Methods of treating solid tumors

Abstract

Methods of treating a solid tumor using a WEE1 inhibitor are provided.

Description

[0001] HE 269663 METHODS OF TREATING SOLID TUMORS FIELD OF THE INVENTION The present invention generally relates to the treatment of solid tumors. More specifically, the present invention relates to the use of a WEE1 inhibitor to treat solid tumors in patients in need thereof. BACKGROUND Solid tumors account for approximately 90 percent of adult cancers. Cancer is known to appear when the cell cycle is disrupted. The cell cycle is a tightly regulated process interrupted by cell-cycle checkpoints that allow for repair of damaged DNA before cell division. Cell-cycle checkpoints are therefore crucial to maintain genomic integrity and have been identified at the growth 1-synthesis (G1-S) transition (G1 checkpoint), during the S phase, and at the growth 2-mitosis (G2-M) transition (G2 checkpoint) of the cell cycle. The p53 tumor suppressor protein is a key regulator of the G1 checkpoint, whereas WEE1 is one of the key tyrosine kinases governing the G2 checkpoint. In response to DNA damage, Check Point kinase 1 phosphorylates and activates WEE1 to induce cell-cycle arrest and DNA damage repair. WEE1 inhibition results in G2 checkpoint abrogation, driving the cell into mitosis with unrepaired DNA followed by cell death. Recently there has been an increasing interest in personalized medicine approaches that use specific patient or tumor characteristics such as genetic mutations or expression levels of certain gene products such as mRNA or proteins (biomarkers) to guide treatment decisions. HE 269663 For example, it was described preclinically that inhibition of WEE1 by AZD1775 selectively kills histone H3K36me3-deficient cancers by dNTP starvation (Pfister etal. 2015, Cancer Cell 28, 557- .However, in cancer patients, AZD1775 failed to achieve an objective response in SETD2-altered ccRCC and other solid tumor malignancies (Maldonado et al., 2023, American Society of Clinical Oncology, Poster #3104: A Phase 2 Study of the WEE1 Inhibitor AZD1775 in SETD2-Deficient Advanced Solid Tumor Malignancies (NCI 10170)). Thus, there remains an unmet medical need for effective treatments tailored towards carefully selected patient groups suffering from solid tumors, especially based on their tumor biomarker status. SUMMARY OF THE INVENTION The present invention relates to a WEE1 inhibitor for use in, or for use in the preparation of a medicament for, treating a solid tumor in a patient in need thereof, as well as to methods of treating a solid tumor in a patient in need thereof, comprising administering a therapeutically effective amount of a WEE1 inhibitor. The present invention further relates to pharmaceutical compositions and kits for use in such uses and methods, as set forth in the appended claims and as further described in the detailed description below. It is to be understood that any reference to a WEE1 inhibitor also encompasses the pharmaceutically acceptable salt thereof, even if not explicitly mentioned as such. In some aspects of the uses or methods according to the present invention, the WEE1 inhibitor is a compound of formula (I) HE 269663 (I), or a pharmaceutically acceptable salt thereof. In the same or other aspects, the present invention relates to the WEE1 inhibitor and / or the uses thereof, or to methods of manufacturing medicaments for use and / or methods for treatment according to the specific numbered items below: 1. Selective WEE1 inhibitor for use in treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation; use of a selective WEE1 inhibitor in treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation; use of a selective WEE1 inhibitor in a method of manufacturing a medicament for treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation; and / or method of treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation, which involves administration of a selective WEE1 inhibitor. 1a. Selective WEE1 inhibitor for use in treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone H3K36 trimethylation (H3K36me3) or loss of H3K36 trimethylation (H3K36me3); use of a selective WEE1 inhibitor in treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone H3K36 trimethylation (H3K36me3) or loss of H3K36 trimethylation (H3K36me3); use of a selective WEE1 inhibitor in a method of manufacturing a medicament for treating a patient having a solid tumor, wherein the solid tumor exhibits a HE 269663 biomarker indicative of reduced histone H3K36 trimethylation (H3K36me3) or loss of H3K36 trimethylation (H3K36me3); and / or method of treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone H3K36 trimethylation (H3K36me3) or loss of H3K36 trimethylation (H3K36me3), which involves administration of a selective WEE1 inhibitor. The following numbered items 2 to 13 expressly characterize specific aspects of the selective WEE1 inhibitor for use of item 1 or 1a, but they should be understood as also characterizing specific aspects of the use, method of manufacturing a medicament and method of treatment as specified under item 1 or 1a above. Likewise, unless the context dictates otherwise, all other disclosures of specific aspects provided in the present disclosure should be understood as disclosures applicable to the “selective WEE1 inhibitor for use in treating a patient”, the “use of a selective WEE1 inhibitor in treating a patient”, the “method of manufacturing a medicament for treating a patient”, and the “method of treating a patient” and any variants thereof. 2. Selective WEE1 inhibitor for use according to item 1 or 1a, wherein the WEE1 inhibitor is a compound of formula (I) (I), or a pharmaceutically acceptable salt thereof. 3. Selective WEE1 inhibitor for use according to item 1, 1a or 2, wherein the biomarker indicative of reduced histone methylation is a reduced histone H3K36 trimethylation (H3K36me3), or a loss of histone H3K36 trimethylation (H3K36me3). HE 269663 Selective WEE1 inhibitor for use according to any of items 1 to 3, wherein the biomarker indicative of reduced histone methylation is at least one of - mutation of a histone methyltransferase (HMT) gene or reduced expression of an HMT gene product, - mutation of SETD2 gene or reduced expression of a SETD2 gene product, - mutation of ASH1L gene or reduced expression of an ASH1L gene product, - mutation of NSD1 gene or reduced expression of an NSD1 gene product, - mutation of NSD2 gene or reduced expression of an NSD2 gene product, - mutation of NSD3 gene or reduced expression of an NSD3 gene product, - mutation of SETD3 gene or reduced expression of a SETD3 gene product, - mutation of SETMAR gene or reduced expression of a SETMAR gene product, - mutation of SMYD2 gene or reduced expression of a SMYD2 gene product, - overexpression of a histone demethylase (HDM) of the KDM4 family, such as KDM4A, KDM4B or KDM4C, or - overexpression of a histone demethylase (HDM) of the KDM2 family such as KDM2A or KDM2B. Selective WEE1 inhibitor for use according to item 4, wherein the biomarker indicative of reduced histone methylation is a homozygous loss of functional SETD2. HE 269663 Selective WEE1 inhibitor for use according to any one of the preceding items, wherein the solid tumor is or is associated with breast cancer, in particular triple-negative breast cancer (TNBC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer, prostate cancer or high-grade glioma and wherein the solid tumor is optionally an advanced solid tumor. Selective WEE1 inhibitor for use according to any one of the preceding items, wherein the solid tumor has recurred or progressed after initial or prior treatment. Selective WEE1 inhibitor for use according to any one of the preceding items, wherein the WEE1 inhibitor is administered in monotherapy. Selective WEE1 inhibitor for use according to any one of the preceding items, wherein the WEE1 inhibitor is administered orally. Selective WEE1 inhibitor for use according to any one of the preceding items, wherein the WEE1 inhibitor is administered a) at a dose ranging from 30 to 1000 mg of free base per treatment day, preferably a dose ranging from 30 to 720 mg of free base per treatment day, more preferably a dose ranging from 100 to 720 mg of free base, even more preferably a dose ranging from 100 to 520 mg of free base per treatment day, or b) at a dose of about 30, about 60, about 90, about 120, about 150, about 200, about 260, about 350, or about 460 mg of free base per treatment day, and / or c) at a dose ranging from 120 to 260 mg of free base per treatment day, preferably at a dose of about 260 mg of free base per treatment day, and / or d) as a single dose or twice a day (BID) on a treatment day. HE 269663 11. Selective WEE1 inhibitor for use according to any one of the preceding items, wherein the WEE1 inhibitor is administered a) daily over a 21-day cycle, or b) on 3, 4 or 5 consecutive days per week of a 21-day cycle, or c) on days 1 to 3 of a 21-day cycle, or d) on days 1 to 3 and 8 to 10 of a 21-day cycle, or e) on days 1 to 3, 8 to 10 and 15 to 17 of a 21-day cycle, or f) on days 1 to 5 of a 21-day cycle, or g) on days 1 to 5 and 8 to 12 of a 21-day cycle, or h) on days 1 to 5, 8 to 12 and 15 to 19 of a 21-day cycle, or i) on days 1 to 14 of a 21-day cycle, or j) on days 1 to 5 of a 28-day cycle, or k) on days 1 to 5 and 8 to 10 of a 28-day cycle, or l) on days 1 to 5 and 8 to 12 of a 28-day cycle, or m) on days 1 to 5, 8 to 10 and 15 to 17 of a 28-day cycle, or n) on days 1 to 5, 8 to 12 and 15 to 19 of a 28-day cycle, or o) on days 1 to 3 of a 28-day cycle, or p) on days 1 to 3 and 8 to 10 of a 28-day cycle, or q) on days 1 to 3, 8 to 10 and 15 to 17 of a 28-day cycle. 12. Selective WEE1 inhibitor for use according to any one of the preceding items, wherein the WEE1 inhibitor is administered at approximately the same time on each treatment day. 13. Selective WEE1 inhibitor for use according to any of items 11-12, wherein the WEE1 inhibitor is administered over 1, 2, 3, 4, 5, 6 or more 21-day cycles or 28-day cycles. 14. Pharmaceutical composition comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, for use in treating a patient having a solid tumor, wherein the use is as described in any of items 1- HE 269663 13; use of a pharmaceutical composition comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof in treating a patient having a solid tumor, wherein the use is as described in any of items 1-13; a method of manufacturing a medicament, using the pharmaceutical composition comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the medicament is for use in a method of treating a patient having a solid tumor, wherein the use is as described in any of items 1-13, as well as a method of treating a patient having a solid tumor comprising use of a pharmaceutical composition comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the method is as described in any of items 1-13. 15. Kit comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, for use in treating a patient having a solid tumor, wherein the use is as described in any of items 1-13; use of a kit comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof in treating a patient having a solid tumor, wherein the use is as described in any of items 1-13; a method of manufacturing a medicament, using the kit comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the medicament is for use in a method of treating a patient having a solid tumor, wherein the use is as described in any of items 1-13, as well as a method of treating a patient having a solid tumor comprising use of a kit comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the method is as described in any of items 1-13. The present invention further relates to a method for determining whether a solid tumor exhibits a reduced H3K36 trimethylation (H3K36me3) or loss of H3K36 trimethylation (H3K36me3) using an antibody-based detection technique, comprising: HE 269663 a) in an H3K36me3-stained tumor biopsy section, confirming the presence of at least one H3K36me3 stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining as an intrinsic positive control; b) determining, in said stained tumor biopsy section, a percentage of tumor cells that are unstained (0) or weakly stained (1+) for H3K36me3, wherein the solid tumor is considered as having “reduced H3K36 trimethylation or loss of H3K36 trimethylation” (also referred to as “reduced H3K36me3 or loss of H3K36me3”), if more than 25% of tumor cells are either unstained or weakly stained for H3K36me3. The present invention further relates to a WEE1 inhibitor and / or the uses thereof, or to methods of manufacturing medicaments for use and / or methods of treating a patient having a solid tumor using a WEE1 inhibitor according to any aspect described under items 1 to 13, wherein the solid tumor exhibits a reduced H3K36me3 or loss of H3K36me3, as determined by the above determination method. In this aspect, the WEE1 inhibitor may not be a selective WEE1 inhibitor, wherein the other features of items 1 to 13 apply. The present invention further relates to a selective WEE1 inhibitor and / or the uses thereof, or to methods of manufacturing medicaments for use and / or methods of treating a patient having a solid tumor using a selective WEE1 inhibitor according to any one of items 1 to 13, wherein the solid tumor exhibits a reduced H3K36me3 or loss of H3K36me3, as determined by the above determination method. The present invention also relates to a method for determining the eligibility of a subject having a solid tumor for treatment with a WEE1 inhibitor, the method comprising: a) in an H3K36me3-stained tumor biopsy section, confirming the presence of at least one H3K36me3 stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining as an intrinsic positive control; HE 269663 b) determining, in said stained tumor biopsy section, a percentage of tumor cells that are unstained (0) or weakly stained (1+) for H3K36me3, wherein the subject is considered eligible for treatment with a WEE1 inhibitor if more than 25% of tumor cells are either unstained or weakly stained for H3K36me3. The present invention further relates to a WEE1 inhibitor and / or the uses thereof, or to methods of manufacturing medicaments for use and / or methods of treating a subject having a solid tumor using a WEE1 inhibitor according to any aspect described under items 1 to 13, comprising determining the eligibility of a subject having a solid tumor for treatment with a WEE1 inhibitor by the above method. In this aspect, the WEE1 inhibitor may not be a selective WEE1 inhibitor, wherein the other features of items 1 to 13 apply. The present invention further relates to a selective WEE1 inhibitor and / or the uses thereof, or to methods of manufacturing medicaments for use and / or methods of treating a subject having a solid tumor using a selective WEE1 inhibitor according to any one of items 1 to 13, comprising determining the eligibility of a subject having a solid tumor for treatment with a WEE1 inhibitor by the above method. In some aspects, the tumor may be considered as having “reduced H3K36me3 or loss of H3K36me3” or the subject may be considered eligible for treatment with a WEE1 inhibitor if more than 50% of tumor cells are either unstained or weakly stained for H3K36me3. BRIEF DESCRIPTION OF THE DRAWINGS The patent application file contains at least one drawing executed in color. Certain aspects of the following detailed description are best understood when read in conjunction with the accompanying drawings. According to common HE 269663 practice, the various features of the drawings (e.g. Figures 7 to 9) are not on scale and dimensions of the various features are expanded or reduced for clarity. Figure 1 depicts results obtained in Example 1. Figure 2 depicts results obtained in Example 2. Figure 3 depicts results obtained in Example 3. Figure 4 depicts results obtained in Example 4. Figure 5 depicts results obtained in Example 5. Figure 6 depicts results obtained in Example 6. Figure 7 shows representative IHC images (FOVs) for the different H3K36me3 staining intensities (0, 1+, 2+ and 3+) in tumor cells. Figure 8 shows representative IHC images (FOVs) for the different H3K36me3 staining intensities (0, 1+, 2+ and 3+) in stromal cells (non-tumor cells). Figure 9 shows two representative FOVs (Figure 9a and Figure 9b) for an H3K36me3 stained sample (breast medullary carcinoma) with different staining intensities for tumor (TC) and non-tumor (non-TC) cells as indicated by thick (TC) or thin (non-TC) black (0), green (1+), yellow (2+) and red (3+) arrows according to the legend. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the use of a WEE1 inhibitor, for example a selective WEE1 inhibitor, in the treatment of a patient having a solid tumor, HE 269663 wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation. The compound of formula (I) is an example of a selective WEE1 inhibitor. In some embodiments, the present invention relates to the use of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, in the treatment of a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation. In some aspects, an N-oxide or N-oxide derivative of the compound of formula (I) may be used. The present invention also relates to a method for treating a patient having a solid tumor using a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation. Any disclosure of a use of a WEE1 inhibitor in the treatment of a solid tumor may be understood as relating to the method for treatment of a solid tumor, and vice versa. It has been found that the compound of formula (I) as an example of a WEE1 inhibitor leads to a significant increase in the induction of cell death. In particular, it has been found that the compound of formula (I) as a WEE1 inhibitor provides a synthetic lethal interaction when H3K36me3 is reduced or lost. HE 269663 In vitro, it has been demonstrated through multiple assessments that cells with reduced or low H3K36me3 levels are acutely sensitive to compound of formula (I). This was consistent regardless of whether this reduction was induced through siRNA / CRISPR or native epigenetic scarring. This data supports the synthetic lethal interaction between reduced H3K36me3 and WEE1 inhibition, at least in RCC and breast cancer cell lines. In vivo, the compound of formula (I) is efficacious in significantly inhibiting solid tumor growth as a monotherapy. In RCC, the heterozygous loss of SETD2 leading to reduced H3K36me3 results in a significant growth inhibitory effect of Compound of formula (I) in the Caki-1 model whereas the H3K36me3 high ACHN cells (i.e. ACHN cells having normal H3K36me3 levels) do not respond at all. These results are replicated in vivo in breast cancer where reduced H3K36me3 levels in MDA- MB-231 cells render the tumors sensitive to Compound of formula (I) treatment but the H3K36me3 high T47D cells do not respond. A correlation was observed between levels of H3K36me3 reduction and response to compound of formula (I), where decreasing levels of H3K36me3 lead to concomitant increased sensitivity to WEE1 inhibitors, further supporting the synthetic lethality. In each of the studies performed in vivo, the compound of formula (I) was well tolerated. Definitions So that the invention may be more readily understood, certain terms are specifically defined below. Unless explicitly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning that would be commonly understood by one of ordinary skill in the relevant art. HE 269663 As used herein, including in the appended claims, the singular forms of words such as “a”, “an”, and “the”, include their corresponding plural references unless the context clearly indicates otherwise. It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of” and / or “consisting essentially of” are also provided. The term "and / or" as used herein in a phrase such as "A and / or B" herein is intended to include both "A and B," "A or B," "A," and "B." Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). As used herein, a “WEE1 inhibitor” refers to a compound that inhibits the activity of the WEE1 kinase, for example with an IC50 of <10nM in an ADP-GLO kinase assay or an IC50 of <100nM in an enzyme profiling assay. As used herein, a “selective WEE1 inhibitor” refers to a WEE1 inhibitor that does not inhibit PLK1 / 2 or inhibits PLK1 / 2 with an IC50 greater than 500nM in an ADP-GLO kinase assay. The compound of formula (I) herein is an example of a selective WEE1 inhibitor. For clarity, adavosertib (AZD-1775) and azenosertib (Zn-C3) are not considered as selective WEE1 inhibitors. As used herein, the expression “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic or organic acids. For example, acceptable salts may be those derived from acids such as quaternary salt, acetate, carbonate, carbamate, sulfonate, strong inorganic acids and the like. In general, pharmaceutically acceptable salts may be used for modifying the solubility or hydrolysis characteristics of a compound, or in sustained release formulations. It will be understood that, as used herein, HE 269663 references to a WEE1 inhibitor, such as compound of formula (I), are meant to also include the pharmaceutically acceptable salts unless stated otherwise. As used herein, the term “biomarker”, also sometimes referred to as “biological marker”, is a measurable indicator of a biological state or condition. The biomarker refers to a molecule whose activity, conformation, localization and / or abundance can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or predictor of pharmacologic responses to therapeutic treatment. Biomarkers can be specific cells, molecules, genes, gene products, proteins, enzymes or hormones. They contribute to the understanding of disease mechanisms and the effect of drug treatment. Biomarkers may be measured and evaluated using blood, urine, cells or tissues. The expression “reduced histone methylation” as used herein refers to a level of histone methylation in tumor cells that is lower than the level of histone methylation in a corresponding (or comparable) healthy cell or tissue. Specifically, the corresponding (or comparable) healthy cell may be a stromal cell of said tumor. A reduced histone methylation level may for instance be measured using antibodies directed specifically against to the histone methylation of interest, either by Western Blot, Immunohistochemistry or Immunofluorescence, in tumor cells, and comparing those levels to the levels in corresponding healthy cells or tissue. A reduced histone methylation may also be measured through quantification by ELISA (enzyme-linked immunosorbent assay) in liquid biopsies such as blood samples. As a more specific example herein, the “biomarker indicative of a reduced histone methylation” may, in some specific embodiments, be the level or degree of histone methylation itself. More specifically, the biomarker may be the level or degree of trimethylation of H3K36. Confirmation of the biomarker may encompass an experimental confirmation that the level or degree of histone methylation in a tumor cell is below that of a healthy control cell or tissue. In other specific HE 269663 embodiments, the biomarker may be a mutation in a gene, and / or a reduced or increased expression of a gene product, that is known to influence the level or degree of histone methylation. More specifically, the biomarker may be a mutation in one or more of the genes listed herein, such as SETD2, and / or a reduced or increased expression of the respective gene product. Confirmation of the biomarker in these instances may be experimental confirmation that the gene of interest is mutated and / or the gene product expression in tumor cells deviates from that of a healthy control cell or tissue. It is to be noted that for some biomarkers used in the present invention (such as SETD2 or ASH1L), the same name or acronym is used for the gene and the resulting gene product (e.g. mRNA and / or protein). The person of skill in the art will understand that a mutation or deletion of a given biomarker concerns the biomarker gene, while the mention of expression levels (e.g. reduced expression or overexpression) refers to a corresponding biomarker gene product. The term “Histone H3K36 trimethylation” (H3K36me3) as used herein refers to a post-translational modification to the DNA packaging protein Histone H3. It indicates the trimethylation of the lysine residue at amino acid position 36 within the histone H3 protein. H3K36me3 is required for homologous recombinational repair of DNA damage such as double-strand breaks and facilitates transcriptional activity. The term “Histone H3K36 dimethylation“ (H3K36me2) as used herein refers to a post-translational modification to the DNA packaging protein Histone H3. It indicates the dimethylation at the lysine residue 36 within the histone H3 protein. The terms “reduced H3K36me3”, “H3K36me3 reduction”, “reduced level of histone H3K36 trimethylation”, “reduced level of H3K36me3”, “reduced degree of histone H3K36 trimethylation”, “reduced degree of H3K36me3” and “low H3K36me3 levels” are used interchangeably herein, to refer to tumor cells having reduced HE 269663 levels or degrees of H3K36me3 compared to corresponding healthy cells such as tumor stromal cells. H3K36me3 reduction results in an alteration of the chromatin structure, affecting (reducing) transcriptional activity and the DNA damage response. A reduced H3K36me3 level is for instance measured using antibodies directed specifically against trimethylated lysine 36 of Histone H3, either by Western Blot, Immunohistochemistry or Immunofluorescence, in tumor cells and comparing that level to the level in corresponding healthy cells or tissue. The terms “loss of H3K36me3” and “H3K36me3 loss” are used interchangeably herein to refer to tumor cells that exhibit no or substantially no H3K36me3. They include complete loss of H3K36me3. The H3K36me3 loss is for instance measured using antibodies directed specifically against trimethylated lysine 36 of Histone H3, either by Western Blot, Immunohistochemistry or Immunofluorescence, in tumor cells, and using corresponding healthy cells or tissue, such as tumor stromal cells, as an internal control for normal H3K36me3 levels. The term immunohistochemistry (IHC) as used herein designates an antibody- based detection technique. In said technique antibodies are used to detect cell- associated antigens, such as H3K36me3, and the technique provides semi- quantitative data about target protein expression, modification, distribution, and / or localization. The types of samples used in IHC are generally solid tumor biopsies, e.g. formalin-fixed paraffin-embedded (FFPE) tissue or frozen tissue. IHC traditionally uses chromogenic reagents as visualization agents to detect target antigens. For example, an enzyme such as horseradish peroxidase (HRP) may be conjugated to the antigen-specific antibody which localizes it to the target site. HRP converts a soluble substrate, such as 3,3′-diaminobenzidine (DAB) or 3- amino-9-ethylcarbazole (AEC), into a colored precipitate at the antigen site. The term immunofluorescence (IF) as used herein designates an antibody-based detection technique. In said technique antibodies are used to detect cell- HE 269663 associated antigens, such as H3K36me3, and the technique provides semi- quantitative data about target protein expression, modification, distribution, and / or localization. The types of samples used in IF are generally solid tumor biopsies, e.g. formalin-fixed paraffin-embedded (FFPE) tissue or frozen tissue. IF uses fluorescent compounds (fluorophores), which re-emit light upon light excitation, for fluorescence imaging to detect target antigens. For both chromogenic and fluorescent detection, the label may be conjugated directly to a primary antibody that binds to the antigen. Frequently, IHC and IF use an indirect method of detection in which a secondary antibody, directed against the primary antibody, carries the label (chromogenic or fluorescent). The indirect method may be more sensitive than using a directly labeled primary antibody, because multiple labeled secondary antibodies can bind to a single primary antibody so that the signal is amplified. The term “HMT” or “HMTs” (histone methyltransferases) as used herein refers to histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of a first, a second or a third methyl group to lysine and / or arginine residues of histone proteins. The term “SETD2” (SET Domain Containing 2) as used herein refers to a histone methyltransferase that is specific for the lysine residue 36 within the histone H3 protein. The SETD2 protein has the capability of adding a third methyl moiety to dimethylated H3K36, and reduction or loss of its enzymatic activity can cause a reduction or loss of H3K36me3. Loss of H3K36me3 due to homozygous mutation in or homozygous “deep” deletion of SETD2 gene can lead to a reduction of deoxynucleotide triphosphates (dNTPs, e.g. dATP, dGTP, dCTP, dTTP), required for DNA replication. A SETD2-mutated gene, which may also be referred to herein as a SETD2 gene having an inactivating mutation, or a dysregulated SETD2 gene, is a gene, which fails to produce a or produces reduced quantities of functional HE 269663 SETD2 protein in a cell. Mutations or deletions may for example be assessed by Next Generation Sequencing (NGS), and reduced expression may be assessed by qPCR, western blot, or IHC techniques. The term “ASH1L” (Absent Small And Homeotic Disks Protein 1 Homolog, also called huASH1, ASH1, ASH1L1, ASH1-like, or KMT2H) as used herein refers to a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene and is a histone methyltransferase promoting the dimethylation of H3K36. ASH1L mutation can lead to reduction of H3K36me2. Loss of methylation of H3K36me2 due to mutations in ASH1L can lead to a reduction of deoxynucleotide triphosphates (dNTPs, e.g. dATP, dGTP, dCTP, dTTP). An ASH1L-mutated gene, which may also be referred to herein as an ASH1L gene having an inactivating mutation, or a dysregulated ASH1L gene, is a gene, which fails to produce or produces reduced quantities of functional ASH1L protein in a cell. Mutations may for example be assessed by Next Generation Sequencing (NGS), and reduced expression may be assessed by qPCR, western blot, or IHC techniques. The term “NSD” (the nuclear receptor binding SET domain protein) as used herein refers to a family of histone lysine methyltransferases. The SET domain possesses methyltransferase activity in the multidomain NSDs. NSD1 (KMT3B), NSD2 (WHSC1 / MMSET), and NSD3 (WHSC1L1) are members of the NSD protein lysine methyltransferase family, which modulate the expression of target genes through methylation of lysine 36 on histone H3 (H3K36). An NSD-mutated gene, which may also be referred to herein as an NSD gene having an inactivating mutation, or a dysregulated NSD gene, is a gene, which fails to produce or produces reduced quantities of functional NSD protein in a cell. Mutations may for example be assessed by Next Generation Sequencing (NGS) and reduced expression may be assessed by qPCR, western blot, or IHC techniques. The term “SETD3” (SET Domain Containing 3) as used herein refers to a SET domain-containing protein which acts as methyltransferase for H3K36 and actin. HE 269663 The SETD3 protein has the capability of adding a second and third methyl moiety to mono- and dimethylated H3K36, and reduction or loss of its enzymatic activity may cause a reduction or loss of H3K36me2 and H3K36me3 accordingly. A SETD3-mutated gene, which may also be referred to herein as a SETD3 gene having an inactivating mutation, or a dysregulated SETD3 gene, is a gene, which fails to produce or produces reduced quantities of functional SETD3 protein in a cell. Mutations or deletions may for example be assessed by Next Generation Sequencing (NGS), and reduced expression may be assessed by qPCR, western blot, or IHC techniques. The term “SETMAR” as used herein refers to a SET domain-containing protein that confers its histone methyltransferase activity, on Lys-4 and Lys-36 of Histone H3, both of which are specific tags for transcriptional activation. SETMAR has been identified as a repair protein as it mediates dimethylation at Lys-36 at double- strand break locations. A SETMAR-mutated gene, which may also be referred to herein as an SETMAR gene having an inactivating mutation, or a dysregulated SETMAR gene, is a gene, which fails to produce or produces reduced quantities of functional SETMAR protein in a cell. Mutations may for example be assessed by Next Generation Sequencing (NGS) and reduced expression may be assessed by qPCR, western blot, or IHC techniques. The term “SMYD2” as used herein refers to a SET domain-containing protein. The SET domain of SMYD2 mediates H3K36 dimethylation. A SMYD2-mutated gene, which may also be referred to herein as an SMYD2 gene having an inactivating mutation, or a dysregulated SMYD2 gene, is a gene, which fails to produce or produces reduced quantities of functional SMYD2 protein in a cell. Mutations may for example be assessed by Next Generation Sequencing (NGS) and reduced expression may be assessed by qPCR, western blot, or IHC techniques. The term “KDM4 family” as used herein refers to a group of histone demethylases composed of at least the proteins KDM4A, KDM4B, KDM4C, KDM4D, KDM4E and HE 269663 KDM4F, which are frequently overexpressed in various cancers such as breast cancer. Specifically KDM4A, B and C exert their enzymatic activity on lysine 36 of histone H3. Overexpression of one or several of those histone demethylases can lead to low levels of H3K36me3. The term “KDM4A” (Lysine Demethylase 4A) as used herein refers to a lysine demethylase that plays an oncogenic role in carcinoma by promoting cell migration and invasion. Overexpression of KDM4A can lead to low levels of H3K36me3. A cell overexpressing KDM4A is a cell that exhibits a higher activity of KDM4A than a cell normally expressing KDM4A. The KDM4A overexpression is for instance measured by identifying the expression level of the gene product in a cell (e.g., KDM4A mRNA transcript count or KDM4A protein level) and comparing the same with the expression level of a corresponding healthy cell or tissue. For example, overexpression may be assessed by qPCR, western blot, or IHC techniques. The same considerations apply for “KDM4B” (Lysine Demethylase 4B) and “KDM4C” (Lysine Demethylase 4C). The term “KDM2 family” as used herein refers to a group of histone demethylases affecting the methylation status of H3K36 and is composed of at least KDM2A and KDM2B. The term “KDM2A” (Lysine Demethylase 2A) as used herein refers to a lysine demethylase and plays a role in chromatin remodelling and transcription. Overexpression of KDM2A can lead to low levels of H3K36me3 by removing the third methyl group from H3K36me3 and converting it into H3K36me2. For example, overexpression may be assessed by qPCR, western blot, or IHC techniques. The term “KDM2B” as used herein refers to a lysine demethylase that plays a role in chromatin remodelling and transcription. Overexpression of KDM2B can lead to low levels of H3K36me2 by removing the second methyl group from H3K36me2 HE 269663 and making it inaccessible for histone methyltransferases for trimethylation. For example, overexpression may be assessed by qPCR, western blot, or IHC techniques. In some aspects, the mutation of a certain gene may be a homozygous mutation, which may lead to a complete deletion or knock-out of the concerned gene. For instance a mutation of the SETD2 gene may be a homozygous mutation. In some aspects, the term “reduced expression” or “overexpression” as used herein refers to an abnormal expression level of a given biomarker in tumor cellscompared to the expression level in corresponding (or comparable) healthy cellsor tissue. The person of skill in the art would understand that the reference healthy cell or tissue for “normal” expression levels may vary depending on the solid tumor type considered. In some aspects, it may preferably be a healthy cell or tissue ofthe same origin. For example, reduced expression or overexpression may beassessed by qPCR, western blot, or IHC techniques. As used herein, the expression "solid tumor" refers to a cancerous abnormal mass or lump of tissues that does not contain cysts or liquid areas. Solid tumors can be benign (non-cancerous) or malignant (cancerous) but the present application only refers to cancerous tumors. Solid tumors may occur in several types of tissues and organs in the body including the lungs, colon, breast, prostate, and other areas. Unlike hematological malignancies that affect the blood, lymph nodes and bone marrow, solid tumors are typically localized but can metastasize to other parts of the body. As used herein, the expression "solid tumor is associated with", refers to a solid tumor derived from the primary type of cancer affecting the patient, e.g. by way of metastasis. For instance, a solid tumor that is associated with breast cancer may be a tumor located outside the breast and that is derived from breast cancer. HE 269663 As used herein, the term "subject" refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject. As used herein, terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to therapeutic measures that cure, slow down, lessen symptoms of, and / or halt or reverse progression or severity of a diagnosed pathologic condition, disorder or disease. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder. In certain embodiments, a subject is successfully "treated" for cancer according to the methods of the present invention if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; a reduction in the tumor size or burden; inhibition of or an absence of cancer cell infiltration into peripheral organs; inhibition of or an absence of tumor metastasis; inhibition of or an absence of tumor growth; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; reduction in tumorigenicity, tumorigenic frequency, or tumorigenic capacity, of a tumor; reduction in the number or frequency of cancer stem cells in a tumor; differentiation of tumorigenic cells to a non-tumorigenic state; as well as increased chances to have a complete response (CR), a partial response (PR), increased chances to have the disease under control (e.g. CR, PR, stable disease SD), to live longer without progression, and without disease, to live longer, decreased chances to have a progressive disease (PD) and to increase the time until progression. Collectively for groups or populations of patients, successful treatment may result in endpoints such as increased 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. HE 269663 As used herein, the term “solid tumor treatment” refers to any treatment or therapy approved by at least one health authority such as FDA or EMA, or under clinical trial investigation to treat solid tumors. “Initial solid tumor treatment” refers to the first solid tumor treatment administered to a given patient diagnosed with solid tumor (e.g. first-line therapy). “Prior” or “previous solid tumor treatment” refers to one or more solid tumor treatment administered to a given patient diagnosed with solid tumor before the methods according to the present invention. As used herein when referring to a solid tumor or cancer, or to a patient suffering from such a solid tumor or cancer, the terms “relapse”, “to relapse”, “recurrence”, “to recur” mean a worsening of the disease and / or of the signs and symptoms of the disease after a period of improvement, stabilization or disease absence. As used herein when referring to a solid tumor or cancer, or to a patient suffering from such a solid tumor or cancer, the terms “progression” or “to progress” means when the cancer becomes worse, either due to existing lesions that are growing and / or due to appearance of new lesions. As used herein, the term “treatment day” or “WEE1 inhibitor treatment day” refers to a day on which the WEE1 inhibitor is administered according to the methods of the present invention. As used herein, the term "therapeutically effective amount" refers to an amount of a drug effective to "treat" a disease or disorder in a subject or patient. In some embodiments, the term "therapeutically effective amount" of a given drug when used in monotherapy, such as a "WEE1 therapeutically effective amount” refers to an amount of a drug effective to "treat" a disease or disorder in a subject or patient, whilst keeping an acceptable safety profile. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the tumor size or burden; inhibit (i.e., slow to some extent and in a certain embodiment, stop) cancer cell infiltration into peripheral organs; inhibit (i.e., HE 269663 slow to some extent and in a certain embodiment, stop) tumor metastasis; inhibit, to some extent, tumor growth; relieve to some extent one or more of the symptoms associated with the cancer; and / or result in a favorable response such as increased 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 increased time to tumor progression (TTP) or any combination thereof. See the definition herein of "treating". A “treatment cycle” of e.g. 21 days or 28 days refers to a time period of e.g. 21 consecutive days or 28 consecutive days during which a drug of interest is administered at one or more days of the treatment cycle. As used herein, “RECIST v1.1” or “RECIST 1.1 criteria” refers to the “New response evaluation criteria in solid tumors, Revised RECIST guideline (version1.1)” set out in Eisenhauer E.A. et al., European Journal of Cancer 45 (2009) 228– 247. In some embodiments, the RECIST guideline may evolve in the future and (a) new version(s) may be released and considered. As used herein, "Progression free survival" (PFS) in a clinical trial refers to the time from enrollment, first administration or randomization until disease progression or death from any cause, whichever occurs first. PFS is generally measured using the RECIST 1.1 criteria, and generally summarized using the Kaplan-Meier method. As used herein, "Time to Tumor Progression" (TTP) in a clinical trial refers to the time from enrollment, first administration or randomization to disease progression. TTP is generally measured using the RECIST 1.1 criteria. HE 269663 As used herein, a "complete response" or "complete remission" or "CR" in a clinical trial indicates that there is no detectable evidence of tumor in response to treatment. This does not always mean the cancer has been cured. Complete response in solid tumors is generally measured using the RECIST 1.1 criteria. As used herein, a "partial response" or "PR" in a clinical trial refers to a decrease in the size or volume of one or more tumors or lesions, or in the extent of cancer in the body, in response to treatment according to the RECIST 1.1 criteria. As used herein, a "Stable disease" or "SD" in a clinical trial refers to disease without progression or relapse. In stable disease there is neither sufficient tumor shrinkage to qualify for partial response nor sufficient tumor increase to qualify as progressive disease taking as reference the smallest sum diameters while on the study. Generally measured using the RECIST 1.1 criteria. As used herein, “Progressive disease" or "PD" in a clinical trial or study refers to the appearance of one or more new lesions or tumors and / or the unequivocal progression of existing target and / or non-target lesions and / or at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Generally measured using the RECIST 1.1 criteria. As used herein, “Objective Response Rate” refers to the percentage of subjects in a study, clinical trial or treatment group who have a partial or complete response to the treatment. Generally measured using the RECIST 1.1 criteria. HE 269663 As used herein, “Overall Response” or “Objective Response” refers to the response to treatment of a given patient in a study, clinical trial or treatment group at a given assessment point. Generally measured using the RECIST 1.1 criteria. As used herein, “Best Overall Response” refers to the best response recorded for a given patient in a study, clinical trial or treatment group from the baseline assessment (enrollment, start of the treatment or randomization) until disease progression / recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) or death from any cause. Generally measured using the RECIST 1.1 criteria. As used herein, “Disease Control Rate” refers to the percentage of patients in a study, clinical trial or treatment group who have achieved complete response, partial response or stable disease to a therapeutic intervention. Generally measured using the RECIST 1.1 criteria. As used herein, "Duration of response" (DoR) refers to the time from earlier response (PR or better) to disease progression or death from any cause. Generally measured using the RECIST 1.1 criteria. As used herein, "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 censored at the date last known alive. Improvement in OS includes a prolongation in life expectancy as compared to naive or untreated individuals or patients. Overall survival refers to the situation wherein a patient remains alive for a defined period of time, such as one year, five years, etc., e.g., from the time of randomization or first treatment. As used herein, the term "pharmaceutical formulation" or “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no HE 269663 additional components which are unacceptably toxic to a subject to which the formulation would be administered. As used herein, the expression “oral dosage form” refers to any form of a pharmaceutical composition that is suitable for oral administration. Information introduced in the present disclosure by the wording „in some aspects“, “in specific aspects”, “in some items”, or the like, is to be understood such that it can be freely combined with any other information provided elsewhere in the present disclosure, irrespective whether this is also introduced by the wording „in some aspects“, “in specific aspects”, “in some items”, or any other wording. An exception to this general rule applies however for those instances, where the information to be combined is no consistent or even contradictory or mutually exclusive, so that the resulting combined information would be inconsistent, unclear and / or not technically meaningful. WEE1 inhibitor In the methods of the present invention, the WEE1 inhibitor may be any compound described in the patent applications WO2018090939, WO2022155202, WO2022256680, WO2013126656 and WO2008153207, each of which is fully incorporated herein by reference, with the proviso that adavosertib (AZD-1775) is a WEE1 inhibitor not to be used according to the present invention. Specifically, the WEE1 inhibitor may be a compound of one of the following formulas, or a pharmaceutically acceptable salt thereof: HE 269663 also known as Zn-C3 (azenosertib); also known as IMP7068 (as described in WO2018090939); also known as STC-8123 (as described in WO2022155202); also known as ATRN-W1051 (as described in WO2022256680); HE 269663 also known as PD0407824; also known as CJM061; also known as SC0191; also known as PD0166285; HE 269663 (as described in WO2013126656), or (as described in WO2008153207). In other aspects, the WEE1 inhibitor is any compound described in the patent applications WO2018090939, WO2022155202, WO2022256680, WO2013126656 and WO2008153207, each of which is fully incorporated herein by reference, which meets the definition of a selective WEE1 inhibitor herein, or any specific compound among the structures depicted above, provided it meets the definition of a selective WEE1 inhibitor herein. In some aspects, the WEE1 inhibitor is the compound SY-4835, or any compound described in patent application WO2020192581, especially the compounds disclosed in claims 3 and 6 of this document and the compound of Example 59 of CN111718348 identified as SY-4835 by Q. Ye et al., Bioorganic & Medicinal Chemistry, 2023, 87, 117312, https: / / doi.org / 10.1016 / j.bmc.2023.117312.In other aspects, the WEE1 inhibitor is compound of formula (I) . HE 269663 Methods of treatment The present invention relates to the use of a WEE1 inhibitor, such as a selective WEE1 inhibitor, for treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone methylation. In some aspects of the present invention, the WEE1 inhibitor is compound of formula (I) . In some aspects of the present invention, the solid tumor is characterized by a reduced level of histone H3K36 trimethylation (H3K36me3), or loss of histone H3K36 trimethylation (H3K36me3). In some aspects of the present invention, a therapeutically effective amount of the WEE1 inhibitor is administered to the subject in need thereof, wherein the solid tumor has been previously identified as a solid tumor with reduced histone H3K36 trimethylation (H3K36me3), or loss of histone H3K36 trimethylation (H3K36me3). In some aspects of the present invention, the WEE1 inhibitor induces cell death in a cancer cell with reduced histone H3K36 trimethylation (H3K36me3), or loss of histone H3K36 trimethylation (H3K36me3), wherein the use or method comprises contacting the cancer cell with an effective amount of the WEE1 inhibitor. Such contact preferably occurs in the patient’s body, upon the patient receiving WEE1 inhibitor treatment. HE 269663 In some aspects of the present invention, the histone methylation status, such as reduced histone methylation, may be regarded as a comprehensive indicator for sensitivity to WEE1 inhibitor treatment. In more specific aspects, the H3K36 methylation status, such as H3K36 trimethylation status, may be regarded as a comprehensive read-out for multiple posttranslational-modification alterations linked to impaired DNA damage repair, and thus a comprehensive indicator for sensitivity to WEE1 inhibitor treatment. In some aspects, the H3K36 methylation status, such as H3K36 trimethylation status, is directly used as a biomarker indicative of reduced histone methylation, wherein a reduced histone H3K36 trimethylation (H3K36me3), or a loss of histone H3K36 trimethylation (H3K36me3) is considered to be “biomarker positive”. H3K36me3 reduction or loss can thus be used as a predictive biomarker that enables patient selection, for example through immunohistochemistry (IHC) or immunofluorescence (IF). In more specific aspects, reduction or loss of H3K36me3 may be measured by IHC, for example using an IHC scoring system based on tumor cell staining intensity compared to tumor stromal cell staining intensity. Tumor stromal cells are cells of the connective tissue which are scattered in between tumor cells and build the tumor microenvironment. They represent healthy cells and include, for example, fibroblasts, immune cells and endothelial cells. In a particular instance, scores may be defined as 0, 1, 2 or 3, with a score of 0 or 1 being considered biomarker positive, namely reduction or loss of H3K36me3. More specifically, the scoring could be defined as follows: 0 = H3K36me3 negative tumor cells, i.e. H3K36me3 loss; 1 = predominant staining intensity of tumor cells is lower than predominant staining intensity in tumor stromal cells, i.e. H3K36me3 reduction; HE 269663 2 = predominant staining intensity of tumor cells is equal to predominant staining intensity in tumor stromal cells; and 3 = predominant staining intensity of tumor cells is greater than predominant staining intensity in tumor stromal cells. Alternatively, an H3K36me3 assay and scoring may be used, as further defined in a dedicated section below. In the same or other aspects of the present invention, indirect markers of histone methylation status may be used, such as inactivating or dysregulating mutation, deletion or amplification of genes involved in histone methylation, or expression of the respective gene products. More specifically, one or more such indirect markers of H3K36me3 reduction or loss may be used. A cell having reduced H3K36me3 may for instance be a cell that exhibits a mutation in a gene of a protein that regulates or controls the methylation of lysine 36 of Histone H3. In some aspects of the present invention, the biomarker indicative of reduced histone methylation is at least one of - mutation of a histone methyltransferase (HMT) gene or reduced expression of an HMT gene product, - mutation of SETD2 gene or reduced expression of a SETD2 gene product, - mutation of ASH1L gene or reduced expression of an ASH1L gene product, - mutation of NSD1 gene or reduced expression of an NSD1 gene product, - mutation of NSD2 gene or reduced expression of an NSD2 gene product, - mutation of NSD3 gene or reduced expression of an NSD3 gene product, - mutation of SETD3 gene or reduced expression of a SETD3 gene product, HE 269663 - mutation of SETMAR gene or reduced expression of a SETMAR gene product, - mutation of SMYD2 gene or reduced expression of a SMYD2 gene product, - overexpression of a histone demethylase (HDM) of the KDM4 family, such as KDM4A, KDM4B or KDM4C, or - overexpression of a histone demethylase (HDM) of the KDM2 family, such as KDM2A or KDM2B. These cancer-related genetic alterations have been reported to cause a reduction in H3K36me3 levels, the most frequent being reduced expression and / or mutation of SET domain-containing 2 (SETD2). SETD2 alterations are observed in approximately 5% of all solid tumors, with a high prevalence in e.g. renal cell carcinoma (18% mutated SETD2 (TCGA-data)), breast (generally low SETD2 mRNA levels), and pancreatic cancer (10% mutated SETD2, (TCGA-data). SETD2 is a histone methyl transferase (HMT) with the capability of adding a third methyl moiety to dimethylated lysine-36 of histone H3 (H3K36). Reduction or loss of the enzymatic activity of SETD2, for example due to one or more mutations in the SETD2 gene, accordingly can cause a reduction or loss of H3K36me3. SETD2 protein under-expression and gene mutation may be associated with poor prognosis in breast cancer and renal cancer. Despite the rate of SETD2 perturbations in renal cell carcinoma, i.e., approximately 20%, up to 60% of these tumors have reduced levels of H3K36me3, suggesting that factors other than SETD2 may also impact the methylation status of histone H3. Dysregulation, mutation, loss or alteration of posttranslational histone modifiers other than SETD2, for example of other histone methytransferases (HMTs), can HE 269663 also cause a reduction of H3K36me3. The altered HMT can be one or more of ASH1L, NSD1, NSD2, NSD3, SETD3, SETMAR and SMYD2. In addition to dysregulation, mutation, loss or alteration of HMTs, overexpression of histone demethylases (HDMs), such as KDM4A (Lysine Demethylase 4A), KDM4B (Lysine Demethylase 4B), KDM4C (Lysine Demethylase 4C), KDM2A (Lysine Demethylase 2A), or KDM2B (Lysine Demethylase 2B) may also lead to reduced or low levels of H3K36me3. In some aspects of the present invention, the use or method comprises administering to the subject in need thereof a therapeutically effective amount of the WEE1 inhibitor, wherein the solid tumor has been previously identified as having an inactivating or dysregulating mutation in a histone methyltransferase (HMT) gene, or reduced expression of an HMT gene product. In some aspects of the present invention, the solid tumor has been previously identified as having a reduced level or degree of trimethylation of H3K36, or loss of trimethylation of H3K36. In some aspects, the present invention relates to a method of treating a solid tumor in a patient, comprising - assessing whether the solid tumor exhibits a biomarker indicative of reduced histone methylation, and - treating the patient with a WEE1 inhibitor, such as a selective WEE1 inhibitor, if the assessment is positive (or the tumor is biomarker positive). SETD2 may be one factor that reduces H3K36me3. Heterozygous mutation or loss of SETD2 gene may lead to partial reduction in H3K36me3, whereas homozygous mutation or loss of SETD2 gene may incur complete loss of H3K36me3. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the HE 269663 SETD2 gene, or reduced expression of a SETD2 gene product. In specific aspects of the present invention, the solid tumor has been previously identified as having a homozygous loss of functional SETD2. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the ASH1L gene, or reduced expression of an ASH1L gene product. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the NSD1 gene, or reduced expression of an NSD1 gene product. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the NSD2 gene, or reduced expression of an NSD2 gene product. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the NSD3 gene, or reduced expression of an NSD3 gene product. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the SETD3 gene, or reduced expression of a SETD3 gene product. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the SETMAR gene, or reduced expression of a SETMAR gene product. In some aspects of the present invention, the solid tumor has been previously identified as having an inactivating or dysregulating mutation in the SMYD2 gene, or reduced expression of a SMYD2 gene product. HE 269663 In some aspects, the mutation of a certain gene may be a homozygous mutation, which may lead to a complete deletion or knock-out of the concerned gene. For instance a mutation of the SETD2 gene may be a homozygous mutation. In some aspects of the present invention, the solid tumor has been previously identified as having an overexpression of lysine demethylases (HDMs), for example HMDs of the KDM2 or KDM4 family, such as KDM4A (Lysine Demethylase 4A), KDM4B (Lysine Demethylase 4B), KDM4C (Lysine Demethylase 4C), KDM2A (Lysine Demethylase 2A) or KDM2B (Lysine Demethylase 2B). In some aspects, the solid tumor may be tested for several biomarkers indicative of reduced histone methylation. A reduction of H3K36me3 or loss thereof, irrespective of the underlying molecular change causing such reduction or loss, may sensitize or hypersensitize the solid tumor to WEE1 inhibition, through synthetic lethal interaction. As can be seen from Example 4 herein, H3K36me3 reduction or loss occurs most frequently in renal cell carcinoma (RCC) but also occurs in breast and pancreatic cancers in more than 20% of cases stained. Other types of cancers in which reduced H3K36me3 has been observed include lung cancer, prostate cancer, high grade glioma (between about 5% and about 10% in Example 4). Reduced H3K36me3 was also observed in colorectal cancer, head and neck cancer, ovarian cancer, bladder cancer and melanoma (less than 5% in Example 4). In some aspects of the present invention, the solid tumor is or is associated with breast cancer, in particular triple-negative breast cancer (TNBC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer, prostate cancer or high-grade glioma. HE 269663 In some aspects of the present invention, the solid tumor having a reduced histone H3K36 trimethylation (H3K36me3), or loss of histone H3K36 trimethylation (H3K36me3), is or is associated with a cancer, wherein the cancer is breast cancer, in particular triple-negative breast cancer (TNBC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer, prostate cancer or high-grade glioma. In some aspects of the present invention, the solid tumor is an advanced solid tumor, such as locally advanced or metastatic. In some aspects of the present invention, the cancer is newly diagnosed. In some aspects of the present invention, the cancer is metastatic or locally advanced. In some aspects of the present invention, the solid tumor has recurred or progressed after initial or prior treatment. Doses, schedules and routes of administration As used herein, the term “about” describes a deviation from the indicated value of ±10%. The individual values are to be understood as describing ranges between any of the described values. In the methods of the present invention, the WEE1 inhibitor is used in a therapeutically effective amount for the intended purpose. The WEE1 inhibitor may generally be administered at doses ranging from about 30 to about 1000 mg of free base per treatment day, preferably about 30 to about 720 mg of free base per treatment day. HE 269663 In some aspects of the present invention where the WEE1 inhibitor is compound of formula (I), such compound of formula (I) may be administered at doses ranging from about 30 to about 1000 mg of free base, preferably ranging from about 90 to about 720 mg, or about 100 to about 720 mg of free base, per treatment day, even more preferably ranging from about 100 to about 520 mg of free base, per treatment day. For example, the WEE1 inhibitor, especially 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 free base per treatment day. Preferably, the WEE1 inhibitor 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 free base per treatment day. In a more specific aspect, the WEE1 inhibitor, especially the compound of formula (I), may be administered at doses 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. For example, the WEE1 inhibitor 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 another specific aspect, the WEE1 inhibitor, especially the compound of formula (I), may be administered at doses of about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 520, about 550, HE 269663 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 a more specific embodiment, the WEE1 inhibitor may be administered at doses of about 100, about 150, about 200, about 300, about 400 or about 520 mg of free base per treatment day. In another aspect, the WEE1 inhibitor, especially the compound of formula (I), may be administered at doses ranging from 100 to 1000 mg of free base, preferably ranging from 150 to 720 mg of free base, per treatment day. For example, the WEE1 inhibitor may 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 WEE1 inhibitor may be administered at doses of 100, 150, 200, 300, 400, 520 or 720 mg of free base per treatment day. In a particularly preferred aspect the WEE1 inhibitor, especially the compound of formula (I), may be administered at a dose ranging from 30 to 1000 mg of free base per treatment day, preferably a dose ranging from 30 to 720 mg of free base per treatment day, more preferably a dose ranging from 100 to 720 mg of free base, even more preferably a dose ranging from 100 to 520 mg of free base per treatment day, or at a dose of about 30, about 60, about 90, about 120, about 150, about 200, about 260, about 350, or about 460 mg of free base per treatment day, and / or as a single dose or twice a day (BID) on a treatment day. For example, the WEE1 inhibitor, especially the compound of formula (I), may preferably be administered at a dose of 30, 60, 120, 150, 200, 260, 350 or 460 mg of free base per treatment day. In a preferred aspect, when the WEE1 inhibitor is compound of formula (I), it is administered at a dose ranging between 120 and 260 mg of free base per treatment day, preferably at a dose ranging between 150 and 260 mg of free base per treatment day, preferably at a dose of 260 mg of free base per treatment day. HE 269663 In a particularly preferred aspect the WEE1 inhibitor, especially the compound of formula (I), may be administered as a single dose or twice a day (BID) on a treatment day. In some aspects, the WEE1 inhibitor, especially the compound of formula (I), may be administered a) daily over a 21-day cycle, or b) on 3, 4 or 5 consecutive days per week of a 21-day cycle, or c) on days 1 to 3 of a 21-day cycle, or d) on days 1 to 3 and 8 to 10 of a 21-day cycle, or e) on days 1 to 3, 8 to 10 and 15 to 17 of a 21-day cycle, or f) on days 1 to 5 of a 21-day cycle, or g) on days 1 to 5 and 8 to 12 of a 21-day cycle, or h) on days 1 to 5, 8 to 12 and 15 to 19 of a 21-day cycle, or i) on days 1 to 14 of a 21-day cycle, or j) on days 1 to 5 of a 28-day cycle, or k) on days 1 to 5 and 8 to 10 of a 28-day cycle, or l) on days 1 to 5 and 8 to 12 of a 28-day cycle, or m) on days 1 to 5, 8 to 10 and 15 to 17 of a 28-day cycle, or n) on days 1 to 5, 8 to 12 and 15 to 19 of a 28-day cycle, or o) on days 1 to 3 of a 28-day cycle, or p) on days 1 to 3 and 8 to 10 of a 28-day cycle, or q) on days 1 to 3, 8 to 10 and 15 to 17 of a 28-day cycle. In particularly preferred aspects, the WEE1 inhibitor, especially the compound of formula (I), may be administered daily in a 21-day cycle. In some aspects, a change in the administration days, such as reducing the number of treatment days in a 21-day cycle, may be considered advantageous especially if the patient develops side-effects upon daily administration. For example, it is possible to administer the WEE1 inhibitor daily during a first 21-day HE 269663 cycle, or more, and then administer the WEE1 inhibitor on a reduced number of days in subsequent 21-day cycles. In some aspects, the WEE1 inhibitor, especially the compound of formula (I), may be administered at approximately the same time on each treatment day. The WEE1 inhibitor may be administered for 1, 2, 3, 5, 4, 5, 6 or more 21-day or 28-day cycles. Typically, there are no breaks between any consecutive cycles, i.e. the day following a prior 21-day cycle or prior 28-day cycle may be the first day of the consecutive cycle. In some aspects, the treatment with the WEE1 inhibitor such as compound of formula (I) may continue until progression of disease, unacceptable toxicity, patient’s decision to stop, discontinuation as per physician’s decision, initiation of subsequent antineoplastic treatment, the end of a clinical study, or death. In a preferred aspect, the WEE1 inhibitor is compound of formula (I), administered daily over a 21-day cycle, at a dose of about 260 mg of free base per treatment day. In such aspect, compound of formula (I) may be administered for 1, 2, 3, 5, 4, 5, 6 or more 21-day cycles. Typically, there are no breaks between any consecutive cycles, i.e. the day following a prior 21-day cycle may be the first day of the consecutive cycle. Such schedule of administration of compound of formula (I) may thus also be described as daily, at a dose of about 260 mg of free base per treatment day. The treatment with compound of formula (I) may continue until progression of disease, unacceptable toxicity, patient’s decision to stop, discontinuation as per physician’s decision, initiation of subsequent antineoplastic treatment, the end of a clinical study, or death. In some aspects of the present invention, the WEE1 inhibitor is administered at approximately the same time on each treatment day, e.g. at the same time ± about 60 min, preferably ± 60 min on each treatment day, for example in a given cycle. HE 269663 In more specific embodiments, the WEE1 inhibitor is administered in the morning, for example between 5 a.m and noon. In some aspects of the uses and methods according to the present invention, the WEE1 inhibitor is administered in a fed state. In alternative aspects of the uses and methods according to the present invention, the WEE1 inhibitor is administered orally on an empty stomach. For example, the WEE1 inhibitor is administered after the patient has fasted, preferably for at least 4 hours. In preferred aspects of the uses or methods according to the present invention, the WEE1 inhibitor is administered irrespective of food status of the patient. In some aspects, the treatment schedule or regimen is in accordance with any one of the aspects described herein, wherein the solid tumor has recurred or progressed after initial treatment (second line treatment). In some aspects, the treatment schedule or regimen is in accordance with any one of the aspects described herein, wherein the solid tumor has recurred or progressed after prior treatment. In some aspects, the treatment schedule or regimen is in accordance with any one of the aspects described herein, wherein the patient is naïve of any previous treatment (first line treatment). In some aspects, the treatment schedule or regimen is in accordance with any one of the aspects described herein, wherein the WEE1 inhibitor is administered in monotherapy. HE 269663 In some aspects, the treatment schedule or regimen is in accordance with any one of the aspects described herein, wherein the WEE1 inhibitor is administered orally. In some aspects, the treatment schedule or regimen is in accordance with any one of the aspects described herein, wherein the compound of formula (I) is administered orally by means of a capsule as described herein. In some aspects, the treatment schedule or regimen is in accordance with any one of the aspects described herein, wherein the WEE1 inhibitor, e.g. compound of formula (I), is administered as a single dose per treatment day (QD), or in two doses per treatment day (BID). In some embodiments, the treatment schedule or regimen is in accordance with anyone of the embodiments described herein and presents advantageous properties in increasing anti-tumor activity (e.g. ORR, BOR, DOR and / or DCR such as assessed per RECIST v 1.1) and / or time to event outputs (e.g. PFS and / or OS such as assessed per RECIST v 1.1) in a cancer with which a given patient’s solid tumor is associated, with an acceptable safety profile and no detrimental effect on the patient’s quality of life. In some embodiments, the treatment schedule or regimen is in accordance with anyone of the embodiments described herein, wherein treatment duration is until either progression of disease, unacceptable toxicity, or participant withdrawal. Pharmaceutical compositions Pharmaceutical compositions of the present invention that are suitable for oral administration (oral dosage forms) may be presented in solid or liquid form. Suitable solid oral dosage forms include capsules, tablets, powders or granules and the like, each containing a predetermined amount of the active ingredient. Suitable liquid oral dosage forms include solutions, emulsions or suspensions. HE 269663 Pharmaceutical compositions of the present invention may also be in the form of sustained release formulations. Any inert ingredient that is commonly used as a carrier or diluent may be used as pharmaceutically acceptable excipient in the solid oral formulations of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof. Preferred diluents include, for example, microcrystalline cellulose, anhydrous lactose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium, sodium starch glycolate) and a lubricant (e.g., magnesium stearate), and may additionally 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 solubilizing agent (e.g., cyclodextrin), a plasticizer (e.g., triacetin), an emulsifier (e.g, sodium lauryl sulfate), a stabilizing agent (e.g., povidone, ascorbic acid), a viscosity increasing agent (e.g., hydroxypropyl methylcellulose), a sweetener (e.g., sucrose), a film forming agent (e.g., cellulose based systems, polymers), a colorant (e.g., iron oxide), a flavoring agent or any combination thereof. The oral pharmaceutical compositions of the present invention may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free- flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by HE 269663 molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments of the present invention, the WEE1 inhibitor is formulated in a pharmaceutical composition being an oral dosage form. In more specific embodiments, the WEE1 inhibitor is in the form of a solid oral dosage form, such as tablets or capsules (which may comprise powder or minitablets). Capsules may be soft or hard capsules. For example, the WEE1 inhibitor is formulated in capsules, such as hard gelatin capsules comprising minitablets, each minitablet containing 10 mg of active ingredient. In some embodiments, the WEE1 inhibitor is a compound of 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 may readily be produced to cover alternative dose levels. In some embodiments, the solid oral dosage form is packaged in a blister and / or a bottle. In some embodiments, one, two, three, four, five or six unit dosage forms are administered per intake of the WEE1 inhibitor. Preferably, one or two unit dosage form(s) is administered per intake of the WEE1 inhibitor. For example, when formulated as capsules containing minitablets, the excipients in each minitablet may include microcrystalline cellulose, anhydrous lactose, hydroxypropylcellulose, sodium starch glycolate, anhydrous colloidal silica and magnesium stearate. Alternative excipients may be used in an oral dosage form. Kit The present invention also relates to a kit comprising the WEE1 inhibitor for use, or for use in the preparation of a medicament for, treating solid tumors in a patient in need thereof. In some aspects, the kit comprises a WEE1 inhibitor, in particular HE 269663 the compound of formula (I), as well as instructions for use in treating solid tumors, in particular in accordance with the uses and methods described herein. Optionally, in specific aspects, the kit may comprise, in separate dosage forms or containers, the WEE1 inhibitor, in particular the compound of formula (I), as well as another drug. H3K36me3 assay The present invention further relates to an H3K36me3 assay intended to identify solid tumors with reduced or loss of H3K36 trimethylation (H3K36me3). Such an H3K36me3 assay may be used for determining eligibility of a subject having a solid tumor for treatment with a WEE1 inhibitor. The H3K36me3 assay or determination method may be performed using formalin- fixed, paraffin-embedded (FFPE) biopsy samples or frozen biopsy samples of solid tumors. The FFPE or frozen tissue specimens are standardly cut into sections of a few micrometers, such as 4 µm, and placed on positively charged glass slides under appropriate standard conditions according to the chosen technique. The H3K36me3 assay may be performed using an antibody-based detection technique, such as IHC or IF. Both antibody-based detection techniques comprise preparing the biopsy sample through adequate staining and pathologist assessment. The person of skill in the art understands that the staining conditions and optimized staining protocol may vary depending, for example, on the antibody- based detection technique chosen (IHC or IF), on the H3K36me3 antibody (primary antibody) chosen, and the staining platform chosen. Suitable H3K36me3 antibodies (primary antibodies), for staining of FFPE run control samples and FFPE patient samples, include antibodies that detect histone HE 269663 H3 only when trimethylated on Lys36, and preferably do not cross-react with non- methylated, mono-methylated, or di-methylated Lys36, nor with histone H3 methylated at other lysine positions, nor with other methylated histones. Suitable H3K36me3 antibodies include, for example, clone D5A7 from Cell Signaling (catalog n°4909), or EPR23525-232 from Abcam (reference Ab282572), which are rabbit monoclonal antibodies (mAb) in the IgG format. An automated staining platform may be used, such as Leica Bond Rx, Ventana Benchmark Ultra, Ventana Discovery Ultra, Dako Autostainer Link 48, Dako Autostainer Omnis. In some aspects, the H3K36me3 assay is an IHC assay based on FFPE tissue sample. It may be run on a Leica Bond Rx automated staining platform, using either a concentrated antibody clone D5A7 (catalog n°4909) as primary antibody or a concentrated IgG isotype control (catalog n°3900) from Cell Signaling, diluted in SignalStain® Antibody Diluent (catalog n° 8112) to the appropriate working concentration. Detection may be performed with the Bond Polymer Refine Detection Kit (catalog n° DS9800) and visualization with 3,3’-diaminobenzidine (DAB). Determination of the H3K36me3 expression may then be done by an anatomical pathologist on glass slides using a light microscope. Acceptance criteria for the H3K36me3 assay may be defined, such as an H&E assessment, a run control, an isotype control and / or an intrinsic positive control. Examples of acceptance criteria are further described below. Hematoxylin&Eosin (H&E) assessment A separate H&E-stained slide is standardly used to identify the region to be scoredand suitability of the sample for scoring.Pre-requisites for H3K36me3 scoring may be defined as follows: ^ Tumor present HE 269663 ^ Minimum 100 viable neoplastic cells ^ Invasive and / or invasive component present – carcinoma in situ must be scored ^ Non-tumor cells present ^ Tumor associated stroma present When any of the above criteria are not met, samples are reported as ‘not evaluable’. Run control Control tissue may be included for each staining run as quality control intended to ensure the validity of the staining procedure and instrument performance. A suitable run control sample for the H3K36me3 assay may be an H3k36me3 renal cell or breast carcinoma sample showing a partial loss of H3K36me3 in tumor cells with positivity in the surrounding stroma. Preferably, the run control sample would show different H3K36me3 nuclear expressions levels (i.e. different staining intensities ranging from weak to moderate to strong) in the tumor cells. Control tissues and cells may for example be stained with both the H3K36Me3 primary antibody and the isotype control antibody in each staining run. Isotype control An isotype control antibody is used in each run to assess the extent of non-specific staining or intrinsic pigmentation in the tissue, which could be mistaken for on- target specific IHC staining for H3K36me3. Such a negative control is done by staining a separate tumor biopsy section from the tumor biopsy sample to be analysed with an isotype control antibody. In the case of a primary antibody being a rabbit H3K36me3 antibody, a suitable isotype control antibody includes the rabbit DA1E mAb IgG XP from Cell Signaling (catalog n°3900). HE 269663 Intrinsic positive control An intrinsic positive control for the H3K36me3 assay may be defined in the H3K36me3 stained slide from the tumor FFPE sample to be assessed as follows: stromal cell populations are used as the intrinsic positive control. One or more immune cells, fibroblasts, and / or endothelial cells in the tumor-associated stroma (TAS) must express H3K36me3 in the nucleus. At least one H3K36me3 stained stromal cell, preferably several, such as at least 10, with moderate (2+) and / or strong (3+) nuclear staining must be present. If any deviation of intrinsic control is observed and if no moderate (2+) or strong (3+) stained non-tumor cells are present, the sample is reported as ‘not evaluable’. There is no intrinsic negative control to be assessed for the H3K36me3 assay. H3K36me3 scoring by a trained anatomical pathologist In the case of IHC, the H3K36me3 scoring is performed on glass slides under an inverted light microscope. The scoring of H3K36me3 stained carcinoma samples should be performed in the tumor area only. H3K36me3 IHC stained carcinoma slides may be surveyed at low magnification (5X-10X) to identify the tumor area to be scored and the extent of heterogeneity in H3K36me3 expression in tumor cells and tumor associated stroma. The pathologist may first give a qualitative statement for the predominant stroma intensity score (1+, 2+ or 3+) on immune cells, fibroblasts and / or endothelial cells in the tumor-associated stroma. The predominant intensity category is determined by the most abundant represented intensity of weak (1+), moderate (2+), or strong (3+) staining. HE 269663 It is to be understood that a trained anatomical pathologist knows how to analyse slides derived from FFPE or frozen tissue, for example to confirm the presence of a tumor area and to identify different cell types, such as tumor cells and non-tumor cells (e.g. immune cells, fibroblasts, and / or endothelial cells) in the tumor- associated stroma. A trained anatomical pathologist also knows how to assess the respective staining intensities of cells present on a slide, or a selected field of view (FOV) thereof. Representative IHC images (FOVs) for the different staining intensities (0, 1+, 2+ and 3+) in tumor cells are shown on Figure 7. Representative images (FOVs) for the different staining intensities (0, 1+, 2+ and 3+) in stromal cells (non-tumor cells) are shown on Figure 8. A description of the characteristics of the representative images shown on Figures 7 and 8 is provided in Table A below. Table A: overview of the H3H36 scoring intensity scale in tumor cells and stromal cells (corresponding images in Figure 7 for tumor cells, and Figure 8 for stromal cells). INTENSITYNEGATIVE (0) WEAK (1+) MODERATE (2+) STRONG (3+)SCORE DABNO BROWN DAB LIGHT BROWN MID-BROWN DARK BROWNSIGNAL Tumor No nuclear DAB Low DAB intensity Moderate intensity Strong intensity of Cells staining. staining of the DAB staining of the the nuclei. (nucleus) Hematoxylin nucleus. nucleus. The Chromatin blue-stained chromatin structure is structure is nuclei still visible. The masked. The dominant nuclear dominant nuclear pattern is shown. pattern is shown. Stromal No nuclear DAB Low DAB intensity Moderate intensity Strong intensity of Cells staining. staining of the DAB staining of the the nuclei. (non-TC) Hematoxylin nucleus. nucleus. blue-stained nuclei HE 269663 In some aspects, the predominant staining intensity in the tumor-associated stroma may be used as a pre-requisite for scoring a slide, for example only samples with a predominant staining intensity of at least 2+ in the stroma may be considered acceptable for further scoring. The pathologist may be required to determine the percentage of tumor cells that are either unstained (0), or that show weak nuclear staining (1+). As the H3K36me3 assay is intended to determine the H3K36me3 biomarker status of a tumor biopsy, for example to determine subject eligibility for treatment with a WEE1 inhibitor, it may be helpful in practice to have a binary case status assignment to either “H3K36me3 no loss” (biomarker negative) or “H3K36me3 loss” (biomarker positive). In such a binary case status assignment, it is thus understood that the case status “H3K36me3 loss” includes both biological situations of H3K36me3 reduction and H3K36me3 loss, referred to in the claims or items as “reduced H3K36me3 or loss of H3K36me3”. Case scores may be defined as follows: cases with scores of 0 or 1 may be assigned a case status of “H3K36me3 loss”, altogether corresponding to biomarker positivity; and cases with scores of 2 or 3 may be assigned a case status of “H3K36me3 no loss”, altogether corresponding to biomarker negativity. Criteria for the determination are described in Table B.

[0002] HE 269663 Table B. Overview of case score and case status determinationCASE SCORE CRITERIA* CASE STATUS0 H3K36me3 staining is absent on tumor cells (100%“H3K36me3 loss”, i.e. tumor cells unstained)biomarker positive1 The percentage of H3K36me3 unstained (0) and“H3K36me3 loss”, i.e. weakly stained (1+) tumor cells is more than 25biomarker positive2 The percentage of H3K36me3 unstained (0) and“H3K36me3 no loss”, weakly stained (1+) tumor cells is 25i.e. biomarker negative3 The percentage of H3K36me3 unstained (0) and“H3K36me3 no loss”, weakly stained (1+) tumor cells is less than 25i.e. biomarker negative *intrinsic positive control: presence of at least one stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining. In Table B, the cut off for biomarker positivity is set to >25%. In some aspects, a cut off of >50% for biomarker positivity may be used. In some other aspects, a cut off of >75% for biomarker positivity may be used. In a clinical setting, a solid tumor biopsy assigned a “H3K36me3 loss”, i.e. “biomarker positive”, case status may be considered eligible for treatment with a WEE1 inhibitor, e.g. a selective WEE1 inhibitor. The present invention, when comprising an H3K36me3 biomarker status determination, may be further described by the following aspects: i) Method for determining whether a solid tumor exhibits a reduced H3K36 trimethylation (H3K36me3) or loss of H3K36me3 based on an antibody- based detection technique, comprising: a) in an H3K36me3-stained tumor biopsy section, confirming thepresence of at least one H3K36me3 stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining as an intrinsic positive control; HE 269663 b) determining, in said stained tumor biopsy section, apercentage of tumor cells that are unstained (0) or weakly stained (1+) for H3K36me3, wherein the solid tumor is considered as having “reduced H3K36me3 or loss of H3K36me3” if more than 25% of tumor cells are either unstained or weakly stained for H3K36me3. ii) Method for determining the eligibility of a subject having a solid tumor for treatment with a WEE1 inhibitor, the method comprising: a) in an H3K36me3-stained tumor biopsy section, confirming thepresence of at least one H3K36me3 stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining as an intrinsic positive control; b) determining, in said stained tumor biopsy section, apercentage of tumor cells that are unstained (0) or weekly stained (1+) for H3K36me3, wherein the subject is considered eligible for treatment with a WEE1 inhibitor if more than 25% of tumor cells are either unstained or weakly stained for H3K36me3. iii) Method according to item i) or ii), wherein the tumor is considered as having “reduced H3K36me3 or loss of H3K36me3”, or the subject is considered eligible for treatment with a WEE1 inhibitor, if more than 50% of tumor cells are either unstained or weakly stained for H3K36me3. iv) Method according to any one of items i) to iii), wherein the tumor is considered as having “reduced H3K36me3 or loss of H3K36me3”, or the subject is considered eligible for treatment with a WEE1 inhibitor, if more than 75% of tumor cells are either unstained or weakly stained for H3K36me3. HE 269663 v) Method according to any one of items i) to iv), wherein the tumor biopsy section originates from an FFPE sample or a frozen tissue sample, preferably an FFPE sample. vi) Method according to any one of items i) to v), wherein the antibody- based detection technique is IHC or IF, preferably IHC. vii) Method according to any one of items i) to vi), wherein a moderate (2+) to strong (3+) predominant H3K36me3 nuclear staining intensity level in the tumor stromal cells is required in the H3K36me3-stained tumor biopsy section. *** Embodiments of the present disclosure can be further defined and illustrated by reference to the following non-limiting examples. It will be apparent to those skilled in the art that many modifications or changes, e.g. to the materials and methods described, can be practiced without departing from the scope of the present disclosure. EXAMPLES In the Examples below, references to H3K36me3 high cells are to be understood as references to cells having normal H3K36me3 levels of healthy cells. EXAMPLE 1: Low H3K36me3 due to SETD2 mutation / reduction increases sensitivity of RCC cell lines to Compound of formula (I) Renal cell carcinoma (RCC) 786-O cells were reverse transfected with either scrambled siRNA (non-targeted control, Ctrl siRNA) or siRNA directed to SETD2 (H3K36me3 methylating factor). After 24 hours, cells were treated with concentrations of Compound of formula (I) from 0nM to 1uM for 24 hours. Cell HE 269663 viability was then assessed by resazurin cell viability assay and SETD2 knockdown determined by western blotting. Western blots demonstrated that SETD2 siRNA successfully reduced SETD2 protein levels compared to Ctrl siRNA. SETD2 siRNA cells were significantly more sensitive to Compound of formula (I) leading to a 3-fold lower IC50 than their Ctrl siRNA counterparts. RCC cell lines RCC4 (SETD2wt, H3K36me3 high), A498 (SETD2mut, H3K36me3 low) and LB996 (SETD2mut, H3K36me3 low) cells were plated in adherent cell culture conditions and treated with Compound of formula (I) at concentrations from 0-2.5uM and cell viability assessed by resazurin cell viability assay. H3K36me3 low cell lines (A498 and LB996) were significantly more sensitive to Compound of formula (I) than the H3K36me3 high RCC4 cell line with approximately 3-5-fold lower IC50s. See Figure 1. Collectively these in vitro data show that reduction of H3K36me3 as consequence of SETD2 mutation / reduction results in increased sensitivity to Compound of formula (I) in RCC cell lines. EXAMPLE 2: RCC cell lines with low H3K36me3 are more sensitive to Compound of formula (I) than cell lines with high H3K36me3 Protein extracts collected from a panel of RCC cell lines were assessed for H3K36me3 protein levels by western blotting and normalized to Histone H3 (H3) protein levels for comparison. Western blots demonstrated high H3K36me3 levels in 786-O, ACHN and Caki-2 cells, low H3K36me3 in Caki-1 and 769-P cells and H3k36me3 absence in A-704 and A498 cells. HE 269663 RCC cell lines 786-O (H3K36me3 high) and A498 (H3K36me3 low) were plated into 96 well plates and incubated at 37 °C overnight to adhere. Cells were thentreated with Compound of formula (I) at concentrations from 0-1uM. Following 24 hours treatment cell viability was assessed by cell titer glo assay and log concentration vs viability plotted to determine IC50 (Figure 2). Compound of formula (I) treatment resulted in an approximately 2-fold higher IC50 of 730nM in H3K36me3 high 786-O cells compared to H3K36me3 low A498 cells of 377nM (Table 1). Consistent with results demonstrated in Example 1, these data demonstrate significantly greater sensitivity of H3K36me3 low RCC cell lines. Table 1Cell Line Name Test Article Absolute IC50Max inhibition (uM) 786-O (compoundCpd of formula (I) 0.7304 89.24 %of formula (I))Cisplatin 2.7641 98.11 %A498 (compoundCpd of formula (I) 0.3775 99.18 %of formula (I))Cisplatin 5.2047 95.95 %EXAMPLE 3: H3K36me3 low RCC tumors are more sensitive to Compound of formula (I) than H3K36me3 high tumors in vivo. For Caki-1 (H3K36me3 low): Balb / c nude mice were immobilized and inoculated subcutaneously in the flank region with 1x106Caki-1 RCC tumor cells in 0.1 mL of PBS solution (mixed with Matrigel, 1:1) for tumor development. The randomization was performed when mean tumor size reached approximately 150 mm3and randomly allocated to 2 study groups. For ACHN (H3K36me3 high): Athymic nude mice were immobilized and inoculated subcutaneously in the flank region with 5x106ACHN RCC tumor cells in 0.1 mL of HE 269663 PBS solution (mixed with Matrigel, 1:1) for tumor development. The randomization was performed when mean tumor size reached approximately 150mm3and randomly allocated to 2 study groups. Date of randomization noted as Day 0. After tumor cells inoculation, the animals were checked daily for morbidity and mortality. Mortality and observed clinical signs were recorded for individual animals in detail. Tumor volumes were measured 2 times a week in two dimensions using a caliper, and the volume will be expressed in mm3using the formula: “V = (L x W x W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). The treatment with Vehicle, compound of formula (I) (30mg / kg QD) (referred to as [Cpd of formula (I)]) were initiated immediately after grouping per study design for 20 days (Caki-1) or 28 days (ACHN). Tumor growth inhibition (TGI): TGI% is an indication of antitumor activity and is expressed as: TGI (%) =100 x (1-T / C). T and C are the mean tumor volume (or weight) of the treated and control groups, respectively, on a given day. The results are illustrated in Figure 3. The treatments with compound of formula (I) were well tolerated (no obvious treatment-related body weight loss or adverse clinical sign was observed in either study). For Caki-1 (H3K36me3 low), the mean tumor volume of vehicle treated group reached 1684 mm3at Day 20 after randomization. Monotherapy treatment with compound of formula (I) at 30 mg / kg resulted in a TGI of 41.09% (p<0.01) when compared with control group. For ACHN (H3K36me3 high), the mean tumor volume of vehicle treated group reached 487.5 mm3at Day 28 after randomization. Monotherapy treatment with compound of formula (I) at 30 mg / kg resulted in no significant tumor growth inhibition compared to control (365.9 mm3at day 28, p>0.05). HE 269663 EXAMPLE 4: Prevalence of H3K36me3 low tumors in different indications Tumor samples collected from patients (cancer types indicated in the table below) were fixed and embedded in FFPE and sectioned on to slides for immunohistochemistry staining detection of H3K36me3 using a monoclonal antibody directed against H3K36me3. Figure 4 shows representative images of H3K36me3 scoring (from 0-3) used to determine H3K36me3 levels. Total % of H3K36me3 loss / reduction was then calculated and indications ranked on total prevalence (reduced + low). Table 2Cancer type No. scored % loss % reduced Total (%)Renal 122 18 28.7 46.7Pancreatic 226 12.9 17.2 30.1Breast 88 12.5 10.2 22.7Lung 110 2 8 10.0Prostate 152 1.3 7.9 9.2Adult High38 5.2 2.6 7.8Grade Glioma Pediatric High129 1.5 3.9 5.4Grade GliomaColorectal 493 1 3.3 4.3Head and106 0 3.8 3.8NeckOvarian 158 0.6 2.5 3.1Bladder 970 1.4 0.4 1.8Melanoma 97 0 1 1EXAMPLE 5: Low H3k36me3 levels increase sensitivity to Compound of formula (I) in breast cancer cell lines HE 269663 A panel of breast cancer cell lines was assessed for H3K36me3 protein levels by western blotting and normalised to H3 protein levels. Western blotting demonstrated a range of different H3K36me3 levels across the panel of cell lines. SETD2 KnockOut (KO) cells were generated using CRISPR technology from BT474 and T47D WT cells (H3K36me3 high). Cells were treated with Compound of formula (I) at 5uM. SETD2 KO (reduction of H3K36me3) BT474 and T47D cells are more sensitive to Compound of formula (I) than WT, H3K36me3 high, BT474 and T47D cells (Figure 5, bottom right). Different cell lines with varying levels of H3K36me3 as determined by western blot (Figure 5, top) were treated with Compound of formula (I) at doses 0-5uM and cell viability assessed by resazurin cell viability assay. H3K36me3 levels show a clear correlation with compound of formula (I) sensitivity, where cells with the highest H3K36me3 levels are most resistant and as H3K36me3 levels decrease, sensitivity to compound of formula (I) increases (Figure 5, bottom left). EXAMPLE 6: H3K36me3 low breast cancer tumors are more sensitive to Compound of formula (I) than H3K36me3 high tumors in vivo. For T47D (H3K36me3 high): Athymic nude mice were immobilized and inoculated subcutaneously in the flank region with 1x107T47D breast cancer tumor cells in 0.1 mL of PBS solution (mixed with Matrigel, 1:1) for tumor development. The randomization was performed when mean tumor size reached approximately 150mm3and randomly allocated to 2 study groups. For MDA-MB-231 (H3K36me3 low): Athymic nude mice were immobilized and inoculated subcutaneously in the flank region with 5x106MDA-MB-231 breast cancer tumor cells in 0.1 mL of PBS solution (mixed with Matrigel, 1:1) for tumor development. The randomization was performed when mean tumor size reached approximately 150mm3and randomly allocated to 2 study groups. HE 269663 Date of randomization noted as Day 1. After tumor cells inoculation, the animals were checked daily for morbidity and mortality. Mortality and observed clinical signs were recorded for individual animals in detail. Tumor volumes were measured 2 times a week in two dimensions using a caliper, and the volume will be expressed in mm3using the formula: “V = (L x W x W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). The treatment with Vehicle, compound of formula (I) (30mg / kg QD) (referred to as [Cpd of formula (I)]) were initiated immediately after grouping per study design for 28 days. Tumor growth inhibition (TGI): TGI% is an indication of antitumor activity and is expressed as: TGI (%) =100 x (1-T / C). T and C are the mean tumor volume (or weight) of the treated and control groups, respectively, on a given day. The results are illustrated in Figure 6. The treatments with compound of formula (I) were well tolerated (no obvious treatment-related body weight loss or adverse clinical sign was observed in either study). For MDA-MB-231 (H3K36me3 low), the mean tumor volume of vehicle treated group reached 601mm3at Day 28 after randomization. Monotherapy treatment with compound of formula (I) at 30 mg / kg resulted in a TGI of 37.1% (318.8 mm3at day 28, p<0.01) when compared with control group. For T47D (H3K36me3 high), the mean tumor volume of vehicle treated group reached 428.3 mm3at Day 28 after randomization. Monotherapy treatment with compound of formula (I) at 30 mg / kg resulted in no significant tumor growth inhibition compared to control (409.5 mm3at day 28, p>0.05). EXAMPLE 7: Phase 1 clinical trial involving compound of formula (I) (referred to herein as the Study Drug) A clinical trial is conducted, which is a Phase 1, dose-finding study of Study Drug as monotherapy in adult patients with advanced solid tumors (Part 1), which will be HE 269663 followed by an expansion part to assess safety and preliminary anti-tumor activity (Part 2), comprising 3 arms (A. B and C). Study design:• Part 1: dose escalation of repeated oral dosing of Study Drug administered asmonotherapy to determine the maximum tolerated dose (MTD) and / or the recommended Phase 2 dose (RP2D) in patients with advanced solid tumors that recurred or progressed following prior therapy and / or for whom no standard therapy of proven benefit is available. Patients will receive daily continuous Study Drug dosing at a starting dose of 30 mg (first cohort). Each cohort will consist of 2 to 6 patients at the same dose level. At least 6 patients must be treated with the dose level and regimen identified as the MTD and / or RP2D. A treatment cycle is defined as 21 days. Tumor assessments are to be performed until documentation of disease progression. Patients who discontinue study treatment for other reasons (with the exception of withdrawal of consent, loss to follow-up, or death) will be followed up for disease progression, survival status, and new anti-cancer therapy. In addition, tumor marker assessments will be performed for all patients (if applicable depending on tumor type). After documentation of progression, survival follow up will be performed until the patient’s death, withdrawal of consent, discontinuation as per Investigator’s decision, loss to follow-up, or the overall end of study (EOS), whichever occurs first. The MTD and / or RP2D to be used in Part 2 is decided based on Safety Monitoring Committee (SMC) recommendation. The SMC may also recommend testing an alternative dosing regimen (e.g., 5, 4, or 3 consecutive days per week or a twice a day [BID] regimen). If an alternative dosing regimen, i.e., other than continuous daily administration, is recommended for Part 2, the protocol will be amended accordingly. HE 269663• Part 2: The expansion part will start after MTD and / or RP2D has beendetermined following recommendation by the SMC. It consists of 3 arms. This part will enroll patients who progressed or have recurrence of one of the below specified tumor types (histologically or cytologically confirmed) following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists: - Arm A: Uterine serous carcinoma (USC) - Arm B: High-grade (serous, endometrioid, or clear cell) epithelial ovarian cancer (EOC), primary peritoneal cancer, or fallopian tube cancer with cyclin-E1 overexpression - Arm C: Renal cell carcinoma, pancreatic cancer, or breast cancer, with low levels of trimethylated lysine 36 in histone H3 (H3K36me3). Patients with other solid tumor types and low levels of H3K36me3 may be eligible pending documented agreement between the Sponsor and the Investigator. Patients in all arms will be treated with Study Drug at the RP2D as monotherapy to assess safety and anti-tumor activity. For Part 2, a treatment cycle is also defined as 21 days. The treatment duration for each patient will be until progression of disease, unacceptable toxicity, initiation of a subsequent anti-cancer treatment, withdrawal of consent, Investigator’s decision to discontinue treatment, death, or overall EOS, whichever occurs first. Tumor assessment, efficacy and survival follow-up during Part 2 will be conducted as described above for Part 1. Study objectives: The primary objectives of the study are as follows: Part 1 dose escalation • To determine the MTD and / or the RP2D of Study Drug when administered as monotherapy with repeated dosing in adults with advanced solid tumors that HE 269663 recurred or progressed after prior therapy and / or for whom no standard therapy of proven benefit is available Part 2 expansion • To characterize the safety and tolerability of Study Drug in each study arm and overall when administered as monotherapy at the RP2D determined during the dose escalation (Part 1) of the study • To evaluate the preliminary anti-tumor activity of Study Drug when administered as monotherapy to patients in each study arm The secondary objectives of the study are as follows: Part 1 dose escalation • To characterize the safety and tolerability of Study Drug when administered as monotherapy with repeated dosing in adults with advanced solid tumors • To determine the PK profile of Study Drug (and of its N32-desmethyl metabolite) when administered as monotherapy with repeated dosing in adults with advanced solid tumors • To evaluate preliminary anti-tumor activity of Study Drug when administered as monotherapy with repeated dosing in adults with advanced solid tumors Part 2 expansion • To assess additional parameters relative to anti-tumor activity of Study Drug when administrated as monotherapy to patients in each study arm • To confirm the PK profile of Study Drug (and of its N32-desmethyl metabolite) administered as monotherapy at the RP2D in each study arm and overall Study endpoints The Primary endpoints of the study are as follows. Part 1 dose escalation • For MTD: incidence of Dose Limited Toxicities (DLTs) • For RP2D: incidence of DLTs and cumulative safety data Part 2 expansion HE 269663 • Incidence of serious adverse events (SAEs); incidence and severity of treatment- emergent adverse events (TEAEs) and laboratory abnormalities; incidence of treatment discontinuations and treatment modifications due to AEs and laboratory abnormalities; and changes in vital signs, electrocardiogram (ECG), and echocardiogram measurements • Tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria: overall response rate (ORR) The Secondary end points of the study are as follows. Part 1 dose escalation • Incidence of SAEs; incidence and severity of TEAEs and laboratory abnormalities; incidence of treatment discontinuations and treatment modifications due to AEs and laboratory abnormalities; changes in vital signs and ECG measurements • PK parameters of Study Drug and its N32-desmethyl metabolite in plasma after the first dose (maximum plasma concentration [Cmax], time to reach maximum plasma concentration following drug administration [tmax], area under the concentration curve over the time 0 to 24 h [AUC24h]), after repeated dosing (trough plasma concentration [Ctrough], concentration at 4 hours post dose [C4h]) on different occasions over 21 days and at steady-state (Cmax,ss, tmax,ss, area under the plasma concentration-time curve over the dosing interval tau [AUCtau], trough concentration at steady-state [Ctrough,ss], average steady-state concentration Cav,ss, apparent total body clearance [CL / F], peak-to-trough fluctuation [PTF], accumulation ratio based on AUC [RAUC], accumulation ratio based on Cmax [RCmax] and others, if needed) • Based on tumor response according to RECIST version 1.1 criteria: ORR, best overall response (BOR), progression-free survival (PFS), disease control rate (DCR), and duration of response (DOR) • Overall survival (OS) Part 2 expansion • BOR, DCR, DOR; PFS, time to progression (TTP) by RECIST version 1.1 HE 269663 • OS • PK parameters of Study Drug and its metabolite at steady state including, but not limited to Ctrough,ss. Study population Part 1 dose escalation Patients (≥18 years old) with advanced solid tumors that recurred or progressed following prior lines of therapy and / or for whom no standard therapy of proven benefit is available. Part 2 expansion This part will enroll patients (≥18 years old) who progressed or have recurrence of one of the below-specified tumor types (histologically or cytologically confirmed) following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists: - Arm A: Patients with USC who experienced recurrence or progression following at least 1 prior platinum-based line of therapy. - Arm B: Patients with recurrent or progressive, high-grade (serous, endometrioid, or clear cell) EOC, primary peritoneal cancer, or fallopian tube cancer with cyclin-E1 overexpression by immunohistochemistry (IHC, H score >50). - Arm C: Patients with locally advanced or metastatic renal cell carcinoma, breast cancer, or pancreatic cancer, with low levels of H3K36me by IHC (score 0 or 1). Patients with other solid tumor types and low levels of H3K36me3 may be eligible pending documented agreement between the Sponsor and the Investigator. Biomarker testing for Arm C Reduction or loss of H3K36me3 will be measured by IHC. The IHC staining and pathological assessment / quantification for biomarker testing will initially be centralized. HE 269663 The IHC scoring system is based on tumor cell staining intensity compared to tumor stromal cell staining intensity. The scores are defined as 0, 1, 2 or 3, with a score of 0 or 1 being considered biomarker positive, namely reduction or loss of H3K36me3. More specifically, the scoring is defined as follows: 0 = H3K36me3 negative tumor cells, i.e. H3K36me3 loss; 1 = predominant staining intensity of tumor cells is lower than predominant staining intensity in tumor stromal cells, i.e. H3K36me3 reduction; 2 = predominant staining intensity of tumor cells is equal to predominant staining intensity in tumor stromal cells; and 3 = predominant staining intensity of tumor cells is greater than predominant staining intensity in tumor stromal cells. Inclusion criteria The inclusion criteria of the study include the below. Part 1 dose escalation only • Histologically or cytologically confirmed locally advanced or metastatic solid tumors • Measurable or non-measurable disease per RECIST version 1.1 criteria • Disease progression under or following standard therapy and / or disease for which no available standard therapy of proven benefit Part 2 expansion only • Measurable disease per RECIST version 1.1 criteria for each arm • Patients (≥18 years old) who progressed or have recurrence of one of the tumor types specified in the study arms following standard therapy according to RECIST version 1.1, or for whom, in the opinion of the Investigator, no effective standard therapy exists: - Arm A: Histologically or cytologically confirmed USC that recurred or progressed following at least 1 prior platinum-based line of therapy for management of advanced or metastatic disease. - Arm B: Histologically or cytologically confirmed, recurrent, high-grade (serous, endometrioid, or clear cell) EOC, primary peritoneal cancer, or fallopian tube HE 269663 cancer. Tumors must show cyclin-E1 overexpression by IHC (Hscore >50) on central testing. Patients must have progressed after at least 1 prior platinum- based therapy for advanced / metastatic disease. - Arm C: Histologically or cytologically confirmed, locally advanced or metastatic renal cell carcinoma, breast cancer, or pancreatic cancer. Tumors must show low H3K36me3 levels by IHC (score 0 or 1) on central testing. Patients with other solid tumor types and low levels of H3K36me3 may be eligible pending documented agreement between the Sponsor and the Investigator. Exclusion criteria The exclusion criteria of the study include the below. Part 1 dose escalation and Part 2 expansion • Patients with active second malignancies requiring therapy in the last 6 months, with the exception of superficial bladder cancers, ductal carcinoma in situ or other carcinomas in situ, and non-melanoma skin cancers (basal cell / squamous cell skin cancer) that have been treated surgically. • Current use of an investigational agent or a medical device. • Major surgery ≤4 weeks prior to the first dose of study treatment or who have not recovered from the surgical procedure. • Brain tumors and / or brain metastases unless they are asymptomatic, stable on recent imaging (not dated more than 28 days from the inclusion date) without usage of steroids at least 28 days prior first dose of study treatment, and have not required active treatment in the last month before study entry. • History of myocardial infarction or stroke within 6 months, congestive heart failure greater than New York Heart Association (NYHA) class II, unstable angina pectoris, unexplained recurrent syncope, cardiac arrhythmia requiring treatment, family history of sudden death from cardiac-related causes, or any cardiotoxicity experienced after previous chemotherapy. • Left ventricular ejection fraction (LVEF) <55%. HE 269663 • QT interval corrected using Fridericia’s formula (QTcF) >450 msec, history of congenital long QT syndrome, clinically significant conduction abnormality, or any conduction abnormality that may increase the risk of Torsade de pointes (TdP). • Concomitant use of a drug with a known risk of corrected QT interval (QTc) prolongation. • Concomitant use of a drug or herbal product that is an inhibitor or inducer of CYP3A4, or strong inhibitors of CYP2D6, or of any drug(s) on the prohibited medication list (such as proton pump inhibitors, H2 receptor antagonists, etc.). If such a drug has been used by the patient, a wash-out period of at least 5 half-lives of the drug must occur before first administration of study treatment. For irreversible CYP inhibitors and CYP inducers, a 4-week wash-out period must be applied. • Known infection requiring systemic use of an antibiotic or antiviral agent. • Immunization with live or live-attenuated vaccine within 28 days prior to study inclusion or planned injection of live or live-attenuated vaccines. • Pregnancy or breast-feeding. • Inability or unwillingness to swallow oral medication. • Clinically significant gastro-intestinal abnormality that would affect the absorption of the drug (e.g., ulcerative diseases, gastro-intestinal dysfunction, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, major resection of the small bowel or total gastrectomy, or inflammatory bowel disease). • Chemotherapy, monoclonal antibodies / biologics, or radiotherapy with curative intent within 28 days prior to starting study treatment. Palliative radiation for pain relief is allowed up to 1 week prior to starting study treatment. • Hypersensitivity to Study Drug or any of the excipients found in the formulation for Study Drug. • Unresolved AEs or toxicities due to previous treatments, i.e., >Grade 1. Exceptions will be made for Grade 2 anemia (if hemoglobin is not less than 9 g / dL or 5.6 mmol / L) and >Grade 2 alopecia and endocrinopathies controlled by replacement therapy (e.g., hypothyroidism due to immune checkpoint inhibitors). HE 269663 • Not able to avoid exposure to high levels of ultraviolet (UV) radiation, e.g., occupational exposure to sunlight or sunbathing. • Prior exposure to any WEE1 inhibitor. Investigational product Part 1 dose escalation and Part 2 expansion Study Drug is formulated as 10 mg mini-tablets with microcrystalline cellulose, anhydrous lactose, hydroxypropylcellulose, sodium starch glycolate, anhydrous colloidal silica, and magnesium stearate as excipients, included in hard gelatin capsules. The following strengths are available: 20, 30, 60, 100, 130, and 150 mg. Intermediate capsule strengths may be produced to cover alternative dose levels. Dosing scheme Part 1 dose escalation For the initially intended dose regimen in Part 1 of the study, Study Drug will be taken orally, once a day (QD). Based on the assessment of the SMC, the Study Drug dosing regimen for subsequent cohorts may be modified (e.g., from QD to BID or intermittent administration) or more than 1 dose regimen may be opened simultaneously. The dose can be taken independently of food intake. However, intake with a light meal is recommended. Starting dose: 30 mg (Part 1: dose escalation). Provisional dose levels considered are 30, 60, 90, 120, 150, 200, 260, 350, and 460 mg. Intermediate and higher doses might be tested if supported by the totality of available data and endorsed by the SMC. Part 2 expansion Study Drug dosing will be at the RP2D endorsed by the SMC in Part 1. Results of Part 1 dose escalation 27 pts were treated with 2 pts ongoing (67% female, mean age 63 years; most common primary tumors: ovarian [33%], colon [18%]). Study Drug was escalated from 30 mg to 350 mg. Three pts had dose limiting toxicities (DLTs) [Grade (Gr) 3 HE 269663 fatigue and Gr3 Fridericia-corrected QT (QTcF) prolongation at 350 mg, and Gr3 rash at 260 mg]. The MTD was determined at 260 mg. The most frequent treatment related adverse events (TRAEs) (≥20%) were blood creatinine increased (37%), QTcF prolongation (37%), nausea (33%), vomiting (26%), dysgeusia (22%) and fatigue (22%). The most common TRAEs Gr≥ 3 were QTcF prolongation (n = 3, 11%) and fatigue (n = 2, 7%). Related adverse events led to dose interruptions, reductions, or discontinuations in 6 (22%), 4 (15%) and 2 (7%) pts, respectively. Study Drug plasma exposure increased proportionally with dose from 150 to 350 mg, with steady state achieved after 15-21 days. Target engagement, assessed by reduction of phosphorylated CDC2 levels in skin biopsies, was observed consistently from a dose of 200 mg. Median duration of treatment was 6 weeks (3-30 weeks). Of the 25 pts with post-baseline tumor assessment, 8 (32%) pts had stable disease as best response of ≥5 weeks duration. Two ovarian pts achieved 17% and 20% reduction in the target lesions as per RECIST 1.1, despite requiring dose reductions from 350mg during the 1stcycle. One of these pts had CA-125 (Cancer-Antigen 125) response. Based on cumulative safety, exposure-response data, and additional PK modeling, 260 mg once daily of Study Drug was selected as RP2D. Continuous dosing of Study Drug as monotherapy has a manageable safety profile and linear pharmacokinetics. EXAMPLE 8: Phase 1 clinical trial involving compound of formula (I) (referred to herein as the Study Drug) A clinical trial was conducted as described in Example 7, with the exception that the Biomarker testing for Arm C was carried out as described in Example 9A. HE 269663 EXAMPLE 9: H3K36me3 IHC assay A. Assay description Equipment A Leica Bond Rx staining instrument was used to complete the staining procedure, a Sakura Tissue Tek Prisma stainer and Film coverslipper to dehydrate and coverslip the stained slides, and an inverted light microscope for scoring. Sample specifications FFPE blocks and unstained slides were stored at 2-8°C before staining. All FFPE tissue specimens were cut into sections of 4 µm on positively charged glass slides and baked for 120 minutes at 60±2°C in a calibrated oven. Slides were stained as soon as possible after sectioning, i.e. max 75 days after sectioning. IHC stained slides were kept at ambient temperature (15-25°C). Reagents The reagents used, information about the manufacturer, and storage guidelines are detailed in Table 3. Table 3. Overview of the reagents used for H3K36Me3 IHC.Reagents Manufacturer (cat N°) StorageTri-Methyl-Histone H3 (Lys36) (D5A7) XP® Rabbit Cell Signaling Technologies -20°C mAb (Primary Antibody) 4909SRabbit (DA1E) mAb IgG XP Isotype Control Cell Signaling Technologies-20°C 3900SLeica Bond Wash Solution (Bond Wash) Leica, AR9590 2-8°CEpitope Retrieval #1 (ER1) Leica, AR9961, 2-8°CBond Polymer Refine Detection Kit (includesLeica, DS9800 2-8°CPeroxide Block, Mixed DAB Refine, Hematoxylin and Polymer solution including rabbit-anti-mouse IgG and anti-rabbit Poly-HRP-IgG in animal serum)SignalStain® Antibody Diluent Cell Signaling 8112 2-8°CEthanol 96% VWR (20905.365) 20-25°C HE 269663Ethanol absolute (Ethanol 100%) VWR (20821.330) 20-25°CXylene VWR (28975.360) 20-25°CMillipore water (Deionized water) NA 20-25°CAbbreviations: DAB = 3,3’-diaminobenzidine, HRP = horseradish peroxidase The reagents were prepared as follows:- Primary monoclonal antibody H3K36me3: the antibody (Cell Signaling,4909S) was diluted to a final concentration of 1.53 µg / mL in SignalStain® antibody diluent (Cell Signaling, 8112). It was prepared freshly for each staining run.- Negative control reagent: the Rabbit (DA1E) mAb IgG XP Isotype Controlantibody (Cell Signaling 3900S) was diluted to a final concentration of 1.53 µg / mL in SignalStain® antibody diluent (Cell Signaling, 8112). It was prepared freshly for each staining run. Staining procedure The H3K36Me3 IHC staining procedure applied on FFPE specimens using the Leica Bond RX and Sakura Tissue-Tek Prisma is shown in Table 4. Three total slides per FFPE sample were stained: - 1 H&E (Hematoxylin and Eosin)-stained slide for quality control (pre-requisite for scoring), - 1 H3K36me3-specific stained slide for biomarker assessment, and - 1 IgG isotype control slide (negative control). Table 4. H3K36Me3 IHC staining procedure.Leica Bond Rx Deparaffinization andStandard Leica protocol: *Dewax rehydration Retrieval Standard Leica protocol:*HIER 20 min with ER1 at 100°C Staining protocol Peroxide Block 5 min at RT (150 µl)3x Bond Wash (150 µl) Primary Antibody 30 min at RT (150 µl) 3x Bond Wash (150 µl) Polymer 8 min at RT (150µl) HE 269663 2x Bond Wash 2 min @RT(150 µl) 1x Deionized water (150 µl) Mixed DAB Refine (150 µl) Mixed DAB Refine 10 min at RT (150 µl) 3x Deionized water (150 µl) Hematoxylin 5 min at RT (150 µl) Deionized water (150 µl) Bond Wash (150 µl) Deionized water (150 µl) Sakura Tissue- Dehydration and cover slipping Ethanol 96% - 2x1 minute Tek Prisma Ethanol 100% - 2x1 minute Xylene - 2x2 minute Abbreviations: HIER: heat induced epitope retrieval, RT: room temperature, DAB = 3,3’-diaminobenzidine. Assay interpretation and scoring H3K36me3 scoring required an H&E-stained slide to identify the region to bescored and suitability of the sample for scoring. Pre-requisites for scoring were asfollows: ^ Tumor present ^ Minimum 100 viable neoplastic cells ^ Invasive and / or invasive component present – carcinoma in situ must be scored ^ Non-tumor cells present ^ Tumor associated stroma present When any of the above criteria were not met, samples were reported as ‘not evaluable’. The IgG isotype control slide was used to assess the extent of non-specific staining or intrinsic pigmentation in the tissue which could be mistaken for on- target specific IHC staining for H3K36me3. HE 269663 H3K36me3 scoring was performed on glass slides under an inverted light microscope. The scoring of H3K36me3 IHC stained carcinoma samples was performed in the tumor area only. H3K36me3 IHC stained carcinoma slides were surveyed at low magnification (5X-10X) to identify the tumor area to be scored and the extent of heterogeneity in H3K36me3 expression in tumor cells and tumor associated stroma. The pathologist first gave a qualitative statement for the predominant stroma intensity score (1+, 2+ or 3+) on immune cells, fibroblasts and / or endothelial cells in the tumor-associated stroma. The predominant intensity category was determined by the most abundant represented intensity of weak (1+), moderate (2+), or strong (3+) staining. Only samples with at least one stromal cell showing a nuclear staining intensity of at least 2+ were considered acceptable for further scoring. Representative IHC images (FOVs) for the different H3K36me3 staining intensities (0, 1+, 2+ and 3+) in stromal cells (non-tumor cells) are shown on Figure 8. The pathologist then assessed a percentage of tumor cells at each intensity (0, 1+, 2+ and 3+) nuclear staining. Representative IHC images (FOVs) for the different H3K36me3 staining intensities (0, 1+, 2+ and 3+) in tumor cells are shown on Figure 7. Further representative images (FOVs) for an H3K36me3 stained sample (breast medullary carcinoma) with different staining intensities for tumor (TC) and non- tumor (non-TC) cells are shown on Figure 9a and Figure 9b, as indicated by thick (TC) or thin (non-TC) black (0), green (1+), yellow (2+) and red (3+) arrows according to the legend. Cases with scores of 0 or 1 were assigned a status of “H3K36me3 loss”, altogether corresponding to biomarker positivity and cases with scores of 2 or 3 were assigned a status of “H3K36me3 no loss”, altogether corresponding to HE 269663 biomarker negativity. Such binary case status assignment allowed patient eligibility determination. It is understood that the “H3K36me3 loss” case status includes both biological situations of H3K36me3 reduction and H3K36me3 loss. The criteria used for the determination are described in Table 5, with the cut off for biomarker positivity being >50%. Table 5. Overview of case score and case status determinationCASE SCORE CRITERIA* CASE STATUS0 H3K36me3 staining is absent on tumor cells H3K36me3 loss, i.e.biomarker positive1 The percentage of H3K36me3 unstained (0) andH3K36me3 loss, i.e. weakly stained (1+) tumor cells is more than 50biomarker positive2 The percentage of H3K36me3 unstained (0) andH3K36me3 no loss, i.e. weakly stained (1+) tumor cells is 50biomarker negative3 The percentage of H3K36me3 unstained (0) andH3K36me3 no loss, i.e. weakly stained (1+) tumor cells is less than 50biomarker negative *intrinsic positive control: presence of at least one stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining B. Assay analytical performance Analytical validation of the assay was performed in FFPE samples with expected biomarker status (e.g. sections of human tumor derived FFPE cell pellets labeled with the above described H3K36me3 staining protocol) as well as in FFPE pancreatic, renal and breast cancer tissue samples at 2 different sites in compliance with the College of American pathologists (CAP) standards, the CLSI (clinical laboratories standard institute) guidelines I / LA28-A2 (Quality Assurance for Design Control and Implementation of Immunohistochemistry Assays, second edition) and according to the principles of ISO 13485:2016 and FDA 21 CFR 820.30 requirements. Results of these validation experiments are summarized in Table 6. HE 269663 Table 6: Summary of the performance characteristics of H3K36Me3 (Clone D5A7) IHC assay validation completed at the primary site and secondary site. PARAMETER ACCEPTANCE CRITERIA RESULTS PRIMARY VALIDATION SITEStaining accuracy, i.e. staining Criteria for assay specificity were met specificity and sensitivity, in cells and in cells and control tissues. control tissues should reflect the expected staining pattern described in literature in all samples. Staining in cells All cell lines stained for H3K36me3 Positive cells (786-O, HELA and CAKI- were according to expectations, with 1) should provide moderate to strong 786-O, HELA and CAKI-1 presenting Analytical staining of virtually all cells, while the positive H3K36me3 nuclear staining specificity and A498 cells, carrying a SETD2 and A498 showing no H3K36me3 sensitivity in cells mutation, were expected to show no staining. and reference H3K36me3 staining. tissues Staining pattern in reference (normal) tissue In normal tissue, H3K36me3 is Staining patterns observed in normal expected in the nucleus of every kidney (n=1) and tonsil (n=1) tissues transcriptionally active cell. In addition, were consistent with literature fibrous structures, endothelial and findings. epithelial cells are expected to consistently have strong staining intensities of H3K36me3.

[0003] HE 269663 PARAMETER ACCEPTANCE CRITERIA RESULTS The staining specificity and sensitivity After screening 107 / 124 samples, in carcinoma tissue samples, originating from 41 Breast Cancer containing at least 20 positive and 20 (BC) (incl. 5 biopsy), 43 Pancreatic negative cases with the associated cut- ductal adenocarcinoma (PDAC) (incl. off for biomarker positivity (>50%, see 5 biopsy) and 40 Renal Cell Table 5), should match the expected Carcinoma (RCC), displayed a valid staining pattern described in literature H3K36me3 staining. In all valid (described below) in at least 90% of samples (>90%) the observed the samples. staining pattern was in line with expectations, both in resections and The sample set should represent the biopsies. Therefore, the criteria for range that can be expected in the were met. clinical trial (H3K36me3 loss / no loss). Different H3K36me3 nuclear positivity levels (0, 1+, 2+ and 3+) Tissue specific staining pattern: were observed in the tumor cells. A In FFPE carcinoma samples, a nuclear full range of tumor positivity at any Analytical H3K36me3 expression with varying staining intensity, ranging from 0 to specificity, intensities (low, medium, high) should 100%, was observed in the tested sensitivity & be observed in the majority of the sample set with the lowest measuring range tumor cells. No membrane staining H3K36me3 positivity being 3% tumor should be present. In some samples, a cell staining at 1+ intensity. subpopulation of tumors cells should In BC resections (n=30) the derived show a decreased (loss of) staining. nTPS ranged from 15 to 100%, with Nuclear staining in fibroblasts, 13 (43%) carrying a loss, and 17 endothelial cells and immune cells in (57%) no loss. In RCC resections the tumor stroma and / or surrounding (n=32) the derived nTPS ranged from tissue can be observed as well. 0 to 100% and 20 (62.5%) cases displayed a loss 12 (37.5%) no loss. In PDAC (n=35), the derived nTPS varied between 40 and 100% with 7 (20%) cases categorized as a loss and 28 (80%) no loss. In biopsies (n=5 breast cancer and n=5 PDAC) derived nTPS ranged from 85-95% and only 1 breast cancer sample was identified as a loss. Use of an isotype-matched (IgG) For all 107 (tumor samples (BC, control antibody instead of the primary PDAC and RCC) with a valid Staining control antibody should omit the IHC signal in H3K36me3 stain, the IgG control was (negative reagent FFPE pancreatic, renal and breast deemed acceptable. No specific control) cancer tissue samples known to staining could be detected in the IgG express H3K36me3. control stained slides. HE 269663 PARAMETER ACCEPTANCE CRITERIA RESULTS For each variable, following criteria Precision met all criteria in the 8 must be met when using the associate samples tested at primary site using cut-off: categorical scoring H3K36Me3 loss ^ Intra-Run: OPA of ≥90%, PPA and (0 / 1) or no loss (2 / 3). NPA of ≥85% Intra-Run: ^ Inter-Run: OPA of ≥90%, PPA and ^ 100% OPA (40 / 40) NPA of ≥85% ^ 100% PPA (20 / 20) Precision ^ Inter-Operator: OPA of ≥90%, ^ 100% NPA (20 / 20) Inter-Run: ^ Inter-Instrument: OPA of ≥90% ^ 100% OPA (40 / 40) ^ 100% PPA (20 / 20) ^ 100% NPA (20 / 20) Inter-Operator: ^ 100% OPA (16 / 16) Inter-Instrument: ^ 100% OPA (16 / 16) SECONDARY VALIDATION SITE Analytical The staining specificity and sensitivity Out of 40 pre-characterized BC, specificity, in carcinoma tissue samples, containing at least 20 positiv PDAC and RCC samples for sensitivity & e and 20 negative cases with the associated cu sensitivity assessment at the primary measuring range t- off, should match the expected staining site, 39 samples displayed a valid pattern described in literature H3K36me3 staining. (described below) in at least 90% of An OPA of 97% (38 / 39) compared to the samples. reference status (i.e. the case status The sample set should represent the obtained at the primary site). range that can be expected in the Different H3K36me3 nuclear clinical trial (H3K36me3 loss / no loss). positivity levels (0, 1+, 2+ and 3+) An OPA of ≥85%compared to the case are observed in the tumor cells. All status obtained at the primary site samples display the expected should be obtained. staining pattern.

[0004] HE 269663 PARAMETER ACCEPTANCE CRITERIA RESULTS For each variable, following criteria Precision met all criteria in the 8 BC, must be met when using the PDAC and RCC samples tested at associated cut-off: primary site using categorical scoring ^ Intra-Run: OPA ≥90%, PPA and H3K36Me3 loss (0 / 1) or no loss (2 / 3). NPA of ≥85% Intra-Run: ^ Inter-Run: OPA ≥90%, PPA and ^ 100% OPA (40 / 40) NPA of ≥85% ^ 100% PPA (20 / 20) ^ Inter-Operator: OP ^ 100% NPA (20 / 20) Precision A ≥90%, Inter-Run: ^ Inter-Instrument: OPA ≥90% ^ 100% OPA (40 / 40) ^ 100% PPA (20 / 20) ^ 100% NPA (20 / 20) Inter-Operator: ^ 100% OPA (16 / 16) Inter-Instrument: 100% OPA (16 / 16) BOTH SITESInter-site An OPA of ≥90%, on slide level should OPA of 100% (16 / 16) and thus the comparison be achieved. acceptance criterium (OPA ≥ 90%) was met. Inter-reader concordance: Overall Inter-reader (n=4 pathologist An OPA, NPA and PPA of ≥85% – 200 reads, 37 positive (no loss) Reader should be achieved between readers, and 13 negative (loss) samples) concordance using the associated cut-off ^ 93% OPA (185 / 200) ^ 93% PPA (138 / 148) ^ 90% NPA (47 / 52). Abbreviations: nTPS = nuclear tumor proportion score In the above table, the term “derived nTPS” or “d-nTPS” designates a derived nuclear tumor proportion score, which is calculated as the sum of the proportion (%) of tumor cells staining as weak (1+), moderate (2+) or strong (3+). Statistical analysis In the above table, the overall percent agreement (OPA), positive percent agreement (PPA) and negative percent agreement (NPA) of the positive / negative status at the associated cutoff (>50% for biomarker positivity, see table 5) were obtained through pair-wise comparison of the data (slide level for precision, sample level for pathologist / reader concordance) against a reference value. HE 269663 ^ Overall percent agreement (OPA): the percentage of total samples (for inter-reader concordance) or slides (for intra- and inter-run, inter-instrument and inter-operator precision, inter-site and inter-lot testing) showing a positive / negative status that is concordant with the consensus status. The OPA is calculated as: ^ Positive percent agreement (PPA): the percentage of positive or no loss samples (for inter-reader concordance) or slides (for intra- and inter-run precision, inter-site and inter-lot testing) showing a positive or no loss status that is concordant with the consensus status. The PPA is calculated as: ^ Negative percent agreement (NPA): the percentage of negative or loss samples (for inter-reader concordance) or slides (for intra- and inter-run precision, inter-site and inter-lot testing) showing a negative or loss status that is concordant with the consensus status. The NPA is calculated as:

Claims

HE 269663 Claims 1. Selective WEE1 inhibitor for use in treating a patient having a solid tumor, wherein the solid tumor exhibits a biomarker indicative of reduced histone H3K36 trimethylation (H3K36me3) or loss of H3K36 trimethylation (H3K36me3).

2. Selective WEE1 inhibitor for use according to claim 1, wherein the WEE1 inhibitor is a compound of formula (I)(I), or a pharmaceutically acceptable salt thereof.

3. Selective WEE1 inhibitor for use according to claim 1 or 2, wherein the biomarker indicative of reduced histone methylation is reduced histone H3K36 trimethylation (H3K36me3), or a loss of histone H3K36 trimethylation (H3K36me3).

4. Selective WEE1 inhibitor for use according to any of claims 1 to 3, wherein the biomarker indicative of reduced histone methylation is at least one of - mutation of a histone methyltransferase (HMT) gene or reduced expression of an HMT gene product, - mutation of SETD2 gene or reduced expression of a SETD2 gene product, - mutation of ASH1L gene or reduced expression of an ASH1L gene product, - mutation of NSD1 gene or reduced expression of an NSD1 gene product,HE 269663 - mutation of NSD2 gene or reduced expression of an NSD2 gene product, - mutation of NSD3 gene or reduced expression of an NSD3 gene product, - mutation of SETD3 gene or reduced expression of a SETD3 gene product, - mutation of SETMAR gene or reduced expression of a SETMAR gene product, - mutation of SMYD2 gene or reduced expression of a SMYD2 gene product, - overexpression of a histone demethylase (HDM) of the KDM4 family, such as KDM4A, KDM4B or KDM4C, or - overexpression of a histone demethylase (HDM) of the KDM2 family such as KDM2A or KDM2B.

5. Selective WEE1 inhibitor for use according to claim 4, wherein the biomarker indicative of reduced histone methylation is a homozygous loss of functional SETD2.

6. Selective WEE1 inhibitor for use according to any one of the preceding claims, wherein the solid tumor is or is associated with breast cancer, in particular triple-negative breast cancer (TNBC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer, prostate cancer or high-grade glioma and wherein the solid tumor is optionally an advanced solid tumor.

7. Selective WEE1 inhibitor for use according to any one of the preceding claims, wherein the solid tumor has recurred or progressed after initial or prior treatment.

8. Selective WEE1 inhibitor for use according to any one of the preceding claims, wherein the WEE1 inhibitor is administered in monotherapy.HE 269663 9. Selective WEE1 inhibitor for use according to any one of the preceding claims, wherein the WEE1 inhibitor is administered orally.

10. Selective WEE1 inhibitor for use according to any one of the preceding claims, wherein the WEE1 inhibitor is administered a) at a dose ranging from 30 to 1000 mg of free base per treatment day, preferably a dose ranging from 30 to 720 mg of free base per treatment day, more preferably a dose ranging from 100 to 720 mg of free base, even more preferably a dose ranging from 100 to 520 mg of free base per treatment day, or b) at a dose of about 30, about 60, about 90, about 120, about 150, about 200, about 260, about 350, or about 460 mg of free base per treatment day, and / or c) at a dose ranging from 120 to 260 mg of free base per treatment day, preferably at a dose of about 260 mg of free base per treatment day, and / or d) as a single dose or twice a day (BID) on a treatment day.

11. Selective WEE1 inhibitor for use according to any one of the preceding claims, wherein the WEE1 inhibitor is administered a) daily over a 21-day cycle, or b) on 3, 4 or 5 consecutive days per week of a 21-day cycle, or c) on days 1 to 3 of a 21-day cycle, or d) on days 1 to 3 and 8 to 10 of a 21-day cycle, or e) on days 1 to 3, 8 to 10 and 15 to 17 of a 21-day cycle, or f) on days 1 to 5 of a 21-day cycle, or g) on days 1 to 5 and 8 to 12 of a 21-day cycle, or h) on days 1 to 5, 8 to 12 and 15 to 19 of a 21-day cycle, or i) on days 1 to 14 of a 21-day cycle, or j) on days 1 to 5 of a 28-day cycle, orHE 269663 k) on days 1 to 5 and 8 to 10 of a 28-day cycle, or l) on days 1 to 5 and 8 to 12 of a 28-day cycle, or m) on days 1 to 5, 8 to 10 and 15 to 17 of a 28-day cycle, or n) on days 1 to 5, 8 to 12 and 15 to 19 of a 28-day cycle, or o) on days 1 to 3 of a 28-day cycle, or p) on days 1 to 3 and 8 to 10 of a 28-day cycle, or q) on days 1 to 3, 8 to 10 and 15 to 17 of a 28-day cycle.

12. Selective WEE1 inhibitor for use according to any one of the preceding claims, wherein the WEE1 inhibitor is administered at approximately the same time on each treatment day.

13. Selective WEE1 inhibitor for use according to any of claims 11-12, wherein the WEE1 inhibitor is administered over 1, 2, 3, 4, 5, 6 or more 21-day cycles or 28-day cycles.

14. Pharmaceutical composition comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, for use in treating a patient having a solid tumor, wherein the use is as described in any of claims 1-13.

15. Kit comprising a selective WEE1 inhibitor or a pharmaceutically acceptable salt thereof, for use in treating a patient having a solid tumor, wherein the use is as described in any of claims 1-13.

16. Method for determining whether a solid tumor exhibits a reduced H3K36 trimethylation (H3K36me3) or loss of H3K36me3 based on an antibody-based detection technique, comprising: a) in an H3K36me3-stained tumor biopsy section, confirming the presence of at least one H3K36me3 stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining as an intrinsic positive control;HE 269663 b) determining, in said stained tumor biopsy section, a percentage of tumor cells that are unstained (0) or weakly stained (1+) for H3K36me3, wherein the solid tumor is considered as having “reduced H3K36me3 or loss of H3K36me3” if more than 25% of tumor cells are either unstained or weakly stained for H3K36me3.

17. Method for determining the eligibility of a subject having a solid tumor for treatment with a WEE1 inhibitor, the method comprising: a) in an H3K36me3-stained tumor biopsy section, confirming the presence of at least one H3K36me3 stained stromal cell with moderate (2+) and / or strong (3+) nuclear staining as an intrinsic positive control; b) determining, in said stained tumor biopsy section, a percentage of tumor cells that are unstained (0) or weakly stained (1+) for H3K36me3, wherein the subject is considered eligible for treatment with a WEE1 inhibitor if more than 25% of tumor cells are either unstained or weakly stained for H3K36me3.

18. Method of claim 16 or 17, wherein the tumor is considered as having “reduced H3K36me3 or loss of H3K36me3” or the subject is considered eligible for treatment with a WEE1 inhibitor if more than 50% of tumor cells are either unstained or weakly stained for H3K36me3.

19. WEE1 inhibitor for use in treating a subject having a solid tumor, wherein the solid tumor exhibits a reduced or loss of H3K36 trimethylation (H3K36me3), as determined by the method of claim 16 or 18.

20. WEE1 inhibitor for use in treating a subject having a solid tumor, comprising determining the subject eligibility for treatment with a WEE1 inhibitor according to the method of claim 17 or 18.

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