 125 mg / kg. 10000 ng / ml represents approximately 20 μM. [Diagram 2] 1 shows graphical results of an exemplary rat biodistribution study of ONC206 at 50 mg / kg (PO), showing plasma and tissue concentrations over time following ONC206 dosing. [Diagram 3] 1 shows the mechanism of action of ONC-206. As shown, ONC206 antagonizes DRD2 at the cell surface, leading to activation of the ISR with ATF4 / CHOP induction and upregulation of DR5 and TRAIL gene expression, inducing apoptotic tumor cell death. [Figure 4] Figure 1 shows the in vitro efficacy of ONC206 in human cancer cell lines. Graphical representation of the in vitro sensitivity of >1000 Genomics of Drug Sensitivity in Cancer (GDSC) human cancer cell lines to ONC206 (72h), averaged and organized by tumor type. Results are shown as the completeness of ONC206 response quantified as the average area under the curve (AUC) in dose-response cell viability curves across all cell lines of each tumor type. Error bars represent standard error of the mean. [Diagram 5] Figure 1 shows the in vitro efficacy of ONC206 in human cancer cell lines. The mean GI50 from 72 hours of ONC206 (0.078-20 μM) treatment is shown in a panel of Ewing's sarcoma, neuroblastoma, and medulloblastoma cell lines in the GDSC screen. [Figure 6A] Figure 1 shows the in vivo antitumor efficacy of ONC206 at 50 mg / kg once a week without weight loss.Figure 2 shows the tumor volume of HuCCT1 xenografts in athymic nude mice. [Figure 6B]Figure 1 shows the in vivo antitumor efficacy of ONC206 at 50 mg / kg once weekly without weight loss. Shown are relevant body weights (n=6) after consecutive treatments with ONC206 (PO) at 50 mg / kg once weekly and vehicle. *p<0.05 [Figure 7] Graphical representation of data presented as mean plasma ONC206 concentration profiles detected by LC-MS-MS on Day 1 of Cycle 1 (except for the 200 mg data, which is presented as a profile for a single patient who received the 200 mg dose). Error bars represent standard deviation. Nominal times are relative to administration of the first dose at 0 hours. Patients received ONC206 oral capsules. [Figure 8] FIG. 1 is a graphical representation of H4 glioma cells treated with ONC206 at the indicated concentrations ranging from 5.1 nM to 11 μM. At the indicated time points, cells were washed with PBS and the medium was replaced to wash out the ONC206. Cell viability was determined 7 days after the first treatment with Celltiter-Glo. At 72 hours, IC50=337 nM and IC90=715 nM. Error bars represent standard error of the mean (n=4). [Figure 9] 1 is a graphical representation of predicted mean ONC206 plasma concentrations following a 3-day BID dosing regimen in adult patients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] As mentioned above, the majority of recurrent CNS tumors lack effective systemic therapeutic options after surgical resection and adjuvant radiation therapy.ONC201, which may be referred to herein as compound 1 or NSC350625, is a founding member of the small molecule imipridone class and has induced sustained tumor regression in patients with diffuse midline glioma H3 K27M mutant (DMG H3K27M).ONC206, which may be referred to herein as compound 2, is the second imipridone to enter clinical development, a DRD2 antagonist and ClpP agonist, and shows a different receptor pharmacology and gene expression profile in tumors compared to ONC201.

[0023] I. Pharmaceutical Compositions

[0024] One embodiment of the present disclosure includes a pharmaceutical composition comprising ONC-206.

[0025] In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharma- ceutically acceptable mono-salt thereof. In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharma- ceutically acceptable di-salt thereof. In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharma- ceutically acceptable mono- or poly-salt thereof (e.g., a di- or tri-salt, it being understood throughout this disclosure that a di-salt encompasses a tri- or other poly-salt), where the mono- or poly-salt is selected from the group consisting of hydrochloride, hydrobromide, bisulfate, sulfate, phosphate, fumarate, succinate, oxalate, and lactate, bisulfate, hydroxyl, tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate, fumarate, sulfonate, methylsulfonate, formate, and carboxylate. In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharma- ceutically acceptable salt thereof, wherein the salt is selected from the group consisting of p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate, and maleate. In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharma- ceutically acceptable salt thereof, wherein the salt is selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and / or counterions (e.g., methylamino, dimethylamino, diethylamino, and triethylamino counterions). In one embodiment, the pharmaceutical composition comprises ONC-206, its hydrochloride di-salt (e.g., the dihydrochloride salt), or its hydrobromide di-salt (e.g., the dihydrobromide salt).

[0026] In one embodiment, a pharmaceutical composition according to the present disclosure comprises a di-salt (e.g., a dihydrochloride salt) of ONC-206. Salts (e.g., di-, tri-, or poly-salts) of ONC-206 can be prepared from ONC-206, which is either commercially available or can be synthesized using standard chemical synthesis methods known to those of skill in the art.

[0027] The dihydrochloride salts of compounds within the class of impyridones, of which ONC-206 is a member, achieve an unexpected technical effect. As an example, a comparison between the dihydrochloride salt of ONC-201 and the corresponding free base demonstrates that the water solubility of the dihydrochloride salt is greater than 50 mg / mL and less than 1 mg / mL for the free base. In addition, after 2 months at 25°C and 40°C, the percentage of impurities in the dihydrochloride salt is undetectable and 3%, respectively, while for the free base, the percentage of the corresponding impurities is 20% and 24%, respectively. This technical effect appears to extend to the class of impyridones as well.

[0028] In one embodiment, the pharmaceutical composition according to the present disclosure comprises at least one pharma- ceutically acceptable carrier.Suitable pharma-ceutically acceptable carriers include, but are not limited to, those found in Handbook of Pharmaceutical Excipients, 7th Edition, edited by Raymond C. Rowe et al., American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London and previous editions.

[0029] Exemplary pharma- ceutically acceptable carriers, pharmaceutical compositions and methods for making various dosage forms, as well as modes of administration, are well known in the art and are described in detail, for example, in Pharmaceutical Dosage Forms: Tablets, edited by Larry L. Augsburger and Stephen W. Hoag., London: Informa Healthcare, 2008, and in L. V. Allen, Jr. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th Ed., Philadelphia, Pa.: Lippincott, Williams & Wilkins, 2004, in A. R. Gennaro, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed., 2005, especially chapter 89, and in J. G. Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill Professional, 10th Ed. ed., 2001.

[0030] The pharmaceutical composition of the present disclosure can be administered to a subject via any suitable route of administration. In one embodiment, the pharmaceutical composition is administered to a subject orally, parenterally, transdermally, or transmucosally. In one embodiment, the pharmaceutical composition is administered to a subject in a parenteral dosage form. In one embodiment, the pharmaceutical composition is administered to a subject parenterally. In one embodiment, the pharmaceutical composition is administered to a subject via a parenteral route of administration selected from one or more of the group consisting of intravenous (IV), subcutaneous (SC), intramuscular (IM), and intrathecal. In one embodiment, the pharmaceutical composition is administered to a subject via a route of administration selected from rectal (PR) and transdermal. In one embodiment, the pharmaceutical composition is administered to a subject in a dosage form selected from the group consisting of a sterile solution, suspension, suppository, tablet, and capsule. In one embodiment, the pharmaceutical composition is administered to a subject in an oral dosage form selected from the group consisting of a tablet, caplet, capsule, lozenge, syrup, liquid, suspension, and elixir. In one embodiment, the pharmaceutical composition is administered to the subject in an oral dosage form selected from the group consisting of a tablet, a hard shell capsule, a soft gelatin capsule, a bead, a granule, an agglomerate, a powder, a gel, a solid, and a semi-solid.

[0031] In some embodiments, the pharmaceutical composition is administered to the subject in a dosage form selected from the group consisting of a sustained release form, a controlled release form, a delayed release form, and a responsive release form.

[0032] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for ocular administration. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for topical ocular administration. In some embodiments, the pharmaceutical compositions are formulated as ointments, drops, or liquids. In some embodiments, the pharmaceutical compositions of the present disclosure can include conventional pharmaceutical carriers, such as aqueous, powder, or oily bases, thickeners, etc.

[0033] In some embodiments, the pharmaceutical composition of the present disclosure is formulated as an intravenous formulation. In one embodiment, the intravenous formulation comprises ONC-206 or a pharma- ceutically acceptable salt of ONC-206 dissolved in a solvent. In one embodiment, the solvent comprises water. In one such embodiment, the intravenous formulation comprises ONC-206 or a pharma- ceutically acceptable salt of ONC-206 dissolved in water at a concentration of 25 mg / ml. In some embodiments, the intravenous formulation comprises a higher or lower concentration of ONC-206 or a pharma- ceutically acceptable salt thereof. In one embodiment, the intravenous formulation comprises a concentration of ONC-206 or a pharma- ceutically acceptable salt thereof from about 5 mg / ml to about 100 mg / ml. In one embodiment, the intravenous formulation comprises a concentration of ONC-206 or a pharma- ceutically acceptable salt thereof at about 50 mg / ml. In one embodiment, the intravenous formulation comprises a concentration of ONC-206 or a pharma- ceutically acceptable salt thereof at about 5 mg / ml. In one embodiment, the intravenous formulation contains from about 0.5% to about 10% ONC-206 or a pharma- ceutically acceptable salt thereof.In one embodiment, the intravenous formulation contains from about 5% ONC-206 or a pharma- ceutically acceptable salt thereof.

[0034] In some embodiments, the intravenous formulation has a pH of about 3. In one embodiment, the pH of the intravenous formulation is adjusted to pH 3 with a phosphate buffer. In some embodiments, the intravenous formulation comprises dextrose or sodium chloride. In one embodiment, an intravenous formulation comprising ONC-206 or a pharma- ceutically acceptable salt thereof at a concentration of about 5 mg / ml and a pH of 3 forms a stable solution. In one embodiment, an intravenous formulation comprises ONC-206 or a pharma- ceutically acceptable salt thereof at a concentration of about 5 mg / ml and a pH < 5 forms a stable solution. In one embodiment, an intravenous formulation comprises ONC-206 or a pharma- ceutically acceptable salt thereof and one or more antioxidants. In one embodiment, an intravenous formulation comprises a mixture of the monohydrochloride and dihydrochloride salts of ONC-206. In one embodiment, an intravenous formulation comprises ONC-206 or a pharma- ceutically acceptable salt thereof as a 1% solution having a concentration of ONC-206 or a pharma- ceutically acceptable salt thereof at about 10 mg / ml. In one such embodiment, the intravenous formulation is a solution having a pH of about 3.3. In one embodiment, the pH is less than 4.0.

[0035] In one embodiment, a pharmaceutical composition according to the present disclosure comprises about 0.1-99% of a salt of ONC-206 or a pharma- ceutically acceptable salt thereof. In one such embodiment, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier. In one embodiment, a suitable pharma- ceutically acceptable carrier comprises an oil. In one embodiment, a suitable pharma- ceutically acceptable carrier comprises sterile water. In one embodiment, a suitable pharma- ceutically acceptable carrier comprises an aqueous carrier.

[0036] In some embodiments, the intravenous formulation comprises dextrose and / or sodium.

[0037] In one embodiment, the intravenous formulation comprises 25 mg / ml of ONC-206 or the dihydrochloride salt of ONC-206 dissolved in water. In one such embodiment, the intravenous formulation is adjusted to pH 3 with phosphate buffer. In one such embodiment, the intravenous formulation comprises dextrose or sodium chloride. In one such embodiment, the intravenous formulation comprises a higher or lower, increased or decreased concentration of the dihydrochloride salt of ONC-206. In one embodiment, the intravenous formulation comprises about 5 mg / ml of ONC-206 or the dihydrochloride salt of ONC-206. In one embodiment, the intravenous formulation comprises about 5 mg / ml of ONC-206 or the dihydrochloride salt of ONC-206 and a pH of 3 forms a stable solution. In one embodiment, the intravenous formulation comprises about 5 mg / ml of ONC-206 or the dihydrochloride salt of ONC-206 and a pH of <5 forms a stable solution. In one embodiment, the intravenous formulation comprises ONC-206 or a dihydrochloride salt of ONC-206 and one or more antioxidants. In one embodiment, the intravenous formulation comprises a mixture of the monohydrochloride and dihydrochloride salts of ONC-206. In one embodiment, the intravenous formulation comprises ONC-206 or a dihydrochloride salt of ONC-206 as a 1% solution having a concentration of about 10 mg / ml of ONC-206 or a dihydrochloride salt of ONC-206. In one such embodiment, the intravenous formulation is a solution having a pH of about 3.33. In one embodiment, the pH is less than 4.0.

[0038] In one embodiment, the intravenous formulation comprises about 0.5% to about 10% (or about 5 mg / ml to about 100 mg / ml) of ONC-206 or a di-salt of ONC-206. In one embodiment, the intravenous formulation comprises about 5% (or about 50 mg / ml) of ONC-206 or a di-salt of ONC-206. In one embodiment, the intravenous infusion rate may be slowed to reduce side effects of ONC-206 or a di-salt of ONC-206.

[0039] In one embodiment, a pharmaceutical composition according to the present disclosure comprises about 0.1-99% of a salt of ONC-206 and a pharma- ceutically acceptable carrier (e.g., an oil or sterile water or other aqueous carrier).In one embodiment, a pharmaceutical composition according to the present disclosure, for oral dosage forms, comprises a mono- or di-salt of ONC-206 in the range of about 5% to about 50%.

[0040] In some embodiments, the pharmaceutical composition of the present disclosure comprises an antioxidant. Suitable antioxidants include ascorbic acid derivatives (e.g., ascorbic acid, erythorbic acid, sodium ascorbate), thiol derivatives (e.g., thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione), tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sulfites (e.g., sodium sulfate, sodium bisulfite, sodium acetone bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate), nordihydroguaiaretic acid, and the like. It should be noted that antioxidants used in aqueous formulations typically include sodium sulfite, sodium metabisulfite, sodium formaldehyde sulfoxylate, and ascorbic acid, and combinations thereof, while antioxidants used in oil-based solutions, organic solvents include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and propyl gallate, and combinations thereof. In yet other embodiments, the antioxidant can be one or more of flavanoids, isoflavones, monothioglycerol, L-cysteine, thioglycolic acid, α-tocopherol, 6-palmitoyl ascorbic acid, dihydrolipoic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, propyl gallate, β-carotene, and ascorbic acid. Antioxidants can typically be used at about 0.1% to 1.0% by weight, more typically at about 0.2% by weight.

[0041] In one embodiment, a pharmaceutical composition comprises ONC-206, or a pharma- ceutically acceptable salt thereof, and at least one other therapeutic agent.

[0042] As used throughout this disclosure, additional, other, or second therapeutic agent can also include therapies such as curative, preventative, diagnostic, staging, debulking, palliative, supportive, or reparative surgical treatments (e.g., radiation or surgery).

[0043] In one such embodiment, the at least one other therapeutic agent is selected from the group consisting of hormone analogs and antihormones, aromatase inhibitors, LHRH agonists and antagonists, inhibitors of growth factors, growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors, antimetabolites, antitumor antibiotics, platinum derivatives, alkylating agents, antimitotic agents, tubulin inhibitors, PARP inhibitors, topoisomerase inhibitors, serine / threonine kinase inhibitors, tyrosine kinase inhibitors, protein interaction inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, E rbB receptor inhibitors, rapamycin analogues, BTK inhibitors, CRM1 inhibitors (e.g., KPT185), P53 modulators (e.g., Natrin), antiangiogenic agents (e.g., axitinib, aflibercept, sorafenib, and regorafenib), amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer, 2-chlorodesoxyadenosine, 2-fluorodesoxycytidine, 2-fluorodesoxycytidine, 2-fluoro- ... , 2-Methoxyestradiol, 2C4,3-Arettin, 131-1-TM-601, 3CPA, 7-Ethyl-10-Hydroxycamptothecin, 16-Aza-Epothilone B, A105972, A204197, Abiraterone, Aldesleukin, Alitretinoin, Allobectin-7, Altretamine, Alvocidib, Amonafide, Anthrapyrazole, AG-2037, AP-5280, Apaziquone, Apomine, Alanose, Arglavin, Arzoxifene, Atamestane, Atrasentan, Auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY162, ARRY438162, ARRY-300, ARRY-142886 / AZD-6244 (selumetinib), ARRY-704 / AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ680, AS-703026 (pimasertib), Avastin, AZD-2014, azacitidine, azaepothilone B, azonafide, BAY-43-9006, BAY80-6946,BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricoderm dicitrate, BCX-1777, BKM-120, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992 (afatinib, tomtobok), BIBF1120 (valgatef), BI836845, BI2536, BI6727, BI836845, BI847325, BI853520, BUB -022, bleomycin acid, bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib, brostallicin, busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1, cefixime, cefratonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655 / RO-4 987655, chlorotrianisene, cilengitide, cyclosporine, CDA-II, CDC-394, CKD-602, CKI-27, clofarabine, colchicine, combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-Thera, CMT-3, cryptophycin 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D24851, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide , Desoxyepothilone B, Dexamethasone, Dexrazoxanet, Diethylstilbestrol, Diflomotecan, Didox, DMDC, Dolastatin 10, Doranidazole, DS-7423, E7010, E-6201, Edatrexate, Edotreotide, Efaproxiral, Eflornithine, EGFR inhibitors, EKB-569, EKB-509, Enzastaurin, Enzalutamide, Elsamitrucin, Epothilone B, Epratuzumab, ER-86526, Erlotinib, ET-18-0CH3, Ethinylcytidine, Ethinylestradiol,Exatecan, Exatecan Mesylate, Exemestane, Exisulind, Fenretinide, Figitumumab, Floxuridine, Folic Acid, FOLFOX, FOLFOX4, FOLFIRI, Formestane, Fotemustine, Galarubicin, Gallium Maltolate, Gefitinib, Gemtuzumab, Gimatecan, Glufosfamide, GCS-100, GDC-0623, GDC-0941 (Pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT Immunogen, GMK, GPX-100 , gp100 peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptin, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate Sirt, Idenestrol, IDN-5109, IGF-1R inhibitor, IMC-1C11, IMC-A12 (cixutumumab), Immunol, Indisulam, Interferon α-2a, Interferon α-2b, Pegylated interferon α-2b, Interleukin-2, INK-1117, INK-128, INSM-18, Ionafarnib, Ipilimumab, Iproplatin, Irofulven, Isohomohalichondrin-B, Isoflavone, Isotretinoin, Ixabepilone, JRX-2, JSF-154, J-107088, Conjugated estrogens , Kahalid F, Ketoconazole, KW-2170, KW-2450, Lobaplatin, Leflunomide, Lenograstim, Leuprolide, Leuporelin, Lexidonam, LGD-1550, Linezolid, Lutetium texaphyrin, Lometrexol, Rosoxantrone, LU223651, Lurototecan, LY-S6AKT1, LY-2780301, Mahosfamide, Marimastat, Mechloroethamine, MEK inhibitor, MEK-162, Methyltestosterone, Methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf in gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage, oncoVEXGM-CSF, olmiplatin, orthostat Taxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-1BB antibody, oxantrazole, estrogen, panitumumab, patupilone, PI3Ki inhibitor, paxilisib, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P 54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillyl alcohol, pertuzumab, PI3K inhibitors, PI3K / mTOR inhibitors, PG-TXL, PG2, PLX-4032 / RO-5185426 (vemurafenib), PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI166, previtrexed, plicamycin, polyprenoic acid, porfiromycin, prednisone , prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY869766, RDEA-436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, regorafenib, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG7440, rhizoxin, rhu-MAb, rinfavert, risedronate, rituximab, lobatumumab, rofecoxib, RO-31-7453, RO-5126766, RO-5068760,RPR109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalbicine, SAHA, sargramostim, satraplatin, SB408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spirop latin, squalamine, suberanilohydroxamic acid, sutent, T900607, T138067, TAK-733, TAS-103, tacedinaline, talaporfin, tarceva, taliquitar, tasisulam, taxotere, taxoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, tela Rubicin, Thymalfasin, Timectasin, Tiazofurin, Tipifarnib, Tirapazamine, Tocladesine, Tomudex, Tremofin, Trabectedin, TransMID-107, Trans-retinoic acid, Trazumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Triciribine, Trimetrexate, TLK-286TXD258, Tykerb / Tyverb, Urocidine, Valrubicin, Vatalanib, Vincristine, Vinfluni and combinations thereof.

[0044] In one embodiment, the at least one other therapeutic agent comprises one or more hormone analogs and / or antihormones selected from the group consisting of tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more LHRH agonists and / or antagonists selected from the group consisting of goserelin acetate, luprolide acetate, triptorelin pamoate, and combinations thereof, and the LHRH antagonists are selected from the group consisting of degarelix, cetrorelix, abarelix, ozarelix, degarelix, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more growth factor inhibitors selected from the group consisting of inhibitors of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER), and hepatocyte growth factor (HGF). In one embodiment, the at least one other therapeutic agent comprises one or more inhibitors of human epidermal growth factor selected from the group consisting of HER2, HER3, and HER4. In one embodiment, the at least one other therapeutic agent comprises one or more tyrosine kinase inhibitors selected from the group consisting of cetuximab, gefitinib, imatinib, lapatinib, and trastuzumab, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more aromatase inhibitors selected from the group consisting of anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more antimetabolites that are antifolates selected from the group consisting of methotrexate, raltitrexed, and pyrimidine analogs. In one embodiment, the at least one other therapeutic agent comprises one or more antimetabolites that are antifolates selected from the group consisting of 5-fluorouracil, capecitabine,and gemcitabine. In one embodiment, the at least one other therapeutic agent comprises one or more antimetabolites that are purine and / or adenosine analogs selected from the group consisting of mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more antitumor antibiotics selected from the group consisting of anthracyclines, doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more platinum derivatives selected from the group consisting of cisplatin, oxaliplatin, carboplatin, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more alkylating agents selected from the group consisting of estramustine, mechlorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises a nitrosourea selected from the group consisting of carmustine, lomustine, thiotepa, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises an antimitotic agent selected from the group consisting of vinca alkaloids and taxanes. In one embodiment, the at least one other therapeutic agent comprises one or more taxanes selected from the group consisting of paclitaxel, docetaxel, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more vinca alkaloids selected from the group consisting of vinblastine, vindesine, vinorelbine, vincristine, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more topoisomerase inhibitors that are epipodophyllotoxins. In one embodiment, the at least one other therapeutic agent comprises one or more topoisomerase inhibitors that are epipodophyllotoxins. In one embodiment, the at least one other therapeutic agent comprises one or more topoisomerase inhibitors that are epipodophyllotoxins.and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more serine / threonine kinase inhibitors selected from the group consisting of PDK1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3K inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK1 inhibitors, inhibitors of CDKs, Aurora kinase inhibitors, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more tyrosine kinase inhibitors that are PTK2 / FAK inhibitors. In one embodiment, the at least one other therapeutic agent comprises one or more protein interaction inhibitors selected from the group consisting of IAP, Mcl-1, MDM2 / MDMX, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more rapamycin analogs selected from the group consisting of everolimus, temsirolimus, ridaforolimus, sirolimus, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more therapeutic agents selected from the group consisting of amifostine, anagrelide, clodronate, filgrastin, interferon, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer, and combinations thereof. In one embodiment, the at least one other therapeutic agent comprises one or more therapeutic agents selected from the group consisting of 2-chlorodesoxyadenosine, 2-fluorodesoxy-cytidine, 2-methoxyestradiol, 2C4,3-arretin, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abiraterone, aldesleukin, alitretinoin, Allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, alanose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY162, ARRY438162, ARRY-300,ARRY-142886 / AZD-6244 (selumetinib), ARRY-704 / AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ680, AS-703026 (pimasertib), Avastin, AZD-2014, azacitidine, azaepothilone B, azonafide, BAY-43-9006, BAY80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, bilirubin dicitrate, BCX-177 7, BKM-120, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992 (afatinib, tomtobok), BIBF1120 (valgatef), BI836845, BI2536, BI6727, BI836845, BI847325, BI853520, BUB-022, bleomycin acid, bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib Zomib, Brostallicin, Busulfan, BYL-719, CA-4 prodrug, CA-4, CapCell, Calcitriol, Canertinib, Canfosfamide, Capecitabine, Carboxyphthalatoplatin, CCl-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1, Cefixime, Cefratonin, Ceftriaxone, Celecoxib, Celmoleukin, Cemadotin, CH4987655 / RO-4987655, Chlorotrianisene, Cilengitide, Cyclosporine, CDA-II, CDC-394, CKD- 602, CKI-27, Clofarabine, Colchicine, Combretastatin A4, COT inhibitor, CHS-828, CH-5132799, CLL-Thera, CMT-3, Cryptophycin 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, Cyanomorpholinodoxorubicin, Cytarabine, D24851, Decitabine, Deoxorubicin, Deoxyrubicin, Deoxycoformycin, Depsipeptide, Desoxyepothilone B, Dexamethasone, Dexrazoxane, Diethylstilbestrol, Diflomotecan,Didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010, E-6201, edatrexate, edotreotide, efaproxiral, eflornithine, EGFR inhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3, ethinylcytidine, ethinyl estradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, figitumumab, furo Xuridine, folic acid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fotemustine, galarubicin, gallium maltolate, gefitinib, gemtuzumab, gimatecan, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp100 peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trametinib) tinib), GSK-2118436 (dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183, GSK-2141795, GW2016, granisetron, herceptin, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab, idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12 (sixtu Mumab), Immunol, Indisulam, Interferon α-2a, Interferon α-2b, Pegylated Interferon α-2b, Interleukin-2, INK-1117, INK-128, INSM-18, Ionafarnib, Ipilimumab, Iproplatin, Irofulven, Isohomohalichondrin-B, Isoflavone, Isotretinoin, Ixabepilone, JRX-2, JSF-154, J-107088, Conjugated Estrogens, Kahalid F, Ketoconazole, KW-2170, KW-2450, Lobaplatin, Leflunomide, Lenograstim,Leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxantrone, LU223651, lurtotecan, LY-S6AKT1, LY-2780301, mafosfamide, marimastat, mechloroethamine, MEK inhibitor, MEK-162, methyltestosterone, methylprednisolone, MEDI-5, 73, MEN-10755, MDX-H210, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf in gadolinium, MS-209, MS-275, MX6, neridronate, neratinib, nexavar, neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage, onco VEXGM-CSF, Ormiplatin, Ortataxel, OX44 antibody, OSI-027, OSI-906 (linsitinib), 4-1BB antibody, Oxantrazole, Estrogen, Panitumumab, Patupilone, PI3Ki inhibitor, Paxilisib, Pegfilgrastim, PCK-3145, Pegfilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, Albumin-stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillyl alcohol, pertuzumab, PI3K inhibitors, PI3K / mTOR inhibitors, PG-TXL, PG2, PLX-4032 / RO-5185426 (vemurafenib), PLX-3603 / RO-5212054, PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI166, previtrexed, plicamycin, polyp uremic acid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, RDEA-119 / BAY869766, RDEA-436, rebeccamycin analogs, receptor tyrosine kinase (RTK) inhibitors, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG7440, rhizoxin, rhu-MAb, rinfavert, risedronate, rituximab, lobatumumab, rofecoxib, RO-31-7453, RO-5126766,RO-5068760, RPR109881A, rubidazone, rubitecan, R-flurbiprofen, RX-0201, S-9788, sabalbicine, SAHA, sargramostim, satraplatin, SB408075, Se-015 / Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib , spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T900607, T138067, TAK-733, TAS-103, tacedinaline, talaporfin, tarceva, taliquitar, tasisulam, taxotere, taxoplexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, tela Rubicin, Thymalfasin, Timectasin, Tiazofurin, Tipifarnib, Tirapazamine, Tocladesine, Tomudex, Tremofin, Trabectedin, TransMID-107, Trans-retinoic acid, Trazumab, Tremelimumab, Tretinoin, Triacetyluridine, Triapine, Triciribine, Trimetrexate, TLK-286TXD258, Tykerb / Tyverb, Urocidine, Valrubicin, Vatalanib, Vincristine, Vinflunine, Virulizine The therapeutic agent comprises one or more therapeutic agents selected from the group consisting of cyclosporine, WX-UK1, WX-554, Vectibix, Xeloda, XELOX, XL-147, XL-228, XL-281, XL-518 / R-7420 / GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronate, zosuquidar, and combinations thereof.

[0045] In some embodiments, the at least one other therapeutic agent comprises a steroid. Steroids include, but are not limited to, dexamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, triamcinolone, betamethasone, and cortivazol. In some embodiments, the at least one other therapeutic agent comprises an antiemetic. Antiemetics include 5-HT3 receptor agonists (e.g., dolasetron, granisetron, ondansetron, tropisetron, palonosetron, and mirtazapine), dopamine agonists (e.g., domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine, alizapride, prochlorperazine, and metoclopramide), NK1 receptor antagonists (e.g., aprepitant and casopitant), antihistamines (e.g., serotonin ... For example, these include, but are not limited to, cyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine, promethazine, hydroxyzine), cannabinoids (e.g., cannabis, dronabinol, nabilone, and sativex), benzodiazepines (e.g., midazolam and lorazepam), anticholinergics (e.g., hyoscine), trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol, and ajowan.

[0046] In some embodiments, the at least one other therapeutic agent comprises an anti-cancer agent comprising an antimitotic agent. In one embodiment, the antimitotic agent comprises a taxane. In one embodiment, the antimitotic agent comprises a taxane selected from the group consisting of paclitaxel and docetaxel.

[0047] In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharma- ceutically acceptable salt thereof and at least one anti-cancer agent, including, but not limited to, acivicin, aclarubicin, acodazole, acronine, adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin, amethanthrone, amifostine, aminoglutethimide, amsacrine, anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimatin, or the like. Stats, benzodepa, bevacizumab, bicalutamide, bisantrene, visnafide dimesylate, bizelesin, bleomycin, brequinar, bropirimine, busulfan, cactinomycin, calsterone, capecitabine, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, celecoxib, chlorambucil, ciloremycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, Dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, droloxifene, dromostanolone, duazomycin, edatrexate, eflomitine, elsamitrucin, enloplatin, enpromate, epipropizine, epirubicin, elbrozole, esorubicin, estramustine, etanidazole, etoposide, etoprine, fadrozole, fazarabine, fenretinide, floxuridine, fludarabine, fluorouracil, flurocitabine, fosquidone, fostriecin , fulvestrant, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irmofosine, interleukin II (including IL-2, recombinant interleukin II or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan, lanreotide, letrozole, leuprolide, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine,Mechlorethamine hydrochloride, megestrol, megestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, metoprine, meturedepa, mitindomide, mitocalcin, mitochromine, mitogillin, mitomarcine, mitomycin, mitospel, mitotane, mitoxantrone, mycophenolic acid, nelarabine, nocodazole, nogalampicin, orumunaplatin, oxisuran, paclitaxel Taxel, pegaspargase, periomycin, pentamustine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer, porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, ribopurin, rogletimide, safingol, semustine, simtrazene, sparfosate, spar somycin, spirogermanium, spiromustine, spiroplatin, streptonigrin, streptozocin, sulofenur, tallysomycin, tamoxifen, tecogalan, tegafur, teloxantrone, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, topotecan, toremifene, trestron, triciribine, trimetrexate, triptorelin, tubrozole, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine, vinepidine, vinglisinate, vinleurosine, vinorelbine, vinrocidine, vinzolidine, vorozole, zeniplatin, zinostatin, zoledronate, zorubicin, and combinations thereof.

[0048] In one embodiment, the at least one additional therapeutic agent provides an immunotherapy. In one embodiment, the at least one additional therapeutic agent is one or more checkpoint inhibitors. In one embodiment, the at least one additional therapeutic agent is an adaptive cell therapy.

[0049] In one embodiment, the at least one additional therapeutic agent is a device, such as a device that uses an electric field to disrupt the division of cancer cells, including technology referred to as Tumor Treating Fields (also referred to as TTFields), provided, for example, by Novocure.

[0050] Examples of suitable anti-cancer agents as additional therapeutic agents include, but are not limited to, one or more of Afinitor (everolimus), Afinitor dispersible tablets (everolimus), Avastin (bevacizumab), bevacizumab, BiCNU (carmustine), carmustine, carmustine implant, Danielza (naxitamab-gqgk), everolimus, Gliadel wafers (carmustine implant), lomustine, Mvasi (bevacizumab), naxitamab-gqgk, Temodar (temozolomide), temozolomide, and Zirabev (bevacizumab).

[0051] In one embodiment, the additional therapeutic agent is two or more additional agents. As an example, the additional therapeutic agent can be PCV, which is a combination of procarbazine hydrochloride, lomustine (gleostine), and vincristine sulfate.

[0052] Examples of suitable anti-cancer agents include, but are not limited to, those described in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Ed., edited by Laurence Brunton, Bruce Chabner, Bjorn Knollman, McGraw Hill Professional, 2010.

[0053] In some exemplary embodiments, the pharmaceutical composition comprises a salt (e.g., mono- or di-salt) of ONC-206 and at least one other therapeutic agent, the at least one other therapeutic agent comprising an anti-angiogenic agent. In one such embodiment, the anti-angiogenic agent is bevacizumab. In one embodiment, the anti-angiogenic agent is aflibercept, axitinib, angiostatin, endostatin, 16 kDa prolactin fragment, laminin peptide, fibronectin peptide, tissue inhibitor of metalloproteinases (TIMP1, 2, 3, 4), plasminogen activator, inhibitor (PAI-1, 2), tumor necrosis factor alpha, (high dose, in vitro), TGF-β1, interferon (IFN-α, β, γ), ELR-CXC chemokines:, IL-12, SDF- 1, MIG, platelet factor 4 (PF-4), IP-10, thrombospondin (TSP), SPARC, 2-methoxyestradiol, proliferin-related protein, suramin, sorafenib, regorafenib, thalidomide, cortisone, linomide, fumagillin (AGM-1470; TNP-470), tamoxifen, retinoids, CM101, dexamethasone, leukemia inhibitory factor (LIF), hedgehog inhibitors, and combinations thereof.

[0054] The pharmaceutical combination according to the present disclosure may contain the first and second therapeutic agents in any desired ratio, so long as a synergistic or cooperative effect still occurs. The synergistic pharmaceutical combination according to the present disclosure preferably contains the first and second therapeutic agents in a ratio of about 1:9 to about 9:1. The synergistic pharmaceutical combination according to the present disclosure preferably contains the first and second therapeutic agents in a ratio of about 1:8 to about 8:1. The synergistic pharmaceutical combination according to the present disclosure preferably contains the first and second therapeutic agents in a ratio of about 1:7 to about 7:1. The synergistic pharmaceutical combination according to the present disclosure preferably contains the first and second therapeutic agents in a ratio of about 1:6 to about 6:1. The synergistic pharmaceutical combination according to the present disclosure preferably contains the first and second therapeutic agents in a ratio of about 1:5 to about 5:1. A synergistic pharmaceutical combination according to the present disclosure preferably contains a first therapeutic agent and a second therapeutic agent in a ratio of about 1:4 to about 4:1. A synergistic pharmaceutical combination according to the present disclosure preferably contains a first therapeutic agent and a second therapeutic agent in a ratio of about 1:3 to about 3:1. A synergistic pharmaceutical combination according to the present disclosure preferably contains a first therapeutic agent and a second therapeutic agent in a ratio of about 1:2 to about 2:1. In one embodiment, a synergistic pharmaceutical combination contains a first therapeutic agent and a second therapeutic agent in a ratio of about 1:1.

[0055] In some preferred embodiments, the second therapeutic agent is selected from the group consisting of allopurinol, arsenic trioxide, azacitidine, bortezomib, bevacizumab, capecitabine, carboplatin, celecoxib, chlorambucil, clofarabine, cytarabine, dacarbazine, daunorubicin HCl, docetaxel, doxorubicin HCl, floxuridine, gemcitabine HCl, hydroxyurea, ifosfamide, imatinib mesylate, ixabepilone, lenalidomide, megestrol acetate, methotrexate, mitotane, mitoxantrone HCl, oxaliplatin, paclitaxel, pralatrexate, romidepsin, sorafenib, streptozocin, tamoxifen citrate, topotecan HCl, tretinoin, vandetanib, vismodegib, vorinostat, and combinations thereof.

[0056] In some preferred embodiments, the second therapeutic agent comprises a small molecule multikinase inhibitor. In one embodiment, the small molecule multikinase inhibitor comprises sorafenib or regorafenib. In some preferred embodiments, the second therapeutic agent comprises a hedgehog pathway inhibitor. In one preferred embodiment, the hedgehog pathway inhibitor comprises vismodegib.

[0057] In some preferred embodiments, the second therapeutic agent includes a member of a drug class listed in Table A below.

[0058] [Table 1-1]

[0059] [Table 1-2]

[0060] In some embodiments, the second therapeutic agent comprises a drug that targets a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor. In one embodiment, the second therapeutic agent comprises a recombinant TRAIL or an agonistic antibody that activates one or more TRAIL receptors. In one embodiment, the second therapeutic agent comprises one or more antibodies or recombinant TRAIL that activate signaling through DR4 and / or DR5. In one embodiment, the second therapeutic agent comprises one or more of mapatumumab, lexatumumab, Apomab, AMG-655, LBY-135, and rhApo2L / TRAIL. In one embodiment, the second therapeutic agent comprises an active agent selected from the group consisting of camptothecin, 5-FU, capecitabine, cisplatin, doxorubicin, irinotecan, paclitaxel, cisplatin, bortezomib, BH3I-2, rituximab, radiation, triterpenoids, sorafenib, gemcitabine, HDAC inhibitors, carboplatin, T-101 (a gossypol derivative), ABT-263, ABT-737, and GX-15-070 (obatoclax), vorinostat, cetuximab, panitumumab, bevacizumab, ganitumab, interferon gamma, sorafenib, XIAP antagonists, Bcl-2 antagonists, and Smac mimetics.

[0061] II. Dose

[0062] In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof in a dose range of about 10 mg to about 2000 mg, and in certain embodiments, the weights may be based on the free base form of ONC-206. In one embodiment, the patient is an adult, and the doses are calculated accordingly. In one embodiment, the patient is a child, and the doses are calculated accordingly. In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof in a dose range of about 25 mg to about 2000 mg, and in certain embodiments, the weights may be based on the free base form of ONC-206. In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof in a dose range of about 50 mg to about 2000 mg, and in certain embodiments, the weights may be based on the free base form of ONC-206. In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof in a dose range of about 60 mg to about 2000 mg, and in certain embodiments, the weights may be based on the free base form of ONC-206. In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof in a dose range of about 10 mg to about 200 mg, about 10 mg to about 300 mg, about 10 mg to about 400 mg, about 10 mg to about 500 mg, about 10 mg to about 600 mg, about 10 mg to about 700 mg, about 10 mg to about 800 mg, about 10 mg to about 900 mg, about 10 mg to about 1000 mg, about 10 mg to about 1100 mg, about 10 mg to about 1200 mg , about 10 mg to about 1300 mg, about 10 mg to about 1400 mg, about 10 mg to about 1500 mg, about 10 mg to about 1600 mg, about 10 mg to about 1700 mg, about 10 mg to about 1800 mg, and about 10 mg to about 1900 mg, and about 10 mg to about 2000 mg.In one embodiment, the pharmaceutical composition according to the present disclosure comprises about 15 mg to about 200 mg, about 15 mg to about 300 mg, about 15 mg to about 400 mg, about 15 mg to about 500 mg, about 15 mg to about 600 mg, about 15 mg to about 700 mg, about 15 mg to about 800 mg, about 15 mg to about 900 mg, about 15 mg to about 1000 mg, about 15 mg to about 1100 mg, about 15 mg to about 1 and about 15 mg to about 1700 mg, about 15 mg to about 1800 mg, and about 15 mg to about 1900 mg, and about 15 mg to about 2000 mg. In one embodiment, the pharmaceutical composition according to the present disclosure comprises a dose of about 20 mg to about 200 mg, about 20 mg to about 300 mg, about 20 mg to about 400 mg, about 20 mg to about 500 mg, about 20 mg to about 600 mg, about 20 mg to about 700 mg, about 20 mg to about 800 mg, about 20 mg to about 900 mg, about 20 mg to about 1000 mg, about 20 mg to about 1100 mg, about 20 mg to about 1 and about 200 mg, about 20 mg to about 1300 mg, about 20 mg to about 1400 mg, about 20 mg to about 1500 mg, about 20 mg to about 1600 mg, about 20 mg to about 1700 mg, about 20 mg to about 1800 mg, and about 20 mg to about 1900 mg, and about 20 mg to about 2000 mg. In one embodiment, the pharmaceutical composition according to the present disclosure comprises a dose of about 25 mg to about 200 mg, about 25 mg to about 300 mg, about 25 mg to about 400 mg, about 25 mg to about 500 mg, about 25 mg to about 600 mg, about 25 mg to about 700 mg, about 25 mg to about 800 mg, about 25 mg to about 900 mg, about 25 mg to about 1000 mg, about 25 mg to about 1100 mg, about 25 mg to about and about 25 mg to about 1700 mg, about 25 mg to about 1800 mg, about 25 mg to about 1900 mg, and about 25 mg to about 2000 mg.In one embodiment, the pharmaceutical composition according to the present disclosure comprises a dose of about 30 mg to about 200 mg, about 30 mg to about 300 mg, about 30 mg to about 400 mg, about 30 mg to about 500 mg, about 30 mg to about 600 mg, about 30 mg to about 700 mg, about 30 mg to about 800 mg, about 30 mg to about 900 mg, about 30 mg to about 10 ...1500 mg, about 30 mg to about 2000 mg, about 30 mg to about 2500 mg, about 30 mg to about 3500 mg, about 30 mg to about 400 mg, about 30 mg to about 500 mg, about 30 mg to about 600 mg, about 30 mg to about 700 mg, about 30 mg to about 800 mg, about 30 mg to about 900 mg, about 30 mg to about 1000 mg, about 30 mg to about 2500 mg, about 30 mg to about 3500 mg, about 30 mg to about 400 mg, about 30 The present invention relates to a method for treating an acute myocardial infarction comprising administering to a patient a therapeutically effective amount of ONC-206 or a pharma- ceutical agent having a dosage level selected from the group consisting of about 30 mg to about 1100 mg, about 30 mg to about 1200 mg, about 30 mg to about 1300 mg, about 30 mg to about 1400 mg, about 30 mg to about 30 mg, about 30 mg to about 1600 mg, about 30 mg to about 1700 mg, about 30 mg to about 1800 mg, and about 30 mg to about 1900 mg. In one embodiment, the pharmaceutical composition according to the present disclosure comprises about 35 mg to about 200 mg, about 35 mg to about 300 mg, about 35 mg to about 400 mg, about 35 mg to about 500 mg, about 35 mg to about 600 mg, about 35 mg to about 700 mg, about 35 mg to about 800 mg, about 35 mg to about 900 mg, about 35 mg to about 1000 mg, about 35 mg to about 1100 mg, about 35 mg to about 1 and about 35 mg to about 1700 mg, about 35 mg to about 1800 mg, and about 35 mg to about 1900 mg, and about 35 mg to about 2000 mg of ONC-206 or a pharma- ceutically acceptable salt thereof. All values ​​are based on the free base form of ONC-206. In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof at a dosage level selected from the group consisting of about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, and about 95 mg to about 100 mg.

[0063] In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206, or a pharma- ceutically acceptable salt thereof, in a dose range of about 0.10 mg / kg to about 40 mg / kg.In one embodiment, the pharmaceutical composition according to the present disclosure comprises about 0.10 mg / Kg to about 40 mg / Kg, about 0.2 mg / Kg to about 40 mg / Kg, about 0.3 mg / Kg to about 40 mg / Kg, about 0.4 mg / Kg to about 40 mg / Kg, about 0.5 mg / Kg to about 40 mg / Kg, about 0.6 mg / Kg to about 40 mg / Kg, about 0.7 mg / Kg to about 40 mg / Kg, about 0.8 mg / Kg to about 40 mg / Kg, about 0.9 mg / Kg to about 40 mg / Kg, about 1 mg / Kg to about 40 mg / Kg, about 2 mg / Kg to about 40 mg / Kg, about 3 mg / Kg to about 40 mg / Kg, about 4 mg / Kg to about 40 mg / Kg, about 5 mg / Kg to about 40 mg / Kg, about 6 mg / Kg to about 40 mg / Kg, about 7 mg / Kg to about 40 mg / Kg, about 8 mg / Kg to about 40 mg / Kg, about 9 mg / Kg to about 40 mg / Kg, about 1 mg / Kg to about 40 mg / Kg, about 2 mg / Kg to about 40 mg / Kg, about 3 mg / Kg to about 40 mg / Kg, about 4 mg / Kg to about 40 mg / Kg, about 5 mg / Kg to about 40 mg / Kg, about 5 mg / Kg to about 40 mg / Kg, about 6 mg / Kg to about 40 mg / Kg, about 7 mg / Kg to about 40 mg / Kg, about 8 mg / Kg to about 40 mg / Kg, about 9 mg / Kg to about 40 mg / Kg, about 1 g / Kg~about 40mg / Kg, about 4mg / Kg~about 40mg / Kg, about 5mg / Kg~about 40mg / Kg, about 6mg / Kg~about 40mg / Kg, about 7mg / Kg~about 40mg / Kg, about 8mg / Kg~about 40mg / Kg, about 9mg / Kg~about 40mg / Kg, about 10mg / Kg~about 40mg / Kg, about 11mg / Kg~about 40mg / Kg, about 12mg / Kg~about 40mg / Kg, about 13mg / Kg~about 40mg / Kg, about 14mg / Kg~about 40mg / Kg, about 15mg / Kg~about 40mg / Kg, about 16mg / Kg~about 40mg / Kg, about 17mg / Kg to about 40mg / Kg, about 18mg / Kg to about 40mg / Kg, about 19mg / Kg to about 40mg / Kg, about 20mg / Kg to about 40mg / Kg, about 21mg / Kg to about 40mg / Kg, about 22mg / Kg to about 40mg / Kg, Approx. 23mg / Kg ~ approx. 40mg / Kg, approx. 24mg / Kg ~ approx. 40mg / Kg, approx. 25mg / Kg ~ approx. 40mg / Kg, approx. 26mg / Kg ~ approx. 40mg / Kg, approx. 27mg / Kg ~ approx. 40mg / Kg, approx. 28mg / Kg ~ approx. 40mg / Kg, approx. 29mg / Kg ~ The dosage level is selected from the group consisting of about 40 mg / Kg, about 30 mg / Kg to about 40 mg / Kg, about 31 mg / Kg to about 40 mg / Kg, about 32 mg / Kg to about 40 mg / Kg, about 33 mg / Kg to about 40 mg / Kg, about 34 mg / Kg to about 40 mg / Kg, about 35 mg / Kg to about 40 mg / Kg, about 36 mg / Kg to about 40 mg / Kg, about 37 mg / Kg to about 40 mg / Kg, about 38 mg / Kg to about 40 mg / Kg, and about 39 mg / Kg to about 40 mg / Kg.

[0064] In one embodiment, the pharmaceutical composition according to the present disclosure comprises about 1 mg / Kg to about 30 mg / Kg, about 2 mg / Kg to about 30 mg / Kg, about 3 mg / Kg to about 30 mg / Kg, about 4 mg / Kg to about 30 mg / Kg, about 5 mg / Kg to about 30 mg / Kg, about 6 mg / Kg to about 30 mg / Kg, about 7 mg / Kg to about 30 mg / Kg, about 8 mg / Kg to about 30 mg / Kg, about 9 mg / Kg to about 30 mg / Kg, about 10 mg / Kg to about 30 mg / Kg, about 11 mg / Kg to about 30 mg / Kg, about 12 mg / Kg to about 30 mg / Kg, about 13 mg / Kg to about 30 mg / Kg, about 14 mg / Kg to about 30 mg / Kg, about 15 mg / Kg to about 30 mg / Kg, about 16 mg / Kg to about 30 mg / Kg, about 18 mg / Kg to about 30 mg / Kg, about 19 mg / Kg to about 30 mg / Kg, about 20 mg / Kg to about 30 mg / Kg, about 21 mg / Kg to about 30 mg / Kg, about 22 mg / Kg to about 30 mg / Kg, about 23 mg / Kg to about 30 mg / Kg, about 24 mg / Kg to about 30 mg / Kg, about 25 mg / Kg to about 30 mg / Kg, about 26 mg / Kg to about 30 mg / Kg, about 27 mg / Kg to about 30 mg / Kg, about 28 mg / Kg to about 30 mg / Kg, about 29 mg / Kg to about 30 mg / Kg, about 3 The present invention further comprises ONC-206 or a pharma- ceutically acceptable salt thereof at a dosage level selected from the group consisting of about 10 mg / Kg to about 30 mg / Kg, about 17 mg / Kg to about 30 mg / Kg, about 18 mg / Kg to about 30 mg / Kg, about 19 mg / Kg to about 30 mg / Kg, about 20 mg / Kg to about 30 mg / Kg, about 21 mg / Kg to about 30 mg / Kg, about 22 mg / Kg to about 30 mg / Kg, about 23 mg / Kg to about 30 mg / Kg, about 24 mg / Kg to about 30 mg / Kg, about 25 mg / Kg to about 30 mg / Kg, about 26 mg / Kg to about 30 mg / Kg, about 27 mg / Kg to about 30 mg / Kg, about 28 mg / Kg to about 30 mg / Kg, and about 29 mg / Kg to about 30 mg / Kg.

[0065] In one embodiment, the pharmaceutical composition according to the present disclosure comprises about 1 mg / Kg to about 20 mg / Kg, about 2 mg / Kg to about 20 mg / Kg, about 3 mg / Kg to about 20 mg / Kg, about 4 mg / Kg to about 20 mg / Kg, about 5 mg / Kg to about 20 mg / Kg, about 6 mg / Kg to about 20 mg / Kg, about 7 mg / Kg to about 20 mg / Kg, about 8 mg / Kg to about 20 mg / Kg, about 9 mg / Kg to about 20 mg / Kg, about 10 mg / Kg to about 20 mg / Kg, about 11 mg / Kg to about 20 mg / Kg, about 12 mg / Kg to about 20 mg / Kg, about 14 mg / Kg to about 20 mg / Kg, about 15 mg / Kg to about 20 mg / Kg, about 16 mg / Kg to about 20 mg / Kg, about 17 mg / Kg to about 20 mg / Kg, about 18 mg / Kg to about 20 mg / Kg, about 19 mg / Kg to about 20 mg / Kg, about 20 mg / Kg to about 20 mg / Kg, about 21 mg / Kg to about 20 mg / Kg, about 22 mg / Kg to about 20 mg / Kg, about 23 mg / Kg to about 20 mg / Kg, about 24 mg / Kg to about 20 mg / Kg, about 25 mg / Kg to about 20 mg / Kg, about 26 mg / Kg to about 20 mg / Kg, about 27 mg / Kg to about 20 mg / Kg, about 28 mg / Kg to about 20 mg / Kg, about 29 mg / Kg to about 20 mg / Kg, about 3 The present invention further comprises ONC-206 or a pharma- ceutically acceptable salt thereof at a dosage level selected from the group consisting of about 10 mg / Kg to about 20 mg / Kg, about 12 mg / Kg to about 20 mg / Kg, about 13 mg / Kg to about 20 mg / Kg, about 14 mg / Kg to about 20 mg / Kg, about 15 mg / Kg to about 20 mg / Kg, about 16 mg / Kg to about 20 mg / Kg, about 17 mg / Kg to about 20 mg / Kg, about 18 mg / Kg to about 20 mg / Kg, and about 19 mg / Kg to about 20 mg / Kg.

[0066] In one embodiment, a pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof at a dose level selected from the group consisting of about 1 mg / Kg to about 10 mg / Kg, about 2 mg / Kg to about 10 mg / Kg, about 3 mg / Kg to about 10 mg / Kg, about 4 mg / Kg to about 10 mg / Kg, about 5 mg / Kg to about 10 mg / Kg, about 6 mg / Kg to about 10 mg / Kg, about 7 mg / Kg to about 10 mg / Kg, about 8 mg / Kg to about 10 mg / Kg, and about 9 mg / Kg to about 10 mg / Kg.

[0067] In one embodiment, the pharmaceutical composition according to the present disclosure has a dosage of about 12.5 mg / m 2 ~about 1500mg / m 2 In one embodiment, the pharmaceutical composition according to the present disclosure comprises ONC-206 or a pharma- ceutically acceptable salt thereof at a dose level ranging from about 15 mg / m 2 ~about 1500mg / m 2 , about 20mg / m 2 ~about 1500mg / m 2 , about 25mg / m 2 ~about 1500mg / m 2 , about 30mg / m 2 ~about 1500mg / m2 、 about 35 mg / m 2 ~ about 1500 mg / m 2 、 about 40 mg / m 2 ~ about 1500 mg / m 2 、 about 45 mg / m 2 ~ about 1500 mg / m 2 、 about 50 mg / m 2 ~ about 1500 mg / m 2 、 about 55 mg / m 2 ~ about 1500 mg / m 2 、 about 60 mg / m 2 ~ about 1500 mg / m 2 、 about 65 mg / m 2 ~ about 1500 mg / m 2 、 about 70 mg / m 2 ~ about 1500 mg / m 2 、 about 75 mg / m 2 ~ about 1500 mg / m 2 、 about 80 mg / m 2 ~ about 1500 mg / m 2 、 about 85 mg / m 2 ~ about 1500 mg / m 2 、 about 90 mg / m 2 ~ about 1500 mg / m 2 、 about 95 mg / m 2 ~ about 1500 mg / m 2 、 about 100 mg / m 2 ~ about 1500 mg / m 2 、 about 105 mg / m 2 ~ about 1500 mg / m 2 、 about 110 mg / m 2 ~ about 1500 mg / m 2 、 about 115 mg / m 2 ~ about 1500 mg / m 2 、 about 120 mg / m 2 ~ about 1500 mg / m 2 、 about 125 mg / m 2 ~ about 1500 mg / m 2 、 about 130 mg / m 2 ~ about 1500 mg / m 2 、 about 135 mg / m 2 ~ about 1500 mg / m 2 、 about 140 mg / m 2 ~ about 1500 mg / m 2 、 about 145 mg / m2 ~ about 1500 mg / m 2 、 about 150 mg / m 2 ~ about 1500 mg / m 2 、 about 155 mg / m 2 ~ about 1500 mg / m 2 、 about 160 mg / m 2 ~ about 1500 mg / m 2 、 about 165 mg / m 2 ~ about 1500 mg / m 2 、 about 170 mg / m 2 ~ about 1500 mg / m 2 、 about 175 mg / m 2 ~ about 1500 mg / m 2 、 about 180 mg / m 2 ~ about 1500 mg / m 2 、 about 185 mg / m 2 ~ about 1500 mg / m 2 、 about 190 mg / m 2 ~ about 1500 mg / m 2 、 about 195 mg / m 2 ~ about 1500 mg / m 2 、 about 200 mg / m 2 ~ about 1500 mg / m 2 、 about 205 mg / m 2 ~ about 1500 mg / m 2 、 about 210 mg / m 2 ~ about 1500 mg / m 2 、 about 215 mg / m 2 ~ about 1500 mg / m 2 、 about 220 mg / m 2 ~ about 1500 mg / m 2 、 about 225 mg / m 2 ~ about 1500 mg / m 2 、 about 230 mg / m 2 ~ about 1500 mg / m 2 、 about 235 mg / m 2 ~ about 1500 mg / m 2 、 about 240 mg / m 2 ~ about 1500 mg / m 2 、 about 245 mg / m 2 ~ about 1500 mg / m 2 、 about 250 mg / m 2 ~ about 1500 mg / m 2 、 about 255 mg / m 2~about 1500 mg / m 2 、about 260 mg / m 2 ~about 1500 mg / m 2 、about 265 mg / m 2 ~about 1500 mg / m 2 、about 270 mg / m 2 ~about 1500 mg / m 2 、about 275 mg / m 2 ~about 1500 mg / m 2 、about 280 mg / m 2 ~about 1500 mg / m 2 、about 285 mg / m 2 ~about 1500 mg / m 2 、about 290 mg / m 2 ~about 1500 mg / m 2 、about 295 mg / m 2 ~about 1500 mg / m 2 、about 300 mg / m 2 ~about 1500 mg / m 2 、about 305 mg / m 2 ~about 1500 mg / m 2 、about 310 mg / m 2 ~about 1500 mg / m 2 、about 315 mg / m 2 ~about 1500 mg / m 2 、about 320 mg / m 2 ~about 1500 mg / m 2 、about 325 mg / m 2 ~about 1500 mg / m 2 、about 330 mg / m 2 ~about 1500 mg / m 2 、about 335 mg / m 2 ~about 1500 mg / m 2 、about 340 mg / m 2 ~about 1500 mg / m 2 、about 345 mg / m 2 ~about 1500 mg / m 2 、about 350 mg / m 2 ~about 1500 mg / m 2 、about 355 mg / m 2 ~about 1500 mg / m 2 、about 360 mg / m 2 ~about 1500 mg / m 2 、about 365 mg / m 2 ~about 1500 mg / m2 , about 370 mg / m 2 to about 1500 mg / m 2 , about 375 mg / m 2 to about 1500 mg / m 2 , about 380 mg / m 2 to about 1500 mg / m 2 , about 385 mg / m 2 to about 1500 mg / m 2 , about 390 mg / m 2 to about 1500 mg / m 2 , about 395 mg / m 2 to about 1500 mg / m 2 , about 400 mg / m 2 to about 1500 mg / m 2 , about 405 mg / m 2 to about 1500 mg / m 2 , about 410 mg / m 2 to about 1500 mg / m 2 , about 415 mg / m 2 to about 1500 mg / m 2 , about 420 mg / m 2 to about 1500 mg / m 2 , about 425 mg / m 2 to about 1500 mg / m 2 , about 430 mg / m 2 to about 1500 mg / m 2 , about 435 mg / m 2 to about 1500 mg / m 2 , about 440 mg / m 2 to about 1500 mg / m 2 , about 445 mg / m 2 to about 1500 mg / m 2 , about 450 mg / m 2 to about 1500 mg / m 2 , about 455 mg / m 2 to about 1500 mg / m 2 , about 460 mg / m 2 to about 1500 mg / m 2 , about 465 mg / m 2 to about 1500 mg / m 2 , about 470 mg / m 2 to about 1500 mg / m 2 , about 475 mg / m 2 to about 1500 mg / m 2, about 480 mg / m 2 ~ about 1500 mg / m 2 , about 485 mg / m 2 ~ about 1500 mg / m 2 , about 490 mg / m 2 ~ about 1500 mg / m 2 , about 495 mg / m 2 ~ about 1500 mg / m 2 , about 500 mg / m 2 ~ about 1500 mg / m 2 , about 505 mg / m 2 ~ about 1500 mg / m 2 , about 510 mg / m 2 ~ about 1500 mg / m 2 , about 515 mg / m 2 ~ about 1500 mg / m 2 , about 520 mg / m 2 ~ about 1500 mg / m 2 , about 525 mg / m 2 ~ about 1500 mg / m 2 , about 530 mg / m 2 ~ about 1500 mg / m 2 , about 535 mg / m 2 ~ about 1500 mg / m 2 , about 540 mg / m 2 ~ about 1500 mg / m 2 , about 545 mg / m 2 ~ about 1500 mg / m 2 , about 550 mg / m 2 ~ about 1500 mg / m 2 , about 555 mg / m 2 ~ about 1500 mg / m 2 , about 560 mg / m 2 ~ about 1500 mg / m 2 , about 565 mg / m 2 ~ about 1500 mg / m 2 , about 570 mg / m 2 ~ about 1500 mg / m 2 , about 575 mg / m 2 ~ about 1500 mg / m 2 , about 580 mg / m 2 ~ about 1500 mg / m 2 , about 585 mg / m 2 ~ about 1500 mg / m 2 , about 590 mg / m2 ~ about 1500 mg / m 2 、 about 595 mg / m 2 ~ about 1500 mg / m 2 、 about 600 mg / m 2 ~ about 1500 mg / m 2 、 about 605 mg / m 2 ~ about 1500 mg / m 2 、 about 610 mg / m 2 ~ about 1500 mg / m 2 、 about 615 mg / m 2 ~ about 1500 mg / m 2 、 about 620 mg / m 2 ~ about 1500 mg / m 2 、 about 625 mg / m 2 ~ about 1500 mg / m 2 、 about 630 mg / m 2 ~ about 1500 mg / m 2 、 about 635 mg / m 2 ~ about 1500 mg / m 2 、 about 640 mg / m 2 ~ about 1500 mg / m 2 、 about 645 mg / m 2 ~ about 1500 mg / m 2 、 about 650 mg / m 2 ~ about 1500 mg / m 2 、 about 655 mg / m 2 ~ about 1500 mg / m 2 、 about 660 mg / m 2 ~ about 1500 mg / m 2 、 about 665 mg / m 2 ~ about 1500 mg / m 2 、 about 670 mg / m 2 ~ about 1500 mg / m 2 、 about 675 mg / m 2 ~ about 1500 mg / m 2 、 about 680 mg / m 2 ~ about 1500 mg / m 2 、 about 685 mg / m 2 ~ about 1500 mg / m 2 、 about 690 mg / m 2 ~ about 1500 mg / m 2 、 about 695 mg / m 2 ~ about 1500 mg / m 2 、 about 700 mg / m 2~about 1500 mg / m 2 、about 705 mg / m 2 ~about 1500 mg / m 2 、about 710 mg / m 2 ~about 1500 mg / m 2 、about 715 mg / m 2 ~about 1500 mg / m 2 、about 720 mg / m 2 ~about 1500 mg / m 2 、about 725 mg / m 2 ~about 1500 mg / m 2 、about 730 mg / m 2 ~about 1500 mg / m 2 、about 735 mg / m 2 ~about 1500 mg / m 2 、about 740 mg / m 2 ~about 1500 mg / m 2 、about 745 mg / m 2 ~about 1500 mg / m 2 、about 750 mg / m 2 ~about 1500 mg / m 2 、about 755 mg / m 2 ~about 1500 mg / m 2 、about 760 mg / m 2 ~about 1500 mg / m 2 、about 765 mg / m 2 ~about 1500 mg / m 2 、about 770 mg / m 2 ~about 1500 mg / m 2 、about 775 mg / m 2 ~about 1500 mg / m 2 、about 780 mg / m 2 ~about 1500 mg / m 2 、about 785 mg / m 2 ~about 1500 mg / m 2 、about 790 mg / m 2 ~about 1500 mg / m 2 、about 795 mg / m 2 ~about 1500 mg / m 2 、about 800 mg / m 2 ~about 1500 mg / m 2 、about 805 mg / m 2 ~about 1500 mg / m 2 、about 810 mg / m 2~about 1500 mg / m 2 、about 815 mg / m 2 ~about 1500 mg / m 2 、about 820 mg / m 2 ~about 1500 mg / m 2 、about 825 mg / m 2 ~about 1500 mg / m 2 、about 830 mg / m 2 ~about 1500 mg / m 2 、about 835 mg / m 2 ~about 1500 mg / m 2 、about 840 mg / m 2 ~about 1500 mg / m 2 、about 845 mg / m 2 ~about 1500 mg / m 2 、about 850 mg / m 2 ~about 1500 mg / m 2 、about 855 mg / m 2 ~about 1500 mg / m 2 、about 860 mg / m 2 ~about 1500 mg / m 2 、about 865 mg / m 2 ~about 1500 mg / m 2 、about 870 mg / m 2 ~about 1500 mg / m 2 、about 875 mg / m 2 ~about 1500 mg / m 2 、about 880 mg / m 2 ~about 1500 mg / m 2 、about 885 mg / m 2 ~about 1500 mg / m 2 、about 890 mg / m 2 ~about 1500 mg / m 2 、about 895 mg / m 2 ~about 1500 mg / m 2 、about 900 mg / m 2 ~about 1500 mg / m 2 、about 905 mg / m 2 ~about 1500 mg / m 2 、about 910 mg / m 2 ~about 1500 mg / m 2 、about 915 mg / m 2 ~about 1500 mg / m 2 、about 920 mg / m 2 ~about 1500 mg / m2 , about 925 mg / m 2 ~ about 1500 mg / m 2 , about 930 mg / m 2 ~ about 1500 mg / m 2 , about 935 mg / m 2 ~ about 1500 mg / m 2 , about 940 mg / m 2 ~ about 1500 mg / m 2 , about 945 mg / m 2 ~ about 1500 mg / m 2 , about 950 mg / m 2 ~ about 1500 mg / m 2 , about 955 mg / m 2 ~ about 1500 mg / m 2 , about 960 mg / m 2 ~ about 1500 mg / m 2 , about 965 mg / m 2 ~ about 1500 mg / m 2 , about 970 mg / m 2 ~ about 1500 mg / m 2 , about 975 mg / m 2 ~ about 1500 mg / m 2 , about 980 mg / m 2 ~ about 1500 mg / m 2 , about 985 mg / m 2 ~ about 1500 mg / m 2 , about 990 mg / m 2 ~ about 1500 mg / m 2 , about 995 mg / m 2 ~ about 1500 mg / m 2 , about 1000 mg / m 2 ~ about 1500 mg / m 2 , about 1005 mg / m 2 ~ about 1500 mg / m 2 , about 1010 mg / m 2 ~ about 1500 mg / m 2 , about 1015 mg / m 2 ~ about 1500 mg / m 2 , about 1020 mg / m 2 ~ about 1500 mg / m 2 , about 1025 mg / m 2 ~ about 1500 mg / m 2 , about 1030 mg / m 2 ~ about 1500 mg / m2 , about 1035 mg / m 2 ~ about 1500 mg / m 2 , about 1040 mg / m 2 ~ about 1500 mg / m 2 , about 1045 mg / m 2 ~ about 1500 mg / m 2 , about 1050 mg / m 2 ~ about 1500 mg / m 2 , about 1055 mg / m 2 ~ about 1500 mg / m 2 , about 1060 mg / m 2 ~ about 1500 mg / m 2 , about 1065 mg / m 2 ~ about 1500 mg / m 2 , about 1070 mg / m 2 ~ about 1500 mg / m 2 , about 1075 mg / m 2 ~ about 1500 mg / m 2 , about 1080 mg / m 2 ~ about 1500 mg / m 2 , about 1085 mg / m 2 ~ about 1500 mg / m 2 , about 1090 mg / m 2 ~ about 1500 mg / m 2 , about 1095 mg / m 2 ~ about 1500 mg / m 2 , about 1100 mg / m 2 ~ about 1500 mg / m 2 , about 1105 mg / m 2 ~ about 1500 mg / m 2 , about 1110 mg / m 2 ~ about 1500 mg / m 2 , about 1115 mg / m 2 ~ about 1500 mg / m 2 , about 1120 mg / m 2 ~ about 1500 mg / m 2 , about 1125 mg / m 2 ~ about 1500 mg / m 2 , about 1130 mg / m 2 ~ about 1500 mg / m 2 , about 1135 mg / m 2 ~ about 1500 mg / m 2 , about 1140 mg / m 2~about 1500 mg / m 2 、about 1145 mg / m 2 ~about 1500 mg / m 2 、about 1150 mg / m 2 ~about 1500 mg / m 2 、about 1155 mg / m 2 ~about 1500 mg / m 2 、about 1160 mg / m 2 ~about 1500 mg / m 2 、about 1165 mg / m 2 ~about 1500 mg / m 2 、about 1170 mg / m 2 ~about 1500 mg / m 2 、about 1175 mg / m 2 ~about 1500 mg / m 2 、about 1180 mg / m 2 ~about 1500 mg / m 2 、about 1185 mg / m 2 ~about 1500 mg / m 2 、about 1190 mg / m 2 ~about 1500 mg / m 2 、about 1195 mg / m 2 ~about 1500 mg / m 2 、about 1200 mg / m 2 ~about 1500 mg / m 2 、about 1205 mg / m 2 ~about 1500 mg / m 2 、about 1210 mg / m 2 ~about 1500 mg / m 2 、about 1215 mg / m 2 ~about 1500 mg / m 2 、about 1220 mg / m 2 ~about 1500 mg / m 2 、about 1225 mg / m 2 ~about 1500 mg / m 2 、about 1230 mg / m 2 ~about 1500 mg / m 2 、about 1235 mg / m 2 ~about 1500 mg / m 2 、about 1240 mg / m 2 ~about 1500 mg / m 2 、about 1245 mg / m 2 ~about 1500 mg / m 2 、about 1250 mg / m2 ~ about 1500 mg / m 2 and about 1255 mg / m 2 ~ about 1500 mg / m 2 and about 1260 mg / m 2 ~ about 1500 mg / m 2 and about 1265 mg / m 2 ~ about 1500 mg / m 2 and about 1270 mg / m 2 ~ about 1500 mg / m 2 and about 1275 mg / m 2 ~ about 1500 mg / m 2 and about 1280 mg / m 2 ~ about 1500 mg / m 2 and about 1285 mg / m 2 ~ about 1500 mg / m 2 and about 1290 mg / m 2 ~ about 1500 mg / m 2 and about 1295 mg / m 2 ~ about 1500 mg / m 2 and about 1300 mg / m 2 ~ about 1500 mg / m 2 and about 1305 mg / m 2 ~ about 1500 mg / m 2 and about 1310 mg / m 2 ~ about 1500 mg / m 2 and about 1315 mg / m 2 ~ about 1500 mg / m 2 and about 1320 mg / m 2 ~ about 1500 mg / m 2 and about 1325 mg / m 2 ~ about 1500 mg / m 2 and about 1330 mg / m 2 ~ about 1500 mg / m 2 and about 1335 mg / m 2 ~ about 1500 mg / m 2 and about 1340 mg / m 2 ~ about 1500 mg / m 2 and about 1345 mg / m 2 ~ about 1500 mg / m 2 and about 1350 mg / m 2 ~ about 1500 mg / m 2 and about 1355 mg / m 2 ~ about 1500 mg / m 2, about 1360 mg / m 2 ~ about 1500 mg / m 2 , about 1365 mg / m 2 ~ about 1500 mg / m 2 , about 1370 mg / m 2 ~ about 1500 mg / m 2 , about 1375 mg / m 2 ~ about 1500 mg / m 2 , about 1380 mg / m 2 ~ about 1500 mg / m 2 , about 1385 mg / m 2 ~ about 1500 mg / m 2 , about 1390 mg / m 2 ~ about 1500 mg / m 2 , about 1395 mg / m 2 ~ about 1500 mg / m 2 , about 1400 mg / m 2 ~ about 1500 mg / m 2 , about 1405 mg / m 2 ~ about 1500 mg / m 2 , about 1410 mg / m 2 ~ about 1500 mg / m 2 , about 1415 mg / m 2 ~ about 1500 mg / m 2 , about 1420 mg / m 2 ~ about 1500 mg / m 2 , about 1425 mg / m 2 ~ about 1500 mg / m 2 , about 1430 mg / m 2 ~ about 1500 mg / m 2 , about 1435 mg / m 2 ~ about 1500 mg / m 2 , about 1440 mg / m 2 ~ about 1500 mg / m 2 , about 1445 mg / m 2 ~ about 1500 mg / m 2 , about 1450 mg / m 2 ~ about 1500 mg / m 2 , about 1455 mg / m 2 ~ about 1500 mg / m 2 , about 1460 mg / m 2 ~ about 1500 mg / m 2 , about 1465 mg / m 2 ~ about 1500 mg / m2 , about 1470mg / m 2 ~about 1500mg / m 2 , about 1475mg / m 2 ~about 1500mg / m 2 , about 1480mg / m 2 ~about 1500mg / m 2 , about 1485mg / m 2 ~about 1500mg / m 2 , about 1490mg / m 2 ~about 1500mg / m 2 , and about 1495 mg / m 2 ~about 1500mg / m 2 and ONC-206 or a pharma- ceutically acceptable salt thereof at a dose level selected from the group consisting of:

[0068] III.Dosage form

[0069] Suitable pharmaceutical compositions for use with the disclosed methods can be formulated into any dosage form that can be administered to a patient. In one embodiment, the pharmaceutical composition is in the form of an oral dosage unit or a parenteral dosage unit. In one embodiment, the pharmaceutical composition is in the form of an oral dosage unit. In some embodiments, the oral dosage unit is fractionated into several smaller doses that are administered to the subject over a period of time to reduce the toxicity of the administered therapeutic agent. In some embodiments, the oral dosage unit is administered by a tablet or capsule that includes a controlled release formulation that may include multiple particles, granules, pellets, mini tablets, or tablets. In one embodiment, the pharmaceutical composition is in the form of a parenteral dosage unit. In one embodiment, the pharmaceutical composition is in the form of a parenteral dosage unit, the parenteral dosage unit being selected from the group consisting of intravenous (IV), subcutaneous (SC), and intramuscular (M), rectal (PR), and transdermal dosage units. In one embodiment, the pharmaceutical composition is in a dosage form selected from the group consisting of a sterile solution, a suspension, a suppository, a tablet, and a capsule. In one embodiment, the composition is an oral dosage form selected from the group consisting of tablets, caplets, capsules, lozenges, syrups, liquids, suspensions, and elixirs, each of which includes a packaging configuration that allows for reconstitution. In one embodiment, the composition is administered to the subject in an oral dosage form selected from the group consisting of tablets, hard shell capsules, soft gelatin capsules, beads, granules, aggregates, powders, gels, solids, and semi-solids. In one embodiment, the composition is an oral dosage form that includes a compound of the present disclosure suspended in a liquid such as water or a sports drink such as Gatorade®. The compound of the present disclosure or a salt thereof may be provided in a powder form for mixing with a liquid prior to administration to a patient in need thereof.

[0070] In some embodiments, suitable forms of pharmaceutical compositions for use in the methods of the present disclosure include dermatological compositions suitable for topical administration to the skin. In some such embodiments, the dermatological compositions include a cosmetically or pharma- ceutically acceptable medium. In some embodiments, the dermatological compositions for topical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. In some embodiments, conventional pharmaceutical carriers, aqueous, powder or oil bases, thickeners, skin enhancers, and the like may be necessary or desirable and can therefore be used. Examples of suitable enhancers include ethers (e.g., diethylene glycol monoethyl ether (commercially available as Transcutol®) and diethylene glycol monomethyl ether), surfactants (e.g., sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, poloxamers (231, 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Pat. No. 4,783,450)), alcohols (e.g., ethanol, propanol, octanol, benzyl alcohol, and the like), sugars, and the like. These include, but are not limited to, alcohols or polyols (e.g., mannitol, erythritol, lactitol, maltitol, sorbitol, xylitol, etc.), polyethylene glycol and its esters (e.g., polyethylene glycol monolaurate), amides and other nitrogen compounds (e.g., urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine), terkenes, alkanones, and organic acids (especially citric acid and succinic acid). Sulfoxides such as Azone® and DMSO and CIOMSO can also be used, but are less preferred.

[0071] In some embodiments, the pharmaceutical composition of the present disclosure is in a dosage form selected from the group consisting of a sustained release form, a controlled release form, a delayed release form, and a responsive release form.

[0072] IV. How to use

[0073] The compositions and methods of the present disclosure are useful in the treatment of many disease states, including cancer (e.g., colon cancer, brain cancer, and glioblastoma). In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as ocular melanoma, desmoplastic round cell tumor, chondrosarcoma, leptomeningeal disease, diffuse large B-cell lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendix cancer, astrocytoma, and atypical teratoid / rhabdoid tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as basal cell carcinoma, basal cell nevus syndrome, Gorlin nevus syndrome, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, and malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, and spinal tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as carcinoid tumors, cancer of unknown primary, central nervous system atypical teratoid / rhabdoid tumors, leptomeningeal disease, central nervous system embryonal tumors, central nervous system lymphoma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, and cutaneous T-cell lymphoma, including but not limited to Sézary syndrome and mycosis fungoides (MF). In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as central nervous system embryonal tumors, endometrial cancer, epithelial blastoma, epithelioma, esophageal cancer, Ewing's sarcoma family of tumors, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, and eye cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as gallbladder cancer, gastric cancer (stomach cancer), gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, and gliomas. In one embodiment, the compositions and methods of the present disclosure are used to treat cancers selected from the group consisting of hairy cell leukemia, head and neck cancer, hepatocellular carcinoma (liver cancer), histiocytosis, Hodgkin's lymphoma, and hypopharyngeal carcinoma. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as Kaposi's sarcoma and kidney cancer (renal cell carcinoma).In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lung cancer, non-Hodgkin's lymphoma, and primary central nervous system lymphoma. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), malignant fibrous histiocytoma of bone and osteosarcoma, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell cervical cancer of unknown primary, multiple endocrine neoplasia syndrome, oral cavity cancer, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, and myeloproliferative disorders. In one embodiment, the compositions and methods of the present disclosure are used to treat cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as nasal and paranasal sinus cancer, nasopharyngeal cancer, and neuroblastoma. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer, and ovarian low malignant potential tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat diseases such as pancreatic cancer, papilloma, paranasal and paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pleuropulmonary blastoma, gestational breast cancer, primary central nervous system lymphoma, and prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat cancers selected from the group consisting of rectal cancer, renal cell carcinoma (kidney cancer), renal pelvis and ureter cancer, airway cancer involving the NUT gene on chromosome 15, retinoblastoma, and rhabdomyosarcoma. In one embodiment, the compositions and methods of the present disclosure are used to treat aggressive prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat intermediate-grade prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat indolent prostate cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat castration-resistant prostate cancer.

[0074] In one embodiment, the use or method relates to the treatment of one or more adult central nervous system (CNS) tumors, which are diseases in which abnormal cells form in the tissues of the brain and / or spinal cord.

[0075] In one embodiment, the use or method relates to the treatment of one or more pediatric central nervous system (CNS) tumors, which are diseases in which abnormal cells form in the tissues of the brain and / or spinal cord of patients aged from about 0 to about 18 years.

[0076] Tumors that start in another part of the body and spread to the brain are called metastatic brain tumors. There are different types of brain and spinal tumors for which the present compounds, alone or in combination with additional therapeutic agents, may be therapeutically effective: astrocytic tumors, oligodendroglial tumors, mixed gliomas, epithelial tumors, medulloblastomas, pineal parenchymal tumors, meningeal tumors, germ cell tumors, and craniopharyngiomas (grade I). Certain genetic syndromes may increase the risk of central nervous system tumors, and the present disclosure contemplates screening for them. Certain factors affect prognosis (chance of recovery) and treatment options, and the present disclosure contemplates screening for them as well.

[0077] In one embodiment, the compositions and methods of the present disclosure are used to treat proliferative skin disorders. In one embodiment, the compositions and methods of the present disclosure are used to treat proliferative skin disorders, and the proliferative skin disorder is psoriasis. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, eye cancer, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical carcinoma of unknown primary, and supratentorial primitive neuroectodermal tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, and gestational trophoblastic tumor. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of carcinoma of unknown primary site, cancer of unknown primary site, rare cancers of childhood, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, and uterine sarcoma. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of vaginal cancer and vulvar cancer. In one embodiment, the compositions and methods of the present disclosure are used to treat a cancer selected from the group consisting of Wilms' tumor and female cancer.

[0078] In some embodiments, the compositions and methods of the present disclosure are used as first-line therapy (sometimes referred to as primary therapy). In some embodiments, the compositions and methods of the present disclosure are used as second-line therapy. In some embodiments, the compositions and methods of the present disclosure are used as third-line therapy. In some embodiments, the compositions and methods of the present disclosure are used as rescue therapy. As used herein, the term "rescue therapy" refers to a therapeutic agent that may be taken in any regimen after a subject's initial treatment regimen has failed or after the subject's condition has not responded to the initial treatment. In some embodiments, the compositions and methods of the present disclosure are used as rescue therapy. In one embodiment of rescue therapy, the compositions of the present disclosure are used as rescue agents to counter the effects of the initial treatment. In one embodiment of rescue therapy, the compositions of the present disclosure are used as rescue agents administered to subjects who have developed resistance to standard or initial treatment. In some embodiments, the compositions and methods of the present disclosure are used as neoadjuvant therapy. In one embodiment, neoadjuvant therapy includes administering one or more of the therapeutic agents of the present disclosure to a subject prior to the main or first-line treatment. In one embodiment, neoadjuvant therapy reduces the size or extent of the cancer being treated before administering a primary or first-line treatment to the subject being treated. In some embodiments, the compositions and methods of the present disclosure are used as adjuvant therapy. In one embodiment, adjuvant therapy includes administering to a subject one or more therapeutic agents of the present disclosure, including one or more therapeutic agents that modify the effect of other therapeutic agents already administered to the subject, or that are administered simultaneously to the subject, or that are subsequently administered to the subject.

[0079] In some embodiments, the compositions and methods of the present disclosure exhibit a reduced likelihood of drug-drug interactions. In some embodiments, the compositions and methods of the present disclosure, ONC-206 and / or pharma- ceutically acceptable salts thereof are removed from the patient's body before they can interact with another pharma- ceutical active agent or therapy.

[0080] In some embodiments, the compositions and methods of the present disclosure, ONC-206 and / or its pharma- ceutically acceptable salts, exhibit a level of tonicity that facilitates co-administration with other agents.

[0081] The usefulness of the disclosed methods and compositions is not limited to any particular animal species. In one embodiment, the subject treated according to the disclosed methods and using the disclosed compositions can be a mammal or a non-mammal. In one embodiment, the mammalian subject can be any mammal, including but not limited to a human, a non-human primate, a rodent (e.g., a mouse, a rat, or a guinea pig), a domesticated pet (e.g., a cat or a dog), a horse, a cow, a pig, a sheep, a goat, or a rabbit. In one embodiment, the non-mammalian subject can be any non-mammal, including but not limited to a bird, such as a duck, a goose, a chicken, or a turkey. In one embodiment, the subject can be of either sex and of any age. The compositions and methods can also be used to prevent cancer. The compositions and methods can also be used to stimulate the immune system.

[0082] The usefulness of the disclosed method and composition is not limited to any particular age of subject.In one embodiment, the subject treated according to the disclosed method and composition can be under 5, 12, 16 or 18 years old (pediatric), over 18 years old, over 20 years old, over 25 years old, over 30 years old, over 35 years old, over 40 years old, over 45 years old, over 50 years old, over 55 years old, over 60 years old, or over 65 years old.In one embodiment, the subject treated using the disclosed method and composition can be under 50 years old, under 55 years old, under 60 years old, or under 65 years old.

[0083] In one embodiment, the subject has received at least one prior therapeutic agent. In one embodiment, the subject has received at least two, at least three, or at least four prior therapeutic agents. In one embodiment, the prior therapeutic agent is ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, cytarabine, cisplatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, or lenalidomide.

[0084] In one embodiment, the subject has been treated with one or more forms of radiation, hi one embodiment, the subject has been treated with one or more forms of surgery.

[0085] In some embodiments of the methods of treating cancer, the cancer no longer responds to treatment with ibrutinib, bortezomib, carfilzomib, temozolomide, bevacizumab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, cytarabine, cisplatin, rituximab, 5-fluorouracil, oxaliplatin, leucovorin, lenalidomide, radiation, surgery, or a combination thereof.

[0086] In some embodiments, the compositions and methods of the disclosure have a dose-response relationship in cancer cells that differs from the dose-response relationship of the same compositions and methods in normal cells.

[0087] In some embodiments, the compositions and methods of the present disclosure are useful for treating cancer in a subject. In one embodiment, the compositions and methods of the present disclosure are useful for treating cancer in a human subject. In one embodiment, the method of treatment comprises administering to a subject in need of such treatment (i) a first therapeutic agent comprising a compound comprising ONC-206 or a pharmaceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent, wherein the first and second therapeutic agents are administered simultaneously or sequentially. The second therapeutic agent can be any suitable therapeutic agent, including any of the pharmaceutically active agents disclosed in the present application. In one embodiment, the pharmaceutically acceptable salt of ONC-206 comprises the dihydrochloride salt.

[0088] It is understood that ONC-206 as the dihydrochloride salt or an alternative di-salt thereof apparent from the teachings of this disclosure may be substituted for ONC-206 in any of the compositions or dosing regimens described herein.

[0089] In some embodiments, the methods of treatment comprise administering to a subject in need of such treatment a pharma- ceutical effective amount of ONC-206, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier.

[0090] In some embodiments, the therapeutic methods of the disclosure comprise administering to a subject in need of such treatment a synergistic pharmaceutical combination, the synergistic pharmaceutical combination comprising (i) a first therapeutic agent comprising ONC-206 or a pharmaceutically acceptable salt thereof, and (ii) a second therapeutic agent. In one embodiment, the therapeutic method comprises administering to a subject in need of such treatment a therapeutically synergistically effective amount of a first therapeutic agent comprising ONC-206 or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent, either simultaneously or sequentially. In one embodiment, the therapeutic method comprises administering to a subject in need of such treatment an effective amount of a first therapeutic agent comprising ONC-206 or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a second therapeutic agent, the combination providing a synergistic effect in the in vivo treatment of a cancer susceptible to the combination, the first therapeutic agent and the second therapeutic agent being administered simultaneously or sequentially. In one embodiment, a method of treatment comprises administering to a subject in need of such treatment an effective amount of a first therapeutic agent comprising ONC-206, or a pharma- ceutically acceptable salt thereof, in combination with an effective amount of a second therapeutic agent, wherein the combination provides a synergistic effect in the in vivo treatment of minimal residual disease susceptible to the combination, and wherein the first and second therapeutic agents are administered simultaneously or sequentially.

[0091] In some embodiments, the second drug may be administered before or prior to ONC-206.

[0092] In one embodiment, the therapeutic method of the present disclosure targets the cancer, wherein the cancer is selected from the group consisting of a solid tumor, a liquid tumor, a lymphoma, a leukemia, or a myeloma.

[0093] In one embodiment, the therapeutic method of the present disclosure targets a solid tumor, the solid tumor being selected from the group consisting of cervical cancer, endometrial cancer, extracranial germ cell tumor, extragonadal germ cell tumor, germ cell tumor, gestational trophoblastic tumor, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer, and ovarian low-grade malignant potential tumor, penile cancer, prostate cancer, gestational breast cancer, high-grade prostate cancer, intermediate-grade prostate cancer, low-grade prostate cancer, castration-resistant prostate cancer, breast cancer, cholangiocarcinoma, extrahepatic bile duct cancer, gallbladder cancer, hepatocellular carcinoma (liver cancer), kidney cancer (renal cell carcinoma), liver cancer, renal cell carcinoma (kidney cancer), renal pelvis and ureter, basal cell carcinoma, basal cell nevus syndrome, Gorlin nevus syndrome, melanoma, Merkel cell carcinoma, papilloma, multiple endocrine neoplasia syndrome, pancreatic cancer, parathyroid cancer, ocular melanoma, eye cancer. , retinoblastoma, malignant fibrous histiocytoma, Ewing's sarcoma family of tumors, desmoplastic round cell tumor, chondrosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, spinal cord tumors, leptomeningeal disease, central nervous system embryonal tumors, chordoma, central nervous system embryonal tumors, ependymoblastoma, ependymoma, neuroblastoma, moderately differentiated pineal parenchymal tumor, pineoblastoma, adrenal cortical carcinoma, bone cancer, osteosarcoma, malignant fibrous histiocytoma and osteosarcoma of bone, osteosarcoma and Malignant fibrous histiocytoma of bone, carcinoid tumor, cancer of unknown primary site, bronchial tumor, lung cancer, pleuropulmonary blastoma, airway cancer involving the NUT gene on chromosome 15, astrocytoma, atypical teratoid / rhabdoid tumor, central nervous system atypical teratoid / rhabdoid tumor, craniopharyngioma, glioma, brain cancer, medulloblastoma, medulloepithelioma, supratentorial primitive neuroectodermal tumor, pituitary tumor, gastric cancer cancer) (stomach cancer), gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), bladder cancer, anal or rectal cancer, appendix cancer, esophageal cancer, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, metastatic squamous cell neck cancer of unknown primary, oral cavity cancer, nasal and paranasal sinus cancer, nasopharyngeal cancer, oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, paranasal and paranasal sinus cancer, pharyngeal cancer, head and neck cancer, and mesothelioma.

[0094] In one embodiment, the therapeutic method of the present disclosure targets lymphoma, wherein the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Sezary syndrome, mycosis fungoides (MF), histiocytosis, Burkitt's lymphoma, and central nervous system lymphoma, non-Hodgkin's lymphoma, and primary central nervous system lymphoma, Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, mycosis fungoides, primary central nervous system lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma.

[0095] In one embodiment, the therapeutic method of the present disclosure targets non-Hodgkin's lymphoma (NHL), wherein the non-Hodgkin's lymphoma is selected from the group consisting of mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, lymphoplasmacytic NHL, Waldenstrom's macroglobulinemia, and cutaneous lymphoma.

[0096] In one embodiment, the therapeutic method of the present disclosure targets leukemia, wherein the leukemia is selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloproliferative disorder, hairy cell leukemia, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and Langerhans cell histiocytosis.

[0097] In one embodiment, the therapeutic method of the present disclosure targets acute leukemia, wherein the acute leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, or myeloproliferative disorder.

[0098] In one embodiment, the therapeutic method of the disclosure targets myeloma, wherein the myeloma is selected from the group consisting of IgA myeloma, IgG myeloma, IgM myeloma, IgD myeloma, IgE myeloma, light chain myeloma, non-secretory myeloma, multiple myeloma / plasma cell neoplasms, multiple myeloma, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, myeloproliferative disorders.

[0099] In one embodiment, the therapeutic method of the present disclosure targets cancer, and the cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal or rectal cancer, appendix cancer, astrocytoma, and atypical teratoid / rhabdoid tumor.

[0100] In one embodiment, the therapeutic method of the present disclosure targets the cancer, wherein the cancer is selected from the group consisting of basal cell carcinoma, basal cell nevus syndrome, Gorlin nevus syndrome, bile duct cancer, bladder cancer, bone cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, and spinal tumor.

[0101] In one embodiment, the therapeutic methods of the present disclosure target cancer, wherein the cancer is selected from the group consisting of carcinoid tumor, cancer of unknown primary, central nervous system atypical teratoid / rhabdoid tumor, central nervous system embryonal tumor, central nervous system lymphoma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, and cutaneous T-cell lymphoma (including, but not limited to, Sézary syndrome and mycosis fungoides).

[0102] In one embodiment, the therapeutic method of the present disclosure targets cancer, and the cancer is selected from the group consisting of central nervous system embryonal tumors, endometrial cancer, epithelioma, epithelioma, esophageal cancer, Ewing's sarcoma family of tumors, desmoplastic round cell tumor, chondrosarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, and eye cancer (including intraocular melanoma and retinoblastoma).

[0103] In one embodiment, the therapeutic method of the present disclosure targets cancer, and the cancer is selected from the group consisting of gallbladder cancer, gastric cancer (stomach cancer), gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, and glioma.

[0104] In one embodiment, the therapeutic method of the present disclosure targets cancer, and the cancer is selected from the group consisting of hairy cell leukemia, head and neck cancer, hepatocellular carcinoma (liver cancer), histiocytosis, Hodgkin's lymphoma, and hypopharyngeal carcinoma.

[0105] In one embodiment, the therapeutic methods of the present disclosure target the cancer, and the cancer is selected from the group consisting of Kaposi's sarcoma and kidney cancer (renal cell carcinoma).

[0106] 2. The method of claim 1, wherein the cancer is selected from the group consisting of Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lung cancer (including non-small cell lung cancer and small cell lung cancer), non-Hodgkin's lymphoma, and primary central nervous system lymphoma.

[0107] In one embodiment, the therapeutic method of the disclosure targets cancer, wherein the cancer is selected from the group consisting of Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), malignant fibrous histiocytoma of bone and osteosarcoma, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell neck carcinoma of unknown primary, multiple endocrine neoplasia syndrome, oral cavity cancer, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, and myeloproliferative disorders.

[0108] In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of nasal and paranasal sinus cancer, nasopharyngeal cancer, and neuroblastoma.

[0109] In one embodiment, the therapeutic methods of the present disclosure are useful for treating neuroendocrine tumors, including one or more of adrenal carcinoma, adrenal cortical carcinoma, desmoplastic small round cell tumor (DSRTC), small cell lung cancer, neuroendocrine prostate cancer, carcinoid tumor, Merkel cell carcinoma, pancreatic neuroendocrine tumor, paraganglioma, and pheochromocytoma. In one aspect, the tumor can be one or more of pheochromocytoma, paraganglioma, adrenocortical carcinoma, DSRTC, small cell lung cancer, and neuroendocrine prostate cancer.

[0110] In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, ovarian germ cell tumor, ovarian epithelial cancer, and ovarian low malignant potential tumor.

[0111] In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of pancreatic cancer, papilloma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, moderately differentiated pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, pleuropulmonary blastoma, gestational breast cancer, primary central nervous system lymphoma, and prostate cancer.

[0112] In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, the cancer being selected from the group consisting of rectal cancer, renal cell carcinoma (kidney cancer), renal pelvis and ureter cancer, respiratory tract cancer involving the NUT gene on chromosome 15, retinoblastoma, and rhabdomyosarcoma.

[0113] In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell cervical carcinoma of unknown primary, and supratentorial primitive neuroectodermal tumor.

[0114] In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, and gestational trophoblastic neoplasia.

[0115] In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of carcinoma of unknown primary site, cancer of unknown primary site, rare cancer of childhood, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, and uterine sarcoma. In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of vaginal cancer and vulvar cancer. In one embodiment, the therapeutic methods of the present disclosure are useful for treating cancer, wherein the cancer is selected from the group consisting of Wilms' tumor and female cancer.

[0116] In some embodiments, treating cancer comprises preventing tumor growth in a cancer subject. In some embodiments, treating cancer comprises preventing the formation of cancer metastases in a cancer subject. In some embodiments, treating cancer comprises targeted treatment of minimal residual disease in a cancer subject known to have or at risk of having minimal residual disease in cancer.

[0117] This may be indicated after primary tumor treatment by surgery and / or after chemotherapy (e.g., radiotherapy) is initiated or determined to be effective. Disseminated tumor cells may be dormant and often cannot be attacked by chemotherapy (radiotherapy). Patients treated in this way are seemingly cured, which is also described as "minimal residual disease". Nevertheless, dormant tumor cells may form metastases when they become metastatic cells due to proliferation stimulation even after a longer dormancy.

[0118] As used herein, "minimal residual disease" refers to a small number of cancer cells remaining in a subject when the subject is in remission (not showing symptoms or signs of the disease) during or after treatment. The methods described herein are preferably applied to any form of the diseases listed herein, including adult and pediatric forms of these diseases.

[0119] In one embodiment, the therapeutic methods of the present disclosure are useful for treating autoimmune diseases, including, but not limited to, alopecia areata, antiphospholipid, autoimmune hepatitis, celiac disease, type 1 diabetes, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, inflammatory myopathy, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, and vitiligo.

[0120] In one embodiment, the therapeutic methods of the present disclosure are useful for treating metabolic disorders including diabetes, B12, and folate vitamin deficiencies, chemotherapy drugs and medications used to treat HIV, poisons that cause peripheral nerve damage, cancers that cause peripheral neuropathy, and autoimmune and inflammatory disorders of the peripheral nervous system such as amyotrophic lateral sclerosis (Lou Gehrig's disease) based on a variety of causes such as paraneoplastic syndromes, alcohol abuse, chronic kidney disease, injuries that cause compression of nerves and other lesions, infections (e.g., Lyme disease), Guillain-Barré syndrome, connective tissue diseases, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, certain inflammatory conditions (e.g., sarcoidosis), celiac disease, genetic diseases (e.g., Charcot-Marie-Tooth syndrome), Friedreich's ataxia, and / or idiopathic diseases.

[0121] In one embodiment, the therapeutic methods of the present disclosure are useful for treating autoimmune and inflammatory disorders with ocular conditions, including, but not limited to, ocular cicatricial pemphigoid, Mooren's corneal ulcer, various forms of uveitis, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, relapsing polychondritis, Wegener's granulomatosis, scleroderma, Behcet's disease, Reiter's disease, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and ankylosing spondylitis, retinitis pigmentosa, macular degeneration, keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, peripheral corneal ulcer, and less common entities such as choroiditis, retinal vasculitis, episcleral segments, retinal detachment, and / or macular edema.

[0122] In one embodiment, the therapeutic methods of the present disclosure are useful for treating acute allograft rejection in transplant patients. In one embodiment, the therapeutic methods of the present disclosure are useful for treating ischemic stroke. In one embodiment, the therapeutic methods of the present disclosure are useful for treating inflammatory diseases, including, but not limited to, arthritis, psoriasis, asthma, and colitis.

[0123] In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject in the method once a day. In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject according to an infrequent dosing regimen (e.g., administered once a week or less frequently). In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject according to a frequent dosing regimen (e.g., administered once a week or more). In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject once a week. In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject once every four weeks. In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject twice a week. In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject once every two weeks. In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject once every three weeks. In some embodiments, the pharmaceutical composition according to the disclosure is administered to the subject in a repeating cycle of once a week, once every two weeks, once every three weeks, once every four weeks, or a combination thereof.

[0124] In one embodiment, the method of treatment comprises administering to a subject in need of such treatment (i) a first therapeutic agent comprising a compound comprising ONC-206 or a pharma- ceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent, wherein the first and second therapeutic agents are administered simultaneously or sequentially, and further comprises assaying expression of endoplasmic reticulum (ER) stress response genes in the biological sample. In some embodiments, the ER stress response genes are selected from the group including, but not limited to, DRD2, ClpP, tyrosine hydroxylase, c-myc, n-myc, DR5, dopamine or its metabolites or catecholamines, C / EBP homologous protein (CHOP), activating transcription factor 3 (ATF3), and both CHOP and ATF3. The biological sample may be a tumor, peripheral blood mononuclear cell, or skin biopsy. The biological sample may be obtained before, during, or after drug administration. In some embodiments, the treatment method further comprises adjusting the dose of ONC-206 to achieve about 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%, or greater than 600% induction of one or more ER stress genes. In some embodiments, the method of treatment further comprises adjusting the dose of ONC-206 to achieve about 50% to about 100%, about 100% to about 150%, about 150% to about 200%, about 200% to about 250%, about 250% to about 300%, about 300% to about 350%, about 350% to about 400%, about 400% to about 450%, about 450% to about 500%, about 500% to about 550%, about 550% to about 600%, or greater than 600% induction of ER stress genes. In some embodiments, the method of treatment further comprises adjusting the dose of ONC-206 to achieve about 50% to about 100%, about 100% to about 200%, about 200% to about 300%, about 300% to about 400%, about 400% to about 500%, about 500% to about 600%, or greater than 600% induction of ER stress genes.

[0125] In one embodiment, the method of treatment comprises administering to a subject in need of such treatment (i) a first therapeutic agent comprising a compound comprising ONC-206 or a pharma- ceutically acceptable salt thereof, in combination with (ii) a second therapeutic agent, wherein the first and second therapeutic agents are administered simultaneously or sequentially, and further comprises assaying the expression of proteasome activity in a biological sample. In some embodiments, the proteasome activity can be chymothricin-like, trypsin-like, and / or caspase-like activity. In some embodiments, the biological sample can be a tumor, peripheral blood mononuclear cells, or skin cells. The biological sample can be obtained before, during, or after drug administration. In some embodiments, the method of treatment further comprises adjusting the dose to achieve about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% inhibition of proteasome activity. In some embodiments, the method of treatment further comprises adjusting the dose to achieve at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% inhibition of proteasome activity. In some embodiments, the method of treatment further includes adjusting the dose to achieve about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or greater than 90% inhibition of proteasome activity.

[0126] In certain aspects, the disclosure provides a method of treatment comprising administering to a subject in need of such treatment a combination of a first therapeutic agent comprising ONC-206 and a second therapeutic agent, the method comprising: (i) administering to a subject a first therapeutic agent comprising ONC-206 or a pharma- ceutically acceptable salt thereof (e.g., a di- or tri-salt); (ii) waiting until a predetermined waiting period has elapsed after administration of the first therapeutic agent to the subject and / or until resolution or resolution of the adverse event; (iii) administering a second therapeutic agent to the subject, the predetermined waiting time being selected to provide a delayed therapeutic effect of the first therapeutic agent without increasing the risk of possible combined toxic effects of the first and second therapeutic agents. In some embodiments of the method of treatment, the predetermined waiting time is determined based on the clearance rate of ONC-206 or a pharma- ceutically acceptable salt thereof. In some embodiments of the method of treatment, the predetermined waiting time is determined by a quantitative assessment of renal function and renal parameters. In some embodiments of the method of treatment, the predetermined waiting time is determined by an assay for determining renal function, the assay being selected from the group consisting of serum levels of ONC-206 or a pharma- ceutically acceptable salt thereof, clearance rate of ONC-206 or a pharma- ceutically acceptable salt thereof, and 24-hour urinary clearance of ONC-206 or a pharma- ceutically acceptable salt thereof, or a metabolite thereof.

[0127] In one embodiment of the method of treatment, the predetermined waiting time is substantially equal to the time required for systemic clearance of ONC-206 or a pharma- ceutically acceptable salt thereof from the subject's body. In one embodiment of the method of treatment, the predetermined waiting time is substantially equal to the time required for renal clearance of ONC-206 or a pharma- ceutically acceptable salt thereof from the subject's body. In one embodiment of the method of treatment, the predetermined waiting time is substantially equal to the time required for hepatic clearance of ONC-206 or a pharma- ceutically acceptable salt thereof from the subject's body. In one embodiment of the method of treatment, the predetermined waiting time is about 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In other embodiments, the waiting time is 1 day. In some embodiments, the waiting time is until the Cmax of ONC-206 has passed. In other embodiments, the waiting time is after the majority of the adverse events have resolved or are past the resolution phase. In one embodiment of the method of treatment, the predetermined waiting time is about 2 days. In one embodiment of the method of treatment, the predetermined waiting time is about 3 days. In one embodiment of the method of treatment, the predetermined waiting time is about 4 days. In one embodiment of the method of treatment, the predetermined waiting time is about 5 days. In one embodiment of the method of treatment, the predetermined waiting time is about 6 days. In one embodiment of the method of treatment, the predetermined waiting time is about 7 days. In one embodiment of the method of treatment, the predetermined waiting time is about 1-7 days. In one embodiment of the method of treatment, the predetermined waiting time is about 1-6 days. In one embodiment of the method of treatment, the predetermined waiting time is about 1-5 days. In one embodiment of the method of treatment, the predetermined waiting time is about 1-4 days. In one embodiment of the method of treatment, the predetermined waiting time is about 1-3 days. In one embodiment of the method of treatment, the predetermined waiting time is about 1-2 days. In some embodiments, the waiting time is up to 3 weeks. The foregoing are considered to be "treatment periods".

[0128] In one embodiment, the administration of ONC-206 is daily. In one embodiment, the administration of ONC-206 is once every two days. In one embodiment, the administration of ONC-206 is every third day. In one embodiment, the administration of ONC-206 is every fourth day. In one embodiment, the administration of ONC-206 is every fifth day. In one embodiment, the administration of ONC-206 is every sixth day. In one embodiment, the administration of ONC-206 is weekly.

[0129] If the order of administration is reversed, the timing of administration of ONC-206 may be after the Cmax of the first administered drug has passed, in some embodiments, administration of ONC-206 may be after most or substantially all of the first administered drug has been cleared from the body, or after the toxic effects of the first administered drug have resolved, or after the resolution phase.

[0130] In some embodiments, the method of treatment further comprises monitoring the level of ONC-206, its pharmaceutically acceptable salt, or its metabolite in the subject using pharmacokinetic profiling. In some such embodiments, monitoring the level of ONC-206, its pharmaceutically acceptable salt, or its metabolite in the subject using pharmacokinetic profiling comprises constructing a pharmacokinetic profile of the subject's ONC-206, its pharmaceutically acceptable salt, or its metabolite using the concentrations of ONC-206, its pharmaceutically acceptable salt, or its metabolite in at least two samples obtained from the subject at a time suitable for constructing the pharmacokinetic profile. In some embodiments of the method comprising monitoring the level of ONC-206, its pharmaceutically acceptable salt, or its metabolite in the subject using pharmacokinetic profiling, the at least two samples are taken from the subject at the point of care or point of use by sampling or self-sampling on a point-of-care or point-of-use device or on a matrix suitable for storage of the at least two samples prior to quantification in the laboratory. In some embodiments of the method of treatment, each of the point-of-care or point-of-use devices is capable of quantifying ONC-206, a pharma- ceutically acceptable salt thereof, or a metabolite thereof. In some embodiments of the method including monitoring the level of ONC-206, a pharma- ceutically acceptable salt thereof, or a metabolite thereof in a subject, one or more samples are taken from the subject at the point-of-care or point-of-use by a biopsy device for analysis at the point-of-care or point-of-use device or for storage prior to analysis by a laboratory. In some embodiments of the method, the biopsy is taken 3 to 8 hours after administration of ONC-206, a pharma- ceutically acceptable salt thereof, or a metabolite thereof to the subject. In some embodiments of the method, the biopsy is taken 3 to 24 hours after administration of ONC-206, a pharma- ceutically acceptable salt thereof, or a metabolite thereof to the subject.In some embodiments of the method, the biopsy is performed 8 to 24 hours after administration of ONC-206, a pharma- ceutically acceptable salt, or a metabolite thereof to the subject. In some embodiments of the method, the biopsy is performed 2 days after administration of ONC-206, a pharma- ceutically acceptable salt, or a metabolite thereof to the subject. In some embodiments of the method, the biopsy is performed 3 days after administration of ONC-206, a pharma- ceutically acceptable salt, or a metabolite thereof to the subject. In some embodiments of the method, the biopsy is performed 4 days after administration of ONC-206, a pharma- ceutically acceptable salt, or a metabolite thereof to the subject. In some embodiments of the method, the biopsy is performed 1 to 7 days after administration of ONC-206, a pharma- ceutically acceptable salt, or a metabolite thereof to the subject.

[0131] In some embodiments of the method of treatment, the pharmacokinetic profile comprises pharmacokinetic parameters suitable for guiding dosing of ONC-206 or a pharmaceutically acceptable salt thereof to the subject being treated. In some embodiments of the method of treatment, the maximum concentration ("Cmax") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) following administration to the subject ranges from about 10 ng / mL to about 4000 ng / mL over a treatment period other than a daily dosing regimen, such as once a week. In some embodiments, Cmax is less than 4000 ng / mL and greater than 10 ng / mL over a treatment period other than a daily dosing regimen, such as once a week.

[0132] In some embodiments, the maximum concentration ("Cmax") of the first therapeutic agent in the subject's blood (whole blood, plasma, or serum) following administration to the subject is from about 10 ng / mL, about 20 ng / mL, about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 110 ng / mL, about 120 ng / mL, about 130 ng / mL, about 140 ng / mL, about 150 ng / mL, about 160 ng / mL, about 170 ng / mL, about 180 ng / mL ~, approximately 190ng / mL~, approximately 200ng / mL~, approximately 210ng / mL~, approximately 220ng / mL~, approximately 230ng / mL~, approximately 240ng / mL~, approximately 250ng / mL~, approximately 260ng / mL~, approximately 270ng / mL~, approximately 280ng / mL~, approximately 290ng / mL~, approximately 3 00ng / mL~, approx. 310ng / mL~, approx. 320ng / mL~, approx. 330ng / mL~, approx. 340ng / mL~, approx. 350ng / mL~, approx. 360ng / mL~, approx. 370ng / mL~, approx. 380ng / mL~, approx. 390ng / mL~, approx. 400ng / mL~, approx. 410ng / mL~, approx. 420ng / mL~, approx. 430ng / mL~, approx. 440ng / mL~, approx. 450ng / mL~, approx. 460ng / mL~, approx. 470ng / mL~, approx. 480ng / mL~, approx. 490ng / mL~, approx. 500ng / mL~, approx. 510ng / mL~, approx. 520ng / mL~ , approximately 530ng / mL~, approximately 540ng / mL~, approximately 550ng / mL~, approximately 560ng / mL~, approximately 570ng / mL~, approximately 580ng / mL~, approximately 590ng / mL~, approximately 600ng / mL~, approximately 610ng / mL~, approximately 620ng / mL~, approximately 630ng / mL~, approximately 64 0ng / mL~, approx. 650ng / mL~, approx. 660ng / mL~, approx. 670ng / mL~, approx. 680ng / mL~, approx. 690ng / mL~, approx. 700ng / mL~, approx. 710ng / mL~, approx. 720ng / mL~, approx. 730ng / mL~, approx. 740ng / mL~, approx. 750ng / mL~, approximately 760ng / mL~, approximately 770ng / mL~, approximately 780ng / mL~, approximately 790ng / mL~, approximately 800ng / mL~, approximately 810ng / mL~, approximately 820ng / mL~, approximately 830ng / mL~, approximately 840ng / mL~, approximately 850ng / mL~, approximately 860ng / mL~,About 870 ng / mL~, about 880 ng / mL~, about 890 ng / mL~, about 900 ng / mL~, about 910 ng / mL~, about 920 ng / mL~, about 930 ng / mL~, about 940 ng / mL~, about 950 ng / mL~, about 960 ng / mL~, about 970 ng / mL~, about 980 ng / mL~, about 990 ng / mL~, about 1000 ng / mL~, about 1010 ng / mL~, about 1020 ng / mL~, about 1030 ng / mL~, about 1040 ng / mL~, about 1050 ng / mL~, about 1060 ng / mL~, about 1070 ng / mL~, about 1080 ng / mL~, about 1090 ng / mL~, about 1100 ng / mL~, about 1110 ng / mL~, about 1120 ng / mL~, about 1130 ng / mL~, about 1140 ng / mL~, about 1150 ng / mL~, about 1160 ng / mL~, about 1170 ng / mL~, about 1180 ng / mL~, about 1190 ng / mL~, about 1200 ng / mL~, about 1210 ng / mL~, about 1220 ng / mL~, about 1230 ng / mL~, about 1240 ng / mL~, about 1250 ng / mL~, about 1260 ng / mL~, about 1270 ng / mL~, about 1280 ng / mL~, about 1290 ng / mL~, about 1300 ng / mL~, about 1310 ng / mL~, about 1320 ng / mL~, about 1330 ng / mL~, about 1340 ng / mL~, about 1350 ng / mL~, about 1360 ng / mL~, about 1370 ng / mL~, about 1380 ng / mL~, about 1390 ng / mL~, about 1400 ng / mL~, about 1410 ng / mL~, about 1420 ng / mL~, about 1430 ng / mL~, about 1440 ng / mL~, about 1450 ng / mL~, about 1460 ng / mL~, about 1470 ng / mL~, about 1480 ng / mL~, about 1490 ng / mL~, about 1500 ng / mL~, about 1510 ng / mL~, about 1520 ng / mL~, about 1530 ng / mL~, about 1540 ng / mL~, about 1550 ng / mL~, about 1560 ng / mL~, about 1570 ng / mL~, about 1580 ng / mL~, about 1590 ng / mL~, about 1600 ng / mL~, about 1610 ng / mL~, about 1620 ng / mL~, about 1630 ng / mL~, about 1640 ng / mL~, about 1650 ng / mL~, about 1660 ng / mL~, about 1670 ng / mL~, about 1680 ng / mL~, about 1690 ng / mL~, about 1700 ng / mL~,Approximately 1710 ng / mL, approximately 1720 ng / mL, approximately 1730 ng / mL, approximately 1740 ng / mL, approximately 1750 ng / mL, approximately 1760 ng / mL, approximately 1770 ng / mL, approximately 1780 ng / mL, approximately 1790 ng / mL, approximately 1800 ng / mL, approximately 1810 ng / mL, approximately 1820 ng / mL, approximately 1830 ng / mL, approximately 1840 ng / mL, approximately 1850 ng / mL, approximately 1860 ng / mL, approximately 1870 ng / mL, approximately 1880 ng / mL, approximately 1890 ng / mL, approximately 1900 ng / mL, approximately 1910 ng / mL, approximately 1920 ng / mL, approximately 1930 ng / mL, approximately 1940 ng / mL, approximately 1950 ng / mL, approximately 1960 ng / mL, approximately 1970 ng / mL, approximately 1980 ng / mL, approximately 1990 ng / mL, approximately 2000 ng / mL, approximately 2010 ng / mL, approximately 2020 ng / mL, approximately 2030 ng / mL, approximately 2040 ng / mL, approximately 2050 ng / mL, approximately 2060 ng / mL, approximately 2070 ng / mL, approximately 2080 ng / mL, approximately 2090 ng / mL, approximately 2100 ng / mL, approximately 2110 ng / mL, approximately 2120 ng / mL, approximately 2130 ng / mL, approximately 2140 ng / mL, approximately 2150 ng / mL, approximately 2160 ng / mL, approximately 2170 ng / mL, approximately 2180 ng / mL, approximately 2190 ng / mL, approximately 2200 ng / mL, approximately 2210 ng / mL, approximately 2220 ng / mL, approximately 2230 ng / mL, approximately 2240 ng / mL, approximately 2250 ng / mL, approximately 2260 ng / mL, approximately 2270 ng / mL, approximately 2280 ng / mL, approximately 2290 ng / mL, approximately 2300 ng / mL, approximately 2310 ng / mL, approximately 2320 ng / mL, approximately 2330 ng / mL, approximately 2340 ng / mL, approximately 2350 ng / mL, approximately 2360 ng / mL, approximately 2370 ng / mL, approximately 2380 ng / mL, approximately 2390 ng / mL, approximately 2400 ng / mL, approximately 2410 ng / mL, approximately 2420 ng / mL, approximately 2430 ng / mL, approximately 2440 ng / mL, approximately 2450 ng / mL, approximately 2460 ng / mL, approximately 2470 ng / mL, approximately 2480 ng / mL, approximately 2490 ng / mL, approximately 2500 ng / mL, approximately 2510 ng / mL, approximately 2520 ng / mL, approximately 2530 ng / mLApproximately 2540 ng / mL, approximately 2550 ng / mL, approximately 2560 ng / mL, approximately 2570 ng / mL, approximately 2580 ng / mL, approximately 2590 ng / mL, approximately 2600 ng / mL, approximately 2610 ng / mL, approximately 2620 ng / mL, approximately 2630 ng / mL, approximately 2640 ng / mL, approximately 2650 ng / mL, approximately 2660 ng / mL, approximately 2670 ng / mL, approximately 2680 ng / mL, approximately 2690 ng / mL, approximately 2700 ng / mL, approximately 2710 ng / mL, approximately 2720 ng / mL, approximately 2730 ng / mL, approximately 2740 ng / mL, approximately 2750 ng / mL, approximately 2760 ng / mL, approximately 2770 ng / mL, approximately 2780 ng / mL, approximately 2790 ng / mL, approximately 2800 ng / mL, approximately 2810 ng / mL, approximately 2820 ng / mL, approximately 2830 ng / mL, approximately 2840 ng / mL, approximately 2850 ng / mL, approximately 2860 ng / mL, approximately 2870 ng / mL, approximately 2880 ng / mL, approximately 2890 ng / mL, approximately 2900 ng / mL, approximately 2910 ng / mL, approximately 2920 ng / mL, approximately 2930 ng / mL, approximately 2940 ng / mL, approximately 2950 ng / mL, approximately 2960 ng / mL, approximately 2970 ng / mL, approximately 2980 ng / mL, approximately 2990 ng / mL, approximately 3000 ng / mL, approximately 3010 ng / mL, approximately 3020 ng / mL, approximately 3030 ng / mL, approximately 3040 ng / mL, approximately 3050 ng / mL, approximately 3060 ng / mL, approximately 3070 ng / mL, approximately 3080 ng / mL, approximately 3090 ng / mL, approximately 3100 ng / mL, approximately 3110 ng / mL, approximately 3120 ng / mL, approximately 3130 ng / mL, approximately 3140 ng / mL, approximately 3150 ng / mL, approximately 3160 ng / mL, approximately 3170 ng / mL, approximately 3180 ng / mL, approximately 3190 ng / mL, approximately 3200 ng / mL, approximately 3210 ng / mL, approximately 3220 ng / mL, approximately 3230 ng / mL, approximately 3240 ng / mL, approximately 3250 ng / mL, approximately 3260 ng / mL, approximately 3270 ng / mL, approximately 3280 ng / mL, approximately 3290 ng / mL, approximately 3300 ng / mL, approximately 3310 ng / mL, approximately 3320 ng / mL, approximately 3330 ng / mL, approximately 3340 ng / mL, approximately 3350 ng / mL, approximately 3360 ng / mLApprox. 3370ng / mL~, Approx. 3380ng / mL~, Approx. 3390ng / mL~, Approx. 3400ng / mL~, Approx. 3410ng / mL~, Approx. 3420ng / mL~, Approx. 3430ng / mL~, Approx. 3440ng / mL~, Approx. 34 50ng / mL~, approx. 3460ng / mL~, approx. 3470ng / mL~, approx. 3480ng / mL~, approx. 3490ng / mL~, approx. 3500ng / mL~, approx. 3510ng / mL~, approx. 3520ng / mL~, approx. 3530ng / mL~, approx. 3540ng / mL~, approx. 3550ng / mL~, approx. 3560ng / mL~, approx. 3570ng / mL~, approx. 3580ng / mL~, approx. 3590ng / mL~, approx. 3600ng / mL~, approx. 3610ng / mL~ , about 3620ng / mL~, about 3630ng / mL~, about 3640ng / mL~, about 3650ng / mL~, about 3660ng / mL~, about 3670ng / mL~, about 3680ng / mL~, about 3690ng / mL~, about 37 00ng / mL~, approx. 3710ng / mL~, approx. 3720ng / mL~, approx. 3730ng / mL~, approx. 3740ng / mL~, approx. 3750ng / mL~, approx. 3760ng / mL~, approx. 3770ng / mL~, approx. 3780ng / mL~, approx. 3790ng / mL~, approx. 3800ng / mL~, approx. 3810ng / mL~, approx. 3820ng / mL~, approx. 3830ng / mL~, approx. 3840ng / mL~, approx. 3850ng / mL~, approx. 3860ng / mL~ , about 3870ng / mL, about 3880ng / mL, about 3890ng / mL, about 3900ng / mL, about 3910ng / mL, about 3920ng / mL, about 3930ng / mL, about 3940ng / mL, about 3950ng / mL, about 3960ng / mL, about 3970ng / mL, about 3980ng / mL, about 3990ng / mL, and about 4000ng / mL.

[0133] In some embodiments of the method, total drug exposure over time, measured as the area under the curve ("AUC") of a plot of the concentration of drug in the subject's blood (whole blood, plasma, or serum) after administration of the drug versus time after administration of the drug, ranges from about 10 ng-hr / ml to about 20,000 ng-hr / ml. In some embodiments, the AUC is less than 20,000 ng-hr / ml, 19,000 ng-hr / ml, 18,000 ng-hr / ml, 17,000 ng-hr / ml, 16,000 ng-hr / ml, 15,000 ng-hr / ml, 14,000 ng-hr / ml, 13,000 ng-hr / ml, 12,000 ng-hr / ml, 11,000 ng-hr / ml, 10,000 ng-hr / ml, 9,000 ng-hr / ml, 8,000 ng-hr / ml, 7,000 ng-hr / ml, 6,000 ng-hr / ml, 5,000 ng-hr / ml, 4,000 ng-hr / ml, or less than 20,000 ng-hr / ml. h / ml, 3000ngh / ml, 2000ngh / ml, 1000ngh / ml, 900ngh / ml, 800ngh / ml, 700ngh / ml, 600ngh / ml, 500ngh / ml, 400ngh / ml, 300ngh / ml, 200ngh / ml, 100ngh / ml, 90ngh / ml, 80ngh / ml, 70ngh / ml, 60ngh / ml, 50ngh / ml, 40ngh / ml, 30ngh / ml, 20ngh / ml, and 10ngh / ml.

[0134] In another aspect, the disclosure provides a therapeutic method or use of a composition for treating a disease condition, comprising administering to a subject in need of such treatment a combination of a first therapeutic agent and a second therapeutic agent, the method comprising: (i) administering to a subject a first therapeutic agent comprising ONC-206 or a pharma- ceutically acceptable salt thereof; (ii) monitoring the levels of ONC-206, or a pharma- ceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling; (iii) administering a second therapeutic agent conditional on the level of the first therapeutic agent in the subject. In some embodiments of the method, the monitoring step comprises constructing a pharmacokinetic profile of ONC-206, or a pharmaceutically acceptable salt thereof, or a metabolite thereof, for the subject using the concentrations of ONC-206, or a pharmaceutically acceptable salt thereof, or a metabolite thereof, in at least two samples obtained from the subject at a time suitable for constructing the pharmacokinetic profile. In some embodiments of the method, the at least two samples are taken at the point of care or point of use by sampling or self-sampling on a point of care or point of use device or on a matrix suitable for storing the at least two samples, prior to quantification of ONC-206, or a pharmaceutically acceptable salt thereof, or a metabolite by a laboratory. In some embodiments of the method, each point of care or point of use device is capable of quantifying ONC-206, or a pharmaceutically acceptable salt thereof, or a metabolite. In some embodiments of the method, the pharmacokinetic profile comprises pharmacokinetic parameters suitable for guiding dosing of ONC-206 or a pharmaceutically acceptable salt thereof in the subject. In some embodiments of the method, the at least two samples comprise 2-12 samples. In some embodiments of the method, the at least two samples are taken over a period of up to 8 hours, up to 24 hours, up to 48 hours, or up to 72 hours. In some embodiments of the method, the pharmacokinetic parameters comprise at least one parameter selected from the group consisting of AUC, AUCinf, Tmax, Cmax, time over threshold, steady-state concentration, absorption rate, clearance rate, distribution rate, terminal phase T1 / 2, or a parameter obtained from a non-compartmental pharmacokinetic (PK) analysis or a compartmental PK analysis, including a physiological model-based compartmental PK analysis. In some embodiments of the method, the treatment method further comprises generating a report comprising the pharmacokinetic profile of the subject. In some embodiments of the method, the report comprises a recommendation regarding dosing based on the pharmacokinetic profile of the subject.In some embodiments of the method, a reduction in the dose of ONC-206 or a pharmaceutically acceptable salt thereof is shown to reduce the risk of toxicity based on one or more pharmacokinetic parameters. ... the time above a threshold, the threshold being one or more of the drug concentration above which toxicity occurs, or AUC, AUCinf, mean residence time (MRT), an exponential function defining the pharmacokinetic profile, volume of distribution at steady state (Vss), volume of distribution at terminal phase (Vz), or a combination of groups of pharmacokinetic variables to adequately describe the pharmacokinetic profile. In some embodiments of the method, a dose adjustment of ONC-206 or a pharmaceutically acceptable salt thereof is shown to increase efficacy based on one or more pharmacokinetic parameters. In some embodiments of the method, the dose increase of ONC-206 or a pharmaceutically acceptable salt thereof is indicated based on one or more of AUC, AUCinf, MRT, an exponential function defining the pharmacokinetic profile, a steady-state volume of distribution (Vss), a volume of distribution at the terminal phase (Vz), or a combination of groups of pharmacokinetic variables to adequately describe the pharmacokinetic profile. In some embodiments of the method, the dose of ONC-206 or a pharmaceutically acceptable salt thereof is adjusted to within 5%-25% of a desired target value. In some embodiments of the method, each of the at least two samples is applied to a point-of-care or point-of-use device for determining the concentration of ONC-206, or a pharmaceutically acceptable salt thereof, or a metabolite thereof, the point-of-care or point-of-use device comprising a lateral flow strip having a structure and composition such that application of one or more of the at least two samples to the lateral flow strip causes a portion of the drug in the sample to bind to a component of the lateral flow strip, thereby generating a detectable signal proportional to the concentration of the drug in the applied sample. In some embodiments of the method, the at least two samples are applied to a matrix suitable for storage of the at least two samples prior to quantification by the laboratory.In some embodiments of the method, at least two samples are stored as dried blood spots. In some embodiments of the method, the drug concentration is measured by ELISA, LC MS MS, LC UV, or LCMS. In some embodiments of the method, the pharmacokinetic parameters include at least one of steady-state concentration, absorption rate, and terminal phase T1 / 2. In some embodiments of the method, at least one of the at least two samples is whole blood.

[0135] V. Multimodal Treatment Methods

[0136] In one aspect, the present disclosure is directed to a multimodal method of treatment in which administration of ONC-206 or a pharma- ceutically acceptable salt thereof to a subject in need of such treatment is supplemented by administration of other treatment modalities. In one embodiment, the multimodal method of treatment of the present disclosure comprises administering to the subject a pharmaceutical composition comprising ONC-206 or a pharma- ceutically acceptable salt thereof in conjunction with radiation therapy or after it has been determined that radiation therapy has been ineffective. In one embodiment, the multimodal method of treatment of the present disclosure comprises administering to the subject a pharmaceutical composition comprising ONC-206 or a pharma- ceutically acceptable salt thereof in conjunction with radiation therapy, the pharmaceutical composition comprising ONC-206 or a pharma- ceutically acceptable salt thereof and radiation therapy being administered simultaneously or sequentially in any order. In one embodiment, the multimodal method of treatment of the present disclosure comprises administering to the subject a pharmaceutical composition comprising ONC-206 or a pharma- ceutically acceptable salt thereof in conjunction with radiation therapy in a sequential manner. In one embodiment, the multimodal treatment method comprises administering to a subject in need of such treatment a pharmaceutical composition comprising ONC-206 or a pharma- ceutically acceptable salt thereof, simultaneously with radiation therapy. In one embodiment, the multimodal treatment method of the present disclosure is used for the treatment of cancer. In one embodiment, the multimodal treatment method comprises administering to a cancer subject in need of such treatment a pharmaceutical composition comprising ONC-206 or a pharma- ceutically acceptable salt thereof, and irradiating the cancer cells with a radiation beam. In one embodiment, the multimodal treatment method uses conformal radiation therapy (CRT) techniques to deliver a prescribed dose volume histogram (DVH) to the cancer subject. In one embodiment, the multimodal treatment method uses intensity modulated radiation therapy (IMRT) techniques to deliver radiation to the cancer cells. In one embodiment, the multimodal treatment method uses techniques to compensate for tumor motion in the subject during treatment (e.g., doses of radiation must be administered to a breast tumor that moves with the patient's breathing). In one embodiment, the multimodal treatment method uses four-dimensional computed tomography (4D CT) scanning technology to adjust the delivered radiation field to compensate for tumor motion over the respiratory cycle.

[0137] Any suitable type of radiation can be used with the multimodal treatment methods of the present disclosure, including fractionation, IMRT (intensity modulated radiation therapy), gamma knife, proton therapy, and brachytherapy. Radiation therapy and ONC-206 or a pharma- ceutically acceptable salt thereof can be used to treat brain tumors, such as glioblastoma, or brain metastases from lung cancer, neuroendocrine tumors, or endometrial cancer. The multimodal treatment methods of the present disclosure can be used to treat lung cancer, pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostate cancer, gynecological malignancies, and lymphoma. Gamma knife is frequently used to treat brain metastases. In one embodiment, the multimodal treatment methods of the present disclosure include the use of proton therapy to treat cancer, including brain tumors, prostate cancer, and any tumors in close proximity to vital organs, where minimizing toxicity to nearby normal tissues is critical.

[0138] In one embodiment, the multimodal therapeutic method of the present disclosure eliminates minimal residual disease without adding to the toxicity resulting from treatment with ONC-206 or a pharma- ceutically acceptable salt thereof, hi one embodiment, the multimodal therapeutic method of the present disclosure improves prognosis in the subject being treated and / or reduces adverse side effects associated with a disease state or condition.

[0139] VI. Derivatives, Analogues, and Salts of ONC-206 and Related Compounds In one aspect, the disclosure provides analogs and related salts of ONC-206, and processes for making them. Those skilled in the art will appreciate that the same general principles and concepts described above in conjunction with ONC-206 and its salts, including those principles and concepts related to the present methods and pharmaceutical compositions, apply equally to derivatives and analogs and salts of ONC-206 and its salts.

[0140] In one embodiment, a compound related to ONC-206 has the structure of compound (10):

[0141] [ka]

[0142] wherein R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, and heterocyclic radicals. In another embodiment, a compound related to ONC-206 has the structure of compound (10), wherein R1 and R2 independently represent H, C 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, C 1-4 Benzylpiperazine, and C 1-4 alkylthienyl, 1-4 Alkyl, C 1-4 Alkylphenyl, C 1-4 Alkyl phenyl ketones, and C 1-4 The benzylpiperazine is optionally 1-4 It is substituted with alkyl, hydroxyl, or halo. In yet another embodiment, a compound related to ONC-206 has the structure of compound (10), where R1 and R2 are independently selected from the group consisting of H, CH3, CH2Ph, CH2-((2-Cl)-Ph), CH2-(2-thienyl), CH2CH2Ph, CH2CH2(4-N-benzyl-piperazine), CH2-(2,4-diF-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph. In some embodiments, when R1 represents CH2Ph, R2 does not represent CH2-((2-CH3)-Ph).

[0143] As shown in Schemes 1 and 2, compound (10) can be synthesized starting from methyl 1-R1-4-oxo-3-piperidinecarboxylate (6) or by reacting compound (12) with compound (6).

[0144] [ka]

[0145] Scheme 1 shows the synthesis of compound (10) starting from compound (6). In one embodiment, compound (6) was converted to 4-amino-3-pyridine carboxylic acid ester methyl ester (7) (or methyl 4-amino-1-R1-1,2,5,6-tetrahydro-3-pyridine carboxylate) by reaction with ammonia as shown in Scheme 3. In one embodiment, compound (7) (or 4-amino-3-pyridine carboxylic acid ester methyl ester (7)) was treated with 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole (8) to produce compound (9), where R2X was alkylated, where R2 is as defined above and X is a halogen or an equivalent leaving group, to produce compound (10) with different values ​​for the R2 substituent.

[0146] [ka]

[0147] Scheme 2 illustrates the synthesis of compound (10) starting from compound (6) and compound (12). In one embodiment, compound (12) is prepared from compound (8), as shown in Scheme 4. In one embodiment, compound (12) is treated with compound (6) to generate compound (10) having a different value for the R2 substituent.

[0148] [ka]

[0149] Scheme 3 shows the synthesis of compound (10) starting from compound (11). In one embodiment, as shown in Scheme 5, compound (11) having a nitrogen protecting group (P) at the N atom at ring position 7 was first deprotected and then acylated with R1X, where R1 is as defined above and X is a halogen or an equivalent leaving group, to generate compound (10) having different values ​​for the R1 substituent. In some embodiments, compound (10) can be prepared as a salt (e.g., a di-TFA salt or a di-hydrochloride salt). In some embodiments, compound (10) can be prepared as a di-hydrochloride salt.

[0150] [Table 2] EXAMPLES

[0151] It should be understood that the description and specific examples provided below are for illustrative purposes only and are not intended to limit the scope of the present disclosure. The following examples are intended to illustrate the disclosed embodiments and should not be construed as limitations thereon. Additional compounds other than those described below can be prepared using the following reaction schemes described above or suitable variations or modifications thereof.

[0152] Example 1. Synthesis of 2-chlorobenzylamino-2-imidazoline hydroiodide

[0153] To a stirred solution of 2-methylthio-2-imidazoline hydroiodide (244 mg, 1.00 mMol) in dry dioxane (2.0 mL) was added 2-chlorobenzylamine (141 mg, 1.0 mMol). The reaction mixture was stirred at 70 C under argon atmosphere for 90 min. The solution was cooled to room temperature, filtered through a sintered funnel, washed with cold dioxane (2 mL) and dried under vacuum. Compound 4·HI (R2=2-chlorobenzyl) was obtained (242 mg, 72%) as a white solid and used without further purification.

[0154] Example 2. Synthesis of 2-chlorobenzylamino-2-imidazoline

[0155] To a stirred solution of 2-chlorobenzylamino-2-imidazoline hydroiodide (242 mg, 0.72 mMol) in water (3 mL) was added 1.0 N sodium hydroxide (2 mL) at 7° C. The reaction mixture was stirred at 7° C. for 30 min under argon. Methylene chloride (5 mL) was then added and the mixture was stirred for an additional 5 min. The reaction mixture was extracted with methylene chloride (2×2.5 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The resulting free base (150 mg, 100%) was obtained as a viscous liquid and used in the next reaction without further purification. MS (ESI) 210 (M+H).

[0156] Example 3. Synthesis of methyl-1-benzyl 4-oxo-3-piperidinecarboxylate (compound (6)).

[0157] To stirred methyl-1-benzyl 4-oxo-3-piperidinecarboxylate hydrochloride (5.7 g, 20 mMol) in ethyl acetate (50 mL) was added triethylamine (6 mL) at 7° C. The reaction mixture was stirred at 7° C. for 30 min under argon atmosphere. The reaction mixture was extracted with ethyl acetate (2×50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The free base residue (5, R1=benzyl) obtained as a viscous oil was used in the next reaction without further purification. MS (ESI) 248 (M+H).

[0158] Example 4. Synthesis of ONC202 (compound (14))

[0159] To a solution of 2-chlorobenzylamino-2-imidazoline (150 mg, 0.72 mMol), methyl 1-benzyl 4-oxo-3-piperidinecarboxylate (5, R1=benzyl) (195 mg, 0.79 mMol) in 1-butanol (2 mL) was added PPTS (10 mg) and the mixture was stirred at room temperature for 48 h. The reaction mixture was then refluxed at 125°C-130°C for 2 h. The solvent was removed under vacuum, extracted with ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (2 x 10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude free base was purified by RP HPLC (10%-40% acetonitrile / water) to give the TFA salt of ONC902 as a white solid (228 mg, 50% yield). MS(ESI) 407 (M+H).

[0160] Starting with different benzylamines, the same process was used to prepare various analogs (eg, ONC203, 204, 205, and 206).

[0161] Description of manufacturing process and process control

[0162] The chemical synthesis of ONC206 and its conversion to its dihydrochloride salt (ONC206·2HCl) was achieved according to the process shown in Scheme 1 .

[0163] In this route, piperidone ester (Cpd2·HCl) was converted to Cpd2 (free base) and condensed with benzyl imidazoline (Cpd10) to give ONC206 free base. ONC206 free base was converted to the dihydrochloride salt and the final product ONC206·2HCl was crystallized from ethanol. The stepwise procedure is summarized in Table 3 and the key equipment is listed in Table 4, followed by a process description.

[0164] [ka]

[0165] Steps and procedures

[0166] 1. Compound 2·HCl is added in small portions to a stirred aqueous solution of NaHCO3. 2. Add n-butanol to the above mixture. Stir for 30 minutes. 3. Separate the n-butanol phase and dry over MgSO4. 4. A three-neck flask equipped with a mechanical stirrer, Dean-Stark trap, condenser, thermocouple, and N2 inlet is charged with compound 10, (pyridinium p-toluenesulfonate) PPTS, and the above solution of compound 2 in n-butanol. 5. Heat the mixture to reflux. 6. When the product peak area by HPLC remains constant over time, the reaction is stopped. 7. Wash the mixture with water. 8. Dilute the organic phase with methyl tert-butyl ether (MTBE). 9. Wash the combined organic phase with water. 10. Transfer the organic phase to a washed flask. 11. Dilute 4N HCl in dioxane with MTBE to 2N HCl solution. Add 12.2H HCl solution to the organic phase and continue adding HCl until no solid precipitates on the surface. 13. Heat the mixture at reflux for 2 hours. Separate the water in a Dean-Stark trap. 14. After cooling to room temperature, filter the solids. 15. Wash the solid with a 1:2 mixture of n-butanol and MTBE. 16. Dry the solid under vacuum. 17. The dried solids are charged to a flask followed by ethanol. 18. Heat the mixture until all solids are dissolved and filter. 19. Cool the mixture and filter off the solids. 20. Wash the solid with ethanol. 21. Dry the solid under vacuum until a constant weight is reached.

[0167] [Table 3]

[0168] Equipment related to the synthesis of ONC206·2HCl.

[0169] A brief description of the manufacturing process

[0170] In a 50 L reactor, a stirred aqueous solution of NaHCO3 was charged with NaHCO3 (859 g, 10.2 mol) in 8400 mL of distilled water and benzyl piperidinone ester hydrochloride (compound 2 hydrochloride (2743 g, 9.667 mol, 1.70 equiv.)) was added in small portions. Then n-butanol (8400 mL) was added to the mixture. The mixture was stirred for 30 min and transferred to a separatory funnel. The organic phase was separated and dried by stirring over 1000 g for 2 h. The MgSO4 was filtered off, washed with 1000 mL of n-butanol, and transferred to a 22 L reactor equipped with a mechanical stirrer, N2 inlet, thermocouple, condenser, and Dean-Stark trap. Imidazoline compound 10 (1200 g, 0.5685 mol, 1.00 equiv.) and PPTS (71.5 g, 0.237 mol, 4.2 mol%) were added to a reactor and stirred overnight. The mixture was heated to reflux and refluxed until the product peak area by HPLC remained constant over time. After this condition was met, the mixture was cooled to room temperature after 4 hours.

[0171] The mixture was transferred to a 50 L reactor equipped with a bottom valve and washed with 8400 mL of water. The organic phase was diluted with MTBE (16800 mL), washed with water (2 x 8400 mL), and transferred to a 50 L reactor equipped with a mechanical stirrer, N2 inlet, thermocouple, condenser, and Dean-Stark trap. HCl (2N in dioxane, 3128 mL) was diluted with an equal volume of MBTE (3128 mL) and HCl (5600 mL) was added to a solution of 1N HCl in dioxane-MTBE until no solid precipitated on the surface. The mixture was heated to reflux at 60-65 °C for 2 h and the water was separated in a Dean-Stark trap. After cooling to room temperature, the solid was filtered off using a table top ceramic filter and washed with n-butanol:MTBE (1:2, 7200 mL). The solid was dried in a drying tray in a vacuum oven at 55° C. for 4 hours and then at room temperature for 60 hours to give 2305 g (84% yield) of crude product as a yellow solid.

[0172] The crude solid (2300 g) was added to a 22 L reactor equipped with a mechanical stirrer, nitrogen inlet, thermocouple, and condenser, followed by ethanol (11500 mL). The mixture was heated (67 °C) until complete dissolution, and the hot solution was filtered. The solution was allowed to cool slowly to room temperature overnight with stirring, then cooled to 15 °C for 1 h. The solid was filtered, washed with ethanol (3 × 1400 mL), transferred to a drying tray, and dried at 75 °C in a vacuum oven until a constant weight was reached. 1492 g of ONC206·2HCl was obtained as an off-white solid in 65% yield.

[0173] Example 5. Synthesis of ONC206

[0174] Compound (3) (239.7 g, 0.845 mol, 1.6 eq) was added in small portions to 800 mL of stirred saturated NaHCO3 in a 2 L round bottom flask. n-Butanol (500 mL) was added to the resulting mixture, and the mixture was stirred for 30 minutes and then transferred to a separatory funnel. The organic phase containing compound (4) was separated and transferred to a 2 L three-neck round bottom flask equipped with a mechanical stirrer, N2 inlet, thermocouple, condenser, and Dean-Stark trap. Compound (5) (100 g, 0.528 mol, 1 eq) and pyridinium p-toluenesulfonate (PPTS) (6.63 gm, 0.026 mol, 5 mol%) were added to the contents of the flask. The resulting mixture was heated to reflux for 6 hours. Water in the reaction mixture was separated into the Dean-Stark trap as required. The reflux temperature was increased from 93 °C to 118 °C. The progress of the reaction was monitored by HPLC. The reaction was stopped when the peak area of ​​ONC-206 on HPLC with reaction time remained constant.

[0175] Example 6. Synthesis of a disalt of ONC206

[0176] Without isolating ONC-206, the reaction mixture from Example 8 was washed with 500 mL of water and diluted with methyl tert-butyl ether (MTBE) (800 mL). The organic phase was washed with water (500 mL x 2) and transferred to a 3 L three-neck round-bottom flask equipped with a mechanical stirrer, N2 inlet, thermocouple, condenser, and Dean-Stark trap. While stirring the reaction mixture, 1 N HCl in dioxane-MTBE solution (4 N HCl in dioxane: 300 mL, 1.2 mol, 2.27 equiv.; MTBE: 1200 mL) was added dropwise until no solid precipitated from the reaction mixture upon addition of HCl. The reaction mixture was heated to reflux at 60-65 °C for 2 h. Water was separated into the Dean-Stark trap if necessary. After cooling to room temperature, the solid precipitate was filtered through a sintered glass funnel and washed with n-butanol-MTBE (1:2, 600 mL) and MTBE (600 mL), respectively. The solid was dried in a vacuum oven at 65° C. overnight (16 h) to give 200 g of a yellow solid.

[0177] To a 2 L three-necked round bottom flask equipped with a mechanical stirrer, N2 inlet, thermocouple, and condenser, the above solid (200 g) was added, followed by ethanol (1000 mL). The mixture was heated to reflux at 78° C. for 2 h. After cooling to room temperature, the solid was filtered through a sintered glass funnel and washed with ethanol (200 mL×3). The wet solid was dried in a vacuum oven at 85° C. for 3 days until the residual solvent met specifications. 120 g of compound (2) was obtained as a white solid in 49% yield with 99.7% HPLC purity.

[0178] Biological Examples

[0179] ONC-206 is orally bioavailable, penetrates the blood-brain barrier, and has demonstrated anti-cancer efficacy without toxicity in several preclinical cancer models, with remarkable efficacy in myc-overexpressing CNS tumors.

[0180] A first-in-human, open-label, dose escalation, and food effect Phase I study of oral ONC206 (NCT04541082) will be conducted. Criteria include patients aged 18 years or older and diagnosed with recurrent primary CNS tumors. Diseases of interest include recurrent glioblastoma, WHO grade 2 and 3 invasive glial tumors, DMG H3K27M, ependymoma, medulloblastoma, malignant meningioma, and other rare primary CNS tumors. Dose escalation will follow a standard 3+3 design, initially with weekly dosing. After the maximum tolerated dose ("MTD") is established, a food effect cohort will be enrolled in a balanced single-dose, two-arm, two-period crossover design. The primary endpoint is to determine dose-limiting toxicities ("DLTs") during the first 28-day cycle, if applicable. Secondary endpoints include objective response rate by RANO criteria, overall and progression-free survival, and disease control rate. Exploratory biomarker analyses based on preclinical correlations with efficacy include expression of DRD2, DRD2 dimer, ClpP, DRD5, c-myc, and n-myc.

[0181] ONC206 is a small molecule that antagonizes the G protein-coupled receptor (GPCR) dopamine receptor D2 (DRD2) and D3 (DRD3). Downstream of target engagement, ONC206 causes activation of the ISR in tumor cells, inactivation of pro-survival Akt and ERK signaling, and induction of the DR5 / TRAIL pathway (see, e.g., Ishida et al., 2018 and Wagner et al., 2017, each of which is incorporated by reference for such teachings).

[0182] Studies in human tumor xenograft mouse models have revealed that weekly dosing results in antitumor effects. Thus, the mechanism and kinetics of ONC206 suggest that ONC206 can be effective on a less frequent dosing schedule. ONC206 has demonstrated antitumor efficacy in several preclinical cancer models, and at doses that induce cell death in human cancer cells, it does not significantly affect cell viability in normal human fibroblasts (see, e.g., Ishida et al., 2018 and Wagner et al., 2017, each of which is incorporated by reference for such teachings).

[0183] The preclinical safety profile of ONC206 has been demonstrated in non-GLP and GLP studies. At the highest dose tested, the drug did not achieve the maximum tolerated dose by oral administration in the GLP study. The GLP study with oral ONC206 revealed adverse events associated with the highest dose of ONC206, but these were mild and reversible. Findings observed in both rats and dogs were reduced body weight and / or weight gain (food intake was not affected). These results support a NOAEL of 50 mg / kg in Sprague-Dawley rats and 16.7 mg / kg in Beagle dogs. The human starting dose was calculated based on the NOAEL, which is approximately equivalent to a starting dose of 50 mg in the adult dose escalation study.

[0184] Based on the initial nonclinical safety profile and its solubility, stability, and in vivo activity, oral administration of ONC206 was selected as the route of administration in clinical trials. Preclinical studies suggest that ONC206 crosses the intact blood-brain barrier, achieves micromolar concentrations in the brain, and exhibits efficacy in tumor types that overexpress DRD2, including neuroblastoma, pheochromocytoma, Ewing's sarcoma, high-grade glioma, cholangiocarcinoma, and medulloblastoma. These observations support the development of ONC206 as a potential treatment for multiple advanced solid tumors.

[0185] ONC206 is a member of the imipridone class of anticancer small molecules that share a unique triheterocyclic core chemical structure and target GPCRs. ONC206 has been shown to have broad-spectrum activity in vitro and has been found to have activity in tumor xenograft mouse models that warrant clinical investigation. The drug also has a good preclinical safety and therapeutic PK profile in animals. The efficacy and safety of ONC206 are related to its mechanism of action, which involves antagonism of DRD2, which results in activation of the ISR and induction of the DR5 / TRAIL pathway, resulting in antitumor efficacy in vitro and in vivo.

[0186] The initial safety profile of ONC206 is favorable compared to the observed anticancer activity. GLP studies with oral ONC206 revealed adverse events associated with the highest dose of ONC206, but these were mild and reversible. Findings observed in both rats and dogs were reduced body weight and / or weight gain (food intake was unaffected). The efficacy of ONC206 has been demonstrated in vitro and in vivo. Furthermore, ONC206 has an attractive profile including oral bioavailability, preclinical safety, high stability, water solubility, and blood-brain barrier penetration.

[0187] ONC206 has not previously been tested in humans. The initial ONC206 clinical development program will evaluate the safety and potential clinical activity of this compound as an orally administered treatment for adults with recurrent and rare primary central nervous system tumors. Oral administration was selected as the intended route of administration in clinical trials based on its bioavailability and anti-cancer activity in preclinical models involving oral dosing.

[0188] composition

[0189] In one aspect, ONC206 may be provided as a drug substance. In one embodiment, the drug substance may be provided in a single-dose amber glass bottle, allowing ONC206 to be dissolved in water or other aqueous solvents or solvent systems, including pediatric beverages or other flavored solvent systems and purees (e.g., applesauce or other fruit purees). Detailed procedures for dissolving, labeling, and dosing the drug substance are described in the study protocol or investigational drug manual.

[0190] In one aspect, ONC-206 may be provided as a pharmaceutical product. In one embodiment, the pharmaceutical product may consist of a hydroxypropyl methylcellulose (HPMC) capsule filled with the active ingredient ONC206 dihydrochloride intended for oral administration. In one embodiment, the pharmaceutical product may be provided as a capsule containing one or more of microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[0191] As reflected below, the anticipated starting dose for the first-in-human clinical trials is an adult dose of 50 mg.

[0192] [Table 4]

[0193] As described herein, the amount per capsule reflects an equivalent amount based on the free base. The amount of ONC-206 dihydrochloride can be adjusted based on the salt, potency, and moisture content of the drug substance batch.

[0194] Storage Conditions: Capsules may be stored in the original sealed container at room temperature (15-30°C). Based on current stability data, room temperature (25°C / 60% relative humidity) is used for storage of the drug. At this time, a shelf life has not been established for this product; however, representative clinical trial batches will be placed in stable condition. Out-of-specification batches will be removed from use.

[0195] Packaging: The product may be stored in a multi-dose container. Capsules are packaged in high density polyethylene (HDPE) white opaque bottles, sealed with an induction seal, and capped with a white ribbed SecuRx® Polypropylene (PPE) cap. Capsules are stored in the original airtight container at room temperature (15-30°C).

[0196] Non-clinical trials

[0197] Nonclinical Pharmacology

[0198] overview

[0199] ONC206 has been shown to have broad-spectrum anti-cancer activity in vitro and has been found to have anti-tumor activity in xenograft mouse models of human cancer (Prabhu et al., 2017; Wagner et al., 2017, each of which is incorporated herein by reference for its teachings). The efficacy and safety of this molecule is related to its mechanism of action, which involves antagonism of DRD2, which leads to activation of the ISR and induction of the DR5 / TRAIL pathway, causing tumor-specific apoptosis resulting in anti-tumor efficacy in vitro and in vivo (Prabhu et al., 2017; Wagner et al., 2017, each of which is incorporated herein by reference for its teachings). This therapeutic mechanism does not confer cytotoxicity to normal human fibroblasts (e.g., human fibroblasts) (Allen et al., 2015, each of which is incorporated herein by reference for its teachings). This has been validated with ONC206 in normal human fibroblasts at effective nanomolar doses. Pharmacokinetic analysis in studies in Sprague-Dawley rats and Beagle dogs revealed micromolar plasma concentrations of ONC206. ONC206 has been safely administered to >50 mice to evaluate efficacy. At weekly doses of 50 mg / kg (approximately 250 mg in a 60 kg human), ONC206 demonstrated potent inhibition of cholangiocarcinoma xenograft tumor growth. Single oral doses in C57 / B6 mice revealed an MTD of 300 mg / kg, 5-fold the effective dose. Weekly administration of up to 125 mg / kg of ONC206 to C57 / B6 mice was well tolerated. In addition, single-dose and repeat-dose non-GLP safety studies have been conducted in rats and dogs, which identified tolerated dose levels consistent with therapeutic thresholds.

[0200] GLP toxicity and safety pharmacology studies in Sprague-Dawley rats and Beagle dogs were conducted, including pulmonary, central nervous system (CNS), and cardiovascular readouts, and demonstrated a safety profile for ONC206 consistent with that of ONC201. The NOAEL in rats and dogs was the highest dose level tested, resulting in a human equivalent starting dose of 50 mg (1 / 10 NOAEL) for adult dose escalation clinical trials based on standard allometric scaling and a body weight of 60 kg. The starting dose is expected to provide minimal subtherapeutic exposure for patients enrolled during dose escalation. ONC206 is formulated as the dihydrochloride salt, and all doses in the IND submission have been corrected for water and salt content to represent the free base dose.

[0201] Figure 1 shows an exemplary pharmacokinetic profile of ONC206 in Sprague-Dawley rats after single oral gavage doses (PO) of 50 and 125 mg / kg. 10000 ng / ml represents approximately 20 μM.

[0202] Figure 2 shows a rat biodistribution study of ONC206 at 50 mg / kg (PO). Plasma and tissue concentrations after ONC206 administration are shown over time.

[0203] ONC206 demonstrated a therapeutic PK profile upon oral administration in rats, achieving a Cmax in the micromolar range (4-20 μM) with a terminal half-life of approximately 6 hours (Figure 1). Rat biodistribution studies revealed 5-10 fold higher ONC206 concentrations in the intended target tissues compared to plasma concentrations, including the adrenal gland (10 fold), bile duct (6 fold), brain (5 fold), and bone marrow (6 fold) (Figure 2). This indicates that ONC206 can safely achieve systemic and target tissue concentrations in rats that far exceed its nanomolar GI50.

[0204] Mechanism of action

[0205] ONC206 is a member of the imipridone class of anticancer small molecules that share a unique triheterocyclic core chemical structure (Wagner et al., 2014, incorporated herein by reference for its teachings) and selectively target GPCRs (Prabhu et al., 2017). GPCRs represent an underutilized superfamily of therapeutic targets in oncology, controlling several signaling pathways that have been clinically validated in oncology, including ISR and Ras signaling (Figure 3) (Lappano and Maggiolini, 2011, each incorporated herein by reference for its teachings). Imipridones were created following the discovery of ONC201 (Allen et al., 2013), a DRD2 / 3 antagonist (Madhukar et al., 2017, incorporated herein by reference for its teachings). It has shown encouraging PK and PD safety in advanced cancers such as high-grade glioma, where several patients achieved RANO responses (Arrillaga-Romany et al., 2017), and endometrial cancer, where several patients experienced prolonged PFS compared to historical controls (Allen et al., 2016; Stein et al., 2017, each of which is incorporated by reference herein for such teachings).

[0206] ONC206 is a selective antagonist of DRD2 / 3 that triggers downstream effects of the ISR and DR5 / TRAIL pathways, resulting in tumor-specific apoptosis, and has demonstrated anti-tumor efficacy in vitro and in vivo (Prabhu et al., 2017; Wagner et al., 2017, each of which is incorporated by reference herein for such teachings).

[0207] Figure 3 shows the mechanism of action of ONC206. ONC206 antagonizes DRD2 at the cell surface, leading to activation of the ISR with ATF4 / CHOP induction and upregulation of DR5 and TRAIL gene expression, inducing apoptotic tumor cell death.

[0208] Effects on cancer and normal cells

[0209] ONC206 has demonstrated antitumor efficacy in several preclinical cancer models, including multiple human cancer cell lines, in vitro and in vivo, with the most notable efficacy in neuro-oncology and neuroendocrine tumors. Consistent with its mechanism of action, in vitro efficacy of nanomolar concentrations of ONC206 has been observed in neuroendocrine tumors and gliomas, including neuroblastoma, medulloblastoma, cholangiocarcinoma, pheochromocytoma cells, Ewing's sarcoma, and glioma stem cells. While ONC206 exhibits broad-spectrum activity across multiple preclinical solid tumors, its efficacy is remarkable at doses that do not appear to cause adverse effects in normal cells (Table 4).

[0210] [Table 5]

[0211] In vitro single agent

[0212] ONC206 demonstrated broad spectrum anti-cancer efficacy in vitro across most solid tumor types tested in a panel of >1,000 human cancer cell lines with nervous system tumors appearing to be most responsive (Figures 4 and 5). Consistent with its mechanism of action, in vitro efficacy of nanomolar concentrations of ONC206 was observed in neuroendocrine tumors and gliomas including neuroblastoma, medulloblastoma, cholangiocarcinoma, pheochromocytoma cells, Ewing's sarcoma, and glioma stem cells.

[0213] As shown in Figures 4-7, ONC206 has been tested for in vitro efficacy in human cancer cell lines.

[0214] Figure 4 shows the in vitro sensitivity of >1000 Genomics of Drug Sensitivity in Cancer (GDSC) human cancer cell lines to ONC206 (72h), averaged and organized by tumor type. Results are shown as the completeness of the ONC206 response quantified as the average area under the curve (AUC) in the dose-response cell viability curves across all cell lines of each tumor type. Error bars represent the standard error of the mean. Figure 5 shows the average GI50 from 72h ONC206 (0.078-20μM) treatment in a panel of Ewing sarcoma, neuroblastoma, and medulloblastoma cell lines in the GDSC screen. Figures 6 and 7 show representative dose-response curves (n=2) of ONC206 in MC-IXC neuroblastoma and PC12 pheochromocytoma cells.

[0215] Figure 8 shows the in vitro efficacy of ONC206 in human glioma stem cells. Cell viability dose-response curves for ONC206 in patient-derived glioma stem cells (left) (GI50 < 100 nM) and bulk tumor cells (right) (GI50 100-500 nM) (Jung et al., 2018).

[0216] In vivo single agent

[0217] Preclinical mouse model data revealed inhibition of tumor growth with weekly oral dosing of 50 mg / kg ONC206 in subcutaneous xenografts of cholangiocarcinoma (Figure 7) without weight loss. Given the approximately 5 hour half-life of ONC206 and its extended activity with weekly dosing, pharmacokinetics do not appear to be directly related to ONC206 efficacy. No association between PK and PD has also been observed with ONC201 (the parent compound of ONC206, which also targets DRD2). Based on these observations, weekly dosing will be used in first-in-human trials of ONC206.

[0218] Figure 9 shows the in vivo antitumor efficacy of ONC206 at 50 mg / kg once weekly without weight loss. (A) Tumor volume of HuCCT1 xenografts in athymic nude mice and (B) associated body weight after consecutive treatment with ONC206 (PO) at 50 mg / kg once weekly and vehicle (n=6) (*p<0.05).

[0219] Non-clinical toxicology

[0220] All doses and concentrations of ONC206 are presented as the free base and corrected for the dihydrochloride salt and water content.

[0221] Non-GLP Safety Studies

[0222] Single- and multiple-dose non-GLP safety studies have been conducted in mice, rats, and dogs to identify tolerated dose levels consistent with therapeutic thresholds. These studies recorded clinical observations, body weights, food intake, and gross findings at sacrifice.

[0223] Repeated-dose toxicology in mice

[0224] Repeated-dose oral non-GLP toxicity studies were conducted using experimentally naïve female C57 / Bl6 mice (6-8 weeks old). Animals were dosed via oral gavage. Animals were dosed either once a week (days 1, 8, and 15), three times a week (days 1, 3, 5, 8, 10, 12, and 15), or daily for 15 days. Daily administration of 125 mg / kg ONC206 (>2x effective dose, equivalent to 625 mg in humans) resulted in significant weight loss prompting euthanasia after 1 week. Dosing of 125 mg / kg ONC206 three times a week resulted in tolerable weight loss, which was not observed when the same dose was administered once a week. Blood sampling for PK was performed 1 h on day 7 for the daily group and 1 h on day 15 for the other two groups. The concentrations observed were 6.5, 10.9, and 5 μM in the once-weekly, three-times-weekly, and daily dosing groups, respectively.

[0225] Single-dose toxicology in Sprague-Dawley rats

[0226] A single-dose oral non-GLP toxicity study of ONC206 in Sprague-Dawley rats used 10 experimentally naive rats (5 males and 5 females) that were assigned to treatment groups as shown in the table below. Study groups were administered successive single oral doses of ONC206 at selected dose levels using a dose escalation study design.

[0227] [Table 6]

[0228] No mortality was observed in test article treated animals throughout the study. Animals showed clinical signs at 102.2, 122.6, and 184 mg / kg. No clinical signs were observed at 61.3 mg / kg or 81.8 mg / kg.

[0229] Terminal necropsy on day 8 revealed no visible lesions in any of the animals treated with ONC206 at 61.3, 81.8, 102.2, 122.6, or 184 mg / kg. Based on the results of this study, the NOAEL for ONC206 when administered orally to rats was determined to be 102.2 mg / kg or less, and the maximum tolerated dose was determined to be 122.6 mg / kg or less.

[0230] PBS was used as the vehicle for ONC206 in a non-GLP rat single dose study. The 61.3, 122.6, and 184 mg / kg dose levels were clear liquids with small (very trace) amounts of clear particles / fibers. The 81.8 mg / kg and 102.2 mg / kg dose levels were clear, colorless liquids. After this study, sterile water was used for injections in all subsequent studies because the solubility in water was superior to PBS.

[0231] conclusion

[0232] The NOAEL following a single dose of ONC206 in Sprague-Dawley rats by oral gavage was determined to be ≤102.2 mg / kg.

[0233] Repeated-dose toxicology in Sprague-Dawley rats

[0234] Repeated dose oral non-GLP toxicity studies were also conducted using experimentally naive Sprague-Dawley rats assigned to the treatment groups shown in Table 6 below.

[0235] [Table 7]

[0236] Animals were dosed via oral gavage. Animals were dosed once a week for 28 days (days 1, 8, 15, 22, and 28).

[0237] Male and female Sprague-Dawley rats tolerated a weekly dose of 6 mg / kg ONC206 when administered by gavage, as evidenced by the absence of early mortality / morbidity and no clinical signs (except for piloerection seen in one male on day 29). However, an overall decrease in food intake and body weight was observed over the course of the study (food intake decreased primarily in males, body weight decreased primarily in females). Several hematological and serum chemistry values ​​were above normal historical limits (blood glucose increased, hemoglobin and hematocrit decreased in males and females). Gross necropsy of the animals on day 29 showed no visible lesions. A decrease in the number of zymogen granules in pancreatic acinar cells was observed in 0 of 2 males and 0 of 2 females at 6 mg / kg (group 5). The intensity of this change was generally moderate.

[0238] Weekly doses of 25 and 50 mg / kg ONC206 were tolerated by male and female Sprague-Dawley rats when administered by oral gavage as evidenced by early mortality / morbidity, but clinical observations such as abnormal gait, decreased activity, piloerection, and decreased muscle tone were noted (mainly in females; males appeared normal throughout the study until day 29, when one male exhibited decreased activity, abnormal gait, and piloerection), an overall decrease in food intake and body weight was observed during the study period (mainly in females), and hematological and serum chemistry values ​​were above normal historical limits (red blood cell, hemoglobin, hematocrit, monocyte percentages were all decreased and blood glucose was increased in males; hemoglobin, hematocrit were decreased and aspartate aminotransferase, triglycerides, and blood glucose were increased). Gross necropsy of the animals on day 29 showed no visible lesions. At day 29, for tissues evaluated by microscopic analysis, test article-related observations included a decrease in zymogen granules in pancreatic acinar cells in 25 and 50 mg / kg ONC206 female animals, a finding that did not appear to be adverse.

[0239] Male and female Sprague-Dawley rats did not tolerate a weekly dose of 60 mg / kg ONC206 when administered by oral gavage, as evidenced by the early death of one female on day 13 (although animals appeared normal from days 1-12). Necropsy of this animal revealed dark lungs, a dark-apical spleen, a dark-apical liver with mottled pale areas, dark kidneys, and an air-distended stomach and duodenum. For the single prematurely deceased female in group 6 (animal 2686), there was extensive autolysis of multiple organs, including the stomach, duodenum, jejunum, ileum, cecum, colon, rectum, kidneys, liver, spleen, mesenteric lymph nodes, and bone marrow (sternum). The extent of autolysis precluded microscopic evaluation of these organs. Gross findings in this animal, including dark areas in the liver, spleen, and kidneys, and an air-distended stomach and duodenum, were attributed to autolysis / postmortem changes. The gross observation of dark residual lungs, recorded by the testing laboratory, correlated microscopically with congestion, a change at the time of death. The cause of death in this animal could not be determined.

[0240] Male and female Sprague-Dawley rats did not tolerate a weekly dose of 75 mg / kg ONC206 when administered by oral gavage, as evidenced by the early death of one female on day 12 and the moribund sacrifice of one female on day 12. Blood test values ​​in the female sacrificed moribund (insufficient plasma volume permitted serum chemistry analysis) were above normal historical limits (reduced platelets, lymphocyte percentage, reticulocyte count and percentage, and increased neutrophil count). No visible lesions were noted at necropsy for these two animals. Morbidity / mortality in two Group 4 female animals (75 mg / kg ONC206) was associated with test article-related microscopic findings of single cell necrosis of hepatocytes, reduced bone marrow cells, and single cell necrosis of acinar cells in the liver, and / or reduced zymogen granule numbers in pancreatic acinar cells. In group 4 female animals 1868, reduced lymphocyte counts were noted in the spleen (periarterial lymphatic sheath) and mesenteric lymph nodes (cortical / paracortical). The morphology of single-cell hepatocyte necrosis in these group 4 female animals was suggestive of apoptosis and occurred primarily in a midzone to periportal distribution. Similarly, single-cell necrosis of pancreatic acinar cells was observed, also suggestive of apoptosis. The reduction in myeloid-containing cells appeared to be accompanied by a reduction in both erythroid and myeloid lineage cells, although megakaryocytes appeared to be maintained.

[0241] Male and female Sprague-Dawley rats did not tolerate a weekly dose of 100 mg / kg ONC206 when administered by gavage, as evidenced by mortality in one female on day 11 and one female on day 13, numerous clinical observations such as abnormal gait and posture, decreased activity, piloerection, mild circling, thin hair coat, decreased muscle tone (mainly in females), an overall decrease in food intake and body weight over the study period, and hematological and serum chemistry values ​​that exceeded normal historical limits in males (all decreases in red blood cells, hemoglobin, hematocrit, increases in blood urea nitrogen). Gross necropsy of animals that survived to day 29 showed no visible lesions. Gross necropsy of females that died on day 11 showed no visible lesions, and gross necropsy of females that died on day 13 showed dark areas throughout all lobes of the lungs and liver. Morbidity / mortality in two Group 2 female animals (100 mg / kg ONC206) was associated with test article-related microscopic findings of single cell necrosis of hepatocytes, decreased bone marrow cells, and single cell necrosis of acinar cells in the liver, and / or decreased numbers of zymogen granules in acinar cells of the pancreas.

[0242] Conclusion:

[0243] No NOAEL was reported following repeated dose administration of ONC206 to Sprague-Dawley rats by oral gavage. At 6 mg / kg, no significant clinical signs were observed. At 25 mg / kg, clinical observations such as abnormal gait, decreased activity, piloerection, and decreased muscle tone were observed. At 50 mg / kg, clinical signs were less persistent and of shorter duration when compared to the 100 mg / kg dose group, and no deaths were observed. At 60, 75, and 100 mg / kg, deaths and clinical observations were associated.

[0244] Beagle Canine Single Dose Toxicology

[0245] A single-dose oral non-GLP pyramidal toxicity study was conducted in beagle dogs using two experimentally naive Beagle dogs (one male and one female) assigned to the treatment groups shown below in Table 7. A dose volume of 20 mL / kg was utilized for each oral dose.

[0246]

Table 8

[0247] On day 1, two naive dogs (one male and one female) were administered 12.5 mg / kg of ONC206 (initial dose) by oral gavage. After a washout period of approximately 7 days, the same two dogs were administered 25 mg / kg (dose #2) of ONC206 on day 8. On day 15, both dogs were administered 19 mg / kg (dose #3) of ONC206. On day 22, both dogs were administered a final dose of 12.5 mg / kg (dose #4). There were no early deaths or terminations during the study. There were no clinical findings on days 1-5 after the initial dose of 12.5 mg / kg. However, a small amount of loose stool was observed in the female on day 6, while the male appeared normal. By day 7, both animals appeared normal and continued to appear normal until day 8 (before dose #2). Clinical findings were noted after dose #2 at 25 mg / kg. At 1 hour post-dose, both animals appeared normal, but at an unscheduled observation time point 2 hours post-dose, the male was observed to have moderate vomiting with food particles, and the female was observed to have a small amount of saliva secretion and moderate loose stool. Also at an unscheduled observation approximately 6 hours post-dose, the female was observed to have moderate amount of clear yellow vomiting with food particles and a small amount of loose mucous stool. At approximately 10 hours post-dose, the male had an unscheduled observation of moderate amount of yellow, green, mucous watery stool and a small amount of loose mucous stool. By day 9, the male appeared normal, but the female had loose stool. At day 10, both animals appeared normal. At day 11, the female continued to appear normal, and the male had a small amount of loose stool. From days 12-14, both animals appeared normal. On day 15, prior to dose #3, the male appeared normal, while the female was observed to have a moderate amount of loose stool. On day 15, after the 19 mg / kg dose taper (dose #3), 1-2 hours after dosing, the male had a small amount of salivation and the female had a moderate amount of salivation. Also, an unscheduled observation was made approximately 6 hours after dosing, during which the female was observed to have a small amount of loose mucus and the male had a moderate amount of loose mucus. By day 16, both animals appeared normal, and they continued to appear normal until day 22 (prior to dose #4). No clinical observations were noted after dose 4 of 12.5 mg / kg, but all animals appeared normal from 1-2 hours after dosing until day 29.In conclusion, the test article, ONC206, caused toxic effects when administered orally via gavage to beagle dogs at 19 or 25 mg / kg, and the NOAEL was determined to be ≤ 12.5 mg / kg based on clinical signs, body weight changes, and food intake following dosing.

[0248] Conclusion:

[0249] The NOAEL following single dose administration of ONC206 to Beagle dogs by oral gavage was determined to be ≤12.5 mg / kg.

[0250] [Table 9]

[0251] Male and female Beagle dogs tolerated weekly doses of 8.3 and 12.5 mg / kg ONC206 when administered by oral gavage as evidenced by early mortality / morbidity, clinical signs, relatively stable food intake (a decrease was observed after each dose, with improvement seen prior to the next dose), and relatively stable body weights. Hematology and serum chemistry values ​​were relatively within historical limits (an increase in alanine aminotransferase was observed in Group 1 females). Gross necropsy of all animals in Groups 1 and 2 on Day 29 revealed no notable findings.

[0252] When administered by oral gavage, male and female Beagle dogs receiving weekly doses of 16.7 and 20 mg / kg ONC206 did not tolerate the test article as well as the lower dose groups. No early mortality / morbidity was observed. Test article-related effects observed at these two highest dose levels included occasional vomiting and salivation after dosing. Clinical signs were short-acting and not observed on non-dosing days. Following dosing, reduced food intake was observed at the two highest dose levels, but quickly resolved. This reduced food intake indirectly contributed to a reduction in overall final body weight of the animals in the highest dose group when compared to the starting and ending body weights of the lower dose animals. Some hematological and serum chemistry values ​​were above normal historical limits (aspartate aminotransferase was increased in females in group 3, alanine aminotransferase was increased in females in group 4, and total bilirubin was increased in females in group 3). Gross necropsy of all animals in Groups 3 and 4 on Day 29 revealed no significant findings.

[0253] There were no test article-related microscopic observations. In three dogs, there was mild chronic local inflammation of the alveolar and bronchial regions. The findings were thought to be due to slight aspiration of the dosing solution and not a direct effect of ONC206. There were no test article-related pathological findings.

[0254] Conclusion:

[0255] No NOAEL was reported following repeated administration of ONC206 to Beagle dogs by oral gavage. No significant findings were noted at 8.3 and 12.5 mg / kg. Decreased food intake and decreased body weight were observed at 16.7 and 20 mg / kg. Vomiting and salivation were occasionally observed after administration.

[0256] [Table 10]

[0257] Dose levels and concentrations shown in the table represent the actual API (free base) and 10 animals / sex / group of interest were euthanized on Day 23. Five animals / sex / group of interest remained on the study untreated for a one week recovery period and were euthanized on Day 29.

[0258] ONC206 was tolerated by male and female Sprague-Dawley rats when administered by oral gavage at 0, 5, 25, or 50 mg / kg once weekly for 3 weeks.

[0259] Clinical signs and functional observation battery evaluation revealed no treatment-related signs. No significant ocular pathology was noted by the study ophthalmologist.

[0260] Animals in the 25 and 50 mg / kg groups weighed less than controls at the completion of the dosing phase on day 22, however the differences in group mean body weights were minimal and demonstrated to be reversible during the recovery phase.

[0261] There were sporadic differences in group mean food intake that did not appear to be related to treatment.

[0262] At the terminal clinical pathology evaluation on day 23, there were slight treatment-related increases in hematology and serum chemistry parameters, including increases in relative monocytes (25 mg / kg and 50 mg / kg), glucose (25 mg / kg and 50 mg / kg), sodium (25 mg / kg and 50 mg / kg), chloride (25 mg / kg and 50 mg / kg), and alkaline phosphatase (50 mg / kg). All of these findings were reversible.

[0263] Necropsies on days 23 and 29 revealed no gross histological or organ weight differences attributable to test article-related toxicity.

[0264] One unscheduled death occurred in the 50 mg / kg group. A male animal was found to be dead 22 days after the last dose. The cause of death could not be determined. Mortality was limited to one animal out of a total of 48 animals in the 50 mg / kg treatment group. Given the low mortality rate and the lack of evidence of adverse test article-related toxicity in any of the animals in the 50 mg / kg group, the death was determined to be spontaneous.

[0265] The NOAEL and HNSTD for ONC206 were >50 mg / kg.

[0266] Conclusion:

[0267] Based on the results of this study, the NOAEL and HNSTD following oral administration of ONC206 to Sprague-Dawley rats at repeated doses of 5, 25, and 50 mg / kg is considered to be 50 mg / kg.

[0268] [Table 11]

[0269] The dose levels and concentrations shown in the table represent the actual API (free base).

[0270] Three animals / sex / group from groups 1-4 were euthanized on day 23.

[0271] Two animals / sex / group from Groups 1-4 remained on the study untreated for a 6-day recovery period and were euthanized on day 29.

[0272] Three animals / sex in Group 5 were euthanized on Day 29.

[0273] Animals in groups 1-4 (5 / sex / group) were dosed via oral gavage once daily at dose levels of 0, 1.7, 8.3, and 16.7 mg / kg / day on days 1, 8, 15, and 22. Animals in group 5 (3 / sex / group) were dosed once by intravenous infusion (approximately 30 min) via the cephalic vein using an appropriately sized syringe, indwelling catheter, and a calibrated infusion pump.

[0274] ONC206 was tolerated by male and female beagle dogs when administered by oral gavage at 0, 1.7, 8.3, or 16.7 mg / kg once weekly for 3 weeks (4 doses total). Additionally, male and female dogs tolerated ONC206 when administered as a single dose via intravenous infusion (approximately 30 minutes) at 8.3 mg / kg. The minor effects associated with ONC206 were demonstrated to be reversible during the recovery period.

[0275] No test article-related clinical signs were observed. Food intake was not affected throughout the dosing and recovery periods. Ophthalmologic examinations during the terminal and recovery periods showed no significant ocular lesions. Based on the electrocardiograms evaluated during this study, there were no toxic effects on cardiac rhythm or ECG morphology.

[0276] There were test article-related effects on weight gain. Animals dosed at 16.7 mg / kg had lower weight gain compared to controls. Some female animals had cumulative weight loss over the 3-week dosing phase, ranging from 3-9% total weight loss compared to starting weight. The effects on weight gain appeared to reverse during the 1-week recovery period. Given the relatively slow rate of weight loss and evidence of reversibility, these findings were not considered adverse.

[0277] Clinical pathology evaluation revealed minor findings that may have been related to test article effects but did not indicate overt toxicity. Female animals receiving ONC206 intravenously at 8.3 mg / kg had a slight increase in relative lymphocytes and a decrease in chloride on day 23. These findings were related to individual animal values, which were only slightly outside the range of historical control data and were not considered adverse. There were no test article changes in blood coagulation, red blood cell morphology, or urinalysis parameters.

[0278] There were no ONC206-associated microscopic pathological changes.

[0279] The NOAEL and HNSTD for ONC206 is 16.7 mg / kg when administered by oral gavage once weekly for 3 weeks. The NOAEL for ONC206 is 8.3 mg / kg when administered by a single intravenous infusion (approximately 30 minutes). This dose and route were administered to determine bioavailability.

[0280] conclusion

[0281] Based on the results of this study, the NOAEL and HNSTD following repeated oral administration of ONC206 to Beagle dogs at doses of 1.7, 8.3, and 16.7 mg / kg are considered to be ≥ 16.7 mg / kg.

[0282] Pharmacokinetics / Toxicokinetics

[0283] In rats, exposure to ONC206 after oral gavage of 5, 25, and 50 mg / kg / day ONC206 was dose-dependent and approximately dose-proportional. Exposure to ONC206 was slightly greater in female rats after oral gavage and after 30-minute intravenous infusion. Absolute oral bioavailability after 5, 25, and 50 mg / kg / day was 25%-67%, 51%-84%, and 68%-96%, respectively. Oral Tmax was observed at the first measured time point (0.5 hours), suggesting that the drug was rapidly absorbed. Elimination of ONC206 was similar after single oral and intravenous doses. Plasma T1 / 2,e ranged from 2.0 to 6.1 hours for all eight profiles. Clearance ranged from 2.7 to 8.4 L / hr / kg for seven of the eight profiles. The volume of distribution ranged from 8.9 to 56.2 L / kg for all eight profiles. No significant differences were observed in absorption, exposure, and elimination of ONC206 after single and multiple oral doses.

[0284] In dogs, exposure to ONC206 after oral gavage at 1.7, 8.3, and 16.7 mg / kg / day was dose-dependent and greater than dose-proportional across all dose levels in male and female dogs. Exposure to ONC206 was slightly higher in female dogs after a single oral gavage at the medium dose on day 1 and after four weekly oral doses at the medium and high dose levels on day 22. Exposure to ONC206 was similar after a 30-minute intravenous infusion in male and female dogs. Absolute oral bioavailability after 1.7, 8.3, and 16.7 mg / kg / day was approximately 5%, approximately 23%, and approximately 52%, respectively. Oral Tmax was observed at the first measured time point (0.5 hours), suggesting that the drug was rapidly absorbed. Mean oral plasma T1 / 2, e values ​​ranged from 0.7 to 7.1. Oral clearance was moderately variable, with mean Cl / f values ​​ranging from 5.0 to 101 L / hr / kg. Mean oral volumes of distribution ranged from 25.2 L / kg to 259 L / kg. No real differences were seen in absorption, exposure, and elimination of ONC206 after single and multiple oral doses.

[0285] Safety Pharmacology Testing

[0286] respiratory system

[0287] Respiratory testing was performed as a component of the GLP safety rat study. Twenty-four male rats (6 per group) were trained twice, each for approximately 15 minutes, in a head-out plethysmograph chamber prior to the experimental day. On the dosing day, each animal was placed in its plethysmograph chamber and, after a stabilization period of approximately 5 minutes, baseline values ​​were obtained for 5 minutes. The rats were then removed from the chamber and dosed by oral gavage according to the following schedule:

[0288] [Table 12]

[0289] Twenty-four male rats (6 per group) were trained twice in a head-out plethysmograph chamber for approximately 15 minutes each prior to the experimental day. On the dosing day, each animal was placed in its plethysmograph chamber and after a stabilization period of approximately 5 minutes, baseline values ​​were obtained for 5 minutes. The rats were then removed from the chamber and dosed by oral gavage. After dosing, each animal was returned to its designated plethysmograph chamber and respiratory parameters were recorded 15 minutes (±3 minutes), 1 hour, 2 hours, and 4 hours (±5 minutes) after dose administration of the test article / vehicle. Animals were allowed to stabilize in the plethysmograph for at least 5 minutes before each reading was taken. The following parameters were acquired, recorded, and analyzed using DSI Dataquest Open ART (v.2.3) and PONEMAH Physiology Platform (v.4.2.0): -Respiration rate -Tidal volume - Minute ventilation

[0290] Oral administration of ONC206 at doses of 5, 25, and 50 mg / kg elicited no significant effects on respiratory rate, tidal volume, or minute ventilation compared to vehicle in conscious male rats.

[0291] In conclusion, no significant effects on respiration rate were observed at 5, 25, and 50 mg / kg.

[0292] cardiovascular

[0293] The cardiovascular study was conducted as a component of a GLP safety dog ​​study. Animals were randomly assigned according to study protocol and by sex into five groups of three to five dogs and dosed by oral gavage once weekly for three weeks (a total of four doses).

[0294] ECGs were obtained from all study animals in right lateral recumbency before treatment began (baseline), after dose administration on day 1, after the final dose on day 22, and on day 28 during the recovery period. All recordings were made at a paper speed of 50 mm / sec. Recordings were made using limb leads I, II, III, aVR, aVL, aVF, and two precordial leads V1 and V2. For each tracing, the recordings were visually assessed by a board-certified cardiologist for rhythm abnormalities and changes in the general configuration of the complexes.

[0295] [Table 13]

[0296] Dose levels and concentrations represent the actual API.

[0297] Three animals / sex / group from groups 1-4 were euthanized on day 23.

[0298] Two animals / sex / group from Groups 1-4 remained on the study untreated for a 6-day recovery period and were euthanized on day 29.

[0299] Three animals / sex / group in Group 5 were euthanized on Day 29.

[0300] ONC206 at doses of 1.7, 8.3, and 16.7 mg / kg administered by oral gavage once weekly for 3 weeks (4 doses total) or a single dose by intravenous infusion of 8.3 mg / kg on day 1 had no toxic effects on cardiac rhythm or ECG morphology based on the electrocardiograms evaluated during this study.

[0301] Central nervous system

[0302] A functional observational battery (CNS) study after repeated dose administration (GLP) was performed in rats. The functional observational battery was performed in groups 1-4 (5 animals / sex / group) before the start of treatment and on days 1, 22, and 28.

[0303] [Table 14]

[0304] The dose levels and concentrations shown in the table represent the actual API (free base).

[0305] Ten target animals / sex / group were euthanized on day 23. Five target animals / sex / group remained on study untreated for a one week recovery period and were euthanized on day 29.

[0306] No abnormal observations were noted during the assessment of the functional observation battery on days 1, 22, and 28.

[0307] Conclusions and Dose Selection

[0308] In general, adverse events associated with the highest weekly dose of ONC206 were mild and reversible in GLP toxicity studies. The only findings observed in both rat and dog GLP toxicity studies were weight loss and / or weight gain without any effect on food intake. Rats had higher AUC and Cmax concentrations than dogs at all doses and sexes, except for Cmax in male rats in the high dose group. Despite PK differences, observations were consistent between species. In non-GLP studies, clinical findings, including death, were observed at doses higher than those tested in GLP studies. Given the safety profile of the drug and the intended indication in patients with advanced cancer, the benefit-risk profile of ONC206 justifies evaluation in the proposed first-in-human clinical trial. We utilized the FDA's Guidance for Industry: S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (ICH, March 2010) to calculate the proposed starting dose. The starting dose was allometrically converted as one-tenth of the lowest NOAEL (level at which no adverse events are observed) from GLP safety studies in rats and dogs. The NOAEL after oral administration of ONC206 once weekly for 3 weeks to Sprague-Dawley rats in a GLP study is at least 50 mg / kg. The NOAEL after oral administration of ONC206 once weekly for 3 weeks to Beagle dogs is at least 16.7 mg / kg. The following calculation was used: 50 mg / kg rat * 1 / 10 * 1 / 6.2 standard conversion factor = 0.77 mg / kg. Assuming a 60 kg human adult, this would result in a fixed starting dose of 46.2 mg rounded to 50 mg.

[0309] Nonclinical Pharmacokinetics and Metabolism

[0310] The absorption, distribution, metabolism, and excretion of ONC206 in humans is unknown.

[0311] The pharmacokinetics of ONC206 has been studied in rodents and dogs. Both rats and dogs achieved therapeutic PK based on the preclinical efficacy threshold. For both species, exposure was slightly greater in females. Both rats and dogs had dose-dependent and approximately dose-proportional exposure. At the highest dose tested, rats had an absolute oral bioavailability of approximately 96% and dogs approximately 52%. Both species had rapid absorption with plasma terminal half-lives ranging from 0.7 to 7.1 hours. Rats had higher AUC and Cmax concentrations than dogs at all doses and genders, except for the Cmax of rat males / high doses (Table 14).

[0312] [Table 15]

[0313] No formal metabolism or drug-drug interaction studies have been conducted with ONC206 or any of its metabolites. These studies will be conducted later in the development of this agent.

[0314] Total exposure to ONC206 does not appear to directly correlate with efficacy in nonclinical studies, an observation consistent with the delayed and sustained activity of ONC206 observed with infrequent dosing in vitro or in vivo.

[0315] Given the relatively short plasma half-life of ONC206, drug accumulation with ONC206 is unlikely on a weekly dosing schedule.

[0316] Effects in humans

[0317] ONC206 was administered to one patient in a compassionate use setting. The patient's experience is described below:

[0318] Patient UNMC-CUP-01 was a 39-year-old Caucasian male diagnosed with grade IV H3 K27M mutant diffuse midline glioma on December 2, 2016. Shortly after diagnosis, the patient was treated with temozolomide (75 mg / m2 / day for 42 consecutive days) and radiation (2 Gy per daily dose for a total of 60 Gy). Five cycles of adjuvant temozolomide (150-200 mg / m2, daily, for 5 consecutive days per 28-day cycle) were then administered until radiological progression was observed on brain magnetic resonance imaging (MRI). The patient then began treatment with lomustine at 110 mg / m2 for two cycles every 6 weeks. Further radiological progression was observed on brain MRI at least 6 weeks after initiation of lomustine. Following treatment with lomustine, the patient received the investigational drug ONC201 for approximately 19 months. In May 2019, the patient was observed to have progressive disease and resumed radiation therapy in July 2019. An MRI performed in September 2019 showed increased T2 intensity in the right thalamus, but decreased contrast enhancement in the right thalamic internal capsule region. On October 17, 2019, the treating investigator received approval from the FDA to treat the patient with the investigational molecule ONC206 via a compassionate use protocol. On November 14, 2019, treatment with ONC206 was initiated at a dose of 50 mg weekly. During treatment, the patient experienced adverse events of intermittent confusion (grade 1) and hypophosphatemia (grade 2), both of which were considered by the investigator to be possibly related to ONC206. All other adverse events considered by the investigator to be unrelated to ONC206 included grade 1 events (dysuria, arthralgia, anxiety, dysphagia, and nausea), grade 2 events (depression, shortness of breath, muscle weakness, urinary incontinence, and seizures), and grade 3 events (nephrolithiasis). On December 27, 2019, the patient received his last dose of ONC206. He was discontinued from the study on December 30, 2019, and died on January 8, 2020. The death was considered unrelated to ONC206.

[0319] Overview Guidance

[0320] Dosage and Administration

[0321] The ONC206 investigational product will be prepared in hydroxypropyl methylcellulose (HPMC) capsules intended for oral administration. No excipients are used in the drug product. Each capsule of the drug product contains the equivalent of 50 mg of ONC206. ONC206 should be stored, handled, and administered according to the parameters specified in the clinical trial protocol.

[0322] Patients should take the physician-specified dose of ONC206 2 hours before or 2 hours after consuming food or a meal. If a patient vomits after taking ONC206, the dose should not be restarted. Missed doses will not be made up if more than 3 days have passed since the scheduled dose. ONC206 should be taken with a glass of water and taken as quickly as possible. Patients should swallow the capsule whole without chewing. Capsules should not be crushed or emptied. If vomiting occurs during the course of treatment, patients are not permitted to remedy before the next scheduled dose. The occurrence and frequency of vomiting during a treatment cycle should be recorded as an adverse event.

[0323] contraindication

[0324] ONC206 is contraindicated in patients with known severe (Grade 3 or 4) hypersensitivity reactions to ONC206, its excipients, or related compounds.

[0325] An imipridone, the small molecule ONC206, is a bitopic DRD2 antagonist and ClpP agonist that exhibits enhanced non-competitive efficacy, high specificity, nanomolar potency against glioma cells, disruption of DRD2 homodimers, and blood-brain barrier permeability.

[0326] A first-in-human Phase I study is being completed using a 3+3 dose escalation and food effect study design to evaluate weekly and more frequent dosing of ONC206 in recurrent and rare primary CNS tumors.

[0327] Dose level 1 and dose level 2 were completed with no DLT.

[0328] The MTD of the Phase II study will be established. Secondary endpoints including response rate and survival outcomes will be determined.

[0329] Correlative endpoints assessing expression of DRD2, DRD2 dimer, ClpP, DRD5, MYC, and MYCN will be evaluated during the study.

[0330] ONC-206 dose optimization analysis

[0331] Individual and mean pharmacokinetic data for ONC206 were generated from available patient samples that completed the weekly dose levels. Mean concentration-time profiles over 72 hours following dosing on Day 1 of Cycle 1 at each dose level were analyzed using Genomics of Drug Sensitivity in Cancer (GDSC) and other human cancer cell line survival studies (813 of 1088 tumor lines tested were sensitive to ONC206 treatment, with a mean IC 50 The effective concentration from the 100-fold increase was 562 nM, and the IC for DRD2 and ClpP target engagement 50 The concentration-based target thresholds were overlaid (Figure 7). Due to the high distribution of ONC206 to various tissues, including the brain (brainstem:plasma ratio 2.4), the total concentration of ONC206 in plasma was used for comparison to the target thresholds. As mentioned above, Figure 9 shows the mean plasma ONC206 concentration-time profile over 72 hours for a once-weekly dosing regimen of ONC-206 in adult patients with recurrent central nervous system tumors.

[0332] Peak plasma concentrations of ONC206 above the target threshold were achieved at the 150 mg and 200 mg weekly doses, but not at the 50 mg and 100 mg weekly doses. Across doses, peak concentrations were observed with a median Tmax of approximately 1 to 2 hours, followed by mean tmax ranging from 11.2 to 17.9 hours. 1 / 2 was linearly eliminated.

[0333] Clinical safety data from these cohorts demonstrated that ONC206 was generally well tolerated. Of the 10 patients enrolled in these cohorts, 6 patients experienced grade 2 or grade 3 adverse events considered possibly / probably related to ONC206 as attributable by the investigator. No adverse events met dose-limiting toxicity criteria.

[0334] In addition to the pharmacokinetic data, additional non-clinical in vitro washout experiments in human glioma cells were completed. These in vitro studies with human brain tumor cell lines demonstrated that optimal efficacy required sustained exposure to 5-11,000 nanomolar concentrations of ONC206 for at least 72 hours (Figure 8). A 24 hour incubation period was ineffective in this cell line. Incubation periods of 36, 48, and 60 hours provided incremental improvements in efficacy with a large increase in maximum response observed with 72 hours of incubation.

[0335] Based on these non-clinical data, the plasma concentration profile of ONC206 twice daily (BID) for 3 consecutive days was predicted (Figure 9). Effective concentrations from GDSC and other human cancer cell line viability studies, as well as concentrations of DRD2 and ClpP involvement, were again set as target thresholds and overlaid onto the predicted mean ONC206 concentration profile.

[0336] Based on the predictions, BID dosing does not result in accumulation and produces a Cmax similar to that observed after weekly dosing. BID dosing also provides a larger AUClast than that observed with weekly dosing. The increase in AUClast is proportional to the number of doses, with BID dosing for 3 consecutive days producing an AUClast approximately 5.4 times larger than weekly dosing. Based on the estimated concentrations, BID dosing produces sustained ONC206 concentrations at the target threshold compared to weekly dosing, better mimicking sustained effective concentrations in non-clinical cancer cell studies. Nevertheless, 50 mg BID and 100 mg BID dosing regimens for 3 consecutive days are not predicted to produce ONC206 concentrations that reach the target threshold, as observed with weekly dosing. Dosing of ONC206 at >150 mg BID for 3 days is predicted to produce sustained ONC206 concentrations above the target threshold.

[0337] To confirm these predictions, it is planned to study ONC206 in a cohort (Cohort B) to explore BID dosing of ONC206 on 3 consecutive days, in parallel with continued escalation with a weekly regimen (Cohort A). Separate patients will be enrolled in each cohort. To ensure the safety of the BID dosing regimen, it is planned to first explore 50 mg of ONC206 on 3 consecutive days (BID). This dose regimen would result in a total weekly dose of ONC206 of 300 mg and has a lower predicted AUClast than the highest AUClast observed in the study to date (5270 hr*ng / mL at 200 mg).

[0338] References incorporated herein by reference for such background teachings: Allen,J.E.,Crowder,R.,and El-Deiry,W.S.(2015).First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent.PLoS One 10,e0143082. Allen,J.E.,Kline,C.L.,Prabhu,V.V.,Wagner,J.,Ishizawa,J.,Madhukar,N.,Lev,A.,Baumeister,M.,Zhou,L.,Lulla,A.,et al.(2016).Discovery and clinical introduction of first-in-class imipridone ONC201.Oncotarget. Allen,J.E.,Krigsfeld,G.,Mayes,P.A.,Patel,L.,Dicker,D.T.,Patel,A.S.,Dolloff,N.G.,Messaris,E.,Scata,K.A.,Wang,W.,et al.(2013).Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation,TRAIL gene induction,and potent antitumor effects.Sci Transl Med 5,171ra117. Arrillaga-Romany,I.,Chi,A.S.,Allen,J.E.,Oster,W.,Wen,P.Y.,and Batchelor,T.T.(2017).A phase 2 study of the first imipridone ONC201,a selective DRD2 antagonist for oncology,administered every three weeks in recurrent glioblastoma.Oncotarget. Ishida,C.T.,Zhang,Y.,Bianchetti,E.,Shu,C.,Nguyen,T.T.,Kleiner,G.,Sanchez-Quintero,M.,Quinzii,C.M.,Westhoff,M.A.,Karpel-Massler,G.,et al.(2018).Metabolic Reprogramming by Dual AKT / ERK Inhibition Through Imipridones Elicits Unique Vulnerabilities in Glioblastoma.Clin Cancer Res. Jung,J.,Dowdy,T.,Tabouret,E.,Reynolds,B.,Allen,J.,Larion,M.,Gilbert,M.,and Park,D.(2018).ONC206,an imipridone family member,suppresses glioblastoma cells via blocking cancer stemness pathways.Neuro-Oncology 20,vi97. Lappano,R.,and Maggiolini,M.(2011).G protein-coupled receptors:novel targets for drug discovery in cancer.Nat Rev Drug Discov 10,47-60. Madhukar,N.S.,Khade,P.,Huang,L.,Gayvert,K.,Galletti,G.,Stogniew,M.,Allen,J.E.,Giannakakou,P.,and Elemento,O.(2017).A New Big-Data Paradigm For Target Identification And Drug Discovery.bioRxiv. Prabhu,V.V.,Madhukar,N.,Wagner,J.,Tarapore,R.,Garnett,M.J.,McDermott,U.,Benes,C.,Charter,N.,Deacon,S.,VanEngelenburg,A.,et al.(2017).Potent anti-cancer activity of the imipridone ONC206:A selective dopamine D2-like receptor antagonist.In:Proceedings of the 107th Annual Meeting of the American Association for Cancer Research;Apr 1-5;Washington,DC Philadelphia(PA):AACR;2017 Abstract nr 4147A. Stein,M.N.,Bertino,J.R.,Kaufman,H.L.,Mayer,T.,Moss,R.,Silk,A.,Chan,N.,Malhotra,J.,Rodriguez-Rodriguez,L.,Aisner,J.,et al.(2017).First-in-human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors.Clin Cancer Res. Wagner,J.,Kline,C.L.,Pottorf,R.S.,Nallaganchu,B.R.,Olson,G.L.,Dicker,D.T.,Allen,J.E.,and El-Deiry,W.S.(2014).The angular structure of ONC201,a TRAIL pathway-inducing compound,determines its potent anti-cancer activity.Oncotarget 5,12728-12737.

[0339] Wagner, J., Kline, CL, Ralff, MD, Lev, A., Lulla, A., Zhou, L., Olson, GL, Nallaganchu, BR, Benes, CH, Allen, JE, et al. (2017). Preclinical evaluation of the imipridone family of analogs of the clinical-stage anticancer small molecule ONC201 reveals potent anticancer effects of ONC212.

[0340] Those skilled in the art will understand that changes can be made to the exemplary embodiments shown and described above without departing from the broad inventive concept thereof. Insofar as the described method does not depend on the specific order of steps shown herein, the specific order of steps should not be interpreted as a limitation on the claims. Claims regarding the methods of the present disclosure should not be limited to performing those steps in the order written, and those skilled in the art can easily understand that the steps may be varied and still remain within the spirit and scope of the present disclosure.

[0341] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0342] Although the specification contains many specific implementation details, these should not be construed as limitations on the scope of any disclosure or what may be claimed, but rather as descriptions of features that may be specific to certain embodiments of a particular disclosure. Certain features described in the specification in the context of separate implementations may also be implemented in combination in a single implementation. Conversely, various features described in the context of a single implementation may also be implemented in multiple implementations separately or in any suitable subcombination. Furthermore, although features may be described above as acting in a particular combination and may initially be claimed as such, one or more features from the claimed combination may, in some cases, be separated from the combination, and the claimed combination may be directed to a subcombination or a variation of the subcombination. Particular implementations of the subject matter have been described. Other implementations, modifications, and permutations of the described implementations will be apparent to those skilled in the art and are within the scope of the following claims. For example, the actions recited in the claims may be performed in a different order and still achieve desirable results. Thus, the above description of exemplary implementations does not define or constrain the present disclosure. Other changes, substitutions, and alterations are also possible without departing from the spirit and scope of this disclosure.

[0343] Several embodiments of the present disclosure have been described. Although the present specification contains many details of specific embodiments, the details of the specific embodiments should not be interpreted as limitations on the scope of any disclosure or what may be claimed, but rather as descriptions of features specific to particular embodiments of the present disclosure. Nevertheless, it should be understood that various modifications may be made without departing from the spirit and scope of the present disclosure as claimed.

Claims

1. In the preparation of a medicament for treating one or more cancers, Use of 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one (ONC-206), or a salt thereof.

2. 2. The use of claim 1, wherein the cancer is a CNS cancer.

3. The use according to claim 1, wherein the cancer is brain cancer.

4. The use according to claim 1, wherein the cancer is glioma.

5. The cancer is selected from the group consisting of glioma, glioneuronal tumor, and neuronal tumor, adult diffuse glioma, astrocytoma IDH mutant, oligodendroglioma IDH mutant, and 1p / 19q codeletion, glioblastoma, IDH wild type, pediatric diffuse low grade glioma, diffuse astrocytoma, MYB or MYBL1 mutant, angiocentric glioma, polymorphic low grade neuroepithelial tumor of the young, diffuse low grade glioma, MAPK pathway mutant, pediatric diffuse high grade glioma, diffuse midline glioma, H3 K27 mutant, diffuse hemispheric glioma, H3 G34 mutant, diffuse juvenile high-grade glioma, H3 wild type and IDH wild type, infantile hemispheric glioma, focal astrocytoma, pilocytic astrocytoma, high-grade astrocytoma with pilocytic features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordomatoid glioma, astroblastoma, MN1 alteration, glioneuronal and neuronal tumors, ganglioglioma, desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma, dysembryoplastic neuroblastoma Epithelial tumors, Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, Papillary glioneuronal tumor, Rosette-forming glioneuronal tumor, Myxoid glioneuronal tumor, Diffuse leptomeningeal glioneuronal tumor, Gangliocytoma, Multinodular and vacuolar neuroma, Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), Central neurocytoma, Extraventricular neurocytoma, Cerebellar liponeurocytoma, Ependymal tumor, Supratentorial ependymoma, Supratentorial Ependymoma ZFTA fusion positive, supratentorial ependymoma YAP1 fusion positive, posterior fossa ependymoma, posterior fossa ependymoma PFA group, posterior fossa ependymoma PFB group, spinal cord ependymoma, spinal cord ependymoma MYCN amplified, myxopapillary ependymoma, subependymoma, choroid plexus tumor, choroid plexus papilloma, atypical choroid plexus papilloma, choroid plexus carcinoma, embryonal tumor, medulloblastoma, medulloblastoma (molecular definition), medulloblastoma WNT active, medulloblastoma SHH active and TP53 wild type, medulloblastoma SHH active and TP53 mutant, Medulloblastoma non-WNT / non-SHH, Medulloblastoma (histological definition), Other CNS embryonal tumors, Atypical terato / rhabdoid tumor, Cribriform neuroepithelial tumor, Embryonal tumor with multilayered rosettes, CNS neuroblastoma FOXR2 activated, CNS tumor with BCOR internal tandem duplication, CNS embryonal tumor, Pineal tumor, Pineocytoma, Moderately differentiated pineal parenchymal tumor, Pineoblastoma, Papillary tumor of the pineal region, Desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant,Cranial nerve tumors and paraspinal nerve tumors, schwannoma, neurofibroma, perineurioma, hybrid nerve sheath tumor, malignant melanotic nerve sheath tumor, malignant peripheral nerve sheath tumor, paraganglioma, meningioma, mesenchymal meningioma, non-meningothelial tumor, soft tissue tumor, fibroblastic tumor and myofibroblastic tumor, solitary fibrous tumor, vascular tumor, hemangioma and vascular malformation, hemangioblastoma, skeletal muscle tumor, rhabdomyosarcoma (unknown differentiation), intracranial mesenchymal tumor FET-CREB fusion positive, CIC rearrangement sarcoma, primary cranial Intracranial sarcoma DICER1 mutant, Ewing's sarcoma, cartilage and bone forming tumors, chondrogenic tumors, mesenchymal chondrosarcoma, chondrosarcoma, notochord tumor, chordoma (including poorly differentiated chordoma), melanocytic tumor, diffuse meningeal melanocytosis and meningeal melanomatosis, localized meningeal melanocytoma, meningeal melanocytoma and meningeal melanoma, hematolymphoid tumors, lymphoma, CNS lymphoma, primary CNS diffuse large B-cell lymphoma, immune Deficiency-associated CNS lymphoma, lymphomatoid granulomatosis, intravascular large B-cell lymphoma, other rare lymphomas of the CNS, meningeal MALT lymphoma, other low-grade B-cell lymphomas of the CNS, anaplastic large cell lymphoma (ALK+ / ALK-), T-cell and NK / T-cell lymphomas, histiocytic neoplasms, Erdheim-Chester disease, Rosai-Dorfman disease, juvenile xanthogranuloma, Langerhans cell histiocytosis, histiocytic sarcoma, germ cell tumors, mature teratoma, anaplastic large cell lymphoma, anaplastic granulomatosis ... granulomatosis, anaplastic granulomatosis, anaplastic granulomatosis, anaplastic granulomatosis, anaplastic granulomatosis, anaplastic granulomatosis, anaplastic granulomatosis, anaplastic gran 2. The use according to claim 1, wherein the tumor is selected from the group consisting of one or more of mature teratomas, teratomas with somatic malignancies, germinomas, embryonal carcinomas, yolk sac tumors, choriocarcinomas, mixed germ cell tumors, sellar tumors, ameloblastoma craniopharyngiomas, papillary craniopharyngiomas, pituitary cell tumors, sellar granular cell tumors, and spindle cell oncocytomas, pituitary adenomas / PitNETs, ​​pituitary blastomas, metastases to the CNS, metastases to the brain and spinal cord parenchyma, and metastases to the meninges.

6. 2. The use of claim 1, wherein the cancer is one or more of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglial tumor, ependymal tumor, medulloblastoma, pineal tumor, meningeal tumor, and germ cell tumor.

7. The use of claim 1, wherein administration of ONC-206 or a salt thereof alleviates one or more symptoms of the cancer.

8. The use of claim 1, wherein administration of ONC-206 or a salt thereof reduces tumor growth.

9. The use of claim 1, wherein administration of ONC-206 or a salt thereof provides one or more of the following: (i) reduction in tumor size, (ii) progression-free survival, (iii) overall survival, (iv) patient-reported outcomes, (v) disease-free survival, (vi) objective response, (vii) complete response, (viii) increased time to progression, (ix) reduction in corticosteroid use, (x) reduction in supportive medications, (xi) reduction in incidence of seizures, (xii) reduction in use of anti-seizure medications, (xiii) improved quality of life, (xiv) reduction in neuropathy, and (xv) other objective responses.

10. The use of claim 1, wherein administration of ONC-206 or a salt thereof is in combination with one or more additional therapies or therapeutic agents.

11. The use of claim 1, wherein the dose of ONC-206 or a salt thereof is from about 25 mg to about 75 mg based on the free base form.

12. 12. The use of claim 11, wherein the dose of ONC-206 or a salt thereof is about 50 mg.

13. The use of claim 1, wherein the dose of ONC-206 or a salt thereof is from about 5 mg / kg to about 1000 mg / kg.

14. 14. The use of claim 13, wherein the dose of ONC-206 or a salt thereof is about 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg.

15. 2. The use of claim 1, wherein the dose of ONC-206 or a salt thereof in a volume of 10 ml / kg is from about 0.6 mg / l to about 10 mg / ml.

16. 16. The use of claim 15, wherein the dose of ONC-206 or a salt thereof is about 5 mg / ml.

17. The use of claim 1, wherein the dose of ONC-206 or a salt thereof is from about 12.5 mg / kg / day to about 25 mg / kg / day.

18. 18. The use of claim 17, wherein the dose of ONC-206 or a salt thereof is about 12.5 mg / kg / day.

19. The use of claim 1, wherein the dose of ONC-206 or a salt thereof is from about 8 mg / kg to about 20 mg / kg.

20. The use of claim 1, wherein the dose of ONC-206 or a salt thereof is from about 5 mg / kg / day to about 50 mg / kg / day.

21. 21. The use of claim 20, wherein the dose of ONC-206 or a salt thereof is less than about 50 mg / kg / day.

22. The use of claim 1, wherein the dose of ONC-206 or a salt thereof is from about 1.7 mg / kg / day to about 16.7 mg / kg / day.

23. 23. The use of claim 22, wherein the dose of ONC-206 or a salt thereof is greater than about 16.7 mg / kg / day.

24. 2. The use of claim 1, wherein the dose of ONC-206 or a salt thereof provided is once a day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, or once a month.

25. 25. The use of claim 24, wherein the dose of ONC-206 or a salt thereof is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

26. 2. The use of claim 1, wherein the Cmax is from about 4 μM to about 20 μM.

27. 27. The use of claim 26, wherein the terminal half-life is about 6 hours.

28. 2. The use of claim 1, wherein the target tissue distribution relative to the plasma concentration of ONC-206 is at least one of 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher.

29. 2. The use of claim 1, wherein the ONC-206 is provided as a dihydrochloride salt.

30. 2. The use according to claim 1, wherein the treatment is for a recurrent tumor.

31. 2. The use according to claim 1, wherein the treatment is other than a first line treatment.

32. 2. The use according to claim 1, wherein the treatment is for advanced cancer.

33. 2. The use of claim 1, wherein the treatment is administered at least 30 days after radiation.

34. 2. The use of claim 1, wherein the treatment is administered at least 60 days after radiation.

35. 2. The use of claim 1, wherein the treatment is administered at least 90 days after radiation.

36. 2. The use of claim 1, wherein the treatment is administered after surgical resection.

37. 2. The use of claim 1, wherein the CNS tumor is one or more of recurrent glioblastoma, WHO grade 1, 2, 3, or 4 CNS tumor types, invasive glial tumors, DMG H3K27M, DMG H3 K27 mutation, DMG H3 K27me deletion (H3K27me3), ependymoma, medulloblastoma, malignant meningioma, and other rare primary CNS tumors.

38. 2. The use of claim 1, wherein administration of ONC-206 or a salt thereof is monitored by one or more of DRD2, DRD2 dimer, ClpP, ClpP substrates SDHA, SDHB, and markers of oxidative phosphorylation, DRD5, c-myc, and n-myc expression.

39. 2. The use of claim 1, wherein the objective response rate is measured by one or more of the following: RANO criteria, overall survival, progression-free survival, and disease control rate.

40. 1. A pharmaceutical composition for treating one or more cancers, comprising: A pharmaceutical composition comprising 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one (compound ONC-206), or a salt thereof.

41. 41. The pharmaceutical composition of claim 40, wherein the cancer is a CNS cancer.

42. The pharmaceutical composition of claim 40, wherein the cancer is brain cancer.

43. The pharmaceutical composition of claim 40, wherein the cancer is glioma.

44. The cancer is selected from the group consisting of glioma, glioneuronal tumor, and neuronal tumor, adult diffuse glioma, astrocytoma IDH mutant, oligodendroglioma IDH mutant, and 1p / 19q codeletion, glioblastoma, IDH wild type, pediatric diffuse low grade glioma, diffuse astrocytoma, MYB or MYBL1 mutant, angiocentric glioma, polymorphic low grade neuroepithelial tumor of the young, diffuse low grade glioma, MAPK pathway mutant, pediatric diffuse high grade glioma, diffuse midline glioma, H3 K27 mutant, diffuse hemispheric glioma, H3 G34 mutant, diffuse juvenile high-grade glioma, H3 wild type and IDH wild type, infantile hemispheric glioma, focal astrocytoma, pilocytic astrocytoma, high-grade astrocytoma with pilocytic features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordomatoid glioma, astroblastoma, MN1 alteration, glioneuronal and neuronal tumors, ganglioglioma, desmoplastic infantile ganglioglioma / desmoplastic infantile astrocytoma, dysembryoplastic neuroblastoma Epithelial tumors, Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters, Papillary glioneuronal tumor, Rosette-forming glioneuronal tumor, Myxoid glioneuronal tumor, Diffuse leptomeningeal glioneuronal tumor, Gangliocytoma, Multinodular and vacuolar neuroma, Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), Central neurocytoma, Extraventricular neurocytoma, Cerebellar liponeurocytoma, Ependymal tumor, Supratentorial ependymoma, Supratentorial Ependymoma ZFTA fusion positive, supratentorial ependymoma YAP1 fusion positive, posterior fossa ependymoma, posterior fossa ependymoma PFA group, posterior fossa ependymoma PFB group, spinal cord ependymoma, spinal cord ependymoma MYCN amplified, myxopapillary ependymoma, subependymoma, choroid plexus tumor, choroid plexus papilloma, atypical choroid plexus papilloma, choroid plexus carcinoma, embryonal tumor, medulloblastoma, medulloblastoma (molecular definition), medulloblastoma WNT active, medulloblastoma SHH active and TP53 wild type, medulloblastoma SHH active and TP53 mutant, Medulloblastoma non-WNT / non-SHH, Medulloblastoma (histological definition), Other CNS embryonal tumors, Atypical terato / rhabdoid tumor, Cribriform neuroepithelial tumor, Embryonal tumor with multilayered rosettes, CNS neuroblastoma FOXR2 activated, CNS tumor with BCOR internal tandem duplication, CNS embryonal tumor, Pineal tumor, Pineocytoma, Moderately differentiated pineal parenchymal tumor, Pineoblastoma, Papillary tumor of the pineal region, Desmoplastic myxoid tumor of the pineal region, SMARCB1 mutant,Cranial nerve tumors and paraspinal nerve tumors, schwannoma, neurofibroma, perineurioma, hybrid nerve sheath tumor, malignant melanotic nerve sheath tumor, malignant peripheral nerve sheath tumor, paraganglioma, meningioma, mesenchymal meningioma, non-meningothelial tumor, soft tissue tumor, fibroblastic tumor and myofibroblastic tumor, solitary fibrous tumor, vascular tumor, hemangioma and vascular malformation, hemangioblastoma, skeletal muscle tumor, rhabdomyosarcoma (unspecified), intracranial mesenchymal tumor FET-CREB fusion positive, CIC rearrangement sarcoma, primary cranial DICER1 mutated endothelial sarcoma, Ewing's sarcoma, cartilage and bone forming tumors, chondrogenic tumors, mesenchymal chondrosarcoma, chondrosarcoma, notochord tumor, chordoma (including poorly differentiated chordoma), melanocytic tumor, diffuse meningeal melanocytosis and meningeal melanoma, localized meningeal melanocytoma, meningeal melanocytoma and meningeal melanoma, hematolymphoid tumors, lymphoma, CNS lymphoma, primary CNS diffuse large B-cell lymphoma, immunodeficiency Associated CNS lymphomas, lymphomatoid granulomatosis, intravascular large B-cell lymphoma, other rare lymphomas of the CNS, meningeal MALT lymphoma, other low-grade B-cell lymphomas of the CNS, anaplastic large cell lymphoma (ALK+ / ALK-), T-cell and NK / T-cell lymphomas, histiocytic neoplasms, Erdheim-Chester disease, Rosai-Dorfman disease, juvenile xanthogranuloma, Langerhans cell histiocytosis, histiocytic sarcoma, germ cell tumors, mature teratomas, immature teratomas 41. The pharmaceutical composition of claim 40, wherein the cancer is selected from the group consisting of one or more of the following: pericytoma, teratoma with somatic malignancy, germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, mixed germ cell tumor, sellar tumor, ameloblastoma craniopharyngioma, papillary craniopharyngioma, pituitary cell tumor, sellar granular cell tumor, and spindle cell oncocytoma, pituitary adenoma / PitNET, pituitary blastoma, metastases to the CNS, metastases to the brain and spinal cord parenchyma, and metastases to the meninges.

45. 41. The pharmaceutical composition of claim 40, wherein the cancer is one or more of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglial tumor, ependymal tumor, medulloblastoma, pineal tumor, meningeal tumor, and germ cell tumor.

46. ​​The pharmaceutical composition of claim 40, wherein administration of the pharmaceutical composition alleviates one or more symptoms of the cancer.

47. 41. The pharmaceutical composition of claim 40, wherein administration of the pharmaceutical composition reduces tumor growth.

48. 41. The pharmaceutical composition of claim 40, wherein administration of the pharmaceutical composition provides one or more of: (i) reduction in tumor size, (ii) progression-free survival, (iii) overall survival, (iv) patient-reported outcomes, (v) disease-free survival, (vi) objective response, (vii) complete response, (viii) increased time to progression, (ix) reduction in corticosteroid use, (x) reduction in supportive medications, (xi) reduction in incidence of seizures, (xii) reduction in use of anti-seizure medications, (xiii) improved quality of life, (xiv) reduction in neuropathy, and (xv) other objective responses.

49. 41. The pharmaceutical composition of claim 40, wherein administration of the pharmaceutical composition is in combination with one or more additional therapies or therapeutic agents.

50. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof is from about 25 mg to about 75 mg based on the free base form.

51. 51. The pharmaceutical composition of claim 50, wherein the dose of ONC-206 or a salt thereof is about 50 mg.

52. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof is from about 5 mg / kg to about 1000 mg / kg.

53. 53. The pharmaceutical composition of claim 52, wherein the dose of ONC-206 or a salt thereof is about 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg.

54. 41. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof in a volume of 10 ml / kg is from about 0.6 mg / l to about 10 mg / ml.

55. 55. The pharmaceutical composition of claim 54, wherein the dosage of ONC-206 or a salt thereof is about 5 mg / ml.

56. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof is from about 12.5 mg / kg / day to about 25 mg / kg / day.

57. 57. The pharmaceutical composition of claim 56, wherein the dose of ONC-206 or a salt thereof is about 12.5 mg / kg / day.

58. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof is from about 8 mg / kg to about 20 mg / kg.

59. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof is from about 5 mg / kg / day to about 50 mg / kg / day.

60. 60. The pharmaceutical composition of claim 59, wherein the dose of ONC-206 or a salt thereof is less than about 50 mg / kg / day.

61. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof is from about 1.7 mg / kg / day to about 16.7 mg / kg / day.

62. 62. The pharmaceutical composition of claim 61, wherein the dose of ONC-206 or a salt thereof is greater than about 16.7 mg / kg / day.

63. 41. The pharmaceutical composition of claim 40, wherein the dose of ONC-206 or a salt thereof provided is once daily, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, once weekly, once every two weeks, or once monthly.

64. 64. The pharmaceutical composition of claim 63, wherein the dose of ONC-206 or a salt thereof is three times a day, twice a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

65. 41. The pharmaceutical composition of claim 40, wherein the Cmax is from about 4 μM to about 20 μM.

66. 66. The pharmaceutical composition of claim 65, having a terminal half-life of about 6 hours.

67. 41. The pharmaceutical composition of claim 40, wherein the target tissue distribution relative to the plasma concentration of ONC-206 is at least one of 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold higher.

68. 41. The pharmaceutical composition of claim 40, wherein the ONC-206 is provided as a dihydrochloride salt.

69. 41. The pharmaceutical composition of claim 40, wherein the treatment is for a recurrent tumor.

70. 41. The pharmaceutical composition of claim 40, wherein the treatment is other than a first line treatment.

71. 41. The pharmaceutical composition of claim 40, wherein the treatment is for advanced cancer.

72. 41. The pharmaceutical composition of claim 40, wherein the treatment is administered at least 30 days after radiation.

73. 41. The pharmaceutical composition of claim 40, wherein the treatment is administered at least 60 days after radiation.

74. 41. The pharmaceutical composition of claim 40, wherein the treatment is administered at least 90 days after radiation.

75. 41. The pharmaceutical composition of claim 40, wherein the treatment is administered after surgical resection.

76. 41. The pharmaceutical composition of claim 40, wherein the CNS tumor is one or more of recurrent glioblastoma, WHO grade 2 and 3 infiltrative glial tumors, DMG H3K27M, DMG H3 K27 mutation, DMG H3 K27me deletion (H3 K27me3), ependymoma, medulloblastoma, malignant meningioma, and other rare primary CNS tumors.

77. 41. The pharmaceutical composition of claim 40, wherein administration of the pharmaceutical composition is monitored by one or more of DRD2, DRD2 dimer, ClpP, ClpP substrates SDHA, SDHB, and markers of oxidative phosphorylation, DRD5, c-myc, and n-myc expression.

78. 41. The pharmaceutical composition of claim 40, wherein the objective response rate is measured by one or more of the following: RANO criteria, overall survival, progression-free survival, and disease control rate.

79. The pharmaceutical composition of claim 40, wherein the ONC-206 or a salt thereof is administered in a weekly regimen at a dose of 5 mg to 100 mg per kg of patient body weight continuously for one or more days.

80. The pharmaceutical composition of claim 79, wherein the ONC-206 or a salt thereof is administered for three consecutive days followed by four days of not being administered in a weekly regimen.

81. The pharmaceutical composition described in claim 79, wherein the cancer is a CNS cancer.

82. The pharmaceutical composition described in claim 79, wherein the cancer is brain cancer.

83. The pharmaceutical composition described in claim 79, wherein the cancer is glioma.

84. The pharmaceutical composition of claim 79, wherein the dose of ONC-206 or a salt thereof is about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

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