Methods for Treating Small Cell Lung Cancer

Abstract

Methods of treating small cell lung cancer (SCLC) with a WEE1 inhibitor are provided.

Description

[Technical field]

[0001] The present invention generally relates to the treatment of small cell lung cancer (SCLC). More specifically, the present invention relates to the use of a WEE1 inhibitor for treating small cell lung cancer (SCLC) in patients in need thereof. [Background technology]

[0002] Lung cancer is the most common cancer worldwide, with approximately 2.2 million new cases and 1.8 million deaths in 2020, making it the second most common cancer and the most common cause of cancer-related mortality. The World Health Organization (WHO) classifies lung cancer into two major classes based on biology, treatment, and prognosis: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC accounts for approximately 15% of newly diagnosed lung cancers. SCLC is an aggressive, high-grade neuroendocrine tumor with short doubling times, high proliferation fractions, and early onset of widespread metastases, contributing to extremely poor survival outcomes. At the time of diagnosis, approximately one-third of patients with SCLC have localized disease (LD-SCLC), with tumors confined to the ipsilateral chest, mediastinum, and supraclavicular nodes, while two-thirds of patients have more extensive widespread disease (ED-SCLC), with an even worse prognosis. Patients diagnosed with LD-SCLC have a median survival of less than two years, while patients diagnosed with ED-SCLC have a median survival of less than one year.

[0003] Combination chemotherapy is currently considered the standard first-line therapy for ED-SCLC. Surgery and / or chemoradiotherapy are standard options for LD-SCLC. Platinum-based chemotherapy, including platinum drugs such as cisplatin or carboplatin, in combination with other agents such as etoposide or irinotecan, is the most common chemotherapy regimen for a period of 4 to 6 months. More recently, immunotherapy (e.g., atezolizumab, durvalumab), in combination with standard chemotherapy, may be incorporated as part of the first-line therapy for some patients and may become one of the potential standard treatments. Unfortunately, despite the initial high response rates to first-line chemotherapy, long-term survival is rare, as patients generally progress or relapse to first-line therapy (relapse rate of approximately 90%).

[0004] Second-line therapy, i.e., the treatment options available to patients with SCLC who relapse or progress after first-line therapy, varies depending on the time of failure from standard first-line platinum-based chemotherapy. Patients whose SCLC relapses, regresses, or progresses during treatment or within 90 days after the last dose of platinum therapy have limited treatment options in the second line. Such patients can receive other chemotherapy such as topotecan, lurbinectedin (as of February 2022, available in the United States only under accelerated approval by the U.S. Food and Drug Administration), sometimes CAV (cyclophosphamide, doxorubicin, also known as adriamycin, vincristine) treatment, and potentially immunotherapy. Patients whose SCLC relapses, regresses, or progresses more than 90 days after the last dose of platinum therapy can benefit from the above treatment options in addition to rechallenge with platinum-based chemotherapy treatment. Even with second-line therapy, survival of patients with recurrent SCLC remains limited.

[0005] SCLC may also present high mutation burden and genomic instability. WEE1 tyrosine kinase is activated upon DNA damage and regulates G2-M and S-phase cell cycle checkpoints. Inhibiting WEE1 in DNA repair pathways, such as by genetic modification and / or combined use with DNA damaging agents, leads to mitotic catastrophe and apoptosis in cancer cells, providing an attractive approach for cancer treatment. However, preliminary data in different patient populations of SCLC show limited antitumor activity of the WEE1 inhibitor adavosertib, for example in combination with olaparib (Non-Patent Document 1) or in combination with carboplatin in platinum-refractory SCLC (Non-Patent Document 2). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Li B et al, Abstract 1785P, ESMO 2020-Annals of Oncology(2020)31(suppl_4):S974-S987.10.1016 / annonc / annonc290 [Non-Patent Document 2] BALTIC study,Arm B,NCT02937818 Summary of the Invention [Problem to be solved by the invention]

[0007] This aspect of SCLC disease and patient population, and the limited success of current available standard therapies, have highlighted the medical need for the development of new treatments for SCLC. [Means for solving the problem]

[0008] The present invention relates to a WEE1 inhibitor for use in the treatment of small cell lung cancer (SCLC) in a patient in need thereof or for the preparation of a medicament therefor, and to a method of treating SCLC in a patient in need thereof comprising administering a therapeutically effective amount of a WEE1 inhibitor. In one embodiment of the use or method according to the invention, the WEE1 inhibitor has the following formula (I):

[0009] [ka] or a pharma- ceutically acceptable salt thereof.

[0010] In other embodiments, the WEE1 inhibitor is any compound described in WO 2018 / 090939, WO 2022 / 155202, WO 2022 / 256680, WO 2013 / 126656, and WO 2008 / 153207, each of which is fully incorporated by reference herein. Specifically, the WEE1 inhibitor has the following formula:

[0011] [ka] AZD-1775 (adavosertib);

[0012] [ka] Zn-C3 (azenosertib);

[0013] [ka] IMP7068 (described in WO 2018 / 090939);

[0014] [ka] STC-8123 (described in WO 2022 / 155202);

[0015] [ka] ATRN-W1051 (described in International Publication No. 2022 / 256680)

[0016] [ka] PD0407824;

[0017] [ka] CJM061;

[0018] [ka] SC0191;

[0019] [ka] PD0166285;

[0020] [ka] (as described in WO 2013 / 126656), or

[0021] [ka] (described in WO 2008 / 153207) or a pharma- ceutically acceptable salt thereof. In a particularly preferred embodiment of the uses and methods according to the invention, the WEE1 inhibitor is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In the same or another embodiment of the use or method according to the invention, the WEE1 inhibitor is combined with carboplatin and / or etoposide. The WEE1 inhibitor may also be combined with carboplatin and etoposide.

[0022] In one embodiment of the uses or methods according to the invention, the SCLC has recurred or progressed after a first or previous SCLC treatment, for example, the SCLC has recurred or progressed 45 days or more since the last dose of standard platinum-based therapy, or 90 days or more since the last dose of standard platinum-based therapy. In one embodiment of the use or method according to the invention, the patient has not undergone any previous treatment for SCLC. In one embodiment of the uses or methods according to the invention, the WEE1 inhibitor is administered orally. In one embodiment of the uses or methods according to the invention, the WEE1 inhibitor is administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle. In one embodiment of the use or method according to the invention, the WEE1 inhibitor is administered at a dose ranging from 150 to 720 mg per treatment day. For example, the WEE1 inhibitor may be administered at a dose ranging from 100 to 520 mg per treatment day.

[0023] In one embodiment of the uses or methods according to the invention, the WEE1 inhibitor is administered at about the same time on each treatment day, for example, at the same time ± about 60 minutes, preferably ± 60 minutes, on each treatment day. In one embodiment of the use or method according to the invention, the WEE1 inhibitor is administered after fasting, preferably 4 hours. In the same or other embodiment, the WEE1 inhibitor administration may be after fasting, preferably 2 hours.

[0024] In one embodiment of the uses or methods according to the invention, etoposide is administered by infusion. For example, etoposide is administered on days 1, 2, and 3 of a 21 day cycle. When administered by infusion, etoposide is administered at a dose of 70-100 mg / m per infusion. 2 in the range of 100 mg / m 2 may be administered at a dose of In one embodiment of the use or method according to the invention, etoposide is administered at 100-200 mg / m on days 1-5 of a 21-day cycle. 2When administered orally, etoposide is also administered at doses ranging from 100 to 200 mg / m on days 1 to 5 of every 3 to 4 weeks. 2 / day, or 200 mg / m on days 1, 3, and 5 every 3 to 4 weeks. 2 / day. In one embodiment of the uses or methods according to the invention, carboplatin is administered by infusion at a dose corresponding to an AUC ranging from 2-6 mg / ml x min, preferably 5 mg / ml x min, for example according to the Calvert Formula. Carboplatin may be administered on day 1 of a 21 day cycle. In some embodiments of the uses or methods according to the invention, administration of the WEE1 inhibitor is administered prior to administration of etoposide and / or carboplatin on the day of WEE1 inhibitor treatment. For example, on the day of WEE1 inhibitor treatment, etoposide administration is initiated about 5 minutes to 1 hour after administration of the WEE1 inhibitor. For example, on the day of WEE1 inhibitor treatment, carboplatin administration is initiated about 5 minutes to 1 hour after administration of the WEE1 inhibitor or after etoposide administration has ended.

[0025] In certain embodiments of the uses or methods according to the invention, the WEE1 inhibitor is administered for 1, 2, 3, 4, 5, 6 or more cycles.

[0026] The present invention also relates to a pharmaceutical composition comprising a WEE1 inhibitor, in particular a compound of formula (I), for use in the treatment of small cell lung cancer (SCLC) in a patient in need thereof, or for use in the preparation of a medicament therefor. The present invention also relates to a kit comprising a WEE1 inhibitor, particularly a compound of formula (I), for use in treating small cell lung cancer (SCLC) in a patient in need thereof, or for use in preparing a medicament therefor. In an embodiment, the kit comprises a WEE1 inhibitor, particularly a compound of formula (I), and instructions for use in treating SCLC, particularly according to the uses and methods described herein. The present invention also relates to etoposide, or a pharma- ceutically acceptable salt thereof, for use in the treatment of small cell lung cancer (SCLC) in a patient in need thereof, or for use in the preparation of a medicament therefor, wherein etoposide is in combination with a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and, optionally, carboplatin, preferably wherein the uses are as further described herein. The present invention also relates to carboplatin, or a pharma- ceutically acceptable salt thereof, for use in the treatment of small cell lung cancer (SCLC) in a patient in need thereof, or for use in the preparation of a medicament therefor, wherein carboplatin is in combination with a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and, optionally, etoposide, or a pharma- ceutically acceptable salt thereof, preferably wherein the uses are as further described herein. Hereinafter, an embodiment of the present invention will be described with reference to the drawings. [Brief description of the drawings]

[0027] [Figure 1] FIG. 2 shows Bliss synergy scores over a dose range between the compound of formula (I) (0-10 μM) and carboplatin (0-300 μM) in the in vitro assay described in Example 1. [Diagram 2] FIG. 1 shows the mean tumor volume as a function of time for each treatment group in the CDX in vivo model described in Example 2 where a compound of formula (I) is administered alone or in combination with carboplatin. [Diagram 3] FIG. 1 shows the mean tumor volume as a function of time for each treatment group in the CDX in vivo model described in Example 2 where a compound of formula (I) is administered alone or in combination with etoposide. [Figure 4] FIG. 1 shows the mean tumor volume as a function of time for each treatment group in the CDX in vivo model described in Example 2, where a compound of Formula (I) is administered alone, in combination with etoposide, or in combination with carboplatin and etoposide. [Diagram 5]FIG. 1 shows the mean tumor volume as a function of time for each treatment group in the CDX in vivo model described in Example 3 where a compound of formula (I) is administered alone or in combination with carboplatin. [Figure 6] FIG. 1 shows the mean tumor volume as a function of time for each treatment group in the PDX in vivo model described in Example 4 where a compound of formula (I) is administered alone or in combination with etoposide. [Figure 7] FIG. 2 is a study diagram showing the dosing schedule of the triple combination of compound of formula (I), carboplatin and etoposide in the dose escalation (DE) and expansion part of the clinical trial described in Example 5b. [Figure 8] FIG. 1 shows Bliss synergy scores over a range of doses between compound of formula (I) and carboplatin / etoposide in five SCLC organoid models as described in Example 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The present invention relates to WEE1 inhibitors for use in the treatment of SCLC in patients in need thereof. In one embodiment, the present invention provides a method for the treatment of SCLC in a patient in need thereof, comprising administering to the patient a compound of formula (I):

[0029] [ka] The present invention relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. The present invention also relates to methods for treating SCLC in patients in need thereof with a compound of formula (I), or a pharma- ceutically acceptable salt thereof, including combination treatments as described herein. Any disclosure of the use of a WEE1 inhibitor in the treatment of SCLC may be understood as relating to a method of treating SCLC, and vice versa.

[0030] The compound of formula (I) was found to synergize with carboplatin and etoposide in vitro and significantly induce cell death. In vivo, the compound of formula (I) is effective in significantly improving SCLC tumor growth inhibition in monotherapy, in combination with either carboplatin or etoposide, or in combination with both carboplatin and etoposide. For example, the compound of formula (I) significantly improved the tumor growth inhibition effect of etoposide and carboplatin in PDX and CDX models of SCLC in vivo. Also, the triple combination of carboplatin, etoposide, and the compound of formula (I) significantly improved tumor response when compared to carboplatin and etoposide treatment alone or the double combination of the compound of formula (I) with either carboplatin or etoposide. The compound of formula (I) was also well tolerated in either monotherapy or combination.

[0031] 《Definition》 So that the present invention may be more readily understood, certain terms are specifically defined below. Unless expressly defined elsewhere herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art. As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" (sic) also refer to their corresponding plurals unless the context clearly and explicitly dictates otherwise. Whenever the term "comprising" is used in an embodiment, it is understood that other similar embodiments in which the terms "consisting of" and / or "consisting essentially of" are also provided. As used herein, the term "and / or" in a statement such as "A and / or B" is intended to include both "A and B," "A or B," "A" and "B." Similarly, the term "and / or" in a statement such as "A, B, and / or C" is intended to encompass each of the following embodiments: A or C; A or B; A and C; A and B, B and C, A (alone), B (alone), C (alone).

[0032] The term "WEE1 inhibitor" as used herein refers to a compound that inhibits the activity of WEE1 kinase, for example, with an IC50 of <10 nM in an ADP-GLO kinase assay or an IC50 of <100 nM in an enzyme profiling assay.

[0033] The phrase "pharmaceutical acceptable salts" used herein when referring to a compound of formula (I) refers to salts prepared from pharmaceutical acceptable non-toxic acids, including inorganic or organic acids. For example, quaternary salts, acetates, carbonates, carbamates, sulfonates, strong inorganic acids, and other acceptable salts derived from acids. In general, pharmaceutical acceptable salts can be used to modify the solubility or hydrolysis properties of a compound, or in sustained release formulations. It will be understood that the term "compound of formula (I)" used herein is intended to include pharmaceutical acceptable salts, unless otherwise specified.

[0034] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., who is to be the recipient of a particular treatment. In general, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects.

[0035] As used herein, administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order. As used herein, the terms "treating" or "treatment" or "to treat" or "palliating" or "to alleviate" and the like refer to therapeutic measures that cure, slow, alleviate the symptoms, and / or halt or reverse the progression or severity of a diagnosed condition, disorder, or disease. Thus, those in need of treatment include those already diagnosed with a disorder or those suspected of having a disorder. In certain embodiments, a subject is successfully "treated" for cancer by the methods of the invention if the patient exhibits one or more of the following: a reduction or complete absence of cancer cell number; a reduction in tumor size or tumor burden; an inhibition or absence of cancer cell invasion into peripheral organs; an inhibition or absence of tumor metastasis; an inhibition or absence of tumor growth; an alleviation of one or more symptoms associated with a particular cancer; a reduction in morbidity and mortality; an improvement in quality of life; a reduction in the tumorigenicity, tumorigenic frequency, or tumorigenic potential of a tumor; a reduction in the number or frequency of cancer stem cells in a tumor; differentiation of tumor-forming cells to a non-tumorigenic state; and an increased chance of a complete response (CR), partial response (PR), an increased chance of controlling the disease (e.g., CR, PR, stable disease SD), an increased chance of not progressing and surviving longer without disease, a reduced chance of progressing disease (PD), and an increased time to progression. For a group or population of patients collectively, successful treatment improves an endpoint, such as overall response rate (ORR), best overall response (BOR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), time to progression (TTP), or any combination thereof. As used herein, the term "SCLC treatment" refers to any treatment or therapy approved by at least one health authority, such as the FDA or EMA, or under clinical trial investigation for treating SCLC. "Primary SCLC treatment" refers to the first SCLC treatment administered to a given patient diagnosed with SCLC. "Prior" or "prior SCLC treatment" refers to one or more SCLC treatments administered to a given patient diagnosed with SCLC prior to the method of the present invention. As used herein, the term "standard platinum-based (chemo)therapy" refers to the current standard of care (e.g., first-line) therapy for SCLC, i.e., platinum drugs such as cisplatin or carboplatin in combination with other drugs commonly used for these regimens, e.g., etoposide or irinotecan. Such "standard platinum-based therapy" may also be used as a second-line therapy, e.g., when a previous first-line therapy with additional agents, such as immunotherapy, has been used.

[0036] As used herein, the terms "recur", "recurrent", and the like when referring to SCLC or a patient afflicted therewith, refer to a worsening of the disease and / or signs and symptoms of the disease after a period of improvement, stabilization, or absence of disease. As used herein, the term "progression" or "progressing" when referring to SCLC or a patient afflicted therewith, means when the cancer gets worse due to existing lesions growing and / or due to the appearance of new lesions. As used herein, the term "treatment day" or "WEE1 inhibitor treatment day" refers to the day on which a WEE1 inhibitor is administered according to the methods of the present invention.

[0037] The term "therapeutically effective amount" as used herein refers to an amount of drug effective to "treat" a disease or disorder in a subject or patient. In the case of cancer, a therapeutically effective amount of drug can reduce the number of cancer cells; reduce tumor size or tumor mass; inhibit (i.e., slow to a certain extent, and in certain embodiments, stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow to a certain extent, and in certain embodiments, stop) tumor metastasis; inhibit tumor growth to a certain extent; alleviate to a certain extent one or more symptoms associated with cancer; and / or produce a favorable response, such as an increase in overall response rate (ORR), best overall response (BOR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR) rate, partial response (PR) rate, or in some cases stable disease (SD) rate, a decrease in progressive disease (PD), an increase in time to tumor progression (TTP), or any combination thereof. See the definition of "treatment" herein.

[0038] In one embodiment, the term "therapeutically effective amount" of a given drug when used in monotherapy, such as "therapeutically effective amount of WEE1", "therapeutically effective amount of carboplatin", or "therapeutically effective amount of etoposide", refers to an amount of drug effective to "treat" a disease or disorder in a subject or patient while maintaining an acceptable safety profile. In one embodiment, when a WEE1 inhibitor and carboplatin are administered in combination, the therapeutically effective amount may be referred to as a "WEE1 carbo combined therapeutically effective amount" and a "carboplatin combined therapeutically effective amount", respectively. In one embodiment, when a WEE1 inhibitor and etoposide are administered in combination, the therapeutically effective amount may be referred to as a "WEE1 inhibitor etoposide combined therapeutically effective amount" and a "etoposide combined therapeutically effective amount", respectively. In some embodiments, when a WEE1 inhibitor, carboplatin, and etoposide are administered in combination, the therapeutically effective amounts may be referred to as "WEE1 triple combination therapeutically effective amount", "carboplatin triple combination therapeutically effective amount", and "etoposide triple combination therapeutically effective amount", respectively. When the WEE1 inhibitor is a compound of formula (I), the "WEE1 therapeutically effective amount" of the compound of formula (I) when administered as a monotherapy may be different from the "WEE1 carbo combination therapeutically effective amount", and may be different from the "WEE1 etopo combination therapeutically effective amount", and may be different from the "WEE1 triple combination therapeutically effective amount" of the compound of formula (I) when administered in combination. Similar considerations apply to the therapeutically effective amounts of carboplatin and etoposide, depending on whether they are used in monotherapy, in combination with the compound of formula (I), or in a triple combination. Similar considerations apply to other WEE1 inhibitors or combinations thereof.In the case of cancer, a therapeutically effective amount of a drug may reduce the number of cancer cells; reduce tumor size or tumor mass; inhibit (i.e., slow to a certain extent, and in certain embodiments, stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow to a certain extent, and in certain embodiments, stop) tumor metastasis; inhibit tumor growth to a certain extent; alleviate to a certain extent one or more symptoms associated with cancer; and / or result in a favorable response, such as an increase in overall response rate (ORR), best overall response (BOR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR) rate, partial response (PR) rate, or in some cases stable disease (SD) rate, a decrease in progressive disease (PD), an increase in time to tumor progression (TTP), or any combination thereof. See the definition of "treatment" herein.

[0039] The term "RECIST v1.1" or "RECIST 1.1 criteria" as used herein refers to "New response evaluation criteria in solid tumours, Revised RECIST guideline (version 1.1)" set out in Eisenhauer EA et al., European Journal of Cancer 45 (2009) 228-247. It should be understood that a revised version of the RECIST guideline may be issued in the future. As used herein, the term "progression-free survival" (PFS) in clinical trials refers to the time from enrollment, first dose, or randomization to the first occurrence of disease progression or death from any cause. PFS is generally measured using RECIST 1.1 criteria and is generally summarized using the Kaplan-Meier method. As used herein, the term "time to tumor progression" (TTP) in clinical trials refers to the time from enrollment, first dose, or randomization to disease progression. TTP is generally measured using RECIST 1.1 criteria. As used herein, the term "complete response" or "complete remission" or "CR" in clinical trials refers to the absence of detectable evidence of tumor responding to treatment. This does not necessarily mean that cancer has been cured. Complete response in solid tumors such as SCLC is generally measured using RECIST 1.1 criteria. As used herein, the term "partial response" or "PR" in a clinical trial refers to a reduction in the size or volume of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment according to RECIST 1.1 criteria. As used herein, the term "stable disease" or "SD" in clinical trials refers to disease without progression or recurrence. Stable disease does not involve sufficient tumor shrinkage to be considered a partial response, nor sufficient tumor growth to be considered progressive disease based on the smallest combined diameter during the study. Generally, it is measured using RECIST 1.1 criteria.

[0040] As used herein, the term "progressive disease" or "PD" in a clinical trial or study refers to the appearance of one or more new lesions or tumors, and / or overt progression of existing target and / or non-target lesions, and / or at least a 20% increase in the sum of the diameters of the target lesions based on the minimum sum on the study (which includes the baseline sum, if it is the minimum on the study). In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5. (Note: the appearance of one or more new lesions also counts as progression). Generally measured using RECIST 1.1 criteria.

[0041] As used herein, the term "response rate" refers to the proportion of subjects in a study, clinical trial, or treatment group that responds partially or completely to a treatment, generally as measured using RECIST 1.1 criteria. The term "overall response" or "response" as used herein refers to the response of a given patient to treatment in a study, clinical trial, or treatment group at a given endpoint, generally as measured using RECIST 1.1 criteria. The term "best overall response" as used herein refers to the best response recorded for a given patient in a study, clinical trial, or treatment group from baseline assessment (enrollment, initiation of treatment, or randomization) to disease progression / recurrence (the minimum measurement recorded since the start of treatment is taken as the reference for progressive disease) or death from any cause. Generally, it is measured using RECIST 1.1 criteria. As used herein, the term "disease control rate" refers to the proportion of patients in a study, clinical trial, or treatment group who achieve a complete response, partial response, or stable disease to a therapeutic intervention, generally measured using RECIST 1.1 criteria. As used herein, the term "duration of response" (DoR) refers to the time from an earlier response (PR or better) to disease progression or death from any cause. Generally, it is measured using RECIST 1.1 criteria.

[0042] As used herein, the term "overall survival" (OS) in a clinical trial refers to the time from patient enrollment, first treatment administration, or randomization to death from any cause or discontinuation to the date of last known survival. Improved OS includes an increase in life expectancy compared to naive or untreated individuals or patients. Overall survival refers to the situation in which a patient remains alive for a defined period of time, such as 1 year, 5 years, etc., from the time of randomization or first treatment. The term "pharmaceutical formulation" or "pharmaceutical composition" as used herein refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. As used herein, the term "oral dosage form" refers to any form of a pharmaceutical composition suitable for oral administration.

[0043] Treatment method In one embodiment of the present invention, a WEE1 inhibitor is used in the treatment of SCLC as a monotherapy. In another embodiment of the invention, a WEE1 inhibitor is used in combination with carboplatin for the treatment of SCLC. In yet another embodiment of the invention, a WEE1 inhibitor is used in combination with etoposide for the treatment of SCLC. In yet another embodiment of the invention, a WEE1 inhibitor is used in combination with carboplatin and etoposide for the treatment of SCLC. In any one of the embodiments of the invention described herein, the WEE1 inhibitor has the following formula (I):

[0044] [ka] or a pharma- ceutically acceptable salt thereof. In certain embodiments of the methods of the invention, the SCLC has recurred or progressed after a first or previous SCLC treatment. In certain embodiments of the methods of the invention, the SCLC has recurred or progressed after a previous SCLC treatment. In a more specific embodiment, the SCLC has recurred or progressed 45 days or more since the last dose of standard platinum-based therapy. In other more specific embodiments, the SCLC has recurred or progressed 90 days or more since the last dose of standard platinum-based therapy. In yet another more specific embodiment, the SCLC has recurred or progressed 180 days or more since the last dose of standard platinum-based therapy. In an alternative embodiment, the patient has not undergone any previous treatment for SCLC. In one embodiment, the treatment methods according to the invention exhibit favorable properties of prolonged anti-tumor activity (e.g., ORR, BOR, DOR and / or DCR) and / or time to event (e.g., PFS and / or OS) in SCLC, e.g., as assessed by RECIST v1.1, with an acceptable safety profile and no adverse impact on patient quality of life, e.g., compared to rechallenge with platinum-based chemotherapy.

[0045] Dosage, Schedule and Route of Administration WEE1 inhibitors In the methods of the invention, the WEE1 inhibitor is used in a therapeutically effective amount for the intended purpose, which amount can vary depending, for example, on whether the WEE1 inhibitor is used as a monotherapy or in combination with etoposide, carboplatin, or both. In certain embodiments, a therapeutically effective amount of WEE1, a therapeutically effective amount of WEE1 carbo combination, a therapeutically effective amount of WEE1 etopo combination, or a therapeutically effective amount of WEE1 triple combination can be administered. As used below, the term "about" describes a deviation from the indicated value of ±10%. Individual values ​​can be understood as describing a range between any of the stated values.

[0046] WEE1 inhibitors may generally be administered at dosages ranging from about 10 to about 1000 mg of the free base per treatment day, preferably from about 100 to about 720 mg of the free base per treatment day. In embodiments of the invention where the WEE1 inhibitor is a compound of formula (I), the compound of formula (I) may be administered at a dose ranging from about 30 to about 1000 mg of the free base per treatment day, preferably from about 90 to about 720 mg, or from about 100 to about 720 mg of the free base, and even more preferably from about 100 to about 520 mg of the free base per treatment day. For example, the compound of formula (I) may be administered at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 130, about 150, about 200, about 220, about 250, about 260, about 300, about 320, about 350, about 360, about 400, about 420, about 450, about 460, about 500, about 520, about 550, about 600, about 620, about 650, about 700, about 720, about 750, about 800, about 820, about 850, about 900, about 920, about 950 or about 1000 mg of the free base per treatment day. Preferably, the compound of formula (I) may be administered at a dose of 30, 60, 75, 90, 100, 120, 130, 150, 200, 220, 250, 260, 300, 320, 350, 360, 400, 420, 450, 460, 500, 520, 550, 600, 620, 650, 700, 720, 750, 800, 820, 850, 900, 920, 950 or 1000 mg of the free base per treatment day. In more specific embodiments, the compound of formula (I) may be administered at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550 or about 720 mg of free base per treatment day. Preferably, the compound of formula (I) may be administered at a dose of 30, 60, 75, 90, 100, 120, 150, 200, 250, 260, 300, 350, 360, 400, 450, 460, 500, 520, 550 or 720 mg of free base per treatment day. In other specific embodiments, the compound of formula (I) may be administered at a dose of about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 520, about 550, about 600, about 620, about 650, about 700, about 720, about 750, about 800, about 820, about 850, about 900, about 920, about 950 or about 1000 mg of free base per treatment day. In more specific embodiments, the compound of formula (I) may be administered at a dose of about 100, about 150, about 200, about 300, about 400 or about 520 mg of free base per treatment day. In a preferred embodiment of the present invention where the WEE1 inhibitor is a compound of formula (I), the compound of formula (I) can be administered at a dose ranging from 100 to 1000 mg of free base per treatment day, preferably from 150 to 720 mg of free base per treatment day. For example, the compound of formula (I) can be administered at a dose of 100, 150, 200, 250, 300, 350, 400, 450, 500, 520, 550, 600, 620, 650, 700, 720, 750, 800, 820, 850, 900, 920, 950 or 1000 mg of free base per treatment day. In a more specific embodiment, the compound of formula (I) can be administered at a dose of 100, 150, 200, 300, 400, 520 or 720 mg of free base per treatment day. In certain embodiments of the invention, the WEE1 inhibitor is administered orally. In certain embodiments of the invention, the WEE1 inhibitor is administered as a single dose per treatment day (QD) or two doses per treatment day (BID).

[0047] In one embodiment, the WEE1 inhibitor is administered on days 1, 2, and 3 of a 21-day cycle. In another embodiment of the invention, the WEE1 inhibitor is administered on days 1, 2, and 3 and days 8, 9, and 10 of a 21-day cycle. In one embodiment, when the WEE1 inhibitor, particularly the compound of formula (I), is administered on days 1, 2, and 3 and days 8, 9, and 10 of a 21-day cycle, in some cases, the WEE1 inhibitor, particularly the compound of formula (I), can be administered only on days 1, 2, and 3 of the subsequent 21-day cycle. This change in the number of days of administration can be advantageous, particularly when a patient develops side effects on days 1, 2, and 3 and days 8, 9, and 10 of administration. In certain embodiments, the WEE1 inhibitor can be administered at the doses per treatment day listed above on days 1, 2, and 3 of a 21 day cycle. In certain embodiments, the WEE1 inhibitor can be administered at the doses per treatment day listed above on days 1, 2, 3 and days 8, 9, and 10 of a 21 day cycle. In these embodiments, the WEE1 inhibitor may be administered for 1, 2, 3, 4, 5, 6 or more cycles. In general, there may be a break between any successive cycles, i.e., the first day of the successive cycle may be the day after the previous 21-day cycle. In some aspects, treatment with a WEE1 inhibitor, such as a compound of formula (I), may continue until disease progression, unacceptable toxicity, patient decision to stop, physician decision to discontinue, initiation of subsequent anti-neoplastic treatment, completion of clinical trial, or death.

[0048] In certain embodiments of the invention, the WEE1 inhibitor is administered at about the same time on each treatment day, e.g., in a given cycle, for example, about ±60 minutes, preferably ±60 minutes, on each treatment day. In a more specific embodiment, the WEE1 inhibitor is administered in the morning, e.g., between 5:00 a.m. and noon. In one embodiment of the invention, the WEE1 inhibitor is administered after the patient has fasted, preferably for at least 4 hours. In the same or other embodiments, the fasting is preferably for at least 2 hours following administration of the WEE1 inhibitor. In an alternative embodiment of the uses and methods according to the present invention, the WEE1 inhibitor is administered in the fed state. In yet another alternative embodiment of the use or method according to the invention, the WEE1 inhibitor is administered regardless of the food status of the patient.

[0049] Etoposide In certain embodiments of the methods of the invention, etoposide is used in a therapeutically effective amount for its intended purpose, which amount can vary depending on, for example, whether it is used in combination with a WEE1 inhibitor alone or with a WEE1 inhibitor and carboplatin. In certain embodiments, a therapeutically effective amount of etoposide, a combination therapeutically effective amount of etoposide, or a triple combination therapeutically effective amount of etoposide may be administered. In certain embodiments, the etoposide may be administered on the same day as the WEE1 inhibitor, for example on the same day of a 21 day cycle of the WEE1 inhibitor, or on a different schedule as defined below.

[0050] In one embodiment of the invention, etoposide is administered by intravenous (IV) infusion. In a more specific embodiment, etoposide is administered on days 1, 2, and 3 of a 21-day cycle. When administered by IV infusion, etoposide is administered at a dose of 70-100 mg / m per infusion. 2 , preferably 100 mg / m 2 It may be administered at

[0051] In an alternative embodiment of the invention, etoposide is administered orally. In a more specific embodiment, etoposide is administered at a dose of 100-200 mg / m on days 1-5 of a 21 day cycle. 2 In an alternative more specific embodiment, etoposide is administered at doses ranging from 100 to 200 mg / m on days 1 to 5 of every 3 to 4 weeks. 2 / day, or 200 mg / m on days 1, 3, and 5 every 3 to 4 weeks 2 It is administered at a dose of / day. In certain embodiments, it may be desirable to express the amount of etoposide administered in mg per day of treatment. In such embodiments, the daily dose is expressed as the mg / m 2 / day and the patient's body surface area (BSA), which can be calculated using methods known to those skilled in the art, such as the Du Bois method (see, e.g., Dubois D, Dubois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916; 17: 863-871) or the Mosteller formula (see, e.g., Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987; 317: 1098). Of course, in certain embodiments, etoposide may be used in the form of a pharma- ceutically acceptable salt (such as, but not limited to, etoposide phosphate), in which case the dosage, amount or concentration references herein for etoposide, which are references for the free base, may be appropriately adapted taking into account the molecular weight of the respective salt.

[0052] Carboplatin In certain embodiments of the methods of the present invention, carboplatin is used in a therapeutically effective amount for its intended purpose, which amount may vary depending on, for example, whether it is used in combination with a WEE1 inhibitor alone or with a WEE1 inhibitor and etoposide. In certain embodiments, a therapeutically effective amount of carboplatin, a combination therapeutically effective amount of carboplatin, or a triple combination therapeutically effective amount of carboplatin can be administered. In certain embodiments of the invention, carboplatin is administered by intravenous (IV) infusion. In a more specific embodiment, carboplatin is administered on day 1 of a 21-day cycle.

[0053] In one embodiment, carboplatin is administered by IV infusion at a dose corresponding to an AUC in the range of 2-6 mg / ml x min, preferably 5 mg / ml x min, according to the Calvert formula. The Calvert formula generally determines the optimal carboplatin dosage, and can be easily determined by one skilled in the art. Since the bone marrow toxicity and clinical efficacy of carboplatin are inversely correlated with the clearance of the drug, which correlates with the glomerular filtration rate (GFR), the dosing of this drug is more accurate by considering the GFR, compared to dosing based only on the patient's body surface area. The GFR, i.e., the clearance of carboplatin, is different for each patient, regardless of body region. As a result, some patients will have a higher systemic exposure (expressed as the area under the plasma concentration / time curve (AUC)) than others when the dose of carboplatin is given based on the body surface area. A higher AUC correlates with increased toxicity, thus increasing the risk of treatment, whereas a lower AUC reduces the efficacy of treatment. This indicates that individual dosing strategies may be advantageous to obtain an optimal AUC. Using the Calvert formula, the carboplatin dose can be accurately calculated to achieve the target AUC. To determine the dosage of carboplatin, the Calvert formula shown below may be used. Dose (mg) = Target AUC (mg / ml x min) x [GFR*ml / min + 25ml / min] *GFR is the glomerular filtration rate, which can be estimated by calculating creatinine clearance, for example, using the Cockcroft-Gault formula. The Cockcroft-Gault formula for estimating creatinine clearance (CrCl) is: CrCl (male) = ([140-age] x weight (kg)) / (serum creatinine x 72) That is correct. GFR can also be estimated using the 2021 CKD / EPI creatinine equation. It is expressed as a single expression. eGFRcr = 142 × min(Scr / κ,1)α × max(Scr / κ,1)-1.200 × 0.9938 age × 1.012 [for women] where Scr = normalized serum creatinine (mg / dL) κ = 0.7 (females) or 0.9 (males) α = -0.241 (female) or 0.302 (male) min(Scr / κ,1) is the minimum value of Scr / κ, i.e., 1.0. max(Scr / κ,1) is the maximum value of Scr / κ, which is 1.0 Age (years) The factor 1.012 applies only to female subjects. The 2021 CKD / EPI creatinine equation is described, for example, on the Internet page of the National Kidney Foundation, and further information is cited in Levey AS, et al., Ann Intern Med. 2009; 150(9): 604-612; Levey AS, Stevens LA., Am J Kidney Dis. 2010; 55(4): 622-627; Matsushita K, et al., Am J Kidney Dis. 2010; 55(4): 648-659; White SL, et al., Am J Kidney Dis. 2010; 55(4): 660-670; and Becker BN, et al., Am J Kidney Dis. 2009; 55(1): 8-10. In embodiments in which carboplatin is administered at a dose corresponding to an AUC in the range of 2-3 mg / ml×min, carboplatin may be administered on a more frequent schedule, such as weekly in a 21 day cycle. For example, carboplatin may be administered at a dose corresponding to an AUC in the range of 2-3 mg / ml×min on days 1, 8, and 15 of a 21 day cycle.

[0054] Combination therapy including a WEE1 inhibitor In certain embodiments of the invention in which a WEE1 inhibitor is combined with etoposide and / or carboplatin, the WEE1 inhibitor is administered prior to administration of etoposide and / or carboplatin on the day of WEE1 inhibitor treatment. In one embodiment, on the day of WEE1 inhibitor treatment, etoposide administration is initiated about 5 minutes to 1 hour, preferably about 5 to 30 minutes, and more preferably about 5 to 15 minutes, after WEE1 inhibitor administration. In one embodiment of the invention, on the day of WEE1 inhibitor treatment, carboplatin administration is initiated about 5 minutes to 1 hour after WEE1 inhibitor administration or, preferably, about 5 to 30 minutes after etoposide administration has ended.

[0055] In some combination embodiments, dexamethasone and / or granisetron may be administered as antiemetic prophylaxis prior to administration of any treatment. For example, dexamethasone and / or granisetron may be administered on days 1, 2, and 3 of each cycle prior to administration of the WEE1 inhibitor. In one embodiment of the invention, the combination of a WEE1 inhibitor with either carboplatin or etoposide, or both, shows synergistic effects in the treatment of SCLC. In any of the above combination embodiments, the WEE1 inhibitor may be a compound of formula (I). In particular, in some embodiments, the combination of a compound of formula (I) with either carboplatin or etoposide has an acceptable safety profile and exhibits synergistic effects in the treatment of SCLC. In some embodiments, the triple combination of a compound of formula (I) with carboplatin and etoposide has an acceptable safety profile and exhibits synergistic effects in the treatment of SCLC.

[0056] As used below, the term "about" describes a deviation from the indicated value of ±10%. The individual values ​​may be understood as describing a range between any of the stated values. In all of the following aspects of the uses or methods according to the invention where the WEE1 inhibitor is a compound of formula (I), the administered dose of the compound of formula (I) ranges from about 30 to about 1000 mg of the free base, preferably from about 90 to about 720 mg, or from about 100 to about 720 mg of the free base, and even more preferably from about 100 to about 520 mg of the free base per day of treatment. For example, the compound of formula (I) may be administered at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 130, about 150, about 200, about 220, about 250, about 260, about 300, about 320, about 350, about 360, about 400, about 420, about 450, about 460, about 500, about 520, about 550, about 600, about 620, about 650, about 700, about 720, about 750, about 800, about 820, about 850, about 900, about 920, about 950 or about 1000 mg of the free base per treatment day. Preferably, the compound of formula (I) may be administered at a dose of 30, 60, 75, 90, 100, 120, 130, 150, 200, 220, 250, 260, 300, 320, 350, 360, 400, 420, 450, 460, 500, 520, 550, 600, 620, 650, 700, 720, 750, 800, 820, 850, 900, 920, 950 or 1000 mg of the free base per treatment day.

[0057] In all the following embodiments of the use or method according to the present invention, where the WEE1 inhibitor is a compound of formula (I), the compound of formula (I) can be preferably administered at a dose of about 30, about 60, about 75, about 90, about 100, about 120, about 150, about 200, about 250, about 260, about 300, about 350, about 360, about 400, about 450, about 460, about 500, about 520, about 550 or about 720 mg of free base per treatment day. Preferably, the compound of formula (I) can be administered at a dose of 30, 60, 75, 90, 100, 120, 150, 200, 250, 260, 300, 350, 360, 400, 450, 460, 500, 520, 550 or 720 mg of free base per treatment day. In all the following aspects of the use or method according to the present invention, where the WEE1 inhibitor is a compound of formula (I), the compound of formula (I) may be administered at a dose of about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 520, about 550, about 600, about 620, about 650, about 700, about 720, about 750, about 800, about 820, about 850, about 900, about 920, about 950 or about 1000 mg of free base per treatment day, more preferably. In more specific embodiments, the compound of formula (I) may be administered at a dose of about 100, about 150, about 200, about 300, about 400, about 520 or about 720 mg of free base per treatment day. In even more specific embodiments, the compound of formula (I) may be administered at a dosage of about 100, about 150, about 200, about 300, about 400 or about 520 mg of the free base per treatment day. In all the following aspects of the use or method according to the invention, where the WEE1 inhibitor is a compound of formula (I), the compound of formula (I) may be administered in a dose of 100-1000 mg of free base, preferably 150-720 mg of free base, per treatment day, particularly preferably. For example, the compound of formula (I) may be administered in a dose of 100, 150, 200, 250, 300, 350, 400, 450, 500, 520, 550, 600, 620, 650, 700, 720, 750, 800, 820, 850, 900, 920, 950 or 1000 mg of free base per treatment day. In a more specific embodiment, the compound of formula (I) may be administered in a dose of 100, 150, 200, 300, 400, 520 or 720 mg of free base per treatment day. In even more specific embodiments, the compound of formula (I) may be administered at doses of 100, 150, 200, 300, 400 or 520 mg of the free base per treatment day.

[0058] In one embodiment of the use or method according to the invention, the combination treatment schedule or regimen with etoposide comprises the following alternative or supplementary items: a) a WEE1 inhibitor administered on days 1, 2, and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered on days 1, 2, and 3 of a 21 day cycle, preferably by intravenous (IV) infusion; b) a compound of formula (I) administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered on days 1, 2 and 3 of a 21 day cycle, preferably by intravenous (IV) infusion; c) a WEE1 inhibitor administered on days 1, 2, and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered on days 1, 2, and 3 of a 21 day cycle, preferably by intravenous (IV) infusion, wherein The WEE1 inhibitor is administered at a dose of about 10 to 1000 mg, preferably about 100 to about 720 mg of free base per treatment day; d) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, preferably by intravenous (IV) infusion, in combination with etoposide administered on days 1, 2, and 3 of a 21 day cycle, wherein the compound of formula (I) is administered in a dosage as defined herein, preferably at a dosage of about 100 to about 720 mg of the free base per treatment day; e) A compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Etoposide is 70-100 mg / m per injection. 2 , preferably 100 mg / m 2 is administered at a dose of; f) a compound of formula (I) administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9 and 10 of a 21 day cycle, in combination with etoposide, preferably administered orally on days 1 to 5 of a 21 day cycle; g) a compound of formula (I) administered on days 1, 2 and 3 of a 21 day cycle or on days 1, 2, 3 and 8, 9 and 10 of a 21 day cycle in combination with etoposide, preferably administered orally, on days 1 to 5 of a 21 day cycle, wherein The compound of formula (I) is administered in dosages as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day; h) the co-administration of a compound of formula (I) administered on days 1, 2 and 3 of a 21 day cycle or on days 1, 2, 3 and 8, 9 and 10 of a 21 day cycle with etoposide, preferably administered orally on days 1 to 5 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Etoposide: 100-200 mg / m 2 Administered at doses ranging from 1 mg / day; i) a compound of formula (I) administered on days 1, 2 and 3 of a 21-day cycle or on days 1, 2, 3 and 8, 9 and 10 of a 21-day cycle, preferably orally at 100 to 200 mg / m on days 1 to 5 every 3 to 4 weeks 2 / day, or 200 mg / m on days 1, 3, and 5 every 3 to 4 weeks 2 / day, wherein The compound of formula (I) is administered in dosages defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day; It can be defined as follows:

[0059] In one embodiment of the use or method according to the invention, the combination treatment schedule or regimen with carboplatin is as follows: p) administration of a WEE1 inhibitor administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with carboplatin administered on day 1 of a 21 day cycle, preferably by intravenous (IV) infusion; q) a compound of formula (I) administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with carboplatin administered on day 1 of a 21 day cycle, preferably by intravenous (IV) infusion; r) a WEE1 inhibitor administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, and 10 of a 21 day cycle in combination with carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The WEE1 inhibitor is administered at a dose of about 10 to 1000 mg, preferably about 100 to about 720 mg of free base per treatment day; s) the administration of a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, and 10 of a 21 day cycle in combination with carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in dosages defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day; t) the administration of a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, and 10 of a 21 day cycle in combination with carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Etoposide is administered at 70-100 mg / m per injection. 2 , preferably 100 mg / m 2 is administered at a dose of; u) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, 10 of a 21 day cycle in combination with carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Carboplatin is administered at a dose corresponding to an AUC (area under the curve) in the range of 2-6 mg / ml x min, preferably 5 mg / ml x min, according to the Calvert formula; v) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Etoposide is administered at 70-100 mg / m per injection. 2 , preferably 100 mg / m 2 is administered at a dose of; Carboplatin is administered at a dose corresponding to an AUC in the range of 2-3 mg / ml × min using the Calvert formula; w) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Carboplatin is administered at a dose corresponding to an AUC in the range of 2-3 mg / ml × min using the Calvert formula; x) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Etoposide is administered at 70-100 mg / m per injection. 2 , preferably 100 mg / m 2 is administered at a dose of; Carboplatin is administered at a dose corresponding to an AUC in the range of 2-3 mg / ml × min using the Calvert formula; It can be defined as follows:

[0060] In one embodiment of the use or method according to the invention, the triple combination treatment schedule or regimen using etoposide and carboplatin when administered by intravenous (IV) infusion comprises the following alternative or supplementary items: y) a WEE1 inhibitor administered on days 1, 2, and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle, and carboplatin administered, preferably by intravenous (IV) infusion, on day 1 of a 21 day cycle; z) a compound of formula (I) administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2 and 3 of a 21 day cycle, and carboplatin administered, preferably by intravenous (IV) infusion, on day 1 of a 21 day cycle; aa) a WEE1 inhibitor administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2 and 3 of a 21 day cycle, and carboplatin administered, preferably by intravenous (IV) infusion, on day 1 of a 21 day cycle, wherein The WEE1 inhibitor is administered at a dose of about 10 to 1000 mg, preferably about 100 to about 720 mg of free base per treatment day; bb) a compound of formula (I) administered on days 1, 2 and 3 of a 21 day cycle, or on days 1, 2, 3 and 8, 9 and 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2 and 3 of a 21 day cycle, and carboplatin administered, preferably by intravenous (IV) infusion, on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in dosages defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day; cc) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle, and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Etoposide is 70-100 mg / m per injection. 2 , preferably 100 mg / m 2 is administered at a dose of; dd) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or days 1, 2, 3, and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle, and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day; and Carboplatin is administered at a dose corresponding to an AUC (area under the curve) in the range of 2-6 mg / ml x min, preferably 5 mg / ml x min, according to the Calvert formula; ee) a compound of Formula (I) administered on days 1, 2, and 3 of a 21 day cycle, or days 1, 2, 3, and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle, and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day; Etoposide is 70-100 mg / m per injection. 2 in the range of 100 mg / m 2 and Carboplatin is administered according to the Calvert formula at a dose corresponding to an AUC (area under the curve) in the range of 2-6 mg / ml x min, preferably 5 mg / ml x min; ff) a compound of formula (I) administered on days 1, 2, and 3 of a 21 day cycle or on days 1, 2, 3, 8, 9, and 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle, and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in a dosage as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day, and Carboplatin was administered at a dose corresponding to an AUC in the range of 2-3 mg / ml × min according to the Calvert formula; gg) a compound of Formula (I) administered on days 1, 2, and 3 of a 21 day cycle or days 1, 2, 3, and 8, 9, 10 of a 21 day cycle, in combination with etoposide administered by intravenous (IV) infusion on days 1, 2, and 3 of a 21 day cycle, and carboplatin administered by intravenous (IV) infusion on day 1 of a 21 day cycle, wherein The compound of formula (I) is administered in dosages as defined herein, preferably in a dosage of about 100 to about 720 mg of the free base per treatment day; Etoposide is 70-100 mg / m per injection. 2 in the range of 100 mg / m 2 and Carboplatin is administered according to the Calvert formula at doses corresponding to an AUC in the range of 2-3 mg / ml × min; It can be defined as follows:

[0061] Other WEE1 inhibitors may be substituted for the compound of formula (I). Thus, in certain embodiments, the combination treatment schedule or regimen follows any of the embodiments a)-gg), but instead of the compound of formula (I), a WEE1 inhibitor (any WEE1 inhibitor, particularly the specific WEE1 inhibitors specified above) is used, as exemplified in embodiments a), c), j), l), p), r), y), and aa). In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), wherein the SCLC has relapsed or progressed after a first SCLC treatment (second line treatment). In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), wherein the SCLC has relapsed or progressed after a previous SCLC treatment. In one embodiment, the combination treatment schedule or regimen is for SCLC that has recurred or progressed 45 days or more since the last dose of standard platinum-based therapy. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), wherein the SCLC has recurred or progressed 90 days or more since the last dose of standard platinum-based therapy. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), and the SCLC has relapsed or progressed 180 days or more since the last dose of standard platinum-based therapy. In one embodiment, the combination treatment schedule or regimen is according to any one of the embodiments a) to gg), and the patient has not received any previous SCLC treatment (first line treatment). In certain embodiments, the combination treatment schedule or regimen according to any one of embodiments a)-gg) exhibits advantageous properties in increasing anti-tumor activity (e.g., ORR, BOR, DOR and / or DCR as assessed according to RECIST v1.1) and / or time to event (e.g., PFS and / or OS as assessed according to RECIST v1.1) in SCLC, with an acceptable safety profile and no adverse impact on patient quality of life, e.g., compared to rechallenge with platinum-based chemotherapy. In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a) to gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered as a single dose per treatment day (QD) or two doses per treatment day (BID). In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a) to gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered on days 1, 2, and 3 of a 21-day cycle. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a) to gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered on days 1, 2, 3 and days 8, 9, 10 of a 21-day cycle. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a) to gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered for 1, 2, 3, 4, 5, 6 or more 21-day cycles. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a) to gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered at about the same time on each treatment day, e.g., at about the same time ± about 60 minutes, preferably ± 60 minutes, e.g., in a given cycle. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered in the morning, e.g., between 5:00 and 12:00 noon. In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a) to gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered after the patient has fasted, preferably for at least 4 hours, or is administered in a fed state. In the same or other embodiments, the fasting is preferably for at least 2 hours following administration of the WEE1 inhibitor. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a) to gg), where etoposide and / or carboplatin are administered on a WEE1 inhibitor treatment day, administration of the WEE1 inhibitor precedes administration of etoposide and / or carboplatin on said WEE1 inhibitor treatment day. In one embodiment, according to any one of embodiments a) through gg), the combination treatment schedule or regimen is such that on a WEE1 inhibitor treatment day, when etoposide is administered on said WEE1 inhibitor treatment day, etoposide administration begins about 5 minutes to 1 hour, preferably about 5 to 30 minutes, and more preferably about 5 to 15 minutes, after WEE1 inhibitor administration. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a) through gg), where carboplatin and / or etoposide are administered on the WEE1 inhibitor treatment day, carboplatin administration begins about 5 minutes to 1 hour after WEE1 inhibitor administration or, preferably about 5 to 30 minutes after etoposide administration has ended. In certain embodiments, according to any one of embodiments a) through gg), the combination treatment schedule or regimen may include dexamethasone and / or granisetron administered as antiemetic prophylaxis prior to administration of any therapeutic agent. For example, dexamethasone and / or granisetron may be administered on days 1, 2, and 3 of each cycle prior to administration of the WEE1 inhibitor. In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a) through gg), wherein the WEE1 inhibitor, eg, a compound of Formula (I), is administered orally. In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a) through gg), wherein the compound of Formula (I) is administered orally via a capsule as described herein. In one embodiment, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), wherein the WEE1 inhibitor, e.g., a compound of Formula (I), is administered orally at a dosage of 100-520 mg of free base per treatment day. In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), wherein the WEE1 inhibitor, eg, a compound of Formula (I), is administered orally on an empty stomach. In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a)-e) or p)-x), where on a WEE1 inhibitor treatment day, when etoposide is administered on said WEE1 inhibitor treatment day, the etoposide is administered at 100 mg / m 2 It is administered at a dose of 0.001 mg / kg / day, with the infusion period lasting 30 minutes to 1 hour. In one embodiment, the triple combination treatment schedule or regimen is according to any one of embodiments p) through x), wherein carboplatin is administered at a dose based on AUC 5 mg / mL·min with an infusion starting within 30 minutes after the end of the etoposide infusion, and the infusion duration of carboplatin is between 30 minutes and 1 hour. In certain embodiments, the combination treatment schedule or regimen is according to any one of embodiments a)-gg), and the treatment duration is until disease progression, unacceptable toxicity, or participant withdrawal, whichever occurs first. In certain embodiments, the patient to be treated is characterized by one or more of the inclusion and / or exclusion criteria identified in Examples 5a and / or 5b.

[0062] Pharmaceutical Compositions The pharmaceutical composition of the present invention suitable for oral administration (oral dosage form) can be provided in solid or liquid form. Suitable solid oral dosage forms include capsules, tablets, powders, or granules, each containing a predetermined amount of active ingredient. Suitable liquid oral dosage forms include solutions, emulsions, or suspensions. The pharmaceutical composition of the present invention can also be in the form of a sustained release formulation.

[0063] Any inert ingredient commonly used as a carrier or diluent can be used as a pharma- ceutically acceptable excipient in the solid oral formulations of the present invention, such as gums, starches, sugars, cellulosic materials, acrylates, or mixtures thereof. Preferred diluents include, for example, microcrystalline cellulose, anhydrous lactose. The composition may further comprise a disintegrant (e.g., croscarmellose sodium, sodium starch glycolate) and a lubricant (e.g., magnesium stearate), and may further comprise one or more additives selected from a binder (e.g., hydroxypropylcellulose), a glidant (e.g., silicon dioxide), a buffer (e.g., citric acid), a surfactant (e.g., tween 80), a solubilizer (e.g., cyclodextrin), a plasticizer (e.g., triacetin), an emulsifier (e.g., sodium lauryl sulfate), a stabilizer (e.g., povidone, ascorbic acid), a thickener (e.g., hydroxypropylmethylcellulose), a sweetener (e.g., sucrose), a film former (e.g., cellulosic, polymeric), a colorant (e.g., iron oxide), a flavoring, or any combination thereof.

[0064] The oral pharmaceutical composition of the present invention can be prepared by any pharmaceutical method, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, together with any one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0065] WEE1 inhibitors In one embodiment of the present invention, the WEE1 inhibitor is formulated in a pharmaceutical composition that is an oral dosage form.In a more specific embodiment, the WEE1 inhibitor is in the form of a solid oral dosage form, such as a tablet or capsule (which may include powder or mini-tablet).The capsule may be a soft capsule or a hard capsule. For example, the WEE1 inhibitor is formulated in a capsule, such as a hard gelatin capsule, containing mini-tablets, each mini-tablet containing 10 mg of active ingredient. In an embodiment, the WEE1 inhibitor is a compound represented by formula (I). The following capsule strengths may be available: 20, 30, 60, 100, 130, 150 and 200 mg of active ingredient (free base). Intermediate capsule strengths can be easily manufactured to cover other dosage levels.

[0066] In some embodiments, the solid oral dosage form is packaged in a blister and / or bottle. In some embodiments, 1, 2, 3, 4, 5 or 6 unit dosage forms are administered per intake of the WEE1 inhibitor. Preferably, 1 or 2 unit dosage forms (multiple) are administered per intake of the WEE1 inhibitor. For example, when formulated as a capsule containing mini-tablets, the excipients in each mini-tablet may include microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium starch glycolate, anhydrous colloidal silica, and magnesium stearate. Alternative excipients may be used in oral dosage forms.

[0067] Etoposide In one embodiment of the present invention, etoposide is formulated in a pharmaceutical composition that is a concentrated solution for injection. In a more specific embodiment, etoposide is in the form of a 20mg / ml concentrated solution for injection, such that each 5ml vial contains 100mg of etoposide, each 10ml vial contains 200mg of etoposide, each 12.5ml vial contains 250mg of etoposide, each 20ml vial contains 400mg of etoposide, each 25ml vial contains 500mg of etoposide, and each 50ml vial contains 1000mg of etoposide. For example, a 20 mg / ml concentrated solution of etoposide for injection contains benzyl alcohol and absolute ethanol, excipients with known effects. In concentrated etoposide solutions for infusion embodiments, the complete list of excipients may include anhydrous citric acid, benzyl alcohol, polysorbate 80, macrogol 300, and absolute ethanol. Alternative excipients may be used in solutions that are bioequivalent.

[0068] In another embodiment of the present invention, etoposide is formulated into a pharmaceutical composition that is an oral dosage form. In a more specific embodiment, the pharmaceutical composition containing etoposide is a soft capsule. For example, each capsule may contain 50 mg of etoposide, as well as sodium ethyl parahydroxybenzoate (E215) and sodium propyl parahydroxybenzoate (E217), excipients with known effects. Alternative excipients may be used in oral dosage forms that are bioequivalent. In an embodiment of a soft etoposide capsule, the capsule may contain citric acid, anhydrous (E330), macrogol 400 (E1521), glycerol (85%) (E422) and water (purified). The capsule shell may contain glycerol (85%) (E422), gelatin (E441), sodium ethyl parahydroxybenzoate (E215), sodium propyl parahydroxybenzoate (E217), titanium dioxide (E171) and red iron oxide (E172). Alternative excipients may be used in oral dosage forms that are bioequivalent.

[0069] In one embodiment of the invention, an oral dosage form, such as a solid oral dosage form, may incorporate both a compound of formula (I) and etoposide as active ingredients. Of course, in certain embodiments, etoposide may be used in the form of a pharma- ceutically acceptable salt (e.g., but not limited to, etoposide phosphate), in which case the dosage, amount or concentration indications herein for etoposide, which are indications for the free base, may be appropriately adapted taking into account the molecular weight of the respective salt.

[0070] Carboplatin In one embodiment of the invention, carboplatin is formulated as a solution for intravenous (IV) infusion, hi a more specific embodiment, the solution is a 10 mg / ml solution of carboplatin for injection. For example, the infusion solution may include carboplatin and water for injection. At the time of use, the carboplatin solution for injection can be further diluted with glucose 5% and administered as an intravenous infusion, or the carboplatin solution for injection can be further diluted with sodium chloride 0.9% and administered as an intravenous infusion. ***

[0043] Embodiments of the present disclosure may be further defined and illustrated by reference to the following non-limiting examples. For example, it will be apparent to those skilled in the art that numerous modifications or variations to the materials and methods described may be practiced without departing from the scope of the present disclosure. EXAMPLES

[0071] In vitro synergistic effect of compound of formula (I) in combination with carboplatin in SCLC cell line NCI-H446 NCI-H446 tumor cells were plated in 96-well plates at a density of 5000 cells / 90 μl. Cells were treated with the compound of formula (I) and / or carboplatin alone or in combination with nine different doses (3-fold serial dilutions starting at 10 μM for the compound of formula (I) and 300 μM for carboplatin) for 72 hours. Viability was then assessed by the CellTiter-Glo viability assay, and the synergy of the drug combination at each dose was calculated using the Bliss synergy method (e.g., Foucquier et al., 2015, Pharma Res Per, 3(3), 2015, e00149, doi:10.1002 / prp2.149; original reference Bliss CI, Annals of Applied Biology, Volume 26, Issue 3, August 1939, Pages 585-615), where a score >5 demonstrates synergy of the combination. These in vitro studies demonstrate that compounds of formula (I) in combination with carboplatin provide potent synergistic antitumor activity (increased tumor cell death) over a wide range of doses (Figure 1). A similar synergistic effect was also observed in vitro with etoposide. EXAMPLES

[0072] In vivo efficacy and tolerability in the NCI-H1048 cell line-derived xenograft (CDX) model Female Balb / c nude mice were 6 NCI-H1048 SCLC tumor cells were inoculated subcutaneously. 3 Animals were randomized when the 100% CI of the compound of formula (I) was reached. Animals were treated with vehicle (0.5% methylcellulose, 1% Tween 80 PO and saline IV), compound of formula (I) (30 mg / kg QD, PO) formulated as a suspension in 0.5% methylcellulose and 1% Tween 80, carboplatin (50 mg / kg QW, IV) or etoposide (25 mg / kg or 12.5 mg / kg QW, IP) administered alone or in combination over a 21-day cycle (8 animals per group in double combination studies; 10 animals per group in triple combination studies). In the combination arm, compound of formula (I) was administered 2 hours before chemotherapy. Tumor growth was monitored twice weekly by caliper measurements and tumor volume was calculated using the formula V=(L×W×W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). During regular monitoring, animals were checked for tumor growth and any effect of treatment on behavior such as mobility, food and water consumption, weight gain / loss three times a week, eye / hair matting, and any other abnormalities. Mortality and observed clinical signs were recorded for individual animals. No significant weight loss was observed during the study, indicating that administration of a compound of formula (I) as monotherapy, in combination with carboplatin, in combination with etoposide, or in a triple combination was well tolerated. In this replicate of the NCI-H1048 tumor model, single agent (monotherapy) treatment with the compound of formula (I) resulted in a moderate but significant tumor growth inhibition (TGI) of up to 54% (p=0.016; see, e.g., Figures 2 and 3). Combination treatment of the compound of formula (I) with either carboplatin (Figure 2) or etoposide (Figure 3) resulted in significant antitumor activity with a TGI of approximately 68% (p=0.0026) and 78% (p=0.00015), respectively, compared to vehicle controls. Furthermore, treatment of NCI-H1048 tumors with the compound of formula (I), carboplatin (50 mg / kg) and etoposide (12.5 mg / kg) also resulted in significant antitumor activity, resulting in a TGI of 72% compared to vehicle control (p<0.0001) and a TGI of 44% when compared to tumors treated with the combination of carboplatin and etoposide, thus demonstrating a significant improvement in the antitumor activity of the triple combination (compound of formula (I), carboplatin and etoposide) compared to the standard of care carboplatin+etoposide treatment (p=0.0043) (FIG. 4). Thus, the triple combination of carboplatin, etoposide and a compound of formula (I) was well tolerated and resulted in significantly improved tumor responses when compared with carboplatin and etoposide treatment alone or the double combination. EXAMPLES

[0073] In vivo efficacy and tolerability in the NCI-H446 CDX model Female Balb / c nude mice were 6 NCI-H446 SCLC tumor cells were inoculated subcutaneously. 3Animals were randomized when the tumor volume reached 100 mg / kg / day. Animals were treated with vehicle (0.5% methylcellulose, 1% Tween 80 PO and saline IV), compound of formula (I) formulated as a suspension in 0.5% methylcellulose and 1% Tween 80 (30 mg / kg QD, 3 consecutive days per week, PO), or carboplatin (50 mg / kg QW, IV) administered alone or in combination over a 16-day cycle (5 animals per group). In the combination arm, compound of formula (I) was administered 2 hours before chemotherapy. Tumor growth was monitored twice weekly by caliper measurement, and tumor volume was calculated using the formula V=(L×W×W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). During regular monitoring, the animals were checked for tumor growth and any effects of treatment on behavior such as mobility, food and water consumption, weight gain / loss three times a week, matting of eyes / fur, and any other abnormalities. Mortality and observed clinical signs were recorded for each individual animal. No significant weight loss was observed during the study and the combination of the compound of formula (I) and carboplatin was well tolerated. In this NCI-H446 model, treatment with either the compound of formula (I) or carboplatin in monotherapy did not result in a significant TGI effect compared to vehicle. However, the combination of the compound of formula (I) and carboplatin treatment resulted in a statistically significant TGI of 67% compared to vehicle (p=0.028) (Figure 5). EXAMPLES

[0074] In vivo efficacy and tolerability in the SC6 patient-derived xenograft (PDX) model Female athymic nude mice were inoculated subcutaneously with tumor fragments from SC6 PDX tumors. Tumor volumes were approximately 60–200 mm. 3Animals were randomized when the tumor volume reached 100 mg / kg. Animals were treated with vehicle (0.5% methylcellulose, 1% Tween 80 PO and saline IV), compound of formula (I) (30 mg / kg QD, PO), carboplatin (25 mg / kg QW, IP) or etoposide (6 mg / kg QD [3d on / 4d off], IP) formulated as a suspension in 0.5% methylcellulose and 1% Tween 80, administered alone or in combination over a 21-day cycle (7 animals per group). In the combination arm, compound of formula (I) was administered 2 hours before chemotherapy. Tumor growth was monitored twice weekly by caliper measurement and tumor volume was calculated using the formula V=(L×W×W) / 2, where V is tumor volume, L is tumor length (longest tumor dimension), and W is tumor width (longest tumor dimension perpendicular to L). During regular monitoring, the animals were checked for tumor growth and any effects of treatment on behavior such as mobility, food and water consumption, weight gain / loss three times a week, matting of eyes / fur, and any other abnormalities. Mortality and observed clinical signs were recorded for each individual animal. Although some transient weight loss was observed immediately following combination treatment with the compound of formula (I) and etoposide in this PDX model, all animals recovered rapidly and remained on the study and were evaluable, demonstrating that the combination was well tolerated. In this SC6 PDX model of SCLC, compound of formula (I) in combination with etoposide induced observable TGI of 34% on day 7 and 61% on day 11 compared to vehicle control (p=0.012). In the combination group, 4 / 7 mice remained below the ethical criterion for maximum tumor volume at the end of treatment (day 21), whereas all mice in all other groups had reached this criterion and were no longer included in the study (Figure 6). EXAMPLES

[0075] Example 5a: Phase 1 Clinical Trial Involving a Compound of Formula (I) (Test Drug) The clinical trial is a multicenter, open-label, non-randomized, non-controlled, dose-escalation study of the compound of Formula (I) (Study Drug) in combination with carboplatin and etoposide in adult participants with SCLC that has recurred or progressed after prior standard platinum-based therapy, followed by an expansion in adult participants with SCLC that has recurred or progressed after prior standard platinum-based therapy. The clinical trial design consists of two parts. ■ Part 1: Dose escalation of oral once-daily dosing of study drug given on days 1 to 3 and days 8 to 10 in combination with etoposide (intravenous [IV] infusion) on days 1 to 3 and carboplatin (IV infusion) on day 1 of a 21-day cycle. The study population in Part 1 consisted of adult participants with histologically or cytologically confirmed small cell lung cancer (SCLC) that had recurred or progressed a minimum of 45 days after the last dose of prior standard platinum-based therapy. The starting dose of study drug at dose level 1 (DL1) was at least one dose level lower than the highest dose of study drug found to be safe in the 101 study that included study drug in combination with carboplatin. The maximum tolerated dose (MTD) and / or recommended phase 2 dose (RP2D) to be used in Part 2 will be determined based on the recommendation of the Safety Monitoring Committee (SMC). ■ Part 2: Growth begins after the MTD and / or RP2D of Part 1 are supported by SMCs. The Part 2 study population consists of adult participants with histologically or cytologically confirmed SCLC that has recurred or progressed a minimum of 90 days after the last dose of prior standard platinum-based therapy. Participants will be treated with the MTD and / or RP2D of study drug in combination with etoposide and carboplatin. Participants will be followed for safety, antitumor activity, and survival status until the end of the study. In Part 1 and Part 2, a treatment cycle is defined as 21 days.

[0076] The primary objectives and endpoints of the clinical trial include:

[0077] [Table 1] Secondary objectives and endpoints of the clinical trial include:

[0078] [Table 2] The study population for this clinical trial was as follows: Part 1 (dose escalation): Adult participants (age 18 years or older) with histologically or cytologically confirmed SCLC that has recurred or progressed at least 45 days after the last dose of prior standard platinum-based therapy. Part 2 (expansion): Adult participants (≥ 18 years) with histologically or cytologically confirmed SCLC that has recurred or progressed at least 90 days after the last dose of prior standard platinum-based therapy.

[0079] Inclusion criteria for this clinical trial included: Histologically or cytologically confirmed SCLC Nonhemorrhagic tumors Previous platinum-based chemotherapy (carboplatin and / or cisplatin) Part 1 (dose escalation): Recurrence or progression at least 45 days after the last dose of prior standard platinum-based therapy Part 2 (expansion): Recurrence or progression at least 90 days after the last dose of prior standard platinum-based therapy Measurable disease by RECIST 1.1 Able and willing to undergo a tumor biopsy unless an archived tumor sample is available. ECOG performance score 0-1 Life expectancy of at least 3 months according to the investigator's best judgment Suitable values ​​for: Bone marrow: absolute neutrophil count (ANC) ≥ 1500 / μL, platelets ≥ 100,000 / μL, hemoglobin ≥ 9 g / dL or 5.6 mmol / L, and no transfusions within the last 2 weeks of study treatment initiation; Liver biochemistry: AST and ALT ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN for participants with liver metastases; serum total bilirubin ≤ 1.5 ULN and direct / indirect bilirubin ≤ ULN; alkaline phosphatase (ALP) < 2.5 × ULN or ≤ 5 × ULN for participants with liver metastases; Renal function: calculated creatinine clearance ≥ 50 ml / min (as determined by the Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] formula); Coagulation status: International normalized ratio (INR) or prothrombin time ≦1.5×ULN; activated partial thromboplastin time (aPTT) ≦1.5×ULN.

[0080] Exclusion criteria for this clinical trial included: Prior treatment with more than one line of therapy for extensive SCLC disease, unless the participant has received one line of prior immunotherapy without chemotherapy, in which case two lines of treatment are permitted (one of the lines must be platinum-based chemotherapy). Current use of the investigational drug or device. History of an active second malignancy requiring treatment within the past 6 months, except for surgically treated superficial bladder cancer, ductal carcinoma in situ or other noninvasive carcinomas, and nonmelanoma skin cancer (basal cell / squamous cell skin cancer). Clinically significant gastrointestinal abnormalities that may affect the absorption of orally administered drugs (e.g., ulcer disease, gastrointestinal dysfunction, uncontrolled nausea, vomiting, diarrhea, malabsorption syndromes, major resection of the small intestine or total gastrectomy, or inflammatory bowel disease). Radiographic evidence of interstitial lung disease (ILD) that is considered clinically significant (e.g., symptomatic). Known infection requiring systemic use of antibiotics or antivirals. Immunization with live or live attenuated vaccine within 28 days prior to the first dose of study treatment. Pregnancy or breastfeeding. Unable or unwilling to swallow oral medications. Unresolved AE or toxicity from prior treatment > Grade 1. Note: Participants with ≦Grade 2 alopecia or endocrinopathy (e.g., hypothyroidism due to immune checkpoint inhibitors) controlled by replacement therapy are exceptions and may be eligible for the study. Hypersensitivity to the study drug, etoposide, or carboplatin, or to any of the excipients found in the formulation of the study drug, etoposide, or carboplatin.

[0081] The investigational drugs used in this clinical trial are as follows: The study drug will be formulated as 10 mg mini-tablets contained in hard gelatin capsules. Study drug will be taken orally on an empty stomach (i.e., participants must fast for 4 hours [h] before and 2 hours [h] after ingestion [only water is allowed]). For Part 1, the starting dose at DL1 will be at least one dose level lower than the highest dose of study drug found to be safe in Study 101, which included study drug in combination with carboplatin. Etoposide is in concentrate for solution for IV infusion. Participants receive etoposide on three consecutive days during each cycle, i.e., days 1, 2, and 3. Etoposide infusions are administered at a dose of 100 mg / m 2 The infusion period begins 5 to 15 minutes after the morning administration of the study drug at a dose of 0.01 mg / kg / day, and the duration of the infusion is 30 minutes to 1 hour. Carboplatin is in concentrate for solution for IV infusion. Participants receive carboplatin on day 1 of each cycle. Carboplatin infusion is initiated within 30 minutes after the end of the etoposide infusion with a dose based on AUC 5 mg / mL·min. Infusion duration is 30 minutes to 1 hour.

[0082] Each participant will be treated until disease progression, unacceptable toxicity, participant withdrawal, investigator decision to discontinue, or study termination. Overall study termination will occur at the data cutoff for the primary analysis, i.e., when the last enrolled participant has received 12 months of treatment or when the last active participant has discontinued, whichever occurs first. Approximately 54 evaluable patients are estimated to be enrolled in the clinical trial.

[0083] Example 5b: Phase 1 Clinical Trial Involving a Compound of Formula (I) (Herein, Test Agent) The clinical trial is a two-part, dose-escalation and expansion, phase 1, open-label, multicenter study to evaluate the safety and preliminary antitumor activity of the investigational agent in combination with carboplatin and etoposide in adult participants with small cell lung cancer that has recurred or progressed after prior standard platinum-based therapy. Part 1 (dose escalation): Dose escalation of oral once-daily dosing of study drug on days 1 through 3 and days 8 through 10 of a 21-day cycle in combination with etoposide (intravenous [IV] infusion) on days 1 through 3 and carboplatin (IV infusion) on day 1. The study population in Part 1 consists of adult participants with histologically or cytologically confirmed small cell lung cancer (SCLC) that has recurred or progressed a minimum of 45 days after the last dose of prior standard platinum-based therapy. The starting dose of study drug at dose level 1 (DL1) is 200 mg based on available data from Study 101, which includes study drug in combination with carboplatin. Participants will be enrolled in cohorts of at least three participants treated at the same dose level. Dose recommendations for dose escalation of study drug in combination with etoposide and carboplatin will be made by the Safety Monitoring Committee (SMC) during Part 1. The maximum tolerated dose (MTD) and / or recommended phase 2 dose (RP2D) to be used in Part 2 will be determined based on the SMC recommendation. Part 2 (Extended): Expansion will begin after the RP2D for Part 1 is endorsed by SMC. The study population for Part 2 will consist of adult participants with histologically or cytologically confirmed SCLC that has recurred or progressed at least 90 days after the last dose of prior standard platinum-based therapy. Participants will be treated with the study drug at RP2D in combination with etoposide and carboplatin. In Part 2, participants will be followed for safety until a safety follow-up visit (and thereafter for all serious adverse events [SAEs] and related AEs until the end of study (EOS)) and for antitumor activity until disease progression. Follow-up of vital status will be performed until withdrawal of consent, death, or end of study, whichever occurs first. Additionally, quality of life will be assessed over the course of the study until the EOT visit. In both Part 1 and Part 2, a treatment cycle is defined as 21 days. Abbreviations used in the tables and text of this Example 5b: AE = adverse event. AUC = area under the concentration versus time curve. AUC24 = area under the curve up to 24 hours. AUCinf = area under the curve to infinity. AUClast = area under the curve to the last measurable concentration; BOR = best overall response. CL / F=apparent total body clearance. Cmax = maximum plasma concentration; CR = complete response; CSF=cerebrospinal fluid. Ctrough = trough plasma concentration; CV = coefficient of variation. DCR=disease control rate; DMET = drug metabolizing enzymes and transporters. DOR=duration of response; DLT=Dose-limiting toxicity. ECG=electrocardiogram. ECOG=Eastern Cooperative Oncology Group. EOT=end of procedure. FACT-G=Functional Assessment of Cancer Therapy General. FACT-L=Functional Assessment of Cancer-Treated Lung. NCI-CTCAE 5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. OR=objective response ORR = objective response rate; OS=overall survival. PFS=progression-free survival; PK=pharmacokinetic(s); PR=partial response. PS=Performance Status. QoL=Quality of Life RECIST1.1=Response Evaluation Criteria in Solid Tumors, version 1.1; RP2D=recommended phase 2 dose; SCLC=small cell lung cancer. SD=standard deviation TEAE = treatment-emergent adverse event. T1 / 2 = apparent terminal half-life tmax = time to Cmax; TOI = Test Outcome Index. Vd = volume of distribution; Vd / F = apparent Vd The primary objectives and evaluation measures (including endpoints) of the clinical trial include the following:

[0084] [Table 3] TIFF2025509278000018.tif177170Secondary objectives and estimates (including endpoints) of the clinical trial include the following:

[0085] [Table 4] TIFF2025509278000020.tif143170The exploratory objectives of the clinical trial include:

[0086] [Table 5] The study population for this clinical trial was as follows: Part 1 (dose escalation): Adult participants (ages 18 years or older) with histologically or cytologically confirmed SCLC that has recurred or progressed a minimum of 45 days after the last dose of prior standard platinum-based therapy. Part 2 (expansion): Adult participants (age 18 years or older) with histologically or cytologically confirmed SCLC that has recurred or progressed at least 90 days after the last dose of prior standard platinum-based therapy. Inclusion criteria for this clinical trial included: Histologically or cytologically confirmed SCLC. Non-bleeding tumor. Previous platinum-based chemotherapy (carboplatin and / or cisplatin) Part 1 (dose escalation): Recurrence or progression at least 45 days after the last dose of prior standard platinum-based therapy Part 2 (expanded): Recurrence or progression at least 90 days after the last dose of prior standard platinum-based therapy For extensive stage (ES) SCLC, only one prior systemic treatment (i.e., platinum-based chemotherapy with or without immunotherapy) is permitted. Exception: Participants who have received prior lurbinectedin as monotherapy in addition to one prior platinum-based chemotherapy treatment will also be considered eligible. Measurable disease by RECIST 1.1. Willingness and ability to undergo a tumor biopsy unless an archived tumor sample is available ECOG performance status 0-1 Life expectancy of at least 3 months according to the investigator's best judgment Suitable values ​​for: Bone marrow: absolute neutrophil count (ANC) ≥ 1500 / μL, platelets ≥ 100 000 / μL, hemoglobin ≥ 9 g / dL or 5.6 mmol / L, and no blood transfusions within the last 2 weeks prior to starting study treatment Liver biochemistry: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN), or ≤ 5 × ULN for participants with liver metastases; serum total bilirubin ≤ 1.5 × ULN; alkaline phosphatase (ALP) < 2.5 × ULN or ≤ 5 × ULN for participants with liver metastases. Renal function: calculated creatinine clearance ≥ 50 ml / minute (min) (determined by the Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] formula). Coagulation status: International normalized ratio (INR) or prothrombin time ≤ 1.5 x ULN; activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN I would like to see highly effective methods of birth control implemented.

[0087] Exclusion criteria for this clinical trial included: Use of an investigational drug or medical device within 28 days prior to the first dose of study treatment History of other malignancies requiring active treatment within the past 2 years prior to the first dose of study treatment (excluding superficial bladder cancer, ductal carcinoma in situ or other noninvasive carcinomas, and nonmelanoma skin cancer (basal cell / squamous cell skin cancer) treated with curative intent) Brain metastases were not asymptomatic, were stable for at least 1 month (maximum steroid dose of prednisone 10 mg / day or maximum steroid dose of dexamethasone 4 mg / day), and did not require active treatment during the last month prior to the first administration of study treatment History of myocardial infarction or stroke within 6 months prior to the first dose of study treatment, congestive heart failure greater than New York Heart Association (NYHA) class II, unstable angina, unexplained recurrent syncope, cardiac arrhythmias requiring treatment, known family history of sudden death from cardiac causes before age 50 years, or any cardiac toxicity experienced after previous chemotherapy Left ventricular ejection fraction (LVEF) less than 55% Heart rate-corrected QT interval (QTc) using the Fridericia formula (QTcF) >450 ms, history of congenital long QT syndrome, or clinically significant conduction abnormality or any conduction abnormality that may increase the risk of torsade de pointes (TdP) Concomitant use of any medication with a known risk of TdP / QTc prolongation or any medication(s) listed in the Prohibited Medications section of the protocol. If such medication is used by the participant, a washout period of at least five half-lives of the medication must occur prior to the first dose of study treatment. Concomitant use of inhibitors or inducers of cytochrome P450 (CYP) 3A4, drugs or herbal products that are strong inhibitors of CYP2D6, or any of the drugs listed in the Prohibited Medications section of the protocol (e.g., proton pump inhibitors, H2 receptor antagonists). If such drugs are used by the participant, a washout period of at least five half-lives of the drug must occur before the first dose of study treatment. Clinically significant gastrointestinal abnormalities that may affect the absorption of orally administered drugs (e.g., ulcer disease, gastrointestinal dysfunction, uncontrolled nausea, vomiting, diarrhea, malabsorption syndromes, major resection of the small intestine or total gastrectomy, or inflammatory bowel disease) Major surgery within 4 weeks prior to the first dose of study treatment, or incomplete recovery from a surgical procedure at the time of the first dose of study treatment Exposure to high levels of ultraviolet (UV) light, e.g., occupational exposure to sunlight or sunbathing Radiographic findings show tumor involvement with large blood vessels or poor margins from them, which increases the risk of bleeding. Radiographic evidence of interstitial lung disease (ILD) that is considered clinically significant (e.g., symptomatic) Uncontrolled pleural, pericardial, or ascites effusion requiring repeated drainage Any infection requiring systemic use of antibiotics or antivirals Known hepatitis C virus (HCV), hepatitis B virus (HBV), or human immunodeficiency virus (HIV) infection. Participants with past infections who have been cured may be enrolled. Immunization with live or live attenuated vaccines within 28 days prior to the first dose of study treatment Unable or unwilling to swallow oral medications Chemotherapy, monoclonal antibodies / biologics, or radiation therapy with curative intent within 28 days prior to the first dose of study treatment. Palliative radiation (e.g., for pain relief) is permitted up to 1 week before the start of study treatment. Unresolved AE or toxicity from prior treatment > Grade 1. Note: Participants with ≦Grade 2 alopecia or endocrinopathy (e.g., hypothyroidism due to immune checkpoint inhibitors) controlled by replacement therapy are exceptions and may be eligible for the study. Hypersensitivity to the study drug, etoposide or carboplatin, or to any of the excipients found in the formulation of the study drug, etoposide or carboplatin. If previous hypersensitivity to carboplatin was observed but successful desensitization was performed for the participant, the participant may be eligible for the study. Prior exposure to any WEE1 inhibitor.

[0088] The investigational drugs, doses and modes of administration used in this clinical trial are as follows: The study drug will be formulated as 20, 30, 60, 100, 130, and 150 mg hard gelatin capsules. The capsules will contain different amounts of 10 mg uncoated mini-tablets (excipients are as follows: microcrystalline cellulose, anhydrous lactose, hydroxypropyl cellulose, sodium starch glycolate, anhydrous colloidal silica, and magnesium stearate). Intermediate capsule strengths can be produced to cover alternative dose levels. Participants will receive study medication 3 consecutive days per week for the first 2 weeks of each 21-day cycle (days 1, 2, and 3, and days 8, 9, and 10). Study medication will be taken orally on an empty stomach (i.e., participants must have fasted for at least 4 hours before and 2 hours after ingestion [only water allowed]). In Part 1, the starting dose (DL1) is 200 mg per day.

[0089] Etoposide is in concentrate for solution for IV infusion. Participants receive etoposide on three consecutive days during each cycle, i.e., days 1, 2, and 3. Etoposide infusions are administered at a dose of 100 mg / m 2 The infusion period begins 5 to 15 minutes after the morning administration of the study drug at a dose of 0.01 mg / kg / day, and the duration of the infusion is 30 minutes to 1 hour. Carboplatin is in concentrate for solution for IV infusion. Participants receive carboplatin on day 1 of each cycle. Carboplatin infusion is initiated within 30 minutes after the end of the etoposide infusion, with dosing based on AUC 5 mg / mL min. Infusion duration is 30 minutes to 1 hour. Each participant will be treated until disease progression, unacceptable toxicity, participant withdrawal, investigator-determined withdrawal, death, or complete completion of the study. It is estimated that up to approximately 54 evaluable participants will be enrolled in the study.

[0090] Figure 7 provides a study diagram showing the dosing schedule of the triple combination in both the dose escalation (DE) and expansion parts of the clinical trial. The following abbreviations are used in Figure 7: AE = adverse event; C = cycle; D = day; DE = dose escalation; DLT = dose-limiting toxicity; EOS = end of study; EOT = end of treatment; PO = oral; SAE = serious adverse event; SFU = safety follow-up. In Figure 7, a footnote specifies the following: 1Up to progressive disease / toxicity 2. After the end of the SFU period, until the participant's EOS, collect all SAEs (regardless of causality assessment) and AEs considered related to study treatment per investigator assessment. 3. Survival tracking of the enlarged area only. A cycle is defined as 21 days. EXAMPLES

[0091] Activity of Compounds of Formula (I) as Monotherapy and in Combination with Carboplatin and Etoposide in SCLC Organoid Models SCLC organoids from 16 models were prepared as follows: SCLC organoid models were grown in 6-well plates with each well containing 2 ml of organoid medium. On the day of organoid seeding, 20 μL of 100× dispase solution was added to each well and the plate was incubated at 37° C. for 30 min. Organoids were passed through a pre-wet 100 μm filter into a 50 ml plastic tube and then further filtered through a wet 20 μm filter. Matrigel was added to a final concentration of 5% v / v and 40 μL of cell suspension was added to each well of a 384-well plate by a Multidrop dispenser. The treatments tested for each organoid model were as follows: (a) Compounds of formula (I) in monotherapy (b) carboplatin and etoposide (5:1 ratio, considered as a single treatment), or (c) A compound of formula (I) in combination with carboplatin and etoposide The following concentrations were used in a matrix format: compound of formula (I) in six concentrations from 0.047 to 1.5 μM, carboplatin in six concentrations from 0.156 to 5 μM, and etoposide in six concentrations from 0.031 to 1 μM). Thus, for carboplatin and etoposide treatments (considered as single treatments in this experiment), the lowest concentration of carboplatin was combined with the lowest concentration of etoposide in a 5:1 ratio, while maintaining a 5:1 ratio, and the second lowest dose of both agents was combined. Each of these combinations was then further combined alone (carboplatin / etoposide treatment) or with each concentration of compound of formula (I). Screening plates were incubated with treatments for 5 days. All treatments were performed in technical triplicates and biological replicates. Plates were assayed for luminescent Cell Titer Glow (CTG) signal by adding 40 μL per well of CTG 3D with a Multidrop dispenser, mixing for 5 minutes, and incubating for 30 minutes at room temperature in the dark. Luminescent signal was then measured on an Envision plate reader. Percent survival and percent inhibition were calculated for each treatment as follows: Survival rate (%) = (LumTest product - LumMedium control) / (LumVehicle control - LumMedium control) x 100%. Inhibition rate (%) = 100-survival rate (%) For the calculation of synergy and the creation of heat maps, the Bliss independent models can be treated by SynergyFinder·org (Zheng, S.; Wang, W.; Aldahdooh, J.; Malyutina, A.; Shadbahr, T.; Tanoli Z; Pessia, A.; Jing, T. SynergyFinder Plus: Towards Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics, Proteomics & Bioinformatics 2022. doi:10.1016 / j.gpb.2022.01.004) considering carboplatin / etoposide as a single treatment for the compound represented by formula (I). Nine of the 16 models had a Bliss synergy score of 5 or more between the compound represented by formula (I) and carboplatin / etoposide treatment. Surface plots of the bliss independent models in the synergy analysis are presented in FIG. 8 for five of these models, with highly significant synergy scores >10. Furthermore, 12 of 16 SCLC organoids were sensitive to treatment with the compound represented by formula (I) alone (i.e., as monotherapy), as demonstrated by an IC50 value lower than 1.5 μM (corresponding to the plasma concentration achieved in humans) and a maximum inhibition rate (cell death rate) higher than 60% at 1.5 μM (the highest dose tested for the compound represented by formula (I)).

Claims

1. A WEE1 inhibitor for use in the treatment of small cell lung cancer (SCLC) in patients where it is necessary.

2. The following equation (I): 【Chemistry 1】 The WEE1 inhibitor according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

3. A WEE1 inhibitor according to claim 1, which is used in combination with carboplatin and / or etoposide.

4. A WEE1 inhibitor according to claim 3, which is used in combination with carboplatin and etoposide.

5. The WEE1 inhibitor according to claim 1, wherein SCLC had recurred or progressed after initial or previous treatment for SCLC.

6. The aforementioned SCLC, a) More than 45 days since the last dose of standard platinum-based therapy, or b) More than 90 days after the last dose of standard platinum-based therapy, The WEE1 inhibitor according to claim 5, which has relapsed or progressed.

7. The WEE1 inhibitor according to claim 1, wherein the patient has not previously received any treatment for SCLC.

8. A WEE1 inhibitor according to claim 1, administered orally.

9. a) The first, second, and third days of a 21-day cycle, or b) Administered on days 1, 2, 3 and 8, 9, and 10 of the 21-day cycle. The WEE1 inhibitor according to claim 1.

10. a) a dose in the range of 150 to 720 mg per treatment day or a dose in the range of 100 to 520 mg per treatment day, and / or b) The WEE1 inhibitor according to claim 1, administered as a single dose on the treatment day.

11. a) The WEE1 inhibitor is administered at approximately the same time on each treatment day, and / or b) The WEE1 inhibitor is preferably administered after a 4-hour fast, and / or c) After administration of the WEE1 inhibitor, a 2-hour fast is preferably performed. The WEE1 inhibitor according to claim 1.

12. A WEE1 inhibitor according to any one of claims 3 to 11, wherein etoposide is administered by infusion.

13. Etoposide a) On the first, second and third days of the 21-day cycle, and / or b) 70-100 mg / m² per injection ２ The range is preferably 100 mg / m². ２ The WEE1 inhibitor according to claim 12, administered in the specified dose.

14. A WEE1 inhibitor according to any one of claims 3 to 11, wherein etoposide is administered orally.

15. Etoposide a) 100-200 mg / m² on days 1-5 of the 21-day cycle ２ A dose within the range of / day, or b) 100-200 mg / m² on the 1st to 5th day every 3-4 weeks ２ A dose within the range of / day, or c) 200 mg / m² on the 1st, 3rd, and 5th days every 3-4 weeks. ２ The WEE1 inhibitor according to claim 14, administered in a daily dose.

16. Carboplatin a) By infusion, according to the Calvert formula, at a dose corresponding to the AUC in the range of 2 to 6 mg / ml × min, preferably 5 mg / ml × min, and / or b) A WEE1 inhibitor according to any one of claims 3 to 11, administered on the first day of a 21-day cycle.

17. A WEE1 inhibitor according to any one of claims 3 to 11, administered on the day of WEE1 inhibitor treatment, prior to the administration of etoposide and / or carboplatin.

18. On the day of WEE1 inhibitor treatment, a) Etoposide administration is initiated approximately 5 minutes to 1 hour after WEE1 inhibitor administration, and / or b) Carboplatin administration is initiated approximately 5 minutes to 1 hour after WEE1 inhibitor administration, or after the completion of etoposide administration. A WEE1 inhibitor according to any one of claims 3 to 11.

19. A WEE1 inhibitor according to any one of claims 9 to 11, administered over one, two, three, four, five, six or more cycles.

20. A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of small cell lung cancer (SCLC) in patients for which such treatment is necessary, and used as described in any one of claims 3 to 11.

21. A kit comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of small cell lung cancer (SCLC) in patients for which it is necessary, the kit being used as described in any one of claims 3 to 11.

22. Etoposide or a pharmaceutically acceptable salt thereof for use in the treatment of small cell lung cancer (SCLC) in patients in need thereof, wherein etoposide is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and optionally used in combination with carboplatin, preferably as described in any one of claims 3 to 11.

23. Carboplatin for use in the treatment of small cell lung cancer (SCLC) in patients in need thereof, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and optionally in combination with etoposide or a pharmaceutically acceptable salt thereof, and used as described in any one of claims 3 to 11.

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