Pharmaceutical compositions and uses thereof for the treatment of PCPG: pheochromocytomas and paragangliomas

Abstract

This disclosure relates, at least in part, to a method of treatment with ONC206 in a selective patient population. ONC206 is an orally active caseinolytic protease proteolytic subunit (ClpP) agonist and dopamine receptor D2 (DRD2) antagonist. Pheochromocytoma and paraganglioma (PCPG) tumors secrete catecholamines and highly express the DRD2 receptor that is antagonized by ONC206. This disclosure provides efficacy and safety of ONC206 in patients with PCPG in an open-label, multicenter, two-stage Phase 2 clinical study evaluating the efficacy and safety of ONC206 in patients with advanced PCPG who have locally advanced or metastatic disease and have exhausted or declined available therapy. The primary objective of the analysis is to determine the antitumor activity of ONC206 in this patient population.

Description

PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WG)PHARMACEUTICAL COM POSITIONS AND USES THEREOF FOR THE TREATMENT OF PCPG: PHEOCHROMOCYTOMASAND PARAGANGLIOMAS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit from U.S. Provisional Application No.63 / 779,908, filed March 28, 2025, and U.S. Provisional Application No. 63 / 924,260, filed November 24, 2025, each of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] The majority of neuroendocrine tumors lack effective systemic therapy options. ONC201 , which may be referred to as Compound 1 or NSC 350625, herein, is a founding member of the imipridone class of small molecules, and has demonstrated induced durable tumor regressions in patients with diffuse midline glioma, H3 K27M-mutant (DMG H3K27M).

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

[0004] The structures for each of compounds is as follows:oONC-201Compound 1ONC-206Compound 2PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[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(1 H)-one, and in one embodiment is provided as a 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(1 H)-one, and in one embodiment, is provided as a dihydrochloride salt.

[0007] Pheochromocytomas and paragangliomas (PCPGs) are rare, beleived heritable neuroendocrine tumors (up to 40% hereditary) arising from chromaffin tissue, with 10% being metastatic and posing high mortality risk. Histopathological classification of PCPG tumors, including molecular subtyping and identifying distinct, targetable pathways (pseudohypoxia, kinase signaling, Wnt-altered) may guide treatment, particularly for metastatic diseases.

[0008] Treatment options for PCPG are limited. Surgical resection and radiotherapy are standard for localized tumors, but systemic options for malignant PCPG, such as traditional chemotherapies, have shown only limited impact on overall survival and patient quality of life.BRIEF SUMMARY OF THE INVENTION

[0009] The present disclosure includes a method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:ONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

[0010] The present disclosure includes such method, as demonstrated by an overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

[0011] The present disclosure includes evaluating PCPG growth and symptoms by one or more of Duration of response (DOR), Time to response (TTR), Disease control rate (DCR), Progression-free survival (PFS), Overall survival (OS) (up to 3 years), ChangePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)from baseline in antihypertensive medication dose, and Change from baseline in biochemical response (metanephrines / disease markers)).

[0012] The present disclosure includes evaluating the PCPG growth and symptoms is by monitoringthe change from baseline in a biochemical response.

[0013] The present disclosure includes wherein a biochemical response is evaluated by a diagnostic marker; and wherein the diagnostic marker is a catecholamine, a normetanephrine, a metanephrine, a methoxytyramine, a chromogranin A, a synaptophysin, or a glucose analog.

[0014] The present disclosure includes wherein a diagnostic marker is a metanephrine.

[0015] The present disclosure includes evaluating positron emission tomography (PET) imaging, and the biochemical response is uptake of a glucose analog.

[0016] The present disclosure includes further comprising evaluating one or more of:a. incidence of adverse events (AEs), comprising one or more of:i. overall,ii. treatment related,iii. Grade 3 or higher in severity,iv. serious, andv. those resulting in study treatment discontinuation;b. change from baseline in clinical laboratory parameters;c. distribution of graded clinical laboratory parameters; andd. change from baseline in electrocardiogram parameters.

[0017] The present disclosure includes a method of treating a patient diagnosed with one or more of pheochromocytoma (PC) and paraganglioma (PG), who have locally advanced or metastatic disease, and have exhausted or declined available therapies, comprising administering a therapeutically effective amount of:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

[0018] The present disclosure includes a method of treating a patients with histologically confirmed PCPG, said patient having failed prior PCPG therapy, and ineligible for curative surgery, comprising administering a therapeutically effective amount of:O FONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

[0019] The present disclosure includes administering 50 to 350 mg ONC206 weekly.

[0020] The present disclosure includes administering in a dose schedule of one or more of: 50 mg BID / TIW, 150 m QD / TIW, 350 mgQD / TIW, 100 mg BID / TIW, and 150 mg BID / TIW.

[0021] The present disclosure includes administering from 50 mg to 350 mg ONC206 on 3 consecutive days per week in a 28-day cycle.

[0022] The present disclosure includes administering ONC206 BID / TIW on each of day 1 , day 2, and day 3 of a 7-day cycle.

[0023] The present disclosure includes administering ONC206 BID / TIW on each of day 1 , day 2, day 3, day 8, day 9, day 10, day 15, day 16, day 17, day 22, day 12, and day 24, of a 28-day cycle.

[0024] The present disclosure includes administering 150 mg or 200 mg of ONC206 BID / TIW.

[0025] The present disclosure includes administering ONC206 QD / TIW on each of day 1 , day 2, and day 3 of a 7-day cycle.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0026] The present disclosure includes administering ONC206 QD / TIW on each of day 1 , day 2, day 3, day 8, day 9, day 10, day 15, day 16, day 17, day 22, day 12, and day 24, of a 28-day cycle.

[0027] The present disclosure includes administering 350 mg of ONC206 QD / TIW.

[0028] The present disclosure includes administering ONC206 QD on day 1 of a 7-day cycle.

[0029] The present disclosure includes administering QNC206 QD on a day on day 1 , day 8, day 15, and day 22 of a 28-day cycle.

[0030] The present disclosure includes administering 350 mg of ONC206 QD.

[0031] The present disclosure includes furthercomprising a staged protocol, which comprises: an initial treatment, with monitoring for response; and if a response is observed, advancing the patient to a second stage comprising comparing dose levels and creating a final dose schedule.

[0032] The present disclosure includes a method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:ONC-206 Compound 2, or a pharmaceutically acceptable salt thereof, comprising a fixed frequency with variable dose.

[0033] The present disclosure includes a method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:ONC-206 Compound 2, or aPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)pharmaceutically acceptable salt thereof, comprising: establising an effective AUC and dosing for a recovery window.

[0034] The present disclosure includes administering ONC206 at one of a variable dose levels.

[0035] The present disclosure includes wherein ONC206 is administered orally in a 28-day cycle.

[0036] The present disclosure includes a method of treating one or more of neuroendocrine tumors in a patient in need thereof comprising administering a therapeutically effective amount of:N ONC-206 Compound 2, or a pharmaceutically acceptable salt thereof.

[0037] The present disclosure includes wherein the neuroendocrine tumor provides a signature for sensitivity tumor types.

[0038] The present disclosure includes wherein the neuroendocrine tumor is PCPG.

[0039] The present disclosure includes wherein PCPG is identified as a sensitive tumor.

[0040] The present disclosure includes wherein the neuroendocrine tumor is an adrenal tumor.

[0041] The present disclosure includes wherein the neuroendocrine tumor is an extra-adrenal tumor.

[0042] The present disclosure includes wherein the adrenal tumor is adrenal corticol carcinoma.

[0043] The present disclosure includes a method of treating a tumor characterized with one or more of an SDH mutation or a FH mutation, in a patient in need thereof comprising administering a therapeutically effective amount of:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

[0044] The present disclosure includes wherein the tumor is characterized with SDH mutation.

[0045] The present disclosure includes wherein the SDH mutation is SDHB.

[0046] The present disclosure includes wherein the tumor is characterized with FH mutation.

[0047] The present disclosure includes wherein the SDH mutation or FH mutation is a loss-of-function driver mutation.

[0048] The present disclosure includes wherein the tumor is a pheochromocytoma or paraganglioma.

[0049] The present disclosure includes a method of treating a tumor characterized with one or more ClpP mutations, in a patient in need thereof comprising administering a therapeutically effective amount of:N N ONC-206 Compound 2Npharmaceutically acceptable salt thereof.

[0050] The present disclosure includes wherein the patient has failed prior pheochromocytoma / paraganglioma (PCPG) therapy.

[0051] The present disclosure includes wherein the patient is ineligible for curative surgery.

[0052] The present disclosure includes, wherein the tumor is unresectable.

[0053] The present disclosure includes a method of treating a neuroendocrine tumor responsive to agonism of caseinolytic protease proteolytic subunit (ClpP) in aPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)patient, said method comprising administering a compound:ONC-206 Compound 2pharmaceutically acceptable salt thereof, to the patient.

[0054] The present disclosure includes use of a compound,ONC-206 Compound 2pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a neuroendocrine tumor responsive to agonism of caseinolytic protease proteolytic subunit (ClpP) in a patient.

[0055] The present disclosure includes a method of treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of:ONC-206 Compound 2pharmaceutically acceptable salt thereof, wherein adminstration allows for a reduction in use of anti-hypertensives.

[0056] The present disclosure includes a method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206 Compound 2pharmaceutically acceptable salt thereof; and comprising one or more of: a) combining said treatment with one or more additional chemotherapeutic agent; and b) combining said treatment with one more for multimodal therapy.

[0057] The present disclosure includes wherein the multimodal therapy is radiation.

[0058] The present disclosure includes administering ONC206 or a pharmaceutically acceptable salt thereof, concurrently or sequentially in any order with the radiation.

[0059] The present disclosure includes wherein ONC206 is administered concurrently or sequentially with the radiation.

[0060] The present disclosure includes wherein ONC206 is administered sequentially with the radiation.

[0061] The present disclosure includes wherein ONC206 is administered concurrently with the radiation

[0062] The present disclosure includes wherein the radiation comprises irradiating cancer cells with a radiation beam.

[0063] The present disclosure includes wherein the radiation comprises conformal radiotherapy (CRT).

[0064] The present disclosure includes wherein the conformal radiotherapy (CRT) delivers a dose volume histogram (DVH) prescribed to a patient.

[0065] The present disclosure includes wherein the radiation comprises intensity modulated radiation therapy (IMRT) to deliver radiation to cancer cells.

[0066] The present disclosure includes wherein the multimodal therapy is surgery.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0067] The present disclosure includes a compound:ONC-206 Compound 2pharmaceutically acceptable salt thereof, for use in a method for reducing tumor size relative to baseline of total tumor burden for pheochromocytoma (PC) or paraganglioma (PG) in a patient.

[0068] The present disclosure includes a compound:ONC-206 Compound 2or a pharmaceutically acceptable salt thereof, for use in a method for reducing tumor burden of pheochromocytoma (PC) or paraganglioma (PG) in a patient.

[0069] The present disclosure includes wherein the tumor burden is measured by one or more of (a) reduction in tumor size relative to baseline of total tumor burden; and (b) reduction in tumor volume relative to baseline.

[0070] The present disclosure includes wherein the tumor burden and / or tumor size is measured with one or more of (a) CT scan and (b) MRI.

[0071] The present disclosure includes wherein the tumor burden and / or tumor size is measured after one or more treatment cycles.

[0072] The present disclosure includes wherein the tumor size is less than about 80%, less than about 60%, less than about 30%, less than about 20%, or less than about 10% relative to baseline of total tumor burden in the patient.

[0073] The present disclosure includes a method of identifying whether a patient having a condition is likely to be responsive to administration of a compound:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206 Compound 2, or a pharmaceutically acceptable saltthereof, comprising: (i) obtaining a biological sample from the patient; (ii) measuring expression levels of caseinolytic protease proteolytic subunit (ClpP) in the sample; (iii) comparing the expression levels measured in the sample to those fora pre-determined standard; and (iv) determining whether the patient is likely to be responsive to the administration of ONC206 or a pharmaceutically acceptable salt thereof, based on the levels of expression measured in the sample to those for the pre-determined standard.

[0074] The present disclosure includes wherein the step of measuring the expression level includes the steps of (a) analyzing the sample in a binding diagnostic for ClpP, said diagnozstic is one or more of physical and functional; and (b) measuring the amount of ClpP binding to inform therapy.

[0075] The present disclosure includes wherein the step includes one or more of affinity chromatography, mass spectrometry, peptidase activity, knockdown study, or crystallography or structure analysis.

[0076] The present disclosure includes a method of identifying whether a patient having a condition is likely to be responsive to administration of a compound,N N ONC-206 Compound 2pharmaceutically acceptable salt thereof, comprising: (i) obtaining a biological sample from the patient; (ii) measuring mutations in succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) gene in the sample; (iii) comparing the mutations found in the sample to those fora pre-determined standard; and (iv) determining whether the patient is likely to be responsive to the administration of ONC206 or a pharmaceuticallyPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)acceptable salt thereof, based on the mutations found in the sample to those for the pre-determined standard.

[0077] The present disclosure includes wherein an increase in mutations measured in the sample relative to the pre-determined standard indicates that the patient is likely to be responsive to administration of ONC206, or a pharmaceutically acceptable salt thereof.

[0078] The present disclosure includes a step of administering to the patient a therapeutically effective amount of ONC206 or a pharmaceutically acceptable salt thereof.

[0079] The present disclosure includes a step of selecting the dosage, the frequency of administration, or both, of ONC206 or a pharmaceutically acceptable salt thereof, based on the levels or identity of mutations found.

[0080] The present disclosure includes a method of assessing the effectiveness of or monitoring a patient having a condition and undergoing administration of aFONC-206 Compound 2Ncompound:, ora pharmaceutically acceptable saltthereof, comprising: (i) obtaining a biological sample from the patient; (ii) measuring a level of ClpP in the sample; (iii) comparing the level measured in the sample to those for a pre-determined standard; and (iv) determining whether the patient is responsive to the administration of ONC206 or a pharmaceutically acceptable salt thereof, based on the level of ClpP measured in the sample to those forthe pre-determined standard.

[0081] The present disclosure includes wherein the step of measuring the level further comprises the steps of (a) analyzing the sample in a binding diagnostic for ClpP, said diagnozstic is one or more of physical and functional; and (b) measuring the amount of ClpP binding to inform therapy.

[0082] The present disclosure includes a method of assessing the effectiveness of or monitoring a patient having a condition and undergoing administration of aPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)Q FONC-206 Compound 2■t 'N compound:' - ' , ora pharmaceutically acceptable saltthereof, comprising: (i) obtaining a biological sample from the patient; (ii) measuring the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) in the sample; (iii) comparing the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) found in the sample to those for a pre-determined standard; and (iv) determining whether the patient is responsive to the administration of the ONC206 or a pharmaceutically acceptable saltthereof, based on the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) found in the sample to those forthe pre-determined standard.

[0083] The present disclosure includes wherein an increased level of the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) measured in the sample relative to the pre-determined standard indicates that administration of ONC206 or a pharmaceutically acceptable salt thereof to the patient is not effective.

[0084] The present disclosure includes administering an effective amount of ONC206 or a pharmaceutically acceptable salt thereof, to the patient.

[0085] The present disclosure includes a step of adjusting the dosage, the frequency or both of administration of ONC206 or a pharmaceutically acceptable salt thereof, based on the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) found.

[0086] One embodiment of the present disclosure includes a method of treating one or more neuroendocrine cancer, including one or more PCPG, with the administration to a patient in need thereof an effective amount of Compound 2 (ONC-206), or a pharmaceutically acceptable salt thereof.

[0087] One embodiment of the present disclosure includes a method of treating one or more neuroendocrine tumors that arise from the neural crest, including one or more tumors that arise from the adrenal medulla (pheochromocytoma) orsympathetic / parasympathetic ganglia (paraganglioma) with the administration to aPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)patient in need thereof an effective amount of Compound 2 (ONC-206), or a pharmaceutically acceptable salt thereof.

[0088] One embodiment of the present disclosure includes a method of treating one or more of:(i) PCPG Cluster 1 : Psuedohypoxia Subtype,(ii) PCPG Cluster 2: Kinase Signlaing Subtype,(iii) PCPG Cluster 3: Wnt-Altered Subtype, and(iv) Cortical Admixture Subtype,with the administration to a patient in need thereof an effective amount of Compound 2 (ONC-206), or a pharmaceutically acceptable salt thereof.

[0089] Based on The Cancer Genome Atlas (TCGA) and other molecular studies, PCPG may be categorized into four main molecular subtypes based on one or more of underlying driver mutations, gene expression profiles, and signalingpathways. Pseudohypoxia Subtype (Cluster 1 ) group is characterized by the activation of hypoxia-inducible factors (HIFs) under normal oxygen levels (normoxia), leading to pseudohypoxia, neoangiogenesis, and metabolic reprogramming. SDHx-related (Cluster 1 A) involves germline mutations in succinate dehydrogenase complex genes (SDHA, SDHB, SDHC, SDHD) and assembly factor SDHAF2. SDHB mutations are often associated with higher metastatic risk. VHL-related (Cluster 1 B) involves mutations in the VHL gene, often resulting in adrenal tumors. Other Pseudohypoxic Drivers include mutations in EPAS1 (HIF2A), EGLN1 , EGLN2, and FH. In an embodiment the mutation includes SDHB. In an embodiment the mutation includes FH. Kinase Signaling Subtype (Cluster 2) group is driven by alterations in kinase signaling pathways, affecting protein synthesis and neural differentiation. Primary drivers include NF1, RET, TMEM127, MAX, and HRAS. Subgroups are often further divided, namely to provide subclasses 2A, 2B, and 2C, which include sporadic (non-hereditary) cases as well as germline mutations. Wnt-Altered Subtype (Cluster 3) group is characterized by mutations or fusions that activate the Wnt signaling pathway, which is often associated with more aggressive or metastatic behavior. Key Drivers include MAML3 fusion genes, CSDE1 mutations, and sometimes UBTF-MAML3. In addition, there is a recognized Cortical Admixture Subtype, which is identified by the presence of molecular markers that resemblePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)normal adrenal cortex tissue. It suggests a distinct cell-of-origin or differentiation pattern within the tumor.

[0090] One embodiment of the present disclosure includes a method of treating one or more of a PCPG cancer categorized by (i) anatomical location, (ii) clinical behavior, and (iii) metabolic profiling.

[0091] PCPG may be characterized based on anatomical location, including pheochromocytoma (adrenal) compared to paraganglioma (extra-adrenal); clinical behavior, including benign compared to metastatic (where metastatic disease is believed to be highly associated with SDHB mutations and MAML3 fusions); and metabolic profiles, including noradrenergic (Cluster 1 , often SDHx or VHL) compared to adrenergic (Cluster ).

[0092] It is believed that up to 40% of all PCPG cases are associated with hereditary susceptibility genes, while 30-40% are sporadic.

[0093] As set forth herein Compound 2 may be referred to as ONC-206, or as 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1 ,2-a]pyrido[3,4-e]pyrimidin-5(1 H)-one, or a salt thereof.

[0094] In one aspect, the administration reduces one or more symptom of PCPG.

[0095] In one aspect, the administration reduces tumor growth.

[0096] In one aspect, the 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, and (viii) increased time to progression.

[0097] In one aspect, the administration is made in combination with one or more additional therapy or therapeutic agent.

[0098] In one aspect, the dose of ONC-206 or a salt thereof is from about 25 mg to about 300 mg, based on free base form. In one aspect, an upper dose may be about 2 to 3 grams.

[0099] In one aspect, the dose is about 150 mg.

[0100] In one aspect, the dose provided is dose provided is daily, twice a week, three times a week, four times a week, five times a week, six times a week, weekly, biweekly, or monthly. In one aspect, the dose is three times a day, twice daily, daily,PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)every other day, every third day, every fourth day, every fifth day, every sixth day, or weekly.

[0101] In one aspect, the dose is 150 mg twice daily, on 3 consecutive days per 7-day week, in a 28-day cycle.

[0102] In one aspect, a total weekly dose of ONC-206 is about 900 mg.

[0103] In one aspect, the ONC-206 is the di-HCl salt.

[0104] In one aspect, the treatment is administered at least 30 days post-radiation. In one aspect, the treatment is administered at least 60 days post-radiation. In one aspect, the treatment is administered at least 90 days post-radiation.

[0105] In one aspect, the treatment is administered after surgical resection.

[0106] In one aspect, an objective response rate is measured by one or more of RANG criteria, overall survical, progression-free survival, and disease control rate.

[0107] One embodiment of the present disclosure includes 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(1 H)-one, or a salt thereof, in the preparation of a medicament for treating one or more PCPG.

[0108] In one aspect, the administeringfor three consecutive days is followed by four days without dosing ONC-206, which may be referred to as a drug holiday. In one aspect, the administration reduces one or more symptom of the cancer. In one aspect, the administration reduces tumor growth. In one aspect, the 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, and (viii) increased time to progression.

[0109] Certain embodiments of the present disclosure may be phrased in a method of treatment format. The present disclosure includes any alternative jurisdictional claiming format, including but not limited to first and second medical use claims, including EPC2000 format, composition for use claims, purpose-limited composition claims, general composition claims, Swiss-type use claims, use claims, kit claims, omnibus claims, means-plus-function claims, and parametier-based claims.

[0110] The preceding is a summary to provide an introduction and understanding of some embodiments of the present disclosure. This summary is neither an extensivePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)nor exhaustive presentation of the present disclosure and its various embodiments. As will be appreciated, other embodiments of the present disclosure are possible utilizing, alone or in combination, one or more of the features, embodiments, and aspects set forth above or described in detail below. Each of those combinations of features, embodiments, and aspects should be considered as disclosed embodiments themselves.BRIEF DESCRIPTION OF THE DRAWINGS

[0111] This brief description, as well as the following detailed description of embodiments of the present disclosure, will be better understood when read in conjunction with the appended drawings of an exemplary embodiment. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities shown.

[0112] Figure 1 illustrates a schematic of a Study Design of the present disclosure.

[0113] Figure 2 illustrates a proposed ONC206 mechanism of action.

[0114] Figure 3 illustrates ONC206 inhibition of cell viability of pheochromocytoma cells in vitro.

[0115] Figure 4 illustrates that ONC206 induces apoptosis in pheochromocytoma cells in vitro.

[0116] Figure 5 illustrates that ONC206 inhibits cell viability in pheochromocytoma cells with SDHB or FH knockout in vitro.

[0117] Figure 6 illustrates that ClpP expression is essential for ONC206 efficacy in pheochromocytoma cells.

[0118] Figure 7 illustrates that ONC206 downregulates mitochondrial proteins, neuroendocrine markers and upregulates stress response in pheochromocytoma cells.

[0119] Figure 8 illustrates the impact of ONC206 treatment duration on cell viability.

[0120] Figure 9 illustrates the mean ONC206 plasma concentrations after single oral administration of ONC206 to rats (50 mg / kg) and dogs (16.7 mg / kg) [linear and log plots].

[0121] Figure 10 illustrates liver chemistry stopping criteria and increased monitoring algorithm.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0122] Figure 11 illustrates representative dose-response curves for ONC206, sunitinib (SUN), and temozolomide (TMZ) in indicated cell lines after 3 days of treatment. ONC206 demonstrates superior cell viability inhibition and apoptosis in PC cell lines relative to TMZ and SUN.

[0123] Figure 12 illustrates PC and fibroblast cell lines with indicated concentrations of ONC206, SUN, and TMZ.

[0124] Figure 13 illustrates acquired resistance to ONC206 in hPheol cells.Treatment to generate acquired resistance was initiated at 0.2 pM ONC206 and drug concentration was doubled when cells were able to proliferate.

[0125] Figure 14 illustrates that seahorse analysis of hPheol cells with acquired resistance to ONC206 reveals impaired effects on glycol and mito ATP compared to parental cells.

[0126] Figure 15 illustrates that ONC206 inhibits cell migration in PCPG cell lines.

[0127] Figure 16 illustrates that ONC206 inhibits cell invasion in PCPG cell lines.

[0128] Figure 17 illustrates that ONC206 inhibitsTGF-pi-mediated induction of EMT biomarkers in PCPG cells.

[0129] Figure 18 ilustrates a proteomics analysis illustrating that ONC206 inhibits mitochondrial metabolism including OXPHOS and TCA cycle in hPheol cells. In more detail, Volcano plot showing differentially abundant proteins between ONC206-treated (0.55uM, 24h) and control hPheol cells. Green dots represent proteins with a false discovery rate (FDR) below 5%. Score: -log10(adjusted p-value); logFC: log2(ONC206 / Ctrl). As shown, an overrepresentation analysis (bar chart) of depleted proteins, highlights the most significantly enriched biologicalterms.

[0130] Figure 19 illustrates an metabolomic analysis which reveals ONC206 elevated a-ketoglutaric acid, 2-hydroxyglutaric acid and reduced succinic acid, fumaric acid in a ClpP-dependent manner in hPheol cells. In more detail, box plots show the effect of ONC206 treatment (0.55pM 48hrs) on selected metabolites in wild-type (WT) and ClpP knockout (KO) hPheol cells. * p<0.05 (Welch's t-test).

[0131] Figure 20 illustrates ATACseq showing altered chromatin accessibility in response to ONC206 treatment in hPheol cells. In more detail, a volcano plot shows differentially accessible chromatin regions identified byATAC sequencing of hPheolPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)cells treated with 0.55 pM ONC206 for 48 h vs. control untreated cells. Dots represent regions with an FDR below 5%. Score: -log10(p-value); logFC: log2(Ctrl / ONC206).

[0132] Figure 21 illustrates an RNAseq analysis which demonstrates ONC206 upregulated stress response, apoptosis and downregulated cell cycle, metabolism-related pathways in hPheol cells. An overrepresentation analysis of biological processes enriched or depleted (FDR < 5%) in significantly altered mRNAs following ONC206 (0.55pM) treatment of Pheol cells. The panels show the most significantly enriched terms at 24 and 48 hours post-treatment.

[0133] Figure 22 illustrates positions of ClpP mutations identified in ONC206 resistant hPheol cells. As shown, Q137X is a termination. Whole exome sequencing was performed at Novogen.

[0134] Figure 23 illustrates ClpP expression in hPheol cells with acquired resistance to ONC206. RT-PCR and Western blot analysis for ClpP and Actin expression in clones with acquired resistance to ONC206 (1.6 pM). Lines A, B, C were selected under 3 days on / 4 days off regimen. Lines D, E, F were selected under constant ONC206.

[0135] Figure 24 illustrates overexpression of wild type ClpP in ONC206-resistant hPheol lines, reverses resistance.

[0136] Figure 25 illustrates overexpression of wt and mutant ClpP in parental hPheol . Representative dose-response curves of ONC206 in wild-type hPheol cells transduced with mutant ClpP lentiviruses or empty vector control lentivirus (EV). Cells were plated in 96-well plates with indicated concentrations of ONC206 and readout with CTG (measures cell ATP content) after 4 days treatment. As otherwise noted herein, Q137X is a termination mutation and is not expected to express protein.

[0137] Figure 26 illustrates that ONC206 inhibits cell viability in PC cells with DRD2 overexpression in vitro. Figure 26 shows representative dose-response curves of ONC206 (after 96-hour treatment) in human hPheol cells with orwithout DRD2 overexpression. Cells were plated in 96-well plates with indicated concentrations of ONC206 and readout with CTG (measures cell ATP content) after 4 days treatment. In more detail, immunofluorescence staining is shown in hPheol -NTC and DRD2 overexpression cell lines.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)DETAILED DESCRIPTION OF THE INVENTION

[0138] ONC206, which may be referred to as Compound 2 herein, is the second imipridone to enter clinical development, is a DRD2 antagonist and ClpP agonist that exhibits differentiated receptor pharmacology and gene expression profiles in tumors relative to ONC201.I. COMPOUNDS

[0139] 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(1 H)-one, and in one embodiment, is provided as a dihydrochloride salt.

[0140] One embodiment of the present disclosure includes a pharmaceutical composition, comprising ONC-206, or a salt thereof.ONC-206 Compound 2

[0141] In one embodiment, a pharmaceutical composition comprises ONC-206 or a pharmaceutically acceptable mono-salt thereof. In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharmaceutically acceptable disalt thereof. In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharmaceutically acceptable mono- or multi-salt (e.g., di-salt or tri-salt, where it is understood that throughout this disclosure a di-salt encompasses a tri-salt or other multi-salt) thereof selected from the group consisting of hydrochloride, hydrobromide, hydrogensulphate, sulfates, phosphates, fumarates, succinates, oxalates and lactates, bisulfates, 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 pharmaceutically acceptable salt thereof selected from the group consisting of p-toluene-sulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumaratePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)and maleate. In one embodiment, the pharmaceutical composition comprises ONC-206 or a pharmaceutically acceptable salt selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and / orwith counter-ions such as methylamino, dimethylamino, diethylamino and triethylamino counter-ions. In one embodiment, the pharmaceutical composition comprises ONC-206, a hydrochloride di-salt thereof (e.g., di-hydrochloride salt) or a hydrobromide disalt thereof (e.g., di-hydrobromide salt).

[0142] In one embodiment, a pharmaceutical composition in accordance with the present disclosure includes a di-salt (e.g., a di-hydrochloride salt) of ONC-206. Salts (e.g., di-salts, tri-salts, or mutli-salts) of ONC-206 can be prepared from ONC-206, which can be obtained commercially or synthesized using standard chemical synthetic methodology known to one of ordinary skill in the art.

[0143] Dihydrochloride salts of compounds within the class of impiridones of which ONC-206 is a member, achieve unexpected technical effects. As one example, a comparison between the a dihydrochloride salt of ONC-201 and the corresponding free base demonstrates that the solubility of the dihydrochloride salt in water is greater than 50 mg / mL, while it is less than 1 mg / mLforthe free base. In addition, after two months at 25 °C and at 40 °C, the percentage of impurities in the dihydrochloride salt is not detected and 3%, respectively; while for the free base the corresponding the percentage of impurities is 20% and 24%, respectively. This technical effect appears to extend to the class of impiridones.II. DOSE

[0144] In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose ranging from about 10 mg to about 2000 mg, where the weight can, in certain embodiments be based on ONC-206 in its free base form.

[0145] In one embodiment, ONC206 will be administered on a BID TIW dosing schedule every 12 hours (±2 hours) on 3 consecutive days per week (Days 1 , 2, and 3, during Week 1 ; Days 8, 9, and 10, during Week 2; Days 15, 16, and 17, during Week 3; and Days 22, 23, and 24, during Week 4) for each 28-day cycle until one or more ofPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)disease progression, unacceptable toxicity, patient / physician decision to withdraw from the study, and the end of treatment occurs.

[0146] In one emboidment, a patient is an adult and the dose is calculated accordingly. In one embodiment, the patient is pediatric and the dose is calculated accordingly. In one embodiment, a pharmaceutical composition accordingto the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose ranging from about 25 mg to about 2000 mg, where the weight can, in certain embodiments be based on ONC-206 in its free base form. In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose ranging from about 50 mg to about 2000 mg, where the weight can, in certain embodiments be based on ONC-206 in its free base form. In one embodiment, a pharmaceutical composition accordingto the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose ranging from about 60 mg to about 2000 mg, where the weight can, in certain embodiments be based on ONC-206 in its free base form. In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected for oral dosing from the group consisting of from about 10 mg to about 200 mg, from about 10 mg to about 300 mg, from about 10 mg to about 400 mg, from about 10 mg to about 500 mg, from about 10 mg to about 600 mg, from about 10 mg to about 700 mg, from about 10 mg to about 800 mg, from about 10 mg to about 900 mg, from about 10 mg to about 1000 mg, from about 10 mg to about 1100 mg, from about 10 mg to about 1200 mg, from about 10 mg to about 1300 mg, from about 10 mg to about 1400 mg, from about 10 mg to about 1500 mg, from about 10 mg to about 1600 mg, from about 10 mg to about 1700 mg, from about 10 mg to about 1800 mg, and from about 10 mg to about 1900 mg, and from about 10 mg to about 2000 mg. In one embodiment, a pharmaceutical composition accordingto the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 15 mg to about 200 mg, from about 15 mg to about 300 mg, from about 15 mg to about 400 mg, from about 15 mg to about 500 mg, from about 15 mg to about 600 mg, from about 15 mg to about 700 mg, from about 15 mg to about 800 mg, from about 15 mg to about 900 mg,PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)from about 15 mg to about 1000 mg, from about 15 mg to about 1100 mg, from about 15 mg to about 1200 mg, from about 15 mg to about 1300 mg, from about 15 mg to about 1400 mg, from about 15 mg to about 1500 mg, from about 15 mg to about 1600 mg, from about 15 mg to about 1700 mg, from about 15 mg to about 1800 mg, and from about 15 mgto about 1900 mg, and from about 15 mgto about 2000 mg. In one embodiment, a pharmaceutical composition accordingto the disclosure comprises ONC-206 ora pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 20 mgto about 200 mg, from about 20 mgto about 300 mg, from about 20 mg to about 400 mg, from about 20 mg to about 500 mg, from about 20 mgto about 600 mg, from about 20 mgto about 700 mg, from about 20 mgto about 800 mg, from about 20 mg to about 900 mg, from about 20 mg to about 1000 mg, from about 20 mgto about 1100 mg, from about 20 mg to about 1200 mg, from about 20 mg to about 1300 mg, from about 20 mg to about 1400 mg, from about 20 mg to about 1500 mg, from about 20 mg to about 1600 mg, from about 20 mg to about 1700 mg, from about 20 mgto about 1800 mg, and from about 20 mgto about 1900 mg, and from about 20 mg to about 2000 mg. In one embodiment, a pharmaceutical composition accordingto the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 25 mgto about 200 mg, from about 25 mg to about 300 mg, from about 25 mg to about 400 mg, from about 25 mgto about 500 mg, from about 25 mgto about 600 mg, from about 25 mgto about 700 mg, from about 25 mg to about 800 mg, from about 25 mg to about 900 mg, from about 25 mgto about 1000 mg, from about 25 mg to about 1100 mg, from about 25 mg to about 1200 mg, from about 25 mg to about 1300 mg, from about 25 mg to about 1400 mg, from about 25 mg to about 1500 mg, from about 25 mg to about 1600 mg, from about 25 mgto about 1700 mg, from about 25 mg to about 1800 mg, from about 25 mgto about 1900 mg, and from about 25 mgto 2000 mg. In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 30 mg to about 200 mg, from about 30 mg to about 300 mg, from about 30 mg to about 400 mg, from about 30 mg to about 500 mg, from about 30 mgto about 600 mg, from about 30 mgto about 700 mg, from about 30 mgto about 800PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)mg, from about 30 mg to about 900 mg, from about 30 mg to about 1000 mg, from about 30 mg to about 1100 mg, from about 30 mg to about 1200 mg, from about 30 mg to about 1300 mg, from about 30 mg to about 1400 mg, from about 30 mg to about 30 mg, from about 30 mg to about 1600 mg, from about 30 mg to about 1700 mg, from about 30 mg to about 1800 mg, and from about 30 mg to about 1900 mg based on ONC-206 in its free base form. In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 35 mg to about 200 mg, from about 35 mg to about 300 mg, from about 35 mg to about 400 mg, from about 35 mg to about 500 mg, from about 35 mg to about 600 mg, from about 35 mg to about 700 mg, from about 35 mg to about 800 mg, from about 35 mg to about 900 mg, from about 35 mg to about 1000 mg, from about 35 mg to about 1100 mg, from about 35 mg to about 1200 mg, from about 35 mg to about 1300 mg, from about 35 mg to about 1400 mg, from about 35 mg to about 1500 mg, from about 35 mg to about 1600 mg, from about 35 mg to about 1700 mg, from about 35 mg to about 1800 mg, and from about 35 mg to about 1900 mg, and from about 35 mg to about 2000 mg. All values are based on ONC-206 in its free base form. In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, and from about 95 mg to about 100 mg.

[0147] In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose ranging from about 0.10 mg / kgto about 40 mg / kg. In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the groupPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)consisting of from 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, from about 2 mg / Kg to about 40 mg / Kg, from about 3 mg / Kg to about 40 mg / Kg, from about 4 mg / Kg to about 40 mg / Kg, from about 5 mg / Kg to about 40 mg / Kg, from about 6 mg / Kg to about 40 mg / Kg, from about 7 mg / Kg to about 40 mg / Kg, from about 8 mg / Kg to about 40 mg / Kg, from about 9 mg / Kg to about 40 mg / Kg, from about 10 mg / Kg to about 40 mg / Kg, from about 11 mg / Kg to about 40 mg / Kg, from about 12 mg / Kg to about 40 mg / Kg, from about 13 mg / Kg to about 40 mg / Kg, from about 14 mg / Kg to about 40 mg / Kg, from about 15 mg / Kg to about 40 mg / Kg, from about 16 mg / Kg to about 40 mg / Kg, from about 17 mg / Kg to about 40 mg / Kg, from about 18 mg / Kg to about 40 mg / Kg, from about 19 mg / Kg to about 40 mg / Kg, from about 20 mg / Kg to about 40 mg / Kg, from about 21 mg / Kg to about 40 mg / Kg, from about 22 mg / Kg to about 40 mg / Kg, from about 23 mg / Kg to about 40 mg / Kg, from about 24 mg / Kg to about 40 mg / Kg, from about 25 mg / Kg to about 40 mg / Kg, from about 26 mg / Kg to about 40 mg / Kg, from about 27 mg / Kg to about 40 mg / Kg, from about 28 mg / Kg to about 40 mg / Kg, from about 29 mg / Kg to about 40 mg / Kg, from about 30 mg / Kg to about 40 mg / Kg, from about 31 mg / Kg to about 40 mg / Kg, from about 32 mg / Kg to about 40 mg / Kg, from about 33 mg / Kg to about 40 mg / Kg, from about 34 mg / Kg to about 40 mg / Kg, from about 35 mg / Kg to about 40 mg / Kg, from about 36 mg / Kg to about 40 mg / Kg, from about 37 mg / Kg to about 40 mg / Kg, from about 38 mg / Kg to about 40 mg / Kg, and from about 39 mg / Kg to about 40 mg / Kg.

[0148] In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 1 mg / Kg to about 30 mg / Kg, from about 2 mg / Kg to about 30 mg / Kg, from about 3 mg / Kg to about 30 mg / Kg, from about 4 mg / Kg to about 30 mg / Kg, from about 5 mg / Kg to about 30 mg / Kg, from about 6 mg / Kg to about 30 mg / Kg, from about 7 mg / Kg to about 30 mg / Kg, from about 8 mg / Kg to about 30 mg / Kg, from about 9 mg / Kg to about 30 mg / Kg, from about 10 mg / Kg to about 30PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)mg / Kg, from about 11 mg / Kg to about 30 mg / Kg, from about 12 mg / Kg to about 30 mg / Kg, from about 13 mg / Kg to about 30 mg / Kg, from about 14 mg / Kg to about 30 mg / Kg, from about 15 mg / Kg to about 30 mg / Kg, from about 16 mg / Kg to about 30 mg / Kg, from about 17 mg / Kg to about 30 mg / Kg, from about 18 mg / Kg to about 30 mg / Kg, from about 19 mg / Kg to about 30 mg / Kg, from about 20 mg / Kg to about 30 mg / Kg, from about 21 mg / Kg to about 30 mg / Kg, from about 22 mg / Kg to about 30 mg / Kg, from about 23 mg / Kg to about 30 mg / Kg, from about 24 mg / Kg to about 30 mg / Kg, from about 25 mg / Kg to about 30 mg / Kg, from about 26 mg / Kg to about 30 mg / Kg, from about 27 mg / Kg to about 30 mg / Kg, from about 28 mg / Kg to about 30 mg / Kg, and from about 29 mg / Kg to about 30 mg / Kg.

[0149] In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 1 mg / Kg to about 20 mg / Kg, from about 2 mg / Kg to about 20 mg / Kg, from about 3 mg / Kg to about 20 mg / Kg, from about 4 mg / Kg to about 20 mg / Kg, from about 5 mg / Kg to about 20 mg / Kg, from about 6 mg / Kg to about 20 mg / Kg, from about 7 mg / Kg to about 20 mg / Kg, from about 8 mg / Kg to about 20 mg / Kg, from about 9 mg / Kg to about 20 mg / Kg, from about 10 mg / Kg to about 20 mg / Kg, from about 11 mg / Kg to about 20 mg / Kg, from about 12 mg / Kg to about 20 mg / Kg, from about 13 mg / Kg to about 20 mg / Kg, from about 14 mg / Kg to about 20 mg / Kg, from about 15 mg / Kg to about 20 mg / Kg, from about 16 mg / Kg to about 20 mg / Kg, from about 17 mg / Kg to about 20 mg / Kg, from about 18 mg / Kg to about 20 mg / Kg, and from about 19 mg / Kg to about 20 mg / Kg.

[0150] In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 1 mg / Kg to about 10 mg / Kg, from about 2 mg / Kg to about 10 mg / Kg, from about 3 mg / Kg to about 10 mg / Kg, from about 4 mg / Kg to about 10 mg / Kg, from about 5 mg / Kg to about 10 mg / Kg, from about 6 mg / Kg to about 10 mg / Kg, from about 7 mg / Kg to about 10 mg / Kg, from about 8 mg / Kg to about 10 mg / Kg, and from about 9 mg / Kg to about 10 mg / Kg.

[0151] In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dosePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)level ranging from about 12.5 mg / m2to about 1500 mg / m2. In one embodiment, a pharmaceutical composition according to the disclosure comprises ONC-206 or a pharmaceutically acceptable salt thereof in a dose level selected from the group consisting of from about 15 mg / m2to about 1500 mg / m2, from about 20 mg / m2to about 1500 mg / m2, from about 25 mg / m2to about 1 500 mg / m2, from about 30 mg / m2to about 1500 mg / m2, from about 35 mg / m2to about 1500 mg / m2, from about 40 mg / m2to about 1500 mg / m2, from about 45 mg / m2to about 1500 mg / m2, from about 50 mg / m2to about 1500 mg / m2, from about 55 mg / m2to about 1500 mg / m2, from about 60 mg / m2to about 1500 mg / m2, from about 65 mg / m2to about 1500 mg / m2, from about 70 mg / m2to about 1500 mg / m2, from about 75 mg / m2to about 1500 mg / m2, from about 80 mg / m2to about 1500 mg / m2, from about 85 mg / m2to about 1500 mg / m2, from about 90 mg / m2to about 1500 mg / m2, from about 95 mg / m2to about 1500 mg / m2, from about 100 mg / m2to about 1500 mg / m2, from about 105 mg / m2to about 1500 mg / m2, from about 110 mg / m2to about 1500 mg / m2, from about 115 mg / m2to about 1500 mg / m2, from about 120 mg / m2to about 1500 mg / m2, from about 125 mg / m2to about 1500 mg / m2, from about 130 mg / m2to about 1500 mg / m2, from about 135 mg / m2to about 1500 mg / m2, from about 1 0 mg / m2to about 1500 mg / m2, from about 145 mg / m2to about 1500 mg / m2, from about 150 mg / m2to about 1500 mg / m2, from about 155 mg / m2to about 1500 mg / m2, from about 160 mg / m2to about 1500 mg / m2, from about 165 mg / m2to about 1500 mg / m2, from about 170 mg / m2to about 1500 mg / m2, from about 175 mg / m2to about 1500 mg / m2, from about 180 mg / m2to about 1500 mg / m2, from about 185 mg / m2to about 1500 mg / m2, from about 190 mg / m2to about 1500 mg / m2, from about 195 mg / m2to about 1500 mg / m2, from about 200 mg / m2to about 1500 mg / m2, from about 205 mg / m2to about 1500 mg / m2, from about 210 mg / m2to about 1500 mg / m2, from about 215 mg / m2to about 1500 mg / m2, from about 220 mg / m2to about 1500 mg / m2, from about 225 mg / m2to about 1500 mg / m2, from about 230 mg / m2to about 1500 mg / m2, from about 235 mg / m2to about 1500 mg / m2, from about 240 mg / m2to about 1500 mg / m2, from about 245 mg / m2to about 1500 mg / m2, from about 250 mg / m2to about 1500 mg / m2, from about 255 mg / m2to about 1500 mg / m2, from about 260 mg / m2to about 1500 mg / m2, from about 265 mg / m2to about 1500 mg / m2, from about 270 mg / m2to about 1500 mg / m2, from about 275 mg / m2to about 1500 mg / m2, from aboutPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)280 mg / m2to about 1500 mg / m2, from about 285 mg / m2to about 1500 mg / m2, from about 290 mg / m2to about 1500 mg / m2, from about 295 mg / m2to about 1500 mg / m2, from about 300 mg / m2to about 1500 mg / m2, from about 305 mg / m2to about 1500 mg / m2, from about 310 mg / m2to about 1500 mg / m2, from about 315 mg / m2to about 1500 mg / m2, from about 320 mg / m2to about 1500 mg / m2, from about 325 mg / m2to about 1500 mg / m2, from about 330 mg / m2to about 1500 mg / m2, from about 335 mg / m2to about 1500 mg / m2, from about 340 mg / m2to about 1500 mg / m2, from about 345 mg / m2to about 1500 mg / m2, from about 350 mg / m2to about 1500 mg / m2, from about 355 mg / m2to about 1500 mg / m2, from about 360 mg / m2to about 1500 mg / m2, from about 365 mg / m2to about 1500 mg / m2, from about 370 mg / m2to about 1500 mg / m2, from about 375 mg / m2to about 1500 mg / m2, from about 380 mg / m2to about 1500 mg / m2, from about 385 mg / m2to about 1500 mg / m2, from about 390 mg / m2to about 1500 mg / m2, from about 395 mg / m2to about 1500 mg / m2, from about 400 mg / m2to about 1500 mg / m2, from about 405 mg / m2to about 1500 mg / m2, from about 410 mg / m2to about 1500 mg / m2, from about 415 mg / m2to about 1500 mg / m2, from about 420 mg / m2to about 1500 mg / m2, from about 425 mg / m2to about 1500 mg / m2, from about 430 mg / m2to about 1500 mg / m2, from about 435 mg / m2to about 1500 mg / m2, from about 440 mg / m2to about 1500 mg / m2, from about 445 mg / m2to about 1500 mg / m2, from about 450 mg / m2to about 1500 mg / m2, from about 455 mg / m2to about 1500 mg / m2, from about 460 mg / m2to about 1500 mg / m2, from about 465 mg / m2to about 1500 mg / m2, from about 470 mg / m2to about 1500 mg / m2, from about 475 mg / m2to about 1500 mg / m2, from about 480 mg / m2to about 1500 mg / m2, from about 485 mg / m2to about 1500 mg / m2, from about 490 mg / m2to about 1500 mg / m2, from about 495 mg / m2to about 1500 mg / m2, from about 500 mg / m2to about 1500 mg / m2, from about 505 mg / m2to about 1500 mg / m2, from about 510 mg / m2to about 1500 mg / m2, from about 515 mg / m2to about 1500 mg / m2, from about 520 mg / m2to about 1500 mg / m2, from about 525 mg / m2to about 1500 mg / m2, from about 530 mg / m2to about 1500 mg / m2, from about 535 mg / m2to about 1500 mg / m2, from about 540 mg / m2to about 1500 mg / m2, from about 545 mg / m2to about 1500 mg / m2, from about 550 mg / m2to about 1500 mg / m2, from about 555 mg / m2to about 1500 mg / m2, from about 560 mg / m2to about 1500 mg / m2, from about 565 mg / m2to about 1500 mg / m2, from about 570PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)mg / m2to about 1500 mg / m2, from about 575 mg / m2to about 1500 mg / m2, from about 580 mg / m2to about 1500 mg / m2, from about 585 mg / m2to about 1500 mg / m2, from about 590 mg / m2to about 1500 mg / m2, from about 595 mg / m2to about 1500 mg / m2, from about 600 mg / m2to about 1500 mg / m2, from about 605 mg / m2to about 1500 mg / m2, from about 610 mg / m2to about 1500 mg / m2, from about 615 mg / m2to about 1500 mg / m2, from about 620 mg / m2to about 1500 mg / m2, from about 625 mg / m2to about 1500 mg / m2, from about 630 mg / m2to about 1500 mg / m2, from about 635 mg / m2to about 1500 mg / m2, from about 640 mg / m2to about 1500 mg / m2, from about 645 mg / m2to about 1500 mg / m2, from about 650 mg / m2to about 1500 mg / m2, from about 655 mg / m2to about 1500 mg / m2, from about 660 mg / m2to about 1500 mg / m2, from about 665 mg / m2to about 1500 mg / m2, from about 670 mg / m2to about 1500 mg / m2, from about 675 mg / m2to about 1500 mg / m2, from about 680 mg / m2to about 1500 mg / m2, from about 685 mg / m2to about 1500 mg / m2, from about 690 mg / m2to about 1500 mg / m2, from about 695 mg / m2to about 1500 mg / m2, from about 700 mg / m2to about 1500 mg / m2, from about 705 mg / m2to about 1500 mg / m2, from about 710 mg / m2to about 1500 mg / m2, from about 715 mg / m2to about 1500 mg / m2, from about 720 mg / m2to about 1500 mg / m2, from about 725 mg / m2to about 1500 mg / m2, from about 730 mg / m2to about 1500 mg / m2, from about 735 mg / m2to about 1500 mg / m2, from about 740 mg / m2to about 1500 mg / m2, from about 745 mg / m2to about 1500 mg / m2, from about 750 mg / m2to about 1500 mg / m2, from about 755 mg / m2to about 1500 mg / m2, from about 760 mg / m2to about 1500 mg / m2, from about 765 mg / m2to about 1500 mg / m2, from about 770 mg / m2to about 1500 mg / m2, from about 775 mg / m2to about 1500 mg / m2, from about 780 mg / m2to about 1500 mg / m2, from about 785 mg / m2to about 1500 mg / m2, from about 790 mg / m2to about 1500 mg / m2, from about 795 mg / m2to about 1500 mg / m2, from about 800 mg / m2to about 1500 mg / m2, from about 805 mg / m2to about 1500 mg / m2, from about 810 mg / m2to about 1500 mg / m2, from about 815 mg / m2to about 1500 mg / m2, from about 820 mg / m2to about 1500 mg / m2, from about 825 mg / m2to about 1500 mg / m2, from about 830 mg / m2to about 1500 mg / m2, from about 835 mg / m2to about 1500 mg / m2, from about 840 mg / m2to about 1500 mg / m2, from about 845 mg / m2to about 1500 mg / m2, from about 850 mg / m2to about 1500 mg / m2, from about 855 mg / m2to about 1500 mg / m2, from about 860 mg / m2PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)to about 1500 mg / m2, from about 865 mg / m2to about 1500 mg / m2, from about 870 mg / m2to about 1500 mg / m2, from about 875 mg / m2to about 1500 mg / m2, from about 880 mg / m2to about 1500 mg / m2, from about 885 mg / m2to about 1500 mg / m2, from about 890 mg / m2to about 1500 mg / m2, from about 895 mg / m2to about 1500 mg / m2, from about 900 mg / m2to about 1500 mg / m2, from about 905 mg / m2to about 1500 mg / m2, from about 910 mg / m2to about 1500 mg / m2, from about 915 mg / m2to about 1500 mg / m2, from about 920 mg / m2to about 1500 mg / m2, from about 925 mg / m2to about 1500 mg / m2, from about 930 mg / m2to about 1500 mg / m2, from about 935 mg / m2to about 1500 mg / m2, from about 940 mg / m2to about 1500 mg / m2, from about 945 mg / m2to about 1500 mg / m2, from about 950 mg / m2to about 1500 mg / m2, from about 955 mg / m2to about 1500 mg / m2, from about 960 mg / m2to about 1500 mg / m2, from about 965 mg / m2to about 1500 mg / m2, from about 970 mg / m2to about 1500 mg / m2, from about 975 mg / m2to about 1500 mg / m2, from about 980 mg / m2to about 1500 mg / m2, from about 985 mg / m2to about 1500 mg / m2, from about 990 mg / m2to about 1500 mg / m2, from about 995 mg / m2to about 1500 mg / m2, from about 1000 mg / m2to about 1500 mg / m2, from about 1005 mg / m2to about 1500 mg / m2, from about 1010 mg / m2to about 1500 mg / m2, from about 1015 mg / m2to about 1500 mg / m2, from about 1020 mg / m2to about 1500 mg / m2, from about 1025 mg / m2to about 1500 mg / m2, from about 1030 mg / m2to about 1500 mg / m2, from about 1035 mg / m2to about 1500 mg / m2, from about 1040 mg / m2to about 1500 mg / m2, from about 1045 mg / m2to about 1500 mg / m2, from about 1050 mg / m2to about 1500 mg / m2, from about 1055 mg / m2to about 1500 mg / m2, from about 1060 mg / m2to about 1500 mg / m2, from about 1065 mg / m2to about 1500 mg / m2, from about 1070 mg / m2to about 1500 mg / m2, from about 1075 mg / m2to about 1500 mg / m2, from about 1080 mg / m2to about 1500 mg / m2, from about 1085 mg / m2to about 1500 mg / m2, from about 1090 mg / m2to about 1500 mg / m2, from about 1095 mg / m2to about 1500 mg / m2, from about 1100 mg / m2to about 1500 mg / m2, from about 1105 mg / m2to about 1500 mg / m2, from about 1110 mg / m2to about 1500 mg / m2, from about 1115 mg / m2to about 1500 mg / m2, from about 1120 mg / m2to about 1500 mg / m2, from about 1125 mg / m2to about 1500 mg / m2, from about 1130 mg / m2to about 1500 mg / m2, from about 1135 mg / m2to about 1500 mg / m2, from about 1140 mg / m2to about 1500 mg / m2, from about 1145 mg / m2to about 1500 mg / m2, from aboutPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)1150 mg / m2to about 1500 mg / m2, from about 1155 mg / m2to about 1500 mg / m2, from about 1160 mg / m2to about 1500 mg / m2, from about 1165 mg / m2to about 1500 mg / m2, from about 1170 mg / m2to about 1500 mg / m2, from about 1175 mg / m2to about 1500 mg / m2, from about 1180 mg / m2to about 1500 mg / m2, from about 1185 mg / m2to about 1500 mg / m2, from about 1190 mg / m2to about 1500 mg / m2, from about 1195 mg / m2to about 1500 mg / m2, from about 1200 mg / m2to about 1500 mg / m2, from about 1205 mg / m2to about 1500 mg / m2, from about 1210 mg / m2to about 1500 mg / m2, from about 1215 mg / m2to about 1500 mg / m2, from about 1220 mg / m2to about 1500 mg / m2, from about 1225 mg / m2to about 1500 mg / m2, from about 1230 mg / m2to about 1500 mg / m2, from about 1235 mg / m2to about 1500 mg / m2, from about 1240 mg / m2to about 1500 mg / m2, from about 1245 mg / m2to about 1500 mg / m2, from about 1250 mg / m2to about 1500 mg / m2, from about 1255 mg / m2to about 1500 mg / m2, from about 1260 mg / m2to about 1500 mg / m2, from about 1265 mg / m2to about 1500 mg / m2, from about 1270 mg / m2to about 1500 mg / m2, from about 1275 mg / m2to about 1500 mg / m2, from about 1280 mg / m2to about 1500 mg / m2, from about 1285 mg / m2to about 1500 mg / m2, from about 1290 mg / m2to about 1500 mg / m2, from about 1295 mg / m2to about 1500 mg / m2, from about 1300 mg / m2to about 1500 mg / m2, from about 1305 mg / m2to about 1500 mg / m2, from about 1310 mg / m2to about 1500 mg / m2, from about 1315 mg / m2to about 1500 mg / m2, from about 1320 mg / m2to about 1500 mg / m2, from about 1325 mg / m2to about 1500 mg / m2, from about 1330 mg / m2to about 1500 mg / m2, from about 1335 mg / m2to about 1500 mg / m2, from about 1340 mg / m2to about 1500 mg / m2, from about 1345 mg / m2to about 1500 mg / m2, from about 1350 mg / m2to about 1500 mg / m2, from about 1355 mg / m2to about 1500 mg / m2, from about 1360 mg / m2to about 1500 mg / m2, from about 1365 mg / m2to about 1500 mg / m2, from about 1370 mg / m2to about 1500 mg / m2, from about 1375 mg / m2to about 1500 mg / m2, from about 1380 mg / m2to about 1500 mg / m2, from about 1385 mg / m2to about 1500 mg / m2, from about 1390 mg / m2to about 1500 mg / m2, from about 1395 mg / m2to about 1500 mg / m2, from about 1400 mg / m2to about 1500 mg / m2, from about 1405 mg / m2to about 1500 mg / m2, from about 1410 mg / m2to about 1500 mg / m2, from about 1415 mg / m2to about 1500 mg / m2, from about 1420 mg / m2to about 1500 mg / m2, from about 1425 mg / m2to about 1500 mg / m2, from about 1430 mg / m2to about 1500 mg / m2, from about 1435 mg / m2to about 1500PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WG)mg / m2, from about 1440 mg / m2to about 1500 mg / m2, from about 1445 mg / m2to about 1500 mg / m2, from about 1450 mg / m2to about 1500 mg / m2, from about 1455 mg / m2to about 1500 mg / m2, from about 1460 mg / m2to about 1500 mg / m2, from about 1465 mg / m2to about 1500 mg / m2, from about 1470 mg / m2to about 1500 mg / m2, from about 1475 mg / m2to about 1500 mg / m2, from about 1480 mg / m2to about 1500 mg / m2, from about 1485 mg / m2to about 1500 mg / m2, from about 1490 mg / m2to about 1500 mg / m2, and from about 1495 mg / m2to about 1500 mg / m2.III. PHARMACEUTICAL COMPOSITIONS / / DOSAGE FORMS

[0152] In one embodiment, a pharmaceutical composition in accordance with the present disclosure includes at least one pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers, included, 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 earlier editions.

[0153] Exemplary pharmaceutically acceptable carriers, methods for making pharmaceutical compositions and various dosage forms, as well as modes of administration are well-known in the art, for example as detailed 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; A. R. Gennaro, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed., 2005, particularly chapter 89; and J. G.Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill Professional, 10th ed., 2001.

[0154] The pharmaceutical compositions of the present disclosure maybe administered to a subject via any suitable route of administration. In one embodiment, the pharmaceutical composition is administered to a subject orally, parenterally, transdermallyortransmucosally. 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 as a parenterally. In one embodiment, the pharmaceutical composition is administered to aPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)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 sterile solutions, suspensions, suppositories, tablets and capsules. 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 a 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.

[0155] In some embodiments, the pharmaceutical composition is in administered to a subject as a dosage form selected from the group consisting of sustained release forms, controlled release forms, delayed release forms and response release forms.

[0156] In some embodiments, the pharmaceutical composition of the present disclosure is formulated as intravenous formulation. In one embodiment, the intravenous formulation comprises ONC-206 or a pharmaceutically 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 pharmaceutically acceptable salt of ONC-206 dissolved in water at a concentration of 25 mg / ml. In some embodiments, the intravenous formulation includes a higher or a lower concentration of ONC-206 or a pharmaceutically acceptable salt thereof. In one embodiment, the intravenous formulation includes ONC-206 or a pharmaceutically acceptable salt thereof in a concentration of from about 5 mg / ml to about 100 mg / ml. In one embodiment, the intravenous formulation includes ONC-206 or a pharmaceutically acceptable salt thereof in a concentration of about 50 mg / ml. In one embodiment, the intravenous formulation includes ONC-206 or a pharmaceutically acceptable salt thereof in a concentration of about 5 mg / ml. In one embodiment, the intravenous formulation includes from about 0.5 % to about 10 % of ONC-206 or a pharmaceutically acceptable salt thereof. In one embodiment, the intravenousPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)formulation includes from about 5 % of ONC-206 or a pharmaceutically acceptable salt thereof.

[0157] In one embodiment, a pharmaceutical composition according to the disclosure comprises about 0.1 -99% of a salt of ONC-206 or a pharmaceutically acceptable salt thereof. In one such embodiment, the pharmaceutical composition further includes a pharmaceutically acceptable carrier. In one embodiment, a suitable pharmaceutically acceptable carrier includes an oil. In one embodiment, a suitable pharmaceutically acceptable carrier includes a sterile water. In one embodiment, a suitable pharmaceutically acceptable carrier includes an aqueous carrier.

[0158] In one embodiment, the intravenous formulation comprises ONC-206 or a dihydrochloride salt of ONC-206 dissolved in water at 25 mg / ml. In one such embodiment, the intravenous formulation is adjusted to pH 3 with phosphate buffer. In one such embodiment, the intravenous formulation includes dextrose or sodium chloride. In one such embodiment, the intravenous formulation includes a higher or a lower increase or decrease the concentration of the di-hydrochloride salt of ONC-206. In one embodiment, the intravenous formulation includes ONC-206 ora dihydrochloride salt of ONC-206 in a concentration of about 5 mg / ml. In one embodiment, the intravenous formulation including ONC-206 ora di-hydrochloride salt of ONC-206 in a concentration of about 5 mg / ml and pH 3 forms a stable solution. In one embodiment, the intravenous formulation includes ONC-206 ora di-hydrochloride salt of ONC-206 in a concentration of about 5 mg / ml and pH < 5 and forms a stable solution. In one embodiment, the intravenous formulation includes ONC-206 or a dihydrochloride salt of ONC-206 and one or more antioxidants. In one embodiment, the intravenous formulation includes a mixture of mono- and di-hydrochloride salt of ONC-206. In one embodiment, the intravenous formulation includes ONC-206 or a dihydrochloride salt of ONC-206 as a 1 % solution having ONC-206 or the dihydrochloride salt of ONC-206 in a concentration of about 10 mg / ml. 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.

[0159] In one embodiment, the intravenous formulation includes from about 0.5 % to about 10 % (or from about 5 mg / ml to about 100 mg / ml) of ONC-206 or a di-salt ofPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206. In one embodiment, the intravenous formulation includes from 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 decrease side effects of ONC-206 or a disalt of ONC-206.

[0160] In one embodiment, a pharmaceutical composition according to the disclosure comprises about 0.1 -99% of a salt of ONC-206; and a pharmaceutically acceptable carrier, e.g., an oil or a sterile water or other aqueous carriers. In one embodiment, a pharmaceutical composition accordingto the disclosure comprises a mono or di-salt of ONC-206 in a range of from about 5% to about 50 %for oral dosage forms.

[0161] In one embodiment, the pharmaceutical composition includes ONC-206 or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent. As used throughout the present disclosure, an additional, other, or second therapeutic agent may include a therapy as well, such as radiation or surgery, such as curative, preventative, diagnostic, staging, debulking, palliative, supporting, or restorative surgical procedures.

[0162] Suitable pharmaceutical compositions for use with the methods of the present disclosure 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 parenteral dosage unit. In one embodiment, the pharmaceutical composition is in the form of an oral dosage unit. In some embodiments, an oral dosage unit is fractionated into several, smaller doses, which are administered to a subject over a predetermined period of time in order to reduce toxicity of the therapeutic agent being administered. In some embodiments, an oral dosage unit is administered by a tablet or capsule comprising a controlled release formulation that can include a plurality of particles, granules, pellets, minitablets 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, wherein the parenteral dosage unit is 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 aPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)dosage form selected from the group consisting of sterile solutions, suspensions, suppositories, tablets and capsules. In one embodiment, the composition is an oral dosage form selected from the group consisting of a tablet, caplet, capsule, lozenge, syrup, liquid, suspension, and elixir, each of which includes a packaging configuration which allows reconstitution. In one embodiment, the composition is 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.

[0163] In some embodiments, suitable forms of pharmaceutical compositions for use in the methods of the present disclosure include dermatological compositions adapted for cutaneous topical administration. In some such embodiments, dermatological compositions include a cosmetically or pharmaceutically 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 oily bases, thickeners, skin enhancers and the like can be necessary or desirable and therefore can be used. Examples of suitable enhancers include, but are not limited to, ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol®) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231 , 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Patent No.4,783,450); alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; polyethylene glycol and esters thereof such as polyethylene glycol monolaurate; amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly citric acid and succinic acid. Azone® and sulfoxides such as DMSO and CiOMSO may also be used, but are less preferred.

[0164] In some embodiments, the pharmaceutical composition of the present disclosure is in a dosage form selected from the group consisting of sustained release forms, controlled release forms, delayed release forms and response release forms. IV. METHODS OF USEPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WG)

[0165] The compositions and methods of the present disclosure have utility in treating PCPG.

[0166] Pheochromocytoma and paraganglioma (PCPG) tumors are rare neuroendocrine tumors originating from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia, respectively. Characterized by their potential to secrete catecholamines, these tumors can cause a spectrum of symptoms, from hypertension to life-threatening cardiovascular complications.

[0167] While pheochromocytomas are generally adrenal based, paragangliomas are found along the sympathetic and parasympathetic nervous systems throughout the body, contributing to their diverse presentations and diagnostic challenges.

[0168] Over 50% of PCPG patients harbor either germline or somatic mutations in genes such as succinate dehydrogenase complex iron sulfur subunit B (SDHB), SDH subunit D, Von Hippel-Lindau (VHL), and RET, which are involved in cellular oxygen sensingand energy metabolism (Lepoutre-Lussey 2016; Mannelli 2015; Pacak2015; Rao 2015). Notably, tricarboxylic acid (TCA) cycle enzyme mutations (e.g., SDHx, FH, and MDH2) are associated with pseudohypoxia and activation of hypoxia inducible signaling pathways involved in tumor transformation, invasiveness, and metastatic potential (Joch manova 2015; Turkova 2015). Other mutations in genes like NF1 , TMEM127, MAX, H-RAS, HIF 2 alpha, ATRX, PHD1, and PHD2 also contribute to the complex pathophysiology of these tumors (Buffet 2012; Burnichon 2011 ; Crona 2013; Crona 2014a; Crona 2014b; Yang 2015).

[0169] Diagnostic markers such as elevated levels of catecholamines, normetanephrine, metanephrines, methoxytyramine, chromogranin A, synaptophysin, and high glucose uptake on18FDG-Positron Emission Tomography (PET) imaging are common in PCPGs. However, approximately 10% of PCPGs may be “biochemically silent,” making diagnosis and treatment challenging (Eisenhofer 2011 ; Moraitis 2014; Taieb 2014; Timmers 2009; Turkova 2015; van Berkel 2014; Vicha 2014; Zelinka 2008).

[0170] Despite the chronic and indolent nature of metastatic PCPG, associated with good performance and excellent quality of life, about half of therapy- naive, newly diagnosed patients experience disease progression within 1 year, with most requiring chronic, life-long antihypertensive medications to control the side effects of excessPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)catecholamine (Hescot 2013). Furthermore, approximately 30% of PCPG patients in the largest series reported from National Institute of Health between 2000 and 2014 succumbed to the disease, underlining its significant morbidity (Turkova 2015). The complexity of PCPG is further highlighted by recent findings from the Uppsala group, which demonstrated considerable genetic heterogeneity within and between PCPG tumors lesions of the same patient (Crona 2014a).

[0171] Current treatment options for metastatic PCPG are limited and include surgical resection, radiofrequency ablation, radiotherapy, and relatively ineffective chemotherapy regimens that may include VEGF inhibitors (McBride 2011 ; Vogel 2014; Moraitis 2014; Favier2012). Experimental treatments such as 131 l-MIBG (iobenguane I-131 , Azedra), a high-specific-activity beta-emitter that binds dopamine receptors, are currently being tested and show promise in reducing hypertension medication requirements in a subset of patients (ClinicalTrials.gov identifier: NCT00874614).

[0172] This complex landscape underscores the importance of continuous research and development of targeted therapies to improve outcomes for PCPG patients, taking into account the considerable genetic heterogeneity and the varied clinical manifestations of these tumors.

[0173] Background of Study Treatment ONC206

[0174] ONC206 (7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1 ,2-a]pyrido[3,4-e] pyrimidin-5(1 H)-one, dihydrochloride) is a novel therapeutic agent from the imipridone class of anticancer small molecules, featuring a unique tri-heterocyclic core structure (Wagner 2017) that selectively engages G-protein-coupled receptors (GPCRs) and the caseinolytic protease proteolytic subunit (ClpP) (Ishizawa 2019;Graves 2019; Prabhu 2017). As an analog of the first-in-class compound dordaviprone, ONC206 has been optimized to enhance receptor selectivity and efficacy, notably through its antagonistic action on the dopamine receptor D2 (DRD2) and its agonistic effects on ClpP. This dual mechanism allows ONC206 to effectively modulate cellular stress pathways and apoptosis, crucial for cancer cell survival.

[0175] ONC206 demonstrates broad-spectrum anticancer activity, with promising results in vitro and in human tumor xenograft mouse models (Hu 2021 ; Prabhu 2020; Przystal 2022; Tucker 2022; Staley 2021). It exhibits robust in vitro efficacy acrossPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)several tumor types, including pheochromocytoma, and shows potent antitumor effects in various nonclinical cancer models without adversely affectin the viability of normal human fibroblasts at therapeutic doses (Prabhu 2020). The efficacy and safety of ONC206 are underpinned by its mechanisms involving agonism of ClpP and antagonism of DRD2 and dopamine receptor D3 (DRD3), which activate the integrated stress response (ISR) and induce the DR5 / TRAIL pathway, leading to pronounced antitumor effects in vitro and in vivo (Ishida 2018; Wagner 2017). Mechanistically, ONC206 disrupts pheochromocytoma cell viability in a ClpP-dependent manner, inducing apoptosis and downregulating key mitochondrial proteins such as the ClpP regulatory subunit ClpX, SDHB, and FH — mutations in which are common in PCPG and contribute to mitochondrial dysfunction (Nolting 2022; Fishbein 2017; Gupta 2022). Furthermore, ONC206’s effectiveness in SDHB or FH knockout PCPG cells and its antagonistic action against the highly expressed DRD2 in PCPG tumors underscore its potential as a targeted therapy for PCPG (Prahbu 2018).

[0176] ONC206’s oral bioavailability and its ability to achieve micromolar concentrations in the plasma, adrenal gland, brain, and various tissues highlight its potential for clinical use. Early nonclinical safety and pharmacokinetic (PK) assessments have shown that ONC206’s therapeutic profile is favorable relative to the observed anticancer activity, with mild and reversible adverse effects observed in animal studies. The no observed adverse effect levels (NOAELs) were determined in each species, allowing for identification of a safe starting dose in human clinical trials; additional data generated in rats with more frequent dosing supported escalation to the Phase 2 clinical dose. This comprehensive background supports further investigation of ONC206 in clinical trials, aiming to establish a safe and effective dosage for Phase 2 development, targeting PCPG where current treatment options are limited.

[0177] Mechanism of Action of ONC206

[0178] Figure 2 provides a schematic of the proposed mechanism of action for ONC206. ONC206 is a selective ClpP agonist (Pathway 1 ) and DRD2 antagonist (Pathway 2), demonstrating nanomolar potency (Ishida 2018; Prabhu 2017; Wagner 2017). In vitro studies have shown that acquired resistance to ONC206 is associated with alterations in ClpP. Furthermore, overexpression of wild-type ClpP has been foundPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)to partially reverse this resistance (Lee 2023). Upon target engagement, ONC206 impairs mitochondrial metabolism downstream (Przystal 2022), activates the ISR involving induction of ATF4and C / EBP homologous protein, and upregulates DR5 and TRAIL gene expression, collectively leading to the induction of apoptotic tumor cell death (Ishida 2018; Prabhu 2017; Prabhu 2020; Wagner 2017).

[0179] Abbreviations: CHOP=C / EBP homologous protein; ClpP=caseinolytic protease proteolytic subunit P; DR5=death receptor 5; p=phosphorylation;TRAIL=tumor necrosis factor-related apoptosis-inducing ligand.

[0180] Co-crystallization of ONC206 with ClpP, which assembles as a tetradecameric complex, revealed allosteric ligand interactions that influence the overall conformation (Lee 2023). ONC206 exhibits nanomolar potency in cell-free human ClpP casein / peptide degradation assays, with half-maximal effective concentration (EC50)values of 820 nM for the casein assay and 310 nM forthe ClpP peptide assay (Prabhu 2020). Human pheochromocytoma (hPheol ) cells lacking ClpP are resistant to ONC206, underscoring the essential role of ClpP in mediating ONC206’s efficacy in PCPG.

[0181] Further downstream of ClpP agonism, proteomics analysis showed that ONC206 inhibits mitochondrial metabolism, specifically oxidative phosphorylation and the TCA cycle in hPheol cells. Metabolomics data support this finding, revealing increases in a-ketoglutaric acid and 2-hydroxyglutaric acid, along with reductions in succinic acid and fumaric acid, dependent on ClpP activity. Epigenetic impacts were observed as well, with ATAC-seq demonstrating altered chromatin accessibility in hPheol cells post-ONC206 treatment.

[0182] Moreover, RNA sequencing revealed that ONC206 modulates gene expression by upregulating stress response and apoptosis pathways, while downregulating cell cycle and metabolism-related pathways in hPheol cells.Corresponding Western blot analyses confirmed downregulation of mitochondrial proteins (ClpX, SDHB) and neuroendocrine markers (tyrosine hydroxylase, enolase-2, synaptophysin), and upregulation of the stress response protein ATF4 in pheochromocytoma cell lines.

[0183] Anticancer Activity in Nonclinical ModelsPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0184] ONC206 demonstrated broad-spectrum anticancer efficacy in vitro across most solid tumor types, as shown in tests with a panel of over 1000 human cancer cell lines. Among 1088 tumor lines tested, 813 were sensitive to ONC206 at nanomolar concentrations, with an average half-maximal inhibitory concentration (IC50) of 562 nM (Prabhu 2020). Importantly, ONC206 does not induce cell death in normal fibroblasts under doses and conditions that are highly cytotoxic to cancer cell lines (Prabhu 2020). In vivo, ONC206 has shown efficacy in mouse models of various cancers, including diffuse midline glioma, medulloblastoma, cholangiocarcinoma, hepatocellular carcinoma, endometrial, and ovarian cancer. Effective dosing regimens included once weekly, twice weekly, and twice daily on 3 consecutive days each week (BID TIW), all resulting in significant antitumor effects (Hu 2021; Prabhu 2020; Przystal 2022; Tucker 2022; Staley 2021 ; Baek 2023; Cao 2024).

[0185] Additionally, human hPheol (IC50: 180 nM), rat PC12 (IC50: 290 nM), and mouse MCP (IC50: 190 nM) pheochromocytoma cell lines exhibit nanomolar sensitivity to ONC206 in CellTiter-Glo (CTG) cell viability assays (Figure 3). hPheol were treated with 0.55pM ONC206 and 3pM ONC201 for 1 , 2, 3, 4-days and wells were replenished with fresh media (no drug). Apoptosis was measured with flow cytometry using SYTOX (cell death) and Annexin V (apoptosis) stains on Day 7. ** p<0.001 *** p<0.0001 (Figure 4). Furthermore, in PCPG cells, where FH and SDH are mutated both germinally and somatically, leading to mitochondrial dysregulation, ONC206 remains equally effective irrespective of SDHB or FH expression (Figure 5) (Nolting 2021 ; Fishbein 2017; Gupta 2022).

[0186] As shown in Figure 3, ONC206 inhibits cell viability of pheochromocytoma cells in vitro. The relevant abbreviations: CTG=CellTiter-Glo; hPheol =human pheochromocytoma; MCP=monocyte chemoattractant protein. Representative doseresponse curve of ONC206 (after 72-hour treatment) in human hPheol , rat PC12, and mouse MCP pheochromocytoma cells. Cells were plated in 96-well plates with indicated concentrations of ONC206 and readout with CTG after 3 days treatment.

[0187] As shown in Figure 4, ONC206 induces apoptosis in pheochromocytoma cells in vitro. hPheol were treated with 0.55pM ONC206 and 3pM ONC201 for 1 , 2, 3, 4-days and wells were replenished with fresh media (no drug). Apoptosis was measuredPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)with flow cytometry using SYTOX (cell death) and Annexin V (apoptosis) stains on Day 7. ** p<0.001 *** p<0.0001.

[0188] As shown in Figure 5, ONC206 inhibits cell viability in pheochromocytoma cells with SDHB or FH knockout in vitro. Abbreviations include: ATP=adenosine triphosphate; CRISPR=Clustered Regularly Interspaced Short Palindromic Repeats; CTG=CellTiter-Glo; FH= fumarate hydratase; hPheol =human pheochromocytoma; KO=knockout; MW=molecularweight; SDHB=succinate dehydrogenase complex iron sulfur subunit B; WB=western blot; WT=wildtype. Representative dose-response curve of ONC206 (after 96-hour treatment) in human hPheol cells with or without CRISPR-mediated SDHB or FH knockout. Cells were plated in 96-well plates with indicated concentrations of ONC206 and readout with CTG (measures cell ATP content) after 4 days treatment.

[0189] The critical role of ClpP in mediating the efficacy of ONC206 is illustrated in Figure 6, which shows the dose-response on ONC206 in human hPheol cells with or without ClpP knockout and emphasizes how essential ClpP expression is for the cytotoxic effects of ONC206 on pheochromocytoma cells. Figure 6 illustrates ClpP expression is essential for ONC206 efficacy in pheochromocytoma cells. Abbreviations include: ATP= adenosine triphosphate; ClpP=caseinolytic protease proteolytic subunit; CRISPR=Clustered Regularly Interspaced Short Palindromic Repeats; CTG=CellTiter-Glo; hPheo1=human pheochromocytoma; KO=knockout; MW=molecular weight;NTC=non-targeting control; WB=western blot; WT=wildtype. Representative doseresponse curve of ONC206 (after 120-hour treatment) in human hPheol cells with or without CRISPR-mediated ClpP knockout. Cells were plated in 96-well plates with indicated concentrations of ONC206 and readout with CTG (measures cell ATP content) after 5 days treatment.

[0190] Figure 7 details the biochemical impact of ONC206 on mitochondrial proteins and neuroendocrine markers. Figure 7 shows how ONC206 downregulates mitochondrial proteins like SDHB and upregulates stress proteins, corroborating ONC206’s mechanism of inducing apoptosis and impairing cancer cell viability.ONC206 Downregulates Mitochondrial Proteins, Neuroendocrine Markers and Upregulates Stress Response in Pheochromocytoma Cells. Abbreviations include:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)hPheol =human pheochromocytoma; MCP=monocyte chemoattractant protein;MW=molecular weight. Western blot analysis in pheochromocytoma cell lines treated with ONC206 (0.55 pM) for 2 days. Actin was used as loading control.

[0191] ONC206 exhibited a nanomolar Ki for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and |3-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism. The half-maximal response concentration (EC50) for ONC206 in DRD2 arrestin reporter assays was 980 nN while the EC50 in DRD2 radioligand competition assays was 323 nM. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites (Prabhu 2020).

[0192] An analysis of The Cancer Genome Atlas (TCGA) data revealed PCPG to have the highest DRD2 expression of all cancers. Immunohistochemical analysis of tissue microarrays corroborated TCGA observations that malignant DRD2 expression was highest in PCPG and overexpressed relative to normal adrenal gland cells (Anderson 2022; Prabhu 2020).

[0193] An in vitro evaluation of varying treatment durations of ONC206 was performed in hPheol and MCP pheochromocytoma cells. Cells were treated with ONC206 at concentrations ranging from 19.5 nM to 10 pM for 24, 48, 72 or 96 hours. At the end of the designated exposure timepoints, wells were replenished with fresh media (no ONC206).

[0194] All readouts were performed 7 days after the addition of ONC206. Cell survival after washout indicated that 72 hours of ONC206 exposure was optimal for maximal reduction of cell viability (Figure 8). These data suggest that sustained exposure of ONC206 for 72 hours at concentrations between 200 to 400 ng / mL is the target therapeutic range. Figure 8 ilustrates the impact of ONC206 treatment duration on cell viability. Abbreviations include : ATP= adenosine triphosphate; CTG=CellTiter-Glo; hPheol =human pheochromocytoma; MCP=monocyte chemoattractant protein;

[0195] MCP and hPheol pheochromocytoma cells plated in 96-well plates were treated with ONC206 at concentrations ranging from 19.5 pM to 10 pM for 24, 48, 72 or 96 hours. At the end of the designated exposure timepoints, wells were replenished with fresh media (no ONC206). ATP content in cells was measured by CTGPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)luminescence as a readout of cellular survival. All readouts were performed 7 days after the addition of ONC206. Cell survival after washout was measured as percent survival relative to control (vehicle treated) cells.

[0196] Nonclinical Safety Profile

[0197] The nonclinical safety profile of ONC206 has been characterized in Good Laboratory Practice (GLP) and / or non-GLP studies with once weekly orTIW oral administration for 1 to 4 weeks in rats and / or dogs. Additionally, safety pharmacology studies evaluating the effects of 4, once weekly doses of ONC206 on central nervous system (CNS) and cardiovascular function have been conducted in rats and dogs, respectively, and the effect of a single oral dose of ONC206 on respiratory function was assessed in rats.

[0198] Dose escalation studies conducted to assess maximum tolerated doses (MTD) showed that dose limiting toxicities were associated with extra pyramidal CNS signs (i.e., twitching, tremors, and abnormal gait and stance) in rats and salivation, emesis, diarrhea, and body weight loss in dogs. Non-GLP repeat-dose studies administering 5, once weekly oral doses to rats demonstrated adverse CNS-related clinical signs, which increased in severity with escalating dose and resulted in mortality, in females only, at non-tolerated doses. The toxicity in females was driven by significantly increased exposures and reduced clearance compared to male rats.Additionally, a non-adverse finding of decreased zymogen granules in pancreatic acinar cells were observed in all ONC206 treated groups and histopathologic findings were identified in the liver, bone marrow, and pancreas of moribund female rats at nontolerated dose levels. In dogs administered 5 doses of ONC206 once weekly, salivation, emesis, diarrhea, and body weight loss remained the only dose-limiting toxicities and were not accompanied by the CNS-related clinical signs or adverse histopathological findings observed in rats.

[0199] The safety pharmacology studies and toxicology studies with once weekly dosing in rats and dogs are described in detail in the Investigator’s Brochure (IB). No adverse effects were observed in the respiratory system of rats after a single oral dose or in electrocardiogram (ECG) assessments in dogs administered ONC206 once weekly for 22 days. The effects of ONC206 on ionic currents in voltage-clamped cells thatPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)stably express hERG were determined in vitro. While the IC50forthe inhibitory effect of ONC206 on hERG potassium current was 5.1 pM, ONC206 is approximately 95% protein bound in human plasma which, with a 200 mg clinical dose, yields a free maximum observed concentration (Cmax) approximately 20-fold below the hERG IC5o. Cardiovascular effects were also monitored in dogs via ECG monitoring performed on Days 1 , 22, and 28 in male and female dogs administered <16.7 mg / kg ONC206 once weekly via oral gavage for 3 weeks (total of 4 doses). ONC206 did not demonstrate any toxicologic effects on cardiac rhythm or electrocardiogram (ECG) morphology. The Cmax measured in the dogs were approximately 3-fold the maximum exposures observed clinically in patients administered 150 m ONC206 BIDTIW.

[0200] In non-GLP studies exploring the effects of multiple daily and weekly dosing in rats, significantly higher plasma concentrations were again observed in female rats resulting in adverse clinical signs and mortality at non-tolerated doses. CNS-related clinical observations including decreased activity, circling, and wobbling were observed in female animals and increased in severity with dose. Onset of CNS-related clinical signs occurred 24 to 48 hours post-dose and, in animals that survived, recovered by 24 to 72 hours after onset. Additional studies which administered higher doses to male rats confirmed male sensitivity to similar plasma exposures. No ONC206-related changes were observed in hematology, erythrocyte morphology, coagulation, clinical chemistry or urinalysis parameters measured in moribund, recovered or unaffected animals. Additionally, there were no ONC206-related macroscopic findings, organ weight changes or microscopic pathology observations observed in any animal, including moribund animals with severe clinical signs prior to euthanasia.

[0201] The mean Cmax measured in female rats given 75 mg / kg ONC206 once weekly, a well-tolerated dose with no adverse signs or target organ toxicity, was 7330 ng / mL. This Cmaxis approximately 4-fold the maximum plasma concentration measured in a patient given 350 mg ONC206.

[0202] The Cmax after 150 mgtwice-daily for 3 consecutive days is >10-fold below the well-tolerated Cmax in rats and >3-fold below the NOAEL in dogs given 16.7 mg ONC206 once weekly for 22 days.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0203] Weekly plasma area under the concentration-time curve (AUG) exposures were calculated in rats, dogs and humans to enable relative comparison across dosing frequencies. The total weekly exposure (AUG) measured in female rats given 15 mg / kg ONC206 BID for 3 days, a well-tolerated dose with no adverse signs or target organ toxicity, was 20,520 ng*hr / mL. This AUC is approximately 1.2-fold the plasma exposure measured in a patient given a 150 mg ONC206 BID TIW.

[0204] Nonclinical Toxicokinetics

[0205] The toxicokinetics (TK) of ONC206 has been studied in rats and dogs after single and multiple (4 or 5) once weekly ONC206 administrations. Rapid absorption of ONC206 was observed in both rats and dogs, with peak concentrations generally observed at the first plasma timepoint (0.5- to 1-hour post-dose; Figure 9). In general, no changes in ONC206 exposure parameters (difference within 2-fold) after repeated once weekly administration were observed. ONC206 exposure parameters were greater in female rats (>2-fold) compared to males, but the sex difference in dogs was generally not notable (<2-fold). Overall, ONC206 concentrations increased with increasing doses over the range studied in rats (5 to 100 mg / kg) and dogs (1.7 to 25 mg / kg). In studies with sufficient animal numbers (n=3 to 5 / sex / timepoint) and plasma sampling (0.5-, 1 -, 2-, 4-, 8-, 12-, and 24-hours post-dose), the increase in ONC206 exposure (Cmaxand AUC) was approximately dose proportional in rats over the dose range of 5 to 50 mg / kg ONC206 and supra-proportional in dogs over the dose range of 1.7 to 16.9 mg / kg ONC206. The ONC206 plasma t1 / 2 ranged from approximately 2 to 6 hours in rats and approximately 1 to 4 hours in dogs.

[0206] As shown in Figure 9, mean ONC206 plasma concentrations after single oral administration of ONC206 to rats (50 mg / kg) and dogs (16.7 mg / kg) [linear and log plots] are provided. Abbreviations include : h=hour(s); F=female; M=male. Mean concentrations following the first administration of 50 mg / kg to rats and 16.7 mg / kg to dogs.

[0207] Table : Average Cmax and AUC Values for Rats and Dogs Following First Weekly Oral Dose of ONC206Dose (mg / kg) Cmax(ng / mL) AUCO-inf (ng*hr / mL)Rat Dog Rat Dog Rat DogPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)Male Female Male Female Male Female Male Female Low 5 1.7 161 297 31.1 23.4 253 1210 37 24 Mid 25 8.3 961 1337 374 721 2980 7686 477 949High 50 16.7 919 2863 2560 2304 7669 14995 3762 3612

[0208] Abbreviations include : AUC=area under the concentration-time curve;AUC0-inf=AUC extrapolated to infinity; Cmax=maximum observed concentration.Note: Cmax and AUG parameters after the last ONC206 dose on Day 22 were similar (difference <2-fold) to those shown following the first dose.

[0209] Single and Multiple Daily and Weekly Oral Administration

[0210] In an exploratory dose-range finding study, the ONC206 plasma TK were determined in male and female rats following a single dose of 50, 75, and 100 mg / kg, daily doses of 50, 75, and 100 mg / kg ONC206 on 3 consecutive days, and 25 and 50 mg / kg twice daily on 3 consecutive days. In general, concentrations peaked at 0.25 to 0.5 hours with dose proportional increases in Cmaxand AUC observed overthe dose range 50 to 100 mg / kg. A slight decrease in ONC206 Cmax and AUC was seen in both sexes following consecutive daily and twice daily doses, except in females receiving 50 mg / kg twice daily for 3 days where higher (3- to 7-fold) exposure was observed after the last (sixth) dose compared with the second dose. Following all dose regimens, higher ONC206 Cmax and AUC were observed in female rats (2- to 8-fold) compared with males. Higher concentrations were observed in tissue compared to plasma (tissue:plasma ratio generally >3). The tissues with the highest ONC206 concentrations included excretory, female reproductive and endocrine organs. The tissue:plasma ratio for brain was 2. ONC206 was eliminated from plasma and tissues with a similar halflife, ~3 hours.

[0211] In the second phase of the dose range finding study, the plasma TK parameters were determined in females following administration of ONC206 at 15, 25, or 30 mg / kg twice daily for 3 consecutive days, or 10, 15, or 25 mg / kg twice daily for 5 consecutive days. Due to sex differences in ONC206 exposures, males were dosed at higher doses: 25, 75, or 150 mg / kg twice daily for 3 consecutive days, or 15, 45, or 60 mg / kg twice daily for 5 consecutive days. With the dose adjustment, the plasma exposures were generally similar (<2-fold) between male and female animals. MeanPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)Cmax and AUG parameters across the dosing period were used to determine tolerated and non-tolerated exposures for comparison to human ONC206 exposures.

[0212] Metabolism

[0213] After incubation of ONC206 at a concentration of 1 pM with mixed-sex human liver microsomes, the disappearance of ONC206 followed log-linear decline. The ONC206 metabolic pathways involved N-dealkylation, oxidation, dehydrogenation, and hydrogenation. No formal drug-drug interaction studies with ONC206 or any metabolites have been performed.

[0214] Clinical Experience

[0215] The safety and PK of ONC206 have been assessed in ongoing Phase 1 dose escalation studies in adult and pediatric patients with CNS tumors.

[0216] Table : Ongoing ONC206 Clinical StudiesPlannedNumber of Dosage and Primary Study Number Study Design Subjects Population Dosage Regimen Objective Dose-escalationdesign, withstarting dose of To evaluate Dose 50 mgQW, the safety, ONC206-001 escalation escalated tolerability, (NIH 20C0069) Open- label, and Adults with QW doses through and PKof [NCT04541082] single-center, expansion: up recurrent, Cohort 6; then single dose to 102 primary CNS higher intermittent weekly or (Chimerix escalation subjects neoplasms dosing schedule multiple-day sponsored) depending on (i.e., once to twice weekly dose the MTD daily for regimens of 3 successive days ONC206 per week) startingwith Cohort 7.ONC206-701 Open-label, Dose Children and Dose escalation To determine (PNOC023) multi-arm dose escalation and young adults design starting at the safety and [NCT04732065] escalation and expansion with DMG, 0.83 mg / kg tolerability of target validation enrollment up and with ONC206 once ONC206, the (Investigator- to 168 subjects. primary weekly. Study MTD in children initiated trial) malignant subjectswill and young Target CNS receive ONC206 adults, and validation up neoplasms. according to the assess target to 40 subjects. assigned dose validation of level.ONC206.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0217] Abbreviations include : CNS=central nervous system; MTD=maximum tolerated dose; NIH=National Institutes of Health; PK=pharmacokinetics; QW=once weekly.

[0218] Adult Patient PK and Safety from Dose Levels 1 Through 10

[0219] Adult patients (n=3 per dose level) with recurrent CNS tumors have been enrolled and treated with ONC206 once weekly at 50, 100, 150, 200, 250 and 350 mg (Dose Levels 1 to 6) and with once daily (150 mg) or BID (50, 100, and 150 mg) dosing for 3 consecutive days (Dose Levels 7 to 10). A dosing regimen of 200 mg administered BID TIW (Dose Level 11 ) is currently enrolling in this trial.

[0220] An additional embodiment includes QDTIW : 3 days on / 4 days off, at any one of the dosage levels, including 350 mg.

[0221] Out of 30 patients enrolled in these cohorts, 12 patients experienced Grade 2 adverse events (AEs), and no patients experienced Grade 3 or 4 AEs considered possibly / probably related to ONC206. The most common treatment-related AEs (all causalities) in adult patients with glioma CNS tumors (in >10% of patients) were fatigue, headache and vomiting. These events were generally mild or moderate in severity and occur in a minority of patients. There were no substantial changes in the AE profile as a function of dose or frequency in dose escalation. No AEs have met dose-limiting toxicity criteria.

[0222] The preliminary ONC206 patient concentration profiles observed following a once weekly dosing regimen are characterized by an absorption phase with median time to maximum observed concentration (Tmax) of approximately 1 to 2 hours across doses (50 mg once weekly to 350 mg once weekly). The absorption phase is followed by apparent multiphasic elimination with mean t1 / 2 ranging from 12 to 20 hours across doses (50 mg once weekly to 350 mg once weekly); see Table 8. This elimination is rapid in relation to the once weekly dosing interval.

[0223] Table : ONC206 Preliminary PK Parameters Following Once Weekly Dosing (Cycle 1, Day 1)AUCinfDose (mg); (n) Dose Frequency (hr) (ng / mL) (hr*ng / mL) (hr) 50 (n=3) QW 2.0(1.1-2.0) 163 (49%) 993 (54%) 14.1 (63%)PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)100 (n=2) QW 1.5 (1.0-1.9) 162 (63%) 1041 (46%) 13.3 (45%) 150 (n=4) QW 1.0 (0.5-1.0) 594 (49%) 2781 (38%) 11.5 (28%)0.99 (0.97- 200 (n=4) QW 1434 (54%) 7756 (80%) 19.8 (38%)1.0)250 (n=3) QW 0.72 (0.5-1.0) 1400 (35%) 8777 (29%) 17.6 (42%) 350 (n=3) QW 1.9 (0.6-4.2) 1710 (64%) 11800 (21%) 17.0 (38%)

[0224] Abbreviations include : AUCinf=area under the concentration-time curve extrapolated to infinity; Cmax=maximum observed concentration; CV=coefficient of variation; t1 / 2=terminal half-life; Tmax=time of maximum observed concentration;QW=once weekly.

[0225] Data presented as Mean (%CV). Median (minimum, maximum) presented for Tmax.

[0226] Dosing BID resulted in sustained ONC206 concentrations at target thresholds better mimickingthe in vitro sustained concentrations in nonclinical cancer cell studies that demonstrate improved cell kill in more resistant cell lines.

[0227] The Cmaxexposures observed after multiple once-daily or twice daily administration (Cycle 1 Day 3) were slightly higher compared to Cmax after once weekly administration due to slight accumulation ofONC206with more frequent dosing, but was similar to that seen with once weekly administration. The weekly AUC exposure increased as the total weekly dose increased and was comparable to population PK estimates based on ONC206 concentration simulations from once weekly ONC206 administration (data not shown).

[0228] ONC206 Preliminary PK Parameters Following Once or Twice Daily Dosing for 3 Consecutive Days (Cycle 1 , Day 3)Dose(mg) (n) Dose Frequency Total Weekly Weekly AUCaDose (mg) (hr) (ng / mL) (hr*ng / mL) 50 (n=1) BIDTIW 300 2.1 166 4662 150 (n=3) QDTIW 450 0.70 (0.55-1.3) 823 (22%) 11937 (47%) 100 (n=3) BIDTIW 600 1.0 (0.6-2.0) 536 (66%) 15795 (54%) 150 (n=3) BIDTIW 900 0.98 (0.87-1.0) 709 (39%) 17483 (39%)PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0229] Abbreviations: AUCinf=area under the concentration-time curve extrapolated to infinity; AUCtau=area under the concentration-time curve over the dosing interval, tau; BID TIW= twice daily, on 3 consecutive days per week;Cmax=maximum observed concentration; CV=coefficient of variation; t1 / 2=terminal half-life; NA=not available; Tmax=time of maximum observed concentration; QD TIW=once daily, on 3 consecutive days per week.

[0230] Data presented as Mean (%CV). Median (minimum, maximum) presented for T max. A Maximum estimated weekly AUG determined as follows: (2*C1 D1 AUCinf) + (4*C1 D3 AUCtau).

[0231] Benefit / Risk Assessment

[0232] ONC206 has demonstrated promising efficacy in preclinical models and clinical settings but also presents potential risks that require careful monitoring. While animal studies have indicated reversible adverse effects such as extrapyramidal signs in the CNS and gastrointestinal issues, clinical trials with patients have generally reported mild to moderate AEs. The most common treatment-related AEs in patients, including fatigue, headache, and vomiting, were manageable and did not escalate beyond Grade 2 in severity, with no Grade 3 or 4 events directly attributed to ONC206. These findings support the manageable safety profile of ONC206, but warrant close surveillance, particularly as dosing and frequency are adjusted in the clinical setting.

[0233] A Safety Review Committee is in place to monitor and manage potential adverse effects, ensuring the safety of patients and the integrity of the study outcomes.

[0234] Benefit Assessment

[0235] ONC206 has demonstrated significant anticancer activity in preclinical studies, showing effects against various cancer cell lines including those specific to PCPG. Its dual mechanism of action, targeting both DRD2 and ClpP, effectively disrupts critical pathways essential for cancer cell survival and apoptosis. This has led to a notable inhibition of tumor growth and reduction of catecholamine secretion, pivotal forthe therapeutic management of PCPG.

[0236] In clinical settings, ONC206 has shown a manageable safety profile, generally being well tolerated in early-phase trials involving patients with CNS tumors.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WG)The safety and PK evaluated indicate mild to moderate AEs without any dose-limiting toxicities, which support its continued development in clinical settings.

[0237] Given the limited treatment options for PCPG, the investigation of ONC206 could significantly enhance the therapeutic landscape. Patients enrolled in this study may experience improved clinical outcomes including delayed disease progression, reduced tumor burden, and better symptom management due to the targeted action of ONC206. Additionally, the structured monitoring protocol in this study ensures comprehensive disease and safety assessment, offering further benefits to patients while also enhancingthe broader understanding of PCPG management through rigorous data collection and analysis.

[0238] Overall Benefit / Risk Conclusion

[0239] Given the targeted mechanism of ONC206 and the preliminary data suggesting its efficacy and manageable safety profile, the potential benefits are considered to outweigh the risks for patients with PCPG. PCPG patients often encounter recurrent disease and have limited therapeutic options, especially in advanced stages where current treatments often fail to effectively manage the tumor’s secretory effects or prevent metastatic spread. This highlights a significant unmet need for more effective and targeted therapies. ONC206, with its novel mechanism targeting specific molecular pathways involved in tumor growth and catecholamine production, represents a promising therapeutic strategy with the potential to address these gaps by significantly improving management strategies and outcomes for PCPG patients.

[0240] One embodiment of the present disclosure includes a method of treating one or more neuroendocrine cancer, including one or more PCPG, with the administration to a patient in need thereof an effective amount of Compound 2 (ONC-206), or a pharmaceutically acceptable salt thereof.

[0241] One embodiment of the present disclosure includes a method of treating one or more neuroendocrine tumors that arise from the neural crest, including one or more tumors that arise from the adrenal medulla (pheochromocytoma) or sympathetic / parasympathetic ganglia (paraganglioma) with the administration to a patient in need thereof an effective amount of Compound 2 (ONC-206), or a pharmaceutically acceptable salt thereof.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0242] One embodiment of the present disclosure includes a method of treating one or more of:(v) PCPG Cluster 1 : Psuedohypoxia Subtype,(vi) PCPG Cluster 2: Kinase Signlaing Subtype,(vii) PCPG Cluster 3: Wnt-Altered Subtype, and(viii) Cortical Admixture Subtype,with the administration to a patient in need thereof an effective amount of Compound 2 (ONC-206), or a pharmaceutically acceptable salt thereof.

[0243] Based on The Cancer Genome Atlas (TCGA) and other molecular studies, PCPG may be categorized into four main molecular subtypes based on one or more of underlying driver mutations, gene expression profiles, and signalingpathways. Pseudohypoxia Subtype (Cluster 1) group is characterized by the activation of hypoxia-inducible factors (HIFs) under normal oxygen levels (normoxia), leading to pseudohypoxia, neoangiogenesis, and metabolic reprogramming. SDHx-related (Cluster 1 A) involves germline mutations in succinate dehydrogenase complex genes (SDHA, SDHB, SDHC, SDHD) and assembly factor SDHAF2. SDHB mutations are often associated with higher metastatic risk. VHL-related (Cluster 1 B) involves mutations in the VHL gene, often resulting in adrenal tumors. Other Pseudohypoxic Drivers include mutations in EPAS1 (HIF2A), EGLN1, EGLN2, and FH. Kinase Signaling Subtype (Cluster 2) group is driven by alterations in kinase signaling pathways, affecting protein synthesis and neural differentiation. Primary drivers include NF1, RET, TMEM127, MAX, and HRAS. Subgroups are often further divided, namely to provide subclasses 2A, 2B, and 2C, which include sporadic (non-hereditary) cases as well as germline mutations. Wnt-Altered Subtype (Cluster 3) group is characterized by mutations or fusions that activate the Wnt signaling pathway, which is often associated with more aggressive or metastatic behavior. Key Drivers include MAML3 fusion genes, CSDE1 mutations, and sometimes UBTF-MAML3. In addition, there is a recognized Cortical Admixture Subtype, which is identified by the presence of molecular markers that resemble normal adrenal cortex tissue. It suggests a distinct cell-of-origin or differentiation pattern within the tumor.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WG)

[0244] One embodiment of the present disclosure includes a method of treating one or more of a PCPG cancer categorized by (i) anatomical location, (ii) clinical behavior, and (iii) metabolic profiling.

[0245] PCPG may be characterized based on anatomical location, including pheochromocytoma (adrenal) compared to paraganglioma (extra-adrenal); clinical behavior, including benign compared to metastatic (where metastatic disease is believed to be highly associated with SDHB mutations and MAML3 fusions); and metabolic profiles, including noradrenergic (Cluster 1 , often SDHx or VHL) compared to adrenergic (Cluster 2).

[0246] It is believed that up to 40% of all PCPG cases are associated with hereditary susceptibility genes, while 30-40% are sporadic.

[0247] As set forth herein Compound 2 may be referred to as ONC-206, or as 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1 ,2-a]pyrido[3,4-e]pyrimidin-5(1 H)-one, or a salt thereof.

[0248] In one aspect, the administration reduces one or more symptom of PCPG.

[0249] The utility of the methods and compositions of the present disclosure is not limited to any particular age of the subject. In one embodiment, a subject treated accordingto methods and using compositions of the present disclosure can be under the age of 5, 12, 16, or 18 (pediatrics), over the age of 18 years, over the age of 20 years, over the age of 25 years, over the age of 30 years, over the age of 35 years, over the age of 40 years, over the age of 45 years, over the age of 50 years, over the age of 55 years, over the age of 60 years, or over the age of 65 years. In one embodiment a subject treated according to methods and using compositions of the present disclosure can be under the age of 50 years, under the age of 55 years, under the age of 60 years, or under the age of 65 years.

[0250] 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.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0251] In one embodiment the subject has been treated with one or more form of radiation.

[0252] In one embodiment the subject has been treated with one or more form of surgery.

[0253] In some embodiments of the methods of treating PCPG, the PCPG 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.

[0254] In some embodiments, the compositions and methods of the present disclosure have dose response relation in cancer cells that is different from dose response relation of the same the compositions and methods in normal cells.

[0255] In some embodiments, the compositions and methods of the present disclosure have utility in treating PCPG in a subject. In one embodiment, the compositions and methods of the present disclosure have utility in treating PCPG 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 including a compound comprising ONC-206 or a pharmaceutically acceptable salt thereof in combination with (ii) one or more additional therapeutic agent, wherein ONC-206 or salt thereof, and the one or more additional therapeutic agents are administered either simultaneously or sequentially. The additional therapeutic agents may be any suitable therapeutic agent, including any of the pharmaceutically active agents disclosed in in this application. In one embodiment, the pharmaceutically accetable salt of ONC-206 includes a di-hydrochloride salt.

[0256] It is understood that ONC-206 as the di-HCl or an alternative di-salt thereof apparent from the teaching of this disclosure, may be substitued for a ONC-206 in any of the compositions or dosing regimens described hererin.

[0257] In some embodiments, the method of treatment comprises administeringto a subject in need of such treatment, a pharmaceutically effective amount of ONC-206 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0258] In some embodiments, an additional therapeutic agent may be given before or prior to administration of ONC-206.

[0259] In some embodiments, treatment of cancer comprises prevention of tumor growth in a cancer subject. In some embodiments, treatment of cancer comprises prevention of formation of cancer metastases in a cancer subject. In some embodiments, treatment of cancer comprises targeted treatment of minimal residual disease in a cancer subject known to have the minimal residual disease in a cancer or a subject at risk for having minimal residual disease. This might be indicated after treatment of the primary tumor by surgery and / or after chemotherapy (e.g. radiotherapy) has been initiated or determined to efficaceous. Disseminated tumor cells may be in their dormant state and often cannot be attacked by the chemotherapy (radiotherapy). A thus treated patient seemingly is in a healed state, which is also described as “minimal residual disease”. Nevertheless, the dormant tumor cells have a potential of forming metastases if they become metastasising cells due to a growth stimulus also after a longer dormant state.

[0260] As used herein, “minimal residual disease” denotes a small number of cancer cells that remain in in a subject during treatment, or after treatment when the subject is in remission (exhibiting no symptoms orsigns of the disease). The methods described herein are preferably applied to any form of the diseases listed herein, including adult and childhood forms of these diseases.

[0261] In an aspect, the present disclosure provides a method of treatment, which comprises administering to a subject in need of such treatment a combination of a first therapeutic agent including the following ONC-206 and a second therapeutic agent, the method comprising:(i) administering to the subject the first therapeutic agent including ONC-206 or a pharmaceutically acceptable salt (e.g., a di-salt or tri-salt) thereof;(ii) waiting until a predetermined waiting time has elapsed after the time of administration of the first therapeutic agent to the subject; and / or until adverse events are resolved or resolving; and(iii) administering the second therapeutic agent to the subject, wherein the predetermined waiting time is chosen so as to obtain a delayed therapeutic effect of thePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)first therapeutic agent without an increased 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 the pharmaceutically 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 parameters of renal. In some embodiments of the method of treatment, the predetermined waiting time is determined by an assays for the determination of renal function, wherein the assay is selected from the group consisting of serum level of ONC-206 or the pharmaceutically acceptable salt thereof; ONC-206 or the pharmaceutically acceptable salt thereof clearance rate; 24-hour urinary clearance of ONC-206 or the pharmaceutically acceptable salt thereof or a metabolite thereof.

[0262] In one embodiment of the method of treatment, the predetermined waiting time substantially equals to the time required for systemic clearance of ONC-206 or a pharmaceutically acceptable salt thereof from the body of the subject. In one embodiment of the method of treatment, the predetermined waiting time substantially equals to the time required for renal clearance of ONC-206 or a pharmaceutically acceptable salt thereof from the body of the subject. In one embodiment of the method of treatment, the predetermined waiting time substantially equals to the time required for hepatic clearance of ONC-206 or a pharmaceutically acceptable salt thereof from the body of the subject. In one embodiment of the method of treatment, the predetermined waiting time substantially equals to the time required for total clearance of ONC-206 or a pharmaceutically acceptable salt thereof from the body of the subject. 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 embodimens the waiting time is 1 day. In some embodiments, the wait time is until Cmax of ONC-206 has passed. In other embodiments, the waiting time is after most of the adverse events are resolved or are resolving. 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 timePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)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 to 2 days. In some embodiments, the waiting time is up to 3 weeks. The preceeding are considered “therapeutic time periods.”

[0263] In one embodiment, the administration of ONC-206 is daily. In one embodiment, the administration of ONC-206 is every other day. 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.

[0264] When the order of administration is reveresed, timing for the administration of ONC-206 can be after the Cmax of the first administered drug has passed. In some embodiments, administration of ONC-206 can be after most or substantially all of the first administered drug has been eliminated from the body or the toxicity effects for the first administered drug are resolved or are resolving.

[0265] In some embodiments, the method of treatment further comprises monitoring level of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling. In some such embodiments, monitoring level of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling comprises constructing a pharmacokinetic profile of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof for the subject using concentrations ofPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof in at least two samples obtained from the subject at time points suitable to construct a pharmacokinetic profile. In some embodiments of the method, which include monitoring level of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, at least two samples are collected from the subject at point-of-care or point of use by sampling or selfsampling on point-of-care devices or point of use devices or on matrices suitable for storage of the at least two samples prior to quantitation in a laboratory. In some embodiments of the method of treatment, each of the point-of-care devices or point of use devices is capable of quantitating ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite. In some embodiments of the method, which include monitoring level of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject, one or more samples are collected from the subject at point-of-care or point of use by biopsy device for analysis at the point-of-care or point of use devices or for storage prior to analysis by a laboratory. In some embodiments of the method, a biopsy is taken after a time interval of 3-8 hours following administration of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 3-24 hours following administration of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 8-24 hours following administration of ONC-206, a pharmaceutically acceptable salt thereof, ora metabolite thereof to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 2 days following administration of ONC-206, a pharmaceutically acceptable salt thereof, ora metabolite thereof to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 3 days following administration of ONC-206, a pharmaceutically acceptable salt thereof, or a metabolite thereof to the subject. In some embodiments of the method, a biopsy is taken after a time interval of 4 days following administration of ONC-206, a pharmaceutically acceptable salt thereof, ora metabolite thereof to the subject. In some embodiments of the method, a biopsy isPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)taken after a time interval of 1 -7 days following administration of ONC-206, a pharmaceutically acceptable salt thereof, ora metabolite thereof to the subject.

[0266] In some embodiments of the method of treatment, the pharmacokinetic profile includes pharmacokinetic parameters suitable for uiding dosing of ONC-206 or a pharmaceutically acceptable salt thereof for the subject being treated. In some embodiments of the method of treatment, maximum concentration of the first therapeutic agent in blood (whole blood, plasma, or serum) (“Cmax”) of the subject following its administration to the subject ranges from about 10 ng / mLto about 4000 ng / mLfor a therapeutic time period, such as weekly or other than daily dose regimen. In some embodiments, Cmax is less than 4000 ng / mLand greater than 10 ng / mLfor a therapeutic time period, such as weekly or other than daily dose regimen.V. MULTIMODAL THERAPEUTIC METHODS

[0267] In one aspect, the present disclosure is directed to multimodal therapeutic methods in which administration of ONC-206 ora pharmaceutically acceptable salt thereofto a subject in need of such treatment is supplemented by administration of other therapeutic modalities. In one embodiment, the multimodaltherapeutic method of the present disclosure comprises administering to a subject a pharmaceutical composition comprising the ONC-206 or a pharmaceutically acceptable salt thereof in conjunction with radiation therapy or after radiation is determined to not have been efficacious. In one embodiment, the multimodal therapeutic method of the present disclosure comprises administering to a subject a pharmaceutical composition comprising ONC-206 or a pharmaceutically acceptable salt thereof in conjunction with radiation therapy, wherein the pharmaceutical composition comprising ONC-206 or a pharmaceutically acceptable salt thereof and the radiation therapy are administered concurrently or sequentially in any order. In one embodiment, the multimodal therapeutic method comprises administering to a subject a pharmaceutical composition comprising ONC-206 ora pharmaceutically acceptable salt thereof in conjunction with radiation therapy in a sequential arrangement. In one embodiment, the multimodal therapeutic method comprises administering to a subject in need of such treatment a pharmaceutical composition comprising ONC-206 or a pharmaceutically acceptable salt thereof concurrently with radiation therapy. In onePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)embodiment, the multimodal therapeutic method of the present disclosure is used for the treatment of cancer. In one embodiment, the multimodal therapeutic method includes administeringto a cancer subject in need of such treatment a pharmaceutical composition comprising ONC-206 ora pharmaceutically acceptable salt thereof and irradiating cancer cells with a radiation beam. In one embodiment, the multimodal therapeutic method uses the technique of conformal radiotherapy (CRT) to deliver a dose volume histogram (DVH) prescribed to a cancer subject. In one embodiment, the multimodal therapeutic method uses the technique of intensity modulated radiation therapy (IMRT) to deliver radiation to cancer cells. In one embodiment, the multimodal therapeutic method uses a techniques compensates for motion of tumors in the subject during treatment (e.g., where doses of radiation must be administered to a thoracic tumor which moves as the patient breathes). In one embodiment, the multimodal therapeutic method use Four Dimensional Computed Tomography (4D CT) scanning techniques to adjust the delivered radiation field to compensate for tumor motion over the breathing cycle.

[0268] Any suitable type of radiation, including gamma radiation which is given fractionated, IMRT (intensity modulated radiation therapy), gamma knife, proton therapy and brachytherapy can be used with the multimodal therapeutic method of the present disclosure. Radiation therapy and ONC-206 or a pharmaceutically acceptable salt thereof can be used to treat brain tumors such as glioblastoma or disease that has metastasized to the brain from lung cancer. The multimodal therapeutic method of the present disclosure can be used to treat lung cancer, pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostate cancer, gynecological malignancies, and lymphoma. The gamma knife is used frequently to treat brain metastases. In one embodiment, the multimodal therapeutic method of the present disclosure includes use of proton therapy to treat cancer, including brain tumors, prostate cancer and any tumor proximate vital organs where it is very important to minimize toxicity to nearby normal tissue.

[0269] In one embodiment, the multimodal therapeutic method of the present disclosure eliminates minimal residual disease without adding to any toxicity resulting from treatment ONC-206 ora pharmaceutically acceptable salt thereof. In onePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)embodiment, the multimodal therapeutic method of the present disclosure improves prognosis and / or reduces adverse side-effects associated with a disease state or condition in a subject undergoing treatment.VI. SYNTHESIS : DERIVATIVES, ANALOGS, AND SALTS OF ONC-206

[0270] In one aspect, the present disclosure provides analogs and related salts of ONC-206 and processes of making the same. Persons skilled in the art will understand that the same general principles and concepts described above in conjunction with ONC-206 and salts thereof, including principles and concepts related to methods and pharmaceutical compositions, apply with equal force to derivatives and analogs of and salts of ONC-206 and salts thereof.

[0271] In one embodiment, the compounds related to ONC-206 have the structure of compound (10):, wherein Ri and R2independently 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 heterocycle radicals. In another embodiment, the compounds related to ONC-206 have the structure of compound (10), wherein Ri and R2are independently selected from the group consisting of H, Ci.4alkyl, Ci.4alkylphenyl, Ci.4alkylphenylketone, Ci.4benzyl-piperazine, and Ci.4alkylthienyl wherein Ci-4alkyl, Ci-4alkylphenyl, Ci.4alkylphenylketone, and Ci.4benzyl-piperazine are optionally substituted with Ci.4alkyl, hydroxyl, or halo. In still another embodiment, the compounds related to ONC-206 have the structure of compound (10), wherein Ri and R2are 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-di F-Ph), CH2-((2-CH3)-Ph), CH2CHOHPh, and (CH2)3CO-4F-Ph. In some embodiments, when Ri represents CH2Ph, R2does not represent CH2-((2-CH3)-Ph.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0272] As illustrated in Schemes 1 and 2, compound (10) can be synthesized starting either with methyl 1-Ri-4-oxo-3-piperidinecarboxylate (6) or by reacting compound (12) with compound (6).

[0273] Scheme 1:

[0274] Scheme 1 illustrates the synthesis of compound (10) starting from compound (6). In one embodiment, as illustrated in Scheme 3, compound (6) was converted into 4-amino-3-pyridinecarboxylic acid ester methyl ester (7) (or methyl 4-amino-1 -Ri -1 ,2,5,6-tetrahydro-3-pyridinecarboxylate) by a reaction with ammonia. In one embodiment, compound (7) (or4-amino-3-pyridinecarboxylic acid ester methyl ester (7)) was treated with 2-(Methylsulfanyl)-4,5-dihydro-1 H-imidazole (8) to make compound (9), which when alkylated R2X, wherein R2is as defined above and X is a halogen or an equivalent leaving group, produced compound (10) with different values for the R2substituent.

[0275] Scheme 2:

[0276] Scheme 2 illustrates the synthesis of compound (10) starting from compound (6) and compound (12). In one embodiment, as illustrated in Scheme 4,PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)compound (12) is prepared from compound (8). In one embodiment, compound (12) was treated with compound (6) to produce compound (10) with different values for the R2substituent.

[0277] Scheme 3:

[0278] Scheme 3 illustrates the synthesis of compound (10) starting from compound (11). In one embodiment, as illustrated in Scheme 5, compound (11), having a nitrogen protecting group (P) at the N atom at ring position 7, was first deprotected and then akylated with RiX, wherein Ri is as defined above and X is a halogen or an equivalent leaving group, to produce compound (10) with different values for the Ri substituent. In some embodiments compound (10) can be prepared as a salt, for example a 2TFA salt or 2HCI salt. In some embodiments, compound (10) can be prepared as a 2HCI salt.EXAMPLES OF COMPOUND (10)No. ONC Number Ri R21 ONC201 CH2Ph CH2-((2-CH3)-Ph) 13 CH2Ph CH314 ONC202 CH2Ph CH2-((2-Cl)-Ph) 15 ONC203 CH2Ph CH2-(2-thienyl) 16 ONC204 CH2Ph CH2CH2Ph17 ONC205 CH2Ph CH2CH2(4-N-benzyl- piperazine)18 ONC206 CH2Ph CH2-(2,4-di F-Ph) 19 ONC207 H CH2-((2-CH3)-Ph) 20 ONC208 CH3CH2-((2-CH3)-Ph) 21 ONC209 CH2CH2Ph CH2-((2-CH3)-Ph)PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)No. ONC Number Ri R222 CH2CH2-(4-N-benzyl- CH2-((2-CH3)-Ph)piperizine)23 CH2CHOHPh CH2-((2-CH3)-Ph) 24 (CH2)3CO-4F-Ph CH2-((2-CH3)-Ph) 32 ONC210 CH2CH2NHCOOC(CH3)3CH2-((2-CH3)-Ph) 33 ONC211 CH2CH2CH2NH2CH2-((2-CH3)-Ph)VII. EXAMPLES

[0279] It should be understood that the description and specific examples provided below are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure. The following examples are intended to illustrate the embodiments disclosed and are not to be construed as being limitations thereto.Additional compounds, other than those described below, may be prepared using the following reaction schemes described above or appropriate variations or modifications thereof.

[0280] Example 1. Synthesis of 2-Chlorobenzylamino-2-imidazoline hydriodide

[0281] To a stirred solution of 2-methylthio-2-imidazoline hydriodide (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 for 90 min at 70 C. under an atmosphere of argon. The solution was cooled to room temperature, filtered on a sintered funnel, washed with cold dioxane (2 mL) and dried under vacuum. The white solid compound 4»HI (R2=2-chlorobenzyl) was obtained (242 mg, 72%) and used without further purification.

[0282] Example 2. Synthesis of 2-Chlorobenzylamino-2-imidazoline

[0283] To a stirred solution of 2-chlorobenzylamino-2-imidazoline hydriodide (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 for 30 min at 7 °C under argon. After that methylene chloride (5 mL) was added and the mixture stirred for another 5 min. The reaction mixture was extracted with methylene chloride (2X 2.5 mL), The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The resulting free base (150 mg, 100%)PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)was obtained as a viscous liquid and was used for the next reaction without any further purification. MS(ESI) 210(M+H).

[0284] Example 3. Synthesis of Methyl-1 -benzyl 4-oxo-3-piperidine carboxylate (Compound (6)).

[0285] To a stirred methyl-1 -benzyl 4-oxo-3-piperidine carboxylate hydrochloride (5.7 g, 20 mMol) in ethyl acetate (50 mL), was added triethylamine (6 mL) at 7 °C. The reaction mixture was stirred for 30 min at 7 °C under atmosphere of argon. The reaction mixture was extracted with ethyl acetate (2x50 mL) washed with water (50mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The resulting free base residue (5, Ri=benzyl) as a viscous oil was used in the next reaction without any further purification MS(ESI) 248(M+H)

[0286] Example 4. Synthesis of ONC2Q2 (Compound (14))

[0287] To a solution of 2-chlorobenzylamino-2- imidazoline (150 mg, 0.72 mMol), methyl 1-benzyl4- oxo-3-pi peridine carboxylate (5, Ri=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. Afterthat the reaction mixture was refluxed at 125 °C to 130 °C for 2h. The solvents were removed under vacuum, extracted with ethyl acetate (10 mL), washed with saturated sodium bicarbonate solution (2 x10 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 ONC902 TFA salt as a white solid (228 mg, 50% yield) MS(ESI) 407 (M+H).

[0288] The same process was used starting with different benzylamines to prepare various analogs, e.g., ONC203, 204, 205, and 206.

[0289] Description of Manufacturing Process and Process Controls

[0290] The chemical synthesis of ONC206 and its conversion to the dihydrochloride (ONC206»2HCl) was accomplished following the process shown in Scheme 1.

[0291] In this route, the piperidone ester (Cpd 2»HCl) was converted to the Cpd 2 (free base) and condensed with the benzyl imidazoline (Cpd 10) to yield the ONC206 free base. The ONC206 free base was converted to the dihydrochloride and the final product ONC206«2HCl was crystallized from ethanol. The step-by-step procedure isPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)summarized in Table 3, the major equipment is listed in Table 4, followed by a description of the process.Compound 2 Compound 10ONiC2<35 (Hee base)RscrysiallizationReference standard

[0292] Scheme 1. Schematic of the Synthesis of ONC206*2HCl

[0293] Step, Procedure Description1, To a stirred NaHCO3aqueous solution, charge compound 2»HCl in portions.2, Add n-butanol to the above mixture. Stir for 30 min.3, Separate the n-butanol phase and dry with MgSO4.4, To a three-neck flask equipped with a mechanical stirrer, a Dean-Stark trap, a condenser, a thermocouple and N2inlet, charge compound 10, (Pyridinium p-toluenesulfonate) PPTS and the above compound 2 solution in n-butanol.5, Heat the mixture to reflux.6, Stop the reaction when the peak area of the product by HPLC remains constant over time.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.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)10, Transferthe organic phase to a cleaned flask.11, Dilute 4N HClin dioxane to 2N HCl solution with MTBE.12, Add 2H HCl solution to the organic phase, until no more solid precipitates out on the surface at the addition of HCl.13, Heat the mixture at reflux for 2 hours. Separate the water by a Dean-Stark trap.14, After cooling to room temperature, filter off the solid.15, Wash the solid with a 1 :2 mixture of n-Butanol and MTBE.16, Dry the solid under vacuum.17, Charge the dry solid to a flask, followed by ethanol.18, Heatthe mixture to until all the solid dissolves and filter.19, Cool the mixture and filter off the solid.20, Wash the solid with ethanol.21, Dry the solid under vacuum until it reaches a constant weight.Tablulated Summary of Procedural Steps for Synthesis of ONC206*2HCl Equipment Name22L Reactor50L ReactorTableTop Ceramic FilterDrying TraysVacuum Drying OvenEquipment Involved in Synthesis of ONC206»2HCl.

[0294] Brief description of the manufacturing process

[0295] To a stirred NaHCO3aqueous solution, charge To a stirred solution NaHCO3(859 g; 10.2 mol) in 8400 mL of distilled water in a 50L reactor, was added the benzylpiperidinone ester HCl salt (compound 2 hydrochloride (2743 g, 9.667 mol, 1.70 equiv)) in portions. n-Butanol (8400 mL) was then 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 of for 2 hr. The MgSO4was filtered off andPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)washed with 1000 mL of n-butanol and transferred to a 22L reactor equipped with mechanical stirring, N2 inlet, a thermocouple, a condenserand a Dean-Stark trap. The 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 the reactor and stirred overnight. The mixture was heated to reflux and maintained at reflux until the peak area of the product by HPLC remained constant overtime. This condition was met and the mixture allowed to cool to room temperature after 4h.

[0296] The mixture was transferred to a 50L reactor with a bottom valve and was washed with 8400 mL of water. The organic phase was diluted with MTBE (16800 mL) and washed with water (2 x 8400 mL) and transferred to a 50L reactor equipped with mechanical stirring, N2 inlet, a thermocouple, a condenserand a Dean-Starktrap. HCl (2N in dioxane, 3128 mL) was diluted with an equal volume of MBTE (3128 mL)-and the solution of 1 N HCl in dioxane-MTBE was added until no more solid precipitated out on the surface at the addition of HCl (5600 mL). The mixture was heated at reflux at 60-65°Cfor2 hr with the water separating in the 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 drying trays in a vacuum oven at 55°Cfor4 hr, then room temperature for 60 h, to afford 2305 g (84% yield) of the crude product as a yellow solid.

[0297] To a 22L reactor equipped with mechanical stirring, nitrogen inlet, a thermocouple and a condenser, the crude solid (2300 g) was added, followed by ethanol (11500 mL). The mixture was heated until it completely dissolved (67°C) and the hot solution filtered. The solution was cooled slowly to room temperature overnight with stirring, then to 15 °C for 1 hour. The solid was filtered off, washed with ethanol (3x 1400 mL)-transferred to drying trays, and dried in the vacuum oven at 75°C for until a constant weight was reached. 1492 g of ONC206»2HCl was obtained as an off-white solid in a yield of 65%.

[0298] Example 5. Synthesis of ONC2Q6

[0299] To a stirred 800 mL saturated NaHCO3in a 2 L round bottom flask, compound (3) (239.7 g, 0.845 mol, 1.6 equiv) was added in portions. n-Butanol (500 mL) was added to the resulting mixture and the mixture was stirred for 30 min and thenPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)transferred to a separating funnel. The organic phase, containing compound (4), was separated and transferred to a 2 L three-neck round bottom flask equipped with mechanical stirring, N2inlet, a thermocouple, a condenser and a Dean-Stark trap. Compound (5) (100 g, 0.528 mol, 1 equiv) 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 necessary. Refluxing temperature increased from 93 °C to 118 °C. Reaction progress was monitored by HPLC. When the peak area of ONC-206 on HPLC remained constant with the reaction time, the reaction was stopped.

[0300] Example 6. Synthesis of Pi-Salt of ONC2Q6

[0301] Without isolation of the 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 mechanical stirring, N2 inlet, a thermocouple, a condenser and a Dean-Stark trap. While agitating the reaction mixture, 1 N HCl in dioxane-MTBE solution was added dropwise (4 N HCl in dioxane: 300 mL, 1.2 mol, 2.27 equiv; MTBE: 1200 mL) until no more solid precipitated out of the reaction mixture upon addition of HCl. The reaction mixture was heated to reflux at 60-65 °C for 2 hours. Water was separated into the Dean-Stark trap as necessary. Upon 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 the vacuum oven at 65°C overnight (16 hours) to afford 200 g yellow solid.

[0302] To a 2 L three-neck round bottom flask equipped with mechanical stirring, N2 inlet, a thermocouple and a condenser, the above solid (200 g) was added, followed by ethanol (1000 mL). The mixture was heated to reflux at 78°C for 2 hours. Upon cooling to room temperature, the solid was filtered through a sintered glass funnel and washed with ethanol (200 mLx3). The wet solid was dried in the vacuum oven at 85°C for 3 days until the residual solvent met specification. 120 g of compound (2) was obtained as a white solid in a yield of 49%, with HPLC purity 99.7%.

[0303] Therapeutic ExamplesPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0304] ONC206 is an orally active caseinolytic protease proteolytic subunit (ClpP) agonist and dopamine receptor D2 (DRD2) antagonist, that is a chemical derivative of dordaviprone (ONC201 ) with increased potency being developed as a treatment for advanced cancers. ONC206 impairs the viability of pheochromocytoma cells in a ClpP -dependent manner, induces apoptosis, and degrades mitochondrial proteins such as succinate dehydrogenase complex iron sulfur subunit B.

[0305] Example 7, Allosteric ClpP agonist ONC2Q6 alters mitochondrial metabolism, stress response, chromatin accessibility and cell cycle to elicit apoptosis in pheochromocytoma

[0306] Dordaviprone (ONC201 ), an allosteric caseinolytic protease P (ClpP) agonist and dopamine receptor D2 / 3 (DRD2 / 3) antagonist, has demonstrated durable responses in recurrent H3 K27M-mutant glioma patients. Dordaviprone demonstrated responses in patients with neuroendocrine pheochromocytoma-paraganglioma (PC-PG) including tumors with SDHB / FH loss-of-function driver mutations. ClpP binding, in vitro efficacy, comparison to standard of care (SOC) treatments, downstream signaling and response determinants were characterized for ONC206 in PC. Co-crystallization with ClpP that assembles as a tetradecameric complex revealed an allosteric ligand interaction with distinctions in the ONC206-ClpP resolved crystal structure relative to the dordaviprone-bound or apo complex, including an increase in the resolved pore size and decreased complex height. ONC206 was more potent than dordaviprone in cell-free human ClpP casein / peptide degradation assays.

[0307] As shown in Figure 3, PC lines (hPheol , PC12, MPC10) exhibited increased nanomolar sensitivity to ONC206 (~6 fold) relative to dordaviprone in cell viability assays.

[0308] ONC206 induced dose- and time-dependent apoptosis in PC but not fibroblast (HFF-1 , MRC-5) cells as measured with caspase Gio and / or annexin V assays. With reference to Figures ONC206 generally required a shorter duration of exposure (~24h) and induced enhanced apoptosis in PC cell lines relative to dordaviprone at therapeutically relevant concentrations.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0309] As shown in Figures 11 and 12, ONC206 also demonstrated superior cell viability inhibition and apoptosis induction in PC cell lines relative to temozolomide and sunitinib at equivalent concentrations.

[0310] As shown in Figures 5 and 6, CRISPR-mediated SDHB or FH knockout hPheol cells were equally sensitive to ONC206 as parental cells. Unlike DRD2, CRISPR-mediated ClpP knockout in hPheol cells impaired ONC206 sensitivity.

[0311] As shown in Figure 7, Western blot showed ONC206 downregulated mitochondrial proteins (ClpX, SDHB), neuroendocrine markers (tyrosine hydroxylase, enolase-2, synaptophysin) and upregulated stress response (ATF4) in hPheol cells.

[0312] ONC206 is superior to SOC.

[0313] Example 9. Acquired resistance

[0314] As shown in Figure 13, treatment to generate acquired resistance was initiated at 0.2 pM ONC206 and drug concentration was doubled when cells were able to proliferate. hPheol cells were selected up to 1.6 pM ONC206. Lines A, B, C were selected under 3 days on / 4 days off ONC206 treatment. Lines D, E, F were selected under constant ONC206. Cell viability for 5000 cells treated with CNC201 / 206 at indicated concentrations was measured on Day 4 using CellTiter-Glo (Promega).

[0315] Whole exome sequencing of hPheol cells with acquired resistance to CNC206 (performed at Novogene) reveals ClpP mutations and termination:Clone A: D134N (51.1%)Clone B: Q137X (51.1)% -terminationClone C: Q137X (99.1%) -terminationClone D: Q137X (98.8%) - terminationClone E: Q137X (10.6%); G182E (20.7%); A195E (16.5%)Clone F: Q137X (12.1%); G182E (25.8%); A195E (12.7%)

[0316] A seahorse analysis of hPheol cells with acquired resistance to ONC206 reveals impaired effects on glyco and mito ATP compared to parental cells. As shown in Figure 14, Seahorse analysis was performed using the Seahorse XF Real-Time ATP Rate Assay kit and Seahorse XFe24 Analyzer (Agilent). Data were normalized to cell counts as determined by Hoescht staining on a Cytation 5 plate reader (BioTek) following the Seahorse analysis.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0317] As shown in Figure 15, ONC206 treatment at indicated concentrations for 24 hours inhibits transwell cell migration in dose-dependent manner in PCPG cell lines using the Boyden chamber assay. Moreover, as shown in Figure 16, Invasion assay after 2 days treatments (Treated with TGF 10 ng / ml - / + ONC2060.55 pM / TMZ 23 pM / SUN 3 pM) in flask and 3 days in transwell. Transwell Assays by Calcein AM and Crystal violet.

[0318] As shown in Figure 17, Western blot analysis indicates ONC206 inhibits TGF-P1 -mediated Induction of EMT Biomarkers in PCPG Cells. TGF0 (10 ng / ml). Cells were treated with - / + ONC206 (0.55 pM), temozolomide (TMZ, 23 pM), sunitinib (SUN, 3 pM) for 2 days.

[0319] Based upon this the acquired resistance findings, one emboidiment of the present disclosure includes combination treatments for ONC206 with one or more metabolism-targeted agents. Such agents include, by way of example and not limiting, one or more of glycolysis inhibitors, glutaminase inhibitors, OXPHOS inhibitors, and IDH1 / 2 inhibitors.

[0320] Example 10. PCPG ClinicalTrial

[0321] Pheochromocytoma and paraganglioma (PCPG) tumors secrete catecholamines and highly express the DRD2 receptor that is antagonized by ONC206. Dordaviprone induced tumor regressions in patients with advanced paraganglioma in a clinical trial as a monotherapy. A study represents the first clinical study designed to evaluate the efficacy and safety of ONC206 in patients with PCPG.

[0322] Reference is made to Protocol Number GNC206-002, IND 137528, A Phase 2 Study of ONC206 in Advanced Pheochromocytoma and Paraganglioma, herein incorporated by reference. Figure 1 is a schematic illustration of the study design. Abbreviations: BID TIW=twice daily, on 3 consecutive days per week;PCPG=pheochromocytoma or paraganglioma; R=randomization. Another abbreviation relevant for the present disclosure is QD TIW, namely once daily on 3 consecutive days per week.

[0323] ONC206, 7-benzyl-4-(2,4-difluorobenzyl)-2,4,6,7,8,9-hexahydroimidazo[1 ,2-a]pyrido[3,4-e]pyrimidin-5(1 H)-one, dihydrochloride, is an orally active caseinolytic protease proteolytic subunit (ClpP) agonist and dopamine receptor D2 (DRD2)PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)antagonist, that is a chemical derivative of dordaviprone (ONC201 ) with increased potency being developed as a treatment for advanced cancers. ONC206 impairs the viability of pheochromocytoma cells in a ClpP-dependent manner, induces apoptosis, and degrades mitochondrial proteins such as succinate dehydrogenase complex iron sulfur subunit B. Pheochromocytoma and paraganglioma (PCPG) tumors secrete catecholamines and highly express the DRD2 receptor that is antagonized by ONC206. Dordaviprone induced tumor regressions in patients with advanced paraganglioma in a clinical trial as a monotherapy. This example provides a clinical study designed to evaluate the efficacy and safety of ONC206 in patients with PCPG.

[0324] This is an open-label, multicenter, two-stage Phase 2 clinical study evaluating the efficacy and safety of ONC206 in patients with advanced PCPG who have locally advanced or metastatic disease and have exhausted or declined available therapy. The primary objective of this study is to determine the antitumor activity of GNC206 in this patient population.

[0325] Eligible patients must have histologically confirmed PCPG, have failed prior PCPG therapy, and be ineligible for curative surgery, are not candidates for chemotherapy, or have declined further standard of care.

[0326] This study consists of two stages, both of which will evaluate ONC206 as monotherapy doses that have previously been evaluated in Phase 1 clinical trials (ClinicalTrials.gov identifier: NCT04541082).

[0327] Stage 1 : Patients will receive 150 mg ONC206 twice daily, on 3 consecutive days per week (BID TIW) in each 28-day cycle. A Simon’s two-stage design will be implemented: Part A: An initial number of patients will be treated and monitored for response; and Part B: If a pre-specified number of responses from Part A is observed, additional patients will be enrolled and treated for further evaluation of response.Stage 2: If Stage 1 meets pre-specified response thresholds, the study will advance to Stage 2, where patients will be randomized 1 :1 to receive ONC206 at a specified dose levels). ONC206 will be administered orally in 28-day cycles until patients meet criteria for treatment discontinuation. An individual patient’s duration of treatment will depend on individual response, evidence of disease progression, and tolerability.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0328] For Stage 1 , disease imaging assessments are required approximately every 12 weeks (±7 days) until confirmed radiological progressive disease occurs per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Even after discontinuation of study treatment, imaging assessments will continue until disease progression and all patients will be followed for survival until death for up to 3 years from first dose. If the study is terminated after State 1 , patient follow-up will be halted, unless there are outstanding safety concerns that require further monitoring.

[0329] Number of Patients: This study will enroll up to 90 evaluable patients: up to 30 evaluable patients will be treated in Stage 1 and 60 evaluable patients will be randomized and treated in Stage 2. During Stage 1 , patients who discontinue for reasons other than progressive disease, death due to underlying disease, or related adverse event prior to their first post-baseline scan will be replaced.Objectives EndpointsPrimary* To evaluate the antitumor * Overall response rate by Response Evaluation activity of ONC206 Criteria in Solid Tumors (RECIST) v1.1 Secondary* Duration of response (DOR)* Time to response (TTR)* Disease control rate (DCR)* To evaluate the effect of * Progression-free survival (PFS)ONC206 on PCPG growth and * Overall survival (OS) (up to 3 years)symptoms * Change from baseline in antihypertensive medication dose* Change from baseline in biochemical response (metanephrines / disease markers )* Incidence of adverse events (AEs): overall, treatment-related, Grade 3 or higher in severity, serious, those resulting in study treatment* To assess the safety and discontinuationtolerability of ONC206 * Change from baseline in clinical laboratory parameters* Distribution of graded clinical laboratory parameters * Change from baseline in ECG parametersPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)* To assess plasmaconcentrations and estimate * Plasma concentrations of ONC206 pharmacokinetic (PK) * PK parameters for ONC206parameters for ONC206* Change from baseline in the following QoL * To evaluate the impact ofassessments:ONC206 on health-related** EORTC QLQ-C30quality of life (QoL)** FACT-BPExploratory* Correlation between the molecular profile of the tumor (germline mutations, somatic mutations, * To evaluate the association of and / or fusion genes) with objective response and biomarkers with outcomes survival outcomes* Correlation between pharmacodynamic biomarkers with objective response* To assess the impact ofONC206 on metastatic * Incidence and time to new metastases by location dissemination* Incidence and time to:* To assess the impact of** Subsequent anticancer treatment ONC206 on need for** Radiotherapysubsequent thera py** Surgery* To assess the impact ofONC206 on cardiovascular * Incidence of cardiovascular eventsevent occurrence

[0330] Diagnosis and Main Criteria for Inclusion: This study will enroll male and female adult (>18 years) patients, without restrictions on race or ethnicity.

[0331] Inclusion criteria: A potential patient must meet all the following criteria to be eligible for inclusion in the study: (1 ) Is able to understand the study procedures and agrees to participate in the study by providing written informed consent (by patient or legally authorized representative), and assent when applicable; (2) Has histologically confirmed pheochromocytoma or paraganglioma that is unresectable as determined by the Investigator; (3) Has failed, is not a candidate for, or has declined standard of care treatment for PCPG. There is no limit on the number of prior systemic therapies; and (4)PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)Must have measurable disease per RECIST v1.1 , as assessed by the Investigator. Only measurable lesions per RECIST v1.1 may be selected as target lesions. Irradiated lesions or lesions treated with locoregional therapies should not be used as target lesions unless they clearly demonstrate growth after completion of radiation; (5) Has adequately controlled blood pressure defined as blood pressure <150 / 90 mmHg and with no change in antihypertensive medications (for patients with concomitant hypertension) for at least 14 days before the first dose of study treatment; (6) Is >18 years of age; (7) Is able to swallow oral tablets; (8) Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2, assessed within 7 days before the first dose of study treatment; (9) Has laboratory test results meeting the following parameters within 14 days before the start of study treatment: a) Absolute neutrophil count >1.0x109 / L and platelets >75x109 / L; b) Total bilirubin <1.5xthe upper limit of normal (ULN) (patients with Gilbert’s syndrome may be included with total bilirubin >1.5 x ULN if direct bilirubin is <1.5xULN); c) Aspartate aminotransferase and alanine aminotransferase <2.5xULN, noting that for patients with documented baseline liver metastasis, the following limits will apply: <5xULN for transaminase; and d) Creatinine clearance >50 mL / min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate >60 mL / min / 1.73 m2) or serum creatinine <1.5xULN; (10) Has an expected survival of at least 12 weeks, as predicted by the physician; (11) Has pharmacologic control of catecholamine-associated symptoms if patient has functional disease, noting that patients with secretory PCPG should be evaluated in consultation by hypertension specialist with experience in the management of hypertension in the settingof catecholamine-secretingtumors (usually an endocrinologist, nephrologist, or a cardiologist), and in the setting of hormone-associated hypertension; and (12) Additionally, if available, the study center is to provide >15 unstained formalin-fixed paraffin-embedded slides from the patient’s tumor tissue, noting that if a patient only has 1 measurable lesion per RECIST v1.1 , the biopsy specimen should be obtained from a nontarget lesion or archival tissue. Bone biopsies should not be submitted.

[0332] Exclusion criteria: A potential patient who meets any of the following criteria will not be eligible for inclusion in the study: (1 ) Has known hypersensitivity to ONC206PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)or any excipient used in the ONC206 study treatment formulation; (2) Is unable or unwilling to abide by the study protocol or cooperate fully with the Investigator; and (3) Has active cardiac disease / condition including any of the following a) Corrected QT interval (QTc) >480 msec (based on the mean from triplicate electrocardiograms [ECGs] performed during Screening); b) History of documented congestive heart failure (New York Heart Association function classification lll-IV); and c) Unstable angina, acute myocardial infarction, or arterial bypass or percutaneous transluminal coronary angioplasty within 6 months before the first dose of study treatment; (4) Has previous exposure to ONC206 or dordaviprone (ONC201 ) from any source; (5) Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Exceptions include patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, or Von Hippel-Lindau disease-associated tumors that do not require immediate surgery or intervention; (6) Has received any of the following interventions within the specified time periods before the first dose of study treatment or plans to receive any of the following interventions during study participation: a) Any prior anticancer therapy or investigational agents within 4 weeks or 5 half-lives, whichever is shorter. Note: Denosumab and zoledronic acid are permissible. Noting that any treatment with somatostatin analog or lanreotide within 21 days before the baseline Positron Emission Tomography (PET) scan; b) Strong cytochrome P450 (CYP) inhibitors within 14 days; c) Strong CYP inducers within 14 days; d) Any radiotherapy within 14 days; and e) Any major surgery, open biopsy or significant traumatic injury within 1 month (30 days); (7) Is pregnant, breastfeeding, or planning to become pregnant while receiving study treatment or within 3 months after the last dose. Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment, noting that female patients of childbearing potential or males with reproductive ability should follow contraceptive guidelines during the study and for at least 3 months (90 days) after the last dose of study treatment; (8) Has uncontrolled intercurrent illness or any other medical, psychiatric, or social condition that, in the opinion of the Investigator, may interfere with patient safety or the ability to comply with study requirements; (9) Has unresolvedPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)toxicities from previous locoregional, systemic, or any other therapies, defined as toxicities (other than Grade <2 neuropathy or alopecia) not yet resolved to the National Cancer Institute Common Terminology Criteria for Adverse Events Grade <1, or baseline and considered clinically significant; consult with Medical Monitor; and (10) Has an active infection that requires systemic therapy.

[0333] Treatment Groups:

[0334] During Stage 1 , patients will receive 150 mg ONC206 BID TIW.

[0335] During Stage 2, patients will be randomized 1 :1 to receive ONC206 at 1 of 2 doses (TBD).

[0336] Study Treatment Dosing:

[0337] ONC206 will be provided as 50-mg tablets for oral administration on an empty stomach (no food within 1 hour before or for 1 hour after each dose).

[0338] During Stage 1 , patients will receive a total of 150 mg ONC206, administered as three 50-mg tablets twice daily (BID). Each BID dose should be taken 12 hours (±2 hours) apart. This dosing schedule will occur on 3 consecutive days per week (TIW).

[0339] For Stage 1 , ONC206 will be dosed at the study center during the first week of Cycle 1.

[0340] Criteria for Evaluation:

[0341] Efficacy: Efficacy will be evaluated through radiologic and biochemical disease assessments, survival status, time to treatment failure, and other measures of clinical outcomes. Radiologic disease assessments will be performed using RECIST v1.1 criteria, with Investigator assessments collected for all patients.

[0342] Blinded Independent Central Review (BICR) assessments may also be conducted in addition to Investigator assessments.

[0343] The primary outcome is the ORR, defined as the number of patients with a confirmed complete response (CR) or partial response during the study, as per RECIST v1.1. Response will be determined based on tumor assessment using clinical examination and / or radiographic assessments (MRIZ CT with contrast).

[0344] The secondary outcome measures include the following:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)* DOR, measured from the time criteria are met for CR or partial response, whichever is first recorded, until the first date that progressive disease is objectively documented.* PFS by RECIST v1.1 , defined as the time from first dose to the earlier date of progression or death.* TTR, defined as the time from first dose to the time measurement where criteria are met for CR or partial response, whichever is first recorded.* DCR, defined as the percentage of patients who achieve CR, partial response, or stable disease.* OS, defined as the time from first dose to the date of death.* Change from baseline in biochemical response (metanephrines and other disease-related biomarkers), defined as the best confirmed response of either CR or partial response at any time for any biomarker that was elevated at baseline.* Antihypertensive response, defined as the proportion of patients who achieve at least a 50% reduction in antihypertension medication use or complete discontinuation for a minimum of 6 months.* ECOG performance status assessment with endpoints of time to first response, duration of response, and descriptive summary of changes over time.* Change in baseline in QoL assessments.

[0345] Exploratory outcomes include correlations between tumor molecular profiles or pharmacodynamic biomarkers and clinical outcomes, as well as the incidence and timingof new metastases, subsequent anticancer treatments, radiotherapy, surgery, and cardiovascular events.

[0346] Pharmacokinetics: Plasma concentrations and pharmacokinetic (PK) parameters for ONC206 will be determined. The relationship between concentrations of ONC206 and select efficacy and safety endpoints will be investigated.

[0347] Safety: Safety will be evaluated based on the incidence of treatment-emergent adverse events (AEs), clinical laboratory results, vital signs, and ECG assessments. All AEs will be collected and recorded in the Case Report Form (CRF) from the first dose of study treatment until 30 days after the last dose of study treatment.

[0348] Imaging: All available imaging files related to the diagnosis and ongoing monitoring of the patient’s PCPG will be collected for pre-baseline (if available),PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)baseline, while the patient is receiving ONC206, and any additional scans obtained until initiation of subsequent anticancer therapy.

[0349] Tumor measurements will be performed for all patients during Screening as follows:* Baseline disease assessment: radiographic tumor measurements of the neck, chest, abdomen, and pelvic region. Imaging of the neck, chest, abdomen, and pelvic region (CT with contrast or MRI; MRI preferred for abdomen and pelvis) will be performed at Screening / Baseline within 28 days of the first dose of study treatment, and then every 12 weeks (±7 days) thereafter until disease progression occurs per RECIST.vl .1.o Note: For each patient, it is important to maintain the same imaging modality (MRI / CT) and use of contrast, as well as consistent image acquisition and processing parameters, throughout the study to ensure accurate and consistent visualization of tumor burden.* Patients will also undergo a baseline Dotatate PET scan to identify bone metastases unless a relevant bone scan performed within 2 months (60 days) prior to the first dose of study treatment is available. Thereafter, tumor measurements and disease response assessments will be performed as follows: * Radiographic disease assessment by Investigator: every 12 weeks (±1 week) until disease progression occurs per RECIST v1.1.* Patients with bone lesions at Screening / Baseline will undergo subsequent Dotatate PET scans every 12 weeks (±7 days) until disease progression occurs per RECIST v1.1.* Patients with neck lesions at Screening / Baseline will also undergo subsequent CT scans every 12 weeks (±7 days) until disease progression occurs per RECIST v1.1.

[0350] Anatomical measurements will be documented during the Screening / Baseline visit and at each subsequent evaluation every 12 weeks (±7 days). To ensure consistency and minimize variability, the same qualified physician will interpret these measurements whenever possible. All radiographic images will be sent to a central image collection warehouse. Starting with Stage 2, a third-party vendorwith expertise in image data evaluation will perform central reading of some or all scans.

[0351] Sample Size:

[0352] Stage 1 : Under the Simon’s 2-stage minimal design criterion, a sample size of 14 patients in Part A and 16 patients in Part B is required to test a null hypothesis of Ho:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)it <0.1 versus an alternative hypothesis ofn >0.3 with a one-sided significance level of 0.025 and >82.5% power, where n is the true proportion of successes.

[0353] Stage 2: A sample size of 30 patients randomized to each dose is required to test a null hypothesis of Ho: n <0.1 versus an alternative hypothesis of Hn: it >0.3 with a one-sided significance level of 0.025 and >81.2% power, where n is the true proportion of successes. No adjustment is made for multiple comparisons.

[0354] Statistical Considerations:

[0355] Analysis Sets: All efficacy endpoints will be analyzed using the Evaluable Analysis Set, with a supportive analysis conducted for the primary endpoint using the Safety Analysis Set. All safety endpoints will be analyzed using the Safety Analysis Set.

[0356] Efficacy: Stage 1 will be analyzed as a single group, while Stage 2 will be analyzed by treatment as received. If the 150 mgBIDTIWdose of ONC206is used in Stage 2, additional analyses will be presented, pooling information forthat dose across Stages 1 and 2. The primary endpoint will be summarized as a proportion with corresponding 95% exact confidence intervals. Nominal exact p-values will be provided, testing ONC206 against a fixed 10% in Stage 1 and testing each ONC206 group versus a fixed 10% in Stage 2.

[0357] Interim Analyses

[0358] Futility Interim Analyses

[0359] Futility interim analyses will be completed during Stage 1 of the study. A patient is considered evaluable if they have initiated and received at least 1 dose of ONC206 and have at least 1 post-baseline disease imaging assessment that is evaluable for response per RECIST v1.1 criteria by Investigator. Patients who discontinue treatment due to progressive disease, die due to underlying disease, or discontinue due to a related AE prior to the first post-baseline imaging assessment will be considered evaluable. Treated patients who are deemed unevaluable will be replaced.

[0360] The first interim analysis will be completed after the first 14 evaluable patients in Stage 1 , Part A are treated and followed for response and confirmation. In the event that <1 patient experiences a confirmed response, the study will be stopped for futility. Otherwise, the study will proceed to Part B of Stage 1.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WG)

[0361] The second interim analysis will be completed after the remaining 16 patients in Stage 1 , Part B are treated and followed for response and confirmation. In the event that <6 patients of the cumulative 30 patients enrolled in Stage 1 of the study experience a confirmed response, the study will be stopped for futility. Otherwise, the study will proceed to Stage 2 with no further interim analysis.

[0362] Safety Interim Analyses: A Safety Review Committee will conduct a safety interim analysis as part of its prespecified monitoring of safety and safety signal detection. The committee will review safety data after the first 7 patients have completed at least 2 cycles of treatment and will review safety data as part of the futility interim analyses to assess benefit-risk after 14 and 30 patients have been treated.

[0363] If unacceptable treatment-related toxicity (defined as any Grade 4 toxicity, any recurrent Grade 3 toxicity, or any Grade 3 toxicity persisting more than 4 weeks) is observed at a frequency of >33% during safety reviews in Stage 1 (i.e. after 7, 14, and 30 patients have been treated in Stage 1 ), accrual will be paused, pending prompt safety committee review and re-evaluation of the dosage of ONC206 in this study. In the event of a fatal toxicity that is deemed to be at least possibly related to ONC206 (i.e., the death is not clearly related to underlying disease or extraneous causes), accrual will be paused, pending safety committee review and discussion with the study Medical Monitor, relevant Investigator(s), and others as necessary. The evaluation may result in continuing the study at the same dose, amending the protocol to change the dose, or stopping the study.

[0364] Table: Objectives and EndpointsObjectives EndpointsPrimaryTo evaluate the antitumor activity of Overall response rate by Response Evaluation Criteria in ONC206 Solid Tumors (RECIST) v1.1SecondaryDuration of response (DOR)Time to response (TTR)Disease control rate (DCR)To evaluate the effect of ONC206 Progression-free survival (PFS)on PC PG growth and symptoms Overall survival (OS) (up to 3 years)Change from baseline in antihypertensive medication dose Change from baseline in biochemical response(metanephrines / disease markers))PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)Incidence of adverse events (AEs): overall, treatment- related, Grade 3 or higher in severity, serious, those resulting To assess the safety and tolerability in study treatment discontinuationof ONC206 Change from baseline in clinical laboratory parameters Distribution of graded clinical laboratory parameters Change from baseline in ECG parametersTo assess plasma concentrationsPlasma concentrations of ONC206and estimate pharmacokineticPK parameters for ONC206(PK) parameters for ONC206To evaluate the impact of ONC206 Change from baseline in the following QoL assessments: on health-related quality of life EORTC-QLQ-C30(QoL) FACT-BPExploratoryCorrelation between the molecular profile of the tumor (germline mutations, somatic mutations, and / orfusion To evaluate the association ofgenes) with objective response and survival outcomes biomarkers with outcomesCorrelation between pharmacodynamic biomarkers with objective responseTo assess the impact of ONC206 onIncidence and time to new metastases by location metastatic disseminationIncidence and time to:To assess the impact of ONC206 on Subsequent anticancer treatmentneed for subsequent therapy RadiotherapySurgeryTo assess the impact of ONC206 onIncidence of cardiovascular eventscardiovascular event occurrence

[0365] Study Design

[0366] This is an open-label, multicenter, two-stage Phase 2 clinical studyevaluating the efficacy and safety of ONC206 in patients with advanced PCPG who have locally advanced or metastatic disease and have exhausted or declined available therapy. The primary objective of this study is to determine the antitumor activity of ONC206 in this patient population.

[0367] Eligible patients must have histologically confirmed PCPG, have failed prior PCPG therapy, and be ineligible for curative surgery, are not candidates for chemotherapy, or have declined further standard of care.

[0368] This study will consist of two stages, both of which will evaluate ONC206 as monotherapy doses that have previously been previously evaluated in Phase 1 trials (ClinicalTrials.gov identifier: NCT04541082). A study schematic is shown in Figure 1, illustrating the sequential phases and treatment regimen:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)Stage 1 : Patients will receive 150 mg ONC206 BID TIW (twice daily, on 3 consecutive days per week) in each 28-day cycle. A Simon’s two-stage design will be implemented:Part A: An initial number of patients will be treated and monitored for response.Part B: If a pre-specified number of responses from Part A is observed, additional patients will be enrolled and treated for further evaluation of response.Stage 2: If Stage 1 meets pre-specified response thresholds, the study will advance to Stage 2, where patients will be randomized 1 :1 to receive ONC206 at 1 of 2 dose levels (TBD).

[0369] ONC206 will be administered orally in 28-day cycles until patients meet criteria for treatment discontinuation. An individual patient’s duration of treatment will depend on individual response, evidence of disease progression, and tolerability.

[0370] For Stage 1 , disease imaging assessments are required approximately every 12 weeks (±7 days) until confirmed radiological progressive disease occurs per RECIST v1.1. Even after discontinuation of study treatment, imaging assessments will continue until disease progression and all patients will be followed for survival until death for up to 3 years after the last dose of study treatment. If the study is terminated after Stage 1 , patient follow-up will be halted, unless there are outstanding safety concerns that require further monitoring. Scientific Rationale for Study Design.

[0371] ONC206 is an orally active ClpP agonist and DRD2 antagonist, derived from dordaviprone with increased potency, and is being developed for the treatment of advanced cancers. ONC206 impairs the viability of pheochromocytoma cells in a ClpP-dependent manner, induces apoptosis, and degrades mitochondrial proteins such as SDHB.

[0372] PCPG tumors secrete catecholamines and highly express the DRD2 receptor, which is antagonized by ONC206, supporting its potential efficacy in this disease. In a prior clinical trial, dordaviprone induced tumor regressions in patients with advanced paraganglioma when administered as monotherapy.

[0373] This study represents the first clinical study designed to evaluate the efficacy and safety of ONC206 in patients with PCPG.

[0374] End-of-Study DefinitionPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0375] This is an event-driven study. AU patients will be followed for survival for up to 3 years or withdrawal of consent to collection of follow-up information. End-of-study is defined as the time at which all patients have discontinued from the study, are lost to follow-up, or have withdrawn consent or when the Sponsor decides to terminate the study.

[0376] ONC206 will be administered on a BID TIW dosing schedule every 12 hours (±2 hours) on 3 consecutive days per week (Days 1 , 2, and 3 during Week 1 ; Days 8, 9, and 10 during Week 2; Days 15, 16, and 17 during Week 3; and Days 22, 23, and 24 during Week 4) for each 28-day cycle until disease progression, unacceptable toxicity, patient / physician decision to withdraw from the study, or the end of study occurs.

[0377] The study will evaluate 2 dose regimens of ONC206. In Stage 1 , patients will receive 150 mg ONC206 BID TIW. For Stage 2, the dose regimens will be selected based on available data from Stage 1, along with safety and pharmacokinetic (PK) findings from Phase 1 dose escalation studies.

[0378] The BID TIW dosing schedule was chosen to maintain sustained ONC206 concentrations at levels identified as effective in in vitro PCPG models. Plasma concentrations in patients receiving 150 mg exceed the IC50 observed in PCPG cell lines, and the multiple daily and weekly dosing schedule is designed to maximize the duration of exposure above the IC50 threshold. Additionally, PK analysis in rodents demonstrated high tissue:plasma ratios, including >4-fold higher adrenabplasma ONC206 concentrations. Increased tissue concentrations may allow for extended exposure above the IC50 threshold established in PCPG models.

[0379] The safety and PK of the Stage 1 dose regimen have been evaluated in ongoing Phase 1 dose escalation studies in adult patients with CNS tumors. In Study CNC206-001 (NCT04541082), adult patients (n=3 per dose level) with recurrent CNS tumors were enrolled and treated with ONC206 once weekly at doses of 50, 100, 150, 200, 250, and 350 mg, as well as with once daily (150 mg) or twice daily (50, 100, and 150 mg) dosing for 3 consecutive days. Out of 30 patients enrolled, 12 patients experienced Grade 2 AEs, while no patients experienced Grade 3 or 4 AEs considered possibly or probably related to ONC206. The most common treatment-related AEs (all causalities) in adult patients with glioma CNS tumors (in >10% of patients) were fatigue,PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)headache, and vomiting, which were generally mild or moderate in severity and occurred in a minority of patients. No substantial changes in the AE profile were observed as a function of dose or dosing frequency in dose escalation.

[0380] Drug Formulation and Appearance

[0381] ONC206 will be provided as 50 mg tablets for oral administration. Each tablet is round, convex, and blue film-coated, with “CMX” debossed on one side and “50” on the other side. The drug product consists of ONC206.2HCI, formulated with microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium stearate, and OpadryAMB II blue.

[0382] Dosing and Administration: Dosing Schedule and Administration Instructions

[0383] Patients will be orally administered ONC206 BID TIW every 12 hours (±2 hours) on 3 consecutive days per week. AM Dose: The first dose of the day, taken in the morning. PM Dose: The second dose of the day, taken in the evening approximately 12 hours after the AM dose. Daily Dose: The total ONC2Q6 dose taken in 1 day, consisting of 1 AM dose and 1 PM dose. Weekly Dose: The total ONC206 dose taken in 1 week, consisting of 6 doses (3 AM doses and 3 PM doses) over 3 consecutive days.

[0384] Patients will follow this schedule for each 28-day cycle, with an AM and PM ONC206 dose administered on: Week 1 : Days 1 , 2, and 3; Week 2: Days 8, 9, and 10; Week 3: Days 15, 16, and 17; Week 4: Days 22, 23, and 24.

[0385] Each patient will receive a sufficient quantity of ONC206 for each cycle. Patients should take ONC206 on the same days each week and at approximately the same times each day, ensuring a 12-hour interval (±2 hours) between the AM and PM doses.

[0386] Each ONC206 AM and PM dose should be taken with a glass of water and consumed as quickly as possible on an empty stomach (no food 1 hour before or 1 hour after each dose).

[0387] Outcome Measures - Primary Outcome Measure

[0388] The primary outcome is the overall response rate (ORR) as assessed by RECIST v1.1 , based on MRI / CT with contrast.

[0389] ORR is defined as the number of patients with a confirmed complete response (OR) or partial response during the study, as per RECIST v1.1.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)

[0390] Response will be determined based on tumor assessment using clinical examination and / or radiographic assessments (MRI / CT with contrast). For full RECIST v1.1 criteria and response assessment details. Note: A confirmed CR by RECIST v1.1 requires an initial response detection followed by a verification scan 12 weeks (±7 days) later to confirm the durability and accuracy of the response. Note: Dotatate PET will not be used for response rate assessment orto determine disease progression.

[0391] Outcome Measures - Secondary Outcome Measures

[0392] The secondary outcome measures include the following: Duration of response (DOR), measured from the time criteria are met for CR or partial response, whichever is recorded first, until the first date that progressive disease is objectively documented.

[0393] Progression-free survival (PFS) by RECIST v1.1 , defined as the time from first dose of study treatment to the earlier date of progression or death.

[0394] Time to response (TTR), defined as the time from first dose to the time measurement where criteria are met for CR or partial response, whichever is recorded first.

[0395] Disease control rate (DCR), defined as the percentage of patients who achieve CR, partial response, or stable disease.

[0396] Overall survival (OS), defined as the time from first dose to the date of death.

[0397] Change from baseline in biochemical response (metanephrines and other disease-related biomarkers.).

[0398] Biochemical response is defined as the best confirmed response of either CR or partial response at any time for any biomarker that was elevated at baseline (>1.5xULN). Biochemical CR: Normalization of biomarker levels; Biochemical partial response: >50% decrease from baseline in biomarker level.

[0399] Antihypertensive response, defined as the proportion of patients who achieve at least a 50% reduction in antihypertension use or complete discontinuation fora minimum of 6 months.

[0400] The 50% reduction is determined separately for each baseline medication, based on the total daily dose of the antihypertensive medication(s) on the day of thePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)first therapeutic dose during which no new, long-term antihypertensive medication is introduced.

[0401] The end date for which the duration of the >50% reduction of all antihypertensive medications will be determined as the earlier of: the date that the patient no longer meets the criteria of having a >50% reduction of all baseline antihypertensive medications (i.e., the start data of a new long-term continuing antihypertensive medication; OR a dose change in an existing regimen of antihypertensive medication that exceeds the >50% reduction of the baseline dose that is greater than 14 days in duration and continues without a reduction to the >50% level.

[0402] The following endpoints will be derived from available antihypertensive use data: Time to first antihypertensive response, defined as time from the first dose of study treatment to the nominal analysis timepoint when the response criteria are first met.Duration of first antihypertensive response, defined as time from first response to end of first response.Antihypertensive dose and change from baseline over time will be summarized descriptively.Time to antihypertensive use deterioration.Incidence of AEsChange from baseline in clinical laboratory parametersDistribution of graded clinical laboratory parametersChange from baseline in ECG parameters, as assessed through routine ECG monitoring. This includes evaluating changes in heart rate, PR interval, QRS duration, QT interval, and QTc interval at specified time points.Change from baseline in QoL assessments:EORTC-QLQ-C30FACT-BP (for patients with bone metastases at baseline)Plasma concentrations and PK parameters for ONC206.

[0403] Other Outcome Measures: Other outcome measures include the following: Correlation between: The molecular profile of the tumor (germline mutations, somatic mutations, and / or fusion genes) with objective response and survival outcomesPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)Pharmacodynamic biomarkers with objective response. Incidence and time to: New metastases by location; Subsequent anticancer treatment; Radiotherapy; Surgery; and Incidence of cardiovascular events.

[0404] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concept thereof. To the extent that a described method does not rely on the particular order of steps set forth herein, the particular order of the steps should not be construed as limitation on the claims. The claims directed to a method of the present disclosure should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the steps may be varied and still remain within the spirit and scope of the present disclosure.

[0405] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0406] Although this specification contains many specific implementation details, these should not be construed as limitations on the scope of any disclosure or on the scope of what may be claimed, but rather as descriptions of features that may be specific to particular implementations of particular disclosures. Certain features that are described in this specification in the context of separate implementations may also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation may also be implemented in multiple implementations separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination may in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or variation of a sub-combinations. Particular implementations of the subject matter have been described. Other implementations, alterations, and permutations of the described implementations are within the scope of the following claims as will be apparent to those skilled in the art. For example, the actions recited in the claims may be performed in a different order andPCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)still achieve desirable results. Accordingly, the above description of example implementations does not define or constrain this disclosure. Other changes, substitutions, and alterations are also possible without departing from the spirit and scope of this disclosure.

[0407] A number of embodiments of the present disclosure have been described. Although this specification contains many specific implementation details, the specific implementation details should not be construed as limitations on the scope of any disclosures or of what may be claimed, but rather as descriptions of features specific to particular embodiments of the present disclosure. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the claimed disclosure.

Claims

1. PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)In the Claims:

1. A method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:O FONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , as demonstrated by an overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

3. The method of claim 1 or 2, further comprising evaluating PCPG growth and symptoms by one or more of Duration of response (DOR), Time to response (TTR), Disease control rate (DCR), Progression-free survival (PFS), Overall survival (OS) (up to 3 years), Change from baseline in antihypertensive medication dose, and Change from baseline in biochemical response (metanephrines / disease markers)).

4. The method of claim 3, wherein evaluating the PCPG growth and symptoms is by monitoring the change from baseline in a biochemical response.

5. The method of claim 4, wherein the biochemical response is evaluated by a diagnostic marker; and wherein the diagnostic marker is a catecholamine, a normetanephrine, a metanephrine, a methoxytyramine, a chromogranin A, a synaptophysin, or a glucose analog.

6. The method of claim 5, wherein the diagnostic marker is a metanephrine.

7. The method of claim 4, further comprising evaluating positron emission tomography (PET) imaging, and the biochemical response is uptake of a glucose analog.

8. The method of any one of claims 1 to 7, further comprising evaluating one or more of:e. incidence of adverse events (AEs), comprising one or more of:i. overall,ii. treatment related,PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)iii. Grade 3 or higher in severity,iv. serious, andv. those resulting in study treatment discontinuation;f. change from baseline in clinical laboratory parameters;g. distribution of graded clinical laboratory parameters; andh. change from baseline in electrocardiogram parameters.

9. A method of treating a patient diagnosed with one or more of pheochromocytoma (PC) and paraganglioma (PG), who have locally advanced or metastatic disease, and have exhausted or declined available therapies, comprising administering a therapeutically effective amount of:O FONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

10. A method of treating a patients with histologically confirmed PCPG, said patient having failed prior PCPG therapy, and ineligible for curative surgery, comprising administering a therapeutically effective amount of:ONC-206 Compound 2or a pharmaceutically acceptable salt thereof.11.The method of any one of claims 1 to 10, further comprising administering 50 to 350 mg ONC206 weekly.

12. The method of any one of claims 1 to 10, further comprising administering in a dose schedule of one or more of: 50 mg BID / TIW, 150 mg QD / TIW, 350 mg QD / TIW, 100 mg BID / TIW, and 150 mg BID / TIW.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)13. The method of any one of claims 1 to 10, further comprising administeringfrom 50 mg to 350 mg ONC206 on 3 consecutive days per week in a 28-day cycle.

14. The method of any one of claims 1 to 10, comprising administering ONC206 BID / TIW on each of day 1 , day 2, and day 3 of a 7-day cycle.

15. The method of any one of claims 1 to 10, comprising administering ONC206 BID / TIW on each of day 1 , day 2, day 3, day 8, day 9, day 10, day 15, day 16, day 17, day 22, day 12, and day 24, of a 28-day cycle.

16. The method of claims 14 or 15, comprising administering 150 mg or 200 mg of ONC206 BID / TIW.

17. The method of claim 1 to 10, comprising administering ONC206 QD / TIWon each of day 1 , day 2, and day 3 of a 7-day cycle.

18. The method of claim 1 to 10, comprising administering ONC206 QD / TIWon each of day 1 , day 2, day 3, day 8, day 9, day 10, day 15, day 16, day 17, day 22, day 12, and day 24, of a 28-day cycle.

19. The method of claims 17 or 18, comprising administering 350 mg of ONC206 QD / TIW.

20. The method of any one of claims 1 to10, comprising administering ONC206 QD on day 1 of a 7-day cycle.21.The method of any one of claims 1 to 10, comprising administering ONC206 QD on a day on day 1 , day 8, day 15, and day 22 of a 28-day cycle.

22. The method of claim 20 or 21 , comprisingadministering350 mg of ONC206 QD.

23. The method of any one of claims 2 to 22, further comprising a staged protocol, which comprises:i. an initial treatment, with monitoring for response; andj. if a response is observed, advancing the patient to a second stage comprising comparing dose levels and creating a final dose schedule.

24. A method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206 Compound 2or a pharmaceutically acceptable salt thereofcomprising a fixed frequency with variable dose.

25. A method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:ONC-206 Compound 2or a pharmaceutically acceptable salt thereof,comprising: establising an effective AUG and dosing for a recovery window 26. The method of claim 24 or 25, further comprising administering ONC206 at one of a variable dose levels.

27. The method of claim 26, wherein ONC206 is administered orally in a 28-day cycle.

28. A method of treating one or more of neuroendocrine tumors in a patient in need thereof comprising administering a therapeutically effective amount of:ONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein the neuroendocrine tumor provides a signature for sensitivity tumor types.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)30. The method of 28, wherein the neuroendocrine tumor is PCPG.

28. The method of claim 30, wherein PCPG is identified as a sensitive tumor.31.The method of claim 25, wherein the neuroendocrine tumor is an adrenal tumor.

32. The method of claim 28, wherein the neuroendocrine tumor is an extra-adrenal tumor.

33. The method of claim 32, wherein the adrenal tumor is adrenal corticol carcinoma.

34. A method of treating a tumor characterized with one or more of an SDH mutation or a FH mutation, in a patient in need thereof comprising administering a therapeutically effective amount of:O FONC-206 Compound 2or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein the tumor is characterized with SDH mutation.

36. The method of claim 35, wherein the SDH mutation is SDHB.

37. The method of claim 34, wherein the tumor is characterized with FH mutation.

38. The method of any of claims 34 to 37, wherein the SDH mutation or FH mutation is a loss-of-function driver mutation.

39. The method of any of claims 34 to 38, wherein the tumor is a pheochromocytoma or paraganglioma.

40. A method of treating a tumor characterized with one or more ClpP mutations, in a patient in need thereof comprising administering a therapeutically effective amount of:ONC-206 Compound 2PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)or a pharmaceutically acceptable salt thereof.

41. The method of any of claims 34 to 40, wherein the patient has failed prior pheochromocytoma / paraganglioma (PCPG) therapy.

42. The method of any of claims 34 to 41 , wherein the patient is ineligible for curative surgery.

43. The method of any of claims 34 to 43, wherein the tumor is unresectable.

44. A method of treating a neuroendocrine tumor responsive to agonism of caseinolytic protease proteolytic subunit (ClpP) in a patient, said method comprising administering a compoundO FONC-206 Compound 2or a pharmaceutically acceptable salt thereof, to the patient.

45. Use of a compound,O FONC-206 Compound 2or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a neuroendocrine tumor responsive to agonism of caseinolytic protease proteolytic subunit (ClpP) in a patient.

46. A method of treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of:PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)ONC-206 Compound 2or a pharmaceutically acceptable salt thereof,wherein adminstration allows for a reduction in use of anti-hypertensives.

47. A method of treating one or more of pheochromocytoma (PC) and paraganglioma (PG) in a patient in need thereof comprising administering a therapeutically effective amount of:O FONC-206 Compound 2or a pharmaceutically acceptable salt thereof; andcomprising one or more of: a) combining said treatment with one or more additional chemotherapeutic agent; and b) combining said treatment with one more for multimodal therapy.

48. The method of claim 40, wherein the multimodaltherapy is radiation.

49. The method of claim 48, further comprising administering ONC206 or a pharmaceutically acceptable salt thereof, concurrently or sequentially in any order with the radiation.

50. The use of claim 42, wherein ONC206 is administered concurrently or sequentially with the radiation.51.The use of claim 48, wherein ONC206 is administered sequentially with the radiation.

52. The use of claim 48, wherein ONC206 is administered concurrently with the radiation.

53. The use of any of claims 48 to 52, wherein the radiation comprises irradiating cancer cells with a radiation beam.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)54. The use of any of claims 48 to 52, wherein the radiation comprises conformal radiotherapy (CRT).

55. The use of claim 54, wherein the conformal radiotherapy (CRT) delivers a dose volume histogram (DVH) prescribed to a patient.

56. The use of any of claims 48 to 52, wherein the radiation comprises intensity modulated radiation therapy (IMRT) to deliver radiation to cancer cells.

57. The method of claim 47, wherein the multimodal therapy is surgery.

58. AcompoundONC-206 Compound 2or a pharmaceutically acceptable salt thereof, for use in a method for reducing tumor size relative to baseline of total tumor burden for pheochromocytoma (PC) or paraganglioma (PG) in a patient.

59. AcompoundONC-206 Compound 2or a pharmaceutically acceptable salt thereof, for use in a method for reducing tumor burden of pheochromocytoma (PC) or paraganglioma (PG) in a patient.

60. The compound for use according to claim 59, wherein the tumor burden is measured by one or more of (a) reduction in tumor size relative to baseline of total tumor burden; and (b) reduction in tumor volume relative to baseline.61.The compound for use of any of claims 58 to 60, wherein the tumor burden and / ortumor size is measured with one or more of (a) CT scan and (b) MRI.

62. The compound for use of any of claims 58 to 60, wherein the tumor burden and / ortumor size is measured after one or more treatment cycles.PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)63. The compound for use accordingto anyone of claims 58 to 60, wherein the tumor size is less than about 80%, less than about 60%, less than about 30%, less than about 20%, or less than about 10% relative to baseline of total tumor burden in the patient.

64. A method of identifying whether a patient having a condition is likely to be responsive to administration of a compoundO FONC-206 Compound 2or a pharmaceutically acceptable salt thereof, comprising:(i) obtaining a biological sample from the patient;(ii) measuring expression levels of caseinolytic protease proteolytic subunit (ClpP) in the sample;(iii) comparing the expression levels measured in the sample to those for a predetermined standard; and(iv) determining whether the patient is likely to be responsive to the administration of ONC206 or a pharmaceutically acceptable salt thereof, based on the levels of expression measured in the sample to those for the predetermined standard.

65. The method according to claim 64, wherein the step of measuring the expression level includes the steps of (a) analyzingthe sample in a binding diagnostic for ClpP, said diagnozstic is one or more of physical and functional; and (b) measuring the amount of ClpP binding to inform therapy.

66. The method according to claim 65, wherein the step includes one or more of affinity chromatography, mass spectrometry, peptidase activity, knockdown study, or crystallography or structure analysis.

67. A method of identifying whether a patient having a condition is likely to be responsive to administration of a compound,PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)O FONC-206 Compound 2or a pharmaceutically acceptable salt thereof, comprising:(i) obtaining a biological sample from the patient;(ii) measuring mutations in succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) gene in the sample;(iii) comparing the mutations found in the sample to those fora pre-determined standard; and(iv) determining whether the patient is likely to be responsive to the administration of ONC206 or a pharmaceutically acceptable salt thereof, based on the mutations found in the sample to those for the pre-determined standard.

68. The method according to claim 67, wherein an increase in mutations measured in the sample relative to the pre-determined standard indicates that the patient is likely to be responsive to administration of ONC206, or a pharmaceutically acceptable salt thereof.

69. The method of claim 67 or 68, further comprising the step of administering to the patient a therapeutically effective amount of ONC206 or a pharmaceutically acceptable salt thereof.

70. The method of claim 69, further comprisingthe step of selecting the dosage, the frequency of administration, or both, of ONC206 or a pharmaceutically acceptable salt thereof, based on the levels or identity of mutations found.

71. A method of assessing the effectiveness of or monitoring a patient having a condition and undergoing administration of a compoundO FONC-206 Compound 2PCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)or a pharmaceutically acceptable salt thereof, comprising:(i) obtaining a biological sample from the patient;(ii) measuring a level of ClpP in the sample;(iii) comparing the level measured in the sample to those for a pre-determined standard; and(iv) determining whether the patient is responsive to the administration of ONC206 or a pharmaceutically acceptable salt thereof, based on the level of ClpP measured in the sample to those for the pre-determined standard.

72. The method of claim 71 , wherein the step of measuring the level further comprises the steps of (a) analyzing the sample in a binding diagnostic for ClpP, said diagnozstic is one or more of physical and functional; and (b) measuring the amount of ClpP bindingto inform therapy.

73. A method of assessing the effectiveness of or monitoring a patient having a condition and undergoing administration of a compoundo FONC-206 Compound 2or a pharmaceutically acceptable salt thereof, comprising(i) obtaining a biological sample from the patient;(ii) measuring the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) in the sample;(iii) comparing the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) found in the sample to those for a pre-determined standard; and (iv) determining whether the patient is responsive to the administration of the ONC206 or a pharmaceutically acceptable salt thereof, based on the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) found in the sample to those for the pre-determined standard.

74. The method of claim 73, wherein an increased level of the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) measured in the samplePCT International Application Attorney Docket No. 81877-438037 (CHI-1110-WO)relative to the pre-determined standard indicates that administration of ONC206 or a pharmaceutically acceptable salt thereof to the patient is not effective.

75. The method of claim73, further comprising the step of administering an effective amount of ONC206 or a pharmaceutically acceptable salt thereof, to the patient.

76. The method according to claim 75, further comprising the step of adjusting the dosage, the frequency or both of administration of ONC206 or a pharmaceutically acceptable salt thereof, based on the level of succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) found.

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