Treatment of pediatric cancer using glycogen synthase kinase type B inhibitors

Abstract

A method of treating cancer in a pediatric patient in need thereof comprises administering to the patient 9-ING-41 in combination with an additional therapeutic agent.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 493,909, filed April 3, 2023, and U.S. Provisional Patent Application No. 63 / 494,858, filed April 7, 2023. The entire contents of each of the foregoing applications are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to methods of treating cancer in pediatric patients. BACKGROUND

[0003] Glycogen synthase kinase-3 (GSK-3) is a serine / threonine kinase originally described as a key regulator of metabolism, particularly glycogen biosynthesis. Through its regulation of numerous substrates, GSK-3 plays a role in the progression of a variety of diseases, including cancer, immune disorders, metabolic disorders, and neurological disorders. GSK-3 has two widely expressed and highly conserved isoforms, GSK-3a and GSK-3b.

[0004] GSK-3b is particularly important in tumor progression and the regulation of oncogenes (including beta-catenin, cyclin D1, and c-Myc), cell cycle regulators (such as p27 Kip1 ), and epithelial-mesenchymal transition mediators (such as zinc finger protein SNAI1, Snail). Aberrant overexpression of GSK-3b has been shown to promote tumor growth and chemoresistance of various solid tumors, including colon cancer, ovarian cancer, pancreatic cancer, and glioblastoma, through different effects on pro-survival activated nuclear factor kappa-light chain enhancer of B cells (NF-kB) and c-Myc signaling pathways, as well as effects on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and p53-mediated apoptosis mechanisms.

[0005] 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione (“9-ING-41” or “elraglusib”) is a GSK-3b inhibitor with the chemical structure: .

[0006] 9-ING-41 is the first-in-class small-molecule potent and selective GSK-3b inhibitor based on a maleimide used by intravenous injection with significant preclinical and clinical anti-tumor activity involving G0-G1 phase and G2-M phase arrest.

[0007] The synthesis, properties, and / or biological activity of 9-ING-41 are set forth in U.S. Patent No. 8,207,216; Gaisina et al., From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863; and Hilliard et al., Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth, Anti-Cancer Drugs 2011, 22 :978-985. 9-ING-41 has been reported to be useful in the treatment of certain cancers, including brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, and pancreatic cancer, and also in the treatment of traumatic brain injury. SUMMARY

[0008] The present disclosure provides methods of treating cancer in a pediatric patient in need thereof, comprising administering 9-ING-41 to the patient in combination with an additional therapeutic agent.

[0009] In some aspects, the cancer is alveolar rhabdomyosarcoma, embryonal CNS tumor NOS, neuroblastoma, osteosarcoma, progressive ependymoma, Ewing’s sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG) / diffuse midline glioma (DMG), Wilm’s tumor, recurrent ependymoma, CIC-rearranged sarcoma, high-grade astrocytoma, adrenocortical carcinoma, embryonal CNS, ependymoma, glioma, astrocytoma, or adrenocortical carcinoma.

[0010] In some aspects, the cancer is a refractory or recurrent cancer. DETAILED DESCRIPTION

[0011] The present disclosure can be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods described herein in the context of separate aspects can also be provided in combination in a single aspect. Alternatively, features of the disclosed compositions and methods described with reference to a single aspect can also be provided independently of, or in different combinations with, features of the other aspects.

[0012] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0013] As employed above, the following terms and abbreviations are understood to have the following meanings:

[0014] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. References to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise.

[0015] When expressing a range of values, exemplary embodiments include from one particular value and / or to another particular value. All ranges are inclusive of the end values and can be combined. Moreover, recitation of ranges of values includes each value within that range. When a value is expressed as an approximation by use of the

[0016] It should be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable

[0017] As used herein, the term "pediatric patient" refers to a human patient 23 years of age or younger.

[0018] As used herein, whether used alone or in combination with another term or terms, it is understood that the phrases "method of treatment" and "therapeutic method" are used interchangeably with the phrase "for treating" a particular disease.

[0019] As used herein, whether used alone or in combination with another term or terms, “treats,” “treating,” “treated,” and “treatment” refer to and include ameliorative, palliative, and / or curative uses and outcomes, or any combination thereof.

[0020] As used herein, whether used alone or in combination with another term or terms, “therapeutic agent” refers to a compound or composition that (a) treats a particular condition, symptom, disorder, or disease described herein; (b) attenuates, ameliorates, or eliminates one or more symptoms of a particular condition, disorder, or disease described herein; (c) delays onset or recurrence (reoccurrence) of a particular condition, symptom, disorder, or disease described herein; (d) prevents onset of a particular condition, symptom, disorder, or disease described herein. It is understood that the terms “therapeutic” and “therapeutically effective” include any of the foregoing effects (a) - (d), either alone or in combination with any other (a) - (d).

[0021] The term “administering” refers to the direct administration of a compound or composition of the present application, or the administration of a prodrug, derivative, or analog that will form an equivalent amount of the active compound or substance in the body.

[0022] As used herein, the term “refractory cancer” refers to a cancer that is resistant to prior chemotherapy treatment. Refractory cancer includes a cancer that exhibits resistance at the start of prior chemotherapy treatment, or a cancer that becomes resistant during prior chemotherapy treatment.

[0023] As used herein, the term “recurrent cancer” refers to a cancer that typically recurs (returns) after a period of time during which the cancer cannot be detected. The cancer can return to the same location as the original (primary) tumor or to another location in the body.

[0024] As used herein, the term “CIC-rearranged sarcoma” refers to a class of small round cell tumors that belong to the Ewing sarcoma category of cancers. Although historically grouped together with Ewing sarcoma, these tumors are genetically distinct and, on average, have a more aggressive metastatic tendency than Ewing sarcoma.

[0025] Methods of use In some aspects, the present disclosure provides a method of treating a cancer in a pediatric patient in need thereof, the method comprising administering 9-ING-41 in combination with an additional therapeutic agent to the patient.

[0026] In some embodiments of the disclosed methods, the cancer is alveolar rhabdomyosarcoma, embryonal CNS tumor NOS, neuroblastoma, osteosarcoma, progressive ependymoma, Ewing sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG) / diffuse midline glioma (DMG), Wilms’ tumor, recurrent ependymoma, CIC-rearranged sarcoma, high-grade astrocytoma, adrenocortical carcinoma, embryonal CNS carcinoma, ependymoma, glioma, astrocytoma, or adrenocortical carcinoma.

[0027] In some embodiments of the disclosed methods, the cancer is a sarcoma.

[0028] In some embodiments of the disclosed methods, the sarcoma is alveolar rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, or CIC-rearranged sarcoma.

[0029] In some embodiments of the disclosed methods, the sarcoma is alveolar rhabdomyosarcoma.

[0030] In some embodiments of the disclosed methods, the sarcoma is rhabdomyosarcoma.

[0031] In some embodiments of the disclosed methods, the sarcoma is osteosarcoma.

[0032] In some embodiments of the disclosed methods, the sarcoma is Ewing sarcoma.

[0033] In some embodiments of the disclosed methods, the sarcoma is CIC-rearranged sarcoma.

[0034] In some embodiments of the disclosed methods, the cancer is embryonal CNS tumor NOS (not otherwise specified).

[0035] In some embodiments of the disclosed methods, the cancer is neuroblastoma.

[0036] In some embodiments of the disclosed methods, the cancer is progressive ependymoma.

[0037] In some embodiments of the disclosed methods, the cancer is pediatric glioblastoma multiforme (GBM).

[0038] In some embodiments of the disclosed methods, the cancer is diffuse intrinsic pontine glioma (DIPG) / diffuse midline glioma (DMG).

[0039] In some embodiments of the disclosed methods, the cancer is Wilms’ tumor.

[0040] In some embodiments of the disclosed methods, the cancer is recurrent ependymoma.

[0041] In some embodiments of the disclosed methods, the cancer is high-grade astrocytoma.

[0042] In some embodiments of the disclosed methods, the cancer is adrenocortical carcinoma.

[0043] In some embodiments of the disclosed methods, the cancer is embryonal CNS cancer.

[0044] In some embodiments of the disclosed methods, the cancer is ependymoma.

[0045] In some embodiments of the disclosed methods, the cancer is glioma.

[0046] In some embodiments of the disclosed methods, the cancer is astrocytoma.

[0047] In some embodiments of the disclosed methods, the cancer is adrenocortical carcinoma.

[0048] In some embodiments of the disclosed methods, the cancer is refractory or recurrent cancer.

[0049] In some embodiments of the disclosed methods, the cancer is refractory cancer.

[0050] In other embodiments of the disclosed methods, the cancer is recurrent cancer.

[0051] In some embodiments of the disclosed methods, the cancer is refractory and recurrent cancer.

[0052] In some aspects, the methods of the present disclosure are performed on a pediatric patient.

[0053] In some embodiments of the disclosed methods, the pediatric patient is 0-23 years old, for example one of: 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 12 months old, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, 18 years old, 19 years old, 20 years old, 21 years old, 22 years old, or 23 years old.

[0054] In some embodiments of the disclosed methods, the pediatric patient is 0-18 years old, for example one of: 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 12 months old, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, or 18 years old.

[0055] In some embodiments of the disclosed methods, the pediatric patient is 0-14 years old, for example one of: 1 month old, 2 months old, 3 months old, 4 months old, 5 months old, 6 months old, 7 months old, 8 months old, 9 months old, 10 months old, 11 months old, 12 months old, 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, or 14 years old.

[0056] In some embodiments of the disclosed methods, 9-ING-41 is administered in an amount of about 5-20 mg / kg of patient body weight, for example about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg.

[0057] In some embodiments of the disclosed methods, 9-ING-41 is administered intravenously.

[0058] In some embodiments of the disclosed methods, 9-ING-41 is administered in an amount of about 7 mg / kg.

[0059] In some embodiments of the disclosed methods, 9-ING-41 is administered in an amount of about 9.3 mg / kg.

[0060] In some embodiments of the disclosed methods, 9-ING-41 is administered in an amount of about 12.4 mg / kg.

[0061] In some embodiments of the disclosed methods, 9-ING-41 is administered in an amount of about 15 mg / kg.

[0062] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of once per week over a 21 -day cycle.

[0063] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of twice per week for a 21-day cycle.

[0064] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of three times per week for a 21-day cycle.

[0065] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of four times per week for a 21-day cycle.

[0066] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of five times per week for a 21-day cycle.

[0067] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of six times per week for a 21-day cycle.

[0068] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of seven times per week for a 21-day cycle.

[0069] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of twice per week for a 21-day cycle in an amount of about 7 mg / kg.

[0070] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of twice per week for a 21-day cycle in an amount of about 9.3 mg / kg.

[0071] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of twice per week for a 21-day cycle in an amount of about 12.4 mg / kg.

[0072] In some embodiments of the disclosed methods, 9-ING-41 is administered at a frequency of twice per week for a 21-day cycle in an amount of about 15 mg / kg.

[0073] In some embodiments of the disclosed methods, the additional therapeutic agent comprises irinotecan, cyclophosphamide, topotecan, temozolomide, a PI3 kinase, a protein kinase B (AKT) inhibitor, or an mTOR inhibitor.

[0074] In some embodiments of the disclosed methods, the additional therapeutic agent comprises irinotecan.

[0075] In some embodiments of the disclosed methods, the irinotecan is administered at 20-50 mg / m 2 / day, for example, one of the following doses: 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / m² 2 / sky.

[0076] In some embodiments of the disclosed method, irinotecan is administered intravenously.

[0077] In some implementations of the disclosed method, irinotecan is administered on days 1–5 of every 21-day cycle.

[0078] In some embodiments of the publicly disclosed method, irinotecan is administered at 50 mg / m². 2 Administer intravenously at a dose per day.

[0079] In some embodiments of the publicly disclosed method, irinotecan is administered at a dose of 50 mg / m² on days 1–5 of every 21-day cycle. 2 Administer intravenously at a dose per day.

[0080] In some embodiments of the publicly disclosed method, irinotecan is administered at a dose of 50 mg / m² on days 1–5 of every 21-day cycle. 2 The daily dose is administered intravenously over 90 minutes.

[0081] In some embodiments of the disclosed method, the additional therapeutic agent includes temozolomide.

[0082] In some embodiments of the disclosed method, temozolomide is administered orally.

[0083] In some embodiments of the disclosed method, temozolomide is administered on days 1-5 of every 21-day cycle.

[0084] In some embodiments of the disclosed method, the surface area is at least 0.5 m². 2 Patients at 100 mg / m 2 Temozolomide is administered orally at a dose of / dose.

[0085] In some embodiments of the disclosed method, the surface area is less than 0.5 m². 2 Patients were given temozolomide orally at a dose of 2.5 mg / kg.

[0086] In some embodiments of the disclosed method, temozolomide is administered at 100 mg / m² on days 1–5 of every 21-day cycle. 2 / Dosage to be administered orally.

[0087] In some embodiments of the disclosed methods, the additional therapeutic agent comprises both irinotecan and temozolomide, wherein each of irinotecan and temozolomide is administered as disclosed herein.

[0088] In some embodiments of the disclosed methods, the additional therapeutic agent comprises cyclophosphamide.

[0089] In some embodiments of the disclosed methods, cyclophosphamide is administered intravenously.

[0090] In some embodiments of the disclosed methods, cyclophosphamide is administered on days 1-5 of each 21 -day cycle.

[0091] In some embodiments of the disclosed methods, cyclophosphamide is administered intravenously at an amount of 400 mg / m 2 per dose on days 1-5 of each 21 -day cycle.

[0092] In some embodiments of the disclosed methods, cyclophosphamide is administered intravenously at an amount of 400 mg / m 2 per dose over 30 minutes on days 1-5 of each 21 -day cycle.

[0093] In some embodiments of the disclosed methods, the additional therapeutic agent comprises topotecan.

[0094] In some embodiments of the disclosed methods, topotecan is administered intravenously.

[0095] In some embodiments of the disclosed methods, topotecan is administered on days 1-5 of each 21 -day cycle.

[0096] In some embodiments of the disclosed methods, topotecan is administered intravenously at an amount of 1.2 mg / m 2 per dose over 30 minutes on days 1-5 of each 21 -day cycle.

[0097] In some embodiments of the disclosed methods, topotecan is administered intravenously at an amount of 1.2 mg / m 2 per dose over 30 minutes on days 1-5 of each 21 -day cycle.

[0098] In some embodiments of the disclosed methods, the additional therapeutic agent comprises both cyclophosphamide and topotecan, wherein each of cyclophosphamide and topotecan is administered as disclosed herein.

[0099] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a PI3K inhibitor, such as, e.g., one or more of copanlisib, idelalisib, umbralisib, duvelisib, alpelisib, inavolisib, gedatolisib, or paxalisib.

[0100] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a protein kinase B (AKT) inhibitor, such as, e.g., capivasertib, miransertib, or ipatasertib.

[0101] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a mTor inhibitor, such as, e.g., sirolimus, everolimus, and temsirolimus.

[0102] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a PD-L1 inhibitor, such as, e.g., atezolizumab (Tecentriq), avelumab (Bavencio), or durvalumab (Imfinzi).

[0103] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a PD-1 inhibitor, such as, e.g., pembrolizumab (Keytruda), nivolumab (Opdivo), or cemiplimab (Libtayo).

[0104] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a CTLA-4 inhibitor, such as, e.g., ipilimumab (Yervoy) and tremelimumab (Imjuno).

[0105] In some embodiments, the methods of the present disclosure result in a complete response according to RECIST 1.1 criteria.

[0106] In some embodiments, the methods of the present disclosure result in a partial response according to RECIST 1.1 criteria.

[0107] In some embodiments, the methods of the present disclosure result in stable disease according to RECIST 1.1 criteria.

[0108] In some embodiments, the methods of the present disclosure increase overall survival (OS) of the patient. As used herein, the term “overall survival” is defined as the time from treatment initiation to death from any cause.

[0109] In some embodiments, the methods of the present disclosure increase patient progression free survival (PFS). As used herein, the term "progression free survival" is defined as the time from treatment initiation to objective tumor progression or death.

[0110] It will be appreciated that in the methods of the present disclosure, 9-ING-41 can be administered as a pharmaceutical composition comprising 9-ING-41 and at least one pharmaceutically acceptable excipient.

[0111] Similarly, the additional therapeutic agent used in the methods of the present disclosure can be administered as a pharmaceutical composition comprising the therapeutic agent and at least one pharmaceutically acceptable excipient.

[0112] It will be appreciated that reference herein to a method of treating cancer using a disclosed compound or composition should also be interpreted as a reference to: (i) a method of treating cancer using a disclosed compound or composition; and / or (ii) the use of a disclosed compound or composition in the manufacture of a medicament for treating cancer.

[0113] Examples Example 1. Human pharmacokinetics of 9-ING-41 from study NCT03678883:

[0114] Example 2. Clinical study

[0115] Results: 9-ING-41 was well tolerated in this largely pre-treated pediatric patient population. Infusion volume limitations and twice weekly dosing regimen highlight the need for an oral dosage form.

[0116] Recurrent Ewing’s sarcoma patients had radiographic and pathological complete responses after 3 cycles of elraglusib / cyclophosphamide / topotecan. Six patients (26.1%) had stable disease (2 NBL, 1 aRMS, 1 EP, 1 OS, 1 GBM). Eight patients (35%) were still on study treatment for > 3 months (2 NBL, 2 EP, 1 OS, 1 aRMS, 1 ES, 1 PB). Median duration of treatment was 40 days (range 1-126).

[0117] Table 1. Interim data

[0118] “OS” = overall survival; “CR” - complete response.

[0119] Five-year survival for newly diagnosed Ewing’s sarcoma patients is > 70%, but patients with relapsed disease, such as those enrolled in this study, have a 5-year survival of < 30%. Despite 2 or more chemotherapy regimens, patients with metastatic and progressive disease have very short survival of less than 6 months. There is no treatment regimen that has meaningfully prolonged survival in Ewing’s sarcoma patients with metastatic, refractory disease.

[0120] Clinical data has been obtained in patients with refractory pediatric malignancies treated with 9-ING-41 and cyclophosphamide / topotecan combination therapy. Patients enrolled in this study were patients who had been treated with standard of care therapy in their particular disease and, despite these treatments, had disease progression. Of the 25 evaluable patients enrolled in this study, seven (7) were enrolled with metastatic, refractory Ewing’s and Ewing’s-like sarcoma.

[0121] The seven Ewing’s patients enrolled in this trial all appeared to have metastatic disease and, despite prior chemotherapy and radiation, had disease progression prior to joining this study. Four of the seven patients received two or more prior chemotherapy regimens. All patients received elraglusib + cyclophosphamide / topotecan combination. One patient had complete resolution of her tumor at her first tumor assessment (2 months of treatment), stopped all treatment after 4 months, and continues in disease-free remission almost 2 years after treatment termination. A second patient had partial remission at the first tumor assessment with 52% tumor reduction; a third patient had partial remission at the first tumor assessment with 96% tumor reduction. Four of the seven patients remain alive and three of the seven patients continue treatment. See Table 2.

[0122] Table 2. Survival and best response of Ewing’s sarcoma patients treated with elraglusib and chemotherapy in this trial (unaudited data)

[0123] “FUP” = Follow-up; “CR” = Complete Response; “PR” = Partial Response; “PD” = Progressive Disease; “SD” = Stable Disease; “NAP” = Not assessable.

[0124] Table 3. Survival and best response of other pediatric cancer patients treated with elraglusib and chemotherapy in this trial (unaudited data)

[0125] “FUP” = Follow-up; “CR” = Complete Response; “PR” = Partial Response; “PD” = Progressive Disease; “SD” = Stable Disease.

[0126] Example 3. Immune stimulatory effects of 9-ING-41 on NK and T cells in human liposarcoma and osteosarcoma cell lines.

[0127] The small molecule GSK-3 inhibitor 9-ING-41 (elraglusib) was used at IC50 72Pre-treatment of Saos-2 osteosarcoma and 93T449 liposarcoma cell lines. After 48 hours of treatment, cells were collected for Western blot analysis. In addition, both cancer cell lines as well as TALL-104 T cells and NK-92 NK cells were treated with 0.5 mM 9-ING-41 for 24 hours and harvested for Luminex cytokine analysis. Western blotting showed an increase in the apoptosis marker cPARP in both cancer cell lines after 9-ING-41 treatment. In addition, an increase in PD-L1 expression was observed. Cytokine analysis showed that 9-ING-41 stimulated immune cell activity. CXCL11 was increased in treated T cells, which is associated with T cell recruitment; and IL-18 levels were increased, which was shown to induce an increase in IFN-g in Th1 cells. In addition, NK-92 cells exhibited an increase in IL-8 chemokine and an increase in soluble TRAIL (TRAIL / TNFSF10). These cancer cell lines showed a uniform increase in the growth factor TGF-a, however, only the Saos-2 osteosarcoma cell line exhibited an increase in IL-6. Subsequent cytokine analysis is ongoing. The increase in immune stimulatory cytokines and the increase in PD-L1 expression provide a rationale for the use of 9-ING-41 in combination with immune checkpoint blockade therapies. The potential synergistic effect of these two therapies is currently being investigated through co-culture experiments with sarcoma and immune cells. Treatment groups for these experiments include 9-ING-41 in combination with anti-PD-L1, anti-PD-1, or anti-CTLA-4 immune checkpoint inhibitors. These results suggest that this is a promising combination therapy strategy for soft tissue and bone sarcoma patients, and future work will aim to better elucidate the mechanism of efficacy.

Claims

1. A method of treating cancer in a pediatric patient in need thereof, the method comprising administering 9-ING-41 in combination with an additional therapeutic agent to the pediatric patient.

2. The method of claim 1, wherein the cancer is alveolar rhabdomyosarcoma, embryonal CNS tumor NOS, neuroblastoma, osteosarcoma, progressive ependymoma, Ewing’s sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG) / diffuse midline glioma (DMG), Wilms’ tumor, recurrent ependymoma, CIC-rearranged sarcoma, high-grade astrocytoma, adrenocortical carcinoma, embryonal CNS, ependymoma, glioma, astrocytoma, or adrenocortical carcinoma.

3. The method of claim 1 or claim 2, wherein the cancer is a sarcoma.

4. The method of claim 3, wherein the sarcoma is alveolar rhabdomyosarcoma, osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, or CIC-rearranged sarcoma.

5. The method of claim 4, wherein the sarcoma is alveolar rhabdomyosarcoma.

6. The method of claim 4, wherein the sarcoma is rhabdomyosarcoma.

7. The method of claim 4, wherein the sarcoma is osteosarcoma.

8. The method of claim 4, wherein the sarcoma is Ewing’s sarcoma.

9. The method of claim 4, wherein the sarcoma is CIC-rearranged sarcoma.

10. The method of any one of claims 1-9, wherein the cancer is a refractory or recurrent cancer.

11. The method of any one of the preceding claims, wherein the 9-ING-41 is administered in an amount of about 5-20 mg / kg of patient body weight.

12. The method of claim 11, wherein the 9-ING-41 is administered at a frequency of twice per week over a 21-day cycle.

13. The method of claim 11, wherein the 9-ING-41 is administered in an amount of about 9.3 mg / kg at a frequency of twice per week over a 21-day cycle.

14. The method of claim 11, wherein the 9-ING-41 is administered in an amount of about 12.4 mg / kg at a frequency of twice per week over a 21-day cycle.

15. The method of claim 11, wherein the 9-ING-41 is administered in an amount of about 15 mg / kg at a frequency of twice per week over a 21-day cycle.

16. The method of any one of the preceding claims, wherein the additional therapeutic agent comprises irinotecan, cyclophosphamide, topotecan, temozolomide, a PI3 kinase inhibitor, a protein kinase B (AKT) inhibitor, an mTOR inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, or a CTLA-4 inhibitor.

17. The method of claim 16, wherein the additional therapeutic agent comprises irinotecan.

18. The method of claim 17, wherein the irinotecan is administered intravenously over 90 minutes in an amount of 50 mg / m 2 per day on days 1-5 of each 21 -day cycle.

19. The method of any one of claims 16-18, wherein the additional therapeutic agent comprises temozolomide.

20. The method of claim 19, wherein the temozolomide is administered orally at a dose of 100 mg / m 2 2 on days 1-5 of each 21 -day cycle.

21. The method of claim 16, wherein the additional therapeutic agent comprises cyclophosphamide.

22. The method of claim 21, wherein the cyclophosphamide is administered intravenously over 30 minutes at a dose of 400 mg / m 2 2 on days 1-5 of each 21 -day cycle.

23. The method of any one of claims 16-22, wherein the additional therapeutic agent comprises topotecan.

24. The method of claim 23, wherein the topotecan is administered intravenously over 30 minutes at a dose of 1.2 mg / m 2 per day on days 1 to 5.

25. The method of claim 16, wherein the additional therapeutic agent comprises a PI3 kinase inhibitor.

26. The method of claim 16, wherein the additional therapeutic agent comprises an mTor inhibitor.

27. The method of any one of the preceding claims, wherein the patient is 0-23 years old.

28. The method of claim 27, wherein the patient is 0-18 years old.

29. The method of claim 27, wherein the patient is 0-14 years old.

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