Treatment of pediatric cancers using glycogen synthase kinase inhibitors SS form

Description

1 / 43 Treatment of pediatric cancers using glycogen synthase kinase β-form inhibitors. Cross-referencing related requests

[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 entirety of each of the aforementioned applications is incorporated herein by reference in its entirety. Technical field

[0002] The revelation refers to cancer treatment methods in pediatric patients. Background

[0003] GSK-3 is a serine / threonine kinase initially described as a key regulator of metabolism, specifically glycogen biosynthesis. It plays a role in various disease processes, including cancer, immunological disorders, metabolic disorders, and neurological disorders, through the modulation of many substrates. GSK-3 has two ubiquitously expressed and highly conserved isoforms, GSK-3a and GSK3β.

[0004] GSK-3p is particularly important in tumor progression and modulation of oncogenes (including beta-catenin, cyclin D1, and c-Myc), cell cycle regulators (e.g., p27Kipl), and mediators of epithelial-mesenchymal transition (e.g., zinc finger protein SNAI1, Snail). Aberrant overexpression of GSK-3p has been shown to promote tumor growth and chemotherapy resistance in several solid tumors, including colon, ovarian, and pancreatic cancers, as well as glioblastoma, through differential effects on survival mechanisms mediated by activated B-cell kappa light chain-enhancing nuclear factor (NF-κB) and c-Myc pathways, as well as on mechanisms Petition 870250089267, dated 10 / 01 / 2025, page 17 / 72 2 / 43 apoptotic reactions mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and p53.

[0005] 3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H[1,3]dioxolo[4,5-f]indol-7-yl)pyrrol-2,5-dione (9-ING-41 or elraglusib) is a GSK-3p inhibitor that has the following chemical structure:

[0006] 9-ING-41 is a potent and selective first-class GSK-3p inhibitor, consisting of a small maleimide-based molecule, administered intravenously (IV), with significant antitumor activity in preclinical and clinical studies, involving arrest in the G0-G1 and G2-M phases.

[0007] The synthesis, properties and / or biological activity of 9ING-41 are established in US Patent number 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 treating certain types of cancer, including brain, lung, breast, ovarian, bladder, neuroblastoma, kidney, and pancreatic cancer, as well as in treating traumatic brain injury. Summary

[0008] The present disclosure provides methods of treating cancer in a pediatric patient in need thereof, Petition 870250089267, dated 10 / 01 / 2025, page 18 / 72 3 / 43 comprising administering to the said patient 9-ING-41 in combination with an additional therapeutic agent.

[0009] In some respects, the cancer is an alveolar rhabdomyosarcoma, embryonal tumor of the CNS not otherwise specified (NOS), neuroblastoma, osteosarcoma, progressive ependymoma, Ewing's sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse interstitial pontine glioma (DIPG) / diffuse midline glioma (DMG), Wilms' tumor, recurrent ependymoma, sarcoma with CIC rearrangement, high-grade astrocytoma, adrenocortical carcinoma, Embryonic CNS, ependymoma, glioma, astrocytoma or adrenocortical.

[0010] In some respects, cancer is refractory or recurrent. Detailed description of illustrative options

[0011] The disclosure can be better understood with reference to the following description, including the following definitions and examples. Certain features of the compositions and methods disclosed, which are described here in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, several features of the compositions and methods disclosed that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0012] Unless otherwise defined in this document, scientific and technical terms used in connection with this patent application shall have the meanings that are commonly understood by those skilled in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural terms and plural terms shall include singular terms.

[0013] As used above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, should be understood to have the following meanings. Petition 870250089267, dated 10 / 01 / 2025, p. 19 / 72 4 / 43

[0014] As used in the descriptive report, including the attached claims, the singular forms a, an, oea include the plural and reference to a specific numerical value includes at least that specific value, unless the context clearly indicates otherwise.

[0015] When a range of values ​​is expressed, an exemplary modality includes from a specific value and / or up to another specific value. All ranges are inclusive and combinable. Furthermore, reference to values ​​stated in intervals includes each and every value within that interval. When values ​​are expressed as approximations, by using the preposition about, it will be understood that the specific value constitutes another modality. The term about, as used herein when referring to a measurable value, such as a quantity, a time duration and the like, is intended to cover reasonable variations of the value, such as, for example, ± 10% of the specified value. For example, the phrase about 5 to 20 mg / kg may include ± 10% of 5, ± 10% of 20 or from 4.5 to 22, including 5 to 20.

[0016] It is worth noting that certain features of revelation which are, for clarity, described here in the context of different modalities, may also be provided in combination in a single modality. Conversely, several features of revelation which are, for brevity, described in the context of a single modality, may also be provided separately or in any subcombination.

[0017] As used herein, the term pediatric patient(s) refers to a human patient aged 23 years or younger.

[0018] As used herein, whether alone or in conjunction with other term(s), the expressions treatment method and method of treating may be Petition 870250089267, dated 10 / 01 / 2025, p. 20 / 72 5 / 43 used interchangeably with the expression for use in the treatment of a specific disease.

[0019] As used herein, whether alone or in conjunction with other term(s), treats, treat, treated and treatment refer to and include attenuating, palliative and / or curative uses and outcomes, or any combination thereof.

[0020] As used herein, whether used alone or in conjunction with another term, therapeutic agent refers to a compound or composition that (a) treats a specific condition, symptom, disorder or disease described herein; (b) alleviates, improves or eliminates one or more symptoms of a specific condition, disorder or disease described herein; (c) delays the onset or relapse (recurrence) of a specific condition, symptom, disorder or disease described herein; (d) prevents the onset of a specific condition, symptom, disorder or disease described herein. It should be understood that the terms therapeutic and therapeutically effective encompass any of the effects mentioned (a) to (d), whether alone or in combination with any of the others (a) to (d).

[0021] The term administer means to directly administer a compound or composition of the present invention, or to administer a prodrug, derivative or analogue that will form an equivalent amount of the compound or active substance within the body.

[0022] As used herein, the term refractory cancer refers to cancer that is resistant to previous chemotherapy treatments. Refractory cancers include those that have shown resistance at the start of previous chemotherapy treatments, or that have become resistant during the course of previous chemotherapy treatments.

[0023] As used herein, the term recurrent cancer refers to a cancer that has reappeared (returned), usually after Petition 870250089267, dated 10 / 01 / 2025, page 21 / 72 6 / 43 a period of time during which the cancer could not be detected. The cancer may return to the same location as the original (primary) tumor or to another location in the body.

[0024] As used herein, the term CIC rearrangement sarcoma refers to a class of small round cell tumors that fall within the Ewing sarcoma group of cancers. Although historically grouped with Ewing sarcomas, these tumors are genetically distinct and tend to be more aggressively metastatic than Ewing sarcomas, on average. Methods of use

[0025] In some respects, the disclosure provides methods for treating cancer in a pediatric patient in need thereof, comprising administering to the patient 9-ING-41 in combination with an additional therapeutic agent.

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

[0027] In some forms of the methods revealed, the cancer is a sarcoma.

[0028] In some modalities of the methods disclosed, the sarcoma is an alveolar rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, or sarcoma with CIC rearrangement.

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

[0030] In some forms of the methods disclosed, the sarcoma is rhabdomyosarcoma. Petition 870250089267, dated 10 / 01 / 2025, p. 22 / 72 7 / 43

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

[0032] In some forms of the methods disclosed, the sarcoma is Ewing's sarcoma.

[0033] In some modalities of the methods disclosed, the sarcoma is a sarcoma with CIC rearrangement.

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

[0035] In some of the methods revealed, the cancer is a neuroblastoma.

[0036] In some forms of the methods revealed, the cancer is a progressive ependymoma.

[0037] In some modalities of the methods revealed, the cancer is a pediatric glioblastoma multiforme (GBM).

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

[0039] In some forms of the methods revealed, the cancer is a Wilms tumor.

[0040] In some of the methods revealed, the cancer is a recurrent ependymoma.

[0041] In some modalities of the methods revealed, the cancer is a high-grade astrocytoma.

[0042] In some modalities of the methods revealed, the cancer is an adrenocortical carcinoma.

[0043] In some forms of the methods revealed, the cancer is an embryonic cancer of the CNS.

[0044] In some of the methods revealed, the cancer is an ependymoma.

[0045] In some forms of the methods revealed, the cancer is a glioma. Petition 870250089267, dated 10 / 01 / 2025, page 23 / 72 8 / 43

[0046] In some of the methods revealed, the cancer is an astrocytoma.

[0047] In some forms of the methods revealed, the cancer is an adrenocortical cancer.

[0048] In some modalities of the methods revealed, the cancer is a refractory or recurrent cancer.

[0049] In some forms of the methods revealed, the cancer is a refractory cancer.

[0050] In other modalities of the methods revealed, the cancer is a recurrent cancer.

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

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

[0053] In some modalities of the disclosed methods, the pediatric patient is between 0 and 23 years of age, such as, for example, one of the following: 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 years old.

[0054] In some modalities of the disclosed methods, the pediatric patient is between 0 and 18 years of age, such as, for example, one of the following: 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 Petition 870250089267, dated 10 / 01 / 2025, page 24 / 72 9 / 43 age, 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 modalities of the disclosed methods, the pediatric patient is between 0 and 14 years of age, such as, for example, one of the following: 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-ING41 is administered in an amount of about 5 to 20 mg / kg of the patient's 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-ING41 is administered intravenously.

[0058] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 7 mg / kg.

[0059] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 9.3 mg / kg.

[0060] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 12.4 mg / kg.

[0061] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 15 mg / kg. Petition 870250089267, dated 10 / 01 / 2025, p. 25 / 72 10 / 43

[0062] In some modalities of the disclosed methods, 9-ING41 is administered at a frequency of once a week in a 21-day cycle.

[0063] In some modalities of the disclosed methods, 9-ING41 is administered at a frequency of twice a week over a 21-day cycle.

[0064] In some modalities of the disclosed methods, 9-ING41 is administered at a frequency of three times per week over a 21-day cycle.

[0065] In some modalities of the disclosed methods, 9-ING41 is administered at a frequency of four times per week over a 21-day cycle.

[0066] In some modalities of the disclosed methods, 9-ING41 is administered at a frequency of five times per week over a 21-day cycle.

[0067] In some modalities of the disclosed methods, 9-ING41 is administered at a frequency of six times per week over a 21-day cycle.

[0068] In some forms of the disclosed methods, 9-ING41 is administered at a frequency of seven times per week over a 21-day cycle.

[0069] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 7 mg / kg, given twice weekly over a 21-day cycle.

[0070] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 9.3 mg / kg, given twice weekly over a 21-day cycle.

[0071] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 12.4 mg / kg, given twice weekly over a 21-day cycle. Petition 870250089267, dated 10 / 01 / 2025, p. 26 / 72 11 / 43

[0072] In some embodiments of the disclosed methods, 9-ING41 is administered in an amount of approximately 15 mg / kg, given twice weekly over a 21-day cycle.

[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, irinotecan is administered in an amount of 20 to 50 mg / m2 / day, such as, for example, one of the following: 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 / day.

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

[0077] In some embodiments of the disclosed methods, irinotecan is administered on days 1 to 5 of each 21-day cycle.

[0078] In some embodiments of the disclosed methods, irinotecan is administered intravenously in an amount of 50 mg / m2 / day.

[0079] In some embodiments of the disclosed methods, irinotecan is administered intravenously at a rate of 50 mg / m2 / day on days 1 to 5 of each 21-day cycle.

[0080] In some embodiments of the disclosed methods, irinotecan is administered intravenously over 90 minutes at a rate of 50 mg / m2 / day on days 1 to 5 of each 21-day cycle.

[0081] In some embodiments of the disclosed methods, the additional therapeutic agent comprises temozolomide. Petition 870250089267, dated 10 / 01 / 2025, p. 27 / 72 12 / 43

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

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

[0084] In some embodiments of the disclosed methods, temozolomide is administered orally at a dose of 100 mg / m2 / dose to patients with a body surface area of ​​at least 0.5 m2.

[0085] In some embodiments of the disclosed methods, temozolomide is administered orally in an amount of 2.5 mg / kg to patients with a body surface area less than 0.5 m2.

[0086] In some embodiments of the disclosed methods, temozolomide is administered orally in an amount of 100 mg / m2 / dose on days 1 to 5 of each 21-day cycle.

[0087] In some embodiments of the disclosed methods, the additional therapeutic agent comprises both irinotecan and temozolomide, wherein each, 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 to 5 of each 21-day cycle.

[0091] In some embodiments of the disclosed methods, cyclophosphamide is administered intravenously at a rate of 400 mg / m2 / dose on days 1 to 5 of each 21-day cycle.

[0092] In some embodiments of the disclosed methods, cyclophosphamide is administered intravenously for 30 Petition 870250089267, dated 10 / 01 / 2025, p. 28 / 72 13 / 43 minutes at a dose of 400 mg / m2 / dose on days 1 to 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 methods disclosed, topotecan is administered intravenously.

[0095] In some forms of the methods revealed, topotecan is administered from Day 1 to Day 5 of each 21-day cycle.

[0096] In some embodiments of the disclosed methods, topotecan is administered intravenously over 30 minutes at a dose of 1.2 mg / m2 / dose on Days 1 to 5 of each 21-day cycle.

[0097] In some embodiments of the disclosed methods, topotecan is administered intravenously over 30 minutes at a dose of 1.2 mg / m2 / dose once on Days 1 to 5.

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

[0099] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a PI3K inhibitor, such as, for example, 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 capivasertib, miransertib, or ipatasertib.

[0101] In some embodiments of the disclosed methods, the additional therapeutic agent comprises an mTOR inhibitor, such as, for example, sirolimus, everolimus, and temsirolimus.

[0102] In some embodiments of the disclosed methods, the additional therapeutic agent comprises a PD-L1 inhibitor, such as, for example Petition 870250089267, dated 10 / 01 / 2025, page 29 / 72 14 / 43 For example, 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, for example, 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 ipilimumab (Yervoy) and tremelimumab (Imjuno).

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

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

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

[0108] In some modalities, disclosure methods increase the patient's overall survival (OS). As used herein, overall survival is defined as the time from the start of therapy until death from any cause.

[0109] In some modalities, the methods of disclosure increase the progression-free survival (PFS) of patients, as used herein, the term progression-free survival is defined as the time from the start of therapy until objective tumor progression or death.

[0110] It should be understood that, in the methods of disclosure, 9-ING-41 may be administered in a pharmaceutical composition comprising 9-ING-41 and at least one pharmaceutically acceptable excipient.

[0111] Similarly, the additional therapeutic agent used in the disclosure methods may be administered in a Petition 870250089267, dated 10 / 01 / 2025, page 30 / 72 15 / 43 pharmaceutical composition comprising the therapeutic agent and at least one pharmaceutically acceptable excipient.

[0112] It should be understood that references made herein to methods of treating cancer using the disclosed compounds or compositions should also be interpreted as references to: (i) the disclosed compounds or compositions for use in methods of treating cancer; and / or (ii) the use of the disclosed compounds or compositions in the manufacture of a medicament to treat cancer. Examples Example 1. Human pharmacokinetics of the 9-ING-41 study NCT03678883: Table 1 Dose 9.3 mg / kg (current dose) Cmax, ng / mL 6,414 ± 3,550 T1 / 2, h 18.9 ± 6.3 AUC(o-24), ng-h / mL 42,043 ± 12,437 AUC(o-inf), ng-h / mL 45,734 ± 14,139 Petition 870250089267, dated 10 / 01 / 2025, page 31 / 72 Example 2 - Clinical study Table 2 Investigational Product 9-ING-41 Title Phase 1 / 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3 Beta (GSK-3p) Inhibitor, as a Single Agent or with Irinotecan, Temozolomide / Irinotecan, or Cyclophosphamide / Topotecan in Pediatric Patients with Refractory Malignancies Number of Patients Approximately 100 evaluable Primary Objectives Phase 1: • To determine the maximum tolerated dose (MTD) and / or the recommended dose for Phase 2 (RDF2) of 9-ING-41 as a single agent and in combination with Irinotecan in pediatric patients with refractory malignancies; • To describe the toxicity profile and TLD of 9-ING-41 as a single agent and in combination with irinotecan, temozolomide / irinotecan, and cyclophosphamide / topotecan in pediatric patients with refractory malignancies.Phase 2 (neuroblastoma-specific arms): • To evaluate the efficacy of 9-ING-41 in combination with temozolomide / irinotecan and cyclophosphamide / topotecan in patients with refractory neuroblastoma, as defined by response rates, duration of responses, and progression-free survival (PFS); and • To characterize the safety profile of 9-ING-41 in combination with temozolomide / irinotecan and cyclophosphamide / topotecan in pediatric patients with refractory neuroblastoma. Secondary Objectives • To explore the efficacy of 9-ING-41 as a single agent and in combination with irinotecan in this patient population, as defined by response rates, duration of responses, and PFS; and. 16 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 32 / 72 • To characterize the pharmacokinetics of 9-ING-41 in combination with irinotecan, temozolomide / irinotecan, and cyclophosphamide / topotecan when administered to pediatric patients with refractory malignancies. Open-label, non-randomized, multicenter, Phase 1 / 2 design. Outcomes: Safety, via (CTCAE v5.0), will be monitored during the period beginning at the start of study therapy and ending 30 days after the final administration of 9-ING-41. All patients receiving any dose (any amount) of 9-ING-41 will be included in the safety data summaries and lists. The overall safety and tolerability profile will be characterized by the type, frequency, severity, timing, duration, and relationship of the study drug to adverse events and laboratory abnormalities. The efficacy outcomes are as follows: • Objective response rate (ORR), defined as the percentage of patients with complete response (CR), partial response (PR) according to RECIST 1 criteria.1 or other specific response criteria for malignancies, relative to the efficacy population, such as INRC for neuroblastoma; • Duration of response (DoR), defined as the time from documentation of tumor response to disease progression; and • Progression-free survival (PFS), defined as the time from study enrollment to objective tumor progression or death. Overall survival (OS), defined as the time from study entry to death from any cause. 17 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 33 / 72 Population Inclusion Criteria: Patients must meet ALL of the following criteria to be eligible for this study: 1. Age < 22 years. 2. Diagnosis of recurrent or refractory malignancy with histological verification of malignancy at original diagnosis or recurrence, except for patients with extracranial germ cell tumors who have elevated serum tumor markers, including alpha-fetoprotein or beta-HCG, and / or patients with intrinsic brainstem tumors or patients with CNS germ cell tumors and elevated serum or CSF tumor markers, including alpha-fetoprotein or beta-HCG (applies only to Phase 1; for the Phase 2 arm, see Inclusion Criterion #4). 3. Have measurable or assessable disease.Evaluable disease is defined as a tumor assessment that cannot be measured using a ruler or caliper, but which can be used to determine disease progression or response, for example, positive MIBG (metaiodobenzylguanidine) test (with or without bone marrow histology) or bone scan; metastatic bone marrow disease; elevated tumor markers; or presence of a malignant pleural effusion. (Applies only to Phase 1; for the Phase 2 arm, see Inclusion Criterion #4). 4. For the Phase 2 neuroblastoma-specific arm: Patients must have had histological verification of neuroblastoma or ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with elevated urinary catecholamines (i.e., > 2x ULN) at the time of initial diagnosis. Disease documentation (Patients must have at least ONE of the following at the time of inclusion): 18 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 34 / 72 a. Measurable tumor on MRI (magnetic resonance imaging) or CT (computed tomography). Measurable is defined as > 10 mm in at least one dimension on spiral / helical computed tomography that is MIBG-avid or demonstrates increased FDG (fluorodeoxyglucose) uptake on PET scan; b. MIBG-avid lesion detected on MIBG scan with positive uptake in at least two locations. This location must represent disease recurrence after completion of therapy, disease progression during therapy, or refractory disease during induction. If there are 1 to 2 MIBG-avid locations, then a biopsy is necessary at any time from at least one location to verify neuroblastoma or ganglioneuroblastoma; c. Patients with resistant / refractory soft tissue disease that is not MIBG-avid or does not demonstrate increased FDG uptake on PET scan may undergo biopsy to document the presence of viable neuroblastoma; and d.Patients with elevated catecholamines (i.e., > 2 x ULN) are NOT eligible for this part of the study. 5. Present a current disease state for which there is no known curative therapy or proven therapy that prolongs survival with an acceptable quality of life. 6. Have a performance level: Karnofsky > 50% for patients >16 years of age and Lansky >50% for patients ^16 years of age. 19 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 35 / 72 7. Neurological deficits in patients with CNS tumors must have been relatively stable for at least 7 days prior to study inclusion. Patients with CNS tumors receiving steroids must be on a stable or tapering dose for at least 7 days prior to study entry. Patients who are unable to walk due to paralysis but are in a wheelchair will be considered ambulatory for performance score assessment purposes. 8. The patient has fully recovered from the clinically significant acute toxic effects of prior anticancer therapy. • Myelosuppressive chemotherapy: On the first day of treatment, it must be at least 7 days after the last dose of myelosuppressive chemotherapy for the single-agent 9-ING-41, and at least 14 days after the last dose of myelosuppressive chemotherapy for the combination arms of 9-ING41 plus chemotherapy; • Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor or 7 days for a short-acting growth factor; • Biological (antineoplastic agent): At least 7 days after the last dose of a biological agent or retinoid; • Monoclonal antibodies: At least 28 days after the last dose of a monoclonal antibody; • Radiotherapy: At least 14 days after local palliative radiotherapy (small field); at least 100 days must have passed if previous TBI, craniospinal radiotherapy, or if > 50% radiation to the pelvis; at least 42 days must have passed if other substantial bone marrow radiation: Specific arms for neuroblastoma: No intervening time is required before study entry following prior radiotherapy for non-target lesions. However, patients must not have received radiation for a minimum of 14 days prior to study entry at the site. 20 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 36 / 72 Any lesion that will be identified as a target lesion to measure tumor response. Lesions that have been previously irradiated cannot be used as target lesions unless there is radiographic evidence of progression at the site after radiation or a biopsy performed after radiation shows viable neuroblastoma. Palliative radiotherapy is permitted at sites that will not be used to measure response during this study.• Stem cell transplants (SCTs): No evidence of active graft-versus-host disease and at least 42 days must have passed since the transplant or stem cell infusions, provided that hematological and other eligibility criteria have been met; • 131I-MIBG therapy: Patients are eligible > 6 weeks after 131I-MIBG therapy, provided that all other eligibility criteria are met; • Patients undergoing a major surgical procedure or laparoscopic procedure are eligible for inclusion at least 28 days after the procedure, 14 days after an open biopsy; • Central line placement or subcutaneous port placement is not considered major surgery; • Core biopsy within 3 days prior to inclusion. 21 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 37 / 72 • Fine needle aspiration within 3 days prior to inclusion; and • Surgical or other wounds must be adequately healed prior to inclusion. 9. Have received at least one first-line therapy for the treatment of their malignancy; in the chemotherapy combination arms, patients may have received prior treatment with the same agent. 10. Have adequate organ and bone marrow function on the first day of study treatment, as follows: a. For single agent 9-ING-41: ANC > 500 / mm3 For 9-ING-41 plus chemotherapy: ANC > 750 / mm3; b. For single agent 9-ING-41: Platelets > 50,000 / mm3 For 9-ING-41 plus chemotherapy: Platelets > 75,000 / mm3; c. Patients known to have bone marrow involvement with neuroblastoma are eligible, provided the minimum ANC and platelet count criteria are met, but are not evaluable for hematologic toxicity; d. Total bilirubin < 1.5x ULN for age and ALT (SGPT) < 5.0x ULN for age (< 225 U / L).For the purposes of this study, the ULN for TGP is 45 U / L; and e. Creatinine clearance or GFR estimated by radioisotope > 70 mL / min / 1.73 m2 or serum creatinine based on age / sex, as follows: Age Maximum Serum Creatinine (mg / dL) Maximum Serum Creatinine (mg / dL) Male Female 1 month to <6 months 0.4 0.4 6 months to <1 year 0.5 0.5 1 to <2 years 0.6 0.6. 22 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 38 / 72 2 to <6 years 0.8 0.8 6 to <10 years 1.1 10 to <13 years 1.2 1.2 13 to <16 years 1.5 1.4 > 16 years 1.7 1.4 11. Pregnancy tests should be performed on girls who have already experienced menarche. Girls of childbearing age should have a negative blood or urine pregnancy test performed within 72 hours before the start of the first study therapy. Patients with the potential to become pregnant should agree to use hormonal or barrier contraceptive methods with spermicidal gel, or opt for total abstinence to avoid pregnancy during study participation and for 100 days after discontinuation of study treatment. 12. All patients and / or their parents or legal guardians must sign a written informed consent form. The investigative nature and objectives of the study, the procedures and treatments involved, as well as their associated risks and discomforts and potential alternative therapies will be carefully explained to the patient or to the patient's parents or guardian, if the patient is a child, and signed informed consent and assent will be obtained in accordance with institutional guidelines. 23 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 39 / 72 Population (cont.) Exclusion criteria: Patients who meet any of the following criteria will be excluded from trial entry: 1. Have hypersensitivity to any of the components of 9-ING-41 and / or chemotherapy or to the excipients used in its formulation. 2. Have uncontrolled concomitant disease that would limit compliance with study requirements. 3. Have clinically significant retinal disease. 4. Patients with symptoms of congestive heart failure are not eligible. 5. Have current malignancy in addition to the target malignancy, except for surgically treated local tumors or are currently receiving other anticancer therapies, including radiation. 6. Have not recovered from clinically significant toxicities as a result of prior anticancer therapy, except for alopecia, infertility, and ototoxicity. Recovery is defined as < Grade 2 severity according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (v5.0). 7.1. Are you pregnant or breastfeeding? 2. Have you received a previous solid organ transplant? 3. Are you receiving any other investigational medicinal product or participating in another interventional clinical trial? 4. For neuroblastoma - patients with disease detectable only in the bone marrow (bone marrow aspirate or biopsy) are NOT eligible for the study. Treatments and Regimens 9-ING-41 as a Single Agent: • 9-ING-41 is administered by intravenous infusion twice weekly, on Days 1 and 4 of each week, for a cycle duration of 21 days; • Treatment is continued until disease progression, unacceptable toxicity, or withdrawal of consent. 24 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 40 / 72 The initial dose level in this study corresponds to 62% of the highest dose level currently tolerated in the adult 1801 study (15 mg / kg). Dose Levels: Dose Level 3 15.0 mg / kg / dose Dose Level 2 12.4 mg / kg / dose Dose Level 1 (Initial Dose Level) 9.3 mg / kg / dose Dose Level -1 7.0 mg / kg / dose 9-ING-41 and Irinotecan: 9-ING-41 was administered at Dose Level 1, or 9.3 mg / kg / dose, and escalation followed a 6-rotation design as per single-agent dose levels. Dose reduction of 9-ING-41 is permitted for patients who experience suspected 9-ING-41-related toxicity. • Irinotecan is administered at the following dose and schedule: Irinotecan 50 mg / m2 / day administered intravenously over 90 minutes on Days 1 to 5 every 21 days (the cycle duration is 21 days); and on days when irinotecan is administered, the 9-ING-41 infusion should begin at least 1 hour after the irinotecan infusion has finished.• Dose reduction of irinotecan is permitted for irinotecan-related toxicity according to the schedule below: Dose Level 1 (Initial dose level) 50 mg / m2 / day Dose Level -1 40 mg / m2 / day Dose Level -2 30 mg / m2 / day Dose Level -3 20 mg / m2 / day. 25 / 43 Petition 870250089267, dated 10 / 01 / 2025, p. 41 / 72 9-ING-41 plus Temozolomide / Irinotecan: Treatment cycles are repeated every 21 days (3 weeks): Day 1 Day 2 Day 3 Day 4 Day 5 Day 8 Day 11 Day 15 Day 18 TMZ TMZ TMZ TMZ TMZ IRIN IRIN IRIN IRIN IRIN 9-ING-41 9-ING-41 9-ING-41 9-ING-41 9-ING-41 9-ING-41 • TMZ = Temozolomide 100 mg / m2 / dose PO daily on Days 1 to 5; administered at least 1 hour before irinotecan. For patients whose body surface area (BSA) is <0.5 m2, the temozolomide dosage is based on body weight in kg. For patients with BSA < 0.5 m2, 2.5 mg / kg is used; • IRIN = Irinotecan: 50 mg / m2 / dose IV daily on Days 1 to 5 (90 min infusion); • 9-ING-41: Treatment begins at Dose Level 1, or 9.3 mg / kg / dose, and is escalated according to the single-agent dose levels. Dose reduction of 9-ING-41 is permitted for patients with suspected toxicity related to 9-ING-41. Treatment is administered twice weekly on Days 1 and 4 of each week, for a 21-day cycle. (The infusion should last 2 to 4 hours.) On days when irinotecan and temozolomide are administered, the 9-ING-41 infusion should begin at least 1 hour after the irinotecan infusion has finished and 2.5 hours after oral administration of TMZ. • Diarrhea prophylaxis according to institutional standards; and • Pneumocystis prophylaxis according to institutional standards. 9-ING-41 plus Cyclophosphamide / Topotecan: 26 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 42 / 72 Petition 870250089267, dated 10 / 01 / 2025, p. 43 / 72 Treatment cycles are repeated every 21 days (3 weeks): Day 1 Day 2 Day 3 Day 4 Day 5 Day 9 Day 12 Day 16 Day 19 CYCLE CYCLE CYCLE CYCLE CYCLE TOP TOP TOP TOP TOP 9-ING-41 9-ING-41 9-ING-41 9-ING-41 9-ING-41 9-ING-41 • CICLO = Cyclophosphamide. The cyclophosphamide dose is set at 400 mg / m² / dose for AUC > 0.6 m². For AUC < 0.6 m², see the dosage table below: Cyclophosphamide AUC (m2) Dose 0.25 to 0.29 68 mg 0.3 to 0.34 100 mg 0.35 to 0.39 12 4 mg 0.4 to 0.44 14 8 mg 0.45 to 0.49 18 0 mg 0.5 to 0.54 200 mg 0.55 to 0.59 22 0 mg > 0.6 400 mg / m2 • Cyclophosphamide is administered intravenously over 30 minutes once daily for 5 days every 21 days; • TOPO = Topotecan. The dose of topotecan is set at 1.2 mg / m² / dose for AUC > 0.6 m². For AUC < 0.6 m², see the dosage table below: 27 / 43 TOPOTECAN AUC (m2) Dose 0.25 to 0.29 0.32 mg 0.3 to 0.34 0.3 8 mg 0.35 to 0.39 0.44 mg 0.4 to 0.44 0.5 mg 0.45 to 0.49 0.56 mg 0.5 0.54 0.62 mg 0.55 to 0.59 0.68 mg > 0.6 1.2 mg / m2 • Topotecan is administered intravenously over 30 minutes once daily for 5 days every 21 days, following cyclophosphamide; • 9-ING-41: Treatment begins at Dose Level 1, or 9.3 mg / kg / dose, and is escalated according to the single-agent dose levels. Dose reduction of 9-ING-41 is permitted for patients with suspected toxicity related to 9-ING-41. Treatment is administered twice weekly on Days 2 and 5 of each week, for a cycle duration of 21 days. (The infusion should take 2-4 hours): On days when cyclophosphamide and topotecan are administered, the 9-ING-41 infusion should begin at least 1 hour after the topotecan infusion has finished. Growth factor support should be administered according to institutional standards.Duration of Therapy: Patients may continue to receive subsequent cycles of therapy provided they do not present with clinically significant progressive disease and / or unacceptable toxicity or withdrawal of consent. 9-ING-41 Schedule: Intravenous infusion on Days 1 and 4 of each week for a cycle of 3. 28 / 43 Petition 870250089267, dated 10 / 01 / 2025, p. 44 / 72 Administration: 9-ING-41 is administered over 21 days (21 days) when administered as a single agent or in combinations containing irinotecan. For the cyclophosphamide / topotecan arm, 9-ING-41 is administered on Days 2 and 5 of each week in a 21-day cycle. Irinotecan: 90-minute intravenous infusion administered on Days 1 to 5 and repeated every 21 days for a 21-day cycle. When administered on the same day as 9-ING-41, the infusion should end at least 1 hour before the start of the 9-ING-41 infusion. In the temozolomide arm, administer at least 1 hour after temozolomide. Temozolomide: PO or via NG or G-tube, preferably on an empty stomach, at least 1 hour before or 2 hours after meals. Administered on Days 1 to 5 of a 21-day cycle. Administer at least 1 hour before irinotecan administration. When administered on the same day as 9-ING-41, administration should end at least 2.5 hours before the start of the 9-ING-41 infusion.Cyclophosphamide: IV over 15 to 30 minutes, administered on days 1 to 5 of a 21-day cycle. Topotecan: IV over 30 minutes, administered on days 1 to 5 of a 21-day cycle. Administered after cyclophosphamide. When administered on the same day as 9-ING-41, the infusion should end at least 1 hour before the start of the 9-ING-41 infusion. Safety Assessment Safety is assessed throughout the study, including recording and monitoring of adverse events (AEs) (CTCAE v5.0), vital signs (blood pressure, pulse, respiratory rate, body temperature), physical examination findings, serum chemistry and hematology laboratory values, urinalysis, ECG, and concomitant medication use. TDL is defined as any of the following events that are possible. 29 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 45 / 72 Probable or definitely attributable to 9-ING-41 and / or chemotherapy that occur within the first cycle of therapy (21 days). Hematological and non-hematological dose-limiting toxicities are defined differently. Non-Hematological Dose-Limiting Toxicity: Any clinically significant Grade 3 or Grade 4 non-hematological toxicity attributable to 9-ING-41 with the specific exclusion of: • Grade 3 liver enzyme elevations, including ALT / AST, that return to eligibility levels within 7 days of discontinuation of the study drug and do not recur after retesting with the study drug; • Grade 3 bilirubin that return to eligibility levels within 7 days of discontinuation of the study drug and do not recur after retesting with the study drug.• Grade 3 diarrhea lasting < 3 days; • Grade 3 nausea and vomiting lasting less than < 3 days; • Grade 3 or 4 fever lasting < 5 days; • Grade 3 infection lasting < 5 days; • Grade 3 hypophosphatemia, hypokalemia, hypocalcemia, or hypomagnesemia responsive to oral supplementation; and • Grade 3 or 4 amylase or lipase elevation not associated with symptoms or clinical manifestations of pancreatitis; scheduled cycles due to persistent treatment-related toxicities. Dose-Limiting Hematologic Toxicity: • Grade 4 neutropenia lasting > 7 days; • Grade > 4 thrombocytopenia; and. 30 / 43 Petition 870250089267, dated 10 / 01 / 2025, p. 46 / 72 • Grade 3 thrombocytopenia lasting >7 days or associated with clinically significant bleeding. Efficacy Assessment Response and progression are assessed using the revised Response Assessment in Solid Tumors (RECIST) criteria (version 1.1) or specific standard response criteria appropriate for the patient's malignancy, including the Revised Response Criteria for Neuroblastoma (INRC) for neuroblastoma. Evaluable for objective response: Patients who experience objective disease progression before the end of cycle 1 are considered evaluable for response. For all other patients, only those who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease reassessed are considered evaluable for response.Patients with neuroblastoma who present with MIBG-positive lesions that do not meet the definitions of measurable disease are considered evaluable for response according to MIBG response. Evaluable non-target disease response: Patients who present with lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease reassessed are considered evaluable for non-target disease. Response assessment is based on the presence, absence, or unequivocal progression of lesions. Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (the largest diameter to be recorded) such as >20 mm by chest X-ray, >10 mm by CT scan, or >10 mm with calipers by clinical examination. All tumor measurements should be recorded in millimeters (or decimal fractions of centimeters).Unmeasurable disease: All other lesions (or disease sites), including small lesions (longest diameter <10 mm or pathological lymph nodes with a short axis of >10 to <15 mm), are considered unmeasurable disease. Bone lesions, leptomeningeal disease, ascites, isolated bone marrow disease, germ cells or other tumor markers, pleural / pericardial effusions, etc. 31 / 43 Petition 870250089267, dated 10 / 01 / 2025, p. 47 / 72 Cutaneous lymphangitis / pneumonitis, inflammatory breast disease, positive PET lesions, and abdominal masses (not accompanied by CT or MRI) are considered non-measurable. Neuroblastoma-specific response criteria: International Neuroblastoma Response Criteria Revised (INRC) for disease assessment. The updated response criteria incorporate current approaches to neuroblastoma imaging, including functional imaging. In addition, a standardized approach for assessing bone marrow involvement is included. The current INRC does not include disease assessment methods that are less sensitive and / or specific for neuroblastoma (99Tc bone scintigraphy and catecholamine levels). Statistical Considerations Summary of Methods Phase 1: The six-step continuous Phase 1 trial design is being used to conduct the Phase 1 portion of the study.From two to six patients may be enrolled simultaneously at a dose level, depending on (1) the number of patients enrolled at the current dose level, (2) the number of patients who experienced TDL at the current dose level, and (3) the number of patients enrolled but with pending tolerability data at the current dose level. Accumulation is suspended when a group of six has been enrolled or when the study objectives have been achieved.• Patient enrollment began at the initial dose level of the single-agent 9-ING-41 study, following the six-continued clinical trial model and continuing until a RP2D is achieved for 9-ING-41 monotherapy; • Enrollment in the irinotecan combination arm began at the initial single-dose level of 9-ING-41, once it was deemed safe, and followed a six-on-rotation design for a total of 3 dose levels; • Enrollment in the temozolomide / irinotecan combination arm will begin after institutional protocol approval and will follow a six-on-continued design for a total of 3 dose levels; and. 32 / 43 Petition 870250089267, dated 10 / 01 / 2025, page 48 / 72 • Inclusion in the cyclophosphamide / topotecan combination arm will begin after institutional protocol approval and will follow a continuous six-phase design for a total of 3 dose levels. Sample size: It is anticipated that 9 to 18 patients will be included in each of the four treatment regimens, totaling 36 to 72 patients in Phase 1. Phase 2: Following the completion of enrollment in the Phase 1 portion of the study and the determination of a 2DRP for these regimens, a specific cohort for neuroblastoma is opened. This is an exploratory (signal-seeking) Phase 2 cohort for patients with refractory neuroblastoma. The primary objective is to evaluate the ORR (ORC+PR) of 9-ING-41-based combination regimens (cyclophosphamide / topotecan and temozolomide / irinotecan) using INRC criteria and to select a regimen to proceed to confirmatory studies. Secondary objectives include evaluating other efficacy variables, including PFS, duration of tumor response, 1-year survival rate and OS, as well as a further assessment of toxicities. Categorical outcomes (ROIs) are summarized with frequencies, percentiles, and exact two-tailed 95% confidence intervals. Time-to-event outcomes (DoR, PFS, and OS) are summarized using Kaplan-Meier methods, including median, 95% CI, number of events, censored number, and Kaplan-Meier figures. Sample size: The minimum number of respondents required to proceed to the next phase is determined based on Simon's 2-stage design, with 80% statistical power and a two-tailed significance level of 0.05. An ORR of 20% is hypothesized (alternative hypothesis). An ORR of 5% (null hypothesis) is considered the lower limit of activity based on historical data in the population with refractory neuroblastoma. Both regimens (9-ING-41 + temozolomide / irinotecan or cyclophosphamide / topotecan) are enrolled in Phase 1 of the Simon 2 design. 33 / 43 Petition 870250089267, dated 10 / 01 / 2025, pp. 49 / 72 stages (n=10 per cohort, n=20 total). After completion of Phase 1 enrollment (neuroblastoma patients enrolled in the safety introduction arms count toward the total n of each arm in Phase 1), an interim analysis is performed to determine which regimen will advance to Phase 2 (n=19). At the end of the study, of the 39 patients (20 in Stage 1, 19 in Stage 2), 29 will have received the Stage 2 regimen. If >4 of these 29 patients have CR or PR, further evaluation may be performed with confirmatory studies. Petition 870250089267, dated 10 / 01 / 2025, pp. 50 / 72 Stage 1 Futility Regimen Stage 1 continues Interim Analysis Phase 2 Success Criteria 9-ING-41 + cyclophosphamide / topotecan 0 / 10 (60% probability) > 1 / 10 Interim Analysis Choose a regimen > 4 / 29 For Phase 2 9-ING-41 + temozolomide / irinotecan 0 / 10 (60% probability) > 1 / 10 It is projected that 39 evaluable patients will be enrolled in Phase 2. 34 / 43 35 / 43 Results:

[0113] 9-ING-41 was well tolerated in this pediatric population that had previously received many treatments. The limitation of the infusion volume and the twice-weekly dosing schedule highlight the need for oral dosage forms.

[0114] One patient with recurrent Ewing sarcoma had a complete radiographic and pathological response after 3 cycles of elraglusib / cyclophosphamide / topotecan. 6 patients (26.1%) had stable disease (2 NBL, 1 aRMS, 1 EP, 1 OS, 1 GBM). 8 patients (35%) remained on study treatment for > 3 months (2 NBL, 2 EP, 1 OS, 1 aRMS, 1 ES, 1 PB). The median duration of treatment was 40 days (range 1 to 126). Petition 870250089267, dated 10 / 01 / 2025, pp. 51 / 72 Table 3. Intermediate Data Tumor Type | Tumor Group | Dose of 9ING-41 | Combined Treatment | OS (days) | Notes | Alveolar Rhabdomyosarcoma | Rhabdomyosarcoma | 9.3 mg / kg | Irinotecan | 375 | CNS Embryonic Tumor | CNS Embryonic Tumor | 9.3 mg / kg | Irinotecan | 262 | Neuroblastoma | Neuroblastoma | 9.3 mg / kg | Irinotecan | 245 | Osteosarcoma | Osteosarcoma | 9.3 mg / kg | Irinotecan | 234 | Osteosarcoma | Osteosarcoma | 9.3 mg / kg | Irinotecan | 108 | Neuroblastoma | Neuroblastoma | 9.3 mg / kg | Irinotecan | 389 | Neuroblastoma | Neuroblastoma | 12.4 mg / kg | Irinotecan | 360 | Neuroblastoma | Neuroblastoma | 12.4 mg / kg | Irinotecan | 76 | Progressive Ependymoma | Ependymoma | 9.3 mg / kg Cyclophosphamide / topotecan 407 Ewing's sarcoma Ewing's sarcoma 9.3 mg / kg Cyclophosphamide / topotecan 379 pCR - complete response Osteosarcoma Osteosarcoma 9.3 mg / kg Cyclophosphamide / topotecan 389 Rhabdomyosarcoma Rhabdomyosarcoma 15 mg / kg Irinotecan 19 Glioblastoma multiforme (GBM) Glioma 12,4 mg / kg Cyclophosphamide / topotecan 406 Recurrent ependymoma Ependymoma 15 mg / kg Irinotecan 403 Neuroblastoma Neuroblastoma 12.4 mg / kg Cyclophosphamide / topotecan 308 pCR - complete response Ewing's sarcoma Ewing's sarcoma 12.4 mg / kg Cyclophosphamide / topotecan 176, 36 / 43 Petition 870250089267, dated 10 / 01 / 2025, pp. 52 / 72 Tumor Type | Tumor Group | Dose of 9ING-41 | Combined Treatment | OS (days) | Notes | Sarcoma with CIC rearrangement | Ewing's sarcoma | 15 mg / kg Cyclophosphamide / topotecan | 47 | Rhabdomyosarcoma | 15 mg / kg Cyclophosphamide / topotecan | 78 | Neuroblastoma | 15 mg / kg Irinotecan | 68 | High-grade astrocytoma | 15 mg / kg N / A | 97 | Adrenocortical carcinoma | 15 mg / kg Cyclophosphamide / topotecan | 102 | Neuroblastoma | 15 mg / kg Cyclophosphamide / topotecan | 113 SG = overall survival; RC = complete response 37 / 43 Petition 870250089267, dated 10 / 01 / 2025, pp. 53 / 72 38 / 43

[0115] The 5-year survival rate for newly diagnosed Ewing sarcoma patients is >70%, but patients who have recurrent disease (relapse), such as the patients enrolled in this study, have a 5-year survival rate <30%. Patients who develop metastasis and disease progression, despite 2 or more chemotherapy regimens, have a very short survival rate, less than 6 months. There are no treatment regimens that significantly prolong the life of patients with metastatic and refractory Ewing sarcoma.

[0116] Clinical data were obtained from patients with refractory pediatric malignancies treated with the combination of 9-ING-41 and cyclophosphamide / topotecan. Patients enrolled in this study were patients who had previously been treated with standard of care for their specific disease and experienced disease progression despite these treatments. Of the 25 evaluable patients enrolled in this study, seven (7) were enrolled with Ewing sarcoma and metastatic and refractory Ewing-like sarcoma.

[0117] The seven Ewing patients enrolled in this trial appear to have metastatic disease and experienced disease progression prior to study enrollment, despite prior chemotherapy and radiation therapy. Four of the seven patients had received two or more prior chemotherapy regimens. All patients received the elraglusib + cyclophosphamide / topotecan combination. One patient had complete tumor remission at their first tumor assessment (2 months of treatment), discontinued all treatments after 4 months, and remains in remission with no evidence of disease almost 2 years after treatment discontinuation. A second patient had partial remission with a 52% tumor reduction at the first tumor assessment; and a third patient had partial remission with a 96% tumor reduction at the first tumor assessment. Four of the seven Petition 870250089267, dated 10 / 01 / 2025, pp. 54 / 72 39 out of 43 patients are still alive and three of the seven remain under treatment. See Table 4. Petition 870250089267, dated 10 / 01 / 2025, pp. 55 / 72 Table 4. Survival and best response for patients with Ewing's sarcoma treated with elraglusib and chemotherapy in this trial (unaudited data) Tumor Type Elraglusib Dose Chemotherapy Backbone Status Last FUP Survival (days) Best Response Ewing's Sarcoma 9.3 mg / kg Cyclophosphamide / topotecan Alive 804 CR Ewing's Sarcoma 12.4 mg / kg Cyclophosphamide / topotecan Deceased 177 DE Sarcoma with CIC rearrangement 15 mg / kg Cyclophosphamide / topotecan Deceased 48 PD Ewing's Sarcoma 15 mg / kg Cyclophosphamide / topotecan Deceased 272 DE Ewing's Sarcoma 15 mg / kg Cyclophosphamide / topotecan Alive 318 NAP Ewing's Sarcoma 15 mg / kg Cyclophosphamide / topotecan Alive 145 DP Ewing's Sarcoma 15 mg / kg Cyclophosphamide / topotecan Alive 130 DP 40 / 43 FUP = follow-up; RC = complete response; RP = partial response; DP = progressive disease; DE = stable disease; NAP = no assessment possible. Table 5. Survival and best response for other pediatric cancer patients treated with elraglusib and chemotherapy in this trial (unaudited data) Tumor Type Elraglusib Dose Chemotherapy Backbone Status Last FUP Survival (days) Best Response Glioblastoma multiforme (GBM) 12.4 mg / kg Cyclophosphamide / topotecan Alive 407 DE Neuroblastoma 9.3 mg / kg Irinotecan Deceased 245 DE Petition 870250089267, dated 10 / 01 / 2025, pp. 56 / 72 Tumor Type Elraglusib Dose Chemotherapy Backbone Status Last FUP Survival (days) Best Response Neuroblastoma 9.3 mg / kg Irinotecan Deceased 389 PD Neuroblastoma 12.4 mg / kg Irinotecan Deceased 360 DE Neuroblastoma 12.4 mg / kg Cyclophosphamide / topotecan Deceased 438 RC Neuroblastoma 15 mg / kg Cyclophosphamide / topotecan Alive 440 DE Rhabdomyosarcoma 9.3 mg / kg Irinotecan Deceased 375 DE Osteosarcoma 9.3 mg / kg Cyclophosphamide / topotecan Alive 481 DE Ependymoma 12.4 mg / kg N / A Deceased 440 DE Ependymoma 9.3 mg / kg Cyclophosphamide / topotecan Alive 182 PD Ependymoma 15 mg / kg Irinotecan Dead 757 DE Ependymoma 15 mg / kg Irinotecan Dead 526 DE FUP = follow-up; RC = complete response; RP = partial response; DP = progressive disease; DE = stable disease. 41 / 43 Petition 870250089267, dated 10 / 01 / 2025, pp. 57 / 72 42 / 43 Example 3. Immunostimulatory effects on NK and T cells by 9ING-41 in human liposarcoma and osteosarcoma cell lines.

[0118] The osteosarcoma cell lines Saos-2 and liposarcoma 93T449 were pretreated at IC5Ü72 with the small molecule inhibitor GSK-3, 9-ING-41 (elraglusib). Cells were collected for western blot analysis after 48 hours of treatment. In addition, both cancer cell lines and TALL-104 T cells and NK-92 NK cells were treated with 0.5 μM of 9-ING-41 for 24 hours and harvested for Luminex cytokine profiling. Western blots demonstrated an increase in cPARP, an apoptotic marker, in both cancer cell lines after treatment with 9-ING41. Furthermore, an increase in PD-L1 expression was observed. Cytokine analysis revealed stimulation of immune cell activity in response to 9-ING-41. The treated T cells showed an increase in CXCL11, which is associated with T cell recruitment, as well as an increased level of IL-18, which has been shown to induce an increase in IFN-γ in Tl cells.Furthermore, NK-92 cells demonstrated an increase in the chemokine IL-8 and an increase in soluble TRAIL (TRAIL / TNFSF10). Cancer cell lines showed a homogeneous increase in the growth factor TGF-α; however, only the Saos-2 osteosarcoma cell line demonstrated an increase in IL-6. Follow-up cytokine profiling is ongoing. The increase in immunostimulatory cytokines, as well as the increased expression of PD-L1, suggests a rationale for combining 9-ING-41 with immune checkpoint blockade therapy. The potential synergistic effect of these two therapies is currently under investigation with co-culture experiments of sarcoma cells and immune cells. Treatment groups for these experiments include 9-ING-41 combined with anti-PD-L1 and anti-PD-1 immune checkpoint inhibitors. Petition 870250089267, dated 10 / 01 / 2025, pp. 58 / 72 43 / 43 or anti-CTLA-4. These results suggest a promising combination therapy strategy for patients with soft tissue and bone sarcomas, and future work will strive to better elucidate the mechanisms of efficacy. Petition 870250089267, dated 10 / 01 / 2025, pp. 59 / 72

Claims

1 / 4 CLAIMS 1. Use of 9-ING-41 and one or two additional therapeutic agents, characterized in that it is for the preparation of a first pharmaceutical composition comprising 9-ING-41, a second and, optionally, a third pharmaceutical composition comprising the additional therapeutic agent(s) for the treatment of cancer in a pediatric patient.

2. Use of a kit comprising 9-ING-41 and at least one additional therapeutic agent, characterized in that it is for the preparation of a medicament for the treatment of cancer in a pediatric patient.

3. Use according to claim 1 or 2, characterized in that the cancer is an alveolar rhabdomyosarcoma, CNS embryonal tumor (NOS), neuroblastoma, osteosarcoma, progressive ependymoma, Ewing's sarcoma, rhabdomyosarcoma, pediatric glioblastoma multiforme (GBM), diffuse interstitial pontine glioma (DIPG) / diffuse midline glioma (DMG), Wilms' tumor, recurrent ependymoma, CIC rearrangement sarcoma, high-grade astrocytoma, adrenocortical carcinoma, CNS embryonal tumor, ependymoma, glioma, astrocytoma, or adrenocortical carcinoma.

4. Use in accordance with any one of claims 1 to 3, characterized in that the cancer is a sarcoma.

5. Use according to claim 4, characterized in that the sarcoma is an alveolar rhabdomyosarcoma, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, or sarcoma with CIC rearrangement.

6. Use according to claim 5, characterized in that the sarcoma is alveolar rhabdomyosarcoma.

7. Use according to claim 5, characterized in that the sarcoma is rhabdomyosarcoma.

8. Use according to claim 5, characterized in that the sarcoma is osteosarcoma. Petition 870250089267, dated 10 / 01 / 2025, pp. 64 / 72 2 / 4 9. Use according to claim 5, characterized in that the sarcoma is Ewing's sarcoma.

10. Use according to claim 5, characterized in that the sarcoma is a sarcoma with CIC rearrangement.

11. Use in accordance with any of claims 1 to 10, characterized in that the cancer is a refractory or recurrent cancer.

12. Use in accordance with any of claims 1 to 11, characterized in that the pharmaceutical composition comprising 9-ING-41 is formulated to provide an amount of about 5 to 20 mg of 9-ING-41 / kg of the patient's weight.

13. Use according to claim 12, characterized in that the pharmaceutical composition comprising 9-ING-41 is formulated to be administered twice weekly over a 21-day cycle.

14. Use according to claim 12, characterized in that the pharmaceutical composition comprising 9-ING-41 is formulated to provide an amount of approximately 9.3 mg of 9ING-41 / kg twice a week over a 21-day cycle.

15. Use according to claim 12, characterized in that the pharmaceutical composition comprising 9-ING-41 is formulated to provide an amount of approximately 12.4 mg of 9ING-41 / kg twice a week over a 21-day cycle.

16. Use according to claim 12, characterized in that the pharmaceutical composition comprising 9-ING-41 is formulated to provide an amount of approximately 15 mg of 9ING-41 / kg twice a week over a 21-day cycle.

17. Use in accordance with any of claims 1 to 16, characterized in that 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. Petition 870250089267, dated 10 / 01 / 2025, pp. 65 / 72 3 / 4 18. Use according to claim 17, characterized in that the additional therapeutic agent comprises irinotecan.

19. Use according to claim 18, characterized in that the pharmaceutical composition comprising irinotecan is formulated to deliver intravenously, over 90 minutes, an amount of 50 mg of irinotecan / m2 / day on days 1 to 5 of each 21-day cycle.

20. Use in accordance with any one of claims 17 to 19, characterized in that the additional therapeutic agent comprises temozolomide.

21. Use according to claim 20, characterized in that the pharmaceutical composition comprising temozolomide is formulated to provide an oral amount of 100 mg of temozolomide / m2 / dose on days 1 to 5 of each 21-day cycle.

22. Use according to claim 17, characterized in that the additional therapeutic agent comprises cyclophosphamide.

23. Use according to claim 22, characterized in that the pharmaceutical composition comprising cyclophosphamide is formulated to deliver intravenously, over 30 minutes, an amount of 400 mg of cyclophosphamide / m2 / dose on days 1 to 5 of each 21-day cycle.

24. Use in accordance with any one of claims 17 to 23, characterized in that the additional therapeutic agent comprises topotecan.

25. Use according to claim 24, characterized in that the pharmaceutical composition comprising topotecan is formulated to deliver intravenously, over 30 minutes, an amount of 1.2 mg of topotecan / m2 / dose once on days 1 to 5. Petition 870250089267, dated 10 / 01 / 2025, pp. 66 / 72 4 / 4 26. Use according to claim 17, characterized in that the additional therapeutic agent comprises a PI3 kinase inhibitor.

27. Use according to claim 17, characterized in that the additional therapeutic agent comprises an mTOR inhibitor.

28. Use in accordance with any of claims 1 to 27, characterized in that the patient is between 0 and 23 years of age.

29. Use according to claim 28, characterized in that the patient is between 0 and 18 years of age.

30. Use according to claim 28, characterized in that the patient is between 0 and 14 years of age.

31. Invention of a product, method, composition, kit or use, characterized by comprising one or more elements disclosed in this patent application. Petition 870250089267, dated 01 / 10 / 2025, pp. 67 / 72