Method for treating patients with locally advanced and / or metastatic solid tumors using DGK zeta inhibitors

Abstract

The present disclosure is directed to a method for treating a patient having a progressive and / or metastatic tumor, wherein the patient is treated with an effective amount of at least one diacylgycerol kinase zeta (DGKζ) inhibitor and / or a pharmaceutical composition comprising the same. In some embodiments, the progressive and / or metastatic tumor is selected from melanoma and non-small cell lung cancer (NSCLC).

Description

Technical Field

[0001]

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 353,789, filed on June 20, 2022, the entire content of which is incorporated herein by reference.

Background Art

[0002]

[0002] Cancer is one of the leading causes of death in the United States. In 2018, an estimated 1.7 million new cases were diagnosed in the United States, and approximately 609,000 people died [National Cancer Institute, 2019]. New treatment strategies for cancer treatment utilize the body's own immune system to initiate an anti-tumor response. However, the endogenous immune response is frequently unable to inhibit tumor growth. This deficiency appears to be due to the immunosuppressive nature of the tumor microenvironment (TME). Tumor-infiltrating lymphocytes (TILs) are "exhausted" or suppressed in the context of multiple signals in the TME that result in significantly reduced proliferative capacity and effector function [Lantis et al., 2017].

[0003]

[0003] Cancer immunotherapies targeting immune checkpoints are revolutionary in the practice of oncology treatment. However, only a subset of patients with almost all cancer types respond effectively to these therapies. For example, in advanced melanoma of the skin, the overall survival rate (OS) has improved dramatically over the last decade from approximately 9 months in 2011 to at least 2 years in 2017 [Luke et al., 2017]. However, approximately 60% - 70% of patients receiving anti-programmed cell death protein 1 (anti-PD-1) therapy (e.g., ipilimumab) or cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitors (e.g., nivolumab and pembrolizumab) do not respond to the treatment. Furthermore, acquired resistance is common, and some patients who initially respond to the therapy experience disease progression later. Similarly, even though immunotherapy has improved the survival of non-small cell lung cancer (NSCLC), tumors often acquire resistance, and the pattern of disease progression beyond immunotherapy resistance is not fully understood. Thus, the 5-year survival rate of NSCLC remains low at 24% [National Cancer Institute, United States, 2020]. Therefore, the high unmet need for persistent immunotherapy against immune checkpoint inhibitor-resistant cancers remains unfulfilled.

[0004]

[0004] Diacylglycerol kinase (DGK) is a large enzyme family of 10 mammalian DGK isozymes. DGK has several alternative splicing products, and its isoforms are associated with the etiology of a wide range of cancers. In T cells, DGK inhibits DAG-mediated signals following T cell receptor (TCR) engagement by catalyzing the conversion of diacylglycerol (DAG) to phosphatidic acid (PA) [Zhong et al., 2008]. Even when programmed cell death protein 1 (PD-1) is blocked by an anti-PD-1 antibody, DAG downstream signaling can be partially inactivated by DGK. DAG is produced by TCR stimulation and activates the RAS-ERK-AP-1 signaling pathway and the PKC / PKD-IKK-NFκB signaling pathway in T cells, leading to enhanced cytokine production and proliferation.

[0005]

[0005] Upregulation of DGK restricts RAS activation and induces exhaustion in T cells [Zhong et al., 2008]. Thus, DGK inhibitors have the potential to enhance DAG downstream signaling and promote T cell activation despite PD-1 signaling [Wee et al., 2019]. Data suggest that DGKζ (zeta) isoform, one of the DGK family members, is a negative regulator of DAG-mediated signaling pathway by enzymatically converting DAG to PA and a dominant regulator of TCR-driven T cell activation. This is consistent with its observed potent anti-tumor immune response [Wee et al., 2019].

[0006]

[0006] In single-cell RNA sequencing analysis, DGKζ is expressed in CD8 + T cells in biopsy samples of various tumor types, and the positive rate of DGKζ is relatively high in melanoma and NSCLC. In addition, its expression significantly correlates with T cell exhaustion markers in these tumor types. Thus, DGKζ is thought to contribute to T cell exhaustion in some tumor types, and DGKζ inhibition can exhibit anti-tumor efficacy by releasing T cells from the exhausted state.

[0007]

[0007] N-[4-(2-Fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (referred to herein as "Compound I") is a selective small molecule inhibitor of DGKζ. The chemical structure of Compound I is shown below:

[0008]

Chem.

[0009] [

[0008] ]Non-clinical pharmacological studies have shown that Compound I inhibits DGKζ activity and enhances the activation of the DAG downstream pathway and T cell activation upon TCR stimulation. The putative mechanism of action is shown in Figure 1. Furthermore, oral administration of Compound I has shown antitumor efficacy in inflammatory tumor and tumor-infiltrating lymphocyte (TIL)-poor tumor models. Further disclosure of Compound I, as well as other small molecule inhibitors of DGKζ suitable for the disclosed methods and compositions, can be found in WO2022114164, published on June 2, 2022, which is hereby incorporated by reference into this specification.

Summary of the Invention

Means for Solving the Problems

[0010] [

[0009] ]The present disclosure relates to methods for treating patients having advanced and / or metastatic tumors (i.e., cancers). [

[0010] ]In some embodiments of the methods disclosed herein, the advanced and / or metastatic tumors are selected from solid tumors. In some embodiments, the solid tumors are selected from sarcomas, carcinomas, and lymphomas. In some embodiments, the solid tumors are selected from skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, and stomach cancer.

[0011] [

[0011] ]In some embodiments of the methods disclosed herein, inhibition of DGKζ-mediated functions is useful.

[0012] In some embodiments of the methods disclosed herein, the advanced and / or metastatic tumors have elevated DGKζ levels. [

[0012] ]

[0013] In some embodiments of the methods disclosed herein, the advanced and / or metastatic tumors are tumors with reduced tumor-infiltrating lymphocytes (TIL).

[0014] In some embodiments, the advanced and / or metastatic tumors are inflammatory tumors. [

[0013] ]

[0015] In some embodiments, the advanced and / or metastatic tumors are selected from melanoma and NSCLC.

[0016] In some embodiments, the methods disclosed herein include administering to a patient an effective amount of at least one entity selected from Compound I and pharmaceutically acceptable salts thereof.

[0014]

[0017] In some embodiments, the methods disclosed herein include administering to a patient a pharmaceutical composition comprising an effective amount of at least one entity selected from Compound I and pharmaceutically acceptable salts thereof.

[0015]

[0018] The following detailed description and examples illustrate certain embodiments of the present disclosure. Those skilled in the art will recognize that many changes and modifications of the present disclosure are encompassed within its scope. Accordingly, the description of certain embodiments should not be considered as limiting the scope of the present disclosure.

[0016]

[0019] All references described herein, including but not limited to published and unpublished applications, patents, and reference documents, are hereby incorporated by reference in their entirety and thereby become a part of this specification. To the extent that the described references conflict with the disclosure of this specification, this specification shall prevail.

Brief Description of the Drawings

[0017]

Figure 1

[0020] Figure 1 shows a putative mechanism of the action of Compound I in T cells.

Figure 2

[0021] Figure 2 shows the scheme of the test design described in the present disclosure.

Figure 3

[0022] Figure 3 shows the scheme of the test visit described in the present disclosure.

Figure 4-1

[0023] Figure 4 shows the schedule of the evaluation described in the present disclosure.

Figure 4-2

[0023] Figure 4 shows the evaluation schedule described in the present disclosure.

Figure 4-3

[0023] Figure 4 shows the evaluation schedule described in the present disclosure.

Figure 4-4

[0023] Figure 4 shows the evaluation schedule described in the present disclosure.

Figure 5-1

[0024] Figure 5 shows the sample collection schedule described in the present disclosure.

Figure 5-2

[0024] Figure 5 shows the sample collection schedule described in the present disclosure.

Figure 6-1

[0025] Figure 6 shows an alternative schedule for the evaluation in response to a crisis.

Figure 6-2

[0025] Figure 6 shows an alternative schedule for the evaluation in response to a crisis.

Figure 6-3

[0025] Figure 6 shows an alternative schedule for the evaluation in response to a crisis.

Figure 6-4

[0025] Figure 6 shows an alternative schedule for the evaluation in response to a crisis.

Mode for Carrying Out the Invention

[0018]

[0026] The present disclosure relates to a method for treating a patient having a progressive and / or metastatic tumor.

[0027] In some embodiments, the method disclosed herein comprises administering to a patient an effective amount of at least one entity selected from Compound I

[0019]

Chemical Formula

[0020] and its pharmaceutically acceptable salts.

[0028] In some embodiments, the method disclosed herein comprises administering to a patient a pharmaceutical composition comprising an effective amount of at least one entity selected from Compound I and its pharmaceutically acceptable salts.

[0021]

[0029] In some embodiments, the methods disclosed herein include the step of orally administering to a patient at least one entity selected from (1) Compound I and pharmaceutically acceptable salts thereof and / or (2) a pharmaceutical composition comprising the same.

[0022]

[0030] In some embodiments of the methods disclosed herein, the at least one entity is in the form of a pharmaceutically acceptable solvate, mixed solvate, or complex. In some embodiments, the at least one entity is in the form of an amorphous solid. In some embodiments, the at least one entity is in the form of a crystalline solid.

[0023]

[0031] In some embodiments of the methods disclosed herein, the at least one entity is Compound I. In some embodiments, the at least one entity is selected from pharmaceutically acceptable salts of Compound I. Non-limiting examples of pharmaceutically acceptable salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid. Pharmaceutically acceptable salts can be obtained, for example, using standard procedures well known in the art of pharmacy.

[0024]

[0032] In some embodiments of the methods disclosed herein, at least one entity is in the form of a pharmaceutically acceptable salt of Compound I selected from hydrochloride salts, mesylate salts, succinate salts, L-malate salts, L-tartrate salts, and fumarate salts. In some embodiments, at least one entity is in the form of a hydrochloride salt. In some embodiments, at least one entity is in the form of a mesylate salt. In some embodiments, at least one entity is in the form of a succinate salt. In some embodiments, at least one entity is in the form of an L-malate salt. In some embodiments, at least one entity is in the form of an L-tartrate salt. In some embodiments, at least one entity is in the form of a fumarate salt. In some embodiments, at least one entity is in the form of a monosuccinate salt. In some embodiments, at least one entity is in the form of a hemisuccinate salt. In some embodiments, at least one entity is in the form of a monolithium L-malate salt. In some embodiments, at least one entity is in the form of a hemolithium L-malate salt.

[0025]

[0033] As used herein, the singular forms of words also include the plural forms unless the context clearly dictates otherwise; for example, the terms "a", "an", and "the" are to be understood to be singular or plural. By way of example, "an element" means one or more elements.

[0026]

[0034] The terms "at least one" and "one or more" are intended to be synonymous and refer to one or more, but possibly a plurality, for example one, two, three, etc. For example, the term "at least one entity" refers to one or more entities, for example one entity, two entities, etc.

[0027]

[0035] The term "or" as used herein is used to mean "and / or" unless the context clearly dictates otherwise and is used interchangeably therewith. The term "and / or" as used in a phrase such as "A and / or B" is intended to include the following embodiments: "A and B", "A or B", "A", and "B".

[0028]

[0036] Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: "A, B, and C"; "A, B, or C"; "A or C"; "A or B"; "B or C"; "A and C"; "A and B"; "B and C"; "A" (alone); "B" (alone); and "C" (alone).

[0029]

[0037] The term "treating" or "treatment" or "treat" refers to a therapeutic means (e.g., administration of a medicament to a patient) that cures, slows down, reduces symptoms, and / or halts the progression of a condition. Treatment need not result in a complete cure of the condition; a partial inhibition or alleviation of the condition being treated is encompassed by the term.

[0030]

[0038] The terms "patient" and "subject" are used interchangeably and refer to an adult human individual.

[0039] "Effective amount" refers to an amount of at least one entity of the present disclosure or a pharmaceutical composition comprising at least one such entity of the present disclosure that is effective to produce at least one therapeutic effect when administered to a patient, either as a single dose or as part of a series of doses. The dose may depend on the body mass, weight, and / or blood volume of the patient. The patient can generally be monitored for treatment effectiveness using an assay suitable for the condition being treated. The level of the compound administered to the patient can be monitored by determining the level of the compound (or metabolite of the compound) in a biological fluid from the patient, such as blood, a blood fraction (e.g., serum), urine, and / or other biological samples. Any method practiced in the art for detecting the compound, or its metabolite, can be used to measure the level of the compound during the course of the treatment regimen. The doses of the compounds described herein may depend on the patient's condition, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the general state of health, as well as age, gender, and weight, and other factors apparent to those of ordinary skill in the medical arts.

[0031]

[0040] In some embodiments, a method for treating a patient having a progressive and / or metastatic tumor is provided.

[0041] In some embodiments of the methods disclosed herein, in progressive and / or metastatic tumors, DGKζ levels are elevated.

[0032]

[0042] In some embodiments of the methods disclosed herein, progressive and / or metastatic tumors are tumors with reduced TIL.

[0043] In some embodiments of the methods disclosed herein, progressive and / or metastatic tumors are inflammatory tumors.

[0033]

[0044] In some embodiments of the methods disclosed herein, progressive and / or metastatic tumors are selected from solid tumors. In some embodiments, solid tumors are selected from sarcomas, carcinomas, and lymphomas. In some embodiments, solid tumors are selected from skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, and stomach cancer.

[0034]

[0045] In some embodiments of the methods disclosed herein, progressive and / or metastatic tumors are selected from melanoma and NSCLC. In some embodiments, the progressive and / or metastatic tumor is melanoma. In some embodiments, the progressive and / or metastatic tumor is NSCLC.

[0035]

[0046] In some embodiments of the methods disclosed herein, the patient has received, declined, or has a contraindication to one or more conventional therapies with established clinical benefit for these malignant lesions. In some embodiments, the patient has received one or more conventional therapies with established clinical benefit for these malignant lesions. In some embodiments, the patient has previously declined one or more conventional therapies with established clinical benefit for these malignant lesions. In some embodiments, the patient has a prior contraindication to one or more conventional therapies with established clinical benefit for these malignant lesions.

[0036]

[0047] In some embodiments of the methods disclosed herein, the patient has been pre-treated with an anti-PD-1 therapy. In some embodiments, the patient has been pre-treated with pembrolizumab, nivolumab, and / or cemiplimab.

[0037]

[0048] In some embodiments of the methods disclosed herein, the patient does not have human immunodeficiency virus (HIV) and / or a compromised immune system. In some embodiments, the patient does not have HIV. In some embodiments, the patient does not have a compromised immune system.

[0038]

[0049] In some embodiments of the methods disclosed herein, the patient is a female assigned at birth. In some embodiments of the methods disclosed herein, the patient is a male assigned at birth.

[0039]

[0050] In some embodiments of the methods disclosed herein, the patient meets at least one of the following criteria: (a) the patient is considered an adult according to regional regulations at the time of treatment; (b) the patient has locally advanced (unresectable) or metastatic solid tumor malignant lesions, and the malignant lesions are confirmed by available pathology records or a biopsy at that time; (c) The patient has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and a lesion located in the previously irradiated area is considered measurable if progression is demonstrated by such a lesion; (d) The patient has progressed after receiving all approved standard therapies and / or is no longer eligible for standard treatment; (e) The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; (f) The last administration of any prior antineoplastic agent treatment, including any immunotherapy, was at least 21 days before treatment by the methods disclosed herein; however, for patients with solid tumors having a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without known acquired resistance mutations, or for patients with non-small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations, prior treatment with an NTRK inhibitor or an EGFR tyrosine kinase inhibitor (TKI) or an ALK inhibitor is permitted up to 4 days before treatment by the methods disclosed herein; (g) Patients receiving radiotherapy including stereotactic radiotherapy need to complete radiotherapy at least 2 weeks before treatment by the methods disclosed herein; (h) Adverse events (excluding alopecia) in the patient from prior therapy have improved to Grade 1 or baseline within 14 days before treatment by the methods disclosed herein; provided that patients with type 1 diabetes, endocrine disorders stably maintained with appropriate replacement therapy, or skin disorders not requiring systemic treatment are permitted; (i) The patient has appropriate organ function before treatment as indicated by the following test values, and the test values need to be obtained more than 2 weeks after any blood transfusion: (i) Absolute neutrophil count (ANC) level ≥ 1500 / μL; (ii) Platelet level ≥ 100,000 / μL; (iii) Hemoglobin level ≥ 9 g / dL; (iv)Either creatinine level ≤ upper limit of normal (ULN) calculated by the Cockcroft - Gault formula or creatinine clearance (CLer) ≥ 60 mL / min; (v)Total bilirubin level ≤ 1.5 × ULN; or for participants with Dubin - Johnson syndrome, either direct bilirubin ≤ ULN and total bilirubin < 3 × ULN; (vi)In the absence of liver metastases, levels of aspartate aminotransferase (AST) (serum glutamate oxaloacetate transaminase (SGOT)) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) ≤ 2.5 × ULN, or in the presence of liver metastases, ≤ 5 × ULN; (vii)Serum potassium level ≥ 3.4 mEq / L; (viii)Serum magnesium level ≥ 1.7 mg / dL; and (ix)Serum ionized calcium level ≥ 4.7 mg / dL; (j)The patient has an activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN and is not receiving anticoagulation; (k)If the patient is a female assigned at birth, she is not pregnant and at least one of the following conditions applies: (i)The patient is a female with no possibility of pregnancy; (ii)The patient is a female of childbearing potential who agrees to follow contraceptive guidance during and for at least 30 days after the treatment by the methods disclosed herein; (l)If the patient is a female assigned at birth, she agrees not to breastfeed during the period from the start of screening, during the treatment by the methods disclosed herein, and for at least 30 days after the treatment; (m)If the patient is a female assigned at birth, she does not provide eggs during and for at least 30 days after the treatment by the methods disclosed herein; If the patient is a male assigned at birth and has one or more female partners (including lactating partners) who may become pregnant, consent to use contraception during and for at least 30 days after the end of treatment by the methods disclosed herein; (o) If the patient is a male assigned at birth, consent not to provide sperm during and for at least 30 days after the end of treatment by the methods disclosed herein; (p) If the patient is a male assigned at birth and has one or more pregnant partners, consent to continue abstinence during pregnancy or to use a condom during and for at least 30 days after the end of treatment by the methods disclosed herein; (q) Consent not to participate in another interventional study while the patient is being treated by the methods disclosed herein.

[0040]

[0051] In some embodiments of the methods disclosed herein, the patient meets at least two of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least three of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least four of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least five of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least six of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least seven of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least eight of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least nine of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least ten of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least eleven of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least twelve of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least thirteen of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least fourteen of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least fifteen of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets at least sixteen of the conditions (a) through (q) above. In some embodiments of the methods disclosed herein, the patient meets each of the conditions (a) through (q) above.

[0041]

[0052] In some embodiments of the methods disclosed herein, the patient has a locally advanced (unresectable) or metastatic solid tumor malignancy. In some embodiments, the locally advanced (unresectable) or metastatic solid tumor malignancy is confirmed by available pathology records. In some embodiments, the locally advanced (unresectable) or metastatic solid tumor malignancy is confirmed by a biopsy at that time.

[0042]

[0053] In some embodiments of the methods disclosed herein, the patient has at least one measurable lesion according to RECIST v1.1. In some embodiments, the patient has at least one measurable lesion located in a previously irradiated area. In some embodiments, the progression is indicated by a lesion located in a previously irradiated area.

[0043]

[0054] In some embodiments of the methods disclosed herein, the last administration of any prior antineoplastic agent treatment, including any immunotherapy, was at least 21 days prior to being treated by the methods disclosed herein. In some embodiments, the patient has a solid tumor with an NTRK gene fusion without a known acquired resistance mutation. In some embodiments of the methods disclosed herein, it is possible for the patient to remain on an NTRK inhibitor. In some embodiments of the methods disclosed herein, the patient has EGFR or ALK mutation-positive NSCLC until 4 days prior to being treated by the methods disclosed herein. In some embodiments of the methods disclosed herein, it is possible for the patient to remain on an EGFR TKI until 4 days prior to being treated by the methods disclosed herein. In some embodiments of the methods disclosed herein, it is possible for the patient to remain on an ALK inhibitor therapy until 4 days prior to being treated by the methods disclosed herein.

[0044]

[0055] In some embodiments of the methods disclosed herein, the patient's adverse events (excluding alopecia) from prior therapy have improved to Grade 1 or baseline within 14 days prior to being treated by the methods disclosed herein.

[0045]

[0056] In some embodiments of the methods disclosed herein, the patient has type 1 diabetes, an endocrine disorder that is stably maintained with appropriate replacement therapy, or a skin disorder that does not require systemic treatment. In some embodiments of the methods disclosed herein, the patient has type 1 diabetes, an endocrine disorder that is stably maintained with appropriate replacement therapy, or a skin disorder selected from vitiligo vulgaris, psoriasis, and alopecia areata that does not require systemic treatment.

[0046]

[0057] In some embodiments of the methods disclosed herein, the patient has appropriate organ function prior to treatment.

[0058] In some embodiments of the methods disclosed herein, the patient has an aPTT and INR ≤ 1.5 × ULN.

[0047]

[0059] In some embodiments of the methods disclosed herein, the patient is a female assigned at birth, is not pregnant, and the patient is a female with no possibility of pregnancy.

[0060] In some embodiments of the methods disclosed herein, the patient is a female assigned at birth, is not pregnant, and the patient is a female with a possibility of pregnancy who agrees to follow contraceptive guidance during and for at least 30 days after treatment with the methods disclosed herein.

[0048]

[0061] In some embodiments of the methods disclosed herein, the patient is excluded from treatment if at least one of the following conditions is met: (r) the patient has received any investigational pharmacotherapy (excluding, in the case of patients with EGFR activating mutations, EGFR TKIs, in the case of patients with ALK mutations, ALK inhibitors, or in the case of patients with solid tumors having an NTRK gene fusion without a known acquired resistance mutation, NTRK inhibitors) within 21 days or within the shorter of 5 half-lives prior to being treated with the methods disclosed herein; (s) The patient requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to being treated by the methods disclosed herein; provided, however, that patients using physiological replacement doses of hydrocortisone or its equivalent (defined as up to 30 mg of hydrocortisone per day and up to 10 mg of prednisone) are permitted; (t) The patient requires a strong or moderate CYP2D6 inhibitor during treatment by the methods described herein; (u) The patient requires a strong CYP3A4 inhibitor during treatment by the methods described herein; (v) The patient has evidence of symptomatic central nervous system (CNS) metastases or asymptomatic but unstable CNS metastases; provided, however, that patients with pre-treated CNS metastases are eligible if clinically stable, have no evidence of CNS progression by imaging for at least 4 weeks prior to being treated by the methods described herein, and do not require immunosuppressive administration of systemic steroids within 2 weeks, where the immunosuppressive administration of systemic steroids includes more than 30 mg of hydrocortisone per day or more than 10 mg of prednisone per day or equivalent; (w) The patient has an active autoimmune disease; provided, however, that patients with type 1 diabetes, endocrine disorders maintained stably with appropriate replacement therapy, or skin disorders not requiring systemic treatment are permitted; (x) The patient has discontinued prior immunomodulatory therapy due to drug-related grade ≥3 toxicity; (y) It is known that the patient has HIV infection; provided, however, that HIV patients having a CD4+ T cell count ≥350 cells / μL and no history of opportunistic infections defining AIDS within the past 6 months are eligible; (z) The patient has any of the following according to screening serological tests: (i) Hepatitis A virus (HAV) antibody (immunoglobulin M [IgM]); (ii) Positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA; provided that patients with negative HBsAg, positive hepatitis B core antibody (anti-HBc) and negative hepatitis B surface antibody (anti-HBs) are eligible if hepatitis B DNA is undetectable; (iii) Hepatitis C virus (HCV) antibody unless HCV RNA is undetectable (aa) The patient has received a live vaccine against an infectious disease within 28 days prior to being treated by the method described herein; (bb) The patient has a history of drug-induced pneumonia (interstitial lung disease), or currently has pneumonia, or has a previous history of ILD or non-infectious pneumonia that requires high-dose corticosteroids regardless of whether it has resolved; (cc) The patient has an infection that requires systemic therapy within 14 days prior to being treated by the method described herein; (dd) The patient has previously received an allogeneic bone marrow or solid organ transplant; (ee) The patient is expected to require another form of anti-neoplastic agent treatment during treatment by the method described herein; (ff) The patient has had a myocardial infarction or unstable angina within 6 months prior to being treated by the method described herein, or currently has an untreated disease including, for example, symptomatic congestive heart failure, clinically significant heart disease, unstable angina, arrhythmia, or a mental disorder / social situation that limits compliance with treatment; (gg) The patient has inadequately controlled hypertension, where inadequately controlled hypertension includes a systolic blood pressure greater than 150 and / or a diastolic blood pressure greater than 100 mmHg on antihypertensive medication; (hh) The patient has a corrected QT interval (ECG alone) (QTcF) using the Fridericia formula greater than 450 ms prior to being treated by the method described herein; (ii) The patient has another malignant lesion that requires active therapy excluding locally treatable malignant lesions including, for example, basal or squamous cell skin cancer, superficial bladder cancer, and cervical or breast intraepithelial carcinoma; (jj) The patient has had major surgery and has not fully recovered within 28 days prior to being treated by the methods described herein; (kk) The patient has a history of bleeding tendency; (ll) The patient requires the use of anticoagulant therapy; (mm) The patient has been previously treated with a DGK inhibitor; (nn) The patient has a known allergy or suspected allergy to at least one entity or any component of the pharmaceutical composition used.

[0049]

[0062] In some embodiments of the methods disclosed herein, the patient is excluded from treatment if the patient requires systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to being treated by the methods disclosed herein. In some embodiments of the methods disclosed herein, the patient is excluded from treatment if the patient has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to being treated by the methods disclosed herein.

[0050]

[0063] In some embodiments of the methods disclosed herein, the patient is excluded from treatment if the patient requires one or more strong or moderate CYP2D6 inhibitors during treatment by the methods described herein, and the one or more strong or moderate CYP2D6 inhibitors are selected from bupropion, fluoxetine, paroxetine, duloxetine, and abiraterone. In some embodiments of the methods disclosed herein, the patient is excluded from treatment if the patient requires one or more strong CYP2D6 inhibitors during treatment by the methods described herein. In some embodiments of the methods disclosed herein, the patient is excluded from treatment if the patient requires one or more moderate CYP2D6 inhibitors during treatment by the methods described herein.

[0051]

[0064] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient requires one or more strong CYP3A4 inhibitors during treatment with the methods described herein, and the one or more strong CYP3A4 inhibitors are selected from boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole.

[0052]

[0065] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has symptomatic CNS metastases.

[0066] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has evidence of unstable CNS metastases even if asymptomatic.

[0053]

[0067] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has discontinued prior immunomodulatory therapy due to a grade ≥ 3 toxicity that is mechanistically related to the agent (e.g., immune-related).

[0054]

[0068] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient is known to have HIV infection.

[0069] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has HAV antibodies (IgM) according to screening serological tests. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a positive HBsAg according to screening serological tests. In some embodiments, a patient is excluded from treatment if the patient has detectable hepatitis B DNA according to screening serological tests. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has HCV antibodies such that HCV RNA is not undetectable according to screening serological tests.

[0055]

[0070] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a history of drug-induced pneumonitis (interstitial lung disease), regardless of whether the patient has resolved. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient currently has pneumonia. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has ILD, regardless of whether the patient has resolved.

[0056]

[0071] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a previous history of non-infectious pneumonitis that required high-dose corticosteroids, regardless of whether the patient has resolved.

[0057]

[0072] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has previously received an allogeneic bone marrow transplant. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has previously received a solid organ transplant.

[0058]

[0073] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has had a myocardial infarction within 6 months prior to being treated with the methods described herein. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has had unstable angina within 6 months prior to being treated with the methods described herein. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient currently has an untreated disease. In some embodiments, the untreated disease is selected from symptomatic congestive heart failure, clinically significant heart disease, unstable angina, arrhythmia, and mental illness / social situations that limit compliance with treatment.

[0059]

[0074] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has poorly controlled hypertension. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a systolic blood pressure over 150 and / or a diastolic blood pressure over 100 mmHg while on antihypertensive medication. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a systolic blood pressure over 150 while on antihypertensive medication. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a diastolic blood pressure over 100 mmHg while on antihypertensive medication.

[0060]

[0075] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has another malignancy that requires active therapy. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has another malignancy that requires active therapy, excluding locally treatable malignancies. In some embodiments, locally treatable malignancies are selected from basal or squamous cell skin cancer, superficial bladder cancer, and cervical or breast intraepithelial neoplasia.

[0061]

[0076] In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a known allergy to at least one entity or any component of the pharmaceutical composition used. In some embodiments of the methods disclosed herein, a patient is excluded from treatment if the patient has a suspected allergy to at least one entity or any component of the pharmaceutical composition used.

[0062]

[0077] In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same can result in the activation of immune cells. In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same can result in the activation of T cells. In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same suppresses the growth of at least one tumor.

[0063]

[0078] In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same suppresses the growth of at least one tumor by activation of T cells. In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same suppresses the growth of at least one tumor by inhibiting DGKζ.

[0064]

[0079] In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same slows the progression of cancer. In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same reduces the symptoms of cancer. In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same halts the progression of cancer. In some embodiments of the methods disclosed herein, treatment with at least one entity or a pharmaceutical composition comprising the same cures cancer.

[0065]

[0080] In some embodiments of the methods disclosed herein, the cancer is melanoma. In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is mismatch repair-deficient colorectal cancer. In some embodiments, the cancer is urothelial cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is bladder cancer.

[0066]

[0081] In some embodiments, the administration is oral administration. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0082] In some embodiments, the pharmaceutical compositions of the present disclosure can be prepared by conventional methods using one or more excipients commonly used in the art, i.e., excipients for pharmaceutical use, carriers for pharmaceutical use, and the like.

[0067]

[0083] In some embodiments, the pharmaceutical composition is in the form of tablets, pills, capsules, granules, powders, solutions, etc. In some embodiments, the pharmaceutical composition is in the form of tablets. In some embodiments, the pharmaceutical composition is in the form of pills. In some embodiments, the pharmaceutical composition is in the form of capsules. In some embodiments, the pharmaceutical composition is in the form of granules. In some embodiments, the pharmaceutical composition is in the form of powders. In some embodiments, the pharmaceutical composition is in the form of solutions.

[0068]

[0084] In some embodiments, the pharmaceutical composition may contain inert additives such as lubricants, disintegrants, stabilizers, and solubilizers. Tablets, powders, granules, or pills may be coated with wax, sugar coating, or a film of gastric-soluble or enteric-soluble substances. Liquid compositions for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and may contain an inert diluent such as purified water or ethanol. Such liquid compositions may contain, in addition to the inert diluent, adjuvants such as solubilizers, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

[0069]

[0085] In some embodiments of the methods disclosed herein, at least one entity is orally administered at a dose equivalent of Compound I of about 5 mg / day, about 10 mg / day, about 30 mg / day, about 60 mg / day, about 100 mg / day, about 150 mg / day, or about 200 mg / day. In some embodiments, at least one entity is orally administered at a dose equivalent of Compound I of about 10 mg / day. In some embodiments, at least one entity is orally administered at a dose equivalent of Compound I of about 30 mg / day. In some embodiments, at least one entity is orally administered at a dose equivalent of Compound I of about 60 mg / day. In some embodiments, at least one entity is orally administered at a dose equivalent of Compound I of about 100 mg / day. In some embodiments, at least one entity is orally administered at a dose equivalent of Compound I of about 150 mg / day. In some embodiments, at least one entity is orally administered at a dose equivalent of Compound I of about 200 mg / day.

[0070]

[0086] In some embodiments of the methods disclosed herein, at least one entity is administered with stepwise increasing dose equivalents of Compound I. In some embodiments, at least one entity is administered with an initial dose equivalent of Compound I of about 5 mg / day for a first period, and a second dose equivalent of Compound I that is approximately 2.0 to 4.0 times higher than the first dose equivalent is administered for a second period. In some embodiments, at least one entity is administered with an initial dose equivalent of Compound I of about 10 mg / day for a first period, and a second dose equivalent of Compound I that is approximately 1.5 to 3.0 times higher than the first dose equivalent is administered for a second period. In some embodiments, at least one entity is administered with an initial dose equivalent of Compound I of about 30 mg / day for a first period, and a second dose equivalent of Compound I that is approximately 1.5 to 3.0 times higher than the first dose equivalent is administered for a second period. In some embodiments, at least one entity is administered with an initial dose equivalent of Compound I of about 60 mg / day for a first period, and a second dose equivalent of Compound I that is approximately 1.5 to 3.0 times higher than the first dose equivalent is administered for a second period. In some embodiments, at least one entity is administered with an initial dose equivalent of Compound I of about 100 mg / day for a first period, and a second dose equivalent of Compound I that is approximately 1.5 to 2.0 times higher than the first dose equivalent is administered for a second period. In some embodiments, at least one entity is administered with an initial dose equivalent of Compound I of about 150 mg / day for a first period, and a second dose equivalent of Compound I that is approximately 1.2 to 1.5 times higher than the first dose equivalent is administered for a second period.

[0071]

[0087] In some embodiments of the methods disclosed herein, the method further comprises, for a third period, administering a third dose equivalent of Compound I that is approximately 1.5 to 2.5 times higher than the second dose equivalent.

[0072]

[0088] In some embodiments of the methods disclosed herein, the duration of each administration is at most 21 days.

[0089] In some embodiments, the escalating dosing regimen provides a safety profile for positive patients and a suitable peak plasma concentration of the drug.

[0073]

[0090] In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 5 mg / day to about 200 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 10 mg / day to about 200 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 30 mg / day to about 200 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 60 mg / day to about 200 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 100 mg / day to about 200 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 5 mg / day to about 100 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 10 mg / day to about 100 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 30 mg / day to about 100 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 60 mg / day to about 100 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 30 mg / day to about 200 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 30 mg / day to about 150 mg / day. In some embodiments, at least one entity is orally administered an equivalent of a daily dose of Compound I of from about 30 mg / day to about 100 mg / day.

[0074]

[0091] In some embodiments, the equivalent of the daily dose is orally administered as a single dose. In some embodiments, the daily dose is orally administered in 2 to 4 divided doses.

[0092] In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or about 200 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of about 10 mg of Compound I. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of about 30 mg of Compound I. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of about 60 mg of Compound I. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of about 100 mg of Compound I. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of about 150 mg of Compound I. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of about 200 mg of Compound I.

[0075]

[0093] In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 5 mg to about 200 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 10 mg to about 200 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 30 mg to about 200 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 60 mg to about 200 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 100 mg to about 200 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 5 mg to about 100 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 10 mg to about 100 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 30 mg to about 100 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 60 mg to about 100 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 30 mg to about 200 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 30 mg to about 150 mg. In some embodiments, the pharmaceutical composition for oral administration comprises an equivalent dose of Compound I from about 30 mg to about 100 mg / equivalent dose of Compound I.

[0076]

[0094] As will be apparent to those skilled in the art, dosages outside these disclosed dosages and ranges may be administered in some cases. It is further noted that a normal skilled clinician or treating physician knows how and when to interrupt, adjust, or terminate therapy, taking into account individual responses.

[0077]

[0095] Those skilled in the art will recognize many modifications and variations that can be made without departing from the spirit or scope of this disclosure. Such modifications and variations are included within the scope of this disclosure. The examples shown do not limit this disclosure in any way.

Examples

[0078] Example 1 Synthesis of Compound 1

[0079]

Chemical formula

[0080]

[0096] 2-Bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene A mixture of 2-bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene (3.00 g), 2-fluorophenol (1.00 mL), potassium carbonate (2.88 g) and NMP (30 mL) was stirred at 50 °C overnight. The mixture was cooled to room temperature, then water, EtOAc and brine were added and the aqueous layer was separated. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hex / EtOAc) to give 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (3.43 g).

[0081]

[0097] tert-Butyl {[(2R)-4-benzyl-1-methylpiperazin-2-yl]methyl}(methyl)carbamate A solution of [(2R)-4-benzyl-1-methylpiperazin-2-yl]methanol (5.27 g), TEA (6.7 mL) and THF (100 mL) was cooled in a MeOH ice bath, and then methanesulfonyl chloride (1.96 mL) was slowly added. The resulting mixture was stirred for 1 hour while cooling in an ice bath, 40% aqueous methylamine solution (40 mL) was added, and then the resulting mixture was stirred at 70 °C for 3 hours and cooled. Then, the reaction liquid was concentrated under reduced pressure, water and CH2Cl2 were added to the residue, and the aqueous layer was separated. The aqueous layer was extracted twice with CH2Cl2, the combined organic layers were dried over Na2SO4, and then concentrated under reduced pressure.

[0082]

[0098] The resulting oily substance (4.95 g) was dissolved in CH2Cl2 (100 mL), and di-tert-butyl dicarbonate (11 g) was added while cooling in an ice bath. The resulting mixture was stirred at room temperature for 2 hours. CH2Cl2 and water were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was extracted with CH2Cl2, the combined organic layers were dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (aqueous ammonia / MeOH / chloroform) to obtain tert-butyl {[(2R)-4-benzyl-1-methylpiperazin-2-yl]methyl}(methyl)carbamate (5.92 g).

[0083]

[0099] tert-butylmethyl{[(2R)-1-methylpiperazin-2-yl]methyl}carbamate A solution of tert-butyl{[(2R)-4-benzyl-1-methylpiperazin-2-yl]methyl}(methyl)carbamate (4.92 g) and EtOH (100 mL) was added with activated carbon (500 mg), and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was filtered through celite, and then the filtrate was concentrated under reduced pressure. To the resulting solution of the oily substance and EtOH (100 mL), 10% Pd / C (hydrous, 510 mg) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and then the filtrate was concentrated under reduced pressure to obtain tert-butylmethyl{[(2R)-1-methylpiperazin-2-yl]methyl}carbamate (3.43 g).

[0084]

[0100] tert-butyl({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate A mixture of tert-butylmethyl{[(2R)-1-methylpiperazin-2-yl]methyl}carbamate (735 mg), 2-bromo-4-(2-fluorophenoxy)-1-nitro-3-(trifluoromethyl)benzene (1.15 g), potassium carbonate (627 mg) and 1,4-dioxane (5.75 mL) was stirred at 110 °C for 24 hours and cooled. Then the reaction mixture was diluted with EtOAc. The mixture was filtered through celite, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex / EtOAc) to obtain tert-butyl({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (1.31 g).

[0085]

[0101] tert-butyl({(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate A solution of tert-butyl({(2R)-4-[3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (3.41 g) in 1,4-dioxane (50 mL) was added to a solution of NH4Cl (3.36 g) in water (25 mL), and then zinc powder (4.11 g) was added while cooling in an ice bath. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and water and then filtered through Celite. The aqueous layer of the filtrate was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain tert-butyl({(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (3.32 g).

[0086]

[0102] tert-butyl({(2R)-4-[3-(2-fluorophenoxy)-6-{[1-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl]amino}-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate To a mixture of tert-butyl({(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (3.22 g), 1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylic acid (1.43 g), DIPEA (3.3 mL) and DMF (50 mL) was added HATU (3.58 g). The reaction mixture was stirred at 50 °C for 12 h and cooled to room temperature. Chloroform and water were added to the reaction mixture and the aqueous layer was separated. The aqueous layer was extracted with chloroform, the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH) to give tert-butyl({(2R)-4-[3-(2-fluorophenoxy)-6-{[1-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl]amino}-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (4.35 g).

[0087]

[0103] N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide A mixture of tert-butyl ({(2R)-4-[3-(2-fluorophenoxy)-6-{[1-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl]amino}-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl}methyl)(methyl)carbamate (4.3 g) and CH2Cl2 (40 mL) was added with TFA (10 mL), and the resulting mixture was stirred at room temperature for 4 hours. The reaction liquid was concentrated under reduced pressure, and the residue was basified by adding water, chloroform and NaHCO3 thereto. The liquid separation process was carried out using a separatory funnel, the aqueous layer was extracted with chloroform, the combined organic layers were dehydrated with Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH / aqueous ammonia). The resulting amorphous substance was washed with EtOAc / Hex to obtain N-[4-(2-fluorophenoxy)-2-{(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl}-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (2.62 g) as a solid substance.

[0088] Example 2 Phase 1 / Phase 2 Trial of Compound I in Participants with Locally Advanced or Metastatic Solid Tumors

[0104] This is a planned Phase 1 / Phase 2, open-label, multi-center, multi-dose, dose-escalation and expansion study of Compound I, a selective small molecule inhibitor of DGKζ, in participants with progressive / metastatic solid tumors.

[0089] Objectives and Endpoints

[0105] The objectives and endpoints of the study are shown in Table 1 below.

[0090]

Table 1

[0091] Rationale for Study Design and Dose Rationale for Study Design and Dose: Overall Study Design

[0106] The trial consists of 2 parts: the dose escalation phase and the dose expansion phase. For all participants, the trial consists of the following periods: screening (up to 28 days); treatment (once-daily dosing in 21-day cycles until the treatment discontinuation criteria are met); end of treatment (after discontinuation of the investigational drug treatment); and follow-up (visits for safety follow-up and survival follow-up).

[0092]

[0107] The evaluation schedule and the sample collection schedule are shown in Figures 4 and 5, respectively.

[0108] After discontinuation of the investigational drug treatment, all participants complete the end of treatment visit within a maximum of 7 days after the decision to discontinue. The participants then enter the safety follow-up period and have a visit for safety follow-up 30 days from the last dose. The only exception to this is if the participant specifically withdraws consent for further contact with the participant or a person previously authorized by the participant to provide this information. If the participant starts a new anti-cancer treatment, the participant is followed for survival.

[0093]

[0109] The participants are then followed for survival at intervals longer than every 12 weeks after the last visit for final safety follow-up outlined in the evaluation schedule (Figure 4), in accordance with the facility guidelines, until either death, withdrawal of consent, or termination of the trial occurs first.

[0094] Part 1: Dose Escalation

[0110] The dose escalation cohort determines the escalating dose levels of Compound I in up to approximately 36 DLT evaluable participants. The cycle is defined as 21 days (3 weeks). Dosing is done daily on each day of the cycle. Participants are evaluated for DLT during the first 21 days (Cycle 1). Safety and tolerability are continuously evaluated from Day 1 through 30 days after the last dose of Compound I.

[0095]

[0111] There is at least a 3-calendar day interval between the start of treatment of the first participant and all subsequent participants at the same dose level for all escalation cohorts.

[0112] The dose escalation or de-escalation is guided according to the time-to-event Bayesian optimal interval (TITE-BOIN) design (Yuan et al., 2018) to determine the next dose level based on the occurrence of DLT until the event occurs.

[0096]

[0113] For each dose level, after a planned number of evaluable participants have completed the observation period for DLT, the safety for that dose level is evaluated. The proposed dose escalation levels listed in Table 2 below are based on the minimum pharmacological activity and non-clinical toxicity test results.

[0097]

Table 2

[0098] TITE-BOIN Design for Escalation Cohorts

[0114] The target toxicity rate for the maximum tolerated dose (MTD) is 0.30. The length of the DLT observation period is 21 days. Dose level 1 enrolls evaluable participants for the initial assessment of DLT. If a participant does not have DLT, the dose is escalated to the next higher dose level. If a participant has DLT, two additional evaluable participants may be added at dose level 1. Thereafter, each dose level enrolls at least three evaluable participants for the initial assessment of DLT. If additional participants are needed for a dose level, at least three additional evaluable participants may be added. The dose escalation / de-escalation process may be stopped when the number of participants treated at that dose reaches at least six and the decision according to the TITE-BOIN design is consistent at that dose. The maximum number of participants in the dose escalation cohort is 12 at each dose level.

[0099]

[0115] The TITE-BOIN design is optimized to minimize the probability of mis-dose assignment and uses the following rules to guide dose escalation / de-escalation: - If the predicted DLT rate at that dose is ≤ 0.236, escalate the dose to the next higher dose level; - If the predicted DLT rate at that dose level is > 0.359, decrease the dose in steps to the next lower dose level; - Otherwise, maintain the dose at that level.

[0100]

[0116] To assign doses to the next cohort of participants, count the number of evaluable participants (evaluable number), the number of participants experiencing DLT (number of DLTs), and the number of ongoing participants (ongoing number), as well as the total standardized elapsed observation period (STFT) weighted by these at that dose level, and then make a dose escalation / de-escalation decision according to the rules corresponding to cumulative numbers of 3, 6, or 9 participants (see Table 3). If the cumulative number of participants is not 3, 6, or 9, the next dose is determined according to the predicted DLT rate and the optimal interval boundary. STFT is defined as follows:

[0101]

Number

[0102]

[0117] The TITE-BOIN design allows for sequential enrollment even if participants have not completed the DLT observation period beforehand, but the suspension rule that delays the dose escalation / de-escalation decision is applied when more than 50% of the participants have not completed the DLT assessment at that dose level from a safety perspective.

[0103]

Table 3-1

[0104]

Table 3-2

[0105] Maximum Tolerated Dose and Encouraged Phase 2 Dose

[0118] The maximum tolerated dose (MTD) is defined as the dose level at which the DLT rate estimated using isotonic regression is closest to the target DLT rate of 30%.

[0106]

[0119] The sponsor determines the RP2D of Compound I considering the data available on the safety, pharmacodynamics and efficacy of Compound I. The RP2D does not exceed the MTD. At least six participants should be enrolled at the dose levels used to determine the MTD and / or RP2D.

[0107] Dose-Limiting Toxicity

[0120] DLT is defined as any of the following adverse events (AEs) (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0, clearly not attributable to causes other than the investigational drug by the treating investigator (or sponsor)): - Grade 4 neutropenia - Grade ≥3 febrile neutropenia - Grade 4 thrombocytopenia - Grade 3 thrombocytopenia with bleeding requiring any transfusion - Grade 4 anemia - Grade 3 anemia requiring transfusion - Grade ≥3 non-hematological AEs (excluding grade 3 elevations of amylase and lipase not related to clinical or radiographic evidence of pancreatitis and symptomatic grade 3 hypophosphatemia) - Grade ≥2 pneumonitis - Grade ≥2 encephalopathy, meningitis, or motor or sensory neuropathy - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 × upper limit of normal (ULN; grade ≥3) in the absence of liver metastases - AST or ALT > 8 × ULN in participants with liver metastases - AST or ALT > 3 × ULN and total bilirubin > 2 × ULN (in participants with Dubin-Johnson syndrome: AST or ALT > 3 × ULN and direct bilirubin > 1.5 × ULN) - Total bilirubin > 3 × ULN (grade ≥3) - Guillain-Barré syndrome or myasthenic syndrome / myasthenia - An unresolved AE of grade ≥ 2 that results in a long-term delay (> 14 days) at the start of Cycle 2 - Any toxicity that causes treatment interruption during Cycle 1 in the participant - Toxicity of grade 5 - Any grade 4 immune-related adverse event (irAE) - Grade 3 irAE or an irAE for which the corticosteroid dose cannot be reduced within a reasonable time frame (e.g., requires systemic immunosuppressive treatment; recurrence of grade 3 immune-mediated reaction where the corticosteroid dose cannot be reduced to prednisone or equivalent ≤ 10 mg per day within 12 weeks of starting steroids) - An increase in liver function tests (LFT) that is clinically significant and lasts longer than 7 days and is considered likely to be at least related to Compound I - Any period of grade 4 fatigue and anorexia and grade 3 fatigue or anorexia lasting longer than 7 days should be considered a DLT

[0121] The following AEs are not considered DLTs: - Electrolyte abnormalities that are not related to clinical sequelae or are considered not clinically significant and are corrected by appropriate management or supplementation within 72 hours of onset - Alopecia - Grade 3 fatigue or anorexia lasting for less than 7 days - An increase in grade 3 LFT that resolves to ≤ grade 1 within 7 days - An irAE that resolves to ≤ grade 1 within 72 hours of onset after treatment is started, including corticosteroids

[0122] Confirmation of DLT is performed by the dose escalation and safety committee (DESC). Participants who tolerate the investigational drug at the dose level under review due to the occurrence of DLT in another participant are not automatically excluded from continued dosing during the safety review and are allowed to continue dosing as long as they are tolerated, unless otherwise instructed as a result of the safety review by the DESC.

[0108] Participant Crossover in Dose Escalation Cohorts

[0123] Participants without DLT who receive less than 80% of the intended dose (cohort dose level) during Cycle 1 (e.g., miss more than 4 daily doses in Cycle 1) or do not complete the Cycle 1 determination for reasons other than DLT (e.g., withdrawal of consent) are switched with another participant at the dose level rather than being considered a DLT that can be determined.

[0109] Part 2: Dose Expansion Stage 1 - Efficacy-Inducing Expansion Cohort

[0124] If the dose escalation cohort proceeds to Part 1, additional participants may be registered in the efficacy expansion cohort at Stage 1 of dose expansion. If a confirmed efficacy (partial response [PR] or complete response [CR]) based on a local assessment of the immune therapy response evaluation criteria in solid tumors (iRECIST) occurs in the dose escalation cohort, the tumor-specific expansion cohort may be removed by DESC and opened to that tumor type at the dose level considered acceptable. Up to 20 participants are initially registered in this Part 2 - Stage 1 efficacy induction expansion cohort. Participants are determined for DLT during Cycle 1 in the expansion cohort for continued safety determination.

[0110] Stage 1 - RP2D Expansion Cohort

[0125] The RP2D expansion cohort is registered following completion of dose escalation (Part 1) and determination of the MTD / RP2D. Up to approximately 20 participants are initially registered in the RP2D expansion cohort (i.e., metastatic melanoma and NSCLC). Participants are determined for DLT during Cycle 1 in the expansion cohort. The RP2D expansion cohort evaluates the safety and tolerability of Compound I and preliminary efficacy at the RP2D.

[0111] Stage 2

[0126] Stage 2 may be opened to specific tumor types based on the pharmacokinetics and antitumor activity observed from Stage 1.

[0112]

[0127] Dose Optimization: One tumor type from the efficacy induction / RP2D expansion cohort in Stage 1 is selected for dose optimization and includes randomization of up to 40 participants between two different dose levels: Dose A (RP2D or efficacy induction dose) and Dose B. The selection of the tumor type (e.g., Tumor Type 1) and the selection of Dose B are made based on the clinical data available from the dose escalation and dose expansion cohorts.

[0113]

[0128] If the first 20 participants at Dose B meet the criteria, up to additional participants can be enrolled for further determination to reach a total of 40 participants treated at Dose B.

[0114]

[0129] Efficacy Induction and RP2D Dose Expansion Cohorts: Up to 20 additional participants can be enrolled for each additional tumor type that meets the criteria for Stage 2 (e.g., Tumor Types 2 and 3).

[0115] Efficacy Monitoring in the Expansion Cohorts (Stages 1 and 2)

[0130] If at least one efficacy induced by iRECIST-based local assessment is observed in the first 20 participants of the expansion cohort induced by efficacy or RP2D from Stage 1 and the dose is confirmed to be tolerable, up to approximately 20 additional participants with specific tumor types can be enrolled respectively. The Bayesian Optimal Phase 2 (BOP2) design [Zhou et al., 2017] is used in the trial to determine efficacy from the perspective of objective response rate for each tumor type at the selected dose level. The optimized stopping boundaries are provided in the following table. The BOP2 design indicates that the dose level is acceptable for the tumor type from the perspective of efficacy if more than 3 responders are observed for the dose level selected in 40 participants for each tumor type at the final analysis. The final decision on the addition of participants to any expansion cohort is made by the sponsor following confirmation of dose tolerance by DESC.

[0116]

[0131] Optimized Efficacy Stopping Boundaries:

[0117]

Table 4

[0118]

[0132] Assuming that the effective overall response rate (ORR) is 10% and the ineffective ORR is 2%, the statistical power is approximately 73.8%, while the type I error rate is controlled at 4.1%.

[0119] Participant Crossover in Expansion Cohorts

[0133] If the participants in the expanded cohort do not have a determinable response (defined as the maximum analysis population), additional participants may be enrolled in the cohort based on the sponsor's decision.

[0120] Dose Escalation and Safety Committee

[0134] The Dose Escalation and Safety Committee (DESC), consisting of the sponsor's agent and the principal investigator of the clinical trial, will be convened once the dose level cohort has completed the DLT observation period and the data become available for review. The DESC's decision on the dose level for the next cohort is guided by TITE-BOIN based on the DLTs observed at each dose level.

[0121]

[0135] The safety data from the DLT observation period of the escalation cohort are the minimum safety data required for the committee's meeting, but all available safety findings, including those that occur after the designated DLT observation period that meets the DLT criteria ("delayed DLT"), are considered by the DESC. The DESC evaluates whether a longer DLT observation period is justified based on the emerging data. In addition, the DESC can choose a more cautious dosing decision than that indicated by TITE-BOIN based on the determination of safety data and available pharmacokinetic data.

[0122]

[0136] The DESC also reviews the safety data aggregated from the expanded cohort. Based on the available data, the DESC can choose a more cautious stopping rule for the expanded cohort than that outlined in the section on justification of sample size below.

[0123]

[0137] Following the DESC review, the sponsor determines the final RP2D based on efficacy and safety in the dose optimization expansion cohort. Rationale for Study Design and Dose: Scientific Rationale for Study Design

[0138] This is a Phase 1 / Phase 2, open-label, multi-site, multiple-dose, dose-escalation and expansion study of Compound I. The antitumor efficacy of Compound I was demonstrated in syngeneic mouse models with reduced responsiveness to anti-PD-1 as well as responsive models. Since the primary objectives are safety and tolerability, blinding to reduce bias is not required and is measured by objective endpoints. Therefore, an open-label design is used. Since this is a FIH study, the primary endpoints of safety, tolerability, MTD and RP2D are clinically relevant to the assessment of this product. The primary endpoint of safety constitutes clinically meaningful effects as it determines the AEs experienced by the participants. Eligibility requirements and safety monitoring are designed to minimize the risk to participants who have received the ongoing non-clinical safety assessments that suggest risks of effects on body weight, gastrointestinal tract, electrocardiogram (ECG) parameters, hemodynamics and body temperature, lymphocyte hematopoiesis system and genitotoxicity. Participants with human immunodeficiency virus (HIV) are excluded as the impaired immune system may affect the immune response induced by Compound I. Overall, the risks associated with participation in this clinical trial of Compound I are considered acceptable for this population of participants with locally advanced or metastatic solid tumor malignancies that are progressive or no longer eligible for standard therapy (not limited to the number of prior treatment regimens).

[0124] Rationale for Study Design and Dose: Rationale for Dose

[0139] Compound I has been tested in many preclinical trials. Data from a 4-week repeated-dose toxicity study in rats and a 4-week repeated-dose toxicity study in cynomolgus monkeys determined the STD10 for rats at 30 mg / kg / day and the HNSTD for cynomolgus monkeys at 3 mg / kg / day. The human equivalent doses based on body surface area conversion (conversion factors: 0.16 for rats and 0.32 for monkeys) of the rat STD10 and the cynomolgus monkey HNSTD are 4.8 mg / kg and 0.96 mg / kg, respectively. For a person weighing 60 kg, one-tenth of the rat STD10 is 28.8 mg (4.8 mg / kg × 1 / 10 × 60 kg), and one-sixth of the HNSTD is 9.6 mg (0.96 mg / kg × 1 / 6 × 60 kg). Cynomolgus monkeys are a more sensitive species. Therefore, based on the cynomolgus monkey HNSTD, the starting dose for humans is determined to be 9.6 mg / participant once daily (QD) given orally (the actual starting dose is 10 mg based on the potency of the 10 mg tablets).

[0125] Rationale for Study Design and Dose: Definition of Study Completion

[0140] The end of the study is defined as the final visit or scheduled procedure as shown in the assessment schedule (Figure 4) for the last participant in the study.

[0126] Study Population

[0141] All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. Unapproved protocol deviations to eligibility criteria (also known as protocol waivers or exemptions) are not permitted.

[0127] Study Population: Inclusion Criteria

[0142] The sex of a participant is defined as male or female assigned at birth. A participant is eligible to participate in the study if all of the following apply: 1. Written informed consent and privacy statements approved by the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) in accordance with domestic regulations (e.g., permission under the law regarding portability and liability of medical insurance for US test facilities) should be obtained from participants prior to any procedures related to the trial (including, if applicable, discontinuation of prohibited medications).

[0128] 2. Participants should be considered adults according to regional regulations at the time they sign the informed consent forms (ICF). 3. Participants should have locally advanced (unresectable) or metastatic solid tumor malignancies confirmed by available pathologic records or biopsies at that time.

[0129] 4. Participants should have at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Lesions located in previously irradiated areas are considered measurable if progression is demonstrated by such lesions.

[0130] 5. Participants should be progressing after receiving all approved standard therapies or should no longer be eligible for standard treatment (not limited to the number of prior treatment regimens). 6. Participants should have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; 7. The last administration of prior antineoplastic agent treatment, including any immunotherapy, should be at least 21 days prior to the start of the investigational drug administration. Participants with solid tumors with known acquired resistance mutations-free neurotrophic receptor tyrosine kinase (NTRK) gene fusions or participants with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC) are allowed to remain on NTRK inhibitor or EGFR tyrosine kinase inhibitor (TKI) or ALK inhibitor treatment until 4 days prior to the first administration of the investigational product (IP).

[0131] 8. Participants receiving radiation therapy need to complete this therapy (including stereotactic irradiation) at least 2 weeks before the first administration of IP. 9. Adverse events (excluding alopecia) in participants from prior therapy have improved to Grade 1 or baseline within 14 days before the first administration of IP. Note: Participants with type 1 diabetes, endocrine disorders stably maintained with appropriate replacement therapy, or skin disorders that do not require systemic treatment (e.g., vitiligo vulgaris, psoriasis, or alopecia) are acceptable.

[0132] 10. Participants have appropriate organ function before the start of the test treatment as indicated by the following test values. If the participant has recently received a blood transfusion, the test values need to be obtained more than 2 weeks after any blood transfusion:

[0133]

Table 5

[0134] 11. The patient has an activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN and is not receiving anticoagulation; 12. Female participants are not pregnant (see Appendix 2) and at least one of the following conditions is met: a. Not a woman at risk of pregnancy (see Appendix 2) b. Women at risk of pregnancy who agree to follow contraceptive guidelines (see Appendix 2) for at least 30 days after the final test intervention administration from the time of informed consent.

[0135] 13. Female participants should agree not to initiate lactation at the time of screening, throughout the study period, and for 30 days after the final test intervention administration. 14. Female participants should not provide eggs at the time of intervention, throughout the study period, and for 30 days after the final test intervention administration.

[0136] 15. Male participants who have a partner who may be pregnant (including partners who are breastfeeding) should agree to use contraception (see Appendix 2) throughout the treatment period and for 30 days after the administration of the final study intervention.

[0137] 16. Male participants should not provide sperm throughout the treatment period and for 30 days after the administration of the final study intervention. 17. Male participants who have a pregnant partner should agree to continue abstinence during pregnancy or use a condom throughout the study period and for 30 days after the administration of the final study intervention.

[0138] 18. Participants should agree not to participate in another interventional study while receiving the study intervention in this trial. Study Population: Exclusion Criteria

[0143] Participants will be excluded from participating in the trial if any of the following apply: 1. The participant has received any investigational therapy (excluding EGFR TKIs in participants with EGFR activating mutations, ALK inhibitors in participants with ALK mutations, or NTRK inhibitors in participants with solid tumors with NTRK gene fusions without known acquired resistance mutations) within 21 days or within the shorter of 5 half-lives before the first administration of the IP. 2. The participant requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days before the first administration of the study intervention. Participants using physiological replacement doses of hydrocortisone or its equivalent (defined as up to 30 mg of hydrocortisone per day and up to 10 mg of prednisone) are permitted.

[0139] 3. The participant requires a strong or moderate CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, duloxetine, abiraterone) during the study.

[0140] 4. The participant requires a strong CYP3A4 inhibitor (e.g., bosentan, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) during the trial.

[0141] 5. The participant has symptomatic central nervous system (CNS) metastases or has evidence of asymptomatic but unstable CNS metastases (e.g., progression on scans). Participants with pre-treated CNS metastases are eligible if they are clinically stable, have no evidence of CNS progression by imaging for at least 4 weeks before the start of the trial treatment, and do not require immunosuppressive steroid administration (more than 30 mg of hydrocortisone per day or more than 10 mg of prednisone per day or equivalent) within 2 weeks.

[0142] 6. The participant has an active autoimmune disease. Participants with type 1 diabetes, endocrine disorders maintained stably with appropriate replacement therapy, or skin disorders that do not require systemic treatment (e.g., vitiligo vulgaris, psoriasis, or alopecia) are acceptable.

[0143] 7. The participant had a prior immunomodulatory therapy interrupted due to a grade ≥ 3 toxicity that is potentially related to the drug (e.g., immune-related) at the discretion of the principal investigator of the clinical trial; 8. It is known that the participant has human immunodeficiency virus (HIV) infection. However, participants with HIV having a CD4+ T cell count ≥ 350 cells / μL and no history of opportunistic infections that define AIDS within the past 6 months are eligible. Note: Screening for HIV infection should be performed according to local requirements.

[0144] 9. The participant has any of the following according to screening serological tests: a. Hepatitis A virus (HAV) antibody (immunoglobulin M [IgM]) b. Positive hepatitis B surface antigen (HBsAg) or detectable hepatitis B DNA. Participants with negative HBsAg, positive hepatitis B core antibody (anti-HBc), and negative hepatitis B surface antibody (anti-HBs) are eligible if hepatitis B DNA is undetectable. c. Hepatitis C virus (HCV) antibody unless HCV RNA is undetectable. 10. The participant has received a live vaccine against an infectious disease within 28 days prior to the start of the first administration of the study intervention.

[0145] 11. The participant has a history of drug-induced pneumonitis (interstitial lung disease), or currently has pneumonia, or has a previous history of ILD or non-infectious pneumonia requiring high-dose corticosteroids regardless of whether it has resolved; 12. The participant has an infection requiring systemic therapy within 14 days prior to the first administration of the study intervention.

[0146] 13. The participant has previously received an allogeneic bone marrow or solid organ transplant. 14. It is expected that the participant will require another form of anti-neoplastic agent treatment during the study treatment.

[0147] 15. The participant has had a myocardial infarction or unstable angina within 6 months prior to the start of the study intervention, or currently has symptomatic congestive heart failure, clinically significant heart disease, unstable angina, arrhythmia, or a mental disorder / social situation that limits compliance with the study requirements, including but not limited to an uncontrolled disease.

[0148] 16. The participant has inadequately controlled hypertension (defined as a systolic blood pressure over 150 and / or a diastolic blood pressure over 100 mmHg on antihypertensive medication). 17. The participant has a corrected QT interval (single ECG) using the Fridericia formula (QTcF) over 450 ms (for male and female participants) during screening. The ECG is performed 3 times during screening.

[0149] 18. The participant has another malignant lesion that requires active therapy, excluding locally treatable malignant lesions such as basal or squamous cell skin cancer, superficial bladder cancer, and cervical or breast intraepithelial neoplasia.

[0150] 19. The participant has had major surgical procedures and has not fully recovered within 28 days prior to the first administration of the test intervention. 20. The participant has a history of bleeding tendency.

[0151] 21. The participant requires the use of anticoagulant therapy. 22. The participant has any condition that, in the opinion of the principal investigator of the clinical trial, makes the participant not suitable for trial participation.

[0152] 23. The participant has been previously treated with a DGK inhibitor. 24. The participant has a known allergy or suspected allergy to Compound I or any component of the formulation used.

[0153] Study Population: Screening Ineligibility

[0144] Screening ineligibility is defined as potential participants who have signed the ICF but do not meet one or more of the criteria required for trial participation and are not registered.

[0154]

[0145] For screening ineligibility, demographic data, the date of signing the ICF, inclusion and exclusion criteria, AEs up to the time of screening ineligibility, and the reasons for screening ineligibility are collected in the eCRF.

[0155] Screening Ineligibility: Rescreening

[0146] Results of screening evaluations that do not meet the parameters required by the eligibility criteria (e.g., clinical tests, vital signs, physical examinations, ECG, etc.) do not need to register the participant as screening ineligible and can be repeated once within the 28-day screening period. If a participant meets an exclusion criterion that cannot be resolved during the screening period or if more than 28 days have elapsed since signing the ICF, the participant must be documented as screening ineligible. A new ICF should be signed for re-screening after a previous screening ineligibility, and the participant should enter the screening with a new participant identification number. Re-screening is only permitted once for each individual participant.

[0156]

[0147] If a participant's electrolyte abnormality does not meet the eligibility criteria, the test can be repeated once within the 28-day screening period without being considered screening ineligible. Study Interventions and Concomitant Therapies

[0148] The test interventions (shown in Table 4) are all pre-specified investigational drugs and non-investigational drugs, medical devices, vaccines, and other interventions (e.g., surgical and behavioral) intended to be administered to the test participants during the test implementation period.

[0157]

Table 6

[0158] Study Interventions and Concomitant Therapies: Preparation / Handling / Recording / Management: Packaging and Labeling

[0149] All sponsor-provided test interventions used in this trial are prepared, packaged, and labeled under the responsibility of qualified personnel in accordance with SOP, current GMP guidelines, ICH GCP guidelines, and applicable local laws / regulations.

[0159]

[0150] Each vial and pouch has a label that complies with regulatory guidelines, GMP, and local laws and regulations to identify the contents as an investigational drug. Refer to the pharmaceutical manual for detailed information on the packaging and labeling of the test intervention.

[0160] Study Interventions and Concomitant Therapies: Preparation / Handling / Recording / Management: Handling, Recording, and Management

[0152] The principal investigator or designee of the clinical trial should confirm that appropriate conditions are maintained during the transfer for all test interventions received, and that any discrepancies are reported and resolved prior to the use of the test intervention.

[0161]

[0153] Only participants registered in the trial can receive the test intervention, and only authorized trial site personnel can supply, prepare, or administer the test intervention. Only test interventions including the appropriate completion / re-test date can be dosed.

[0162]

[0154] All test interventions should be recorded in a safe, environmentally controlled, and monitored (manual or automated) area according to the labeled recording conditions, and access should be restricted to the principal investigator of the clinical trial and authorized trial site personnel.

[0163]

[0155] The principal investigator of the clinical trial, the facility, or the head of the medical facility (if applicable) or authorized facility staff are responsible for management, reconciliation, and record management (i.e., records of final disposal including receipts, reconciliations, and certificates of destruction or equivalents).

[0164]

[0156] The sponsor has the responsibility to provide additional guidance and instructions for the final disposal of test interventions used and unused in the pharmaceutical manual.

[0157] Refer to the pharmaceutical manual for detailed information on the handling, recording, and management of the test intervention.

[0165] Study Interventions and Concomitant Therapies: Allocation to Study Interventions

[0158] This is a non-blind study. Registration and dosing of IP participants are carried out via an Interactive Response Technology (IRT) system. Specific IRT procedures are described in each study manual.

[0166] Study Interventions and Concomitant Therapies: Compliance with Study Interventions

[0159] Compliance of participants to IP is evaluated at each visit. Compliance is evaluated by drug accountability (i.e., counting of returned tablets and / or direct questioning). Deviations from the prescribed dosing regimen are recorded.

[0167]

[0160] If compliance is less than 80%, the principal investigator or designee must counsel the participant and enforce steps to improve compliance. Participants who receive less than 80% of the intended dose during Cycle 1 (e.g., miss more than 4 daily doses in Cycle 1) or who do not complete Cycle 1 for reasons other than DLT (e.g., withdrawal of consent) without a DLT may be switched at the dose level with another participant instead of a determinable DLT.

[0168] Study Interventions and Concomitant Therapies: Dose Modification

[0161] Dose changes of Compound I are not permitted at the individual participant level without prior consultation with the sponsor's medical monitor. For participants in the escalating or expansion cohorts, the investigational treatment may be interrupted at the discretion of the principal investigator if there is any AE, clinical laboratory abnormality, or intervening disease that justifies a delay in dosing of the investigational treatment. Dose reduction is not permitted during the escalating phase of the trial unless the dose level is reviewed and approved by DESC. Dose reduction is not permitted in the dose optimization cohort during the dose expansion phase of the trial. Cycle days continue to be counted regardless of whether the dose was taken to maintain a consistent schedule of visits.

[0169] Toxicity Requiring Interruption of Treatment with Compound I

[0162] Treatment with Compound I is withheld for the following toxicities if there is a reasonable possibility that the event was caused by Compound I.

[0170] - Non-hematological AEs with a grade ≥ 3 - Neutropenia of grade 4 or febrile neutropenia of grade ≥ 3 - Anemia requiring red blood cell transfusions of grade ≥ 3 - Thrombocytopenia with bleeding requiring transfusions (platelets or red blood cells) of grade ≥ 3 - For participants without liver metastases: · AST or ALT > 5 × ULN, or · AST or ALT > 3 × ULN and TBL > 2 × ULN (for participants with Gilbert's syndrome: AST or ALT > 3 × ULN and direct bilirubin > 1.5 × ULN) - For participants with liver metastases: AST or ALT > 8 × ULN - TBL > 3 × ULN (grade ≥ 3) - Cytokine release syndrome (CRS) of grade 3 or higher (graded using the American Society for Transplantation and Cellular Therapy [ASTCT] consensus grading; see Appendix 10, algorithm for the management of cytokine release syndrome) - Any irAE of grade 2 or higher - Any AE, clinical laboratory abnormality, or interventional disease that, in the judgment of the principal investigator of the clinical trial, justifies a delay in the administration of the investigational drug treatment

[0171] Criteria for Resuming Treatment

[0163] The investigational drug treatment can be interrupted for up to 4 weeks to allow recovery from toxicity that requires interruption. After discussion with the medical monitor, the investigational drug treatment can be resumed at the same dose or a reduced dose (one dose level lower than the assigned dose) if the AE has improved to grade 0 or 1, the steroid treatment has been tapered to a physiological replacement dose (hydrocortisone 30 mg or less or prednisone 10 mg or less or equivalent), and the criteria for interruption of the investigational treatment are not met.

[0172] For the list of toxicities that require permanent discontinuation of Compound I, refer to the discontinuation of individual participants from the following test procedures. For any potential immune-related toxicity management algorithm, refer to Appendix 9.

[0173] For participants experiencing CRS, follow the following guidelines: - If Grade 2 CRS is experienced, resume test intervention at the resolution of CRS to Grade ≤ 1.

[0174] - If Grade 3 CRS is experienced, resume test intervention at the resolution of CRS to Grade ≤ 1, with the following restrictions: 〇 The dose of the test intervention must be at least one dose level lower than the dose at that time and will not be escalated if Grade 3 or higher CRS is experienced at a reduced dose.

[0175] 〇 If the reduced dose is tolerated in all cycles with CRS that is not Grade 3, the participant can receive the dose at which Grade 3 CRS occurs. - Participants experiencing Grade 4 CRS or recurrent CRS of Grade ≥ 3 are discontinued (refer to the discontinuation of individual participants from the following test procedures).

[0176]

[0165] The grading of CRS is per the ASTCT consensus grading of the CRS criteria that requires assessment of fever, hypotension, and hypoxemia. Refer to Appendix 10 (algorithm for the management of cytokine release syndrome) and Appendix 11 (algorithm for the management of immune effector cell-associated neurotoxicity syndrome) for the treatment guidelines of CRS.

[0177] Dose Escalation within Participants

[0166] For participants who have not experienced DLT and have completed at least two cycles of treatment, dose escalation within a participant is possible after a higher dose level has been cleared. These participants can then increase to a higher dose level again after a higher dose level has been cleared again (the number of escalations is not limited). The principal investigator must notify the medical monitor before proceeding with dose escalation within a participant.

[0178] Study Interventions and Concomitant Therapies: Continued Access to Study Interventions after Study Completion

[0167] Compound I shall be made unavailable after the completion of the trial. Study Interventions and Concomitant Therapies: Management of Overdose

[0168] In case of suspected overdose of Compound I, the participant must receive supportive care and monitoring. The medical monitor / expert must be contacted if applicable.

[0179]

[0169] For reporting requirements regarding suspected overdose or other dosing errors, refer to the sections on dosing errors, overdose and "off-label use" below. Study Interventions and Concomitant Therapies: Prior Treatments and Concomitant Therapies

[0170] Investigational Medicinal Product: The use of other investigational medicinal products is not permitted during the trial treatment.

[0180]

[0171] Steroids and other immunosuppressive therapies: The use of immunosuppressive agents and immunosuppressive doses of systemic steroids (more than 30 mg hydrocortisone per day or more than 10 mg prednisone per day or equivalent) is not permitted during the trial treatment, unless necessary to manage an adverse event related to the trial treatment. The use of topical, ophthalmic, intra-articular, intranasal, and inhaled corticosteroids (with minimal systemic inhalation) is permitted. Physiological replacement doses of systemic corticosteroids (30 mg or less hydrocortisone per day or ≤ 10 mg or less prednisone per day or equivalent) are permitted. Corticosteroids for prophylaxis (e.g., contrast agent allergy) or short-term treatment of conditions not related to the trial treatment (e.g., delayed hypersensitivity reactions resulting from allergen contact) are also permitted.

[0181]

[0172] Other anti-cancer treatments: The use of other anti-cancer therapies (e.g., chemotherapy, hormonal therapy, immunotherapy, radiation therapy, biological therapy, targeted therapy) is not permitted during the test treatment.

[0173] Palliative (limited field) radiation therapy for bone metastases is permitted. The test treatment should be interrupted during radiation therapy. The use of bisphosphonates and receptor activator of nuclear factor kappa B ligand inhibitors for bone metastases is permitted if initiated before screening. Surgical procedures for isolated or symptomatic lesions for palliative or therapeutic management are also permitted beyond cycle 4. The test treatment should be interrupted until the lesion has healed.

[0182]

[0174] Vaccination: Live vaccines are not permitted during the period when the participant is receiving the test treatment and for 14 days after the final dose of the test treatment. Non-live vaccines (e.g., COVID-19 vaccines) are permitted. The principal investigator of the clinical trial is strongly encouraged to consider any confounding variables related to potential irAEs for Compound I and the vaccine, especially during the DLT window. The principal investigator of the clinical trial is also strongly encouraged to avoid overlapping toxicities that may compromise the safety and tolerability of either treatment. Participants entering a trial that is a candidate for a COVID-19 vaccine are encouraged to receive the first dose during the screening procedure.

[0183]

[0175] Other prohibited drugs / therapies: Herbal supplements that have the potential to cause an increase in the QTc interval or other potential toxic / undesirable effects are not permitted during the test treatment.

[0176] Any over-the-counter drugs that have the potential to cause an increase in the QTc interval are not permitted during the test treatment.

[0184]

[0177] The use of drugs that affect the coagulation cascade, such as vitamin K antagonists, heparin, and direct thrombin inhibitors, or factor Xa inhibitors is not permitted during the test treatment.

[0185]

[0178] The use of strong and moderate CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, duloxetine, abiraterone) is not permitted during the test procedure.

[0186]

[0179] The use of strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is not permitted during the test procedure.

[0187]

[0180] All concomitant treatments are recorded on the eCRF. Study Procedures and Assessments

[0181] The test procedures and their timings are summarized in the evaluation schedule (Figure 4). It is essential to comply with the test design requirements including those specified in the evaluation schedule, which are necessary for the conduct of the test. Anticipated protocol waivers or exemptions are not permitted.

[0188]

[0182] Any change, difference or deviation from the test design or procedure identified in the protocol is considered a protocol deviation. All deviations from the protocol are recorded.

[0183] All screening determinations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The principal investigator of the clinical trial records the details of all screened participants and maintains a screening log to confirm eligibility or, where applicable, record the reasons for screening ineligibility.

[0189]

[0184] Procedures that are part of the participant's normal clinical management (e.g., imaging, blood counts) and are obtained prior to signing the ICF may be used for screening or baseline purposes to provide procedures that meet the criteria specified in the protocol and are conducted within the time frame defined in the evaluation schedule (Figure 4).

[0190]

[0185] In the case of issues of intentional trial continuity (e.g., due to a pandemic), alternative strategies for participant clinic visits, assessments, drug dispensing, and monitoring can be carried out by the sponsor or the investigator responsible for the clinical trial in accordance with the local health authorities' / ethical requirements. These alternative strategies are described in Appendix 7.

[0191] Study Procedures and Assessments: Efficacy Assessments

[0186] All the time points planned for all efficacy assessments are shown in the assessment schedule (Figure 4).

[0192]

[0187] The efficacy and progression of the disease are determined in this trial using the RECIST 1.1 and iRECIST criteria evaluated by the investigator responsible for the clinical trial.

[0188] Tumor evaluations are performed at screening and every 9 weeks (±1 week) from Day 1 of Cycle 1 (C1D1) until immunologically confirmed progressive disease (iCPD). Imaging should include the chest, abdomen, and pelvis, as well as any other anatomical areas appropriate for the participant's disease. The evaluation includes tumor measurements for target and non-target lesions and the assessment of any new lesions. The overall evaluation is characterized for the determination at that time point.

[0193]

[0189] Computerized tomography (CT) or magnetic resonance imaging (MRI) scans are preferred to ensure comparability for this trial; the same technique (CT / MRI) used at screening must be utilized throughout the trial. The same method should be used and evaluated by the same individual at each opportunity, if possible. Imaging should include the chest, abdomen, and pelvis, as well as any other anatomical areas appropriate for the participant's disease.

[0194]

[0190] Imaging should be performed every 9 weeks from C1D1 regardless of treatment interruption or delay and continued through safety follow-up. Scans performed before informed consent as part of the standard of care are acceptable as screening scans if performed within 28 days prior to C1D1. If a biopsy of the target lesion is performed, the baseline scan should be repeated if possible.

[0195]

[0191] The confirmation scan for CR or PR must be performed at least 4 weeks after the scan date on which CR or PR was first observed. The confirmation scan for progressive disease must be performed at least 4 weeks but within 8 weeks after the scan date on which progressive disease was first observed.

[0196]

[0192] All images obtained in the disease evaluation section are read locally. However, copies of all scans from participants in the expanded cohort are submitted to a central vendor and stored for further analysis if justified. Additional information is provided according to the imaging manual.

[0197] Study Procedures and Assessments: Safety Assessments

[0193] All time points planned for safety evaluations are shown in the evaluation schedule (Figure 4).

[0198] Study Procedures and Assessments: Safety Assessments: Evaluation of Clinical Laboratory Tests

[0194] Refer to Appendix 5 for the list of clinical tests to be performed and the evaluation schedule (Figure 4) for timing and frequency.

[0199]

[0195] The principal investigator of the clinical trial must review the reports of the clinical tests, document this review, and record any clinically significant changes occurring during the trial such as AEs. The reports of the clinical tests must be stored together with the source documents.

[0200]

[0196] The clinical significance of clinical findings outside the range should be determined and documented by the principal investigator or sub-investigator, who is a qualified physician. Abnormal clinical findings related to underlying diseases are not considered clinically significant unless the principal investigator determines that they are more severe than expected for the participant's condition.

[0201] Study Procedures and Assessments: Safety Assessments: Vital Signs

[0197] The evaluation of vital signs includes body temperature, pulse rate, respiratory rate, and blood pressure.

[0198] Blood pressure and pulse are measured in the sitting or supine position using a fully automated device. Manual techniques are used only when an automated device is not available.

[0202]

[0199] The measurement of blood pressure and pulse should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, mobile phone). Study Procedures and Assessments: Safety Assessments: Physical Examinations

[0200] A general physical examination is performed at screening and assesses the general appearance, skin, eyes, ears, nose, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, neurological, mental status, and lymphatic system. In subsequent examinations according to the evaluation schedule, the physical examination may be more direct. Each physical examination includes weight; height is required only at screening.

[0203]

[0201] New clinically significant findings or their worsening during a physical examination are recorded as AEs if they meet the criteria for AEs. Study Procedures and Assessments: Safety Assessments: Eastern Cooperative Oncology Group Performance Status

[0202] The ECOG scale [Oken et al., 1982] is used to evaluate the performance status (Table 5) at the time outlined in the evaluation schedule (Figure 4).

[0204]

Table 7

[0205] Study Procedures and Assessments: Safety Assessments: Electrocardiograms

[0203] The standard 12-lead ECG is performed and evaluated as outlined in the assessment schedule (Figure 4). Any clinically significant abnormal findings at screening should be recorded as part of the medical history, and any clinically significant adverse changes in subsequent assessments should be reported as AEs. Additional ECGs or other cardiac assessments (e.g., cardiac enzymes, pulse oximetry) should be performed if clinically indicated or in the event of cardiac symptoms such as chest pain and / or shortness of breath.

[0206]

[0204] Prior to performing the ECG, participants should rest quietly in the supine position (or semi-recumbent if supine is not tolerated) for 10 minutes. The 12-lead ECG is recorded three times (three separate ECGs, with a 1- to 2-minute interval between each) except for the single ECG at the time of the EOT visit. All ECGs are electronically transmitted for central reading.

[0207] Study Procedures and Assessments: Safety Assessments: Order of Assessments

[0205] The following order should be followed if required at the time of two or more assessments.

[0208] - Vital signs - ECG - Blood sampling Study Procedures and Assessments: Adverse Events and Other Safety Aspects

[0206] The definitions of AE or SAE can be found in Appendix 3.

[0209]

[0207] AEs are reported by the participant (or, where appropriate, the caregiver, proxy, or participant's LAR).

[0208] The principal investigator of the clinical trial and any qualified designees are responsible for detecting, documenting, and recording events that meet the definitions of AE or SAE, and for continuing to monitor the course of AEs that are severe and considered related to the study intervention or that interrupt the participant's study intervention and / or study (see Appendix 3).

[0210] The method for recording, determining, and evaluating the causal relationship between AE and SAE, as well as the means for completing and transmitting the SAE report, are provided in (Appendix 3). Adverse Events and Other Safety Aspects: Period and Frequency for Collecting Information on Adverse Events and Serious Adverse Events

[0210] The supporter requests that the principal investigator of the clinical trial start collecting AEs after the ICF is signed. In exceptional circumstances, the reporting of AEs can start at a later point depending on the screening requirements. This should be emphasized in a duly constituted and properly operating committee (SRC / PAC) discussed and approved by the PV product responsible person. The appropriate period during which an AE needs to be reported after the final administration of the test intervention should be identified taking into account the test intervention, dosing period, and characteristics of the disease state.

[0211]

[0211] All SAEs are collected and reported in the eCRF by 30 days after the final administration of the test intervention at the time identified in the evaluation schedule (Figure 4) from the signing of the ICF.

[0212] All AEs are collected and reported in the eCRF by 30 days after the final administration of the test intervention at the time identified in the evaluation schedule (Figure 4) from the signing of the ICF.

[0212]

[0213] If the severity of an SAE / AE increases, an end date should be indicated and the event should be re-recorded in the eCRF with the new severity and new start date.

[0214] If the severity decreases, an end date should be indicated and the SAE / AE should be re-recorded in the eCRF with the new severity and new start date. The exception is an ongoing pre-dose event that continues and improves after dosing. Such events should not be re-recorded.

[0213]

[0215] If the severity of an SAE decreases, the details of the AE must be provided in the SAE worksheet for the medical assessor who can evaluate the course of the event.

[0216] All SAEs are recorded and reported to the backup or designee within 24 hours of obtaining knowledge of the event, without undue delay, as shown in Appendix 3. The principal investigator submits any updated SAE data to the backup within 24 hours of its availability.

[0214]

[0217] The principal investigator is not obliged to actively seek any AEs or SAEs after the termination of trial participation. However, if the principal investigator becomes aware of any SAE with suspected causality to the trial intervention, including death, the principal investigator must promptly report the SAE to the backup at any time after the participant has been discharged from the trial.

[0215] Adverse Events and Other Safety Aspects: Methods for Detecting Adverse Events and Serious Adverse Events

[0218] Care is provided so as not to introduce bias in detecting AEs and / or SAEs. Open-ended, non-leading verbal questioning of the participant is the preferred method of investigating the occurrence of an AE.

[0216] Adverse Events and Other Safety Aspects: Follow-Up of Adverse Events and Serious Adverse Events

[0219] After the initial report of an AE / SAE, the principal investigator needs to actively follow up each participant at subsequent visits / contacts. All SAEs are followed up until resolution, stabilization, the event is otherwise explained, or the participant becomes non-followable (as defined below). Additional information on the follow-up procedure is provided in Appendix 3.

[0217]

[0220] After the AE collection period defined in the protocol described above, if an AE progresses to an SAE, or the principal investigator becomes aware of any (S)AE, including death, and the principal investigator believes there is a reasonable possibility related to the trial intervention or trial participation, the principal investigator must promptly notify the backup.

[0218] Adverse Events and Other Safety Aspects: Regulatory Reporting Requirements for Serious Adverse Events

[0221] Prompt notification of SAEs by the principal investigator to the backup is essential to fulfill the legal obligations and ethical responsibilities regarding the safety of participants and the safety of the trial intervention under clinical research.

[0219]

[0222] The sponsor has the legal responsibility to report to both the local regulatory authorities and other regulatory agencies regarding the safety of the trial intervention under clinical research. The sponsor complies with country-specific regulatory requirements related to safety reporting to regulatory authorities, IRB / IECs, and the investigator responsible for the clinical trial.

[0220]

[0223] The investigator responsible for the clinical trial's safety report must be prepared for SUSARs in accordance with local regulatory requirements and the sponsor's guidelines and transferred to the investigator responsible for the clinical trial as necessary.

[0224] The investigator responsible for the clinical trial who receives a safety report from the sponsor that describes an SAE or other specific safety information (e.g., summary or list of SAEs) shall, after review, file it in accordance with the IB and report it to the IRB / IEC if appropriate according to local requirements.

[0221] Adverse Events and Other Safety Aspects: Disease-Related Events and / or Disease-Related Outcomes Not Considered Adverse Events or Serious Adverse Events

[0225] Under this protocol, the following events are not considered (S)AEs and do not need to be reported: - Disease progression: Events that include defined trial endpoints that clearly match the expected pattern of progression of the underlying disease are not recorded as (S)AEs. These data are obtained as efficacy assessment data outlined in the above efficacy assessment. If there is uncertainty as to whether the event is due to the expected progression of the disease and / or if there is evidence suggesting a causal relationship between the IP and the event, it must be reported as an (S)AE. All deaths up to 30 days after the last dose of the IP, even if due to disease progression, should be reported as SAEs.

[0222] Adverse Events and Other Safety Aspects: Special Circumstances

[0226] Certain specific special circumstances observed in relation to a test intervention, such as misadministration (e.g., incorrect dosage of a test intervention), are reported as protocol deviations and / or may require special reporting as described below. These special circumstances are not considered AEs but need to be communicated to the sponsor according to the timeline defined below.

[0223]

[0227] If a special circumstance is related to an AE or results in an AE, the AE should be evaluated separately from the special circumstance and captured as an AE in the eCRF. If the AE meets the definition of an SAE, the SAE should be reported as described in Appendix 3, and the details of the related special circumstance should be included in the clinical notes on the special circumstance worksheet or pregnancy reporting documents.

[0224]

[0228] Special circumstances are as follows: - Pregnancy - Drug exposure via breast milk - Medication errors, overdose, and off-protocol use - Misuse / abuse - Occupational exposure - Suspected drug-drug interaction

[0229] Instructions and procedures for reporting special circumstances are provided in Appendix 3.

[0225] Test Procedures and Evaluations: Pharmacokinetics

[0230] Blood samples for the analysis of Compound I in plasma are collected as shown in the sample collection schedule (Figure 5). The actual data and time of each blood sample collection are documented.

[0226] Test Procedures and Evaluations: Pharmacodynamics

[0231] Whole blood samples are collected from treated patients to determine the pharmacodynamic effects of Compound I. Preclinical in vitro studies have identified CD69 expression by peripheral blood mononuclear cells (PBMCs) as a candidate for the best pharmacodynamic biomarker. CD69 is an early activation biomarker expressed by many immune cells, including T cells. Blockade of DGKζ by Compound I treatment induces an increase in CD69 expression after TCR-mediated stimulation. To determine the pharmacodynamic effects of Compound I, PBMCs are isolated and stimulated in vitro with CD3 / CD28; CD69 expression is measured by flow cytometry.

[0227]

[0232] Details of the sample collection, labeling, storage, and shipping procedures are provided in separate clinical laboratory manuals.

[0233] Alternative options for monitoring the pharmacodynamic effects of Compound I may include direct monitoring of DGKζ enzyme activity in PBMCs or changes in PBMC gene expression patterns induced by Compound I treatment. Protein extracts and RNA isolations can be prepared from PBMCs for these assays.

[0228]

[0234] The pharmacodynamic activity of Compound I is also estimated using tumor biopsy samples. DGKζ expression levels are measured in CD8 cells in the TME using DGKζ / CD8 immunofluorescence assays. Tumor biopsy samples are collected before Cycle 1 dosing (screening / baseline, up to 28 days prior to Day 1) and on Day 1 of Cycle 2 (at treatment). Tumor biopsies at treatment can be performed up to 5 days prior to Day 1 of Cycle 2. If clinically practical, 3 - 4 biopsy cores are collected at each time point. If at least 3 core samples cannot be provided, the sponsor should be contacted for further guidance. The first biopsy core is processed by formalin fixation and paraffin embedding, and the second core is stored as frozen tissue. The same priority should be given to the 3rd and 4th core samples.

[0229]

[0235] For requirements regarding tumor biopsy collection, refer to the following section on tumor biopsy sample analysis. Test Procedures and Evaluations: Pharmacogenomics

[0236] Pharmacogenomics (PGx) investigations may be conducted in the future to analyze or determine genes related to clinical response, pharmacokinetics, and toxicity / safety issues. For PGx evaluation, samples of 4 - 6 mL of whole blood are collected. The samples are shipped to a contract research organization (CRO) for storage as designated by the sponsor. The details of potential PGx analysis have not yet been established. The sponsor may initiate PGx analysis if evidence suggests that genetic variants may affect the pharmacokinetics, efficacy, and / or safety of the drug. Details of the sample collection, labeling, storage, and shipping procedures are provided in a separate clinical laboratory manual. For further details of the storage procedure, refer to Appendix 6, Pharmacogenomic Analysis of Stored Samples.

[0230] Test Procedures and Evaluations: Biomarkers

[0237] Tumor tissue and blood / serum / plasma samples described in the sample collection schedule (Figure 5) may be used for the purpose of investigations to identify genomic / transcriptomics and / or proteomics biomarkers that may be related to clinical outcomes or dynamic changes associated with Compound I treatment, and to confirm the mechanism of action related to the regulation of the immune response. Details of the planned exploratory biomarker tests are as follows.

[0231] Test Procedures and Evaluations: Biomarkers: Peripheral Blood Samples Including Whole Blood and Plasma Samples for Biomarker Analysis

[0238] Blood samples are collected according to a sample collection schedule (Figure 5). Whole blood samples are used for immune cell profiling focusing on subpopulations of T and B cells. Multicolor flow cytometry analysis is performed to monitor changes in the patient's blood. Additional whole blood samples are collected for PBMC isolation. Direct DGK enzyme activity by Compound I and its expected suppression can be examined in isolated PBMC samples. A second possible test involving PBMC cells should include determination of changes in gene expression patterns induced by Compound I and be examined by an RNA sequencing approach or similar technology.

[0232]

[0239] Separate plasma samples are collected from the patient for determination of peripheral cytokine levels. A multiplex Luminex-based bead assay measuring over 50 cytokines and chemokine factors is used to determine the expected modulation of immune system function induced by Compound I treatment.

[0233]

[0240] Finally, pretreatment and end-treatment plasma samples are collected for determination of potential cell-free tumor DNA (exploratory plasma biomarker) in the patient's blood. The analysis can be performed retrospectively by using one panel for sequencing of cell-free tumor DNA.

[0234]

[0241] All proposed biomarker analyses depend on sufficient material quality and utility. Test Procedures and Evaluations: Biomarkers: Tumor Biopsy Sample Analysis

[0242] The principal investigator shall, if necessary, consult with other experts (e.g., radiation staff) and evaluate the risks associated with the major tissue samples obtained, and determine whether the participants are suitable candidates for the procedure. Biopsies should be obtained in accordance with institutional policies / guidelines that minimize risk. Ensure that participants meet all other eligibility criteria (where applicable) before the biopsy is performed. If clinically practical, participants will undergo a tumor biopsy with 3 - 4 core samples collected at each scheduled biopsy time point. If at least 3 core samples cannot be provided, the sponsor should be contacted for further guidance. Primary tumor lesions are prioritized for biopsy, but samples from metastatic lesions are acceptable. It is strongly encouraged to have baseline and on-treatment biopsy samples taken from the same lesion to rule out variability between different lesions. Further details on the collection procedure are provided in the clinical laboratory manual. Tumor biopsy samples can be analyzed for the pharmacodynamics and exploratory biomarkers described in the pharmacodynamics section above and discussed below.

[0235]

[0243] The purpose of the secondary endpoint includes the analysis and quantification of CD4 and CD8 levels in the TME and is performed by immunohistochemical assays validated in the formalin-fixed paraffin-embedded section of the tumor biopsy. In addition, changes in the activation and proliferation indices of CD8 and CD4 cells in the TME are determined by measuring Ki-67 expression in these cells. An increase in the Ki67 index of CD4 / CD8 within the tumor is a biomarker for the activation and confirmation of the anti-tumor immune response in the mechanism of action (MOA) of Compound I.

[0236]

[0244] The exploratory evaluation of the tumor biopsy may include determination of the expression of programmed death ligand 1 (PD-L1) and DGK in the TME. One of the commercially available PD-L1 assays is used for the determination of PD-L1 expression, and a custom-built assay is used for the determination of DGK expression. The biomarker is considered a candidate for a predictive biomarker that can be used to identify patients who may benefit most from treatment with Compound I. The predictive power of the biomarker should be determined in this trial.

[0237]

[0245] The exploratory determination of tumor biopsy samples may include the analysis of the activity and levels of those TILs. Quantification of CD4, CD8, and FoxP3 positive cells can be monitored in pre-treatment and post-treatment biopsy samples to determine the regulation of the immune response in the TME. The expression of Ki67 and PD-1 by TILs can be measured to determine the level of T cell activation after treatment.

[0238]

[0246] In addition, several multiplex exploratory immunofluorescence assays and immunohistochemistry-based assays can be performed to determine the level of T cell depletion in the TME and its potential regulation by treatment.

[0239]

[0247] Finally, molecular biological profiling of tumor biopsy samples can be performed to identify potential predictive biomarkers, confirm the drug MOA, and identify the mechanisms of resistance to Compound I treatment. Molecular biological exploration of tumor biopsy samples may include the determination of changes in gene expression induced by Compound I treatment in tumor samples. This determination can be performed by RNA sequencing technology. The tumor mutation burden and tumor mutation profile are measured using the FoundationOne panel or may be similar to tumor biopsy samples.

[0240] Test Procedures and Evaluations: Total Blood Volume

[0248] The total amount of blood for each participant varies depending on the course of the participant's disease, the duration of treatment, and local clinical laboratory requirements. At any point during the study, additional blood can be collected for safety monitoring.

[0241]

[0249] The maximum amount of blood collected within 24 hours is approximately 45 mL at C1D1. Interruption of Participation

[0250] Refer to Appendix 1 for information on the interruption of the study site or the entire study.

[0242] Interruption of Participation: Individual Participant Withdrawal from the Test Intervention

[0251] Discontinuation of the trial intervention is defined as a participant who is enrolled in the trial and for whom the investigational intervention is permanently discontinued for any reason.

[0243]

[0252] A participant is free to discontinue the trial intervention and / or withdraw from the trial at any time, for any reason, without giving a reason for doing so and without penalty or prejudice. The principal investigator of the clinical trial is also free to discontinue a participant from the trial intervention at any time or to terminate a participant's involvement in the trial if the participant's clinical condition justifies this.

[0244]

[0253] The reason for discontinuation from the trial intervention should be documented in the participant's medical record. Treatment Discontinuation Criteria:

[0254] A participant must discontinue the trial procedure if any of the following reasons apply: - The participant requests to discontinue the procedure.

[0245] - Any clinical AE, abnormal clinical examination or intervening disease indicates to the principal investigator of the clinical trial that continued treatment is not in the best interests of the participant. - Clinical AEs may include: · A participant who discontinues treatment will be permanently discontinued if the principal investigator or backup determines that the interruption of administration toxicity (detailed above) is clearly not due to a cause other than Compound I and the toxicity does not recover to Grade 0 or 1 within 4 weeks.

[0246] · Encephalopathy, meningitis, or motor or sensory neuropathy of Grade ≥ 2 · Recurrent toxicity: · Recurrent Grade 2 pneumonitis · Recurrent Grade 3 diarrhea / colitis · Pneumonitis of Grade ≥ 3 · Any toxicity of Grade ≥ 4 will be permanently discontinued.

[0247] · Participants who experience CRS of Grade ≥ 4 or recurrent CRS of Grade ≥ 3 will be discontinued. - Progression of the disease defined below: · Progression of the disease confirmed by iRECIST (iCPD) · Progression of the disease according to RECIST 1.1 (i.e., unconfirmed progression by iRECIST, denoted as "iUPD") and the participant is not clinically stable while waiting for subsequent confirmatory scans.

[0248] · Clinical progression of the disease for each evaluation by the principal investigator of the clinical trial - When, in the judgment of the principal investigator of the clinical trial, a change or interruption of therapy is in the best interest of the participant - When the participant becomes ineligible for follow-up - When the participant starts another anti-cancer treatment - When the participant becomes pregnant - When the participant fails to comply with the protocol based on the judgment of the principal investigator of the clinical trial or the medical monitor - Death Interruption of Participation: Individual Participant Withdrawal from the Study

[0255] All participants who discontinue the study treatment must remain in the study and continue to be followed for the safety follow-up procedures specified in the protocol 30 days after the last administration of Compound I as outlined in Figure 4. The only exception to this is if the participant specifically withdraws consent for further contact with the participant or a person previously authorized by the participant to provide this information. If a participant starts a new anti-cancer treatment, the participant will be followed for survival.

[0249]

[0256] For participants who discontinue all study treatment prior to iCPD, the participant enters the post-treatment follow-up period and continues to receive imaging evaluations every 9 weeks until either iCPD or the participant starts another anti-cancer treatment occurs first.

[0250]

[0257] All participants who discontinue the study treatment must be followed for survival in accordance with the institutional guidelines, at intervals longer than every 12 weeks after the final safety follow-up visit outlined in Figure 4, until either death, withdrawal of consent, or termination of the study occurs first.

[0251] Interruption of Participation: Loss to Follow-Up

[0258] All reasonable efforts have been made to complete the evaluations related to the trial, record the raw data, and contact any participant for whom follow-up observations during the trial become impossible in order to resume the trial intervention. These attempts at contact should be documented in the participant's medical record.

[0252] Statistical Considerations Statistical Considerations: Analysis Population

[0259] The number and percentage of participants are characterized for each group.

[0253]

[0260] The following groups are defined:

[0254]

Table 8

[0255] Statistical Considerations: Statistical Analysis

[0261] The Statistical Analysis Plan (SAP) is written to provide details of the analysis in line with the specifications of the tables, listings, and figures to be produced. Changes from the analysis planned in the final SAP that affect the statistical analysis are justified in the CSR.

[0256] Statistical Considerations: Statistical Analysis: General Considerations

[0262] In general, data are summarized by descriptive statistics for continuous endpoints and by frequencies and percentages for categorical endpoints, unless otherwise specified. Percentages by category are based on the number of participants without missing data (i.e., that add up to 100%).

[0257]

[0263] The baseline is defined as the last non-missing observation before the first administration of the trial intervention, unless otherwise specified. Statistical Considerations: Statistical Analysis: Primary Endpoint Analysis

[0264] The primary analysis of this trial is a safety analysis. The safety analysis consists of data summaries of AEs, DLTs, and other safety parameters in the safety analysis population described below.

[0258] Statistical Considerations: Statistical Analysis: Efficacy Analysis

[0265] The ORR, duration of response (DOR), disease control rate, CR rate, PR rate, progression-free survival (PFS), and OS are summarized using descriptive statistics. The median for survival curves and time-to-event variables is estimated using the Kaplan-Meier method and reported along with the corresponding 95% confidence intervals. The efficacy analysis is performed based on the full analysis set (FAS).

[0259] Statistical Considerations: Statistical Analysis: Exploratory Endpoint / Estimand Analysis Pharmacodynamics and Predictive Biomarkers

[0266] Changes in pharmacodynamic biomarkers are summarized using descriptive statistics. The correlation between the drug doses used and the exposure can be determined for the monotherapy cohort. The post-treatment changes in biomarker levels are compared between the monotherapy and combination therapy cohorts. The pretreatment levels of exploratory biomarkers are determined for their correlation with efficacy parameters such as ORR, CR / PR rate, PFS, and OS. Kaplan-Meier survival curves for high and low biomarker populations can be constructed to estimate biomarker predictivity.

[0260] Radiographic Imaging

[0267] A list of tumor imaging (CT / MRI) data is provided. Statistical Considerations: Statistical Analysis: Safety Analysis Adverse Events

[0268] AEs are coded using MedDRA. AEs with onset at any time point from the first dose to the final planned procedure are classified as treatment-emergent AEs (TEAEs) included in the tabulation of summaries. Drug-related TEAEs are defined as any TEAEs with a causal relationship evaluated as "yes" by the principal investigator of the clinical trial or recorded if the relationship is missing.

[0261]

[0269] An overview and separate summaries of the number and percentage of participants with treatment-emergent adverse events (TEAEs), drug-related TEAEs, TEAEs leading to treatment discontinuation, drug-related TEAEs leading to treatment discontinuation, and TEAEs excluding serious adverse events (SAEs) are presented by System Organ Class (SOC), Preferred Term (PT), and dose level. Also included in the overview are the number and percentage of participants with serious TEAEs, drug-related serious TEAEs, TEAEs leading to death, and drug-related TEAEs leading to death.

[0262]

[0270] AE data are enumerated. Evaluation of Clinical Examinations Clinical laboratory parameters are summarized by cohort and dose level using descriptive statistical shifts in change from baseline, and by a list of data on clinically significant abnormalities.

[0263] Vital Signs

[0271] Vital signs and ECG parameters and their changes from baseline are summarized by cohort and dose level using descriptive statistics.

[0264] Electrocardiogram

[0272] The results of 12-lead ECGs are summarized by dose level and time point. A table of shift analysis showing the shift from baseline in the overall ECG (normal and abnormal) is provided.

[0265]

[0273] QT corrected for QTcF interval is summarized for each treatment visit for clinically important values using frequency tables with the following range criteria.

[0266]

Table 9

[0267]

[0274] The QTc interval is also summarized by frequency of participants in terms of changes from a clinically important baseline using the criteria identified below. These summaries are provided for each treatment visit.

[0268]

Table 10

[0269]

[0275] The effect of the serum concentration of Compound I in terms of ΔQTcF (defined as the mean change from baseline in QTcF) is evaluated.

[0276] Further details are provided in the SAP.

[0270] Eastern Cooperative Oncology Group Performance Status

[0277] Summary statistics (number of participants and percentages) are provided for each category of ECOG performance status at each assessment. Changes from baseline to final visit or early termination are also summarized. Negative change scores indicate improvement. Positive scores indicate a decline in performance.

[0271] Statistical Considerations: Statistical Analysis: Pharmacokinetics / Pharmacodynamics Analysis Pharmacokinetic Analysis

[0278] Descriptive statistics include count, mean, standard deviation, coefficient of variation (CV), geometric mean, geometric CV, median, minimum, and maximum. Pharmacokinetic parameters t max and t lag , n only, median, minimum, and maximum are calculated.

[0272] Pharmacokinetic Concentrations

[0279] Descriptive statistics are presented for plasma concentration of Compound I and serum concentration of pembrolizumab by treatment group and at scheduled sample times. Standard graphical algorithms including mean plasma concentration-time profiles (linear and semi-log scales) and overlay (spaghetti) plots are created.

[0273] Estimation of Pharmacokinetic Parameters

[0280] Non-compartmental analysis is used to calculate plasma pharmacokinetic parameters of Compound I using Phoenix version 6.3 or later (Certara L.P., 100 Overlook Center, Suite 101, Princeton, NJ 08540, US). Urine parameters can be calculated using either Phoenix or SAS®, version 9.3 or later.

[0274]

[0281] Plasma pharmacokinetic parameters of Compound I are enumerated and summarized using descriptive statistics. Statistical Analysis of Pharmacokinetic Parameters

[0282] Dose proportionality is determined graphically for the AUC of Compound I 24 (AUC for twice-daily dosing 12 ) and C for single-dose max , as well as AUC for multiple-dose tau and C max using the linearization of the following power model: ln(pharmacokinetic parameter) = β0 + β1·ln(dose) (where β0 is the intercept and β1 is the slope). Dose proportionality is indicated when the 90% CI for β1 falls entirely within the limits

[0275]

Number

[0276] (where r is the ratio of the maximum to minimum doses used in the model)).

[0283] A scatter plot (ln-ln) of the natural logarithm transformation including the regression line and a reference line with a slope of 1 is presented.

[0277]

[0284] Steady state is determined using visual inspection of the individual participant's trough concentration vs. day (spaghetti plot) overlaid with the mean profile. Concentration-Efficacy Relationship Analysis

[0285] The concentration - efficacy relationship can be explored. Details, where applicable, are described in the exposure - efficacy analysis.

[0278] Pharmacodynamics|Immunogenicity Analysis

[0286] Descriptive statistics are used to summarize changes in biomarkers of secondary and exploratory endpoints, such as TILs in the TME and their proliferation indices, plasma levels of serum cytokines, levels of CD69 expression, and subsets of peripheral T and B cells, and changes in protein expression (PD - L1, DGKζ) in the TME. ADA against pembrolizumab is enumerated and summarized. The summary is presented by treatment cohort.

[0279]

[0287] The correlation between predictive biomarkers for clinical trials, such as tumor mutation profiles, tumor mutation burden, PD - L1, DGK, TIL levels in tumor samples, and clinical response parameters (e.g., ORR, DOR, OS, and PFS) is determined.

[0280] Statistical Considerations: Statistical Analysis: Other Analyses Analysis of Exploratory Biomarkers

[0288] The association between biomarkers and clinical outcomes (efficacy, safety, or pharmacodynamics) can be performed in participants with baseline and on - study measurements necessary to provide interpretable results for the specific parameters of interest. Biomarkers can be summarized graphically or descriptively, where applicable, in relation to clinical measurements. Summary statistics can be tabulated. Additional post - hoc analyses, such as alternative modeling approaches, can be performed. All analyses described in this section are based on the availability of data.

[0281]

[0289] Details are described in the Supplementary Biomarker Analysis Protocol. Statistical Considerations: Interim Analysis

[0290] The sponsor conducts an interim analysis of the efficacy of each tumor - specific expansion cohort, which is performed if 20 participants are enrolled with evaluable tumor response data in that cohort.

[0282] Statistical Considerations: Sample Size Determination

[0291] Approximately 196 participants are planned for enrollment in this trial; however, the full sample sizes vary based on the safety and efficacy responses observed for each cohort.

[0283]

[0292] Part 1: Dose Escalation: Up to 36 participants will be enrolled in the dose escalation. Participants who are not considered evaluable during the DLT period can be replaced. The sample size in the dose escalation cohort is based on the TITE - BOIN dose escalation design and not on power calculations.

[0284]

[0293] Part 2: Dose Expansion: Approximately 160 participants will be enrolled in the dose expansion phase. First, 20 participants will be enrolled in each tumor expansion cohort. Based on the responses observed in the expansion cohorts, up to 20 additional participants may be enrolled in the expansion cohort specific to that tumor. The Bayesian Optimal Phase 2 (BOP2) design [Zhou et al., 2017] is used in the trial to determine efficacy from the perspective of the ORR rate for the selected dose levels. Assuming an effective ORR of 10% and a non - effective ORR of 2%, the statistical power is approximately 73.8% while the Type I error rate is controlled at 4.1%.

[0285] Appendix Appendix 1: Ethical Considerations, Regulatory Considerations, and Considerations in Study Conduct Regulatory Considerations and Ethical Considerations

[0294] This trial can be conducted in accordance with the protocol together with: - Consensus ethical principles derived from international guidelines including the Helsinki Declaration and CIOMS International Ethical Guidelines - Applicable ICH GCP guidelines - Applicable laws and regulations

[0295] Protocols, protocol amendments, ICFs, IBs, and other related documents (e.g., advertisements) must be submitted by the investigator-in-charge to the IRB / IEC and reviewed and approved by the IRB / IEC before the trial may begin.

[0286]

[0296] Any protocol amendment requires IRB / IEC approval before changes are made to the study design, except for changes that are necessary to eliminate an immediate hazard to trial participants.

[0287]

[0297] The investigator-in-charge has the responsibility for: - Providing the IRB / IEC with a written summary of the status of the trial annually or more frequently, in accordance with the requirements, policies, and procedures established by the IRB / IEC - Reporting to the IRB / IEC or other significant safety findings of SAEs required by IRB / IEC procedures - Monitoring the conduct of the trial at the facility and providing compliance with the requirements of 21 CFR, ICH guidelines, IRB / IEC, European Regulation 536 / 2014 for clinical trials (where applicable), and all other applicable local regulations Informed Consent of Participants: Process of Informed Consent

[0298] The investigator-in-charge or the investigator-in-charge's delegate shall explain the nature of the trial to potential participants or their legally authorized representatives and answer all questions about the trial.

[0288]

[0299] The information provided shall be in writing: - Enabling the participant or their legally authorized representative to understand: · The nature, purpose, benefits, significance, risks, and disadvantages of the clinical trial; · The conditions under which the clinical trial will be conducted, including the expected duration of the participant's participation in the clinical trial; · Alternatives to the possible treatment, including the measurement of follow-up observations if the participant's participation in the clinical trial is interrupted; - Maintaining comprehensiveness, brevity, clarity, relevance, and understandability for the layperson; - The appropriate and qualified members of the trial team are interviewed in advance. Special attention is paid to the requirements for information on specific patient populations and individual participants, as well as the methods used to provide the information. Care should be taken to confirm that the participants understand the information; - including information on applicable injury compensation systems; - including the trial ISN number and information on the future usefulness of the clinical trial results in terms that are understandable to laypersons;

[0300] Potential participants should be informed that their participation is voluntary and that they have rights that should be protected and guarantees that should be explained. In particular, the right to refuse participation, and the right to withdraw from the clinical trial at any time without being forced to justify the resulting disadvantages or explain the reasons, are explained.

[0289]

[0301] Participants, or their legally authorized representatives, defined as individuals, judicial or other bodies permitted by applicable law to consent to a patient's participation in lieu of the patient expected in the procedures included in the study (45 CFR 46.102[c]), are required to sign an informed consent statement that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements where applicable, and the requirements of the IRB / IEC or the trial center.

[0290]

[0302] If the participant is a minor who can judge and evaluate the information provided, consent is also obtained for participation in the clinical trial.

[0303] Medical records must include a description of the written informed consent obtained before the participant is enrolled in the study, and the date on which the written consent is obtained. The person authorized to obtain the informed consent must also sign the ICF.

[0291]

[0304] Participants must re-consent to the most recent version of the ICF during their participation in the study.

[0305] Copies of the ICF must be provided to the participant or their legally authorized representative.

[0292] Informed Consent of Participants: Written Information, Participant Consent, and Provision of New Important Information Affecting Revisions

[0306] The Investigator or the Investigator's delegate must immediately orally notify the participant of any new information (e.g., reports of serious adverse drug reactions) that may be relevant to the participant's consent or that may affect the participant's willingness to continue participating in the study. The communication should be documented in the participant's medical record as to whether the participant wishes to remain in the study or confirm and document that they should not.

[0293]

[0307] The Investigator must update the participant's ICF and submit it to the IRB / IEC for approval. The Investigator or the Investigator's delegate must obtain written informed consent from the participant for all updated ICFs throughout the course of the study. The Investigator or the Investigator's designee must re-consent the participant with the updated ICF even if the relevant information was provided orally. The Investigator or the Investigator's delegate who obtained the written informed consent and the participant must sign and date the ICF. A copy of the signed ICF should be given to the participant and the original placed in the participant's medical record. Entries should be made in the participant's record documenting the re-consent process.

[0294] Data Protection

[0308] The Sponsor conducts the study and uses the personal data collected from the participants for the conduct of the study and the publication of the results of the study. The participant's personal data is used, for example, through the development program of the study intervention to develop the product, obtain permission to market the product, monitor its safety, and secure coverage under health insurance and reimbursement schemes.

[0295]

[0309] The Sponsor relies on permission (or "consent") to use the participant's data, which is obtained by signing the ICF.

[0310] The principal investigator and / or the facility staff record information from the medical files of the trial participants in the eCRF and external (electronic) data files (e.g., central laboratory data). These trial records identify the participants by code instead of their names or other personal data. Only the principal investigator and the facility staff can match the names and codes of the trial participants held in the medical files at the facility. Non-medical staff acting on behalf of the sponsor and bound by the obligation of confidentiality, as well as health authorities and / or the IRB / IEC, may also access this data at the facility only to confirm that the trial is conducted in compliance with legal quality requirements.

[0296]

[0311] The sponsor collects personal data from the participants that may be used during the trial as follows: - Submission to government regulatory authorities and the IRB / IEC - Use in reports or scientific publications for public release, as well as - Use in current or future research.

[0297]

[0312] However, the identity of the participants is not revealed if the personal data of the trial participants is shared for these purposes.

[0313] The sponsor notifies the participants of their privacy rights and how they will be enforced under the ICF that the participants sign to participate in the trial. The sponsor provides a privacy notice to the principal investigator and the trial staff explaining how the personal data will be used and how the privacy rights will be enforced.

[0298]

[0314] The sponsor acknowledges that it processes personal data in accordance with all applicable privacy laws and regulations.

[0315] The contract between the sponsor and the trial facility specifies the responsibilities of the parties related to data protection, including the handling of data security breaches and the respective communications and cooperation of the parties.

[0299]

[0316] The information technology systems used to collect, process, and store trial-related data are secured by technical and organizational security measures designated to protect such data against accidental or unlawful loss, alteration, or unauthorized disclosure or access.

[0300] Composition of Committees

[0317] The DESC, consisting of the sponsor's agent and the principal investigator of the clinical trial, will convene when the dose-level cohort has completed the DLT observation period and the data become available for review. The DESC's determination of the dose level for the next cohort is guided by TITE-BOIN based on the DLTs observed at each dose level.

[0301]

[0318] The safety data from the DLT observation period of the escalation cohort are the minimum safety data required at the committee meeting, but all available safety findings, including those that occur after the designated DLT observation period that meets the DLT criteria ("delayed DLT"), are considered by the DESC. The DESC will evaluate whether a longer DLT observation period is justified based on the emerging data. In addition, the DESC can choose a more cautious dosing decision than that indicated by TITE-BOIN based on the determination of safety data and available pharmacokinetic data.

[0302]

[0319] The DESC will also review the safety data aggregated from the expansion cohort. Based on the available data, the DESC can choose a more cautious stopping rule for the expansion cohort than that outlined in the section on justification of the sample size below.

[0303]

[0320] In accordance with the DESC's review, the sponsor will determine the final RP2D based on efficacy and safety in the dose-optimized expansion cohort. Distribution of Clinical Trial Data

[0321] The recommended ICH E3 guideline and EU Clinical Trials Regulation 536 / 2014 require that the final CSR forming part of the marketing authorization application be signed by the responsible investigator or the proxy for the principal investigator with whom the final CSR is coordinated. The proxy for the responsible investigator or the principal investigator is responsible for reviewing the final trial results and, to the best of their knowledge, ensuring that the conduct and results of the trial are accurately described. The proxy for the responsible investigator or the principal investigator is selected from the participating investigators supported by a sponsor prior to database lock.

[0304] Data Quality Assurance

[0322] All participant data related to the trial are recorded in the eCRF unless they are electronically transmitted to the sponsor or designee in an external data file (e.g., central laboratory data). The responsible investigator is responsible for ensuring that data entry into the eCRF is accurate and precise by physically or electronically signing the eCRF.

[0305]

[0323] Guidance on the completion of the CRF is provided in a separate eCRF completion guidance.

[0324] The responsible investigator must permit trial-related monitoring, auditing, IRB / IEC review, and regulatory inspections and provide direct access to source data documents.

[0306]

[0325] QTLs are predefined in a plan applicable to identifying systematic issues that may affect the safety of participants and / or the reliability of trial results. These predefined parameters are monitored during the trial, and significant deviations from the QTLs and the treatment actions taken are summarized in the CSR.

[0307]

[0326] Strategies, methods, responsibilities, and requirements including handling of non-compliance issues and monitoring techniques (central, remote or on-site monitoring) that describe the definition of clinical data items and processes of the trial (e.g., risk-based leadership in operations and quality such as risk management and mitigation strategies and analysis risk-based monitoring) are provided in the monitoring plan.

[0308]

[0327] The sponsor or designee is responsible for the data management of this trial, including data quality checks.

[0328] The sponsor assumes management of actions delegated to other individuals (e.g., CRO).

[0309]

[0329] Records and documents, including signed ICFs, related to the conduct of this trial must be retained by the principal investigator in accordance with ICH or regulatory requirements of the applicable region, for the longer of either after the trial is completed. Records may not be destroyed during the retention period without the written approval of the sponsor. Records may not be transferred to another location or party without the written notice of the sponsor.

[0310] Initiation and Closure of the Study and Facilities First Activities of Recruitment

[0330] The trial start date is the date on which the clinical trial is announced for participant enrollment.

[0311]

[0331] The first activity of enrollment is the date on which the first participant signs the ICF. Termination of the Study / Facility

[0332] The sponsor or designee retains the right to close the trial site or terminate the trial at any time, for any reason, at the sole discretion of the sponsor. The trial site is closed at the end of the trial. The trial site is considered closed when all required documents and supplies of the trial have been collected and a site closure visit has been conducted.

[0312]

[0333] The principal investigator of the clinical trial may initiate the closure of the trial facility at any time, provided that there are reasonable grounds and that it is done prior to the termination with sufficient notice intended.

[0334] Reasons for early closure of the trial facility by the sponsor or the principal investigator of the clinical trial may include, but are not limited to, the following:

[0335] Regarding the termination of the trial: - Discontinuation of the development of further trial interventions

[0336] Regarding the closure of the facility: - Failure of the principal investigator of the clinical trial to comply with the protocol, IRB / IEC or local health authority requirements, sponsor procedures or GCP guidelines - Inadequate or no recruitment of participants by the principal investigator of the clinical trial (rising after an appropriate time) - Total number of participants enrolled earlier than expected

[0337] If the trial is terminated or postponed early, the sponsor or designee shall promptly notify the reasons for the termination or postponement as specified in the regulatory requirements applicable to the principal investigator of the clinical trial, IEC / IRB, regulatory authorities, and any CRO used in the trial. The principal investigator of the clinical trial shall promptly notify the participants and shall ensure appropriate treatment and / or follow-up of the participants.

[0313] Quality Assurance

[0338] The sponsor shall implement and maintain a QA and QC system, including written SOPs, to ensure that the trial is conducted and the data are generated, documented, recorded, and reported in compliance with the protocol, GCP, and applicable regulatory requirements. Where applicable, the QA and QC systems and written SOPs of the CRO shall apply.

[0314]

[0339] The sponsor or designee of the sponsor may arrange for an accounting audit of the trial at any or all of the trial facilities and equipment. The accounting audit may include an on-site review of the regulatory documents, CRFs, and source documents. Direct access to these documents is required by the auditor.

[0315] Appendix 2: Contraception Requirements

[0340] Pregnant women who are eligible to participate in the study, including those who choose complete abstinence, must take a pregnancy test as specified in the assessment schedule (Figure 4). The results of the pregnancy test must confirm that the participant is not pregnant.

[0316] Definition of Women of Childbearing Potential and Definition of Contraceptive Laws

[0341] Women are considered fertile (i.e., women at risk of pregnancy) from menarche until menopause, unless they are permanently infertile.

[0317] Women in the following categories cannot be considered women at risk of pregnancy - Before menarche - Before menopause with one of the following (i.e., permanent infertility): · Documented hysterectomy · Documented bilateral salpingectomy · Documented bilateral oophorectomy - After menopause

[0342] The postmenopausal state is defined as at least 12 months after the last menstrual bleeding without alternative medical causes.

[0318]

[0343] If the last menstrual bleeding cannot be clearly determined, confirmation of two or more FSH measurements above at least 40 IU / L (or higher according to the guidelines within the local facility) is required.

[0319]

[0344] Women on HRT with an unconfirmed menopause status need to use one of the highly effective non-estrogen hormonal contraceptive methods if they wish to continue HRT during the study. Otherwise, HRT must be discontinued to enable confirmation of the postmenopausal state by repeating FSH measurements before study enrollment.

[0320]

[0345] Documentation of any of these categories may be derived from a review by the study facility staff of the female participant's medical records, physical examinations, or medical history interviews. Contraception Guidance for Female Participants of Childbearing Potential

[0346] Pregnant or potentially pregnant female participants are eligible to participate in the trial if they agree, at the time of signing the ICF, to use one of the highly effective methods of contraception listed below until completion of the relevant total exposure, defined as 30 days after the last administration of the study intervention. a

[0347] Highly effective methods of contraception (failure rate < 1% per year if used consistently and correctly) b : - Combined hormonal contraceptive methods (containing estrogen and progestogen) related to ovulation suppression · Oral · Vaginal · Transdermal - Progestogen-only hormonal contraceptive methods related to ovulation suppression · Oral · Injection · Implant - Other combined (containing estrogen and progestogen) methods · Vaginal ring · Injection · Implant · Intrauterine hormonal release system or intrauterine contraceptive device - Bilateral tubal occlusion or bilateral tubal ligation - Vasectomized partner: Vasectomy of the partner is a highly effective method of contraception, provided that the partner is the only male sexual partner of the potentially pregnant woman and absence of sperm has been confirmed. Otherwise, a more highly effective method of contraception should be used. a Local laws and regulations may require the use of alternative and / or additional methods of contraception. b The failure rate of typical use may differ from that of consistent and correct use. Use must comply with local regulations regarding the use of contraceptive methods for participants in clinical trials.

[0321] Contraception Guidance for Male Participants with Female Partners of Childbearing Potential.

[0348] Male participants with female partners who may be pregnant are eligible to participate in the study if they agree, during the procedure and until completion of the relevant total body exposure defined as 30 days after the final study intervention administration, to the following: a - Inform all partners of the need to participate in the clinical trial and follow contraceptive instructions as directed by the principal investigator of the clinical trial - Use of condoms

[0349] Female partners of male participants who have not undergone vasectomy or bilateral orchiectomy where absence of sperm has been confirmed must consider using an effective method of contraception. a Local laws and regulations may require the use of alternative and / or additional methods of contraception.

[0322] Contraception Requirements: Highly Effective Methods of Fertility Regulation - Failure Rate < 1% / Year 1. Hormonal contraceptive methods containing combined estrogen and progestogen a. Oral b. Vaginal c. Transdermal, e.g., patch d. Injection, e.g., Cyclofem, Mesigyna 2. Progestogen-only hormonal contraceptive methods a. Oral b. Injection, e.g., DMPA-IM or -SC c. Implant, e.g., Norplant 3. IUD 4. IUS 5. Bilateral tubal occlusion 6. Male partner with vasectomy 7. True abstinence: (If this is directly related to the preferred and usual lifestyle of the participant. Periodic abstinence methods (e.g., calendar method, ovulation method, symptothermal method, postovulatory method) and withdrawal are not acceptable methods of contraception. Sexual abstinence is considered an effective method only if it is defined as refraining from heterosexual intercourse throughout the period of risk associated with the study intervention. If complete abstinence is chosen, there is no need to use any other method of contraception.)

[0323] Methods of Fertility Regulation Considered Unacceptable: 1. Periodic abstinence methods (calendar method, ovulation method, symptothermal method, post-ovulation method) 2. Withdrawal (coitus interruptus) 3. Spermicides only 4. Lactational amenorrhea Appendix 3: Adverse Events: Definitions and Procedures for Recording, Assessment, Follow-up Observation, and Reporting Definition of Adverse Event (AE) AE Definition:

[0350] An AE is any adverse medical occurrence in a patient or clinical trial participant that is temporally associated with the use of a test intervention, whether or not it can be regarded as related to the test intervention.

[0324]

[0351] Note: Thus, an AE can be any unfavorable and unintended sign (including abnormal clinical laboratory findings), symptom, or disease (new or worsening) that is temporally associated with the use of a test intervention. This includes events related to the comparator and events related to (test) procedures.

[0325] Events Meeting the AE Definition

[0352] Any abnormal clinical laboratory result (hematology, clinical chemistry, or urinalysis) or other safety assessment (e.g., ECG, radiological scan, measurement of vital signs) that is considered clinically significant by the medical and scientific judgment of the principal investigator of the clinical trial (i.e., not related to the progression of underlying disease), including those that worsen from baseline.

[0326]

[0353] Worsening of a chronic or intermittent pre-existing condition, including any increase in the frequency and / or intensity of the condition.

[0354] A new condition that is detected or diagnosed after administration of the test intervention, even if it could have existed before the start of the trial.

[0327] Events Not Meeting the AE Definition

[0355] Any clinically significant abnormal clinical laboratory findings or other abnormal safety assessments related to underlying disease, unless judged by the principal investigator of the clinical trial to be more severe than expected for the participant's condition.

[0328]

[0356] The disease / disorder being tested or the expected progression, signs, or symptoms of the disease / disorder being tested, unless more severe than expected for the participant's condition.

[0357] Medical or surgical procedures (e.g., endoscopy, appendectomy): The condition that results in the procedure is an AE.

[0329]

[0358] Situations where no adverse medical events occurred (social and / or favorable hospitalization).

[0359] The expected daily variation of a pre-existing disease or condition that was present or detected at the start of the trial and did not worsen.

[0330] Definition of Adverse Event: Abnormal Test Findings

[0360] Any abnormal clinical test results, such as hematology, biochemistry, or urine tests, or other safety evaluations, such as vital signs, physical examinations, ECG, or X-ray scans, that are considered clinically significant by the medical and scientific judgment of the principal investigator of the clinical trial and that deteriorate from the baseline not related to the underlying disease, should be reported as (S)AE.

[0331]

[0361] Any clinically significant abnormal clinical findings or other abnormal safety evaluations related to the underlying disease do not need to be reported as (S)AE unless determined by the principal investigator of the clinical trial to be more severe than expected for the participant's condition.

[0332]

[0362] Repeating an abnormal clinical test or other safety evaluation does not constitute an AE if none of the above criteria are present. Any abnormal test results determined to be an error do not need to be reported as an AE.

[0333] Definition of Adverse Event: Potential Cases of Drug-induced Liver Injury

[0363] Refer to Attachment 4 for detailed instructions on drug-induced liver injury. Abnormal values of AST and / or ALT that meet the criteria outlined in Attachment 4, or abnormal increases in TBL, in the absence of other causes of liver injury, are considered potential cases of drug-induced liver injury (potential high law cases) and should always be regarded as significant medical events and reported in accordance with the reporting procedures for SAEs.

[0334] Definition of Serious Adverse Event (SAE)

[0364] SAE is defined as any adverse medical occurrence that is any of the following at any dose: - Resulting in death - Being life-threatening

[0365] The term "life-threatening" in the definition of "severe" refers to an event where the participant was at risk of death at the time of the event. It does not refer to an event that could hypothetically cause death, even if it is more severe.

[0335] - Requiring hospitalization or prolongation of an existing hospitalization · Generally, hospitalization means that the participant is placed in a hospital or emergency ward for observation and / or treatment that is not appropriate in a physician's consulting room or outpatient clinic (usually staying at least one night). Complications that occur during hospitalization are AEs. If the complication prolongs the hospitalization or meets any other severe criteria, the event is severe. If it is unconfirmed whether "hospitalization" has occurred or is necessary, the AE should be considered severe.

[0336] · Hospitalization for elective treatment of a pre-existing condition that has not worsened from baseline is not considered an AE. - Resulting in persistent or significant disability / incapacity · The term "disability" means a substantial breakdown of the ability of a person to perform normal life functions.

[0337] · This definition is not intended to include relatively minor medical significance experiences such as headaches, nausea, vomiting, diarrhea, influenza, and acute trauma (e.g., ankle sprain) that may interfere with or disrupt daily life functions but do not constitute a substantial breakdown or involve complications.

[0338] - Being a congenital anomaly / congenital defect - Other situations: · Medical or scientific judgment must be exercised to determine whether an SAE report is appropriate in other situations such as important medical events that do not immediately threaten life or result in death or hospitalization but may place the participant at risk or require medical or surgical intervention to prevent one of the other entries listed in the above definition. These events should generally be considered serious.

[0339] · Examples of such events include invasive or malignant cancer, allergic bronchospasm that does not result in intensive care or hospitalization in the emergency room, home-based intensive care for blood disorders or convulsions, or the onset of drug dependence or drug abuse.

[0340]

[0366] If an event is not an AE according to the definition in "Section 0", it cannot be an SAE even if serious conditions (e.g., hospitalization due to signs / symptoms of the disease under test, death due to disease progression) are met.

[0341] Assessment of Causality

[0367] The principal investigator of the clinical trial has the obligation to evaluate the relationship between the trial intervention, trial procedures, and each occurrence of each AE / SAE.

[0342]

[0368] "A reasonable possibility" of a relationship conveys that there are facts, evidence, and / or arguments suggesting a causal relationship rather than that the relationship can be excluded.

[0369] The principal investigator of the clinical trial uses clinical judgment to determine the relationship.

[0343]

[0370] Underlying diseases, concomitant therapies, and other risk factors, as well as alternative causes such as the temporal relationship to the administration of the test intervention of the event, are considered and studied.

[0371] The principal investigator of the clinical trial also consults the IB and / or product information for the marketed product in the evaluation.

[0344]

[0372] For each AE / SAE, the principal investigator of the clinical trial has to review the AE / SAE and document it in the medical record providing an assessment of the causal relationship.

[0373] An SAE may occur in a situation where the principal investigator of the clinical trial has the minimum information including the first report to the supporter. However, it is very important that the principal investigator of the clinical trial always conducts an assessment of the causal relationship for all events before the first transmission of the SAE data to the supporter.

[0345]

[0374] The principal investigator of the clinical trial can change the judgment of the causal relationship in light of the follow-up information and send a follow-up report of the SAE including the updated assessment of the causal relationship.

[0375] The assessment of the causal relationship between test interventions is one of the criteria used when determining regulatory reporting requirements.

[0346]

[0376] Following the review of the relevant data, the causal relationship between the test intervention and each (S)AE is evaluated by answering "yes" or "no" to the question "Do you think there is a reasonable possibility that the event may be due to the test intervention?"

[0347]

[0377] When an assessment of the causal relationship is made, the following factors should be considered when determining whether there is evidence and / or argument suggesting that there is a "reasonable possibility" that the (S)AE may be due to (rather than the relationship being excluded) the test intervention, or whether there is evidence reasonably negating the causal relationship: - Was the participant administered the test intervention? - Plausibility (i.e., could the event be attributable to a suspect test intervention? Consider biological and / or pharmacological mechanisms, half-life, literature evidence, drug class, preclinical and trial data, etc.) - Discontinuation / reduction / resumption of use: · Discontinuation of use: Did the (S)AE resolve or improve only after the dose of the suspect test intervention was discontinued without any treatment? · Reduction of dose: Did the (S)AE resolve or improve after the dose of the suspect test intervention was reduced? · Resumption of use: Did the (S)AE recur when the suspect test intervention was re-introduced after being discontinued? - Clinical or other test results: Did a specific clinical test support the evaluation of the relationship between the (S)AE and the test intervention (e.g., based on values before, during, and after treatment)? - Exposure to the test intervention; e.g., available alternative explanations independent of risk factors including other concomitant interventions, medical history, concurrent or underlying diseases, medical and family history, season, location, etc., and the strength of the alternative explanations - Temporal relationship between exposure to the test intervention and the onset and / or resolution of the (S)AE. Did the (S)AE occur in a reasonable temporal relationship to the administration of the test intervention? - Finally, based on all of the above, determine which is more likely based on factors of reasonable possibility or confounding factors, and provide a sound overall judgment.

[0348]

[0378] SAEs may occur in circumstances where the investigator has minimal information including the initial report to the sponsor. It is very important that the investigator always assesses causality for all events before the initial transmission of SAE data to the sponsor, but the initial report must be submitted without delay (within 24 hours of awareness). If there is limited or insufficient information about an event for which a medical determination has been made and no indication or evidence of causality, an assessment of "no" causality should be considered. In such instances, the investigator is expected to obtain additional information about the event as soon as possible and re-evaluate causality upon receipt of the additional information. A medically qualified investigator may revise the causality assessment in light of new information about the SAE, send follow-up reports on the SAE, and update the eCRF with the new information and updated causality assessment.

[0349] Assessment of Severity

[0379] Adverse events including abnormal clinical laboratory values are graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines, Version 5.0. Items not defined in the NCI-CTCAE Version 5.0 are evaluated according to the criteria in Table 6 below and entered into the eCRF:

[0350]

Table 11

[0351] Recording and Follow-up Observation of AE and / or SAE Recording of AE and SAE

[0380] It is the responsibility of the investigator to review all documentation related to the event (e.g., cause and course records, clinical laboratory reports, and diagnostic reports) when an AE / SAE occurs.

[0352]

[0381] The investigator then records all relevant AE / SAE information in the eCRF.

[0382] It is not allowed for the principal investigator of the clinical trial to send photocopies of the participants' medical records to the sponsor instead of completing the eCRF.

[0353]

[0383] Copies of medical records may be required from the sponsor in certain circumstances. In this case, all participant identifiers, except for the participant number, are redacted from the copy of the medical record prior to submission to the sponsor.

[0354]

[0384] The principal investigator of the clinical trial attempts to establish a diagnosis of an event based on signs, symptoms, and / or other clinical information. Whenever possible, the diagnosis (not individual signs / symptoms) is documented as an AE / SAE.

[0355] Follow-up Observation of AE and SAE

[0385] The principal investigator of the clinical trial is obliged to perform or arrange for supplementary measurements and / or determinations, as medically necessary or as required by the sponsor, to clarify the nature and / or causality of an AE or SAE as completely as possible. This may include additional clinical tests or investigations, histopathological examinations, or consultations with other healthcare providers.

[0356]

[0386] If a participant dies during the study participation period or the recognized follow-up period, the principal investigator of the clinical trial submits a copy of any autopsy findings, including histopathology, to the sponsor.

[0387] New or updated information is recorded in the originally completed eCRF.

[0357]

[0388] The principal investigator of the clinical trial submits any updated SAE data to the sponsor within 24 hours of receipt of the information. Reporting Procedures for SAE

[0389] The principal investigator of the clinical trial completes an SAE worksheet containing all information required by regional and / or local regulations and submits it to the sponsor by fax or email immediately (within 24 hours of recognition of the event).

[0358]

[0390] The SAE worksheet must be signed by the medically qualified investigator in charge of the trial (as identified by the authority's log). The signature confirms the investigator's assessment of causality, including an explanation of the accuracy and completeness of the SAE data and the assessment of causality.

[0359]

[0391] If the SAE is related to the unblinding by the investigator in charge of the trial as outlined above, this should be recorded on the SAE worksheet. The SAE worksheet should include the circumstances under which the unblinding was carried out in relation to the SAE.

[0360]

[0392] Follow-up information on the event must be sent promptly (as soon as possible but within 7 days of the initial notification).

[0393] Full details of the SAE must be recorded in the medical records and on the SAE / Special Circumstances worksheet.

[0361]

[0394] The following minimum information is required: - International trial number / Trial number - Participant number, gender and age - Date of report - Description of the SAE (criteria for the event and severity) - Causality with the trial intervention (including reasons) - Drugs provided (if any)

[0395] The sponsor or the sponsor's designee shall medically determine the SAE and decide whether the report meets the requirements for prompt reporting (e.g., reporting of SUSAR) based on the severity, causality, and expectations of the event in accordance with the regional / local regulatory requirements at that time. The sponsor or the sponsor's designee shall submit a prompt safety report to the competent authority and the relevant ethics committee in accordance with the regulations of the region at that time and notify the principal investigator of such regulatory reports as necessary. The principal investigator shall submit the safety reports required by the IRB / IEC within the timelines set by local regulations (e.g., EMA, FDA) as necessary. Documentation of the submission of the prompt safety report to the IRB / IEC and receipt by the IRB / IEC shall be maintained at the trial site. In the United States, it shall comply with the FDA's prompt IND reporting guidelines.

[0362]

[0396] The sponsor shall notify all principal investigators who are responsible for continuing the clinical trial for all SUSAR trial interventions and submit to the IRB / IEC / facility head in accordance with regional requirements.

[0363]

[0397] The principal investigator shall provide written documentation of IRB / IEC notification for each report to the sponsor. Reporting Procedures for Pregnancy and Special Situations: Contraception Guidelines and Collection of Pregnancy Information

[0398] Details of all pregnancies of female participants and, if indicated, female partners of male participants shall be collected within 30 days after the start of the trial intervention or discontinuation of dosing.

[0364]

[0399] If a pregnancy is reported, the principal investigator shall record the pregnancy information in the appropriate documents and submit it to the sponsor within 24 hours after becoming aware of the pregnancy of the female participant or the female partner of the male participant (after obtaining the informed consent with the necessary signature from the female partner).

[0365]

[0400] Pregnancy itself is not considered an AE or SAE, but any pregnancy complications or abortions for medical reasons are reported as AEs or SAEs.

[0401] Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and reported as such.

[0366]

[0402] The outcome of pregnancy is determined according to the participant / pregnant female partner. The principal investigator of the clinical trial collects information on the progress of the participant / pregnant female partner and the newborn, and the information is submitted to the sponsor.

[0367]

[0403] Any pregnancy-related SAE reported after the participant's final visit to the trial, which is considered reasonably related to the trial intervention by the principal investigator of the clinical trial, is reported to the sponsor as described above. The principal investigator of the clinical trial has no obligation to actively seek this information for past trial participants / pregnant female partners, but can recognize pregnancy-related SAEs through spontaneous reporting.

[0368]

[0404] Any woman who becomes pregnant while participating in the trial discontinues the trial intervention or withdraws from the trial. Reporting Procedures for Pregnancy and Special Situations: Medication Errors, Overdoses, and "Off-label Use"

[0405] If a medication error (defined as an unintentional failure in the treatment process that causes or has the potential to cause harm to the participant), overdose, or "off-label use" (i.e., use outside the target disease defined in the protocol) is suspected, the principal investigator of the clinical trial must immediately (within 24 hours of recognition) fax or email a special situation worksheet to the sponsor. Any related (S)AE should be reported on the eCRF. If the AE meets the definition of an SAE, the SAE should also be reported as described above, together with the details of the medication error, overdose, and / or "off-label use".

[0369] Reporting Procedures for Pregnancy and Special Situations: Misuse / Abuse

[0406] Definition of misuse: A situation where the trial intervention is intentionally and inappropriately used contrary to the intended use as defined in the protocol.

[0370]

[0407] Definition of abuse: The intentional and excessive use, either continuous or sporadic, of a medicinal product that is accompanied by harmful physical or psychological effects.

[0408] If misuse or abuse of the test intervention is suspected, the investigator responsible for the trial must immediately (within 24 hours of awareness) fax or email a special circumstances worksheet to the sponsor. Any relevant (S)AE must be reported on the eCRF. If the AE meets the definition of an SAE, the SAE must also be reported as described above, together with details of the suspected misuse or abuse of the test intervention.

[0371] Reporting Procedures for Pregnancy and Special Situations: Occupational Exposure

[0409] If an occupational exposure to the test intervention occurs (e.g., accidental exposure of trial facility staff to the test intervention during preparation of administration to participants), the investigator responsible for the trial must immediately (within 24 hours of awareness) fax or email a special circumstances worksheet to the sponsor. Any relevant (S)AE occurring in an individual related to or resulting from the special circumstances must be reported on the special circumstances worksheet.

[0372] Reporting Procedures for Pregnancy and Special Situations: Suspected Drug-Drug Interaction

[0410] If a drug-drug interaction related to the test intervention is suspected, the investigator responsible for the trial must immediately (within 24 hours of awareness) fax or email a special circumstances worksheet to the sponsor. Any relevant (S)AE must be reported on the eCRF. If the AE meets the definition of an SAE, the SAE must also be reported as described above, together with details of the suspected drug-drug interaction.

[0373] Provision of New Information Affecting the Conduct of the Trial

[0411] If new information becomes available that is necessary to enable the proper conduct of the trial, the sponsor must notify all investigators responsible for the trial, as well as the appropriate regulatory authorities. The investigator responsible for the trial must notify the IRB / IEC of such information, if required.

[0374]

[0412] The principal investigator must also notify participants who are required to sign an updated ICF for the trial to continue. Emergency Safety Measures

[0413] USM is an intervention not defined by the protocol and, where applicable, does not require prior approval by the sponsor, the relevant CA, and the IRB / IEC to protect participants from an immediate danger to their health and / or safety and can be used immediately and effectively. Either the principal investigator or the sponsor can initiate USM. The cause of USM can be safety-related, product-related, or procedure-related.

[0375] Reporting of Emergency Safety Measures

[0414] In the event of a potential USM, the principal investigator must contact the trial physician (within 24 hours of awareness). The full details of the potential USM should be recorded in the participant's medical record. The sponsor can request additional information regarding the events that support its determination.

[0376]

[0415] If the event is confirmed to be a USM, the sponsor must take appropriate actions to ensure the safety and well-being of the participants. These actions can include, but are not limited to, changes to the trial procedure or trial intervention, stopping further enrollment in the trial, or stopping the trial altogether. The sponsor or the sponsor's designee must report to the relevant regulatory authorities and the relevant ethics committee within the timeline required by the regulations in that region at that time and notify the principal investigator as necessary. If necessary, the principal investigator must report to the IRB / IEC within the timeline set by the local regulations.

[0377] Appendix 4: Liver Safety Monitoring and Assessment

[0416] The purpose of this appendix is to provide guidance for monitoring drug-induced liver injury during the course of a trial. It should be noted that this section does not specify the end of the test analysis of liver enzymes. The end of the test analysis of liver enzymes is described in the SAP. Any participant enrolled in a trial on active drug therapy in whom an increase in serum AT to >3×ULN or an increase in bilirubin to >2×ULN is evident must undergo a detailed examination of liver enzymes (including at least ALP, ALT, AST, TBL, and INR). The examination should be repeated within 72 hours of notification of the test results. For trials using a central laboratory, warnings are generated by the central laboratory for moderate and severe liver abnormalities and notified to the principal investigator and the trial team. Participants should be questioned if they have any symptoms suggestive of cholestatic liver dysfunction.

[0378] Definition of Liver Abnormality

[0417] Confirmed abnormalities are characterized as moderate and severe if the ULN is as shown in Table 7 below.

[0379]

Table 12

[0380]

[0418] In addition, a participant must be considered to have severe hepatic abnormalities if any of the following apply: - ALT or AST >8×ULN - ALT or AST >5×ULN for more than 2 weeks - ALT or AST >3×ULN and †TBL >2×ULN or INR >1.5 (if an INR test is applicable / judged) - ALT or AST >5×ULN and † (in participants with liver metastases, TBL >2×ULN) - ALT or AST >3×ULN (>5%) accompanied by the appearance of fatigue, nausea, vomiting, right upper abdominal pain or tenderness, fever, rash and / or eosinophilia

[0419] The principal investigator of the clinical trial may determine that abnormal liver function results other than those described above can be regarded as moderate or severe abnormalities and require additional monitoring and follow-up.

[0381] Follow-up Observation Procedures

[0420] Moderate or severe abnormalities identified in liver function must be thoroughly characterized by obtaining appropriate expert consultation, details of the relevant medical history, physical examination, and clinical tests. The personnel of the trial site should complete the LA-CRF. Participants with confirmed abnormal liver function tests should comply with what is described below.

[0382]

[0421] Confirmed moderately abnormal liver function tests need to be repeated at a frequency of 2 - 3 times a week and then once a week or less if the abnormality stabilizes or the trial intervention is interrupted and the participant is asymptomatic.

[0383]

[0422] Severe liver function abnormalities as defined above can be regarded as important medical events and reported as SAEs if no other etiology exists. The sponsor should contact and notify all participants in whom severe liver function abnormalities potentially attributable to the trial intervention are observed.

[0384]

[0423] To further evaluate abnormal clinical findings of the liver, the principal investigator of the clinical trial is expected to: - Obtain a more detailed history of symptoms and pre-existing diseases or complications. Symptoms and newly developed diseases should be recorded as "AE" in the eCRF. Conditions such as hypotensive events, as well as non-compensated heart diseases that can lead to secondary liver abnormalities, should be indicated. NASH is seen in participants with obesity-related hyperlipoproteinemia and / or diabetes and may be associated with fluctuating AT levels. The principal investigator of the clinical trial must ensure that the medical records document any diseases preceding trial enrollment that may be relevant to the evaluation of liver function.

[0385] - Obtain information on the use of concomitant medications (including over-the-counter medications, supplements, and alternative medications), alcohol use, use of recreational drugs, and special diet history. Medications should be entered in the eCRF. Information on alcohol, use of other substances, and diet should be entered in the LA-CRF or appropriate documentation.

[0386] - Obtain a history of exposure to environmental chemicals. - Based on the participant's history, other tests may be appropriate and may include: · Acute viral hepatitis (A, B, C, D, E, or other infectious agents) · Ultrasound or other imaging to evaluate biliary tract disease · Other clinical tests, including INR and direct bilirubin - Consider consultation with a gastroenterologist or hepatologist.

[0387] - Submit the results of any additional tests and possible etiologies from the LA-CRF or appropriate documentation. Interruption of Trial Intervention

[0424] If there is no explanation for elevated liver function tests such as viral hepatitis, pre-existing or acute liver disease, or exposure to other drugs associated with liver injury, the participant may interrupt the study intervention. The principal investigator of the clinical trial may determine that this is not in the best interest of the participant to continue the study intervention. Interruption of the study intervention should be considered in the following cases: - ALT or AST > 8 × ULN - ALT or AST > 5 × ULN for more than 2 weeks - ALT or AST > 3 × ULN and † TBL > 2 × ULN or INR > 1.5 (if the INR test is applicable / determined) - ALT or AST > 5 × ULN and † (for participants with liver metastases, TBL > 2 × ULN) - ALT or AST > 3 × ULN (> 5%) accompanied by the appearance of fatigue, nausea, vomiting, right upper abdominal pain or tenderness, fever, rash, and / or eosinophilia † Samples taken simultaneously or within a maximum of 24 hours.

[0388]

[0425] In addition, if detailed monitoring is not possible for participants with moderate or severe liver clinical tests, the test intervention must be interrupted.

[0426] Jaundice induced by drugs due to hepatocellular injury, without significant obstructive components, has a high probability of having a poor outcome and a mortality rate (or transplantation) of 10% - 50%.

[0389]

[0427] The three "requirements" for Hy's Law are as follows: 1. Evidence that the drug can cause hepatocellular injury, generally indicated by an increase in AT > 3×ULN (an increase of "2×ULN is frequent in identified treated and untreated participants").

[0390] 2. An elevated TBL (at least 2×ULN) accompanied by a concurrent increase in AT of at least 3×ULN and no evidence of intrahepatic or extrahepatic bilirubin obstruction (increase in ALP) or in the case of Dubin - Johnson syndrome [Temple, 2006].

[0391] 3. No other reasons can be found to explain the combined increase in AT and TBL, such as viral hepatitis A, B, or C; pre - existing or acute liver disease; or another drug that can cause the observed disorder.

[0392] Appendix 5: Evaluation of Clinical Tests

[0428] The clinical tests shown in Table 8 below are performed according to the evaluation schedule (Figure 4) and sent to the local laboratory for analysis.

[0393]

Table 13 - 1

[0394]

Table 13 - 2

[0395] Appendix 6: Pharmacogenomic Analysis of Archived Samples Introduction

[0429] The purpose of PGx research is to provide information on how naturally occurring differences in gene expression based on the genes and / or genetic variations of participants can affect which treatment options are optimal for the participants. Through PGx research using techniques such as genotyping, gene sequencing, statistical genetics, and genome-wide association studies, the relationship between gene profiles and the dynamics, efficacy, toxicity, or diseases of interventions can be better understood. Since many diseases can be affected by one or more genetic variations, PGx research can identify which genes are involved in determining whether a participant can respond to a drug or not.

[0396] Purpose

[0430] The obtained blood samples and the PGx research that may be conducted in the future are exploratory. The purpose of this study is to analyze or determine genes related to clinical response, pharmacokinetics and / or toxicity / safety, and / or diseases.

[0397]

[0431] By analyzing genetic variations, it becomes possible to predict the efficacy of individual participants for treatment from the perspectives of efficacy and / or toxicity and / or diseases. Participation of Participants

[0432] Participants who have agreed to participate in this trial will participate in the PGx sub-trial. Participants must provide written consent before providing any blood samples that can be used at a later time for PGx analysis.

[0398] Collection and Storage of Samples

[0433] Participants who agree to participate in this sub-trial will provide a 4 mL sample of whole blood. Each sample is identified by a unique participant number. The samples are shipped to a designated CRO for storage as instructed by the sponsor.

[0399] PGx Analysis

[0434] The details of potential PGx analysis have not yet been established. Sponsors may initiate PGx analysis if evidence suggests that genetic variants may affect the pharmacokinetics, efficacy, and / or safety of the intervention and / or the disease.

[0400] Disposal of PGx Samples / Data

[0435] All collected PGx samples will be stored for a maximum period of 15 years following the test database lock. If no analysis is required, whole blood samples will be destroyed after the planned storage period. Participants have the right to withdraw consent at any time. If a participant's withdrawal notice is received, the PGx samples will be destroyed. Results of any PGx analysis performed on samples prior to a participant's withdrawal will be retained by the sponsor indefinitely, unless otherwise specified by local regulations.

[0401] Disclosure of Information to Participants

[0436] Exploratory PGx analysis, if applicable, may be conducted following the end of the trial. Results of the PGx analysis will not be provided to any trial investigator or participant, nor can the results be requested at a later date. Any information obtained from the PGx analysis is the property of the sponsor.

[0402] Appendix 7: Continuity of Clinical Trials Introduction

[0437] The purpose of this appendix is to provide an acceptable alternative method for appropriately evaluating safety and efficacy parameters in the event that a clinical trial is interrupted at the country, state, facility, or participant level during any crisis (e.g., natural disaster, pandemic).

[0403] Benefit-Risk Rationale

[0438] Maintaining the safety of clinical trial participants and continuing care during a clinical trial is of utmost importance during any crisis. Facilities are expected to follow the protocol and associated evaluation schedule (Figure 4) unless the facility's principal investigator discusses the need with the medical monitor to do otherwise.

[0404]

[0439] The approach outlined in this addendum defines which evaluations are necessary to provide an alternative way that allows participants to maintain the desired benefits / risks, maintain the integrity of the overall study, and complete the evaluations and procedures required for the study when it becomes impossible to conduct the testing activities as described in the above test procedures and evaluation sections due to a crisis.

[0405] Informed Consent

[0440] Participants who need to follow any or all of the alternative means outlined in this addendum are required to provide informed consent that explicitly informs them of the nature and basis of these changes and obtain consent to continue participating in the study before any of these changes occur. If the urgency of conducting an alternative means makes it impossible for the participant to provide written consent prior to implementation, the principal investigator or designee shall document it in writing as soon as practicable after obtaining oral consent from the participant. A separate addendum to the study ICF is provided to document the participant's consent to the changes.

[0406] Evaluation of Participant Procedures

[0441] A facility, including participants enrolled in the clinical trial at that time, may consider conducting an alternative method outlined below if one or more of the following conditions are met due to a crisis: - Local or regional travel is restricted, including mandatory evacuation by appropriate means, making it nearly impossible to travel participants to / from the test facility.

[0407] - The facility is closed for the conduct of the clinical trial. - The facility is restricted to treating patients outside the scope of the study. - The facility's staff has temporarily relocated the conduct of the study to a location that places a burden on participants with respect to time and travel.

[0408] - The participant is temporarily transferred from the current test facility to another test facility to avoid imposing a burden on the participant regarding the travel. - The participant is temporarily transferred from their home location and the new distance from the facility causes an excessive burden regarding time and travel.

[0409] - The participant's travel to the facility has a risk factor that involves additional risks to the participant's health and safety.

[0442] Complying with the unique protocol reflected in the evaluation schedule (Figure 4) is expected in cases of crisis when it seems appropriate. Another means shown in Figure 6 is only allowed after discussing the necessity with the medical monitor for performing another means in the event of a crisis event. This is to enable the continuity of receiving the IP and maintaining the evaluation of clinical safety and effectiveness for the test participants during the crisis.

[0410]

[0443] If one or more of the following alternative means are performed on the participant, the facility should document in the participant's source document the basis for performing the alternative means and the actual alternative means performed along with the corresponding time points.

[0411] Provision of Trial Intervention

[0444] If any of the conditions outlined in the above participant procedure evaluation are met, one or all of the following mitigation strategies should be utilized as necessary to ensure the continuity of the supply of test interventions to the participant: - If the space in the facility allows, increase the inventory of test interventions at the facility to reduce the required number of shipments.

[0412] - Direct-to-participant (DTP) shipment of test interventions from the facility to the participant's home. Requirements for Data Collection

[0445] Additional data can be collected to show how the participation in the test has been affected by the crisis and to adapt the data collection obtained from the alternative means taken to manage the conduct of the test and the safety of the participants.

[0413] - Critical evaluation of safety and effectiveness based on test endpoints identified as deficiencies or modifications (virtually implemented from windows or other changes at alternative positions) due to the crisis.

[0414] Appendix 8: List of Abbreviations and Definitions of Important Trial Terms List of Abbreviations

[0415]

Table 14-1

[0416]

Table 14-2

[0417]

Table 14-3

[0418]

Table 14-4

[0419] Definitions of Important Trial Terms

[0420]

Table 15

[0421] Appendix 9: Monitoring Guidelines for Potential Immune-Related Adverse Events Symptoms of Potential Immune-Related Adverse Events

[0422]

Table 16

[0423] Guidelines Encouraging the Management of Immune-Related Adverse Events

[0424]

Table 17-1

[0425]

Table 17-2

[0426]

Table 17-3

[0427]

Table 17-4

[0428] Appendix 10: Algorithm for the Management of Cytokine Release Syndrome

[0429]

Table 18-1

[0430]

Table 18-2

[0431] Appendix 11: Algorithm for the Management of Immune Effector Cell-Related Neurotoxicity Syndrome

[0432]

Table 19-1

[0433]

Table 19-2

[0434] References

[0446] American Cancer Society. Cancer facts & figures 2020. Atlanta: American Cancer Society; 2020. Available from: https: / / www.cancer.org / content / dam / cancer-org / research / cancer-facts-and-statistics / annual-cancer-facts-and-figures / 2020 / cancer-facts-and-figures-2020.pdf. Accessed on 23 Apr 2021.

[0447] Lanitis E, Dangaj D, Irving M, Coukos G. Mechanisms regulating T-cell infiltration and activity in solid tumors. Ann Oncol. 2017;28:xii18-32.

[0448] Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant 2019;25:625-38.

[0449] Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017;14(8):463-82.

[0450] National Cancer Institute [Internet]. Cancer Statistics; 2018 [cited 2019 Apr 16]. Available from: https: / / www.cancer.gov / about-cancer / understanding / statistics.

[0451] Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55.

[0452] Temple R. Hy’s Law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006;15(4):241-3.

[0453] Wee S, Gu J, Wang C, Cao C, Holzhauer S, Desilva H, et al. Abstract 936: Regulation of CD8+ T-cell function and antitumor activity by DGKα and DGKζ. American Association for Cancer Research (AACR) Annual Meeting 2019 (29 March 03 April 2019); Atlanta Georgia. Available at: https: / / cancerres.aacrjournals.org / content / 79 / 13_Supplement / 936. Accessed 10 May 2021.

[0454] Zhong XP, Guo R, Zhou H, Liu C, Wan CK. Diacylglycerol kinases in immune cell function and self-tolerance. Immunol Rev. 2008;224:249-64.

[0455] Zhou H, Lee JJ, Yuan Y. BOP2: Bayesian optimal design for phase II clinical trials with simple and complex endpoints. Statistics in Medicine. 2017;36(21):3302-14.

Claims

1. Effective amount of compound I 【Chemistry 1】 A pharmaceutical composition for treating patients with advanced and / or metastatic solid tumors, comprising at least one entity selected from pharmaceutically acceptable salts thereof.

2. The pharmaceutical composition according to claim 1, wherein the advanced and / or metastatic solid tumor is selected from skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, and gastric cancer.

3. The pharmaceutical composition according to claim 2, wherein the advanced and / or metastatic solid tumor is selected from melanoma and non-small cell lung cancer.

4. The pharmaceutical composition according to claim 3, wherein the advanced and / or metastatic solid tumor is non-small cell lung cancer.

5. The pharmaceutical composition according to claim 1, wherein the patient satisfies at least one of the following conditions: (a) The patient is considered an adult according to local regulations at the time of treatment; (b) The patient has locally advanced or metastatic solid tumor malignancy, and the malignancy is confirmed by available pathological records or biopsy at that time; (c) The patient has at least one measurable lesion according to the criteria for evaluating the effectiveness of treatment for solid tumors v1.1, and the lesion located in the pre-irradiated area is considered measurable if progression is indicated by such a lesion; (d) The patient has progressed after receiving all approved standard treatments and / or is no longer eligible for standard treatment; (e) The patient has a US East Coast cancer clinical trial group performance status of 0, 1, or 2; (f) The patient's last dose of any prior antineoplastic agent therapy, including any immunotherapy, was at least 21 days prior to the administration of the pharmaceutical composition; however, in the case of patients with solid tumors having a neurotropic receptor tyrosine kinase gene fusion without known acquired resistance mutations, or in the case of patients with NSCLC positive for epidermal growth factor receptor or anaplastic lymphoma kinase mutations, prior treatment with a neurotropic receptor tyrosine kinase inhibitor or epidermal growth factor receptor tyrosine kinase inhibitor or anaplastic lymphoma kinase inhibitor is permissible up to 4 days prior to the administration of the pharmaceutical composition; (g) The patient receiving radiotherapy, including stereotactic radiotherapy, must complete the radiotherapy at least two weeks before the pharmaceutical composition is administered; (h) The patient's adverse events from prior therapy (excluding alopecia) have improved to Grade 1 or baseline within 14 days prior to administration of the pharmaceutical composition; however, patients with type 1 diabetes, endocrine disorders stably maintained with appropriate supplemental therapy, or skin disorders not requiring systemic treatment are permitted; (i) The patient has adequate organ function prior to treatment as indicated by the following laboratory values, but these values ​​must be obtained at least two weeks after any blood transfusion: (i) Neutrophil absolute count level ≥ 1500 / μL; (ii) Platelet level ≥ 100,000 / μL; (iii) Hemoglobin level ≥ 9 g / dL; (iv) Either a creatinine level ≤ upper limit of normal or creatinine clearance ≥ 60 mL / min, calculated using the Cockroft-Gault formula; (v) Total bilirubin level ≤ 1.5 × upper limit of normal; or, for participants with Gilbert's syndrome, either direct bilirubin ≤ upper limit of normal and total bilirubin < 3 × upper limit of normal; (vi) If liver metastases are absent, the levels of aspartate aminotransferase (serum glutamate oxaloacetate transaminase) and alanine aminotransferase (serum glutamate pyruvate transaminase) are ≤2.5 × upper limit of normal, or if liver metastases are present, ≤5 × upper limit of normal; (vii) Serum potassium level ≥ 3.4 mEq / L; (viiii) Serum magnesium level ≥ 1.7 mg / dL; and (ix) Serum ionized calcium level ≥ 4.7 mg / dL; (j) The patient has an activated partial thromboplastin time and an international normalized ratio ≤ 1.5 × upper limit of normal, and is not receiving anticoagulation; (k) If the patient is a woman assigned at birth, she is not pregnant and at least one of the following conditions applies: (i) The patient is a woman who is not capable of becoming pregnant; (ii) The patient is a woman of childbearing potential who agrees to follow contraceptive guidance during the administration of the pharmaceutical composition and for at least 30 days after the end of administration; (l) If the patient is a female assigned at birth, she agrees not to breastfeed during the period from the start of screening, while the pharmaceutical composition is administered, and for at least 30 days after the end of administration; (m) If the patient is a woman assigned at birth, she shall not provide eggs during the administration of the pharmaceutical composition and for at least 30 days after the end of administration; (n) If the patient is a male assigned at birth and has one or more female partners who may become pregnant (including a breastfeeding partner), he agrees to use contraception while the pharmaceutical composition is administered and for at least 30 days after administration; (o) If the patient is a male assigned at birth, he shall not provide sperm during the administration of the pharmaceutical composition and for at least 30 days after the end of administration; (p) If the patient is a male assigned at birth and has one or more pregnant partners, he agrees to continue abstinence during the pregnancy or to use condoms during the administration of the pharmaceutical composition and for at least 30 days after the end of administration; or, (q) The patient agrees not to participate in any other intervention study while the pharmaceutical composition is administered.

6. The pharmaceutical composition according to claim 1, wherein a patient is excluded from administration of the pharmaceutical composition if any of the following conditions are met: (a) The patient has received any investigational drug therapy (excluding, as applicable, an epidermal growth factor receptor tyrosine kinase inhibitor used by patients with epidermal growth factor receptor activating mutations, an anaplastic lymphoma kinase inhibitor used by patients with anaplastic lymphoma kinase mutations, or a neurotropic receptor tyrosine kinase inhibitor used by patients with solid tumors having a neurotropic receptor tyrosine kinase gene fusion without known acquired resistance mutations); (b) The patient requires or is receiving systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to the administration of the pharmaceutical composition; however, patients using physiological replacement doses of hydrocortisone or its equivalent are permitted; (c) The patient requires a potent or moderate CYP2D6 inhibitor while the pharmaceutical composition is administered; (d) The patient requires a potent CYP3A4 inhibitor while the pharmaceutical composition is administered; (e) The patient has evidence of symptomatic central nervous system metastases, or asymptomatic but unstable central nervous system metastases; however, patients with pre-treated central nervous system metastases are eligible if they are clinically stable, have no evidence of central nervous system progression on imaging for at least four weeks prior to administration of the pharmaceutical composition, and do not require systemic steroid immunosuppressant administration for up to two weeks, wherein the systemic steroid immunosuppressant administration includes more than 30 mg of hydrocortisone per day or more than 10 mg of prednisone per day or an equivalent; (f) The patient has an active autoimmune disease; however, patients with type 1 diabetes, endocrine disorders that are stably maintained with appropriate replacement therapy, or skin disorders that do not require systemic treatment are acceptable; (g) The patient discontinued prior immunomodulatory therapy due to drug-related grade ≥ 3 toxicity; (h) The patient is known to have HIV infection; however, HIV patients with a CD4+ T cell count of ≥350 cells / μL and no history of opportunistic infections that would determine AIDS within the past six months are eligible; (i) The patient has one of the following according to screening serological tests: (i) Hepatitis A virus antibodies; (ii) Positive hepatitis B surface antigen or detectable hepatitis B DNA; however, patients with negative HBsAg, positive hepatitis B core antibody, and negative hepatitis B surface antibody are eligible only if hepatitis B DNA is undetectable; (iii) Hepatitis C virus antibodies unless hepatitis C virus RNA is undetectable. (j) The patient has received a live vaccine against an infectious disease within 28 days prior to the administration of the pharmaceutical composition; (k) The patient has a history of drug-induced pneumonitis, or currently has pneumonitis, or has a prior history of interstitial lung disease or non-infectious pneumonitis requiring high doses of glucocorticoids, regardless of whether the pneumonitis has resolved or not; (l) The patient has had an infection requiring systemic therapy within 14 days prior to the administration of the pharmaceutical composition; (m) The patient has previously received an allogeneic bone marrow or parenchymal organ transplant; (n) The patient is expected to require another form of antineoplastic therapy while the pharmaceutical composition is being administered; (o) The patient has had a myocardial infarction or unstable angina within six months prior to the administration of the pharmaceutical composition, or has an uncontrolled illness that currently limits compliance with the treatment; (p) The patient has poorly controlled hypertension, and the poorly controlled hypertension includes a systolic blood pressure greater than 150 and / or a diastolic blood pressure greater than 100 mmHg under the influence of antihypertensive drugs; (q) The patient has a corrected QT interval using the Friderician formula of more than 450 ms prior to the administration of the pharmaceutical composition; (r) The patient has another malignant lesion requiring active therapy, excluding locally treatable malignant lesions; (s) The patient has undergone a major surgical procedure and has not fully recovered within 28 days prior to the administration of the pharmaceutical composition; (t) The patient has a history of bleeding tendencies; (u) The patient requires the use of anticoagulant therapy; (v) The patient has been previously treated with a DGK inhibitor; (w) The patient has a known or suspected hypersensitivity to at least one entity.

7. The pharmaceutical composition according to claim 1, wherein at least one entity is in the form of a pharmaceutically acceptable solvate, a mixed solvate, or a complex.

8. The pharmaceutical composition according to claim 1, wherein at least one entity is in the form of an amorphous solid.

9. The pharmaceutical composition according to claim 1, wherein at least one entity is in the form of a crystalline solid.

10. The pharmaceutical composition according to claim 1, wherein at least one entity is compound I.

11. The pharmaceutical composition according to claim 1, wherein at least one entity is selected from pharmaceutically acceptable salts of compound I.

12. The pharmaceutical composition according to claim 11, wherein at least one entity is selected from the HCl salt, mesylate, succinate, L-malate, L-tartrate, and fumarate of compound I.

13. The pharmaceutical composition according to claim 12, wherein at least one entity is a succinate of compound I.

14. The pharmaceutical composition according to claim 13, wherein the succinate of compound I is the monosuccinate of compound I.

15. The pharmaceutical composition according to claim 12, wherein at least one entity is the L-malate of compound I.

16. The pharmaceutical composition according to claim 15, wherein the L-malate of compound I is the mono-L-malate of compound I.

17. The pharmaceutical composition according to claim 15, wherein the L-malate of compound I is the hemi-L-malate of compound I.

18. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains dose equivalents of compound I in amounts of about 5 mg, about 10 mg, about 30 mg, about 60 mg, about 100 mg, about 150 mg, or about 200 mg.

19. A compound I in the manufacture of a pharmaceutical product for treating a patient having an advanced and / or metastatic solid tumor. 【Chemistry 2】 and use of at least one entity selected from its pharmaceutically acceptable salts.

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